The Proceedings of the 12th Conference of the European Association for Clinical Pharmacology and Therapeutics

Madrid, Spain

June 27-30, 2015

This online only supplement is based on the proceedings of the 12th Conference of the European Association for Clinical Pharmacology and Therapeutics. Abstracts were reviewed and approved for publication by the EACPT 2015 National Organizing Committee and International Advisory Board. The publication of these proceedings was supported by the EACPT.

The authors of the plenary and poster abstracts as presented in this supplement express their personal and professional opinion and these are not necessarily those of the European Association for Clinical Pharmacology and Therapeutics.

Clinical Therapeutics/Volume XX, Number XX, 2015

1 Morphine decreases ticagrelor were systematically collected by Teratology Information Services 65 2 concentrations but not its effects: between 2004 and 2013. 66 3 a randomized, double-blind, Results: We obtained data from 173 exposed pregnancies and 692 67 4 placebo-controlled trial controls. After exclusion of chromosomal syndromes, major birth 68 5 E.-L. Hobl; B. Reiter; T. Stimpfl; C. Schoergenhofer; defects were reported more frequently in pregnancies exposed to pre- 69 6 M. Schwameis; U. Derhaschnig; and B. Jilma gabalin during 1st trimester of pregnancy than in the control group 70 7 Medical University of Vienna, Vienna, Austria (6.6% vs 2.0%; odds ratio 3.5, 95% confidence interval 1.2-9.7, 71 8 Background: This study examines possible drug-drug interactions P = 0.004). Moreover, the rate of live births was lower in the prega- 72 9 between ticagrelor and morphine. Our recent drug interaction trial balin group (71.1% vs 85.4%, P < 0.001), primarily due to a higher 73 10 with clopidogrel shows that morphine decreases the concentrations rate of both elective (10.4% vs 4.8%, P = 0.01) and medically indi- 74 11 and effects of clopidogrel, which could lead to treatment failure in cated (5.2% vs 1.7%, P = 0.02) pregnancy-terminations. The crude 75 12 susceptible individuals. We hypothesized that the pharmacodynamic rate of spontaneous abortion (15.8% vs 8.7%, P = 0.001) was also 76 13 consequences of drug-drug interactions would be less between mor- higher in the pregabalin group. 77 14 phine and ticagrelor. Conclusions: This study raises a signal for a possible increase in 78 15 Material and Methods: Twenty-four healthy subjects received a the risk of major birth defects and spontaneous abortion after first 79 16 loading dose of 180 mg ticagrelor together with placebo or 5 mg trimester exposure to pregabalin. These results call for further con- 80 17 morphine intravenously in a randomized, double-blind, placebo- firmation through independent studies. 81 18 controlled, cross-over trial. Pharmacokinetics were determined by 82 19 liquid chromatography tandem mass spectrometry, and ticagrelor 83 20 effects were measured by platelet function tests. Self-reported confidence in prescribing 84 21 Results: Concomitant i.v. injection of morphine slows drug resorp- skills correlates poorly with assessed 85 22 tion of ticagrelor and its active metabolite (P < 0.05) by one hour competence in fourth-year medical 86 23 and decreases plasma levels of ticagrelor and its active metabolite (by students 87 24 25%–31%; P ≤ 0.03) and the drug exposure (area under the curve by D.J. Brinkman1,2; J. Tichelaar1,2; M.A. van Agtmael1,2; 88 25 22%–23%; P ≤ 0.01). Importantly, however, the effects of ticagrelor Th.P.G.M. de Vries1; and M.C. Richir1,2 89 26 on platelet aggregation in whole blood, platelet plug formation, and 1Research and Expertise Center In Pharmacotherapy Education 90 27 vasodilator-stimulated phosphoprotein (VASP) phosphorylation are (RECIPE), Amsterdam, the Netherlands; and 2VU University 91 28 not affected by morphine. Medical Center, Amsterdam, the Netherlands 92 29 Conclusions: Morphine co-administration moderately decreases Introduction: The objective of this study was to investigate the rela- 93 30 ticagrelor plasma concentrations but does not inhibit its effects. tionship between students’ self-reported confidence and their objec- 94 31 Therefore, a 180 mg loading dose of ticagrelor appears to provide tively assessed competence in prescribing. 95 32 consistent and reliable platelet inhibition when morphine has to be Material and Methods: We assessed the competence in several 96 33 given for pain relief. prescribing skills of 403 fourth-year medical students at the VU 97 34 University Medical Center, the Netherlands, in a formative simu- 98 35 99 lated examination on a 10-point scale (1 = very low; 10 = very 36 Pregnancy outcome following maternal high). Afterwards, the students were asked to rate their confidence 100 37 exposure to pregabalin: a reason for in performing each of the prescribing skills on a 5-point Likert scale 101 38 102 concern? a collaborative entis and (1 = very unsure; 5 = very confident). Their assessments were then 39 motherisk study compared with their self-confidence ratings. 103 40 104 U. Winterfeld1; P. Merlob2; D. Baud1; V. Rousson1; A. Panchaud1; Results: Students’ overall prescribing performance was adequate 41 105 L.E. Rothuizen1; N. Bernard3; T. Vial3; L.M. Yates4; A. Pistelli5; (7.0 ± 0.8), but they lacked confidence in two essential prescrib- 42 106 M. Ellfolk6; G. Eleftheriou7; L.C. de Vries8; P. Bozzo9; ing skills. Overall, there was a weak positive correlation (r = 0.2; 43 107 A.-P. Jonville-Bera10; M. Kadioglu11; J. Biollaz1; and T. Buclin1 P < 0.01; 95% CI, 0.1–0.3) between reported confidence and actual 44 108 1Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; competence. 45 109 2University of Tel-Aviv, Tel-Aviv, Israel; 3Hospices Civils de Lyon, Conclusions: This study suggests that self-reported confidence is not 46 110 Lyon, France; 4Regional and Therapeutics Centre, Newcastle an accurate measure of prescribing competence, and that students 47 111 upon Tyne, UK; 5Azienda Ospedaliero Universitaria Careggi, lack insight into their own strengths and weaknesses in prescrib- 48 112 Florence, Italy; 6HUSLAB and Helsinki University Central ing. Future studies should focus on developing validated and reliable 49 113 Hospital, Helsinki, Finland; 7Poison Control, Bergamo, Italy; instruments so that students can assess their prescribing skills. 50 114 8Pharmacovigilance Centre Lareb, Den Bosch and University 51 115 of Groningen, Groningen, The Netherlands; 9The Hospital for 52 116 Sick Children, Toronto, Canada; 10CHRU, Tours, France; and 53 Adherence to dabigatran among 117 11Technical University, Trabzon, Turkey 54 New Zealand patients 118 Background: While animal studies have shown reproductive toxicity 1 2 3 3 3 55 S.K. Jayathissa ; A. Lim ; J. Wyeth ; S. Garret ; S.A. Yee ; 119 of pregabalin, data on pregnancy outcomes in women exposed to 3 4 56 S. Metcalfe ; and M. Weatherall 120 this drug are lacking, despite accepted use in women of childbearing 1 57 Hutt Valley Health Lower Hutt, Wellington, New Zealand; 121 potential. In this study, we primarily investigated the rate for major 2 3 58 University of Auckland, Auckland, New Zealand; PHARMAC, 122 birth defects and other pregnancy outcomes following maternal use 4 59 Wellington, New Zealand; and University of Otago, Wellington, 123 of pregabalin. 60 New Zealand 124 Material and Methods: This is a multicenter, observational prospec- 61 Background: Dabigatran, a direct thrombin inhibitor, is the only 125 tive cohort study comparing pregnancy outcomes in women exposed 62 drug funded in New Zealand for prevention in patients with 126 to pregabalin with matched controls (exposed neither to any medica- 63 atrial fibrillation. A previous small New Zealand cohort study sug- 127 tions known to be teratogenic nor to any antiepileptic drugs). Data 64 gested an adherence rate of 70% after a median follow-up of eight 128

2015 e1 Clinical Therapeutics

1 months. We studied the demographics of patients taking dabigatran on the implanted prosthesis were found between cohorts, although 65 2 and their adherence over a 3-year period from 1 July 2011 and com- the period from admission to surgery (median [IQR]) (7 [4-9] and 66 3 pared the results with the RELY trial. 5 [2-7] days) and that of hospital stay (16 [12-20] and 13 [10-17] 67 4 Materials and Methods: We examined pharmacy claims from the days) were longer in those treated with antithrombotics. No statisti- 68 5 Ministry of Health National Data Repository. Patients could be iden- cally differences in the haemorrhagic events were observed between 69 6 tified by unique National Health Identification (NHI) number. We cohorts (68.2% and 60.3, P = 0.09), although a higher percentage 70 7 collected data, including age and sex, initiation date of dabigatran, of thromboembolic events (12.1 and 4.8, P = 0.004) and mortality 71 8 and last recorded prescription. We defined adherence as persistence (20.5% and 13.6%, P = 0.05) were described in those treated with 72 9 on dabigatran therapy if a patient did not have a break in dispensing antithrombotics. 73 10 of more than three months from commencing treatment. Conclusions: Patients presented with hip fracture treated with 74 11 Results: Over a three year period, 30,205 patients received at least a antithrombotics had a higher mortality and frequency of thrombo- 75 12 single prescription for dabigatran. The mean age was 71.2 years and embolic events than those not treated with antithrombotics, but the 76 13 60% were male, similar to the RELY trial population (mean age, 71 frequency of haemorrhagic events was not higher. Thus, in patients 77 14 years; male, 64%). Sixty percent of the patients were > 70 years, and treated with antithrombotics, careful attention has to be paid not 78 15 25% were > 80 years. Fifteen percent of the patients did not receive only to the haemorrhagic events but also to the thromboembolic 79 16 dabigatran after the first prescription. After a median follow-up of ones. 80 17 22.3 months, 49% of patients continued to receive dabigatran. This 81 18 is much lower than the adherence rate of 79% after 2 years in the 82 19 RELY trial. The majority of discontinued patients received an alter- Neoadjuvant chemotherapy scheme 83 20 native treatment. customized by BRCA1 levels in Her-2 84 21 Conclusions: Adherence to dabigatran among New Zealand patients negative primary breast cancer patients: 85 22 is much lower than described in the RELY trial. Adverse effects, lack a randomized clinical trial. Bernaq 86 23 of education about the benefits and risk, and other factors may have study 87 24 contributed to the lower adherence. Dabigatran is an important part J. Martinez-Atienza; C.M. Rosso-Fernández; 88 25 of therapy in patients with atrial fibrillation, and efforts need to be B. Solano-Hernández; M. Atienza; and M. Ruiz-Borrego 89 26 directed to optimising its use in the community. Hospital Universitario Virgen del Rocío, Seville, Spain 90 27 Introduction: Neoadjuvant chemotherapy (NAC) is increasingly used 81 28 for early-stage operable breast cancer to improve complete response 92 29 Characteristics and perioperative rates and increase survival. BReast CAncer 1 (BRCA1) plays a crucial 93 30 outcomes of patients admitted for hip role in DNA repair, and its expression has been associated to sensi- 94 31 fracture: a comparison of those treated tivity to platinum and/or resistance to taxanes. Complete response 95 32 and not treated with antithrombotics. rates with NAC may thus be improved using BRCA as a biomarker 96 33 A. GómezE1; M. Fernández1; M.L. Iavecchia1; A. Safiya1; to predict a better response by individualized breast cancer care. 97 34 M. Bosch1; M. Sabaté1; D. Castellà2; P. Lalueza3; J. Teixidor4; and Material and Methods: BERNAQ is an investigator-driven, open- 98 35 A. Agustí1 label, multicenter, randomized controlled trial (RCT). The study was 99 36 1Fundació Institut Català de Farmacologia, Clinical Pharmacology designed to compare the efficacy and tolerability of NAC customized 100 37 Service, Hospital Universitari Vall d’Hebron, Barcelona, Spain; by BRCA1 levels versus a standard chemotherapy, with pathological 101 38 2Blood and Tissue Bank, Hospital Universitari Vall d’Hebron, response as the primary end point. The study is publicly funded (PI- 102 39 Barcelona; 3Pharmacy Service, Hospital Universitari Vall 0233-2012) and is being conducted in 7 public reference hospitals. 103 40 d’Hebron, Barcelona; and 4Orthopaedics and Traumatology We describe the design, network established, organization of clinical 104 41 Service, Hospital Universitari Vall d’Hebron, Barcelona teams, and general management support to effectively carry out an 105 42 Background: Antithrombotic therapy in patients with hip fracture is investigator-driven RCT in a public system setting. 106 43 107 a challenge, and the risk of bleeding often delays surgery. Results: Women with primary Her-2 negative breast cancer (n = 44 Objectives: To compare the characteristics and perioperative out- 30) are randomized 1:1 to receive standard FEC therapy (5-fluo- 108 45 109 comes of patients treated and not treated with antithrombotics admit- rouracil + epirrubicin + ciclofosfamide) (arm 1) or a chemother- 46 ted for hip fracture. apy scheme customized by BRCA1 levels (arm 2). Patients with 110 47 111 Methods: A retrospective analysis of 2 cohorts of patients admitted low expression will receive ECF therapy (epirrubicin + cisplatin 48 112 for hip fracture, 1 treated and another not treated with antithrombot- + 5-fluorouracil); patients with levels of BRCA1 will be treated 49 113 ics, was carried out during a year. Data on demographic characteris- with eight cycles of docetaxel + ciclofosfamide. Definitive surgery 50 tics, pathologic antecedents, and ASA and Bleed-MAP categories and will be performed within 4 weeks after the last chemotherapy 114 51 outcomes (thromboembolic and haemorrhagic events and mortality) cycle. An independent general management team was built for 115 52 were collected from the electronic medical record from admission to handling regulatory affairs, data and safety monitoring, phar- 116 53 three months after surgery. macovigilance tasks, and daily trial operational activities during 117 54 Results: A total of 214 patients treated with antithrombotics and 272 trial implementation. 118 55 not treated were included. Both cohorts differ in most characteristics: Conclusion: Trial implementation requires a coordinated, multidis- 119 56 those treated with antithrombotics were older (median [IQR]) (86 ciplinary team of people with a solid commitment to support the 120 57 121 [81–90] and 83.5 [78–88] years, P < 0.001), with a lower frequency organization, design, and implementation of study procedures in 58 122 of women (70.1% and 80.5%, P = 0.01), and had more cardiovas- compliance with regulatory and ethical requirements for investiga- 59 cular antecedents and a higher percentage of ASA III-IV categories tor-driven RCTs. The challenge of pragmatic design reflecting real 123 60 124 (85% and 64.3%, P < 0.001) and Bleed-MAP 1-2 scores (66.4% practice is fully performed with independent resources. 61 125 and 31%, P < 0.001). No differences on the type of fracture and EudraCT No.: 2011-005843-28 (09/01/2013 registered). 62 126 63 127 64 128

e2 Volume XX Number XX Morphine decreases ticagrelor concentrations but not its Effects

1 Cardiovascular risk and androgen concentrations and platelet aggregation were measured for up to 12 65 2 deprivation therapy for prostate cancer: hours. and plasma concentrations were meas- 66 3 systematic review and meta-analysis ured for up to 24 hours and those of and for 67 4 of randomised controlled trials and up to 48 hours. 68 5 observational studies (METADTCR) Results: Clopidogrel carboxylic acid to clopidogrel area under the 69

6 L.-M. Scailteux; F. Naudet; Q. Alimi; S. Vincendeau; and E. Oger plasma concentration-time curve from 0 h to infinity (AUC0-∞) ratio 70 7 Rennes University Hospital, Rennes, France was 53% smaller in CES1 c.428G/A carriers than in noncarriers 71 8 Introduction: Androgen deprivation therapy (ADT) is the corner- (P = 0.009), indicating impaired hydrolysis of clopidogrel. 72

9 stone therapy in advanced prostate cancer management. Currently, Consequently, AUC0-∞ of clopidogrel and its active cis 5-thiol metabo- 73 10 to study cardiovascular risk, many studies pooled ADT modalities, lite were 123% (P = 0.004) and 67% (P = 0.009) larger in c.428G/A 74 11 sometimes with orchiectomy. Our objective was to compare the carriers than in noncarriers. Consistent with pharmacokinetics, aver- 75

12 coronary and cerebrovascular risk (, ischemic age inhibition of P2Y12-mediated platelet aggregation 0-12 h after 76 13 stroke) and the cardiovascular and overall mortality across the dif- clopidogrel intake and maximum observed platelet inhibition were 77 14 ferent ADT modalities. 19 percentage points higher in c.428G/A carriers than in noncarri- 78

15 Prospero registration: CRD42014010598. ers (P = 0.036 and P = 0.041, respectively). AUC0-∞ of enalaprilat 79 16 Methods: We performed a literature search of randomized controlled was 20% lower in CES1 c.428G/A carriers than in noncarriers (P = 80 17 trials (RCTs) and observational studies using Medline and Embase 0.049). The CES1 c.428G> A genotype had no significant effect on 81 18 since 1950 to July 28, 2014, without language restriction provided quinapril pharmacokinetics. 82 19 that they gave data on prostate cancer patients comparing one ADT Conclusions: The CES1 c.428G> A SNV increased clopidogrel 83 20 modality to another or radiotherapy or total prostatectomy or pla- active metabolite concentrations and antiplatelet effects by reducing 84 21 cebo. ADT modalities were GnRH agonists, GnRH antagonists, hydrolysis of parent clopidogrel to inactive metabolites. Therefore, 85 22 antiandrogens (steroidal or nonsteroidal), and newer drugs (abira- the CES1 c.428A allele may increase clopidogrel efficacy and bleeding 86 23 terone, enzalutamide). Orchiectomy was the relevant alternative. For risk. The CES1 c.428G> A SNV decreased active enalaprilat concen- 87 24 observational studies pooling several ADT modalities, details on each trations by reducing the hydrolysis of enalapril, but had no observ- 88 25 ADT group were requested to the author. We will also perform a able effect on quinapril pharmacokinetics. 89 26 network meta-analysis including RCTs. 90 27 Results: Among 3614 abstracts, 47 cohorts fulfilled inclusion criteria 81 28 and 8 provided sufficient data to be analysed. One study gave details Population pharmacokinetic modeling 92 29 on cardiovascular death and 2 on only coronary and cerebrovascular and simulations of long-acting 93 30 risk, but cardiovascular events definition were too heterogeneous to intramuscular risperidone ISM® 94 31 be pooled (one study added arrhythmia and to ischemic J. Winkler1; E. Snoeck1; J. Llaudó Garin2; I. Ayani2; 95 32 heart disease). For the 6 other studies, as they did not compare the J. Martínez-González2; and I. Gutierro Adúriz2 96 33 same modalities of ADT, they were not meta-analysed for overall 1SGS Exprimo NV, Mechelen, Belgium; and 2Laboratorios 97 34 survival. A total of 153 abstracts mentioning RCT fulfilled inclusion Farmaceuticos ROVI, S.A., Madrid, Spain 98 35 criteria, and data analysis is ongoing. Background/Introduction: The aim of the project was to develop 99 36 Conclusions: Data from observational studies did not support con- a population PK model for a novel and long-acting intramuscular 100 37 sistent evidence that any particular ADT modality may increase car- (i.m.) formulation (ISM®) of the atypical antipsychotic risperidone, 101 38 diovascular risk or overall survival. We are conducting a nationwide including a relatively complex absorption profile combined with a 102 39 population-based prospective cohort of 4 years thanks to the French previously published population PK disposition model of risperi- 103 40 Health Reimbursement Agency database, which allowed us to investi- done and its metabolite 9-OH-risperidone after oral risperidone in 104 41 gate more in depth the association between different ADT modalities schizophrenic patients. 105 42 and cardiovascular risk. Material and Methods: A population PK analysis for risperidone 106 43 ISM® using Monolix software was conducted based on 1520 plasma 107 44 samples from two single-dose studies, ROV-RISP-2009-01(17 healthy 108 45 109 Carboxylesterase 1 C.428G> A single subjects) and PRISMA-1(48 schizophrenic subjects). Simulations 46 nucleotide variation reduces hydrolysis were subsequently undertaken predicting the steady-state PK expo- 110 47 of clopidogrel and enalapril, but not sure of active moiety after risperidone ISM®. 111 48 that of Quinapril Results: The PK disposition models of risperidone and 112 49 113 E.K. Tarkiainen; M.T. Holmberg; A. Tornio; M. Neuvonen; 9-OH-risperidone consisted of two compartments for each com- 50 114 T. Launiainen; P.J. Neuvonen; J.T. Backman; and M. Niemi pound. Four flexible depot compartments were included to describe 51 115 University of Helsinki and Helsinki University Hospital, Helsinki, the relatively complex absorption profile. Exponential models 52 116 Finland described IIV for the structural model parameters, and an addi- 53 117 Background: Carboxylesterase 1 (CES1) hydrolyzes about 90% tive error model in the log domain described residual variability. 54 118 of the prodrug clopidogrel to inactive carboxylic acid metabolite The influence of the CYP2D6 genotype on the formation rate of 55 119 and about 40% to 60% of the prodrugs quinapril and enalapril to 9-OH-risperidone was included in form of a mixture model fixing 56 120 their active metabolites. In vitro studies have shown that the CES1 parameters based on the previously published population PK model. 57 121 c.428G A (p.G143E, rs71647871) single-nucleotide variation (SNV) Goodness of fit plots indicated that the model described the data 58 > 122 can markedly affect metabolism of clopidogrel and ACE inhibitors. well. The residual error was relatively low with 18% to 19% CV. 59 123 Materials and Methods: We studied pharmacokinetics and Simulations were subsequently undertaken, predicting steady-state 60 124 pharmacodynamics of 600-mg oral clopidogrel, 10-mg oral PK exposure of active moiety after multiple doses of 37.5 to 150 mg 61 ® 125 quinapril, and 10-mg oral enalapril in 10 carriers and 12 noncar- risperidone ISM administered every 28 days for 12 weeks. In addi- 62 126 riers of the CES1 c.428G> A SNV. Clopidogrel, its carboxylic acid tion, different possible dose de-escalation schemes with a starting 63 ® 127 acyl- -D-glucuronide, and active cis 5-thiol metabolite plasma dose of 100 mg risperidone ISM were simulated. 64 β 128

2015 e3 Clinical Therapeutics

1 Conclusions: Plasma concentrations of risperidone and Material and Methods: Data were collected for all European 65 2 9-OH-risperidone after single i.m. injections of risperidone ISM® Countries. Statistics on opioids consumption were researched and 66 3 were well described by a population PK model. The predictive per- extracted from the consumption databases of the respective national 67 4 formance was successfully qualified so that this model can be fur- authorities (sales data from health medicines agency or reimburse- 68 5 ther used for simulations aiding to provide a dosing rationale for ment data for national healthcare system). Data were expressed in 69 6 risperidone ISM®. Defined Daily Doses-DDDs/1,000 inhabitants/day (DID). Total opi- 70 7 oid consumption (ATC code N02A) and use of selected substances 71 8 (morphine, oxycodone, fentanyl, codeine, dextropropoxyphene, and 72 9 Infectious risk of biological drugs tramadol) were investigated. 73 10 versus conventional systemic Results: Data collected were mainly represented by sales data col- 74 11 treatments in moderate to severe lected by the national authorities from wholesalers. During the 75 12 psoriasis observed period, total consumption of opioids increased steadily, 76 13 S. Couderc1; R. Bourrel2; C. Paul3; J.L. Montastruc1,4; then decreased suddenly after 2009 (−43% in France from 2009 to 77 14 M. Lapeyre-Mestre1,4; and A. Sommet1,4 2012: 44 to 20 DID). France was the largest consumer of opioids 78 15 1UMR 1027, Inserm, Université Toulouse III, Toulouse, in 2002- 2009 (about 50 DID). Up to 2009, the quantity used were 79 16 France; 2Caisse Nationale d’Assurance Maladie Midi-Pyrénées, mainly represented by dextropropoxyphene combinations (54% of 80 17 Toulouse, France; 3Service de Dermatologie, Centre Hospitalier total consumption in 2009 [25/45 DID] and up to 73% [43/58 DID] 81 18 Universitaire, Toulouse, France; and 4Pharmacologie Médicale et in 2005). In 2012, France, Belgium, and Denmark were the main 82 19 Clinique, Centre Hospitalier Universitaire, Toulouse, France opioids users. While morphine use remained constant or tended to 83 20 Introduction: Moderate to severe psoriasis affects about 0.5% of decrease (except in UK: 1 to 2 DID from 2005 to 2012), use of fen- 84 21 the population. Its management is based on conventional systemic tanyl is increasing in all countries, in particular in the Netherlands 85 22 treatments (TSC: phototherapy, acitretin, methotrexate, and cyclo- (+65% between 2005–2012: 2.3 to 3.8 DID). 86 23 sporine) and biological second-line drugs (etanercept, infliximab, Conclusions: This study highlights the substantial changes in opi- 87 24 ustekinumab, adalimumab, golimumab). Results of studies compar- oids consumption patterns that occurred as a consequence of definite 88 25 ing the infectious risk of TSC and biological drugs are divergent. withdrawal of dextropropoxyphene in March 2011. Opioids con- 89 26 Objective: To compare the infectious risk associated with biological sumption patterns in Europe are now characterized by an increasing 90 27 drugs versus TSC for moderate to severe psoriasis. use of fentanyl and tramadol. 81 28 Material and Methods: We conducted a retrospective cohort in the 92 29 French Health Insurance Database for the Midi-Pyrenees region 93 30 from 01/01/2010 to 31/12/2013, with patients treated incidentally A Novel approach to teaching 94 31 for moderate to severe psoriasis. After a 6-month observation period Pharmacotherapeutics learning by doing 95 32 with all patients exposed to TSC, we compared patients exposed to in a student-run clinic 96 33 biological drugs (“exposed”) versus TSC (“unexposed”). We per- T. Schutte1,2,*; R.S. Dekker1,*; J. Tichelaar1,2; A. Thijs1; 97 34 formed a Cox model on the first infectious event, for up to 6 months Th.P.G.M. de Vries1,*; M.C. Richir1,2; and M.A. van Agtmael1,2 98 35 after the last dispensation of psoriasis drug. An infectious event was 1VU University Medical Center, Amsterdam, the Netherlands; 99 36 defined as delivery of any anti-infectious systemic drug or a hospital and 2RECIPE (Research & Expertise Center In Pharmacotherapy 100 37 diagnosis of infection. Education), Amsterdam, the Netherlands 101 38 Results: The 101 “exposed: patients and 788 “unexposed” *Contributed equally 102 39 patients were comparable in terms of socio-demographic data and Background: Medical students should be better prepared for their 103 40 comorbidities. Considering the first infectious event over a period of future role as prescribers. A new educational concept to achieve this 104 41 2 years, no significant difference was found between “exposed” and is learning by doing. This encompasses legitimate, context-based 105 42 106 “unexposed” (HR = 0.94; 95% CI, 0.71–1.22; P = 0.62). Being a training and gives students responsibility as early as possible in their 43 107 woman (HR = 1.23), benefit from the Universal Health Coverage medical education. Student-run clinics (SRCs) are an example of 44 108 (HR = 1.44), suffering from chronic hepatitis B or C (HR = 2.74), this concept. We describe the development of a new SRC primarily 45 109 history of neoplasia (HR = 1.70), a previous infectious event dur- focused on medical pharmacotherapy education, the learner-centered 46 110 ing the observation period (HR = 1.74), and the number of drugs student-run clinic (LC-SRC), and its feasibility. 47 111 consumed during the observation period (HR = 1.03) significantly Method: A feasibility study was performed in which a team of (1st-, 48 increased the risk of infection. 3rd-, and 5th-year) students treated patients under the supervision of 112 49 Conclusions: We did not reveal any difference in infection risk an internist. Patients were selected from the internal medicine out- 113 50 between the TSC and biological drugs in the management of moder- patient clinic for follow-up in the LC-SRC. Feasibility was evaluated 114 51 ate to severe psoriasis. This risk appears constant the first 2 years using a set of questionnaires for patients, supervisors, and students. 115 52 of use. Results: In total 31 consultations were conducted; 31 students and 116 53 4 clinical specialists participated. A pharmacotherapeutic treatment 117 54 plan was drawn up in 33% of the consultations. Patients were con- 118 55 119 Trends in opioid analgesics use in Europe: tent with the care provided and rated the consultation with a 7.9 (SD 56 1.21) (range, 1–10). Supervisors regarded LC-SRC safe for patients 120 57 a ten-year perspective 121 1 1,2 with guaranteed quality of care. They found the LC-SRC a valuable 58 A. Palmaro ; and M. Lapeyre-Mestre 122 1Medical and Clinical Pharmacology Unit, CHU tool in medical education, although it was time-consuming. Students 59 appreciated their (new) responsibility for patient care and considered 123 Toulouse University Hospital, Toulouse, France; and 60 the LC-SRC a very valuable extracurricular activity. 124 2Pharmacoepidemiology Research Unit, INSERM 1027, 61 Conclusion: The LC-SRC is feasible and could be a valuable addition 125 University of Toulouse, Toulouse, France 62 to the medical curriculum. The benefits and learner effects need to be 126 Background: The aim of this study was to investigate the trends in 63 investigated in a larger study with a longer follow-up. 127 64 opioid analgesics consumption in Europe between 2002 and 2012. 128

e4 Volume XX Number XX Morphine decreases ticagrelor concentrations but not its Effects

1 An epidemiological study for elevation weren’t considered. Data were analyzed using descriptive statistics, 65 2 2 of liver function tests in Japanese χ tests and Spearman’s correlation coefficients. 66 3 patients administered by high dose Results: 1084 questionnaires were collected (response rate of 67 4 acetaminophen 81.1%), and 948 completed questionnaires were selected for analysis. 68 5 Y. Kumagai; I.D. Song; M. Maeda; R. Tanaka; and Y. Sakamoto Of the respondents, 44.1% never heard about SNF. Younger people 69 6 Kitasato University, Sagamihara, Japan and those with a higher education were significantly more likely to 70 7 Background: Acetaminophen is widely used for pain in cancer and be aware of SNF. Only 1 patient had previously reported directly an 71 8 non-cancer patients, and it is known to show liver injury in the case of ADR. Reporting ADRs indirectly through an HCP was preferred by 72 9 overdose. The maximum dose was 1.5 g/d in Japan, which was much 62.4%. The main reasons for patients reporting spontaneous ADR 73 10 lower than in other countries. In 2011, the registered maximum dose would be the severity of reactions (81.1% agreed or strongly agreed) 74 11 was changed to 4.0 g/d in Japan, and concerns for safety in Japanese and worries about their situation (73.4% agreed or strongly agreed). 75 12 patients were raised. Therefore, we performed an epidemiological Only weak and moderate correlations were found between studied 76 13 study for the safety of acetaminophen. statements. 77 14 Methods: Patients administered a high dose (2.4–4.0 g/d) of aceta- Conclusions: Patients are more likely to spontaneously report severe 78 15 minophen for more than 4 weeks were included. Data were col- reactions if they are worried about the symptoms. Tailored and proac- 79 16 lected from hospital medical information systems at 87 hospitals tive information on ADR reporting and educational interventions on 80 17 from January 2011 to October 2013. Abnormal liver function test patients could increase the number of reports from patients in Portugal. 81 18 (LFT) was defined as elevation in ALT greater than 3 times the upper 82 19 limit of normal. Prevalence of abnormal LFT was calculated, and 83 20 relationships with patients’ backgrounds were analysed by a logistic Zagreb medical students’ attitudes 84 21 regression. towards formative assessments of their 85 22 Results: 735 cases were collected and 703 cases that met inclusion knowledge of prescribing 86 23 criteria were analysed. Among them, 371 cases were cancer patients. Robert Likic1,2; Luka Bielen1,2; Viktorija Erdeljic1; Ksenija Makar 87 24 One case showed elevation of AST, ALT, and TBil, which met criteria Ausperger1; Mateja Radacic Aumiler1; Danica Juricic1; and Igor 88 25 by Hy’s law, but the findings were considered to be owing to pre- Francetic1 89 26 existing disease. There was no serious liver injury considered to be 1University Hospital Center Zagreb, Croatia; and 2University of 90 27 induced by acetaminophen. Abnormal LFTs were found in 22 cases Zagreb Medical School, Croatia 81 28 (3.1%), and causality of acetaminophen was not ruled out in 7 cases Introduction: In 2009, an e-learning course comprising 90 clinical 92 29 (1.0%). The logistic regression showed that abnormal LFTs signifi- cases and 300 flash videos developed at the University of Michigan 93 30 cantly related to existence of complicated disease, history of allergic Medical School (Ann Arbor) was in a collaborative manner translated 94 31 disease, and duration of dosage. into Croatian and adopted for use at the Zagreb Medical School by 95 32 Conclusion: The prevalence of elevation of ALT in Japanese patients means of the ctools learning management system (LMS) platform. 96 33 administered by acetaminophen was almost identical with those Materials and methods: formative assessments were performed 97 34 reported in other countries. However, the significant relationship through the course sites platform via 24 quizzes in a timed man- 98 35 between abnormal LFT and duration of dosage indicates a necessity ner and open book format. After the course completion, attitudes 99 36 of continuous collection of data in Japan. of 220 Croatian students towards the online course and formative 100 37 assessments were evaluated with a validated, electronic question- 101 38 naire in 2014. 102 39 Are patients ready to take part in the Results: Feedback obtained from the Zagreb students (response rate, 103 40 Pharmacovigilance system? a portuguese 44%) demonstrated that the majority of them perceived the weekly 104 41 preliminary study concerning adr quizzes as difficult (55%) or very difficult (31%). Furthermore, the 105 42 reporting majority of them agreed (28%) or strongly agreed (66%) with the 106 43 107 C. Matos1; F. van Hunsel2; and J. Joaquim1 usefulness of obtaining immediate feedback to their answers, and more 44 108 1Instituto Politécnico de Coimbra, Coimbra Health School than 50% of students perceived weekly online quizzes as an intellectu- 45 109 – ESTESC, Farmácia, Coimbra, Portugal; and 2Netherlands ally challenging exercise that tested their higher cognitive abilities. 46 110 Pharmacovigilance Centre Lareb,‘s-Hertogenbosch, Conclusion: online formative assessments of students’ prescribing 47 111 the Netherlands knowledge offer a cost effective way to better prepare young doctors 48 112 Background: New pharmacovigilance legislation allows patients to for their future independent medical practice by challenging their 49 113 report adverse drug reactions (ADRs) directly to competent authori- problem-solving and prescribing abilities while simultaneously offer- 50 114 ties in all European Union countries. Patient reporting is available in ing immediate feedback regarding their choices, all in a safe, online 51 115 Portugal since July 2012. In 2013, the National Pharmacovigilance environment and without danger to the lives of patients. 52 116 System (SNF) had received 3461 spontaneous ADR reports, of which 53 117 only 1.4% (n 50) were from patients. Patient reporting could be 54 = 118 one opportunity to reduce underreporting. The aim of this study was 55 Drug-drug interaction database 119 to describe the attitudes and knowledge of the patients regarding 56 SFINX – first results from north Estonia 120 spontaneous reporting and the reasons and opinions that can influ- 57 Medical Centre, Estonia 121 ence patients ADR underreporting. 1,2 1 1 3 58 T. Marandi ; L. Orav ; A. Kändmaa ; and S. Nahkur 122 Material and Methods: A descriptive-correlational study was per- 1 2 59 North Estonia Medical Centre, Tallinn, Estonia; University of 123 formed looking for patients’ attitudes and knowledge regarding 3 60 Tartu, Tartu, Estonia; and Celsius Healthcare, Tallinn, Estonia 124 spontaneous reporting. A 6-month survey was conducted from June 61 Drug treatment is one of the most important tools in health care 125 to November 2013 in general adult patients from a community phar- 62 but is also an important reason for morbidity and mortality. Among 126 macy in Coimbra, Portugal, that used prescribed medicines or OTC 63 different drug-related problems, drug-drug interactions (DDIs) are 127 drugs. Questionnaires from health care professionals or incomplete 64 particularly important and in many cases predictable and avoidable. 128

2015 e5 Clinical Therapeutics

1 To detect DDIs and improve the quality of prescribing, the SFINX is similar. The iPad app and the website are rated the highest (7.9), 65 2 (Swedish, Finnish, INteraction X-referencing) database has been inte- whereas the iPhone app, smartphone app, and tablet app are assessed 66 3 grated to electronic health records in North Estonia Medical Centre slightly lower (7.4, 7.1, and 7.2, respectively). Interestingly, most users 67 4 (NEMC) from the end of the year 2014. The aim of this pilot study of a mobile app continue to use also the website for their study. 68 5 was to describe first-time data of DDIs detected during prescribing Conclusions: The free pharmacology app is readily available for all 69 6 of drugs for outpatient use at NEMC. health care students and professionals worldwide for free. The TRC 70 7 Material and methods: Data about prescribed drugs and detected app is used differently in respect to learning situations compared to 71 8 type D (clinically significant interaction that should be avoided) the website. Due to the success of the apps, further extension of the 72 9 and type C (clinically relevant interactions that can be handled, eg, content (eg, inclusion of animations) is ongoing. 73 10 by dose adjustments) DDIs after prescribing in NEMC has been 74 11 obtained from NEMC during the period from January 1 to January 75 12 31, 2015. All earlier outpatient prescriptions from last 180 days were Effectiveness of Acenocoumarol 76 13 considered in DDI analysis, too. genetic and clinical dosing algorithms 77 14 Results: During the period studied, 25,421 prescriptions were written in predicting stable dose in the greek 78 15 in NEMC: 10,644 for men and 14,777 for women. A total of 23,295 cohort of the Eu-pact trial 79 16 new type D and C DDIs were detected, consisting of 164 unique pairs V.G. Manolopoulos1,2; G. Ragia1; A. Tavridou1,2; V. Kolovou3; 80 17 of type D and 741 pairs of type C DDIs, respectively (Table). G. Kolovou3; E. Maltezos1,2; D. Tziakas1,2; and S. Konstantinides1,2 81 18 1Democritus University of Thrace Medical School, 82 19 Table. Most common drug-drug interactions in North Estonia Medical Alexandroupolis, Greece; 2Academic General Hospital of Evros, 83 20 Centre Alexandroupolis, Greece; and 3Onassis Cardiac Surgery Center, 84 21 Athens, Greece 85 Type D interaction Prevalence Type C interaction Prevalence 22 Introduction: The EU-PACT (Pharmacogenetics of Anticoagulant 86 23 Therapy) trial (ClinicalTrials.gov number NCT01119261) compared 87 24 Propafenone - metoprolol 408 Metoprolol - diclofenac 829 88 Clopidogrel - omeprazole 276 Warfarin - torsemide 515 a genotype-guided dosing algorithm that included clinical variables 25 89 Metoprolol - verapamil 194 Digoxin - spironolactone 492 and genotypes of CYP2C9 and VKORC1 with a dosing algorithm 26 Clopidogrel - esomeprazole 108 Spironolactone - 473 that included only clinical variables for the initiation of acenocoumarol 90 Warfarin - diclofenac 107 - diclofenac 418 27 treatment in patients with atrial fibrillation or venous thromboembo- 81 28 lism. Its main results were published recently (Verhoef et al. NEJM. 92 29 Conclusions: The SFINX database is a powerful tool to detect DDIs 2013;369(24):2294-303). The primary outcome of the trial was per- 93 30 during prescribing process. However, data from the first analysis cent time in INR target range (2.0 to 3.0) in the 12-week period follow- 94 31 indicated a need for targeted education of prescribers about interpre- ing therapy initiation. Several secondary outcomes, such as time to and 95 32 tation of clinical significance of DDIs highlighted in terms of rational 96 number of patients with INR ≥ 4, percentage time spent with an INR 33 pharmacotherapy and planning of systematic follow up of patients 97 ≥ 4 or with an INR < 2, number of minor and major adverse events, and 34 with high risk for DDIs. incidence of coumarin sensitivity and resistance, were also assessed. 98 35 Methods: We performed an ethnicity analysis for the Greek popula- 99 36 tion recruited in the EU-PACT trial. A total of 207 patients (104 in 100 37 Pharmacology E-learning with the the pharmacogenomic arm, 103 in the control arm) starting aceno- 101 38 Mobile teaching resource center coumarol therapy were recruited in Greece. 102 39 103 R. Rissmann1,2; J. Messayeh2; J.H.F.M. Pinckaers1; A.C. Cohen1,2; Results: Percent time in range (PTIR) was 61.1% for patients receiv- 40 104 and J.L. Hay2 ing genotype-guided dosing and 62.7% for those receiving clinically 41 105 1Leiden University Medical Center, Leiden, the Netherlands; and guided dosing (P = 0.68). No differences were observed in PTIR 42 106 2Centre for Human Drug Research, Leiden, the Netherlands for weeks 1 to 4, 4 to 8, and 9 to 12 of the trial and for the other 43 107 Introduction: The free pharmacology Teaching Resource Centre secondary outcomes assessed. We have further tested in the pooled 44 108 (TRC, http://www.coo.lumc.nl/trc) was created to illustrate drug sample the effect of CYP450 enzymes and VKORC1 gene poly- 45 109 action in the (patho)physiological context in a consistent way. With morphisms on acenocoumarol stable dose and time to reach stable 46 110 the introduction of the tablets and smartphones, Leiden students dose. Acenocoumarol stable dose was significantly associated with 47 111 demanded increased accessibility of pharmacological knowledge (ie, CYP2C9 and VKORC1 genotype (P < 0.001 in each case). 48 112 the TRC). The TRC apps were released for iPad (June 2012), iPhone Conclusions: Genotype-guided dosing of acenocoumarol did not 49 113 (November 2012), and Android (November 2013). The objective of improve the PTIR during the 12 weeks after therapy initiation in 50 114 the study was to investigate usage frequency, differences in usage, comparison with the clinical algorithm. However, genetic variants 51 115 and user friendliness of the apps compared to the website in the of CYP2C9 and VKORC1 are significant determinants of individual 52 116 most relevant user population (ie, undergraduate medicine students). dose of acenocoumarol needed to maintain a therapeutic INR in the 53 117 Methods: A survey was sent out via email to medical students at Greek population. 54 118 Leiden University Medical Center. The type of questions were mul- 55 119 tiple choice, multiple answer, or open-ended. The responses were 56 120 then recorded and analyzed. In total, 484 medical undergraduate 57 Pharmacogenetic profile of lipid 121 students responded. 58 response to atorvastatin in children 122 Results: In more than 30 months since its initial release, the apps have 59 and adolescents with familial 123 been downloaded more than 100,000 times throughout the world. The 60 Hypercholesterolemia 124 TRC website is still frequently used with up to 5000 hits per day before 1,2 3 1 3 61 V.G. Manolopoulos ; E. Drogari ; G. Ragia ; V. Mollaki ; 125 exams. The website is the most visited portal for pharmacological 4,5 4 62 L. Elens ; and R.H.N. Van Schaik 126 e-learning with the TRC. The mean overall assessment of the resource 1 63 Democritus University of Thrace Medical School, 127 on a 10-point numerical rating scaling (0, very weak; 10, excellent) 2 64 Alexandroupolis, Greece; Academic General Hospital of Evros, 128

e6 Volume XX Number XX Morphine decreases ticagrelor concentrations but not its Effects

1 Alexandroupolis, Greece; 3University of Athens Medical School, in MATLAB. It was calibrated using serum thromboxane (TX)B2 65 2 Aghia Sophia Children’s Hospital, Athens, Greece; 4Erasmus (proxy of COX-1 activity) recovery data measured in 7 healthy con- 66 3 Medical Center, Rotterdam, The Netherlands; and 5Catholic trols and 2 ET patients during and after aspirin withdrawal and in 67 4 University of Louvain, Brussels, Belgium 21 ET patients on different aspirin regimens. Sensitivity analysis was 68 5 Introduction: In children and adolescents with familial hypercho- performed to identify the set of key parameters that most significantly 69 6 lesterolemia (FH), pharmacotherapy with statins is the cornerstone influenced COX-1 dynamics. 70 7 in the current regimen to reduce low-density lipoprotein cholesterol Results: A good agreement (weighted absolute percentage error 71 8 (LDLc) and premature coronary heart disease risk. There is, how- < 18%, within the experimental variability) was obtained between 72 9 ever, a great interindividual variation in response to therapy, par- data and model prediction. The different recovery pattern observed 73 10 tially attributed to genetic factors. It has been suggested that genetic in healthy vs ET patients was reproduced by altering three key model 74 11 polymorphism of the enzymes POR, CYP3A4, CYP3A5 and solute parameters identified by sensitivity analysis: platelet count (twofold 75 12 carrier SLCO1B1 may influence this variation. We analyzed the asso- increase), Mk lifetime (from 3 to 1 day), and platelet lifetime (from 7 76 13 ciation of alleles POR*28, CYP3A4*22, CYP3A5*3, and SLCO1B1 to 5–6 days). Finally, the model explains an increased COX-1 acety- 77 14 521T> C and 388A> G with response to atorvastatin. lation following a shorter dosing interval (100 mg twice daily) as 78 15 Methods: The study included 105 FH children and adolescents compared to a higher (200 mg) once-daily dose in ET patients. 79 16 treated with atorvastatin (10 to 40 mg). Total cholesterol (TChol) Conclusions: Our in silico model adequately describes aspirin 80 17 and LDLc were measured at baseline and after 6 months of treat- responsiveness, as measured in controls and patients with high drug- 81 18 ment. POR*28 CYP3A4*22, and CYP3A5*3 alleles and SLCO1B1 target turnover, and might be a useful tool to design personalized 82 19 521T> C and 388A> G genotypes were determined with TaqMan or regimens in clinical conditions characterized by altered Mk and/or 83 20 PCR-RFLP methods. platelet kinetics. 84 21 Results: POR*28 carriers had significantly lower percent mean 85 22 reduction of TChol (33.1% in *1/*1, 29.8% in *1/*28, and 25.9% 86 23 in *28/*28 individuals, P = 0.045) and of LDL-c (43.9% in *1/*1, Lethal suicidal attempt with a mixed- 87 24 40.9% in *1/*28, and 30.8% in *28/*28 individuals, P = 0.013). drug intoxication involving metoprolol 88 25 In multivariable linear regression adjusted for confounding fac- and propafenone – a first paediatric case 89 26 tors, POR*28 genotypes, additionally to baseline cholesterol level, report 90 27 account for an estimated 8.3% and 7.3% of overall variability in M. Grundmann1; I. Kacirova1,2; and M. Koleke2 81 28 percent TChol and LDLc reduction (β = 4.05; 95% CI, 1.73–6.37; P 1Faculty of Medicine, University of Ostrava, Czech Republic; and 92 29 = 0.001 and β = 5.08; 95% CI, 1.62–8.54; P = 0.004, respectively). 2University Hospital Ostrava, Czech Republic 93 30 CYP3A4*22, CYP3A5*3, and SLCO1B1 521T> C and 388A> G 94 Introduction: β 1-blocker metoprolol is often prescribed together 31 polymorphisms were not associated with lipid reductions and did with propafenone. Both are metabolized by cytochrome P450 2D6, 95 32 not modify the effect of POR*28 on atorvastatin response. and metoprolol serves as the probe drug for phenotyping of the 96 33 Conclusions: In children with FH, carriage of POR*28 allele was enzyme. Propafenone is also an inhibitor of P450 2D6, and a 2- to 97 34 associated with reduced effect of atorvastatin on TChol and LDLc 5-fold increase of metoprolol steady-state levels has been described 98 35 and therefore identifies FH children who may require higher atorv- in combination with propafenone. There is no case report show- 99 36 astatin doses to achieve full therapeutic benefits. Further studies in ing metoprolol and propafenone ingestion in a suicidal attempt 100 37 different populations are needed to replicate the association. together. 101 38 Key words: atorvastatin, pharmacogenomics, familial hypercholes- Material and Methods: A 14-year-old girl was admitted to the 102 39 terolemia, P450 oxidoreductase, POR*28, CYP3A4*22, CYP3A5*3 emergency department having ingested propafenone (probably 103 40 and SLCO1B1 521T> C and 388A> G, children. 1500–3000 mg) and metoprolol (probably 1000 mg) in a suicide 104 41 attempt with loss of consciousness, seizures, and the widening of the 105 42 QRS complex. Plasma levels of metoprolol and propafenone were 106 43 An in silico model of aspirin- analysed approximately 10 hours after ingestion; however, the cor- 107 44 iduced inactivation of platelet and rect amount of each drug and the time of ingestion were unknown. 108 45 Megakaryocyte Cyclooxygenase-1 Serial samples for measurement of metoprolol and its metabolite 109 46 1 2 1 1 110 A. Giaretta ; B. Rocca ; B. Di Camillo ; G.M. Toffolo ; and α -hydroxymetoprolol were analysed between days 2 and 4, and the 47 2 111 C. Patrono metoprolol/α -hydroxymetoprolol ratio was determined. 48 1Department of Information Engineering, University of Padova, Results: The patient’s clinical condition rapidly deteriorated. She 112 49 Padova, Italy; and 2Department of Pharmacology, Catholic developed cardiac arrest and was fully resuscitated. Extracorporeal 113 50 University School of Medicine, Rome, Italy circulation was started. Her condition gradually worsened, and 114 51 Background: Aspirin is a short-lived, irreversible inhibitor of platelet brain edema and acute renal insufficiency occurred. On the 6th 115 52 cyclooxygenase (COX)-1. We have recently reported that aspirin day the patient died. The first concentrations were 2500 ng/mL 116 53 action throughout the 24-hour dosing interval is impaired under (propafenone) and 2630 ng/mL (metoprolol). The levels of meto- 117 54 118 conditions of accelerated platelet formation such as essential throm- prolol and α -hydroxymetoprolol declined slowly from 689.1 ng/mL 55 bocythemia (ET). An in silico model of aspirin pharmacodynamics (2nd day) to 132.7 ng/mL (fourth day) and 19.1 ng/mL to12.5 ng/mL, 119 56 120 might help elucidating the dynamic features of its action and person- respectively. The metoprolol/α -hydroxymetoprolol ratio determined 57 alize regimens in different cardiovascular disorders. on the second day was 36.1, indicative of a poor metabolizer pheno- 121 58 Methods: We set up a new multi-compartmental mathematical type, declining to 22.9 and 16.1 on the third day and to 10.6 on the 122 59 model that describes the key features of COX-1 dynamics, includ- fourth day. The elimination half-life of metoprolol was prolonged to 123 60 ing its synthesis/degradation in the heterogeneous population of 12.2 hours that is 4-fold longer to normal value. 124 61 developing bone marrow megakaryocytes (Mk), the progressive Conclusions: We report the first pediatric case of death due to a 125 62 platelet formation, and COX-1 acetylation by aspirin in both Mk mixed drug overdose of metoprolol and propafenone. The toxicity 126 63 and peripheral (platelet) compartments. The model, consisting of of metoprolol was potentiated by drug interaction with propafenone 127 64 7 differential equations and 24 parameters, was implemented causing inhibition of P450 2D6. 128

2015 e7 Clinical Therapeutics

1 Electrocardiographic screening for oldest old (≥ 80 years). This study explores the use of the 65 2 drug-induced long qt to reduce sudden Belgian community-dwelling oldest old in relation to their demo- 66 3 cardiac death in Psychiatric patients: a graphic, clinical, and functional characteristics. 67 4 cost-effectiveness analysis Methods: Baseline data were used from the BELFRAIL study, a 68 5 Antoine Poncet1; Baris Gencer2; Marc Blondon2; prospective, observational, population-based cohort of community- 69 6 Marianne Gex-Fabry3; Christophe Combescure1; Dipen Shah2; dwelling subjects (≥ 80 years). General practitioners recorded clinical 70 7 Peter J. Schwartz4; Marie Besson5; and François R. Girardin5,6 problems and . Medications were coded by the Anatomic 71 8 1Department of Health and Community Medicine, University Therapeutic Chemical classification. 72 9 Hospitals and University of Geneva, rue Gabrielle-Perret-Gentil Results: Participants’ (n = 503) mean age was 84.4 years (range, 73 10 4, 1205 Geneva, Switzerland; 2Department of Internal Medicine, 80–102 years), and 61.2% was female. Median chronic medication 74 11 University Hospitals and University of Geneva, rue Gabrielle- use was 5 (range, 0–16). Polypharmacy (≥ 5 medications) was high 75 12 Perret-Gentil 4, 1205 Geneva, Switzerland; 3Department of (57.7%), with excessive polypharmacy (≥ 10 medications) in 9.1%. 76 13 Psychiatry, University Hospitals and University of Geneva, Cardiovascular medications (86.3%) were most used. Nervous sys- 77 14 2 chemin du Petit-Bel-Air, 1225 Chêne-Bourg, Switzerland; tem medications (54.1%), predominantly benzodiazepines and anti- 78 15 4Center for Cardiac Arrhythmias of Genetic Origin, IRCCS depressants, were also frequently consumed. Demographic factors 79 16 Istituto Auxologico Italiano, Milano, Italy; 5Department of related with polypharmacy in univariate analysis were female gender 80 17 Anesthesiology, Intensive Care, and Clinical Pharmacology, (OR 1.58), low education (OR 1.52), and low alcohol use (OR 1.61). 81 18 University Hospitals and University of Geneva, rue Gabrielle- Age, care dependency, and cognitive impairment showed no asso- 82 19 Perret-Gentil 4, 1205 Geneva, Switzerland; and 6Medical ciation with polypharmacy. Except for obesity, the most prevalent 83 20 Directorate, University Hospitals and University of Geneva, rue clinical problems were associated with polypharmacy. In multivariate 84 21 Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland analysis, the predominant association with polypharmacy as outcome 85 22 Background: Sudden cardiac death is a leading cause of mortality was found for multimorbidity (OR 1.77), followed by depression 86 23 in psychiatric patients. Long QT (LQT) triggered by psychotropic (OR 3.73), and physical activity (OR 0.78). 87 24 medication is common and predisposes to torsades-de-pointes (TdP) Conclusions: Polypharmacy was high among Belgian community- 88 25 and subsequent mortality. We estimated the cost-effectiveness of elec- dwelling oldest old. Determinants of polypharmacy were interre- 89 26 trocardiographic screening to detect drug-induced LQT in psychiatric lated but dominated by multimorbidity. Polypharmacy was lower in 90 27 inpatients. physically active patients and higher in patients with more depressive 81 28 Material and methods: We built a decision analytic model based on symptoms. More research on causes and consequences of polyphar- 92 29 a decision tree to evaluate the cost-effectiveness and utility of LQT macy over time is needed. 93 30 screening from a health care perspective. LQT proportion parameters 94 31 were derived from an in-hospital cross-sectional study. We performed 95 32 experts’ elicitation to estimate the risk of TdP, given the extent of Pharmacovigilance at the chuk national 96 33 QT prolongation. A TdP reduction of 65% after LQT detection was referral hospital in rwanda: patterns of 97 34 based on positive drug dechallenge rate and through adequate treat- suspected adverse drug reactions 98 35 ment and electrolyte adjustments. The base-case model uncertainty E. Rutaganda1,2; V. Dusabejambo1,2; J. Nyirigira1,2; and 99 36 was assessed with one-way and probabilistic sensitivity analyses. D.R.J. Singer1,2,3,4 100 37 Finally, the TdP-related mortality and TdP avoidance parameters 1Centre Hospitalier Universitaire de Kigali (CHUK), Kigali, 101 38 were varied in a 2-way sensitivity analysis to assess their effect on Rwanda; 2University of Rwanda, Kigali, Rwanda; 3Human 102 39 the incremental cost-effectiveness ratio (ICER). Resources for Health Program, Rwanda; and 4Yale School of 103 40 Results: In the base-case scenario, the numbers of patients needed to Medicine, New Haven, Connecticut, USA 104 41 screen were 1128 and 2817 to avoid one TdP and one death, respec- Background: Pharmacovigilance increases patient safety. We aimed 105 42 tively. The ICER of systematic ECG screening was $8644 (95% CI, to encourage ADR reporting and assess ADRs among in-patients at 106 43 3144–82,498) per QALY. The probability of cost-effectiveness was our national referral hospital. 107 44 96% at a willingness-to-pay of $50,000 for one QALY. In sensitivity Methods: We used WHO and Ministry of Health ADR reporting 108 45 analyses, results were sensitive to the case-fatality of TdP episodes protocols, including causality reviews, to identify suspected harmful 109 46 and to the TdP reduction following the diagnosis of LQT. responses to one or more medicines, prescribed, OTC, or traditional, 110 47 Conclusions: In psychiatric hospitals, performing systematic ECG known or new. 111 48 screening at admission helps reduce the number of sudden cardiac Results: During a prospective 4-week audit in October 2014, 28 112 49 deaths in a cost-effective fashion. reports were received (27 patients: mean ± SE age, 42 ± 3 years; 113 50 range, 21–86; 11 males: mean ± SE age, 44 ± 4 years; 17 females: 114 51 mean ± SE age, 42 ± 4 years; height, 1.63 ± 0.02 m; weight, 54.7 ± 115 52 Polypharmacy in a Belgian cohort of 3.4 kg; emergency room, 10, internal medicine, 17, renal, 1; capital 116 53 community-dwelling oldest old: baseline city, 16, other areas, 12; comorbidity included: HIV, 10 [TB, 5; 1 117 54 observations and associated risk factors both candidiasis and PCP]; renal disease, 3; , 4, diabetes 118 55 119 Maarten Wauters1; Monique Elseviers1; Bert Vaes2,3; mellitus, 4; anaemia, 3; CLL, 1; none in 5. ADRs were related to tra- 56 120 Jan Degryse2,3; Olivia Dalleur2; Robert Vander Stichele1; ditional medicines (5), NSAIDs (3), antibiotics (8), antiretrovirals (3), 57 121 Luc Van Bortel1; and Majda Azermai1 prednisolone (2), and enoxaparin, metformin, OCP, pethidine, and 58 122 1Ghent University, Ghent, East Flanders, Belgium; 2Université quinine (1 each). One report was for a blood transfusion reaction. 59 123 catholique de Louvain, Saint-luc Brussels, Flemish Brabant, The most common sites affected were GI (bleeding/vomiting 8), liver 60 124 Belgium; and 3Catholic University of Leuven, Leuven, Flemish (6), skin (6), and kidney (4). Six patients had a recurrent ADR with a 61 125 Brabant, Belgium previously used medicine. Most recovered; however, 1 each had per- 62 126 Background: Polypharmacy is highly prevalent among older people sisting severe liver injury and kidney and neurological abnormalities. 63 127 ( 65 years), but little is known about the medication use of the One patient had quinine-associated gangrene. There was one death 64 ≥ 128

e8 Volume XX Number XX Morphine decreases ticagrelor concentrations but not its Effects

1 (acute on chronic liver failure). Twelve ADRs were considered due commonly prescribed drugs, such as antipsychotics, antiepileptics, 65 2 to a single drug, 10 to multiple drugs, and 5 to traditional medicines. antidepressants, and some cardiovascular drugs (eg, warfarin, fle- 66 3 In one patient a metabolic drug interaction with fluconazole was cainide, propafenone, and metoprolol). Evaluation of the metabolic 67 4 implicated. In 6 cases, drugs considered exacerbated prior disease. capacity of an individual by genotyping may help the clinicians 68 5 Conclusions: We were effective in improving ADR reporting, iden- to select the right dose (in order to avoid toxic or subtherapeutic 69 6 tifying important contributions of ADRs to serious morbidity, and plasma concentrations) and/or the best drug for an individual patient, 70 7 identifying preventable patterns of ADRs. Prior similar ADRs, drug- thereby minimizing the risk of side effects or therapeutic failure. 71 8 disease interactions, and traditional medicine use, often unrecog- In the period 2009 to 2014 a total of 529 genotyping analy- 72 9 nized, were common causes of hospital admissions. ses were performed at our department, with a 10% yearly increase 73 10 in the number of tests performed. The most requested test was 74 11 CYP2D6 (55%), followed by CYP2C19 (32%) and CYP2C9 (13%). 75 12 Efficacy, safety and tolerability study The majority of the patients were treated with psychoactive drugs 76 13 of artemisinin-piperaquine combination (75%), particularly antidepressants and classical antipsychotics, 77 14 (ArtequickR) versus artemeter- such as haloperidol and perphenazine, followed by cardiovascular 78 15 lumefantrine (Co-ArtemR) for the drugs, especially warfarin, metoprolol, and propafenone (15%). The 79 16 treatment of uncomplicated plasmodium principal reason for genotyping was lack of optimal drug response/ 80 17 falciparum T Malaria in Ijebu ode local therapeutic failure (50%), followed by side effects (35%), while a 81 18 government health services in Nigeria few subjects were genotyped before starting therapy with drugs, such 82 19 S.S. Onasanya1; R.O. Tijani1; T.O. Onasanya2; M. Alayo3; and as propafenone and tamoxifen. 83 20 A.E Akinbajo4 Gene duplication was detected in a handful of subjects with thera- 84 21 1Moshood Abiola Polytechnic; 2Florson Pharmaceutical Limited; peutic failure, suggesting that non-compliance is still the main reason 85 22 3Olabisi Onabanjo University; and 4Ijebu Ode Local Government for lack of drug response. Conversely, among subjects who had expe- 86 23 Health Centre rienced side effects, the frequency of detrimental alleles was higher 87 24 Background: Artemisinin-based combination therapy (ACT) has than the background incidence. Furthermore, in some cases extensive 88 25 become the standard of care for the treatment of uncomplicated metabolisers with side effects were phenotypically poor metaboliz- 89 26 Plasmodium falciparum malaria in the world. Data guiding opti- ers, due to comedication with potent CYP2D6 inhibitors, such as 90 27 mal choices of ACTs are limited. Artemisinin-based combination paroxetine and bupropion. Based on our experience, we conclude 81 28 therapy of artemether-lumefantrine (CoartemR) is currently used for that genotyping is a valuable complement to plasma concentration 92 29 the first line treatment of uncomplicated Plasmodium falciparum determination when poor or ultrarapid drug metabolism is suspected. 93 30 malaria. However, limited efficacy and tolerability data are available 94 31 on alternative forms of ACT. This study was conducted to compare 95 32 the efficacy and tolerability of two fixed- dose formulation of ACT, St. John’s wort impairs Glucose 96 33 artemisinin-piperaquine (ArtequickR) and (Coartem), for the treat- tolerance by reducing response 97 34 ment of P. falciparum in Nigeria. in healthy Men 98 35 Methods/Materials: A randomized, open-label trial was conducted T.B. Stage1; P. Damkier2; M.M.H. Christensen1; L.B-K. Nielsen2; 99 36 comparing the efficacy of a one-day regimen of Artequick (2.8 mg/ K. Højlund2; and K. Brøsen1 100 37 kg artemisinin plus 17.1 mg/kg of piperaquine per day for 24 hours) 1University of Southern Denmark, Odense, Denmark; and 101 38 and Coartem (24 tablets, total dosage of 3360 mg, eight tablets over 2Odense University Hospital, Odense, Denmark 102 39 three days) for the treatment of adults with uncomplicated falcipa- Background: St. John’s wort is an herbal medicinal plant, which is 103 40 rum malaria. The primary end point was a day 42, PCR-corrected, used for treating depression. St. John’s wort activates the pregnane 104 41 parasitological cure rate; secondary end points were parasites and x receptor and induces transcription of drug metabolizing enzymes, 105 42 fever clearance time. Of 64 patients enrolled, 31 were administered such as CYP3A4. There has been a growing burden of evidence, 106 43 with Artequick and 33 with Coartem. which indicates that pregnane x receptor activation causes glucose 107 44 Result: Of the patients who completed the test, 28 were on Artequick intolerance. Thus, the aim of this study was to examine if the over- 108 45 and 29 were on Coartem. Recrudescence parasitemia was PCR con- the-counter herbal medicinal plant St. John’s wort affects the glucose 109 46 firmed for all patient in each treatment group, with cure rates at day tolerance in healthy men. 110 47 42 of 97% (96% CL: 90–100) for both forms of ACT. Materials and Methods: Ten healthy men were examined by a 2-hour 111 48 Conclusion: The median parasite clearance time was significantly oral glucose tolerance tests at 3 occasions: A: Baseline, B: With 21 days 112 49 slower in the Coartem group compared with the Artequick group pretreatment with St. John’s wort, and C: At least 6 weeks after last 113 50 114 (48 h vs 36 h, P < 0.05), and fever clearance times were shorter in capsule of St. John’s wort was ingested. Plasma glucose, serum insulin, 51 115 the Artequick group (12 h vs 24 h, P < 0.05). The two forms of ACT and C-peptide during the oral glucose tolerance tests were determined 52 were well tolerated with no serious adverse events. and used for estimation of area under the concentration-time curve 116 53 Key words: Malaria; Plasmodium Falciparum; Artemisinin; (AUC) and indices of insulin sensitivity and insulin secretion. 117 54 Piperaquine; Artemether; lumefantrine. Results: Treatment with St. John’s wort increased glucose AUC and 118 55 2-hour plasma glucose levels. Surprisingly, this effect was sustained 119 56 and even further increased 6 weeks after the last capsule of St. John’s 120 57 wort was taken. No effect on indices of insulin sensitivity was seen, 121 58 CYP2D6, CYP2C19 and CYP2C9 Genotyping in 122 a Swedish clinical setting but indices of insulin secretion were reduced even after adjustment 59 for insulin sensitivity. 123 M.G. Scordo1,2 60 Conclusions: This study indicates that long-term treatment with St. 124 1Uppsala University, Uppsala, Sweden; and 2Uppsala University 61 John’s wort impairs glucose tolerance by reducing insulin response. 125 Hospital, Uppsala, Sweden 62 The unregulated use of this over-the-counter drug might be a risk 126 The polymorphic cytochrome P450 enzymes CYP2D6, CYP2C19, 63 factor for impaired glucose tolerance and type 2 diabetes. 127 64 and CYP2C9 catalyze the oxidative metabolism of numerous 128

2015 e9 Clinical Therapeutics

1 Antyhypertensive drugs and Blood rivaroxaban, apixaban, edoxaban) versus warfarin for prevention 65 2 pressure control in patients with of stroke and systemic embolic events (SEE) in patients with non- 66 3 obstructive sleep apnea: a prospective valvular atrial fibrillation (NVAF). We extracted data on stroke/SEE 67 4 observational study (primary efficacy outcome) and major bleeding (primary safety out- 68 5 LN. Diogo1; P. Pinto2; C. Bárbara2; A.L. Papoila1,3; and come) in available subgroups by geographic region (Europe versus 69 6 E.C. Monteiro1 Rest of the World ROW]). Relative risks (RR) and 95% confidence 70 7 1CEDOC, Nova Medical School, Universidade Nova de Lisboa, intervals (CI) were estimated using a random effect meta-analysis 71 8 Lisbon, Portugal; 2Centro Hospitalar Lisboa Norte (CHLN), (RevMan software). A P value for subgroup differences < 0.05 and 72 2 9 Lisbon, Portugal; and 3CEAUL, Lisbon, Portugal an I value > 75% (Higgins test) were qualified as a statistically sig- 73 10 Background: Obstructive sleep apnea (OSA) is an independent risk nificant high heterogeneity. 74 11 factor for hypertension. Continuous positive airway pressure (CPAP) is Results: A total of 75,404 patients from 4 trials were analyzed. Of 75 12 considered the gold standard treatment for symptomatic OSA patients, them, 31,957 (42%) patients were recruited in Europe and 43,447 76 13 but its effectiveness on (BP) control is modest and con- (58%) patients were recruited in the ROW. We found significant 77 14 comitant antihypertensive therapy is still required. The best antihyper- subgroup differences on stroke/SEE depending on the geographic 78 2 15 tensive regimen for BP control in these patients remains unknown. The region (P for subgroup differences = 0.003; I = 89%) with a neutral 79 16 present work aimed to contribute to the identification of the most effec- effect of the DOAC versus warfarin in Europe (RR, 1.02; 95% CI, 80 17 tive antihypertensive regimen prescribed in current treatment practice, 0.86–1.22) and a significant reduction of stroke/SEE in the ROW 81 18 investigating a hypothetical association between ongoing antihyperten- (RR, 0.75; 95% CI, 0.67–0.83). There was a similar reduction in 82 19 sive medication and BP control rates in patients with OSA. risk of major bleeding in Europe (RR, 0.77; 95% CI, 0.62–0.96) 83 20 Methods: We conducted a prospective observational study and in the ROW (RR, 0.81; 95% CI, 0.65–1.02) (P for subgroup 84 2 21 (ClinicalTrials.gov: NCT01803815) in a cohort of 205 patients with differences = 0.74; I : 0%). 85 22 OSA and hypertension who underwent a sleep study and 24-hour Conclusions: The relative efficacy of the DOAC versus warfarin in 86 23 ambulatory blood pressure monitoring (ABPM). Ongoing antihyper- patients with NVAF is influenced by geographic region. No reduction 87 24 tensive medication profile was recorded. Logistic regression models in stroke/SEE versus warfarin was found in the European population 88 25 were used to investigate the association between antihypertensive included in pivotal trials. However, the reduction in risk of major 89 26 regimen and BP control before (n = 205) and, when applicable, after bleeding with the DOAC in comparison with warfarin was consistent 90 27 CPAP adaptation (n = 90). regardless of geographic region. 81 28 Results: According to current guidelines and antihypertensive 92 29 medication and/or 24-hour ABPM, 63.9% (205/321) of the patients 93 30 were diagnosed with OSA and hypertension. One hundred fifty-five PK and PD of a nicotinic anticholineric 94 31 (155/205) were under antihypertensive medication, and 31 different challenge with mecamylamine in 95 32 antihypertensive regimens were found. However, the antihypertensive comparison to scopolamine 96 33 regimens and the number of antihypertensive drugs were not associ- A.C. Baakman; R. Rissmann; E.S. Klaassen; J.M.A. van Gerven; 97 34 ated with BP control (P = 0.847; P = 0.991). After CPAP adaptation, and G.J. Groeneveld 98 35 a decrease in median nighttime systolic and diastolic BP was observed Centre for Human Drug Research, Leiden, The Netherlands 99 36 (P = 0.001; P = 0.006). Nevertheless, the lack of association between Introduction: Cholinesterase inhibitors are frequently prescribed to 100 37 antihypertensive regimens and the number of antihypertensive drugs patients with Alzheimer’s disease. The resulting increase in acetyl- 101 38 and BP control remained (P = 0.864; P = 0.800). choline level in the synaptic cleft has an effect on both muscarinic 102 39 Conclusions: This study shows, for the first time, that BP control and nicotinic acetylcholine receptors, causing cognitive enhancement, 103 40 is independent of both antihypertensive regimen and the number mostly via the nicotinic receptors, but also peripheral side effects, 104 41 of antihypertensive drugs and suggests that none of the currently mostly via the muscarinic receptors. Therefore, nicotinic receptor 105 42 available antihypertensive drugs seem to be effective for the control specific cholinergic agonists are under development. In order to prove 106 43 of BP in patients with OSA. pharmacology of these compounds, an anticholinergic pharmaco- 107 44 Support: CEDOC/FCT (SFRH/BD/48335/2008 and PTDC/SAU- logical challenge with the nicotinic antagonist mecamylamine was 108 45 TOX/112264/2009). developed in healthy volunteers. With the current study we aimed to 109 46 gain more detailed and time-dependent information on pharmaco- 110 47 dynamic effects of mecamylamine. 111 48 Direct oral Anticoagulants versus Materials and Methods: This was a double-blind, placebo-con- 112 49 warfarin for stroke prevention in atrial trolled, randomized 4-way crossover study with mecamylamine 10 113 50 fibrillation: a subgroup meta-analysis in mg or 20 mg p.o. or scopolamine HBr 0.5 mg i.v. in 12 non-smoking 114 51 European patients healthy subjects, aged 18 to 45 years. Pharmacodynamic measure- 115 52 116 A. Gómez-Outes1; M.L. Suárez-Gea1; A.I. Terleira-Fernández2,3; ments consisted of computerized tests for memory, attention, psy- 53 117 E. Vargas-Castrillón2,3; and G. Calvo-Rojas4 chomotor speed, eye movements, subjective scales for mood and 54 118 1Spanish Agency for Medicines and Medical Devices (AEMPS), alertness, stability, and pharmaco-EEG. 55 119 Madrid, Spain; 2Hospital Clínico San Carlos, Madrid, Spain; Results: Mecamylamine more selectively affected memory than alert- 56 120 3Universidad Complutense, Madrid, Spain; and 4Hospital Clinic, ness compared to scopolamine. Mecamylamine 10 mg, mecamyla- 57 121 Barcelona, Spain mine 20 mg, and scopolamine all affected the visual verbal learning 58 122 Introduction: Geographic variation in medical practice may have a test (−2.7; CI, −5.1 to −0.3; −3.6, CI, −5.9 to −1.4; −7.7; 95% CI, 59 123 profound effect on the quality of anticoagulation. −10.1 to −5.4, respectively) and adaptive tracking (−1.89; CI, −3.90 60 124 Material and methods: We searched MEDLINE and CENTRAL to 0.12; −2.06, CI, −3.97 to −0.16; −10.38; 95% CI, 12.38 to −8.39, 61 125 (up to February 2015), regulatory agencies websites, clinical trials respectively), a test for attention. However, mecamylamine did not 62 126 registers, and conference proceedings to identify randomized con- have clear sedative effects, contrary to scopolamine. This is illus- 63 127 trolled trials of the direct oral anticoagulants (DOAC; dabigatran, trated by the simple reaction time task (7.0; CI, −0.8 to 15.5; 3.8; CI, 64 128

e10 Volume XX Number XX Morphine decreases ticagrelor concentrations but not its Effects

1 −3.5 to 11.7; 26.8; CI, 17.6 to 36.8, respectively), a subjective visual Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 65 2 analogue scale for alertness (−1.3; CI, −3.7 to 1.2; −2.5; CI, −4.8 to Ribeirão Preto, Brazil; and 3Faculdade de Medicina de Ribeirão 66 3 −0.2; −5.3; CI, −7.7 to −2.9, respectively) and saccadic peak velocity Preto, Universidade de São Paulo, Ribeirão Preto, Brazil 67 4 (−14.3; CI, 33.5 to 4.8; −10.9; CI, −29.0 to 7.1; −25.4 (CI, −44.2 to Introduction: Increasing age are associated with greater morbidity 68 5 −6.6, respectively), a marker for sedation. Mecamylamine was well and mortality after anesthesia. Rocuronium (ROC), a neuromuscular 69 6 tolerated and had linear pharmacokinetics over the dose range tested. blocking agent used in surgical procedures, is primarily eliminated by 70 7 Conclusion: The pharmacological challenge model with mecamyla- biliary and renal excretion. The objective of this study is to evaluate 71 8 mine 20 mg in healthy subjects leads to a reproducible pattern of the impact of advanced age on ROC pharmacokinetics (PK) and 72 9 cognitive disturbance that is nicotinic receptor specific. This model pharmacodynamics (PD) in ASA I-III patients undergoing elective 73 10 may be more suitable for proof of pharmacology and dose finding surgeries. 74 11 studies of nicotinic receptor agonists than the frequently used sco- Material and methods: Adult patients (aged 20–50 years, n = 13) 75 12 polamine model. and elderly patients (aged 65–85 years, n = 13) submitted to sur- 76 13 gery under general anesthesia were investigated. All patients were 77 14 induced with individual intravenous doses of midazolam, rocuro- 78 15 Benefit-risk of VKA for atrial fibrillation nium, fentanyl and propofol. Serial blood samples were collected up 79 16 before doac: a cohort study in a claims to 360 minutes after administration of ROC. Rocuronium-induced 80 17 and Hospitalization database neuromuscular block was monitored by train of four stimulation 81 18 P. Blin1,2; C. Dureau-Pournin1,2; R. Lassalle1,2; A. Abouelfath1,2; of the adductor muscle of the thumb on the ulnar nerve at the same 82 19 C. Droz-Perroteau1,2; and N. Moore1,3 times of blood collection. The plasma concentration of ROC was 83 20 1INSERM CIC1401, Bordeaux, France; 2ADERA, Pessac, France; analyzed by liquid chromatography coupled to mass spectrometry 84 21 and 3University of Bordeaux, Bordeaux, France with electrospray ionization using positive ion mode. The pharma- 85 22 Background: Vitamin K antagonists (VKA) are a major iatrogenic cokinetic parameters area under the curve normalized by dose (AUC/ 86 23 cause of haemorrhage and hospital admissions, but the incidence of dose) and clearance were calculated by non-compartmental analysis. 87 24 bleeding during VKA exposure for atrial fibrillation (AF), as well as The relationship between rocuronium plasma concentration and the 88 25 ischemic event, is not well established in real life and before intro- neuromuscular blockade was described by a sigmoid maximum effect 89 26 duction of direct oral anticoagulants (DOAC) for non-valvular AF model for each patient. Data are presented as median (interquartile 90 27 (NVAF). range). 81 28 Material and methods: Cohort study of new VKA users between Results: Elderly patients presented decreased clearance (2.1 mL. 92 29 kg -1min-1 [1.6–2.5] vs 2.6 mL.kg -1min-1 [2.2–3.2]) and increased 93 2007 and 2011, with 2-year history and 3-year follow-up censored -1 -1 30 AUC/dose (476.1 μ g.min.mL /[mg.kg ] ([396.4–621.9] vs 386.5 μ g. 94 at end of 2012, was designed in the EGB, a 1/97 random sample of -1 -1 31 the French national health care claims and hospitalization database. min.mL /[mg.kg ] [308.5–459.9]) compared to adults. The concen- 95 32 The AF population was defined as patients with full coverage for trations required to achieve 50% of maximum neuromuscular block 96 33 AF, hospitalization, or probabilistic AF information in the database (EC50) were similar for adult (502.5 ng/mL) and elderly (587.7 ng/ 97 34 and the NVAF population as patients with AF diagnosis information mL) patients. 98 35 (full coverage, hospitalization), without valvular disease history or Conclusion: Elderly patients showed increased AUC/dose and 99 36 other probable cause of VKA prescription. Outcomes were the first reduced total clearance compared to adult patients, probably due to 100 37 hospitalization for bleeding, arterial thrombotic event (ATE), acute the age-related reduced creatinine clearance. Differences in the PK-PD 101 38 coronary syndrome (ACS), and death. Incidence rate of outcomes properties of ROC in elderly population are due to changes in drug 102 39 was estimated during VKA exposure. disposition rather than to alterations in the sensitivity to the drug. 103 40 Results: Among 8894 patients identified, 3530 were classified in AF 104 41 population. Half were male (51%) with a mean age of 75 years, 87% 105 42 106 had a CHA2DS2-VASc score ≥ 2, and 12% a HAS-BLED score > 3. Clustering of rare medical conditions 43 The incidence rate of bleeding was 29 patients (95% CI, 24–34) for based on clinical features which 107 44 1000 PY exposed to VKA, including 6 (95% CI, 4–8) cerebral, 10 determine applicability of investigative 108 45 (95% CI, 7–13) digestive, and 14 (95% CI, 10–17) other bleeds. designs and methods to their study 109 46 Incidence rates were 16 (95% CI, 12–19) for ACS, 14 (95% CI, C. Pontes1; J.M. Fontanet1; M. Gomez-Valent1; J. Rios Guillermo1; 110 47 11–18) for ATE, and 39 (95% CI, 33–45) deaths. Patient charac- R. Vives Vilagut1; R. Morros1; J. Martinalbo2; J. Torrent-Farnell1; 111 48 teristics and incidence rates were very close for the 1 813 patients and F. Torres1 112 49 with NVAF population criteria. For this last population, incidence 1Universitat Autònoma de Barcelona, Barcelona, Spain; and 113 50 rates were 29 (95% CI, 23–34) for bleeding, 15 (95% CI, 11–19) for 2European Medicines Agency, London, United Kingdom 114 51 ACS, 14 (95% CI, 10–18) for ATE, and 37 (95% CI, 31–43) deaths. Background: The EU legislation determines that market access to 115 52 Conclusions: This study provides background reference for bleeding, new drugs requires the same level of evidence regardless of whether 116 53 ischemic events, and deaths before introduction of DOAC for NVAF they are intended for rare or highly prevalent diseases, but the reality 117 54 with quite same frequency for AF and NVAF populations. is that regulators often have to take decisions on orphan medici- 118 55 nal products (OMP) based on limited amounts of evidence. Clinical 119 56 development for new orphan drugs with a cost-efficient design and 120 57 analysis, an optimal fit to needs of patients, and reliable and efficient 121 58 Impact of advanced age on 122 the Pharmacokinetics and to decision making is thus of utmost importance to patients, regula- 59 tors, and the pharmaceutical industry. Within an international FP7 123 60 Pharmacodynamics of Rocuronium in 124 patients undergoing elective surgery collaboration (ASTERIX project), we have established a systematic 61 and clinically based clustering in order to propose designs and analy- 125 N.V. de Moraes1; V.L. Lanchote2; G.O. Filgueira2; B.C.P. Lopes2; 62 ses for trials conducted in small populations. 126 J.S. Lepera1; and G.R. Lauretti2,3 63 Material and methods: A dictionary of 76 characteristics that are 127 1Faculdade de Ciências Farmacêuticas, Universidade Estadual 64 relevant to study design was created, and 27 diverse rare medical 128 Paulista, Araraquara, Brazil; 2Faculdade de Ciências

2015 e11 Clinical Therapeutics

1 conditions were analyzed qualitatively for each characteristic. A data- Nonsignificant differences were found. All-cause mortality rates 65 2 base was created for this purpose, and a Multiple Correspondence were 35.5, 66.6, and 70.4 per 1000 PY (HR VKA, 0.62; 95% CI, 66 3 Analysis (MCA) was performed to guide a first proposal of clusters, 0.56–0.69; P < 0.001; HR antiplatelets, 0.83; 95% CI, 0.75–0.91; 67 4 which has been further validated with expert clinicians and regula- p < 0.001). 68 5 tors. Conclusions: VKA were associated with lower stroke rates and 69 6 Results: A clustering of clinical conditions has been proposed based antiplatelets with higher stroke rates than no antithrombotic use. 70 7 on MCA of 63 of the 76 potential characteristics. Relevant dimen- Bleeding rates were not different in the three groups. Both VKA 71 8 sions explaining data were identified, and 5 potential clusters of con- and antiplatelets were associated with lower mortality rates than 72 9 ditions were proposed based on common methodological approaches no treatment. 73 10 applicable to be conducted in drug development for each cluster. 74 11 A sixth group of disease conditions was identified through clinical 75 12 validation of groups. The time course and prognosis of the condition, Generation of efficacy data to support 76 13 as well as the type of end points, were the clinical features that most routine clinical practice: use of 77 14 influenced the clustering. clonidine as adjunctive to anesthesia 78 15 Conclusions: Six clusters of conditions to which potentially differ- to reduce surgical field bleeding in 79 16 ent clinical trial methodologies may be applied have been proposed. endoscopic naso-sinusal Surgery 80 17 Further validation within the ASTERIX project of the usefulness of C. Pontes1; R. Vives Vilagut1; F. Torres1; A. Cardesín Revilla2; 81 18 these clusters for methodological decision during drug development R. Rosell Ferrer2; Y. Escamilla Carpintero2; J. Marco Valls2; and 82 19 is ongoing. M. Bernal Sprekelsen2 83 20 1Universitat Autònoma de Barcelona, Barcelona, Spain; and 84 21 2Hospital de Sabadell. Institut Universitari Parc Taulí, Sabadell, 85 22 Effectiveness and safety of Spain; and 3Hospital Clínic, Barcelona, Spain 86 23 antithrombotic drugs used for stroke Background: The use of adjuvant hypotensive drugs during anaes- 87 24 prevention in nonvalvular atrial thesia might reduce bleeding and thus reduce risks during surgery. As 88 25 fibrillation (Esc-Fa Study) intense bleeding during functional endoscopic naso-sinusal surgery 89 26 M. Giner-Soriano1,2; R. Morros1,2; C. Vedia Urgell2,3; (FESS) hinders the visualization of the surgical field, some anesthetists 90 27 A. Roso-Llorach1,2; X. Castells4; and D. Capellà4 use them in clinical practice despite the lack of objective evidence on 81 28 1IDIAP Jordi Gol, Barcelona, Spain; 2Universitat Autònoma the efficacy and safety of such approach. In our hospital, surgeons 92 29 de Barcelona, Barcelona, Spain; 3Institut Català de la Salut, contacted the Clinical Pharmacology Unit for methodological and 93 30 Barcelona, Spain; and 4Translab Research Group, Unitat de logistic support to generate such evidence. 94 31 Farmacologia Clínica, Departament de Ciències Mèdiques, Methods: A first observational study was designed that compared 95 32 Facultat de Medicina, UdG, Girona, Spain intraoperative bleeding in routine clinical practice, comparing 96 33 Background: Effectiveness and safety of vitamin K antagonists patients receiving a clonidine-based anesthetic regimen with those 97 34 (VKAs), antiplatelets, or no treatment for stroke prevention in atrial receiving fentanyl or remifentanil-based regimens. Based on the 98 35 fibrillation (AF) have not been assessed in our setting. results of this case series, a randomized controlled observer-blind 99 36 Objectives: To assess effectiveness and safety of VKAs, antiplatelets, clinical trial was designed to compare clonidine and remifentanil 100 37 and no treatment for stroke prevention in nonvalvular AF. based regimens in patients undergoing FESS. 101 38 Material and methods: Results: The observational study described 37 subjects undergoing 102 39 Design: retrospective observational cohort study. FESS and receiving clonidine (N; %) (11; 29.7) or opioid deriva- 103 40 104 Population: Individuals ≥ 18 years old with nonvalvular AF diag- tives (26; 70.3). Intraoperative bleeding, measured by an ordinal 1 41 nosed in primary care during 2007-2012. to 5 scale (Boezaart score) by the operating surgeon, was lower for 105 42 Data Sources: SIDIAP database; anonymized clinical information subjects receiving clonidine (mean [SD], 1.91 [0.53] vs 2.92 [0.79]; 106 43 107 from electronic clinical records in primary care of 5,800,000 people P < 0.0001). A multivariate analysis including bleeding risk factors 44 from Catalonia on sociodemographics, comorbidities, medical proce- showed that the adjuvant hypotensive drug was the best predictor 108 45 109 dures, clinical parameters, laboratory data, and pharmacy invoicing of intense bleeding (Boezaart > 2). The trial randomized 47 sub- 46 110 data. Stroke and bleeding events were linked from hospital discharge jects to clonidine (N = 22) or remifentanil (N = 25) at induction of 47 database. anaesthesia. Differences in intense bleeding (4 [18%] clonidine vs 13 111 48 112 Outcomes: Stroke, hemorrhages, and all-cause mortality. [52%] remifentanil, P = 0.014) as assessed by a third surgeon blind 49 Cohort Groups: Defined by antithrombotics prescribed at to treatment identity from video records obtained during endoscopy 113 50 baseline. were observed. Better visualization of anatomical structures was 114 51 Potential Confounders: sex, age, comorbidities, and treatments at achieved with clonidine, and concordant results were obtained from 115 52 baseline. the unblinded assessment by surgeons. There were no differences in 116 53 Statistics: Descriptive statistics and incidence rates of events per 1000 adverse events. 117 54 patients-year (PY) were obtained for each cohort. Time-to-event Conclusions: The use of clonidine reduces intense bleeding and 118 55 analysis was performed using multivariate cox proportional-hazards improves visualization of anatomical structures during endoscopic 119 56 regression models, adjusting for baseline factors. naso-sinusal surgery. 120 57 Results: We included 22,205 patients with a mean age of 72.8 years 121 58 (SD 13.1); 51.4% were men. Antithrombotics prescribed were VKAs 122 59 in 40.8%, antiplatelets in 33.4% and no antithrombotics in 25.8%. 123 60 Management of Iatrogenically induced 124 Incidence rates for stroke were 6.9, 12.2, and 8.9 per 1000 PY with opioid dependence 61 VKAs, antiplatelets, and no antithrombotics, respectively (adjusted 125 A.M. Peiró1; C. Puga2; B. Planelles3; L. Mira2; M. Puerto2; 62 HR, VKA vs no antithrombotics, 0.65; 95% CI, 0.50–0.86; P 126 = L. Gómez1; J.F. Horga1; and C. Margarit1 63 0.002). Haemorrhage rates were 9.5, 8.7, and 7.1 per 1000 PY. 127 1Hospital General Universitario de Alicante (HGUA), Spain; 64 Cerebral haemorrhage rates were 3.5, 2.3, and 1.9 per 1000 PY. 128 2The Foundation for the Promotion of Health and Biomedical

e12 Volume XX Number XX Morphine decreases ticagrelor concentrations but not its Effects

1 Research of the Valencian. Community (FISABIO), Spain; b2AR allelic variants (Arg16Gly, rs1042713; Gln27Glu, rs1042714; 65 2 and 3Occupational Observatory, University Miguel Hernández Thr164Ile, rs1800888) were determined. 66 3 (UMH), Spain Results: b2AR functionality was significantly decreased in LC and 67 4 Introduction: Opioids are valuable analgesics, capable of providing OA vs control (14 ± 15.5 pmol/mL, 38 ± 21 pmol/mL vs 90 ± 66 68 -5 5 pain relief and functional improvement also in chronic non–cancer- pmol/mL at ISO 10 stimulus, respectively, P < 0.05). This decreased 69 6 related pain (NCP) patients. However, recent data have shown that b2AR functionality was similar in LC patients: (i) in primary or 70 7 the increasing prescription of opioids is associated with a rise in secondary prophylaxis (15 ± 19 and 14 ± 13 pmol/mL, respectively) 71 8 aberrant drug-related behaviour. and (ii) in responder or non-responder to propranolol during HVPG 72 9 Methodology: A prospective study was performed with 70 NCP (14 ± 16 and 14 ± 15 pmol/mL, respectively). The prevalence of dif- 73 10 outpatients diagnosed with opioid iatrogenic DSMIV dependence ferent genotypes did not differ between patients stratified according 74 11 and severe pain intensity. The study focused on analgesic efficacy, to any clinical variable. In cirrhotic patients, the decreased in b2AR 75 12 opioid withdrawal syndrome prevention, adverse side effects, func- functionality was the same for all the studied allelic variants (naive 76 13 tional status, and aberrant drug-related behaviour. We design a con- vs SNP, 15 ± 17 vs 13 ± 16 pmol/mL). 77 14 tractual agreement on opioid therapy, including goals, side effects, Conclusions: In patients with cirrhosis and portal hypertension, the 78 15 and criteria to finish the opioid therapy. Genotyping of the OPRM functionality of b2AR is significantly decreased. This change is not 79 16 (rs1799971), COMT (rs4680), and ABCB (rs1045642) genes was related to b2AR allelic variants. 80 17 performed. 81 18 Results: Results from 73% (50 of 70) of the patients are presented. 82 19 After a structured and progressive opioid conversion to buprenor- Gene expression of anaesthetic 83 20 phine/tramadol, a significant reduction of 47% of the total daily and analgesic drug targets in 84 21 dose (TDD) with no withdrawal symptoms (OWS reduction of 9 Breast tumours predicts metastasis: 85 22 points) was achieved, maintaining a moderate relief and pain inten- relevance to personalized, therapeutic 86 23 sity score. Quality of life tends to improve, as do the number of intervention in the peri-operative period 87 24 adverse reactions reported by the patients throughout the visits. H.C. Gallagher1,2 88 25 OPRM and COMT gene variant distribution but ABCB variants 1University College Dublin, Belfield, Dublin 4, Ireland; and 89 26 were more prevalent (9% C/C, 65% C/T, 26% T/T) vs general popu- 2UCD-Mater Clinical Research Centre, Nelson St, Dublin 7, 90 27 lation distribution (21% C/C, 49% C/T, 25% T/T). Psychosocial risk Ireland 81 28 was associated to a high prevalence of opioid iatrogenic dependence. Introduction: Mortality associated with breast cancer is due, invari- 92 29 Conclusions: The indication for the prescription of opioids must be ably, to the burden of metastasis. Virtually all patients with breast 93 30 very carefully weighed in the presence of any risk factors. In these cancer undergo surgery, which may result in release of tumor cells 94 31 cases the integration into a multimodal, interdisciplinary therapy pro- into the bloodstream. Thus, perioperative factors, including drugs, 95 32 gram is mandatory. are important in minimizing metastatic risk during tumor resection. 96 33 However, retrospective clinical trials suggest that combined vola- 97 34 tile general anesthesia and opioid analgesia, which is routinely used 98 35 99 β 2-Adrenergic receptor functionality during cancer surgery, may promote metastasis. The current study 36 and genotype in two different models investigated a pharmacogenetic basis for this phenomenon. 100 37 of chronic inflammatory diseases: Liver Methods: The publically accessible transcriptomic database, 101 38 Cirrhosis and Osteoarthrosis Breastmark, was interrogated. It currently employs 26 breast cancer 102 39 Ana Peiró1; Pedro Zapater1,2; Reyes Roca3; Annaluciana Comte4; genechip data sets (~17,000 genes in ~4738 samples). Gene expres- 103 40 M. Angeles Pena1; José María Palazón1; and José F. Horga1 sion levels were dichotomized on the basis of median, high, and/ 104 41 1Hospital General Universitario de Alicante (HGUA), Spain; or low stratification, and a global pooled survival analysis was 105 42 2Institute of Health Carlos III, ISCIII, Madrid, Spain; 3The performed for distant disease-free survival (metastasis) and overall 106 43 Foundation for the Promotion of Health and Biomedical survival. Kaplan-Meier estimates and the log-rank P value indicated 107 44 Research of the Valencian Community (FISABIO), Spain; and differences in survival, with values less than 0.05 considered signifi- 108 45 4Occupational Observatory, University Miguel Hernández cant. Cox regression analysis was used to calculate hazard ratios. 109 46 (UMH), Spain Results: Bioinformatic analysis revealed that patients whose breast 110 47 Background: This study was designed to investigate the contribution tumors overexpress mu and delta opioid receptors have a shorter 111 48 of polymorphic b2 adrenoceptors (b2AR) to the proinflammatory disease-free survival and shorter overall survival than those with low 112 49 effects of the sympathetic nervous system in two models of chronic expression of these analgesic drug targets. Importantly, these are not 113 50 inflammatory disease: liver cirrhosis (LC) and osteoarthrosis (OA). established oncogenes, and no such effect is seen for kappa opioid 114 51 115 The b2AR gene contains three single-nucleotide polymorphisms receptors. Furthermore, low expression of the glycine β -receptor was 52 (SNPs) at amino acid positions 16, 27, and 164. Our aim was to strongly associated with metastasis. This receptor is a key target for 116 53 study the potential influence of genotype on lymphocytes b2AR func- volatile anesthetic agents, such as sevoflurane. 117 54 tionality in LC and OA development/progression. Conclusions: The data presented here suggest that the gene expres- 118 55 Methods: We compared 52 cirrhotic patients with esophageal varices sion profile of breast tumors determines the therapeutic response to 119 56 and portal hypertension (hepatic venous pressure gradient [HVPG] anesthetics and analgesics. Thus, an opportunity exists to specifically 120 57 13 ± 4 mm Hg, CHILD 7 ± 2, and MELD 11 ± 4 scores), 32 OA address the prometastatic changes occurring in the critical, periopera- 121 58 (84% Kellgren-Lawrence [KL] severity 4 grade, 14% knee replace- tive period via personalized, therapeutic intervention. It may be pos- 122 59 ment joint), and 26 healthy volunteers as controls. Mononuclear cells sible to pharmacogenetically stratify patients who would most benefit 123 60 were isolated from the whole blood. Basal and stimulated intracel- from alternative anesthetic techniques that avoid volatile anesthetic 124 61 lular cAMP levels (isoproterenol stimulus from 10−8 to 10−3) and drugs and opioids during tumor resection. 125 62 126 63 127 64 128

2015 e13 Clinical Therapeutics

1 The use of a battery of pain models two experimental sessions. They received a single dose of alcohol (0.5 65 2 to detect analgesic properties of g/kg) and four capsules of Super-Absorbable Soy Isoflavones (Life- 66 3 compounds: a two-part, four-way, Extension, US) followed by the same dose of alcohol (2 h later). The 67 4 randomised, placebo-controlled, study was randomized and crossover. They soy extract contained 216 68 5 crossover study mg of total isoflavones, 80 mg of daidzin-daidzein, 108 mg of gen- 69 6 J.L. Hay; P. Okkerse; G. van Amerongen; M.L. de Kam; and istein, and 24 mg of glycitein. Blood samples were obtained. Ethanol 70 7 G.J. Groeneveld subjective and adverse effects (Visual Analogue Scales, Addiction 71 8 Centre for Human Drug Research, Leiden, the Netherlands Research Center Inventory) and vital signs were also measured along 72 9 No single pain model can replicate the complex nature of clinical a 10-hour period. 73 10 pain and can therefore not be used to predict efficacy of analgesics Results: No differences were found in blood ethanol concentrations 74 11 in a clinical setting. This study’s aim was to investigate the ability of between both treatment conditions. Isoflavones showed several peaks 75 12 a battery of pain models to detect analgesic properties of commonly in plasma suggesting enterohepatic recirculation. The soy extract did 76 13 used analgesics in healthy subjects. not modify the subjective and adverse effects of ethanol. Vital signs 77 14 The battery consisted of tests eliciting cutaneous electrical were also very similar in both sessions. 78 15 mechanical and thermal (contact heat and cold pressor) pain and Conclusions: The administration of a soy extract, at a dose twice 79 16 included a UVB model, the thermal grill illusion, and a paradigm the daily recommended for menopausal symptoms, did not interact 80 17 of conditioned pain modulation (CPM). Subjects were administered with ethanol. 81 18 either (part I) a 30-minute intravenous fentanyl 50 µg/kg, phenytoin Acknowledgements: Supported by grants from Ministerio de 82 19 300 mg, (S)-ketamine 10 mg, or placebo (NaCl 0.9%) or (part II) Sanidad-ISCII (Investigación Clínica Independiente EC10-166), 83 20 a single oral dose of imipramine 100 mg, pregabalin 300 mg, ibu- Red Trastornos Adictivos (ISCIII RTA RD12/0028/0009). Clara 84 21 profen 600 mg, or placebo. Pain test measurements were performed Perez-Mañá and Esther Papaseit are Rio Hortega fellows (ISCIII, 85 22 at baseline and up to 10 hours post-dose. End points were analysed CM12/00085, and CM13/00016, respectively). 86 23 using a mixed model analysis of variance. 87 24 Following ethics committee approval, 16 subjects (8 females) 88 25 completed each part. The pain tolerance threshold (PTT) for electri- Clinical pharmacology consultation and 89 26 cal stimulation was increased (all P < 0.05) compared to placebo for outcomes associated with pregnancy 90 27 (S)-ketamine (+10.1%), phenytoin (+8.5%), and pregabalin (+10.8%). exposure to FDA X Drugs 81 28 1 1 1 1,2 92 The PTT for mechanical pain was increased by pregabalin (+14.1%). V. Erdeljić Turk ; I. Francetić ; K. Makar Aušperger ; R. Likić ; 29 1 93 The cold pressor PTT was increased by fentanyl (+17.1%) and prega- and M. Radačić -Aumiler 30 balin (+46.4%). Normal skin heat pain detection threshold (PDT) was 1University Hospital Zagreb, Croatia; and 2Medical School, 94 31 increased by (S)-ketamine (+3.3%), fentanyl (+2.8%), and pregabalin University of Zagreb, Croatia 95 32 (+4.1%). UVB treated skin PDT was increased by fentanyl (+2.6%) Background: FDA pregnancy risk categories are insufficient to 96 33 and ibuprofen (+4.0%). Thermal grill unpleasantness AUC decreased address the complexity of weighing the benefits of treatment against 97 34 after administration of fentanyl (−34.3). No differences in CPM were the possible risk of drug exposure to a category X medication. We 98 35 observed. Adverse events reported were all mild or moderate in severity. conducted a study to assess outcomes and maternal characteristics 99 36 This study shows that these pain models are able to detect changes associated with pregnancy exposure to FDA-X drugs, the strength 100 37 in pain thresholds after administration of different classes of anal- of association between both the clinical pharmacologists’ risk assess- 101 38 gesics in healthy subjects. The analgesic compounds all showed a ment and the FDA risk categorization, and adverse pregnancy out- 102 39 unique profile in their effects on the pain tasks administered. comes. 103 40 Material and methods: We retrospectively reviewed records of 1669 104 41 patients consecutively referred to the clinical pharmacology outpa- 105 42 Effects of a soy isoflavones extract on tient clinic for pregnancy-related drug exposures (2000–2013). Of 106 43 acute Alcohol Intoxication 230 women taking an FDA-X categorized drug during the first or 107 44 108 C. Pérez-Mañá1,2; E. Papaseit1,2; E. Menoyo1; M. Pérez1; second trimester of pregnancy, documented outcomes were avail- 45 109 S. Martín1; R. Martínez3; N. Pizarro1,2; J. Rodríguez-Morató1,4; able for 128 women. Clinical pharmacologists’ risk assessments 46 110 R. de la Torre1,4; and M. Farré1,2 were reviewed in relation to FDA drug categorization and available 47 111 1Hospital del Mar Medical Research Institute-IMIM, Barcelona, pregnancy outcomes. 48 112 Spain; 2Universitat Autònoma de Barcelona-UAB, Barcelona, Results: In pregnancies with available outcomes, the most frequently 49 113 Spain; 3Addiction Unit, Hospital del Mar, Barcelona, Spain; and FDA-X prescribed drugs were oral contraceptives (53%), followed 50 114 4Universitat Pompeu Fabra-UPF, Barcelona, Spain by paroxetin (21%), medroxiprogesterone (8%), retinoids (7%), 51 115 Background: Soy extracts contain isoflavones, polyphenolic com- warfarin (4%), methotrexate, statins, ribavirin, ulipristal-acetate, 52 116 pounds that perform their biological effects mainly through modula- and radioactive iodine. The exposure occured in most women dur- 53 117 tion of estrogenic receptors. Their consumption has been associated ing the 1st trimester of pregnancy (88%). Normal fetal outcomes 54 118 with many health benefits, including protection against hormone- were reported in 93/128 (73%) pregnancies, spontaneous abortions 55 119 dependent cancers, menopausal symptoms, heart disease, and osteo- in 9/128 (7%), artificial abortions in 19/128 (15%), and malfor- 56 120 porosis. Daidzein, and its glycoside form daidzin, can act as natural mations in 4/92 (3%) pregnancies. The drugs involved in reported 57 121 inhibitors of the aldehyde-dehydrogenase-2 enzyme and might be congenital malformations were in all cases oral contraceptives and 58 122 useful to treat alcohol and cocaine dependence. The aim of the study medroxyprogesterone. Clinical pharmacologists’ risk estimation was 59 123 was to assess the potential interaction between a soy extract in the in agreement with the FDA risk categorization system in only 18% of 60 124 pharmacokinetics and pharmacodynamics of alcohol. consulted women with high risk exposure. Clinical pharmacologists’ 61 125 Materials and Methods: The protocol was approved by the local risk assessment confirming high risk drug exposure had a better posi- 62 126 research ethics committee and registered with ClinicalTrials.gov, tive predictive value for adverse pregnancy outcomes than the FDA 63 127 number NCT02309801. Ten healthy male volunteers participated in X categorization (54% vs 20%, respectively). 64 128

e14 Volume XX Number XX Morphine decreases ticagrelor concentrations but not its Effects

1 Conclusions: Additional evaluation beyond the FDA drug classifica- 72.0 from 01/01/2009 to 31/12/2013 (5 y). Exposure was NSAID 65 2 tion is essential, and clinical pharmacologists are ideally placed to or paracetamol dispensation resulting in exposure within 30 days 66 3 consult on how to proceed with a pregnancy following drug exposure before admission. Population exposure was measured as number of 67 4 to high risk drugs. patients using the drugs over the study timeframe as total number of 68 5 DDD-dispensed and average number of DDD per user. 69 6 Results: A total of 75 cases were identified; 15 were exposed to 70 7 Population Pharmacokinetics of NSAIDs and 27 to paracetamol (alone or combined with opiates). 71 8 subcutaneous and intradermal Event rates per million DDD ranged from 0.61 (0.17–1.56) for 72 9 Glucagon in patients with type 1 Diabetes ketoprofen to 1.43 (0.04–7.97) for diclofenac combinations, 0.49 73 (0.28–0.81) for all NSAIDs combined, and 0.68 (0.44–1.00) for 10 T. Yu 1; M. Sinha2; C. Stockmann1; M.A. Hillard2; 74 paracetamol. There was no association with average duration of 11 M.G. Spigarelli1; S.J. Russell2; and C.M.T. Sherwin1 75 treatment. Per patient risk ranged from 24 (8–57) for ibuprofen to 12 1University of Utah, Salt Lake City, Utah, U.S.A.; and 76 101 (3–562) for glucosamine per million users, 43 (24–71) for all 13 2Massachusetts General Hospital, Harvard Medical School, 77 NSAIDs combined, and 62 (40–91) for NOP. There was a relation 14 Boston, Massachusetts, U.S.A 78 between increasing average duration of treatment and increasing risk. 15 Background: The closed-loop control system for type 1 diabetes 79 Conclusions: The risk profiles of NSAIDs and NOP concerning 16 utilizes frequent measurements of blood glucose concentrations and 80 hospital admissions for ALI were similar and indicative of a type 17 delivery of both an insulin analog and glucagon to achieve automated 81 A (pharmacological or toxicological) reaction, in contrast with the 18 glucose control. This study aimed to characterize the population 82 ALFT, which had a pattern suggestive of type B (genetic or allergic) 19 pharmacokinetics (PK) of glucagon administered by subcutaneous 83 reactions. The 3-fold higher risk with paracetamol for ALFT was 20 or intradermal route to facilitate the selection of a desired route of 84 not found for ALI. Event rates for ALI were not predictive of risk of 21 administration. 85 22 ALFT. ALI and ALFT probably have different mechanisms and risks, 86 Methods: This study included 14 patients ≥ 18 years with type 1 23 even if one may be the prelude to the other. 87 diabetes duration ≥ 1 year prior to enrollment. Each patient was 24 randomized to receive 50 µg glucagon by 1 route and was crossed 88 25 over to the other route for 2 repeated visits. Population PK models 89 26 describing glucagon administered by subcutaneous or intradermal High dose favipiravir: first experience in a 90 27 route were developed separately in NONMEM 7.3. patient with Ebola 81 28 Results: A 2-compartment model with a transit compartment A.M. Borobia1; M. Mora-Rillo2; G. Ramírez Olivencia2; 92 29 absorption model was selected for subcutaneous glucagon, while M. Lago2; M. Arsuaga2; F. De la Calle2; F. Arnalich2; J.R. Arribas2; 93 30 a 2-compartment model with first-order absorption was chosen for and A.J. Carcas1 94 31 intradermal glucagon. The population mean (% coefficient of varia- 1Clinical Pharmacology Department, Hospital La Paz-Carlos 95 32 tion [CV%]) for clearance (CL), absorption rate constant (K ), and III, IdiPAZ, Madrid, Spain; and 2Internal Medicina Department, 96 33 a 97 central volume of distribution (Vc) of subcutaneous glucagon were Hospital La Paz-Carlos III, IdiPAZ, Madrid, Spain 34 214 L/hr (36.2%), 3.42 hr−1 (26.6%), and 29.9 L (76.4%), respec- Background: On October 2014, the first case of human-to-human 98 35 tively, scaled by (body weight/median 75.4 kg) to the exponent of transmission of Ebola virus (EVOB) outside Africa was admitted in 99 36 1.78 on CL. For intradermal glucagon, the population mean (CV%) our hospital. Patient received supportive treatment and experimen- 100 37 −1 101 of CL, Ka, and Vc were 237 L/hr (45.4%), 3.52 hr (24.8%), and tal treatment with convalescent plasma and antiviral was consid- 38 73.0 L (58.4%), respectively. Age, body size measures, and disease ered. Favipiravir (Toyama-Chemical) is a RNA polymerase inhibitor 102 39 duration did not influence intradermal glucagon PK parameters approved in Japan for the treatment of influenza, but with no previ- 103 40 within the range of covariates studied. The estimated terminal half- ous experience in human EVOB infected patients. 104 41 life was averagely 25 minutes for both routes. Methods: The rational for favipiravir dose and schedule was based 105 42 Conclusion: The population PK models characterized well the PK on recent in vitro and in vivo data in mice (Oesterech, 2014) show- 106 43 107 profiles of glucagon administered by subcutaneous and intradermal ing an EBOV-IC90: 17 μ g/mL and therapeutic efficacy: 300 mg/ 44 routes in patients with type 1 diabetes. No clinically relevant covari- kg/d. Preclinical toxicology studies in monkeys settled a NOAEL of 108 45 ates were identified as predictors of glucagon PK, with the exception 100 mg/kg/d. Also pharmacokinetic data in healthy volunteers (load- 109 46 of body weight on subcutaneous glucagon PK. ing dose/maintenance: 1200/600 BID) provided by Company was 110 47 111 took in consideration: Cmax: 30–56 μ g/mL, t1/2: 3.4–5.8 hr and plasma 48 albumin binding: 53%. Based on this limited information, we decided 112 49 113 Risk of hospital admission for Liver injury a loading dose of 50 mg/kg BID (3 doses) and maintenance dose of 25 50 mg/kg TID. This schedule aimed to maintain a free C above IC 114 51 in users of nsaids and non-overdose min 90 115 and as close as possible to 60 μ g/mL of total concentration. Similar 52 paracetamol (EPIHAM) 116 S.E. Gulmez; R. Lassalle; J. Jové; G. Caridade; A. Grolleau; and doses had been recommended after our decision (Mentré, 2014). 53 Results: Favipiravir was initiated on day 9 of illness (DOI-9) and 117 54 N. Moore 118 Université de Bordeaux, Bordeaux, France stopped on DOI-20 after two consecutive undetectable EBOV plasma 55 viral loads. Despite the high doses used, favipiravir was well toler- 119 56 Background: The SALT study concluded similar per-user risk of 120 acute liver failure leading to liver transplantation (ALFT) between ated, without adverse events clearly related to the drug. The patient 57 fully recovered and was discharged on DOI-34. 121 58 NSAIDs and a 3- to 4-fold higher rate of ALFT in non-overdose 122 paracetamol (NOP) users. Conclusions: The contribution of favipiravir to disease resolution is 59 difficult to ascertain because the use of other therapies (convalescent 123 60 Objectives: To identify the risks of hospital admission for acute liver 124 injury (ALI) associated with NSAIDs and NOP. plasma and supportive treatment) and the spontaneous evolution 61 of the disease, which can all be related to the cure of our patient. 125 62 Methods: Case-population study in 1/97 sample of the French popu- 126 lation health care database. Cases of ALI were identified in hospital However, considering the time to treatment initiation, the severity 63 of the disease, and the high viral load, contribution of favipiravir to 127 64 discharge summaries with ICD-10 codes K71.1, 71.2, 71.6, 71.9 and 128

2015 e15 Clinical Therapeutics

1 the outcome of our patient must be considered and support its role 5 children (2 girls and 3 boys, mean age: 8 y) and 6 adolescents (2 65 2 as experimental therapy. girls and 4 boys, mean age: 14 y) diagnosed as having ADHD and 66 3 treated with different oral doses of ATX (60, 40, 35, 25, and 18 67 4 mg/d). Samples of blood and oral fluid were obtained before and 68 5 Prescribing pattern for Malaria in India: post-dose (along 24 h). Concentrations of ATX and its metabolites 69 6 a Nationwide Survey using adr cohort 4-hydroxyatomoxetine (4-OH-ATX) and N-desmethylatomoxetine 70 7 event monitoring form (N-des-ATX) were determined using liquid chromatography–tandem 71 mass spectrometry in plasma and oral fluid. 8 P. Gupta1; A. Anvikar2; N. Valecha2; and Y.K. Gupta1 72 Results: ATX, 4-OH-ATX, and N-des-ATX were found in plasma, 9 1All India Institute of Medical Sciences, New Delhi, India; and 73 but only ATX and 4-OH-ATX were detected in oral fluid samples. 10 2National Institute of Malaria Research, New Delhi, India 74 Mean ATX was found in plasma and oral fluid at a peak concentra- 11 Background: The present study aimed to assess the prescribing 75 12 tion of 589.6 and 19.72 ng/mL with a mean t of 1.4 and 2.7 h, 76 pattern of antimalarial drugs and their concordance with national max 13 malaria treatment guidelines, as an adjunct to ongoing cohort event respectively. For 4-OH-ATX detected in oral fluid, peak concentra- 77 14 monitoring. tion was approximately half that in plasma (7.4 vs 13.8) with a 78 15 mean t of 2.6 h in oral fluid and 2.1 in plasma. A good correlation 79 Methods: A prospective, observational cohort study was carried max 16 out using modified WHO cohort event monitoring form. The study between ATX and 4-OH-TX in plasma and saliva was achieved. 80 17 population comprised patients of all age, gender, and pregnancy sta- Conclusion: The correlations between ATX and 4-OH-ATX concen- 81 18 tus who were diagnosed with falciparum, vivax, or mixed infection trations in the 2 biological fluids indicate that oral fluid concentra- 82 19 malaria and receiving treatment from any peripheral or community tions may be an alternative to plasma concentrations. 83 20 health center or government sector hospital in India. Acknowledgements: Supported by Red de Trastornos Adictivos 84 21 Results: A total of 1050 ADR forms were received from 243 report- (ISCIII RTA RD12/0028/0009) and Red SAMID (ISCIII). Esther 85 22 ers from 23 districts in 9 states. Previous self-treatment was observed Papaseit is a Rio Hortega fellow (ISCIII, CM13/00016). 86 23 in 9.3% patients in the form of antibiotics (31) and antimalarials 87 24 (37), primarily chloroquine. For analysis, the patients were divided 88 25 into chloroquine primaquine (CQPQ, 64%) and artesunate-sulf- New insights on the Pioglitazone risk- 89 26 adoxine-pyrimethamine (ACT, 29%) groups. Inappropriate anti- benefit ratio in European Population 90 27 malarials were prescribed in 7% patients (ie, chloroquine alone, S. Arriagada1; F. Gueyffier2; R. Milles1; and I. Marchant1 81 28 primaquine alone, artemisinin monotherapy, and chloroquine with 1Universidad de Valparaíso, Valparaíso, Chile; and 2Université 92 29 ACT). Patients in the CQPQ group were younger, smaller in height, Lyon 1, Lyon, France 93 30 and lighter in weight. There were more males in the CQPQ group. Background: The benefit from antidiabetic drugs in T2DM lies on 94 31 Significantly more patients in the ACT group had higher total number poorly powered clinical trials with high risk of bias and inconclusive 95 32 96 of symptoms as compared to patients in CQPQ group (P < 0.001). meta-analysis results. While pioglitazone and metformin have been 33 Fever disappeared significantly faster in the ACT group (median fever suggested to lower cardiovascular risk, some thiazolinediones have 97 34 98 duration 2 days vs 3 days; P < 0.001). For the reported malaria been associated with an increase in myocardial infarction and heart 35 episode, the national programme recommended dose and duration failure. Evidence on increased bladder cancer risk led to withdrawal 99 36 of treatment was observed in 46% and 59% patients, respectively. of pioglitazone in France. However, both EMA and FDA withheld 100 37 Conclusion: With increasing resistance and drying pipeline of drugs from action arguing that risk-benefit ratio might still be favorable in 101 38 for malaria, high prevalence of inappropriate prescribing observed in a limited population that could not benefit from other treatments. 102 39 the study is unacceptable and requires stringent monitoring. We aimed to investigate whether risks from pioglitazone outweighed 103 40 the benefit. 104 41 Material and Methods: We conducted a simulation study using a 105 42 106 Pharmacokinetiks of Atomoxetine in French Realistic Virtual Population of type 2 diabetic individuals to 43 evaluate the efficacy and safety of pioglitazone. Risk scores allowed 107 44 plasma and oral fluid in pediatric 108 patients with attention deficit/ estimating risk of non-fatal MI, stroke, and bladder cancer. Virtual 45 patients without bladder cancer received pioglitazone by 3 years 109 46 hyperactivity disorder 110 1,2 2,3 2,3 4 (pioglitazone effect: OR = 0.84 for cardiovascular events; OR = 47 E. Papaseit ; O. Garcia-Algar ; G. Aznar ; E. Marchei ; 111 4 4 1,2 1.22 for bladder cancer). We computed the NNT and the number 48 R. Pacifici ; S. Pichini ; and M. Farré 112 1 needed to harm (NNH) by sex and age categories. 49 Hospital del Mar Medical Research Institute-IMIM, Parc de Salut 113 2 Results: Pioglitazone might prevent 47 non-fatal MI and 20 50 Mar, Barcelona, Spain; Universitat Autònoma de Barcelona-UAB, 114 3 while it could provoke 2 bladder cancers for every 10,000 individuals 51 Barcelona, Spain; Hospital del Mar-IMIM-URIE. Parc de Salut 115 4 treated over 3 years. The overall NNT was 148 and the NNH was 52 Mar, Barcelona, Spain; and Istituto Superiore di Sanitá, Rome, 116 Italy 4758. The number of cardiovascular events prevented was greater 53 than the number of bladder cancers whatever the subgroup studied, 117 54 Introduction: Atomoxetine (ATX) is the first non-psychostimulant 118 drug indicated for the treatment of attention-deficit hyperactivity with a ratio ranging from 21 in men over 65 years to 539 in women 55 under 45 years. The absolute benefit is higher in men, especially at 119 56 disorder (ADHD) in pediatric patients as an alternative to methyl- 120 phenidate. The aim of this study was to describe the pharmacokinetic higher baseline cardiovascular risk levels and ages. 57 Conclusions: Risk-benefit ratios allow identifying specific T2DM 121 58 profile of ATX in oral fluid in comparison to plasma in paediatric 122 patients with ADHD. subgroups that could take more benefit than harm from pioglitazone. 59 Evidence from RCT should use modeling approaches as additional 123 60 Material and methods: The protocol was approved by the local 124 research committee. Child’s parent or legal representative signed an support to decide about the relevance of treatments applied on a 61 given population structure. 125 62 informed consent (with assent) before inclusion. Participants were 126 63 127 64 128

e16 Volume XX Number XX Morphine decreases ticagrelor concentrations but not its Effects

1 Clinical Pharmacology Education in 1Translab Research Group, Unitat de Farmacologia 65 2 Europe: a time to act Clínica, Departament de Ciències Mèdiques, Facultat de 66 2 3 J.S. Peñataro1; J. Fernández2; L. Walker3; B. Aydin4; J. Holm5; Medicina, UdG, Girona, Spain; Departament of Biomedical 67 4 E.C.T. Geijteman6; M. Roustit7; S. Chhun8; J. Versmissen6; and Sciences (Pharmacology), Facultad de Medicina y CC de la 68 3 5 M. Ezzeldin1 Salud,Universidad de Alcalá; Servico de Farmacología Clínica, 69 6 1Clinical Pharmacology Department, Hospital Clínic, Barcelona, Hospital Universitario Marqués de Valdecilla, Universidad de 70 4 7 Spain; 2Clinical Pharmacology Department, Hospital Puerta Cantabria, Santander; Sevicio de Farmacología clínica, Hospital 71 5 8 de Hierro, Madrid, Spain; 3Liverpool University, Clinical Universitario Puerta de Hierro, Majadahonda, Spain; IDIAP 72 6 9 Pharmacology Department, Liverpool, United Kingdom; 4Dokuz Jordi Gol, Barcelona, Spain; and Universitat Autònoma de 73 10 Eylul University, Faculty of Medicine, Medical Pharmacology Barcelona, Barcelona, Spain 74 11 Department, Izmir, Turkey; 5Karolinska University Hospital, Objectives: To describe the current structure of the pharmacology, 75 12 Department of Clinical Pharmacology, Stockholm, Sweden; clinical pharmacology, and therapeutics teaching in Spanish schools 76 13 6Erasmus University Medical Center, Department of Hospital of medicine. 77 14 Pharmacy, Rotterdam, The Netherlands; 7Centre d’Investigation Methods: A questionnaire survey was distributed among the professor 78 15 Clinique, CHU de Grenoble, Pharmacologie Clinique,Université in charge for the subject of pharmacology at the Spanish schools of 79 16 Joseph Fourier. Grenoble, France; and 8Hôpital Universitaire medicine. Results were tabulated and descriptive statistics was applied. 80 17 Necker-Enfants Malades, Faculté de Médecine Paris Descartes, Results: Twenty-two (65%) of the 34 schools of medicine responded. 81 18 Service d’Immunologie Biologique All the schools had a course in basic pharmacology (BP) taught 82 19 Background: Core competencies in clinical pharmacology (CP) edu- mainly in the 3rd course of the curricula (90.5%). The mean num- 83 20 cation are well established but poorly harmonized within European ber of teaching hours received by the students was 69.2 hours (SD, 84 21 national training programs, thus limiting cross-border career oppor- 15 h; range, 45–96). The proportion of teaching hours by teacher’s 85 22 tunities for young postgraduates. Opportunities for career develop- specialty extremely varied between the different schools: clinical 86 23 ment in CP differ to some extent in different countries in Europe, and pharmacologists (from 0% in 50% of the schools to 67.6% as a 87 24 much could be gained from international exchange of experiences maximum), pharmacologist-physicians (from 0% in 36.4% of cases 88 25 and collaboration of clinical pharmacology trainees (CPT). to 100%), and pharmacologists-pharmacists (from 0% in 45.5% 89 26 Material and Methods: A European Task Force, with CPT representa- of cases to 100%). A total of 90.5% of the schools had a formal 90 27 tives from Spain, Netherlands, UK, Sweden, France, and Turkey, has been course on clinical pharmacology (CP). However, therapeutics (T) 81 28 created to identify and address the main deficits of and priorities in CP was only included in 42% of cases under this subject. This course 92 29 education across Europe. Two courses of action have been delineated: was mainly taught during the fifth course of the curricula (52.6%). 93 30 The mean number of teaching hours received by the students was 94 31 1. The creation of an online survey directed at CP trainees across 46.1 hours (SD, 19 h; range, 14–84 h). The proportion of teaching 95 32 Europe in order to examine the attitudes and experiences of trainees hours by teacher’s specialty extremely varied between the different 96 33 towards their training and identify key limitations. schools: clinical pharmacologists (from 0% in 14.3% of the schools 97 34 2. A pre-EACPT Congress meeting to be organized, inviting CPTs to 100%), pharmacologists-physicians (from 0% in 71.4% of cases 98 35 from all Europe to attend. An open discussion will be promoted to 100%), and pharmacologists-pharmacists (from 0% in 45.5% of 99 36 between CPTs and potential emerging solutions will be proposed. cases to 30% as a maximum). 100 37 Conclusions: The teaching of BP is present in all the schools of 101 38 Results: The following main topics will be discussed during the medicine in Spain. However, there is a wide variety in the number 102 39 meeting:−The current status of CP training programs in Europe, of teaching hours of CP and of T as well as on the specialty of the 103 40 focusing on the main concerns and challenges identified in the sur- teachers involved. 104 41 vey. A general discussion will be encouraged between CPT in order 105 42 to address potential solutions. 106 43 Assessing Human Papillomavirus (HPV) 107 44 −Career development in CP: opportunities and challenges. Vaccination utilization and access 108 45 −The proposal of the creation of an international European to care in the United States: a cross 109 46 Network of CPTs to foster cross-border collaboration and joint ini- sectnational analysis using the National 110 47 tiatives in CP education programs. Health and Nutrition Examination Survey 111 48 (NHANES) 112 49 Conclusions: There is an urgent need to address the current limi- D.R. Rivera; Q. Tran; and A.N. Freedman 113 50 tations of CP education in a collaborative approach. A European National Cancer Institute, Rockville, MD 114 51 network of CPTs will encourage and promote the integration of joint Background: The human papillomavirus (HPV) currently affects 79 115 52 efforts within European countries. The creation of the network is million people in the United States. HPV is associated with cervical, 116 53 expected to meet this task by fostering the connection and commu- reproductive, and oropharyngeal cancers, and concordantly IARC 117 54 nication between European CPTs. identifies 13 HPV types as carcinogens. There are currently three 118 55 Food and Drug Administration (FDA)-approved vaccines: Gardasil 119 56 (2006), Ceravix (2009), and Gardasil 9 (2014). There is a notable 120 57 Teaching of Pharmacology, clinical gap in the receipt of this vaccination in comparison to other vaccines 121 58 Pharmacology and Therapeutics in in the recommended schedule for young adults, resulting in a need to 122 59 Spanish Medical Schools. preliminary explore vaccine uptake and access. 123 60 results Methods: The data are from the 2011 to 2012 National Health and 124 61 125 D. Capellà1; F. de Abajo2; L. de Cos3; A. Mediavilla4; C. Payares4; Nutrition Examination Survey (NHANES) administered by the CDC. 62 126 A. Portolés5; R. Morros-Pedrós5,6; and on behalf of the Teaching The data set variables include four relevant questionnaire sections 63 127 Working Group of the Spanish Society of Clinical Pharmacology (demographics, immunization, hospital utilization/access to care, and 64 128

2015 e17 Clinical Therapeutics

1 health insurance). The analysis plan includes use of descriptive statis- F. Stanke-Labesque1,2,3; and D. Maubon1,2,4 65 2 1 2 2 tics, χ , and Cochran-Mantel-Haenszel tests for analysis of between- Grenoble University Hospital, Grenoble, France; University of 66 3 groups differences and the use of logistic regression modeling for Grenoble Alpes, Grenoble, France; 3INSERM U1042, Grenoble, 67 4 factors associated with vaccination. France; and 4UMR 5525 CNRS, Grenoble, France 68 5 Results: Nearly 14.81% of women acknowledge receiving the HPV Background: With the constantly growing incidence of invasive fun- 69 6 vaccine, which translates to 15.9 million US women between the ages gal infections, any failure of antifungal treatment is worrying. Azole 70 7 of 9 and 59 years. When surveying males, 3.45% were vaccinated and antifungals present high variability of their plasma trough concen- 71

8 equate to 3.6 million men ages 9 to 59 years. The most frequent age trations (Cmin), justifying their therapeutic drug monitoring (TDM). 72 9 at first dose was 12 to 13 years. In evaluating the doses received over Nevertheless, target concentrations of posaconazole (lower limit of 73 10 the therapeutic duration, 19% received only 1 dose, 20% received 0.7 mg/L) and voriconazole (upper limit from 4 to 6 mg/L) are still a 74 11 2 doses, and 61% of males and females vaccinated completed the matter of debate. The authors aimed to develop a simple bioassay to 75 12 3 dose course. Of those vaccinated, the majority (88%) received determine the in vitro growth inhibition diameter (ID) and to correlate 76

13 Gardasil, whereas only 7.3% received Ceravix. Several analyses are this ID with Cmin in patients treated with voriconazole or posaconazole. 77 14 planned to explore demographic, insurance, and access factors. Material and methods: The bioassay determined the ID for Candida 78 15 Conclusion: The data have implications for understanding patient parapsilosis using a disk diffusion method. Standard curves were built 79 16 adherence to the vaccine regimen and appropriate use of the vac- for posaconazole and voriconazole in water and in 45% plasma. ID 80 17 cines in recommended age group. Nonadherence is a public health was determined in plasma from patients currently undergoing TDM 81 18 concern and has immunologic, cost, and health system implications. for posaconazole (n = 73) or voriconazole (n = 90). 82 19 Additional analyses plan to address potential barriers to vaccine Results: In water or plasma spiked with antifungals and patient 83

20 receipt and explore potential health disparities. samples, cubic regression between ID and Cmin gave coefficient of 84 21 determination values of 0.997, 0.999, and 0.819, respectively, for 85 22 posaconazole and 0.996, 0.990, and 0.925, respectively, for vori- 86 23 Diclofenac/misoprostol during early conazole (P < 0.001 for each curve). Standard curves with or without 87 24 plasma did not differ. For voriconazole, C of 1 mg/L and 4.7 mg/L 88 Pregnancy and the risk of miscarriage – a min 25 Danish Nationwide cohort study corresponded to 54% and 90% of maximal ID, respectively. For 89 26 posaconazole, C of 0.5 mg/L, 0.7 mg/L, and 1 mg/L corresponded 90 J.T. Andersen1; N.L. Andersen2; T.K. Nielsen3; H.E. Poulsen1; and min 27 E. Jimenez-Solem1 to 26%, 40%, and 53% of maximal ID, respectively. 81 28 1Copenhagen University Hospital Bispebjerg, Copenhagen Conclusion: The proposed easy to use bioassay displays a good cor- 92 29 Denmark; 2Mental Health Centre Copenhagen, Copenhagen, relation with TDM. Moreover, bioassay could be helpful to define the 93 30 Denmark; and 3Copenhagen University Hospital Herlev, Herlev, most appropriate therapeutic concentration and to better characterize 94 31 Denmark the antifungal therapeutic range. Last, it brings additional informa- 95 32 tion to the interpretation of TDM in patients for whom C alone is 96 Introduction: Misoprostol can be used in prevention of gastric ulcer min 33 in treatment with diclofenac and is used in rheumatic diseases. Since insufficient to adjust the antifungal dosage. 97 34 misoprostol causes contractions of the uterus, it can also be used to 98 35 induce abortions when administrated vaginally. The aim of the study 99 36 was to investigate if early pregnancy exposure to oral diclofenac/ Do new Cancer drugs offer good 100 37 misoprostol was associated with miscarriage. value for Money? the perspective of 101 38 Method: We conducted a nationwide cohort study identifying all reg- oncologists, payers, patients, and 102 39 istered pregnancies in Denmark from 1997 to 2011. All births were general Population 103 40 identified using the Medical Birth Registry, and all records of induced Tatiana Dilla1; Luís Lizan2; Silvia Paz2; Pilar Garrido3; 104 41 abortion and miscarriage were from the National Hospital Register. Cristina Avendaño-Solá4; Juan J. Cruz5; Javier Espinosa6; and 105 42 Data on drug use were from the National Prescription Register. Cox José A. Sacristán1 106 43 proportional hazard regression models were used to calculate the 1Lilly S.A, Spain; 2Outcomes’10, Jaime I University, Castellón 107 44 hazard of miscarriage in women exposed to diclofenac/misoprostol (Spain); 3Hospital Ramón y Cajal, Madrid (Spain); 4Department 108 45 in early pregnancy. of Clinical Pharmacology, University Hospital Puerta de Hierro 109 46 Result: We identified 1,338,824 pregnancies (970,491 births, Majadahonda, Madrid, Spain; 5Hospital Clínico Universitario, 110 47 142,147 miscarriages, 226,145 induced abortions). One hundred Salamanca (Spain); and 6Hospital General de Ciudad Real, Ciudad 111 48 sixty-six were exposed to diclofenac/misoprostol in the early preg- Real (Spain) 112 49 nancy of which 28.3% (47) ended up in a miscarriage compared Objective: To analyze oncologists, payers, patients, and general 113 50 to 10.6% among unexposed. The adjusted hazard ratio of having population’s views on the cost and value of new cancer treatments. 114 51 a miscarriage after exposure to diclofenac/misoprostol in the first Methods: An electronic self-administered questionnaire was devel- 115 52 trimester was 3.6 (95% CI, 2.6–4.9). oped and randomly distributed to assess participants attitudes towards 116 53 Conclusion: We found an increased risk of miscarriage after expo- new cancer treatment outcomes and costs during reimbursement deci- 117 54 sure to diclofenac/misoprostol during the early pregnancy. This sions. Among the questions asked were two hypothetical scenarios. 118 55 should lead to increased caution when treating women of fertile age First, participants were asked to indicate the minimum survival benefit 119 56 120 with diclofenac/misoprostol. that a new treatment, which cost € 50,000 more than the standard 57 therapy, should have to be funded by the Spanish National Health 121 58 System (NHS). Second, participants were requested to state the highest 122 59 costs to be afforded by the NHS for a medication increasing patient’s 123 60 The contribution of a simple bioassay in 124 effective therapeutic drug monitoring quality of life (QoL) twofold with no changes in survival. Responses 61 were used to calculate incremental cost-effectiveness ratios (ICER). 125 62 of Posaconazole and Voriconazole 126 1 1 1,2,3 1 Results: Fifty-three oncologists, 60 patients, 25 payers, and 50 indi- 63 J. Tonini ; S. Bailly ; E. Gautier-Veyret ; C. Wambergue ; 127 1,2 1 1,2,4 viduals from general population answered the questionnaire. The mini- 64 H. Pelloux ; A. Thiébaut-Bertrand ; M. Cornet ; 128

e18 Volume XX Number XX Morphine decreases ticagrelor concentrations but not its Effects

1 mum improvement median in patient survival that justified the inclusion 5Trousseau Hospital, Paris, France; 6INSERM, UMR938, 65 2 into the NHS was 5.66 months for oncologists, 8.16 for patients, 9.08 Plateforme de microdosages, Paris 06, France; 7Saint Antoine 66 3 for general population, and 10.44 for payers, implying different ICER Hospital, Paris, France; 8Centre hospitalier St Joseph- St Luc, 67 9 4 for oncologists (€ 106,000/QALY), patients (€ 73,520/QALY), general Lyon, France; Hôpital Arnaud de Villeneuve, Montpellier, France; 68 10 11 5 population (€ 66,074/QALY), and payers (€ 57,471/QALY). Centre hospitalier Jacques Coeur, Bourges, France; Société 69 12 6 The cost stated in QoL-enhancing scenario was € 33,167 for Française de Cardiologie; and Université René-Descartes, Paris 70 7 patients, € 30,200 for general population, € 26,000 for oncologists, 05 71 8 and € 17,040 for payers, resulting in ICERs of € 82,917/QALY for Background: Growth hormone/insulin-like I (IGF-I) 72 9 patients, € 75,500/QALY for general population, € 65,000/QALY for axis is being targeted for therapeutic development in diseases such as 73 10 oncologists, and € 42,600/QALY for payers. short stature, cancer, and metabolic disorders. The impact of IGF-I 74 11 Conclusions: All the estimated ICER values were higher than the in cardiovascular disease remains controversial. We therefore studied 75 12 thresholds usually described in the literature (€ 20,000–30,000/ whether IGF-I at admission for acute myocardial infarction (AMI) 76 13 QALY), with relevant differences among the groups. In both sce- predicted death, recurrent AMI, and stroke over a 2-year follow-up. 77 14 narios, payers were less prone to pay for therapeutic improvements Methods: Using data from the FAST-MI registry, we measured IGF-I 78 15 compared to the rest of the participants. On the other hand, oncolo- among all the 1005 patients with AMI who participated in the serum 79 16 gists were the ones that most valued gains in survival for a new treat- databank. As IGF-I decreases with age, a standardized IGF-I score 80 17 ment while patients assigned a higher value for money to a treatment was calculated as previously described (IGF-I score = (log [IGF- 81 18 that enhanced the quality of life. I(µg/L)] + 0.00625 × age − 2.555)/0.104). Impact of IGF-I score 82 19 (continuous and quartiles) on outcomes were compared using Cox 83 20 proportional hazards regression models. 84 21 Impact of age-adjusted insulin- Results: During follow-up, 190 patients died or had a recurrent AMI 85 22 like growth factor i on major or stroke. Patients in the lowest quartile of IGF-I were older and more 86 23 Cardiovascular events Two Years after frequently female and diabetic compared to patients in the other 87 24 acute Myocardial infarction: results quartiles. After adjustment for known cardiovascular factors, an 88 25 from the fast-mi registry increase of 5 units of IGF-I score was associated with a 30% decrease 89 26 Olivier Bourron1,2,3,4; Yves Le Bouc1,3,5,6; Laurence Berard1,7; of the risk of events during follow-up (adjusted HR = 0.70; 95% CI, 90 27 Salma Kotti1,7; Nadège Brunel6; Bernard Ritz8; Florence Leclercq9; 0.54–0.92; P = 0.0093). Similarly, the lowest quartile of IGF-I was 81 28 Xavier Tabone10; Elodie Drouet1,7; Geneviève Mulak11; Nicolas associated with an increased risk of events (adjusted HR = 1.52; 95% 92 29 Danchin1,12; and Tabassome Simon1,3,7 CI, 1.11–2.08; compared with others quartiles; P = 0.010). 93 30 1Assistance Publique-Hôpitaux de Paris, France; 2Diabetology Conclusions: Low IGF-I score is associated with increased risk of 94 31 Department, Pitié Salpétrière Hospital, Paris, France; 3Sorbonne all cause-death, recurrent MI, and stroke in AMI patients. Whether 95 32 Universités, UPMC Univ Paris 06, France; 4INSERM, UMR_S patients treated by IGF-I axis inhibitors have a specific clinical course 96 33 1138, Centre de recherche des Cordeliers, Paris 06, France; after AMI would be worth studying. 97 34 98 35 99 36 100 37 101 38 102 39 103 40 104 41 105 42 106 43 107 44 108 45 109 46 110 47 111 48 112 49 113 50 114 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

2015 e19 Clinical Therapeutics/Volume XX, Number XX, 2015

1 Epidemiological Profile of 75.17, and 71.14 (mean 73.76) DDD/1000 inhabitants/day, respec- 65 2 Benzodiazepine Poisonings In Uruguay: tively. Alprazolam was the most consumed anxiolytic benzodiaz- 66 3 Received Consults At The National epine (mean 25.09) and flunitrazepam was the most consumed 67 4 Poisoning Information Centre During hypnotic benzodiazepine (mean 18.69). If clonazepam is included, it 68 5 2010–2011 becomes the most consumed benzodiazepine (mean 36.51) and global 69 6 V. Domínguez1; M. Tortorella2; N. Speranza1; C. Amigó1; DHD increases up to 106.36, 110.86m and 113.61 (mean 110.28) 70 7 A. Laborde2; A. Goyret1; and G. Tamosiunas1 DDD/1000 inhabitants/day, respectively. Clonazepam showed the 71 8 1Faculty of Medicine, University of the Republic of Uruguay, higher consumption increase from 2010 to 2012 (35.29%), while 72 9 Montevideo, Uruguay; and 2National Poisoning Information the use of midazolam (−46.15%) and diazepam (−18.83%) decreased 73 10 Centre, University of the Republic of Uruguay, Montevideo, gradually. Public health institution was mainly responsible for the 74 11 Uruguay global consumption value, whereas private ones showed the higher 75 12 Background: Since the introduction of benzodiazepines (BZDs) into increase during the evaluated period. 76 13 medical practice during the 1960s, they have become one of the Conclusion: Uruguay showed high benzodiazepines consumption, 77 14 most widely prescribed drugs for anxiety and sleep disorders. Low similar to those reported by other countries, and it seems to be a pub- 78 15 risk perception among health practitioners and patients leads to an lic health concern. Alprazolam, diazepam, and flunitrazepam con- 79 16 irrational use of BZDs. Accidental and intentional drug poisoning are sumption were predominant and clonazepam use showed the highest 80 17 often due to BZDs (27–40% in international series). Our objective increase. These are the first available benzodiazepines consumption 81 18 was to describe the pattern of acute poisoning cases involving BZD data in our country and will be useful to perform future comparisons. 82 19 in Uruguay over the last years. 83 20 Material and Methods: Retrospective descriptive study of all acute 84 21 BZD poisonings received and recorded by the National Poisoning Hepatic Cytolysis Considered Fosfomycin/ 85 22 Information Centre from 2010 to 2011. Tromethamine Related: A Case Report And 86 23 Results: A total of 31,228 toxic agents were related with the reg- Literature Review 87 24 istered poisoning consults and 18,530 were medicines. BZDs rep- M. Deppenweiler1; M. Debette-Gratien2; and C. Monchaud1,3 88 25 resented 28.80% (7123) of the toxic agents and 38.40% (6769) of Departments of 1Pharmacology, Toxicology and 89 26 all the medicines involved. There were 21,452 poisoning consults Pharmacovigilance; 2Hepato-Gastroenterology; and 3INSERM 90 27 between 2010 and 2011. BZDs were attributed as the causal agent in UMR-S850, Univ Limoges, Limoges, France 91 28 6186 (28.80%) of them. Most of them involve adults (4578, 78.10%) Background: Fosfomycin/tromethamine is approved as single dose in 92 29 and occurred in female patients (4600, 74.30%). The intentional the treatment of acute cystitis and recommended in the prophylactic 93 30 intake of BZD for suicide was the most common circumstance of treatment of recurrent cystitis. Although well-tolerated, cases of liver 94 31 poisoning (5235, 89.54%). Clonazepam, diazepam, and alprazolam injury after long-term administration have been reported. 95 32 were the most commonly reported as the implied BZD. Sixty-eight Objectives: This report describes a case of fosfomycin/tromethamine- 96 33 (1.09%) BZD poisonings were classified as severe and only 5 of induced hepatotoxicity after long-term administration and summa- 97 34 them were fatal. rizes the available scientific data on fosfomycin and fosfomycin/ 98 35 Conclusions: National casuistic of BZD poisonings shows the main tromethamine-associated hepatotoxicity cases. 99 36 role of BZD in medicine’s poisonings. Most of the reported cases were Methods: Previously reported cases were identified using a search 100 37 nonserious, which supported the well-known safety profile of BZDs. in PubMed (search terms: fosfomycin, fosfomycin/tromethamine, 101 38 This safety concern should be approached from the consumption and fosfomycin/trometamol, fosfomycin/tromethamine, hepatotoxicity, 102 39 irrational use point of view in our population. hepatic cytolysis) and in the French and American (FDA) pharma- 103 40 covigilance databases. 104 41 Case Summary/Results: A 57-year-old woman was started on fosfo- 105 42 Benzodiazepines consumption in uruguay: mycin/tromethamine, one sachet every 6 days, for disabling recurrent 106 43 a public health concern? cystitis. Prior to treatment initiation, her liver function tests were nor- 107 44 108 N. Speranza1; V. Domínguez1; E. Pagano1; P. Artagaveytia1; mal. Three years later, the occurrence of hepatic cytolysis motivated 45 109 I. Olmos2; M. Toledo2; and G. Tamosiunas1 an extended exploration over 1 year. The discontinuation of fosfo- 46 110 1Faculty of Medicine, University of the Republic of Uruguay, mycin/tromethamine finally resulted in the sustained normalization 47 111 Montevideo, Uruguay; and 2Vilardebó Hospital, Montevideo, of liver enzymes within a few weeks. The literature search identified 48 112 Uruguay only 4 case reports of fosfomycine related hepatic disorders, while 40 49 113 Background: There are no data on the overall Uruguayan patterns and 57 cases of fosfomycine related hepatic disorders have been reg- 50 114 of benzodiazepine use. The aim of this study was to quantify and istered in the French and FDA pharmacovigilance databases. Overall, 51 115 evaluate benzodiazepines consumption in Uruguay between 2010 hepatic cytolysis seems more frequent than cholestasis. The reported 52 116 and 2012. delays between treatment introduction and liver enzymes increase 53 117 Material and Methods: A drug utilization study was performed to vary from a few days to 5 months. The increase of liver enzymes can 54 118 quantify current state of benzodiazepines consumption in our popula- be mild to severe. Normalization of liver enzymes is usually reversible 55 119 tion. Drug utilization data refer to oral benzodiazepines dispensed by after therapy withdrawal, within one week to a few months. 56 120 the pharmacy departments from the participating health institutions. Conclusions: Based on the “Roussel Uclaf Causality Assessment 57 121 The unit of measurement was the defined daily doses (DDD) per Method (RUCAM)” scale, in the case we report, fosfomycin/trometh- 58 122 1000 inhabitants per day (DHD). DHD of hypnotic and anxiolytic amine was plausibly responsible for the hepatic cytolysis. The review 59 123 benzodiazepines and DHD from public and private health care cover- of the literature and French and American cases suggest that liver 60 124 age were compared. Results were described as absolute values and injury is not a frequent side effect of fosfomycin. However, clinicians 61 125 percentage of changes. should be aware of this potential effect, and follow-up of long-term 62 126 Results: The included sample represents the 62% of the Uruguayan treated patients should be recommended. 63 127 population. Global DHD for 2010, 2011, and 2012 were 74.97, 64 128

2015 e1 Clinical Therapeutics

1 The Effectiveness, Safety and Costs of and not a generic medication; and d) the prescription is individual- 65 2 orphan Drugs: An Evidence-Based Review ized. Information and trust are central considerations; the concept 66 3 I.J. Onakpoya1; E.A. Spencer1; M.J. Thompson2; and of “copy” was frequently mentioned to define generics, from an 67 4 C.J. Heneghan1 identical to a forged medication. Using a copy might not be ques- 68 5 1University of Oxford, Oxford, UK; and 2University of tioned when the medications are perceived as being identical and 69 6 Washington, Seattle, Washington efficient; however, it might become a problem in cases in which the 70 7 Introduction: Several orphan drugs have been approved by the copy indicates that the patient thinks he/she is receiving a second- 71 8 European Medicines Agency (EMA) over the past 2 decades. choice medication. 72 9 However, the prices of the drugs are expensive, and in some instances, Conclusion: Our results provide support for generic medication rais- 73 10 the evidence for effectiveness is not convincing at the time of regula- ing many concerns and much lesser perceived need. For patients, 74 11 tory approval. Our objective was to evaluate the clinical effective- economic arguments per se are not sufficient to justify substitution, 75 12 ness of orphan drugs which have been granted marketing licenses and may even raise issues calling upon cognitive dissonance. In this 76 13 in Europe, determine the annual costs of each drug, compare the context, positive cues require further attention and negative cues 77 14 costs of branded orphan drugs against their generic equivalents, and need be de-emphasized - in particular lower price as an indication of 78 15 explore any relationships between orphan disease prevalence and lower quality, and generic status as contradictory with advocating 79 16 annual costs. individualization of medication. 80 17 Methods: We searched the EMA database to identify orphan drugs 81 18 granted marketing authorization up till April, 2014. Electronic 82 19 searches were also conducted in PubMed, Embase, and Google Clinical Outcomes of Implementing 83 20 Scholar to assess data on effectiveness, safety, and annual costs. Two Evidence-Based Practice on Venous 84 21 reviewers independently evaluated the levels and quality of evidence Thromboembolism Prevention for Cancer 85 22 and extracted data. Patients In Qatar, A Retrospective Study 86 23 Results: We identified 74 orphan drugs, with 54 (73%) demon- S. Elazzazy; R. Abd El Wahab; R. Negm; M. A/Wahid; S. Al Yafei; 87 24 strating moderate quality of evidence. Eighty-five percent showed M. Zaidan; and I. Al Hijji 88 25 significant clinical effects, but serious adverse events were reported National Center for Cancer Care and Research (NCCCR), Hamad 89 26 in 86.5%. Their annual costs were between £726 and £378,000. Medical Corporation, Doha, Qatar 90 27 There was a significant relationship between disease prevalence and Background: Venous Thrombo Embolism (VTE) disease is a seri- 81 28 annual costs (P = 0.01); this was largely due to the influence of the ous condition; approximately 20% of VTE cases occur in cancer 92 29 ultra-orphan diseases. We could not determine whether the balance patients and it is a significant cause of morbidity and mortality espe- 93 30 between effectiveness and safety influenced annual costs. For 10 cially during the first year among all types and stages of cancer [1,2]. 94 31 drugs where generic alternatives were available, the branded drugs Most hospitalized patients with cancer require thromboprophylaxis 95 32 were 1.4 to 82,000 times more expensive. throughout hospitalization [3]. Breast cancer is considered a very 96 33 Conclusion: The available evidence suggests that there is inconsist- high risk for VTE due to different factors (malignancy, surgery, chem- 97 34 ency in the quality of evidence of approved orphan drugs, and there otherapy, hormonal therapy, hospitalization, and female gender) [4]. 98 35 is no clear mechanism for determining their prices. In some cases Objectives: This study focuses on the assessment of the clinical out- 99 36 far cheaper generic agents appear to be available. A more robust, come in preventing VTE amongst cancer population in Qatar after 100 37 transparent, and standard mechanism for determining annual costs implementation of evidence based thromboprophylaxis guidelines. 101 38 is imperative. Methods: A retrospective study was conducted to evaluate the inci- 102 39 dence of DVT by evaluating Doppler ultrasound, database for 364 103 40 cases of inpatients and outpatients over 24 months (January 2011– 104 41 Generic Medication In Chronic December 2012), findings were analyzed by a hematologist to identify 105 42 Musculoskeletal Pain Patients: An Issue patients who developed DVT due to current or previous admission 106 43 of Representations, Trust, and Experience (within 30 d). The relationship between the incedence of devloping 107 44 108 V. Piguet; S. D’Incau; M. Besson; J. Desmeules; and C. Cedraschi VTE overtime and the complinece to VTE prevention protocol were 45 109 Geneva University Hospitals and University of Geneva, Geneva, established. 46 110 Switzerland Results: The study showed that the increase in the overall compliance 47 111 Background: Chronic pain patients are frequently confronted with to VTE prophylaxis protocol introduced to inpatients population 48 112 the issue of the prescription and/or substitution of original formula- (n = 2595) increased from 61.5% to 84.6% (P = 0.0297), led to 49 113 tions with generic medications. Information regarding generic substi- decreased DVT incidence by 66.4% (P = 0.0145). Fifty percent of 50 114 tution is not univocal and room for the expression of contradictory cancer cases developed DVT were breast cancer patients (n = 24), 51 115 opinions is ample. Along with an ever stronger advocacy for the use 92% of them were outpatients. 52 116 of generics, various sources of information report concerns regard- Conclusion: Appropriate thrombophylaxis could considerably 53 117 ing substitution. improve the incidence of DVT in cancer patients, breast cancer 54 118 Methods: Semistructured interviews explored patients’ representa- patients are very high risk for VTE, which raises the importance of 55 119 tions (N 25) regarding generics in patients suffering from chronic implementing thromboprophylaxis in both hospital and ambulatory 56 = 120 musculoskeletal pain. Patients’ interviews were transcribed and sub- settings. 57 121 mitted to content analysis. 58 122 Results: Patients’ representations suggest that they might be confi- 59 123 dent in taking a generic medication: when a) he/she has an under- 60 Reference 124 standing of generics as resulting from the loss of original trading 61 1. Lyman GH. Venous thromboembolism in the patient with cancer: 125 license; b) the generic medication is prescribed by the physician (sup- 62 focus on burden of disease and benefits of thromboprophylaxis. 126 ported by the pharmacist); c) each prescription is discussed, that is, 63 Cancer 2011;117:1334–1349. 127 the patient is prescribed the generic version of a given medication 64 128

e2 Volume XX Number XX Epidemiological Profile of BenzodiazepineP oisonings In Uruguay

1 2. Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous coherence tomography (OCT) is a rapid and non-invasive method 65 2 thromboembolism and its effect on survival among patients with of gaining detailed imaging of the retinal and choroidal structures. 66 3 common cancers. Arch Intern Med 2006;166:458–464. Use in patients at high CVD risk is novel. 67 4 3. Gary H. Lyman, Alok A. Khorana, Nicole M. Kuderer, Agnes Y. Lee, Methods: We used the new SPECTRALIS OCT to examine retinal 68 5 Juan Ignacio Arcelus, Edward P. Balaban, Jeffrey M. Clarke, and choroidal structures in 25 patients with hypertension, 25 with 69 6 Christopher R. Flowers, Charles W. Francis, Leigh E. Gates, Ajay K. varying degrees of CKD, and 23 age- and sex-matched healthy con- 70 7 Kakkar, Nigel S. Key, Mark N. Levine, Howard A. Liebman, Margaret trols. One ophthalmologist carried out all scans, blinded to diagnosis. 71 8 A. Tempero, Sandra L. Wong, Ann Alexis Prestrud, and Anna Measurements included retinal thickness, retinal nerve fibre layer 72 9 Falanga; “Venous Thromboembolism Prophylaxis and Treatment in (RNFL) thickness, macular volume, and choroidal thickness. ET-1, 73 10 Patients with Cancer: American Society of Clinical Oncology Practice CRP, and IL6 were assayed by ELISA. 74 11 Guideline Update”, Journal of Clinical Oncology, Vol 31, Issue 17 Results: Retinal thickness was reduced across the outer 4 locations 75 12 (June), 2013: 2189–2204. (P < 0.05), and macular volume (P < 0.001) and choroidal thickness 76 13 4. Alikhan R, Cohen AT, Combe S, et al. Risk factors for venous were reduced (P < 0.01), in CKD patients compared to both patients 77 14 thromboembolism in hospitalized patients with acute medical with hypertension and healthy volunteers. RNFL thickness did not 78 15 illness: analysis of the MEDENOX Study. Arch Intern Med. differ between groups. In CKD, a thinner choroid was associated 79 16 2004;164(9):963–968. with a lower glomerular filtration rate (P < 0.01) and more severe 80 17 proteinuria (P < 0.01), and with raised endothelin-1, CRP, and IL6. 81 18 Conclusions: The decreases in retinal and choroidal thickness seen in 82 19 Antidepressant-Mediated Increase In the CKD may reflect significant microvascular injury, and the close asso- 83 20 Expression and Release of Glial-Derived ciation with evidence of chronic renal damage (reduced eGFR and 84 21 Neurotrophic Factor Leads To Increased proteinuria), suggest they may mirror effects in the renal vasculature. 85 22 Gliogenesis The association of these changes with endothelin-1, CRP, and IL6 86 23 S. Avissar1; M. Golan1; and G. Schreiber1,2 suggests endothelial dysfunction and inflammation may be implicated 87 24 1Ben Gurion University, Beer Sheva, Israel; and 2Barzilai Medical in this pathology, whereas blood pressure and nerve damage do not 88 25 Centre, Ashkelon, Israel emerge as important factors. It remains to be shown whether OCT 89 26 Introduction: Glial cell-derived neurotrophic factor (GDNF), essen- may be a useful way of characterising the systemic vasculature in 90 27 tial for neuronal survival, plasticity and development, has been impli- CKD, and whether it may prove valuable in monitoring the response 81 28 cated in the mechanism of action of antidepressant drugs (ADs). to renoprotective treatment. 92 29 93 β -arrestin1, a member of the arrestin protein family, was found to 30 play a role in AD mechanism of action. The present study aimed 94 31 at evaluating whether the effect of ADs on GDNF in rat glioma Effect of Cilostazol on The 95 32 96 cells which exerted through a betaβ -arrestin1-dependent, CREB- Pharmacodynamics of Cyp3a and 33 interactive pathway leads to increased gliogenesis. Non-Cyp3a-Dependent Statins 97 34 Material and Methods: For chronic AD treatment, C6 rat glioma J.A. Jung1; S.Y. Lee2; H.M. Park1; J.R. Kim1; W. Huh1; S.Y. Lee1; 98 35 cells were treated for 3 days with different classes of ADs. The and J.W. Ko1,2 99 36 research employed short-hairpin RNA transfection, immunoblot- 1Samsung Medical Center, Seoul, Republic of Korea; and 100 37 ting and immunoprecipitation techniques, ELISA assay and FACS. 2Samsung Advanced Institute for Health Sciences and Technology, 101 38 Results: ADs significantly elevated beta-arrestin1 levels in the cyto- Sungkyunkwan University, Seoul, Republic of Korea 102 39 sol, while reducing phospho-beta-arrestin1 levels in the cell nuclear Background: Cilostazol has a modest hypolipidaemic action in addi- 103 40 fraction. ADs significantly increased both GDNF expression and tion to the anti-thrombotic effect. Systemic exposure of simvasta- 104 41 release from the cells, but were unable to induce such effects in beta- tin was increased by 70% when cilostazol was coadministered. We 105 42 arrestin1 knock-down cells. Chronic AD treatment significantly assessed the effect of cilostazol, a CYP3A4 inhibitor, on the phar- 106 43 increased beta-arrestin1/CREB interaction. GDNF elevation resulted macodynamics of simvastatin (CYP3A4 substrate) and rosuvastatin 107 44 in increased cell proliferation and differentiation. (non-CYP3A4 substrate). 108 45 Conclusions: These findings support the involvement of beta-arres- Materials and Methods: This was a single-centre, open-label, ran- 109 46 tin1 in the mechanism of action of ADs that leads to increased levels domized, multiple-dose, crossover study. A total of 62 healthy male 110 47 and release of GDNF, thus enhancing GDNF’s protective action that subjects were administered cilostazol (100 mg, twice daily), simvas- 111 48 promotes cellular proliferation and differentiation when the survival tatin (40 mg, once daily) or rosuvastatin (20 mg, once daily) alone 112 49 and function of glia is compromised as occurs in major depression. and together for 7 consecutive days with a 14-day wash-out period. 113 50 Lipid profiles including total cholesterol, low density lipoprotein- 114 51 cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C) 115 52 and triglyceride were measured before and 7 days after drug admin- 116 53 Clinical Utility Of Optical Coherence 117 Tomography (Oct) In High istration in each period. 54 Results: Decrease in the plasma triglyceride, total cholesterol, LDL-C 118 55 Cardiovascular Risk Patients 119 1 1 1 1 2 and increase in HDL-C by cilostazol was not statistically significant. 56 D.J. Webb ; C. Balmforth ; T. Ruiys ; N. Dhaun ; J. Cameron ; 120 2 2 2 Statins decreased total cholesterol, LDL-C, and triglyceride sig- 57 S. Borooah ; B. Dhillon ; and S. Chandran 121 1 nificantly and these lipid-lowering effects were maintained by the 58 Queens Medical Research Institute, University of Edinburgh, 122 United Kingdom; and 2Anne Rowling Regenerative Neurology coadministration of cilostazol. Coadministration of cilostazol and 59 statins increased HDL-C compared to statin alone (4.53 ± 1.95 for 123 60 Clinic 124 Background: Patients with chronic kidney disease (CKD) have a high simvastatin [P = 0.025], 4.01 ± 1.88 for rosuvastatin [P = 0.039]). 61 Conclusions: Coadministration with statin and cilostazol had 125 62 risk of dying from cardiovascular disease (CVD). There are develop- 126 mental links and similarities in vascular pathology between the eye a beneficial effect on the HDL-C. Pharmacodynamic interac- 63 tion with cilostazol was not different between simvastatin and 127 64 and kidney, suggesting common pathological mechanisms. Optical 128

2015 e3 Clinical Therapeutics

1 rosuvastatin , indicating pharmacodynamic effect was not related Material and Methods: Thirty naive HCV patients were injected 65 2 with the CYP3A4. subcutaneously with PEG-CIFN once per week for 12 weeks. Serum 66 3 HCV RNA levels was measured by a COBAS Taqman HCV Test 67 4 system. Serum cytokines and chemokines, IL-12p40, IL-12p70, MIG, 68 5 The Impact of Cyp4f2 Polymorphism on MIP, IP-10, MCP-1 and TNF were analyzed by Luminex® assays 69 6 The Safety Profile And Regime Dosing of at baseline, 4, 8 and 12 weeks. Fibrosis stages were determined by 70 7 Phenindion In Patients With Valvular fibroscan. 71 8 Atrial Fibrillation Results: The HCV RNA levels in the serum were markedly decreased 72 after therapy. Thirty percent of HCV patients had rapid virological 9 V.S. Shakhidzhanova1; D.A. Sychev1,2; R.E. Kazаkov1,3; 73 responses (RVR), and 66.7% (16/30) had early virologic responses. 10 N.D. Grishenko4; Y.Y. Palamarchuk4; A.V. Kossovskaya3; and 74 The mean log HCV RNA values were 6.43, 1.37, 1.03, and 1.0 IU/ 11 A.Y. Tretyakov4 75 mL at 0, 4, 8, and 12 weeks, respectively, in the EVR group and 12 1I.M. Sechenov First Moscow State Medical University, Ministry of 76 6.65, 4.21, 2.98, and 3.1 IU/mL, respectively, in the non-EVR group. 13 Health of Russia Federation, Moscow, Russia; 2Russian Medical 77 HCV RNA values were less at the EVR group compared to non-EVR 14 Academy of Postgraduate Education, Ministry of Health of Russia 78 group after treatment, P 0.05. IL-4, IP-10, and MIP-1b levels were 15 Federation, Moscow, Russia; 3Federal State Institution “Scientific < 79 lower, and G-CSF levels were higher in EVR group than in the non- 16 Centre of Medical Products Expertise”, Moscow, Russia; 80 EVR group (P 0.05). Fibrosis stage did not change after treatment. 17 and 4Belgorod National Research University, medical faculty, < 81 Correlation coefficient of HCV RNA values with IP-10 and MIP-1b 18 Belgorod, Russia 82 were 0.82 and 0.81, respectively, in the EVR group (P 0.05). IP-10 19 Introduction: In the reason of FDA prohibition in using of “new” < 83 and MIP-1b levels were associated with aminotransferase (ALT and 20 oral anticoagulants, vitamin K antagonists have become uncontested 84 AST) levels. Baseline IP-10 levels less than 435 pg/mL predicted RVR 21 drugs to the patients with valvular atrial fibrillation. The deriva- 85 at 4 weeks and less than 465 pg/mL predicted EVR at 12 weeks. 22 tives of indandion, as fluindione and phenindion, can be used in the 86 Conclusions: PEG-CIFN was well tolerated and effective at inhibit- 23 case of intolerance and coumarins resistance. The role of the main 87 ing HCV RNA. PEG-CIFN may increase or decrease levels of immune 24 genetic factors in individual sensitivity to coumarin’s anticoagulants 88 markers. IFN treatment is associated with changes in markers of 25 is well known. But the influence of gen’s polymorphism CYP4F2 89 immune activation in chronic HCV viral infections. 26 on the safety profile and regime dosing of phenindion haven’t been 90 27 studied yet. 81 28 Materials and Methods: Forty-two patients (20 male and 22 female), 92 29 aged 27 to 80 years, valvular AF, were studied. The using of coumarin Resveratrol and Fenofibrate Ameliorate 93 30 anticoagulants was impossible in all of them. All patients received Fructose-Induced Nash In Rats By 94 31 phenindion in the dose of 30 to 130 mg daily with a target interna- Modulation of Liver and Adipose Tissue 95 32 tional normalized ratio (INR) of 2.0 to 3.0. Genotyping for polymor- Expression of Genes 96 33 phism’s marker V433M gen CYP4F2 were designed using the PCR E.A. Abd El-Haleim; A.K. Bahgat; and S. Samira 97 34 and RFLP (restriction fragment length polymorphism). Statistics were Faculty of Pharmacy, Cairo University, Cairo, Egypt 98 35 performed by Fisher’s exact tests. Background: The intake of high-fructose beverages has been 99 36 Results: Genotype CC was found in 26 patients (62%), genotype increased. The present study evaluates the effect of a polyphenol 100 37 CT in 16 patients (38%), genotype TT wasn’t found at all. In the CC (resveratrol), alone or in combination with fenofibrate, on fructose- 101 38 102 group (n = 26) high dose of phenindion (> 90 mg) was needed only induced metabolic abnormalities in rats. A number genes known 39 103 in 2 patients (8%), versus 6 patients (37.5%) in the CT group (n = to be critically involved in lipid metabolism was investigated. 40 104 16), P = 0.04 (significant statistically). In the CC group bleedings Understanding the molecular basis of a disease could shed light onto 41 were found in 4 patients (9%) and in 1 patient (7%) in CT group, P the beneficial therapeutic effects of drugs. 105 42 106 = 0.63. In the CC group INR increased > 3.0 in 3 patients (8%). In Material and Methods: Giving a fructose-enriched diet (HFD) to rats 43 107 the CT group nobody had INR > 3.0 (P = 0.5). for 12 weeks was used as a model for inducing hepatic dyslipidemia 44 Conclusion: The patients with genotype CT (polymorphism V433M and insulin resistance. Fenofibrate (FENO) (100 mg/kg), resveratrol 108 45 109 gen CYP4F2) are usually needed in high dose of phenindion (> 90 (RES) (70 mg/kg) and combined treatment (FENO+RES) (half the 46 mg) to achieve target INR of 2.0 to 3.0. There was not found out the doses) were given orally from the 9th week till the end of experi- 110 47 influence of gen CYP4F2 polymorphism on the developing of bleed- mental period. Body weight, oral glucose tolerance test (OGTT), 111 48 ings and excessive hypocoagulation. liver index, insulin resistance (HOMA), serum and liver triglycerides 112 49 (TGs), oxidative stress (liver MDA, GSH and SOD), serum AST/ALT 113 50 114 ratio and TNF-α were measured. Additionally, hepatic gene expres- 51 sion of suppressor of cytokine signaling -3 (SOCS-3), sterol regu- 115 52 Association of Immune Response 116 Parameters With Early Virological latory element binding protein-1c (SREBP-1c), fatty acid synthase 53 (FAS), malonyl CoA decarboxylase (MCD), transforming growth 117 54 Response In Hcv Patients Treated With 118 Pegylated Consensus Interferon factor-β 1 (TGF-β 1) and adipose tissue gene expression of leptin and 55 adiponectin was evaluated. 119 56 Y.H. Ding; H. Zhang; H. Chen; X.J. Li; Q. Zhang; C.J. Liu; 120 L.Z. Yang; Q.M. Li; and J.Q. Niu Results: Rats fed HFD showed impairment of glucose tolerance, 57 insulin resistance, oxidative stress, and dyslipidemia. As for gene 121 58 Phase I Clinical Research Center, The First Hospital of Jilin 122 University, Jilin, China expression, there was a change in favour of dyslipidemia and NASH 59 development. Thus, in the liver, FAS, SOCS-3, SREBP-1c, and 123 60 Background or Introduction: The aim of the study was to test 124 antiviral activity of pegylated consensus interferon (PEG-CIFN) in TGF-β 1 were upregulated while MCD was downregulated. In adi- 61 pose tissue, leptin and adiponectin genes were unbalanced. All treat- 125 62 adults with HCV infection and to determine the relationship between 126 immune response markers and virological response. ment regimens showed effective reversal in the observed divergences 63 contributing to hepatic steatosis and insulin resistance. 127 64 128

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1 Conclusions: When resveratrol is given with half the dose of fenofi- Background and Purpose: Impaired wound healing is a common 65 2 brate, the combination improved NASH-related fructose-induced complication of diabetes and is the leading cause of lower extrem- 66 3 disturbances and gene expression similar to a full dose of fenofibrate ity amputation. Treatment with fenofibrate was associated with a 67 4 possibly due to attenuating the elevated transcription factors besides lower risk of amputations, particularly minor amputations without 68 5 antioxidant activity by resveratrol. known large-vessel disease, probably through nonlipid mechanisms. 69 6 Key words: Fructose, NASH, SOCS-3, SREBP-1c, FAS, MCD, leptin, The current study aimed to test our hypothesis that fenofibrate 70 7 adiponectin, TGF-â, TNF-á improves angiogenesis and restore endothelial progenitor cell (EPC) 71 8 function via deregulating NALP3 inflammasome activity in strepto- 72 9 zotocin (STZ)-induced diabetic mice. 73 10 The Frequency of Cyp2c19 Genetic Material and Methods: Male C57BL/6 mice were randomly divided 74 11 Polymorphisms In Russian Patients With into 3 groups: control, STZ-induced diabetic group and fenofibrate 75 12 Peptic Ulcer Treated With Proton Pump treated diabetic group (100 mg/kg/d intraperitoneally for 2 wk). 76 13 Inhibitors Wound closure was assessed by wound area and CD31 positive cap- 77 14 N.P. Denisenko1,2; D.A. Sychev1,2; Zh.M. Sizova2; A.V. Grachev3; illaries. Both the migration and tube formation capacities of EPCs 78 15 and K.A. Velikolug4 were measured. Intracellular NO and O2- levels were determined. 79 16 1Russian Medical Academy of Post-Graduate Education, Moscow, Activity of NALP3 inflammasome in EPCs was assessed by measuring 80 17 Russia; 2I.M. Sechenov First Moscow State Medical University, NALP3, ASC, caspase-1 and TXNIP expression. 81 18 Moscow, Russia; 3SM-Clinic, Moscow, Russia; and 4Out-patient Results: Compared with the untreated diabetic mice, wound clo- 82 19 sure and capillary densities were significantly increased in fenofibrate 83 department No. 51 branch 3, Moscow, Russia 20 Introduction: Proton pump inhibitors, which are widely used as treated group. Fenofibrate treatment restored EPCs function, and 84 21 increased NO production, decreased O - level in EPCs of diabetic 85 acid-inhibitory agents for the treatment of peptic ulcer, are mainly 2 mice. Furthermore, fenofibrate deregulated the activity of NALP3 22 metabolized by 2C19 isoenzyme of cytochrome P450 (CYP2C19). 86 inflammasome by reducing NALP3, ASC, caspase-1, TXNIP expres- 23 CYP2C19 has genetic polymorphisms, associated with extensive, 87 sion in EPCs of diabetic mice. In vitro, fenofibrate improved high 24 poor, intermediate or ultrarapid metabolism of proton pump inhibi- 88 glucose induced EPCs dysfunction and deregulated NALP3 inflam- 25 tors. Genetic polymorphism of CYP2C19 could be of clinical concern 89 masome activity. 26 in the treatment of peptic ulcer with proton pump inhibitors. 90 Conclusion: Fenofibrate could accelerate wound healing in diabetic 27 The aim of the study – to investigate the frequencies of 81 mice, which at least in part was mediated by improving the impaired 28 CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles and genotypes 92 EPCs function through deregulating NALP3 inflammasome activity. 29 in Russian patients with peptic ulcer. 93 30 Materials and Methods: The study involved 971 patients with peptic 94 31 ulcer from the European part of Russia (Moscow), 428 male (44%) 95 32 and 543 female (56%). The mean age was 44.6 ± 11.9 years (range Safe Use of Nsaids and Ras-Inhibitors In 96 33 15–88 y). DNA isolated from blood samples was used for the analysis Agogo, Ghana 97 34 of CYP2C19 genetic polymorphisms (CYP2C19*2, *3, *17 alleles) L. Meulendijks1; E. Adomako2; E. Appiah2; and C. Kramers1,3 98 35 by real-time polymerase chain reaction. 1Radboud University Nijmegen Medical Centre, Nijmegen, the 99 36 Results: Regarding CYP2C19 genotype, 317 patients (32.65%) out Netherlands; 2Agogo Presbyterian Hospital, Agogo Asante- 100 37 of 971 were CYP2C19*1/*1 carriers classified as extensive metabo- Akyem, Ghana; and 3Canisius Wilhelmina Ziekenhuis, Nijmegen, 101 38 lizers. Three hundred eighty-six (39.75%) with CYP2C19*1/*17 the Netherlands 102 39 or CYP2C19*17/*17 genotype were ultrarapid metabolizers. Two Background: Preventable adverse events of medication are an impor- 103 40 hundred fifty-one people (25.85%) were intermediate metabo- tant cause of hospital admissions in the developed world.1 NSAIDs 104 41 lizers with CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*1/*3, and - system (RAS-) inhibitors are drug groups 105 42 CYP2C19*3/*17 genotypes. Seventeen patients (1.75%) with which are frequently involved in these hospital admissions.2 Proper 106 43 CYP2C19*2/*2, CYP2C19*3/*3, CYP2C19*2/*3 genotypes biochemical monitoring or application of gastroprotective agents 107 44 were poor metabolizers. The allele frequencies were the following: (GPA) may prevent these adverse events. NSAIDs and RAS-inhibitors 108 45 CYP2C19*2 – 0.140, CYP2C19*3 – 0.006, CYP2C19*17 – 0.274. are also often used in Ghana. The purpose of this study is to assess 109 46 Conclusion: There is a high frequency of CYP2C19 genotypes associ- whether biochemical monitoring in patients on RAS-inhibitors, and 110 47 ated with modified response on proton pump inhibitors in Russian co-administration of gastroprotective medication in patients on 111 48 patients with peptic ulcer. Genotyping for CYP2C19 polymorphisms NSAIDs, is done properly in Ghana. 112 49 is suggested to be a useful tool for personalized dosing of proton Material and Methods: A retrospective cross-sectional study of 114 113 50 pump inhibitors. out- and inpatients who are on NSAIDs was carried out. The risk for 114 51 gastrointestinal side effects and the frequency of co-administration 115 52 of GPA was determined. A retrospective cross-sectional study of 301 116 53 117 Fenofibrate Improves the Impaired outpatients who are on RAS-inhibitors was carried out. The risk 54 for renal dysfunction and the frequencies of serum creatinine and 118 55 Endothelial Progenitor Cell Function 119 Through Deregulating Nalp3 potassium monitoring within one month after initiation of therapy 56 were determined. 120 57 Inflammasome Activity In Diabetic Mice 121 1 2 3 3 3 1 Results: Co-administration of GPA was done in 1.8% of all patients 58 Y.-P. Deng ; T. Zhao ; F. Huang ; M. Ni ; D.-J. Li ; G.-J. Jiang ; 122 and F.-M. Shen3 on NSAIDs. Serum creatinine and potassium monitoring within one 59 month after initiation of treatment with RAS-inhibitors were per- 123 1Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang, China; 60 formed in 6.3% and 3.7%, respectively. Risk factors were neither 124 2Second Military Medical University, Shanghai, China; and 61 associated with prescription of a GPA in patients on NSAIDs, nor in 125 3Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 62 performing biochemical monitoring in patients on RAS-inhibitors. 126 63 China 127 64 128

2015 e5 Clinical Therapeutics

1 Conclusions: Biochemical monitoring in patients on RAS-inhibitors Background: We recently reported that an antiplatelet drug clopi- 65

2 and use of GPAs in patients on NSAIDs is poorly performed in Ghana. dogrel, the P2Y12 receptor antagonist, increased gastric bleeding 66 3 Improving the already existing Ghanaian guidelines and encouraging induced by intraluminal perfusion with acidified low dose ASA in 67 4 their widespread use among prescribers should be pursued. the rat stomach. In the present study, we compared the effects of fre- 68 5 quently used anti-platelet drugs, such as clopidogrel, ticlopidine, and 69 6 cilostazol, on the gastric bleeding and ulcerogenic responses induced 70 7 References by intraluminal perfusion with 25 mM aspirin acidified with 25 mM 71 8 1. Budnitz DS, Lovegrove MC, et al. Emergency hospitalizations for HCl (acidified ASA) in rats. 72 9 adverse drug events in older Americans. N Engl J Med 2011;365: Materials and Methods: The stomach was perfused with acidified 73 10 2002–2012. ASA at a rate of 0.4 ml/min for 60 minutes under urethane anes- 74 11 2. Pirmohamed M, James S, et al. Adverse drug reactions as cause of thesia, and gastric bleeding was measured as the concentration of 75 12 admission to hospital: prospective analysis of 18.820 patients. BMJ hemoglobin in the luminal perfusate, which was collected every 15 76 13 2004 Jul 3;329(7456):15–19. min. Clopidogrel (10–100 mg/kg), ticlopidine (10-300 mg/kg), or 77 14 cilostazol (3–30 mg/kg) was given p.o. 24 hours or 90 minutes before 78 15 the perfusion of acidified ASA, respectively. 79 16 Effect of Amoxicillin/Clavulanate on the Results: Perfusion of the stomach with acidified ASA alone led to 80 17 Pharmacokinetics of Valproic Acid slight bleeding and lesions in the stomach. The pretreatment with 81 18 clopidogrel, even though it did not cause bleeding or damage by 82 S.Y. Lee1; J.A. Jung2; J.R. Kim1,2; W.S. Huh2; and J.W. Ko1,2 19 itself, dose-dependently increased the gastric bleeding and ulcerogenic 83 1Samsung Advanced Institute for Health Sciences and Technology, 20 responses induced by acidified ASA. Ticlopidine also aggravated the 84 Sungkyunkwan University, Seoul, Republic of Korea; and 21 severity of damage by increasing gastric bleeding, and the effects of 85 2Samsung Medical Center, Seoul, Republic of Korea 22 ticlopidine at 300 mg/kg were equivalent to those of clopidogrel at 86 Background: Valproic acid is used as a first line drug for general- 23 100 mg/kg. In contrast, cilostazol dose-dependently decreased gastric 87 ized tonic clonic seizures, absence seizures, myoclonic seizures, and 24 bleeding and damage in response to acidified ASA. 88 tonic and atonic seizures. A major metabolite of valproic acid is the 25 Conclusions: These results demonstrated that clopidogrel and 89 glucuronide conjugate which is hydrolyzed by -glucuronidase and 26 β ticlopidine, P2Y receptor inhibitors, increased gastric bleeding 90 undergoes enterohepatic circulation. Of note, the administration of 12 27 and ulcerogenic responses to acidified ASA, to the same extent, 81 amoxicillin/clavulanate led to a decrease of -glucuronidase-produc- 28 β while cilostazole, a phosphodiesterase III inhibitor, suppressed these 92 ing bacteria, indicating interruption of the enterohepatic circulation. 29 responses. Therefore, cilostazol may be safely used in dual anti- 93 It can ultimately result in failure to control concentration levels of 30 platelet therapy combined with ASA, without increasing the risk of 94 valproic acid. To maintain concentrations within a narrow therapeu- 31 gastric bleeding. 95 tic range is important, because epileptic patients who failed to control 32 96 seizure can be fatal. The aim of this study was to evaluate the effect 33 97 of amoxicillin/clavulanate on the pharmacokinetics of valproic acid. 34 98 Methods: This was an open-label, 2-period, 1-sequence study in 16 Investigation on Circadian and age- 35 99 healthy volunteers. In period 1, subjects received a single dose of Dependent Variations In Cyclosporine 36 100 valproic acid 500 mg (treatment V). In period 2, multiple doses of (Csa) Concentration Distributions In 37 101 amoxicillin/clavulanate 500/125 mg were administered 3 times daily Liver Transplant Patients 38 102 for 7 days, and then the single dose of valproic acid was administered I. Atanasova; L. Spasov; and D. Terziivanov 39 103 (treatment A V). Serial blood samples were collected up to 48 hours. University Hospital “Lozenetz”, Med Fac, SU “St. Kliment 40 + 104 The pharmacokinetic parameters were calculated by noncompart- Ohridski”, Sofia, Bulgaria 41 105 mental methods. A comparative population pharmacokinetic analysis was per- 42 106 Results: Systemic exposure and peak concentration of valproic acid formed on CsA concentrations, “as withdrawn” in clinical setting, 43 107 were slightly decreased in treatment A V compared with treatment V from a learning group of liver transplant patients. Twenty patients 44 + 108 (AUC , 863.1 vs. 903.1 h·mg/L; C , 52.5 vs. 53.3 mg/L). The par- (8 adults and 12 children) who were on Neoral® post-ortothopic 45 last max 109 tial AUC from 6 to 24 hours (AUC )—an estimate of enterohepatic liver transplantation over 2004 to 2009 were studied. All patients 46 6-24h 110 circulation— was also slightly decreased in treatment A V (AUC , received Neoral® twice daily orally at 08:00 AM and at 08:00 PM. 47 + 6-24h 111 703.1 vs. 750.4 h/mg/L). There were no significant between-treat- Whole blood CsA concentrations were measured by FPIA (Abbott 48 112 ment effects on the pharmacokinetics with respect to geometric least Diagnostics). C0 drug concentrations were recorded in morning 49 113 squares mean ratios (95% CI) of AUC , AUC , and C (95.7 (C0AM) and in evening before each dosing (C0PM) and C2 concen- 50 last 6-24h max 114 [93.2–98.2], 94.6 [91.2–98.1], and 98.3 [94.8–102.0], respectively). trations - in morning and in evening 2 hours post-dosing (C2AM and 51 115 Conclusions: There were no significant effects on the pharmacokinet- C2PM). A total of 323 CsA C0 in children group and 242 C0 in adult 52 116 ics of valproic acid following multiple doses of amoxicillin/clavula- group and a set of 117 CsA C2 in children group and a set of 133 C2 53 117 nate, thereby no dose adjustment is necessary. in adult group were analyzed. Population pharmacokinetic analysis 54 was performed with dose normalized to 1mg/kg cyclosporine con- 118 55 centrations in order to avoid body weight (BW) differences between 119 56 the 2 age groups. No circadian differences in drug concentrations in 120 57 Comparative Effects of The Anti-Platelet 121 Drugs, Clopidogrel, Ticropidine, and both populations were observed. All drug concentration distributions 58 were skewed to the right. The measures of central tendency showed 122 59 Cilostazol, On Aspirin- Induced Gastric 123 Bleeding and Damage In Rats statistically significant higher estimates for adult group. Normalized 60 CsA C0 at Day 2 after liver transplantation in adult patients cor- 124 61 K. Takeuchi1,2; S. Takayama1; and C. Izuhara1 125 related significantly with measured Scr levels (r= 0.62, P = 0.031). 62 1Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan; and 126 2 The findings can’t be explained by body weight between group’s dif- 63 General Incorporated Association, Kyoto Research Center for ferences since normalized cyclosporine concentrations were used. We 127 64 Gastrointestinal Diseases, Kyoto, Japan 128

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1 expect that age-related nongenomic factors, controlling cyclosporine Background: Administration of oral medication to patients with 65 2 metabolism and distribution, could be a plausible reason. enteral feeding tube (EFT) is challenging. Contrary to the hospital 66 3 setting, medication administration via EFT has been poorly investi- 67 4 gated in residential care facilities (RCFs) for individuals with intel- 68 5 The Therapeutic Communication In lectual disability (ID). 69 6 Framework of Patient’s Informing On Objective: To collect observational data on drug administration 70 7 Rational Drug Use practices, to identify barriers for following guidelines, and to map 71 8 A.U. Dzhakubekova staff members’ knowledge on medication administration via EFT. 72 9 I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek, Kyrgyz Method: The observational study was conducted in 6 Belgian RCFs 73 10 Republic for individuals with ID. Observations of medication preparation and 74 11 Background: Irrational use of medicines is a major problem world- administration through EFT were carried out in 2 randomly selected 75 12 wide. One of most impotent factors is the low compliance of patients units per RCF, on two days per unit, using direct observation method. 76 13 to prescribed drugs (WHO, 2003). One of the most commonly advo- Afterwards, recorded observations were compared with international 77 14 cated ways to enhance compliance is the improvement of the doctor- guidelines. Barriers were identified during a focus group study with 78 15 patient relationship. Therefore, we carried out an analysis of the staff members that administer medication via EFT, using vignettes to 79 16 research literature in this aspect. guide discussion. Thematic analysis was performed. Knowledge was 80 17 Material and Methods: Comprehensive literature searches were tested using a self-administered questionnaire. 81 18 undertaken through Medline, Embase, Cochrane Collaboration Results: In total, 862 drug preparations and 268 drug adminis- 82 19 Library from 1990. The following keywords were used: rational trations in 48 residents with EFT were observed. Mixing together 83 20 drug use, patient compliance, adherence, therapeutic communica- multiple drugs, not shaking suspensions/emulsions, and not flushing 84 21 tion, pharmacotherapy, drug therapy, physician-patient relationship the EFT with at least 15 mL water were the most common devia- 85 22 and patient expectations. The topics of interest were: the extent of tions from guidelines. We also observed high variability in working 86 23 compliance, variables that influence compliance and rational drug methods, even between staff members of the same unit. Barriers to 87 24 use; intervention strategies to improve patient compliance; informing following guidelines emerging from the four focus group interviews 88 25 of patients to improve compliance and rational drug use; communica- were: time constraints, lack of medication-related knowledge, clear 89 26 tion in physician–patient relationship. administration instructions, and necessary materials. In the knowl- 90 27 Results: Rational drug use process requires adequate drug informa- edge questionnaire, RCF staff members obtained an average score of 81 28 tion to provide high level of compliance. In this connection, drug 44% (SD14%), with medication preparation guidelines being least 92 29 information must be objective, accurate, complete, up-to-date, acces- known. 93 30 sible and serviceable. Consequently the success of drug therapy is Conclusion: Current guidelines on medication preparation and 94 31 directly dependent on the skills and abilities of the physician in aspect administration through EFT are insufficiently known and imple- 95 32 of adequate informing of patient about the rational drug use. At mented in RCFs for individuals with ID. A number of barriers to 96 33 the same time, it is of vital importance that the patient and doctor guideline adherence were identified. Based on these findings, an edu- 97 34 have good communications. Therefore the study of the therapeutic cational intervention can be set up in order to optimize care for this 98 35 communication in physician-patient relationship in informing on the vulnerable patient population. 99 36 rational drug use is priority direction. It has been suggested that 100 37 training patients, as well as doctors, in communication skills may be 101 38 a cost-effective way to increase compliance and improve the overall Storage and Disposal of Unused 102 39 health of patients. Medications: Knowledge, Behavior, and 103 40 Conclusions: In the world and Kyrgyz Republic the concept of Attitudes Among Serbian People 104 41 105 therapeutic communication is not developed in framework of M. Paut Kusturica; A. Tomas; O. Horvat; Z. Tomić ; and A. Sabo 42 physician-patient relationship on rational drug use. So there is no Faculty of Medicine, Novi Sad, Serbia 106 43 evidence-based approach to a conceptual decision of this problem; Background: Improper disposal of medications potentially poses a 107 44 there is no state support in terms of guaranteed getting of sufficient significant environmental risk and storage of expired and unused 108 45 information and availability of informational materials; there is not medications in households provides an increased risk of accidental 109 46 defined any significant practical steps in healthcare on good inform- childhood poisonings. The objective of this study was to investigate 110 47 ing of patients on the rational drug. In this regard, it is necessary i) to the storage and disposal habits of medications amongst the popula- 111 48 introduce the subject of therapeutic communication at undergradu- tion in the South Backa District of Serbia, and to gain insight into the 112 49 ate and postgraduate level of doctors training; ii) to examine the attitudes and knowledge of the population about the proper disposal 113 50 state of therapeutic communication in physician-patient relationship of medications. 114 51 on rational drug use in Kyrgyz Republic, to identify priority areas Material and Methods: The study was conducted during the 6-month 115 52 for improvement of patient compliance and to develop standards of period from February 2010 to July 2010 and involved a random sam- 116 53 qualitative advisory support of drug therapy. ple of households. The questionnaire-based study was performed by 117 54 a trained interviewer. 118 55 Results: Of 230 families, 208 (108 urban and 100 rural) agreed to 119 56 120 Drug Administration Via Enteral Feeding participate and complete the questionnaire (90 % response rate). 57 Drugs were mostly kept in a specific place-home pharmacy (89.8 121 58 Tube In Residential Care Facilities for 122 Individuals With Intellectual Disability % [urban] and 89.0 % [rural]). Exposure of children to medica- 59 tions in the home environment was similar in urban and rural fami- 123 E. Joos1; E. Mehuys1; J. Van Bocxlaer1; J.P. Remon1; 60 lies (19.6 % [urban] and 23.1 % [rural]). The frequency of expired 124 M. Van Winckel2; and K. Boussery1 61 medications was not observed to be different between the urban and 125 1Ghent University; and 2Ghent University Hospital, Ghent, 62 rural households (10.3 % [urban] and 11.8 % [rural]). The most 126 63 Belgium 127 64 128

2015 e7 Clinical Therapeutics

1 common method for disposal of household medications is disposal guide clinical decision making for seizure prophylaxis and manage- 65 2 in the garbage (85.6 % [urban] and 74.5 % [rural]) or in the toilet ment. The primary objective was to characterize and evaluate anti- 66 3 (8.7 % [urban] and 6.4 % [rural]). However, inconsistent with dis- epileptic drug use for cancer patients in Qatar, secondary objective 67 4 posal practices, half of the urban and rural participants thought that to determine predicting factors for failure of prophylactic regimens. 68 5 throwing medications in the garbage, toilet, or sink has a detrimental Methods: The study was designed as a retrospective electronic 69 6 effect on the environment. healthcare record review from June 1, 2012 through June 1, 2014 70 7 Conclusions: Public services in Serbia, including government and of patients receiving at least 1 anti-epileptic agent (carbamazepine, 71 8 health sectors, need to be more proactive about educating people oxcarbazepine, lamotrigine, levetiracetam, phenytoin, valproic acid) 72 9 on how to store and dispose medications, as well as finding a way with a cancer diagnosis using hospital pharmacy records, the follow- 73 10 for implementation of the law on medications wastage destruction. ing data were extracted: demographics, cancer type, presence and 74 11 location of metastases, history of seizure disorders (on admission or 75 12 in hospital), and anti-epileptic drug regimens. Multivariate logistic 76 13 Knowledge About Stroke and Awarness regression was used to assess these characteristics as predictive factors 77 14 of Its Signals Among Hypertensive for failure of prophylactic regimens. 78 15 Patients Without Prior History of Stroke Results: A total of 58 patients met inclusion for the study. A total of 79 16 P. Juraporn1; and A. Ampai2 28% had glioma with 43% of all patients having brain metastases. 80 17 1Thammasat University, Pathumtani, Thailand; and 2Banpru Levetiracetam and phenytoin were the most commonly used anti-epi- 81 18 Health Care Centre, Songkhla, Thailand leptic drugs (43% and 37%, respectively). The use of levetiracetam 82 19 Background: Stroke is a disabling disease. Prompt recognition of was significantly associated with a lower risk of seizures (odds ratio, 83 20 potential stroke signs and symptoms could increase a chance to 0.15; 95%, CI 0.03–0.76; P = 0.02). No other factor was deemed 84 21 receive appropriate medical managements, thus reducing permanent significant (including glioma and/or brain metastases). 85 22 disability and death. The study surveyed knowledge about stroke Conclusion: This study found that seizures occur commonly in 86 23 as well as awareness of it signals in hypertensive patients without patients with cancer in Qatar, even while taking antiepileptic agents. 87 24 history of stroke. Levetiracetam and phenytoin were the most commonly used agents, 88 25 Material and Methods: The study is cross-sectional and conducted which is in-line with current practice guidelines. However, only the 89 26 in hypertensive patients who received care at a local primary health use of levetiracetam was associated with a lower risk of seizure devel- 90 27 care unit. The patients were chosen by convenient sampling. Only opment. Future prospective studies are needed to optimize care of 81 28 patients without prior history of stroke determined from medical these patients. 92 29 93 records as well as direct patient questioning were included (N = 30 100). The structure questionnaire was used for patient interview. 94 31 Knowledge about stroke covered risk factors, clinical outcomes, and Drug-Induced Nephrotoxicity: A Frequent 95 32 self care once having stroke. Sources of the information was queried. Cause of Hospitalization In Nephrology 96 33 Awareness of signs and symptoms of stroke was also assessed. A. Rey1; M. Berrué1; T. Chambaraud1,2; J.-P. Rerolle1; J. Allard1; 97 34 Results: Of the patients studied, ages were 64 ± 11.4 years, with M. Essig1,2,3; and C. Monchaud1,3 98 35 female being 65%. Almost a half had concurrently either diabetes 1CHU Limoges, Limoges, France; 2Univ Limoges, Limoges, 99 36 mellitus, dyslipidemia, or coronary heart disease; 72% and 68% France; and 3INSERM, France 100 37 denied drinking alcohol and smoking, respectively. Average systolic Introduction: Drug-induced nephrotoxicity (DIN) is involved in 101 38 blood pressure in the past 6 months was greater than 140 mmHg in 20% of acute renal failures, and many cases could be avoided. The 102 39 almost half of the patients. Eleven patients never heard of stroke. purpose of this project was to study DIN in a nephrology setting. 103 40 Among those who knew, 44% could describe at least one signal of Material and Methods: This study was based on an extraction of 104 41 stroke, with limb weakness being the most recognized sign (34.8%). hospital stays in the nephrology department of Limoges University 105 42 Sixty percent would see doctor immediately. Forty percent identified Hospital between May 1, 2013 and May 31, 2014 from the 106 43 hypertension as a risk factor. Majority were aware of end outcomes Medicalized Information System Program. Identification of DIN 107 44 of stroke, and 13.5% received information about stroke from health cases was performed using the extracted database and medical 108 45 care professionals. records. Demographic and clinical data were collected from the 109 46 Conclusions: Over a half of the hypertensive patients who have not medical charts. A descriptive statistical analysis was followed by 110 47 111 yet had stroke in this study were not fully aware of potential signs comparative statistical analyses based on Student t-test and χ 2 test, 48 112 and symptoms of stroke, although a significant number knew its with a level of significance of P < 0.05. 49 consequences. There is a gap as an information provider of health Results: Overall, 72 cases of DIN among 790 hospital stays were 113 50 care professionals. identified. No significant difference was evidenced between patients 114 51 with and patients without DIN on age (69 ± 14 vs. 66 ± 16 y), sex 115 52 (67% vs. 57% males), and length of stay (12 ± 15 vs. 10 ± 11 days). 116 53 The proportion of DIN was significantly lower in renal transplant 117 54 Determination of Predictive Factors 118 Associated With Poor Seizure Control In vs. nontransplant patients (4.3% vs. 10%, RR = 0.42, P = 0.019). 55 Forty four DIN cases (61%) occurred in an outpatient setting. There 119 56 Cancer Patients 120 1 2 was at least one aggravating factor in 46 cases (64%). Drugs involved 57 S. Elazzazy ; and K. Wilby 121 1 were mainly: NSAIDs (54% cases), diuretics (39%), anti-hyperten- 58 National Center of Cancer Care and Research (NCCCR), HMC; 122 and 2College of Pharmacy, Qatar University sive drugs (32%) in outpatients; antibiotics (45% cases), diuretics 59 (34%), anticancer drugs (23%) in inpatients. The drug was stopped 123 Background: Cancer is a leading cause of death worldwide and is 60 in 58 cases, and dialysis was necessary in 10 cases. Basal renal func- 124 associated with many complications that place significant burdens 61 tion was not recovered in 17 cases. 125 on patients, caregivers, and healthcare systems. Seizures, a highly 62 Conclusions: DIN was observed in 9% of hospital stays in nephrol- 126 debilitating neurological complication, occur in cancer patients with 63 ogy. Renal transplantation seemed to be a “protecting” factor against 127 64 primary brain cancer and also brain metastases; little data exists to 128

e8 Volume XX Number XX Epidemiological Profile of BenzodiazepineP oisonings In Uruguay

1 DIN, probably because patients are closely monitored by their neph- benign, the negative result in occult blood with urinary dipstick tests 65 2 rologist. The majority of DIN cases occurred in an outpatient setting, is often required in clinical trial settings. Therefore, we investigated 66 3 in patients with comorbidities, suggesting an underestimation of the the relationship between the results of urinary occult blood tests, 67 4 risk of DIN in outpatients. presence of red blood cells (RBC) in urinary sediment, and the renal 68 5 functions in 3 different age groups of both male and female healthy 69 6 volunteers in order to support the interpretation of test results in 70 7 Future Opportunities for Cerebrospinal clinical trials. 71 8 Fluid (Csf) Assessment In The Clinical Materials and Methods: We collected and evaluated the data of 72 9 Trials- Sampling of Csf In Healthy 10,862 healthy Japanese volunteers from the screening tests of clini- 73 10 Japanese Elderly Volunteers cal trials conducted at our clinical research center from April 2010 to 74 11 K. Sakamoto1; S. Matsuki1; E. Chung2; M. Deguchi1; K. Furusho1; June 2013. The data was then analyzed from the results of a urinary 75 12 R. Hanada3; K. Matsuguma1; M. Kimura1; and Y. Sakata2 dipstick test, microscopic urinary sediment tests, BUN, creatinine, 76 13 1Sugioka Memorial Hospital, Souseikai Global Clinical Research as well as eGFR in three male and three female groups as follows: 77 14 Center, Fukuoka, Japan; 2Hakata Clinic, Souseikai Global three age groups (young: aged, 20–44 y; Middle-age: aged, 45–64 78 15 Clinical Research Center, Fukuoka, Japan; and 3Sumida Hospital, y, elderly; aged: 65 y and older ). Any data with the positive urine 79 16 Souseikai Global Clinical Research Center, Tokyo, Japan protein test was excluded. 80 17 Background: Cerebrospinal fluid (CSF) evaluation helps us to under- Results: Female elderly group had the highest percentage (35%) of 81 18 stand the CNS penetration, PK characteristics, as well as the PK/ positive results (±or severer) in occult blood tests among 6 groups. In 82 19 PD relations of investigational drugs. It also gives us lots of intra- the cases of higher than 2+ occult blood in urinary dipstick tests, RBC 83 20 neuronal information, especially in the areas of psychiatry and neu- counts in the urinary sediment increased significantly. However, other 84 21 rology. Therefore, sampling of CSF became a common procedure in than the RBC counts, no changes were observed in urinary sediment 85 22 healthy subjects in a broad range of CNS drug development as part tests. No relationships between the positive occult blood in urinary 86 23 of phase 1 clinical studies worldwide. However, in contrast to the fact dipstick tests and renal function were observed. 87 24 that clinical studies on neurological disorders of elderly people have Conclusion: When the results of occult blood are ± or ＋ in urinary 88 25 risen considerably, CSF sampling had been limited to only patients dipstick tests, it is useful to consider an integrative assessment in 89 26 in Japan. order to avoid selection bias, especially in the clinical trials of healthy 90 27 Material and Methods: For the first time in Japan, we conducted a female volunteers aged 45 and older. 81 28 clinical trial involving CSF sampling by lumbar puncture in cogni- 92 29 tively and physically healthy Japanese elderly volunteers. Thirty-two 93 30 healthy elderly female and male volunteers (age, 55–71 y) from our Modifications In Heart Resistance Vessels 94 31 panel participated in this study after given a thorough explanation To Angiotensin Ii In Isolated Perfused 95 32 about the procedure. We also performed a survey about the CSF Heart of Hypertensive Rats Treatment 96 33 sampling on healthy elderly people in order to evaluate the possibility Whit Hyperbaric Oxygen 97 34 of future clinical studies with CSF assessment in Japan. E. López1; G. Guevara1; I. Ramírez1; E. Hong2; and M.C. Castillo1 98 35 Results: CSF sampling by lumbar puncture in healthy Japanese 1Escuela superior de medicina, IPN México DF; and 2Centro de 99 36 elderly volunteers was completed without any serious adverse events. Investigaciones Avanzadas, IPN México DF 100 37 We found that the total protein level in CSF was higher in elderly Introduction: High blood pressure (HBP) is a disease with high mor- 101 38 volunteers than the reference level for adults. On the other hand, the bidity worldwide and is considered one of the main etiological factors 102 39 survey results show that more than two thirds of the healthy Japanese of cardiac pathologies. One of the regulatory mechanisms of blood 103 40 elderly people are willing to undertake lumbar puncture for clinical pressure is the Renin Angiotensin System. Nevertheless and despite 104 41 studies in the future. treatment, the occurrence of hypertension changes in cardiac physiol- 105 42 Conclusion: As we anticipate that the markets for both drug devel- ogy and complications remains. It is therefore necessary to consider 106 43 opment and drug consumption in elderly people will continue to adjuvant therapy. One therapy that has been shown clinically to 107 44 grow, it is necessary to consider the establishment of reference values improve of patients with HBP is hyperbaric oxygenation (HBO). 108 45 for healthy elderly regarding CSF. Our results indicate that the CSF The aim of this study is to examine the role of Angiotensin II (Ang 109 46 sampling in healthy elderly volunteers can be successfully conducted II) in resistance vessels of the heart, and in aorta in hypertensive rats 110 47 in Japan to meet global needs. treatment by HBO. 111 48 Methodology: We used rats Wystar in standard conditions, creating 112 49 three groups: healthy, untreated hypertensive, and hypertensive treat- 113 50 ment. Hypertension were induced by a Page method, at the eighth day 114 51 Urinary Occult Blood Tests In Healthy 115 Male and Female Volunteers From Three began therapy OHB, for 20 sessions. At the end of treatment heart 52 and aortas, this was mounted on isolated organ system, and it was 116 53 Different Age Groups 117 1 2 3 4 1 stimulating to logarithmic doses of Ang II. 54 M. Yono ; S. Matsuki ; E. Chung ; A. Mugitani ; T. Tanaka ; 118 4 4 4 Results: We obtained diastolic pressure consistent with hyperten- 55 S. Kan ; T. Chiyoda ; and Y. Kaji 119 1 sion at the eighth day. In coronary arteries, the HBP group without 56 Nishikumamoto Hospital, Souseikai Global Clinical Research 120 2 treatment showed an increase in vascular reactivity; whereas the 57 Center, Kumamoto, Japan; Sugioka Memorial Hospital, Souseikai 121 3 hypertensive group treatment no presented changes. 58 Global Clinical Research Center, Fukuoka, Japan; Hakata Clinic, 122 Souseikai Global Clinical Research Center, Fukuoka, Japan; and The contractile response in thoracic and abdominal aorta was 59 lower in the HBP rats treated with HBO than control. 123 4Sumida Hospital, Souseikai Global Clinical Research Center, 60 Conclusion: This results suggests that HBO therapy could be used in 124 Tokyo, Japan 61 hypertensive patients to reduce the mechanism of renin angiotensin 125 Background: Urinary occult blood without any symptoms is known 62 system improved the life quality. 126 63 to increase with aging, especially in women. While in many cases it is 127 64 128

2015 e9 Clinical Therapeutics

1 Safety of Lisdexamfetamine: A Results: During study period, a total of 4836 plasma concentrations 65 2 Retrospective Cohort Study of LTG were measured in 786 pediatric patients aged 5 months to 66 3 M.V. Hansen1; L. Darling2; and H. Holst1 16 years. The prevalence of TDM markedly increased from 29.0% 67 4 1Bispebjerg Hospital, Copenhagen, Denmark; and 2Glostrup in 2009 to 94.6% in 2014. Also, there was significant change in the 68 5 Hospital, Copenhagen, Denmark target concentration range of LTG (median concentration; 2.46 μ g/ 69 6 Background: Attention-deficit hyperactivity disorder is a common mL in 2009 vs. 5.10 μ g/mL in 2014). The median CD ratios of LTG 70 7 neurobehavioural disorder in children. Pharmacotherapy plays a in group I, II, III, and IV were 1.10, 2.62, 0.56, and 1.31. VPA mark- 71 8 main role in the multimodal treatment plan, albeit adverse effects edly elevated CD ratio in a concentration-dependent manner. Among 72 9 are a concern. Lisdexamfetamine (LDX) is a newer pharmacological the inducers (group II), patients taking phenytoin had a significantly 73 10 option and post-marketing studies on adverse events are limited. We lower CD ratio than patients taking phenobarbital or carbamazepine 74 11 aimed to investigate the treatment-emergent adverse events (TEAEs) (P < 0.001). The effect of VPA and inducers was unchanged regard- 75 12 in a clinical setting. less of the patient’s age, but infants had a higher CD ratio. 76 13 Material and Methods: Retrospective cohort study at one Conclusions: Our findings suggest clinical utility of TDM for LTG 77 14 Department of Child and Adolescent Psychiatry in Copenhagen, and can be used to estimate the inducing or inhibiting effects of 78 15 Denmark including all consecutive patients > 6 years old with an concomitant AEDs. 79 16 ICD-10 diagnosis of ADHD who were initiated on LDX between 80 17 May 2013 and July 2014. TEAEs were assessed by a clinician and a 81 18 subsequent chart audit. Post-Approval Withdrawal of Medicines 82 19 Results: Forty-three patients (91% male) with a median age of 11 Because of Adverse Drug Reactions: 83 20 (range 8–15) were included. Patients received LDX for a median of A Systematic Review 84 21 188 days (range 3–433). In total, 23.3% of the patients discontin- I.J. Onakpoya; C.J. Heneghan; and J.K. Aronson 85 22 ued treatment due to a TEAE. Eighty-eight percent of the patients University of Oxford, Oxford, United Kingdom 86 23 experienced at least one TEAE and the time to first TEAE was within Introduction: Medicinal products may be withdrawn after regulatory 87 24 the first 4 weeks of treatment in 83.8% of the patients. Compared to approval when the benefit-to-harm balance is negative. Withdrawal 88 25 the TEAEs previously experienced by the individual patient on other of medicinal products can be controversial, especially when the link 89 26 ADHD medication, 39.5% of the TEAEs were new. The most com- between the drug and the associated harm is not established. We have 90 27 mon TEAEs (≥ 5%) were decreased appetite, difficulty falling asleep, identified medicinal products that have been withdrawn because of 81 28 tics, stomach ache and weight loss. A subjectively assessed good, or adverse drug reactions after regulatory approval, examined the evi- 92 29 good but time-limited effect was observed in 62.7% of the patients. dence used to support such withdrawals, and explored the pattern 93 30 Conclusions: Treatment with LDX in non-stimulant-naïve patients of withdrawals across countries. 94 31 was tolerable and the types of adverse events were consistent with Methods: We searched PubMed, GoogleScholar, the WHO’s data- 95 32 findings in previous clinical trials. However, both the number of base of drugs, the websites of drug regulatory authorities, and text- 96 33 patients experiencing TEAEs and the rates of discontinuation due to books. We also hand searched references in retrieved documents. We 97 34 TEAEs were substantially higher than previously reported in clinical included medicinal products that were withdrawn between 1950 and 98 35 trials. Furthermore, more than one third of the TEAEs were new for 2014. We assessed the level of evidence used for making withdrawal 99 36 the individual patient compared to those previously experienced on decisions using the criteria of the Oxford Centre for Evidence Based 100 37 other ADHD medication. Medicine. 101 38 Results: We identified 428 medicinal products that were withdrawn 102 39 between 1953 and 2011; 42 were withdrawn worldwide and 232 were 103 40 Therapeutic Drug Monitoring of withdrawn in two or more countries. The evidence used for withdrawal 104 41 Lamotrigine In Pediatric Epilepsy Patients in over 70% of cases consisted of anecdotal reports. In 106 cases 105 42 106 Y. Yamamoto1,2; Y. Takahashi1,2; K. Imai1; Y. Inoue1; and (25%), deaths were reported as one of the reasons for withdrawal. 43 107 Y. Kagawa2 Hepatotoxicity was the most common reason attributed. Withdrawals 44 108 1National Epilepsy Center, Shizuoka Institute of Epilepsy and were significantly less likely in African countries than in Europe (P < 45 109 Neurological Disorders, Shizuoka, Japan; and 2Graduate School 0.0001). The intervals between the first reports and first withdrawals 46 110 of Pharmaceutical Sciences University of Shizuoka, Shizuoka, were shorter when the adverse reactions involved children. The interval 47 111 Japan between the first report of the adverse reaction and the year of the first 48 112 Background: Lamotrigine (LTG) is a new antiepileptic drug (AED) withdrawal has not consistently shortened over time. 49 113 that was approved in Japan in 2008. The purpose of this study was Conclusion: There are discrepancies in the patterns of withdrawal 50 114 to evaluate clinical utility of therapeutic drug monitoring (TDM) for of medicinal products from the market when adverse reactions are 51 115 LTG and the influence of concomitant antiepileptic drugs on plasma suspected. Withdrawals are significantly less likely in low- to mid- 52 116 LTG concentration in pediatric patients. dle-income countries. Greater co-ordination among drug regulatory 53 117 Material and Methods: We retrospectively reviewed routine TDM authorities and increased transparency in the reporting of suspected 54 118 data during 2009 to 2014 and calculated the prevalence of TDM adverse drug reactions would help improve the current flaws in deci- 55 119 and the therapeutic range for each year. Measurement samples were sion making processes. 56 120 grouped whether patients received valproic acid (VPA) or the hepatic 57 121 enzymes inducers, such as phenytoin, carbamazepine, phenobarbital; 58 122 LTG (group I), LTG VPA (group II), LTG inducers (group III), or 59 + + Relability of Animal Models In Biomedical 123 LTG VPA inducers (group IV). We calculated the concentration 60 + + Research: A Word of Caution 124 to dose ratio (CD ratio ( g/ml/mg/kg)) of LTG and compared these 61 μ D.K. Rohra 125 groups. The study protocol was approved by the ethical committee 62 Department of Pharmacology, College of Medicine, Alfaisal 126 of our hospital. 63 University, Riyadh, Saudi Arabia 127 64 128

e10 Volume XX Number XX Epidemiological Profile of BenzodiazepineP oisonings In Uruguay

1 Man had purely relied on observation to study complex physiologic changes between the groups (P < 0.005). Quantitative PCR analysis 65 2 principles for long with hardly any intervention possible. But ever of both the training and validation sets confirmed that mRNA levels 66 3 since scientists started using animal models as human replicas, it has of multidrug and toxin extrusion protein 1 (MATE1 or SLC47A1; 67 4 been possible to employ a lot of interventional and experimental encoded by 1 of the 11 genes) were significantly lower in patients with 68 5 strategies. Spontaneously hypertensive rat (SHR) is considered as FILI. A small experiment in mice (3 per group) showed that Mate1 69 6 one of the best and most widely used models of human hypertension. knockout mice had the elevated serum concentration of 4-nitro-3- 70 7 We have shown that acidosis induces a contraction in aortas from (trifluoromethyl) phenylamine, a major metabolite of flutamide, at 2 71 8 SHR and normotensive Wistar-Kyoto (WKY) rats. Since acidosis h after administration of the drug, suggesting that Mate1 could affect 72 9 is not an uncommon condition in the setting of diabetes mellitus the pharmacokinetics of flutamide. 73 10 and chronic renal failure, which are often co-morbid with hyper- Conclusions: The MATE1 mRNA level in peripheral blood is a pos- 74 11 tension, this change in the behavior of arterial contractility was of sible negative predictive biomarker of FILI. 75 12 immense interest. These findings in rodent animal model compelled 76 13 us to investigate further the underlying mechanisms and the intracel- 77 14 lular signaling pathways involved in contraction. However, much to : anti-Diabetic Effect 78 15 our surprise, when the similar experiments were repeated on human Mediated By Anti- Oxidant/Inflammatory/ 79 16 (both normotensive as well as hypertensive) internal mammary artery, Apoptotic Effects And Improvement of 80 17 acidosis caused relaxation of vessels. Although SHR is a valuable Insulin And Wnt/β-Catenin Signaling 81 18 model of hypertension, its findings were not reproducible in humans. Pathways 82 19 Personal experience and review of literature shows lot of discrepan- H.S. El-Abhar1; M.A. Ali2; M.A. Kamel3; and A.S. Attia1 83 20 cies between the data generated from humans and animals. However, 1Faculty of Pharmacy, Cairo University, Cairo, Egypt; 2Faculty 84 21 it is a usual practice that the results obtained from animal models of Pharmacy and Drug Manufacturing, Pharos University, 85 22 are extrapolated on humans. In this presentation, this issue will be Alexandria, Egypt; and 3Medical Research Institute, Alexandria 86 23 focused, that while animal models are essential for the research and University, Alexandria, Egypt 87 24 development, a critical caution needs to be practiced in interpreting Background: The cholinergic anti-inflammatory pathway is one of 88 25 the results. Uncritical reliance on the results of animal experimenta- the putative biochemical pathways that link diabetes with Alzheimer 89 26 tion can be dangerously misleading and has resulted in damages to disease. Hence, here we aimed to verify the potential antidiabetic 90 27 human health in several cases. This presentation will also discuss the effect and to unveil the possible mechanisms of galantamine, a 81 28 role of certain confounding factors in using animal models. clinically approved acetylcholinesterase (AChE) inhibitor used in 92 29 Alzheimer disease. Additionally, we evaluated its effect as an add-on 93 30 therapy with vildagliptin. 94 31 Association of Decreased Mrna Material and Methods: The neonatal streptozotocin (n5-STZ) rat 95 32 Expression of Multidrug And Toxin model was adopted and the diabetic animals were treated with gal- 96 33 Extrusion Protein 1 In Peripheral Blood antamine (2.5, 5, 10 mg/kg), vildagliptin (5,10, 30 mg/kg) or both 97 34 Cells With The Development Of Flutamide- (5 and 10 mg/kg, respectively) for 4 weeks. 98 35 Induced Liver Injury Results: Galantamine leveled off the n5-STZ-induced elevation in 99 36 K. Nakano1; H. Ando1; S. Kurokawa1; K. Hosohata1; body weight, food intake, and serum levels of glucose, fructosa- 100 37 K. Ushijima1; M. Takada2; M. Tateishi2; A. Yonezawa3; mine, ALT/AST, and the lipid profile (triglycerides, cholesterol, 101 38 K. Matsubara3; S. Masuda4; K. Inui5; T. Morita1; and A. Fujimura1 free fatty acids) assessed in serum, liver, and muscle. Besides, it 102 39 1 2 103 Jichi Medical University, Shimotsuke, Tochigi, Japan; Nagasaki increased the insulin level, HDL-C and % α -cell function, in a 40 International University, Nagasaki, Nagasaki, Japan; 3Kyoto pattern similar to that of vildagliptin. Additionally, galantamine 104 41 University, Kyoto, Kyoto, Japan; 4Kyushu University, Fukuoka, confirmed its antioxidant (nuclear factor-erythroid-2-related factor 105 42 Fukuoka, Japan; and 5Kyoto Pharmaceutical University, Kyoto, 2, total antioxidant capacity, lipid peroxide), anti-inflammatory 106 43 107 Kyoto, Japan (NF-κ B, TNF-α ) and anti-apoptotic (caspase-3 and cytochrome c) 44 Introduction: The ant-prostate cancer drug flutamide occasionally capabilities by altering the n5-STZ effect on all of the aforemen- 108 45 causes hepatotoxicity, and some predictive biomarkers of flutamide- tioned parameters. Galantamine mediated its effect via improv- 109 46 induced liver injury (FILI) are needed to improve a safety of the drug. ing the insulin (phosphorylated insulin receptor, p-AKT, GLUT4, 110 47 111 The aim of this prospective study was to identify such a biomarker by GLUT2) and the Wnt/α -catenin (p-GSK-3α , α -catenin) signaling 48 analyzing peripheral blood samples from patients before flutamide pathways. Galantamine, as expected, lowered dose dependently 112 49 therapy. the n5-STZ-induced activation of AChE in brain, muscle and liver; 113 50 Material and Methods: Blood samples were obtained from 52 nevertheless, the vildagliptin effect was limited to the brain enzyme. 114 51 115 patients with prostate cancer (training set, n = 15; validation set, n On almost all tested parameters, the galantamine effects surpassed 52 116 = 37) before flutamide therapy. FILI was defined as treatment-related that of vildagliptin, while combining both drugs showed the best 53 elevation of serum concentration of aspartate or alanine aminotrans- effect. 117 54 ferase to more than twice the upper limit of the reference range. Conclusion: The present results clearly prove that galantamine 118 55 The patients were monitored for at least 6 months regarding FILI. modulated glucose/lipid profile partly through its anti-cho- 119 56 Microarray and quantitative real-time PCR analyses were conducted linesterase, anti-oxidant, anti-apoptotic and anti-inflammatory 120 57 to compare gene expression profiles between the groups with and properties, along with the improvement of both insulin and 121 58 122 without FILI. Wnt/α -catenin signaling pathways. Additionally, galantamine 59 123 Results: Seventeen patients developed FILI (training set, n = 5; can be strongly considered as a potential antidiabetic agent and 60 124 validation set, n = 12). Microarray analysis of the training set in 15 as an add-on therapy. 61 125 patients detected 11 annotated genes showing > 2-fold expression 62 126 63 127 64 128

2015 e11 Clinical Therapeutics

1 *Correspondence: H S El-Abhar, Faculty of Pharmacy, Cairo and risk of ARF versus amiodarone was performed. HRs adjusted 65 2 University, Kasr El-Aini Str., 11562 Cairo, Egypt. hanan.elabhar@ for covariates potentially associated with election therapy and for 66 3 pharma.cu.edu.eg high-dimensional propensity score were calculated. 67 4 Results: New users without previous episodes of ARF were 56,739, 68 5 dronedarone (1761) or amiodarone (54,978). The mean age of 69 6 Relative Versus Absolute Benefits and patients treated with dronedarone was significantly lower than that 70 7 Harm of Dual Antiplatelet Therapy After of amiodarone ones (70.8 vs. 74.2). The cumulative incidence rate of 71 8 Drug-Eluting Stenting ARF was 1.3% (95% CI, 0.6%–2.8%) among dronedarone group 72 and 3.8% (3.3%–4.4%) among amiodarone group (P from logrank 9 C.R. Kumana; M.F. Tsoi; and B.M.Y. Cheung 73 test 0.001). The unadjusted HR of ARF was 0.34 (0.18–0.64) in 10 Department of Medicine, The University of Hong Kong, < 74 dronedarone compared to amiodarone the adjusted HR was 0.52 11 Hong Kong, China 75 (0.27–0.97). HR adjusted for high dimensional propensity score was 12 Background: Much controversy exists about the duration of dual 76 0.64 (0.34–1.20). 13 antiplatelet therapy (DAPT) after drug-eluting stenting for coronary 77 Conclusions: This large community-based study did not confirm 14 heart disease. Findings from the recently published double blind, 78 the previous signal of an increased nephrotoxicity from dronedar- 15 multicentre, DAPT trial involving 9961 randomised patients, sheds 79 one compared to amiodarone. Actually, our results revealed a lower 16 light on the balance between the benefits and harm of extending 80 risk for dronedarone compared to amiodarone. However, evidence 17 such treatment from 12 to 30 months expressed in relative terms.1 81 of renal failure from dronedarone coming from the post marketing 18 However, to appreciate the true clinical significance of its results, 82 surveillance are growing. It is therefore advisable for clinicians and 19 requires that absolute effects also be considered. 83 patients to be aware of the risk of kidney damage during dronedarone 20 Methods: As previously described,2 we therefore derived unadjusted 84 therapy in order to improve clinical outcomes with early intervention. 21 relative risk (RR) and number needed to treat (NNT)/year values for 85 22 extended duration dual antiplatelet therapy (clopidogrel or prasugrel 86 23 87 + aspirin) versus aspirin only for important reported endpoints, based 24 on the published DAPT trial results. Comparative Safety Profile of Biosimilars 88 25 Results: See table and Originator : Data 89 26 Negative NNTs indicate harm; ∞ Definite or probable; # MACCE From The Italian Spontaneous Adr 90 27 Major adverse cardiovascular or cerebrovascular event (death, myo- Reports Database 81 28 cardial infarct, stroke). M. Donati; L. Marzi; M. Melis; C. Biagi; A. Vaccheri; and 92 29 Conclusions: These parameters for extended duration DAPT indi- D. Motola 93 30 cate statistically significant relative and absolute benefits with respect University of Bologna, Bologna, Italy 94 31 to stent thrombosis and major cardiovascular and cerebrovascular Background or Introduction: Biosimilars are biologic medical prod- 95 32 events, though in absolute terms they were modest. Regarding harms, ucts derived from biological sources, similar to reference products 96 33 the risk of severe/moderate bleeds was significant (though modest in (originators), for which patent is expired. The similarity between 97 34 absolute terms), but there was also a small though not quite statisti- originators and biosimilars is investigated through a stepwise head- 98 35 cally significant increase in all-cause deaths. to-head comparison but some differences, intrinsic to the production 99 36 process, can compromise efficacy and security of biosimilars. Mainly 100 37 for this reason, in Italy, biosimilars of (EPO) are 101 38 102 Reference accepted with skepticism by clinicians. We conducted an analysis 39 to compare the safety profile between originators and biosimilars 103 40 1. Mauri L et al, 2014. DOI:10.1056 NEJMoa1409312. 104 2. Kumana CR et al, 1999. JAMA 282:1899–1901. of EPO, on the basis of adverse drug reaction reports in the Italian 41 database. 105 42 Material and Methods: Reports of suspected Adverse Drug Reactions 106 43 107 Acute Renal Failure In Patients Treated (ADRs) due to EPO, between 1 January 1991 and 1 September 2014, 44 were extracted. ADRs were coded using MedDRA terminology. To 108 45 With Dronedarone or Amiodarone: A 109 Large Population-Based Cohort Study In evaluate the correlation between drug use and occurrence of ADRs 46 a disproportionality analysis through Reporting Odds Ratio (ROR) 110 47 Italy 111 1 2 1 1 1 was performed. An analysis for drug-reaction pairs and a comparison 48 C. Biagi ; V. Conti ; M. Melis ; M. Donati ; A. Vaccheri ; between all originators vs biosimilars was applied. 112 49 M. Venegoni2; and D. Motola1 113 1 Results: Three hundred sixty-eight ADR reports associated with 50 Unit of Pharmacology, Department of Medical and Surgical EPO, 68% related to originator, were retrieved. The main source of 114 51 Sciences, University of Bologna, Bologna, Italy; and 115 2 reporting for both drug categories were hospital doctors. Patients’ 52 Pharmacovigilance Regional Centre of Lombardy, Milan, Italy characteristics were comparable among originators and biosimilars 116 53 Background or Introduction: Acute renal failure (ARF) is a rapid groups, but some differences has been detected between the Italian 117 54 loss of kidney function. Causes of ARF are numerous. Among those, regions. Most reports concerned products containing EPO-alpha 118 55 drugs, such as contrast agents, aminoglycosides, contribute to acute (Eprex®, Binocrit® and Retacrit®). For biosimilars, significant dis- 119 56 renal failure in about 20% of people. In 2012 spontaneous reporting proportionality was observed only for headache (ROR, 4.79; 95% 120 57 showed a possible association between dronedarone and ARF. To CI, 1.48–5.49), sickness (6.65; 1.37–32.3), drug ineffective (3.71; 121 58 further investigate such association a retrospective cohort study on 1.62–8.48) and lack of therapeutic response (9.16; 2.6–32.27). 122 59 health-service claim databases of Lombardy and Emilia-Romagna Conclusions: No alarm signals have been found. The ADRs related 123 60 Regions was performed. to biosimilars “therapeutic inefficacy” probably are not due to qual- 124 61 Material and Methods: All patients receiving at least one prescrip- ity concerns, but they could be interpreted as the attempt to switch 125 62 tion of amiodarone or dronedarone between September 2010 and from biosimilars to originators. Also literature evidence confirm 126 63 December 2012 were selected. Cox regression models to estimate the the similar efficacy and safety profiles between biosimilars and 127 64 hazard ratios (HRs), with 95% confidence intervals, for dronedarone 128

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1 originators containing EPO. Clinicians should be encourage to pre- Material and Methods: A protocol on perioperative management 65 2 scribe biosimilar erythropoietin. of antithrombotics was designed based on the ACCP recommen- 66 3 dations. After protocol implementation (May 2012), information 67 4 on a retrospective (June–October 2011) and a prospective (October 68 5 Netrin-1 Levels Are Reduced In Healthy 2012–February 2013) cohort of eligible patients was collected from 69 6 Subjects In Response to Treatment With the preoperative assessment up to 3 months after surgery. 70 7 Aspirin Results: A total of 379 and 413 patients were included during ret- 71 8 K.A. Layne; T. Goodman; A. Ferro; and G. Passacquale rospective and prospective period, respectively. No differences in 72 9 King’s College London, London, United Kingdom most patients’ characteristics were observed between cohorts. A 73 10 Background: Proinflammatory stimuli and proatherogenic factors higher percentage with a moderate-to-high-thrombotic-risk (67.3% 74 11 are known to reduce the level of endothelial-derived netrin-1, a vs 63.9%, P = 0.04) and with a 1-2 Bleed-MAP score (42.5% vs 75 12 secreted laminin-like protein that attenuates recruitment of circulat- 35.6%, P = 0.09) were observed in the retrospective cohort. Patients 76 13 ing monocytes within atherosclerotic plaques. This study investigated were treated with: antiplatelet agents (72%; mainly aspirin followed 77 14 the effect of aspirin, routinely used for the prevention of cardiovas- by clopidogrel), oral anticoagulants (20%, mainly acenocoumarol), 78 15 cular disease, on serum netrin-1 levels in healthy subjects. combination of two antiplatelet agents (6%) or antiplatelet agent 79 16 Materials and Methods: Serum netrin-1 was measured using an and oral anticoagulant (2%), without differences between cohorts. 80 17 enzyme-linked immunosorbent assay (ELISA) in samples collected After protocol implementation, in patients submitted to a moder- 81 18 from 60 subjects before and after 28 days of treatment with 300 mg ate-to-high or to a clinically-relevant hemorrhagic-risk-surgery and 82 19 aspirin daily. ELISAs were performed to assess serum levels of inter- with a moderate-to-high-thrombotic-risk, aspirin was more often 83 20 cellular adhesion molecule-1 (ICAM-1), E-selectin, and urinary kept (32.5% vs 48.8%, P = 0.01). Clopidogrel and acenocoumarol 84 21 were discontinued in all patients in both cohorts, but in the prospec- 85 11-dehdyro-thromboxane B2 levels (TXB2). Serum creatinine and 22 salicylate levels were measured using the creatininase enzymatic tive cohort less days before surgery: clopidogrel from 8 [7–11.5] 86 23 method on a Roche C8000 analyser and a Cobas Fara automated to 7 [6–10] days (P < 0.05) and acenocoumarol from 6 [5–7.2] to 87 24 analyser (Roche) respectively. Creatinine clearance was calculated 5 [4–6] days (P < 0.05). In patients submitted to a moderate-to-high 88 25 using the Cockcroft-Gault equation. The Research Ethics Committee or to a clinically-relevant hemorrhagic-risk-surgery and with a low- 89 26 approved this study and subjects signed consent forms. thrombotic-risk, time of interruption of aspirin was shorter (from 90 27 Results: Serum netrin-1 levels were reduced following aspirin treat- 7 [4–9] to 5 [4–7] days, P < 0.05). None of the other changes observed 81 28 ment (66.06 ± 22.98 pg/mL versus 79.79 ± 34.91 pg/mL at baseline; were statistically significant. A similar percentage of patients had 92 29 haemorrhagic (34.3% and 37.8%) or thrombotic (5.8% and 4.8%) 93 P = 0.0022). There was a linear association between the percentage 30 2 events in both cohorts. 94 change in netrin-1 and level of serum salicylate (r = 0.413, P = 31 Conclusions: After protocol implementation, aspirin was less 95 .0013). TXB2 levels fell in all subjects post-treatment, confirming 32 adherence to treatment (32.99 ± 18.35 ng/mmol creatinine versus often interrupted and aspirin, clopidogrel and acenocoumarol were 96 33 stopped less days before surgery. 97 143.7 ± 54.25 ng/mmol creatinine at baseline; P < 0.0001). Serum 34 ICAM-1 and E-selectin levels were not modified by treatment. 98 35 Creatinine clearance decreased following aspirin (103.2 ± 26.13 mL/ 99 36 100 min versus 110.5 ± 26.95 mL/min at baseline; P = 0.0011). The interchangeability of gabapentin 37 Conclusion: This study demonstrates that serum netrin-1 is reduced 800 mg tablets: a randomized, 101 38 102 following treatment with aspirin. The TXB2 measurements show controlled trial to establish individual 39 effective platelet inhibition in the whole population. We observed bioequivalence 103 40 no change in ICAM-1 or E-selectin levels suggestive of an effect on E. Van Bever1; P. Colin1; G. Van Lancker1,2; M. Azermai1; 104 41 the vascular endothelial function. Netrin-1 is a known biomarker of B. Delafontaine1,2; K. Boussery1; E.L. Swart3; A. Chahbouni3; 105 42 renal impairment. We propose that the reduction in netrin-1 is sec- J. Van Bocxlaer1; and L. Van Bortel1,2 106 43 ondary to drug-induced renal dysfunction, as evidenced by a decrease 1Ghent University, Ghent, Belgium; 2Ghent University Hospital, 107 44 in creatinine clearance. Ghent, Belgium; and 3VU Medical Center, Amsterdam, 108 45 The Netherlands 109 46 Background: International Nonproprietary Name (INN) prescrib- 110 47 111 Perioperative Management and ing, i.e. using the INN instead of the brand name for prescribing, and/ 48 or generic substitution is allowed in different European countries. For 112 49 Outcomes of Patients Treated With 113 Antithrombotics Submitted To Elective some products it is advised not to switch between medicinal products 50 from different manufacturers once treatment started, because it is 114 51 Surgery 115 1 1 1 1 2 believed that they are not completely interchangeable. Therefore, we 52 M.L. Iavecchia ; A. Safiya ; M. Bosch ; M. Sabaté ; A. Camps ; 116 2 3 4 5 1 aimed to investigate (1) the interchangeability of gabapentin 800mg 53 A. Biarnès ; P. Lalueza ; V. Pons ; M.M. Villar ; and A. Agustí 117 1Fundació Institut Català de Farmacologia, Clinical Pharmacology tablets marketed as Neurontin® and Gabasandoz® following FDA 54 guidelines using the individual bioequivalence (IBE) approach and 118 55 service, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 119 2 (2) the interchangeability in a more real-life situation by including 56 Anaesthesia and Resuscitation Service, Hospital Universitari Vall 120 3 two different batches of each product (Neurontin® & Gabasandoz®, 57 d’Hebron, Barcelona; Pharmacy Service, Hospital Universitari 121 4 both Batch ‘A’ and ‘B’). 58 Vall d’Hebron, Barcelona; Haematology and Hemostasia Service, 122 Hospital Universitari Vall d’Hebron, Barcelona; and 5Internal Materials and Methods: Thirty healthy subjects received 6 times - in 59 randomized order - a single dose of 800 mg Neurontin® (Batch A 123 Medicine Service, Hospital Universitari Vall d’Hebron, Barcelona 60 or B) or 800 mg Gabasandoz® (Batch A or B). Serum concentra- 124 Background: Patients treated with antithrombotics often must 61 tions of gabapentin up to 36 hours after dosing were determined. 125 undergo an elective surgery. The objective of this study was to 62 According to FDA guidelines, IBE can be established if the 95% 126 63 describe the impact of implementing a protocol on the perioperative 127 upper-confidence bound (UCB) ofη (ie, a function of different 64 management and outcomes of these patients. 128

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1 variance terms) is lower than the IBE limit θ , which is 2.5. For healthcare costs. Such a program was implemented at Barzilai 65

2 AUC0-inf and Cmax, η and its 95% UCB were calculated. Medical Center with goals to prevent unnecessary treatment, opti- 66 3 Results: For AUC∞ and Cmax η was 0.58 and 0.19, respectively, and mize dosing, appropriate length of therapy and lower related costs. 67 4 the 95% UCB was 1.32 and 0.63 (both P value < 0.001), respectively. Methods: The program included two measures; antimicrobial restric- 68 5 When including data on batch ‘B’ of Neurontin® and Gabasandoz®, tion criteria and daily surveillance of all patients treated with any 69

6 η was 0.46 and –0.08 for AUC0-inf and Cmax, respectively. The 95% antibiotic. The program was evaluated during a 24 month antimi- 70 7 UCB was 1.20 and 0.40, respectively (both P value < 0.001). All UCB crobial stewardship program. 71 8 were below the IBE limit θ , showing IBE. Results: Antimicrobial length of treatment for restricted drugs 72 9 Conclusion: This study indicates that Neurontin® 800mg (Batch ‘A’) decreased by 10.1% and their DDD/100 hospital beds was reduced 73 10 and Gabasandoz® 800 mg (Batch ‘A’) are individually bioequiva- by 9.9%, both statistically significant. No improvement in hos- 74 11 lent and interchangeable in clinical practice. This interchangeability pitals’ antibiogram was observed. During the study period (years 75 12 remains when resembling a more real-life situation by adding an 2013–2104) 1849 interventions were carried out. Types of interven- 76 13 additional batch of each product (Batch ‘B’). tion evaluated were related to adherence to protocols of treatment 77 14 (33.3%), length of treatment (38.3%), request/reminder for suscep- 78 15 tibility testing (3.8 %), change of drug selection according to cultures 79 16 Perioperative Antimicrobial Prophylaxis (9.7%) and dose optimization (14.9%). 80 17 of Patients Undergoing Joint Conclusions: Decreased antibiotic expenditures were the backbone 81 18 Endoprosthesis Replacement of justification of antimicrobial stewardship programs. Although this 82 19 M. Khudaibergenova1; and A. Ikhambayeva2 study was evaluated for a short period, using tools as information 83 20 1National Scientific Center for Oncology and Transplantation, technology and human resources through a multidisciplinary team 84 21 Astana, Kazakhstan; and 2National Medica University, Astana, approach, it demonstrated to be successful. Proper evaluation of this 85 22 Kazakhstan program, helped to define which method was best for our institution; 86 23 Introduction: There is no doubt that perioperative antibiotic prophy- process measures evaluated quality of care, but did not adequately 87 24 laxis is appropriate and useful. Due to the increasing antimicrobial describe clinical impact at the patient level. Adding improvements 88 25 resistance, many countries have adopted national programs for anti- in clinical outcomes should be the next target of the antimicrobial 89 26 bacterial prophylaxis and therapy. Kazakhstan does not have such stewardship program. 90 27 a program on the national level. At the clinic, we developed our 81 28 own optimal program based on the international recommendations 92 29 according to specifics of the performed operations, predominant Relationship Between Amlodipine 93 30 pathogens of nosocomial infections and their level of resistance. Pharmacokinetics And Cyp3a Activity 94 31 Materials and Methods: We analyzed medical histories of 532 In Lactating Women With Pregnancy- 95 32 patients, which underwent operative intervention for endoprosthe- Induced Hypertension 96 33 sis replacement of knee or hip joints. The first group (included 285 T. Naito1; N. Kubono1; T. Ishida1; S. Deguchi2; M. Sugihara2; 97 34 patients) received Ceftazidime during 5 to 7 days for prophylaxis H. Itoh1; N. Kanayama1; and J. Kawakami1 98 35 purposes. After approval of algorithms of antibiotic prophylaxis, 1Hamamatsu University School of Medicine, Hamamatsu, 99 36 the second group (247 patients) was administered only one dose of Shizuoka, Japan; and 2Sawai Pharmaceutical Co., Ltd., Osaka, 100 37 a medicine (Cefazolin, Cefuroxime or Ampicillin/sulbactam) 30 to Osaka, Japan 101 38 60 minutes before an operation. Background: Pregnancy induces the activity of hepatic cytochrome 102 39 Results: Development of joint replacement infection was identi- P450 (CYP) 3A in humans. Amlodipine, a long-acting 1,4-dihydro- 103 40 fied in both groups. But the first group had 2 patients (5.7%) with pyridine calcium channel blocker, is mainly metabolized by CYP3A. 104 41 infection, while in the second group infection had developed in one Few clinical reports have been published on amlodipine pharma- 105 42 patient (2.47%). When estimating economic costs, we identified that cokinetics in lactating women during the early postpartum period. 106 43 antimicrobial drugs for first group was spent in 2.33% to 22.3% The aim of this study was to evaluate the relationship between the 107 44 108 more funds than in group second patients. Based on the almost equal plasma concentrations of amlodipine and 4β -hydroxycholesterol as 45 percentage of development of joint replacement infection in both endogenous marker of CYP3A4/5 activity in lactating women with 109 46 groups, we conclude that single-stage introduction of antibacterial pregnancy-induced hypertension. 110 47 medicine provides adequate, efficient and comfortable medical care. Material and Methods: Twenty-seven lactating women receiv- 111 48 Conclusion: We developed protocols for perioperative antibiotic ing oral amlodipine once daily for pregnancy-induced hyperten- 112 49 prophylaxis, which help to optimize usage of antimicrobial drugs, sion were enrolled. Predose plasma concentration of amlodipine 113 50 reduce its adverse effects on patients and epidemiological situation, was determined at day 6 or later after starting the medication. The 114 51 and reduce costs of its acquisition. Ceftazidime was excluded from CYP3A activity in lactating women was evaluated using the plasma 115 52 116 the algorithm of perioperative antibacterial prophylaxis, because it 4β -hydroxycholesterol concentration just before the delivery and dur- 53 is pseudomonas drug. ing the early postpartum period. 117 54 Results: The mean dose of amlodipine was 6.5 mg in lactating 118 55 women with pregnancy-induced hypertension. The median and 119 56 120 Process Measures of an Antimicrobial interquartile range (IQR) of the plasma amlodipine concentration 57 were 15.5 and 12.1 to 21.6 ng/mL, respectively. Interindividual vari- 121 58 Stewardship Program 122 A. Lustig; S. Kerekesh; R. Leibowitz; M. Abu-Tzailik; S. Aflalo; ation was observed in the dose-normalized plasma concentration of 59 amlodipine (IQR, 135–206 ng/mL per mg/kg). The median and IQR 123 L. Pomerantz; and E. Tziba 60 of the plasma 4 -hydroxycholesterol concentration were 161 and 124 Barzilai University Medical Center, Ashkelon, Israel β 61 89–254 ng/mL, respectively. The dose-normalized plasma concentra- 125 62 Introduction: Antimicrobial stewardship aims to improve patient 126 tion of amlodipine was inversely correlated with plasma 4β -hydroxy- 63 care and reduce antibiotic overuse or misuse, antimicrobial resist- 127 cholesterol concentration. Median of plasma 4β -hydroxycholesterol 64 ance, adverse drug reactions, length of hospital stay and additional 128

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1 concentration just before and after the delivery within 6 days were Recent studies have shown that the antidepressant fluoxetine induces 65 2 149 and 149 ng/mL, respectively. In contract, the plasma concentra- anti-tumour activity in cancer cell lines such as colon, neuroblastoma, 66 3 tion of 4β -hydroxycholesterol in non-pregnant healthy subjects was breast and ovarian carcinoma cells (Krishnan et al., 2008; Stepulak 67 4 53.5 ng/mL. et al., 2008; Chung et al., 2009). The aim of the present study was 68 5 Conclusions: The lactating women with pregnancy-induced to investigate if treatment with fluoxetine can induce more sensitivity 69 6 hypertension had the higher CYP3A activity based on the plasma to chemotherapeutic drugs such as cis-platin in cis-platin resistant 70 7 4β -hydroxycholesterol concentration during the early postpartum ovarian carcinoma cell line, A2780CP70. 71 8 period. The lactating women with the higher CYP3A activity had A2780 and A2780CP70 cells (American Type Culture Collection) 72 9 the lower plasma concentration of amlodipine. were grown and maintained in RPMI 1640 medium supplemented 73 o 10 with 10% fetal bovine serum at 37 C, 5% CO2 .The cells were 74 11 plated in 96-well culture plates at a density of 1x104 cells/well and 75 o 12 Fosfomycin Versus Meropenem In allowed to adhere at 37 C for 24 hours. The following day, vari- 76 13 Bacteremic Urinary Tract Infections ous doses of cis-platin, fluoxetine, a combination of cis-platin plus 77 14 Caused By Extended-Spectrum fluoxetine or vehicle were added to the cells and further incubated 78 15 Betalactamase Producing Escherichia for 72 hours. After 72 hours the supernatant was removed and MTT 79 16 Coli (Esbl-Ec): Forest Study (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) 80 17 L. Lavín-Alconero1; C.M. Rosso-Fernández1; A. Barriga-Ribera1,2; assay was performed. Cytotoxicity was expressed as a relative per- 81 18 J. Sojo-Dorado2; Z. Palacios2; I. López-Hernández2; V. Merino2; centage of the absorbance measured at 540 nm in the control and 82 19 M. Camean2; A. Pascual2,3; and J. Rodríguez-Baño2,3 drug-treated cells. 83 20 1Hospital Universitario Virgen del Rocío, Seville, Spain; 2Hospital Pre-treatment with both fluoxetine and cis-platin but not vehicle 84 21 Universitario Virgen Macarena, Seville, Spain; and 3Universidad induced dose-dependent cytotoxic effects in A2780 cells with IC50 of 85 22 de Sevilla, Seville, Spain 19.1 µM, 1.19 µM and A2780CP70 cells with an IC50 of 14.4 µM and 86 23 Introduction: Investigating the efficacy of old drugs in infections by 8.04 µM , respectively. A combination of fluoxetine plus cis-platin sig- 87 24 multidrug-resistant Gram negatives are urgently needed. We describe nificantly (P < 0.01) reduced the IC50 to 3.26 µM when compared to 88 25 the design, network established, organization of clinical teams and the single pre-treatment with the above drugs only in A2780CP70 cells. 89 26 general management support in order to effectively carry out an investi- The data showed that pre-treatment with fluoxetine can increase the 90 27 gator-driven randomized clinical trial (RCT) in a public system setting. sensitivity of the cells to cis-platin in resistant ovarian carcinoma cells. 81 28 Material and Methods: An investigator-driven, randomized con- Chung et al. (2009). Basic & Clinical Pharmacology & Toxicology, 92 29 trolled trial endorsed by the Spanish Network for Research in 106:446-453. 93 30 Infectious Diseases was designed to investigate the efficacy of fosfo- Krishnan et al. (2008). Biochem Pharmacol., 75:1924–1934. 94 31 mycin in the treatment of bacteremic urinary tract infections (B-UTI) Stepulak et al (2008). Cancer Biol Ther, 7:1685–1693. 95 32 due to ESBLE-EC. The study is publicly funded (PI13/01282). 96 33 Challenges were: use of a pragmatic design reflecting real practice, 97 34 decisions about comparator, dosing, inclusion/exclusion criteria and Estimation of renal function as a 98 35 outcomes, sponsor, selection of centres, obtaining approval by com- primary endpoint of clinical trials, 99 36 mittees, agreements signatures, and pharmacovigilance. quosque tandem? 100 37 Results: The local public research Foundation is sponsor, with del- A Aldea-Perona1; S. Luis-Lima2; N. Negrín2; M. Cervino1; 101 38 egated specific responsibilities to the CTU. Twenty-two Spanish centres P. Delgado1; R. Miquel1; JA. Ballarín3; V. Lorenzo1; A. Jiménez1; 102 39 were selected using feasibility tests. The study was designed as a phase E. Porrini2; and NEFROVID investigators team 103 40 III, randomised, open, multicentre, non-inferiority trial. Patients hospi- 1Hospital Universitario de Canarias, Tenerife, Spain; 2University 104 41 talized with B-UTI caused by ESBL-EC will be selected and stratified in of La Laguna, Tenerife, Spain; and 3Fundación Puigvert, 105 42 1:1 ratio by centre through the automatic system design for the project Barcelona, Spain 106 43 (e-CRF) to receive early targeted therapy with intravenous disodium Introduction: Estimated GFR (eGFR) by formulas is not precise, 107 44 fosfomycin 4 gr/iv/6h in 60 minutes infusion (experimental arm) or which preclude its use in clinical practice and research. Moreover, 108 45 intravenous meropenem 1g/iv/8h in 15 to 30 minutes infusion (control EMA recommends (EMA/CHMP/355988/2014) the use of measured 109 46 arm), stratified according to previous empirical treatment received (198 GFR (mGFR) in clinical trials. Our aim was to analyze the agreement 110 47 patients in total). The primary outcome is clinical and microbiological between mGFR and eGFR in the NEFROVID clinical trial. 111 48 cure 5 to 7 days after the completion of treatment. Fosfomycin levels Materials and Method: NEFROVID is a controlled CT aimed at 112 49 and ecological impact are being measured in a subset of patients. evaluating renal function after vitamin D supplementation in subjects 113 50 114 Conclusion: The organization of a multidisciplinary team support- with CKD stage II-IV and proteinuria (> 0.5 g/d) on top on RAAS 51 ing the daily work of coordination is a key point regarding issues as treatment. GFR was estimated with 37 creatinine-based formulas and 115 52 design, coordination, regulatory and ethical requirements for the measured with the iohexol plasma clearance (mGFR). The agreement 116 53 development of investigator-drive RCTs according to International between eGFR and mGFR was assessed by Concordance Correlation 117 54 Conference Harmonization-Good Clinical Practice and 20/CE/2001. Coefficient (CCC), Total Deviation Index (TDI) and Coverage 118 55 ClinicalTrials.gov identifier: NCT02142751 (registered 16-May- Probability (CP). TDI is a measure that captures a large propor- 119 56 2014). EudraCT no: 2013-002922-21 (registered 08-May-2014). tion of data within a boundary for allowed differences between two 120 57 measurements Empirical TDI was calculated for a theoretical TDI 121 58 122 of 10% and a coverage probability of 90%. A CCC > 0.90 reflects 59 optimal concordance between measurements. 123 60 The effect of fluoxetine on human 124 ovarian carcinoma cells Funding: Fondos FEDER; Ministerio de Sanidad, Servicios Sociales 61 e Igualdad. ISCIII EC10/248. 125 F.A. Javid1; and S. Afshinjavid2 62 Results: Thirty mGFR procedures were evaluated. Patient’s charac- 126 1University of Huddersfield, Huddersfield, UK; and 2University of 63 teristics included: age 60 ± 13 years, 97% male and 81% diabetic. 127 64 Chester, Chester, UK 128

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1 TDI ranged from 52, 55, 58 and 62 for the Cockroft Gault, CKD-EPI, QT prolongation such as medication or electrolyte abnormalities 65 2 aMDRD and RuleMC formulas, respectively. CP ranged from 0.27 were recorded. 66 3 (0.21), 0.26 (0.21), 0.25 (0.2), and 0.24 (0.19) for Cockroft Gault, Results: Ninety (73.8%) patients were treated with azithromycin 67 4 CKD-EPI, aMDRD and RuleMC, respectively. No formula included (usually in combination with ceftriaxone), and 32 (26.2%) patients 68 5 90% of the estimations within a ±10% error compared with the with other antibiotics (ampicillin-clavulanate, chloramphenicol, dox- 69 6 gold-standard. CCC was < 0.95. Lower precision and accuracy were ycycline, or ceftriaxone); 72.1% (88) of the cohort experienced QT 70 7 observed for the remaining equations (n = 33). lengthening, and 72.7% with QT lengthening had a normal baseline 71 8 Conclusions: Estimated GFR is unreliable in reflecting real renal QTc. QT lengthening was not associated with type of antibiotic, age, 72 9 function. Thus, its use in clinical trials as primary endpoint shall pneumonia score or any specific comorbidity. None of the patients 73 10 be avoided. had other risk factors for QT lengthening such as concomitant medi- 74 11 cations or electrolyte abnormalities. Azithromycin was not associated 75 12 with the post antibiotic QTc. Wide (pathological) post antibiotic 76 13 Immuno Modulator Metallo- QTc was associated with the pneumonia score. Every 10 point 77 14 Improves Inflammatory State In Rats With increase in the pneumonia score raised the risk for a pathological post 78 15 Metabolic Syndrome antibiotic QTc by 1.249 (95% CI, 1.050–1.486). Analysis of patients 79 with non-pathological baseline QTc revealed that pathological post 16 J. Reyes-Esparza; A. Gómez Solis; and Lourdes Rodriguez-Fragoso 80 antibiotic QTc was only associated with previous stroke. Patients 17 Universidad Autónoma del Estado de Morelos, Cuernavaca, 81 with a normal baseline QTc, and history of a previous stroke had 18 Morelos, Mexico 82 an increased risk of 6.459 (95% CI, 1.910–21.838) for developing a 19 Background: Metabolic syndrome is a prothrombotic and pro- 83 pathological QTc after antibiotic treatment, irrespective of the type 20 inflammatory chronic state. In obesity, the adipose tissue secretes 84 of antibiotic used. 21 various adipokines that take part in a variety of physiological and 85 Conclusions: Azithromycin treatment was not associated with QT 22 pathophysiological processes, including immunity and inflammation. 86 prolongation in patients with severe CAP. Nonetheless, in a large 23 Previous studies using a liver damage model treated with the immune- 87 majority of hospitalized CAP patients QT prolongation and patho- 24 modulator metallo-peptide (IMMP) showed lessening in the degree 88 logical QTc develops regardless of the antibiotic used, especially in 25 of inflammation. Therefore, this study was set up to evaluate the 89 patients with previous stroke or a higher pneumonia score. 26 anti-inflammatory effect of IMMP in obese Zucker fa/fa rats. We used 90 27 Zucker-Lepr fa/fa and Zucker-Lean in this protocol. 81 28 Material and Methods: The groups received IMMP 50 ng/kg by i.p., 92 29 3 times per week for 8 weeks. Blood samples were collected by car- Survey of Information Sources on Drug 93 30 diac puncture and the serum was preserved at −80°C until analysis; Safety In Patients Taking Non-Steroidal 94 31 the liver was excised and preserved in formaldehyde 4%. Analyses Anti-Inflammatory Drugs 95 32 were performed to determine cytokine, insulin, glucose, triglyceride N. Jarernsiripornkul1; P. Phueanpinit1; J. Pongwecharak2; and 96 33 and cholesterol levels in serum, and histological analysis was also J. Krska3 97 34 performed. 1Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon 98 35 Results:: IMMP treatment of obese rats resulted in decreased lev- Kaen, Thailand; 2Faculty of Pharmacy, Thammasat University, 99 36 3 100 els of proinflammatory cytokines (leptin, IL-6, IL-1β , IFN-γ ) and Pathumthani, Thailand; and Medway School of Pharmacy, 37 a chemokine (MCP-1), and increased levels of anti-inflammatory Universities of Greenwich and Kent, Kent, UK 101 38 adipokine (adiponectin). In addition, treatment decreased the damage Background: Information on drug use can be provided to patients 102 39 and hepatic steatosis generated in the tissue of obese rats and avoids by health professionals and educational materials. Nonsteroidal 103 40 changes in thymus and spleen in the same animals. anti-inflammatory drugs (NSAIDs) potentially cause serious adverse 104 41 Conclusions: The IMMP exerted an anti-inflammatory effect in effects in those with long-term use. This study aimed to explore 105 42 obese rats and therefore may be an effective and safe therapeutic sources of NSAID information and to evaluate factors related to 106 43 alternative in the treatment of metabolic syndrome. drug information sources receiving by patients. 107 44 Methods: This study was a cross-sectional survey. Self-completed 108 45 questionnaires were distributed directly to 500 outpatients pre- 109 46 scribed any NSAIDs from Orthopedic Unit at a university hospital in 110 47 Azithromycin Is not Associated With Qt 111 Prolongation In Patients Hospitalized Thailand, during 4-month period. Data was analyzed using descrip- 48 tive statistics and logistic regression. 112 49 With Community Acquired Pneumonia 113 1,2 1 1 1,2 Results: There were 474 completed questionnaires (94.8%). The 50 L.H Goldstein ; A. Gabin ; A. Fawaz ; N.A. Freedberg ; 114 1,3 1,2 1,2 average age of patients was 56.14 ± 12.38 years, and 75.4% were 51 N. Schwartz ; M. Elias ; and W. Saliba 115 1Ha’emek Medical Center, Afula, Israel; 2Bruce Rappaport Faculty female. Most of the patients received information about NSAIDs 52 from pharmacists (94.9%) and physicians (78.5%). Other sources 116 53 of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; 117 3 included leaflets (7.6%), internets (5.3%) and relatives (4.2%). 54 and School of Public health, University of Haifa, Haifa, Israel 118 Background: Large data based studies have reported excess cardio- Information involving drug administration (96.2%) and indica- 55 tions (79.7%) were commonly received from healthcare profession- 119 56 vascular mortality in high risk patients treated with azithromycin, 120 but whether or not azithromycin causes QT prolongation remains als. However, Only 39.2% of patients reported that they had ever 57 obtained adverse drug reaction (ADR) information. Patients taking 121 58 controversial. The purpose of this study was to examine the associa- 122 tion of azithromycin treatment on QT prolongation in a cohort of selective COX-2 NSAIDs were significantly less likely to receive 59 information about ADRs (OR, 0.35; 95% CI, 0.21–0.57), ADR 123 60 patients hospitalized with community acquired pneumonia (CAP). 124 Materials and Methods: One hundred twenty-two hospitalized monitoring (OR, 0.20; 95% CI, 0.08–0.47) and ADR management 61 (OR, 0.64; 95% CI, 0.26–0.10) than those taking non-selective 125 62 patients with CAP were enrolled in the study. We compared the 126 baseline QTc, with daily post antibiotic QTc. Other risk factors for NSAIDs. Greater proportion of patients with intermittent NSAID 63 therapy significantly gathered ADR information (OR, 2.19; 95% 127 64 128

e16 Volume XX Number XX Epidemiological Profile of BenzodiazepineP oisonings In Uruguay

1 CI, 1.38–3.48) and ADR monitoring information (OR, 2.17; 95% during regimen A, B, and placebo, respectively. Sinus bradycardia, 65 2 CI, 1.09–4.15). Moreover, older patients obtained less ADR man- palpitations, and dizziness were reported more frequently during 66 3 agement information than younger patients did (OR, 0.18; 95% regimen B compared to regimen A. 67 4 CI, 0.05–0.62). Conclusions: The cardiodynamic first-dose effects of ponesimod are 68 5 Conclusions: Patients generally received inadequate safety informa- mitigated by the novel gradual up-titration. 69 6 tion of NSAIDs including ADRs, ADR monitoring and ADR man- 70 7 agement. Other information sources should be developed to provide 71 8 essential safety data for NSAID users especially those with regular Factors Affecting The Development of 72 9 use and older age. Adverse Drug Reactions of Beta Blockers 73 10 Key words: nonsteroidal anti-inflammatory drugs, adverse drug reac- S. Mugosa1; Z. Todorovic2; M. Sahman-Zaimovic1; 74 11 tions, monitoring, management, information source I. Radosavljevic3; Z. Bukumiric2; and N. Djordjevic3 75 12 1Agency for Medicines and Medical Devices, Podgorica, 76 13 Montenegro; 2Medical School, University of Belgrade, Serbia; and 77 14 A Novel Gradual Up-Titration Regimen 3Faculty of Medical Sciences, University of Kragujevac, Serbia 78 15 Mitigates The First-Dose Effects Of Introduction: Adverse drug reactions (ADRs) are common causes of 79 16 Ponesimod, A Selective S1p1 Receptor morbidity and mortality within the hospital setting. Our main goal 80 17 Modulator was to analyse risk factors, incidence and characteristics of ADRs 81 18 M. Hoch1; A. Vaclavkova1; A. Krause1; A. Strong2; J. Bush2; of beta blockers in hospitalised cardiac patients and to consequently 82 19 J. Dingemanse1; and Pierre-Eric Juif1 suggest measures for rationalization of pharmacotherapy practice 83 20 1Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; and in Montenegro which will contribute to more quality treatment of 84 21 2Covance Clinical Research Unit Ltd, Leeds, United Kingdom patients. 85 22 Introduction: The aim of this study was to compare the effects of Material and Methods: Prospective study, which included 200 86 23 ponesimod on heart rate (HR) and AV-conduction using a novel grad- patients hospitalized at Cardiology Centre of the Clinical Centre 87 24 ual up-titration regimen (regimen A) suggested by PK/PD modelling of Montenegro, was performed. We established system of intensive 88 25 with the up-titration regimen (regimen B) previously used. monitoring of ADRs in hospital setting. Genotyping of CYP2D6 was 89 26 Material and Methods: This was a single-centre, double-blind, pla- performed in order to determine the frequency of poor and rapid 90 27 cebo-controlled, randomized, two-way cross-over study in 32 healthy metabolizers of beta blockers. 81 28 92 male and female subjects (n = 24 on ponesimod, n = 8 on placebo). Results: Twenty percent of all patients experienced at least 1 ADR 29 The 2 regimens consisted of the following once daily ponesimod/ of beta blocker. Genotyping showed that poor metabolizers (slow, 93 30 placebo treatments. Regimen A: Day 1 (D1): placebo, D2–3: 2 mg, very slow and those with no CYP2D6 enzyme activity) experience 94 31 D4–5: 3 mg, D6–7: 4 mg, D8: 5 mg, D9: 6 mg, D10: 7 mg, D11: 8 mg, ADRs of beta blockers significantly more often than rapid and inter- 95 32 2 96 D12: 9 mg, D13–14: 10 mg, D15: 20 mg. Regimen B: D1: placebo, mediate CYP2D6 metabolizers (χ = 25.325, P < 0.001). There is 33 D2–8: 10 mg, D9: 20 mg, D10–15: placebo. Subjects in the placebo a strong positive, statistically significant higher level correlation of 97 34 group received placebo on all study days. the enzyme activity and the given dose of beta blockers. Statistically 98 35 Results: The decrease in HR (Holter ECG) observed after the first important predictors of occurrence of beta blockers’ ADRs in the 99 36 dose of ponesimod was less pronounced with regimen A (maximum multivariate logistic regression model are: duration of hospitalization 100 37 101 mean decrease [±SD]: 6 bpm [±6]) compared to regimen B (12 bpm (B = 0.124; P = 0.008), enzyme activity (B = 3.544; P < 0.001) and 38 102 [±7]). Occurrence of HR < 45 bpm was less frequent during regimen the concomitant use of other medicines metabolized by CYP2D6 (B 39 103 A (12.5%) than B (16.7% of subjects). Fewer subjects experienced = 3.236, P < 0.001). 40 104 a decrease from baseline in HR > 20 bpm following the first dose Conclusions: The implementation of preventive measures for 41 of ponesimod during regimen A (12.5%) than B (20.8%). Fewer patients with detected risk factors, like pharmacotherapy rationali- 105 42 106 AV-blocks (defined as PR interval> 210 ms) were observed during zation and continual education for health care professionals, could 43 regimen A (79 events in 25% of subjects) compared to B (143 / 25%). reduce the occurrence of ADRs. 107 44 Second degree AV-block Mobitz I was observed in 0, 1, and 2 subjects 108 45 109 46 110 47 111 48 112 49 113 50 114 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

2015 e17 Clinical Therapeutics/Volume XX, Number XX, 2015

1 Challenges of generic Material and Methods: The data from questionnaire completed by 65 2 therapy for croatian patients with 400 randomly selected people aged 19 and over was collected. SPSS 66 3 Gastrontestinal Stromal Tumors (GIST) software was used for statistical analysis. 67 4 I. Kraljickovic1; R. Likic1,2; I. Cegec1; M. Radacic Aumiler1; Results: There were statistically significant gender differences with 68 5 K. Makar Ausperger1; V. Erdeljic Turk1; and I. Francetic1,2 regards to clinical trials awareness. Only 44.2% of all male subjects 69 6 1University hospital Zagreb, Zagreb, Croatia; and 2University of versus 70.8% of all female ones were informed about the definition 70 7 Zagreb, Zagreb, Croatia of clinical trials (P < 0.001). Both were mostly informed through 71 8 Despite proven effectiveness and safety during the last 30 years, the media. While 49.8% women thought that medicines on the mar- 72 9 unfounded skepticism about generic prescribing still persists. ket were clinically tested, 47.5% men were not sure about that (P 73 10 Recently, 2 patients on Imakrebin for metastatic GIST were = 0.037). The main motive for clinical trial enrolment for subjects 74 11 admitted for ADR testing. The first reported stomach pain, cramps, under the age of 25 and over the age of 50 was curing the existing 75 12 skin rash, eye swelling, headache and chills while the second one com- disease, while for subjects aged 26-50 was financial reimbursement 76 13 plained of diarrhea, abdominal pain and hemorrhoids. They claimed (37.6% and 44.2% versus 34.9%; P < 0.001). 77 14 symptoms were absent while on Glivec therapy. Conclusions: These results indicate that additional educational 78 15 During hospitalization both were single-blindedly exposed to pla- efforts are needed in order to improve the knowledge of significance 79 16 cebo, Glivec and Imakrebin. While the second patient was asympto- of clinical trials. Therefore, the Agency for Medicines and Medical 80 17 matic during testing, the first developed similar symptoms regardless Devices of Montenegro, in accordance with its competences - educa- 81 18 of the administered substance, without signs or symptoms of acute tion about medicines, will be providing more information relevant to 82 19 allergy. All reported symptoms were listed as ADRs to Glivec, but clinical trials to general public in the future. 83 20 could also be attributed to disease progression or considered psy- 84 21 chosomatic and in our view therapy change in both patients was 85 22 not required. Polypharmacy and associated factors 86 23 In Croatia, all oncology treatments are financed by the National among community-dwelling older 87 24 Health Insurance Fund. Due to budgetary constraints, original drugs persons in a Swiss Canton 88 25 are substituted with generics whenever possible. In case of objective S. Fustinoni1; D. Renard2; B. Santos-Eggimann1; and 89 26 intolerance original drug use is possible. Apart from Glivec, priced L. Seematter-Bagnoud1 90 27 1866€ for 30 pills of 400 mg, there are 4 generic parallels of imatinib 1Center for Aging Studies, Lausanne University Hospital, 91 28 available since 2013 in Croatia: Neopax (1615€ ), Astrea (1307€ ), CH-1010 Lausanne, Switzerland; and 2Division of Clinical 92 29 Imakrebin (1307€ ) and Nibix (1177€ ), with actual prices signifi- Pharmacology, Lausanne University Hospital, CH-1011 93 1 30 cantly lower due to volume discounts. First generic imatinib in the Lausanne, Switzerland 94 31 USA will be launched, after substantial controversy, on February 1, Background: Polypharmacy in older persons has been scarcely stud- 95 2 32 2016 by Sun Pharma. ied in Switzerland. Our aim was to investigate which socio-demo- 96 33 High prices of new inhibitors and Glivec, are sig- graphic factors are associated to polypharmacy in a sample of Swiss 97 34 nificant cost burden for insurers and patients who require therapy older persons. 98 3 35 for prolonged periods of time. Material and Methods: The study population consisted of com- 99 36 100 Better communication among physicians themselves and with munity-dwelling persons aged 69+ years living in the canton de 37 patients is crucial to avoid similar cases in the future. Generic pre- Vaud (Switzerland). Information about current medication was 101 38 scribing promotion is still very much needed. self-reported by 3133 participants in a postal survey nested into a 102 39 1. Croatian Healt Inshurance Fund, web page, January 26, 2015, population-based cohort study (participation rate: 71% of eligible 103 40 http://www.hzzo.hr/zdravstveni-sustav-rh/trazilica-za-lijekove-s- subjects). Data were weighted to reflect the age and sex distribution 104 41 vazecih-lista of the source population. Polypharmacy was defined as currently tak- 105 42 2. Novartis, web page, January 26, 2015, http://www.novartis. ing five or more different registered drugs on a regular basis (further 106 43 com/newsroom/media-releases/en/2014/1785478.shtml referred to as “drugs”). 107 44 3. Experts in Chronic Myeloid Leukemia. The price of drugs for Results: Median age was 77 years; 57% were female. Most (84%) 108 45 chronic myeloid leukemia (CML) is a reflection of the unsustainable were taking at least one drug; the maximum reported was 17. 109 46 prices of cancer drugs: from the perspective of a large group of CML Polypharmacy was present in 27% of our population and increased 110 47 experts. Blood. 2013 May 30;121(22):4439–4442. from 18% among persons aged 69–74 to 29% in those aged 75–84 111 48 112 and 38% in those aged 85+ (P < 0.001). Polypharmacy was observed 49 in 38% of the subgroup reporting two or more chronic diseases versus 113 50 114 Promoting public awareness of clinical 9% of those without comorbidity (P < 0.001). In multivariate logistic 51 trials in Montenegro regression analysis, polypharmacy remained significantly associated 115 52 116 B. Kucevic; M. Rolevski; M. Sahman-Zaimovic; Z. Besovic; and with the number of chronic diseases (adjusted OR 2.14; 53 (per unit increment) 117 S. Mugosa 95% CI, 1.85-2.48) and with oldest age (adjusted OR 54 (85+ versus 69-74) 118 Agency for Medicines and Medical Devices, Podgorica, 2.64; 95% CI, 1.61–4.34). No association was observed between 55 119 Montenegro either education level or gender and polypharmacy. 56 120 Introduction: In order to successfully build a clinical research infra- Conclusions: Polypharmacy was reported in 27% of community- 57 121 structure one of the key imperatives is that the public understand dwelling persons aged 69+ years. Comorbidity and age 85+ were sig- 58 122 and strongly support clinical research. Literature data showed nificantly and independently associated factors. While polypharmacy 59 123 that the general public is not sufficiently informed about the pur- was particularly frequent in the older age group, it already concerned 60 124 pose and importance of clinical trials. The aim of this study is to nearly one in five persons at the age of 69–74. These findings empha- 61 125 investigate awareness of general public in Montenegro regarding size the need for scheduled medication reviews not only in oldest-old, 62 126 clinical trials. but also in the polymorbid youngest-old patients. 63 127 64 128

2015 e1 Clinical Therapeutics

1 Drugs regularly taken by community- Mechanism of the effect of visfatin on 65 2 dwelling older persons in a Swiss human internal thoracic arteries 66 3 Canton Z. Bayram; I. Golbasý; and S.S. Ozdem 67 4 D. Renard1; S. Fustinoni2; L. Seematter-Bagnoud2; and Akdeniz University, Antalya, Turkey 68 5 B. Santos-Eggimann2 Background or Introduction: Visfatin, also known as pre-B-cell col- 69 6 1Division of Clinical Pharmacology, Lausanne University ony-enhancing factor and nicotinamide phosphoriboslytransferase 70 7 Hospital, 1011 Lausanne, Switzerland; and 2Center for Aging (Nampt) is a novel adipocytokine. The present study aimed to inves- 71 8 Studies, Lausanne University Hospital, 1010 Lausanne, tigate the functional effects and the possible underlying mechanism(s) 72 9 Switzerland of visfatin on human left internal thoracic artery (ITA) preparations. 73 10 Background: Studies about polypharmacy may fail to present data Material and Methods: Samples of redundant ITA obtained from 74 11 in a clinically meaningful way. Our aim was to report the frequency patients undergoing a coronary artery bypass surgery were cut into 75 12 of drugs taken by older people according to clinically relevant phar- 3-4 mm wide rings and suspended in 20 mL organ baths. Isometric 76 13 macological classes. tension was continuously recorded with isometric force transducers 77 14 Material and Methods: The study population consisted of com- connected to a computer-based data acquisition system. 78 15 munity-dwelling persons aged 69+ years living in the canton de Results: Contraction responses of human ITA rings to angiotensin II, 79 16 Vaud (Switzerland). Information about current medication was endothelin-1, noradrenaline and phenylephrine did not change sig- 80 17 self-reported by 3133 participants in a postal survey nested into a nificantly before and after incubation with different visfatin concen- 81 18 population-based cohort study (participation rate: 71% of eligible trations. Visfatin (10−12 – 10−7 M) produced concentration-dependent 82 19 subjects). Data were weighted to reflect the age and sex distribution relaxation responses in human ITA rings precontracted with phenyle- 83 20 of the source population. phrine (10−6 M) that were significantly higher in endothelium-intact 84 21 Results: Median age was 77 years; 57% were female; a majority than endothelium-denuded preparations. Incubation of tissues with 85 22 (84%) were currently taking at least one registered drug on a regu- cyclooxygenase inhibitor indomethacin (10−5 M) did not cause a sig- 86 23 lar basis. The frequency of major pharmacological classes was as nificant alteration, while incubations with nitric oxide (NO) synthase 87 24 follows: inhibitor L-NAME (10−4 M) and specific guanylyl cyclase inhibi- 88 −5 25 tor ODQ (5 × 10 M) caused statistically significant decreases in 89 26 Percentage of participants currently relaxant responses to visfatin. Visfatin-induced relaxation responses 90 27 taking at least one such drug on a were almost completely blocked in the presence of Nampt enzyme 81 regular basis (%) 28 inhibitor FK866 (10 µM). Incubation of the tissues with a combina- 92 29 93 ALL CARDIOVASCULAR DRUGS, among which: 69.3 tion of high-conductance Ca2+-activated potassium channel blocker 30 Statins 29.4 charybdotoxin and small- conductance Ca2+-activated potassium 94 31 Renin-angiotensin system inhibitors 40.7 channel blocker apamin (10−7 M, both) did not cause a statistically 95 32 Beta blockers 21.3 significant alteration in visfatin-induced relaxations. Acetylcholine- 96 33 Calcium channel blockers 12.6 −10 −5 97 Diuretics 11.0 induced (10 - 10 M) endothelium-dependent relaxations signifi- −10 −5 34 Aspirin 25.9 cantly increased whereas sodium nitroprusside-induced (10 - 10 98 35 Clopidogrel 2.5 M) endothelium-independent relaxations did not change following 99 36 Vitamin K antagonists 7.7 incubation of human ITA rings with 10−9 and 10−8 M visfatin. 100 37 ANTIDIABETICS 9.3 101 Oral antidiabetic agents 8.9 Conclusions: The findings of the present study demonstrated that 38 0.9 visfatin did not affect contraction responses to various contractile 102 39 ALL DIGESTIVE DRUGS, among which: 15.7 agents, but produced concentration-dependent relaxation responses 103 40 Antacids 12.7 in endothelium-intact human ITA rings through Nampt enzymatic 104 41 Laxatives 3.4 105 CALCIUM AND VITAMIN D 14.2 activity and NO-cGMP pathway. 42 ANALGESICS 13.3 This study was supported by ‘The Scientific Research Projects 106 43 Aspirin and non-steroidal anti-inflammatory 5.9 Coordination Unit of Akdeniz University, Project number: 107 44 drugs (NSAIDs) 2012.03.0122.002. 108 45 Acetaminophen 5.7 109 Opioids 3.0 46 Topical NSAIDs 1.7 110 47 PSYCHOTROPIC DRUGS 17.7 111 Antidepressants 8.5 Intra-Arterial Microdosing (IAM), a novel 48 Drug development approach, proof of 112 49 Anxiolytics 7.3 113 Sedative-hypnotics 6.1 concept in Rats 50 114 Anti-psychotics 0.8 T. Burt; H. Wu; A.T. Layton; D.C. Rouse; B.B. Chin; T.C. Hawk; 51 115 D.H. Weitzel; M. Cohen-Wolkowiez; S. Chow; and R.J. Noveck 52 116 Conclusions: The most frequent class was cardiovascular agents Duke University, Durham, North Carolina, USA 53 117 (almost 70% of participants report taking at least one cardiovascu- Background: Intra-Arterial Microdosing (IAM) is a novel drug 54 118 lar drug, and 9% report taking at least one anti-diabetic) followed development approach combing intra-arterial drug delivery with 55 119 by psychotropic drugs (18%). By contrast, reports of calcium/vita- microdosing. We aimed to demonstrate that IAM leads to similar 56 120 min D (14%) and analgesics (13%) were low, suggesting underuse. target exposure as systemic full-dose administration but with minimal 57 121 Optimizing prescribing in this population should include a) carefully systemic exposure. 58 122 weighing the risk-benefit balance of cardiovascular and psychotropic Methods: Insulin 0.34 IU/kg was administered intra-arterially 59 123 drugs, which may be double-edged swords in a potentially fragile (ipsilateral femoral artery) to 2 CD IGS rats just prior to 60-minute 124 60 population and b) considering the risk of under-prescribing. 61 125 62 126 63 127 64 128

e2 Volume XX Number XX Challenges of Generic Imatinib Therapy for Croatian Patients With Gastrontestinal St Romal Tumors (GIST)

1 18F-FDG uptake imaging of ipsilateral (leg), contralateral (leg), and However at cycle 3 there was no longer any influence of these gene 65 2 systemic (spine) muscles. Area under the curve (AUC) was calculated variants. This was because large alterations in cyclophosphamide 66 3 by the linear trapezoidal method and together with maximum glucose metabolism (both increased and decreased bioactivation) occurred 67 4 uptake (Emax) were summarized by descriptive statistics. in some patients between cycle 1 and cycle 3. 68 5 Results: Contralateral and systemic Emax (mean ± SD: 0.323 ± Discussion: Changes in cyclophosphamide bioactivation, in part due to 69 6 0.129 and 0.297 ± 0.205, respectively) and AUC (mean ± SD: 13.08 an acquired loss of CYP2C19 function, appear to mask the role of inher- 70 7 ± 8.12 and 13.39 ± 10.78, respectively) post IAM were similar but ited variation (pharmacogenetics) after multiple doses of chemotherapy. 71 8 lower than ipsilateral Emax and AUC (0.615 ± 0.367 and 22.13 ± 72 9 15.33, respectively; Figure). 73 10 Conclusion: Target exposure post IAM was similar to systemic full Pharmacokinetics and 74 11 dose administration but with minimal systemic effects. Our findings Pharmacodynamics modeling to optimize 75 12 are being validated in larger studies in animals and humans using dosage regimens of oral Levofloxacin 76 13 different targets and classes of drugs. IAM could enable safe, inex- A. Jaspattananon; S. Jaruratanasirikul; W. Wongpoowarak; and 77 14 pensive and early study of novel drugs at the first-in-man stage and M. Jullangkoon 78 15 the study of established drugs in vulnerable populations. Prince of Songkla University, Hat Yai, Songkla, Thailand 79 16 80 0.7 Background: Levofloxacin, a fluoroquinolone antibiotic, is S isomer 17 Contralateral Ipsilateral Systemic (spine) 81 0.6 of ofloxacin with a broad spectrum of activity against Gram-positive 18 cocci and Gram-negative bacilli bacteria. In common with other fluo- 82 19 0.5 roquinolones, the main pharmacokinetic/pharmacodynamic (PK/PD) 83 20 0.4 index that correlates with its therapeutic efficacy is the AUC/MIC. 84 21 85 0.3 The aims of the study were to: (i) reveal the population pharma- 22 cokinetics, and (ii) assess the efficacy of various dosage regimens in 86 23 0.2 87

Standard Uptake Values (SUVs) achieving the probability of target attainment (PTA) and the cumula- 0.1 24 tive fraction of response (CFR) of levofloxacin. 88 25 0 89 2.5 7.5 12.5 17.5 22.5 27.5 32.5 37.5 42.5 47.5 52.5 57.5 Materials and Methods: The study was conducted in 45 healthy vol- 26 Time (min.) unteers. Each subject received one 500 mg tablet of levofloxacin, after 90 27 which PK studies were carried out, using a Monte Carlo simulation 81 28 to determine the PTA. By referral to the EUCAST MIC distributions 92 29 CYP2C19 Phenoconversion in patients 93 database, the dosage regimens were predicted to achieve CFR≥ 90%. 30 with Breast Cancer and alterations in 94 Results: The population PKs of levofloxacin were; Vd = 29.60 ± 31 Bioactivation of Cyclophosphamide 95 1.84 L, CL = 8.51 ± 1.43 L/h, and AUC = 66.19 ± 1.30 mg*h/L. 32 N. Helsby1; J. Yang1; M. Goldthorpe1; C. Barrett2; G. Wilson2; 96 The predicted CFRs for a target of AUC/MIC= 30 for S. aureus and R. Broom2; M. Findlay1,2,3; and D. Porter2 33 S. pneumoniae were 75.59% and 92.63%, respectively for 500 mg 97 1School of Medical Sciences, University of Auckland, Auckland, 34 levofloxacin and 84.56% and 98.16%, respectively for 750 mg levo- 98 35 New Zealand; 2Auckland Regional Cancer and Blood Service, 99 floxacin. The predicted CFRs for a target of AUC/MIC= 125 for E. Auckland City Hospital, Auckland, New Zealand; and 3Cancer 36 coli and Klebsiella spp. were 84.25% and 88.81%, respectively for 100 Trials New Zealand 37 500 mg levofloxacin and 86.00% and 91.34%, respectively for 750 101 Introduction: Cyclophosphamide (CP) requires activation by liver 38 mg levofloxacin. The PTAs for selected regimens were as follows. 102 39 CYP enzymes to form the cytotoxic precursor 4-hydroxy-cyclo- 103 40 phosphamide (4-OHCP). CYP2C19 and CYP2B6 pharmacogene PTA of AUC/MIC 104 41 variants influence inter-individual variation in cyclophosphamide Dose MIC (mg/L) 105 42 bioactivation. However, an acquired loss of function in CYP2C19 30 125 106 43 activity (phenoconversion) has been reported in up to 37% of cancer 107 44 patients. The influence of this phenotypic discrepancy on bioactiva- 500 mg 0.25 100 92.85 108 45 tion of cyclophosphamide is not known. 0.5 99.96 35.85 109 1 94.23 1.44 46 Aims: (1) To determine the prevalence of acquired loss of CYP2C19 2 39.97 0.00 110 47 activity in women with breast cancer (2) To determine the influence 750 mg 0.25 100 99.40 111 48 of both acquired and inherited loss of function on the bioactivation 0.5 100 75.90 112 49 of cyclophosphamide in these patients. 1 99.95 13.12 113 2 79.17 0.16 50 Methods: Following informed consent women with breast cancer 114 51 receiving cyclophosphamide were recruited (n 26). Prior to receiv- 115 = Conclusion: High PTAs (≥ 90%) achieving AUC/MIC = 30 for an 52 ing chemotherapy, the activity of CYP2C19 was assessed using the 116 MIC of 1 mg/L and AUC/MIC= 125 for an MIC of 0.25 mg/L were 53 probe drug (proguanil 200 mg, p.o.) on two separate occasions (cycle observed when levofloxacin was administered in a 500 mg or 750 mg. 117 54 1 and 3). The bioactivation of cyclophosphamide (plasma ratio of Both regimens had high probabilities of achieving optimal exposure 118 55 CP/4-OHCP) was also assessed at these occasions. The patients against S. pneumoniae. 119 56 were genotyped for common CYP2C19 and CYP2B6 gene variants. 120 57 Associations between CYP2C19 function, genotype and the bioacti- 121 58 vation of cyclophosphamide were then assessed. 122 59 Results: At the first cycle of treatment two women (8%) had Screening for phenotypical variation in 123 60 CYP2C19 poor metaboliser function, which was discordant to geno- CYP activity in patients with therapeutic 124 61 type, indicating phenoconversion. At the third cycle of treatment the problem in psychiatric settings 125 62 prevalence of discordant poor metabolisers was higher (19%). At C. Lloret-Linares; V. Rollason; K. Ing Lorenzini; C. Samer; 126 63 cycle 1 cyclophosphamide bioactivation (CP/4OHCP) was decreased Y. Daali; M. Rebsamen; J. Desmeules; and M. Besson 127 Geneva University Hospitals, Geneva, Switzerland 64 (P < 0.05) in patients with > 1 loss of function CYP2C19 allele. 128

2015 e3 Clinical Therapeutics

1 Background or Introduction: The clinical relevance of seeking for Montelukast. These 10% reports included several PT: Suicidal idea- 65 2 variation in cytochrome P450 activity in case of non-response or tion (447; 66%), Suicide attempt (95; 14%), Intentional self-injury 66 3 adverse effects to drugs is poorly documented. This retrospective (60; 9%), Completed suicide (56; 7%), Self-injurious ideation (44; 67 4 study aimed to assess how much the assessment of CYP activity rec- 7%), Self-injurious behaviour (44; 7%) and, Suicidal behaviour (27; 68 5 ommended by clinical pharmacologist allowed to explain therapeutic 4%). 69 6 problems in patients on psychotropic agents. Within the “Suicidal and self-injurious behaviours” HGLT, 70 7 Material and Methods: We retrospectively collected the results of Completed suicide PT (82%) and Suicide attempt PT (78%) were 71 8 the genetic and phenotypic investigations that were performed from more frequently reported for adolescents and suicidal ideation (66%) 72 9 2005 until November 2014 in patients receiving psychotropic drugs for children (2-11y). The IC values for completed suicide reached 73 10 as well as their indication. According to a semi-quantitative scale, two 3.15 in children and 3.11 in adolescents, however, the IC for the 74 11 clinical pharmacologists determined independently the link between total population was 1.95. 75 12 CYP activities and the clinical or biological event. In case of disagree- Conclusions: The presence of fatal cases without previous anxiety/ 76 13 ment, a third clinical pharmacologist scored the link. depression reported, the positive dechallenge in ideation, attempt 77 14 Results: Among the 695 pharmacological advices involving meta- suicidal or self injurious behaviours and the positive rechallenge in 78 15 bolic exploration, 260 concerned psychotropic drugs. Among them, few cases, support the urgent need to implement well-designed epi- 79 16 135 cases included a complete statement of drug metabolic pathways. demiologic studies that can lead to the quantification of the suicide/ 80 17 Advices mostly concerned antidepressants (n = 90), including tricy- suicide attempt risk level among children using montelukast. 81 18 clic antidepressants (n = 14), followed by antipsychotics (n = 27), 82 19 benzodiazepines and hypnotics (n = 14), and psychostimulants (n = 83 20 4). The phenotype and/or genotype determination was performed for Trends in Antibiotic consumption upon 84 21 the following reasons: side effects (n = 73, 54.1) lack of efficacy (n implementation of Educational measures 85 22 = 44, 32.6%), low concentrations (n = 14, 10.4%), high concentra- 1 1 1,2 86 M. Stanić ; N. Skočibušić ; and V. Vlahović -Palčevski 23 tions (n = 4, 3.0%). There was a good agreement between the two 1University Hospital Center Rijeka, Rijeka, Croatia; and 87 24 clinical pharmacologists, who scored the same way in 97% of cases 2University of Rijeka Medical Faculty, Rijeka, Croatia 88 25 (131/135). Introduction: Despite antibiotic’s remarkable value, their misuse 89 26 According to the statement of the three pharmacologists, in 22% leads to decreased effectiveness. Infection with resistant bacterial 90 27 (n = 30) and 12.6% (n = 17) of the cases, a modified activity of strains requires longer and more expensive therapy and increases 81 28 CYP450 explained the therapeutic problem with a high and inter- morbidity and mortality. Within antimicrobial stewardship program, 92 29 mediate probability, respectively. In patients with side effects, these educational measures pinpointing appropriate antimicrobial use are 93 30 probabilities were 22.3% and 17% respectively whereas for a lack important and well-established tools in fighting irresponsible anti- 94 31 of efficacy, they were 13.6% and 11.4% respectively. biotic use. 95 32 Conclusions: When indicated by clinical pharmacologists, metabolic Patients and methods: Population-based cross sectional survey was 96 33 exploration explained clinical or biological events related to drug conducted in Primorsko-goranska County in Croatia in 2009, 2010, 97 34 intake in approximately 35%. These findings should encourage more 2011 and 2014. Questionnaires were used to investigate general 98 35 systematic assessment of metabolic pathways in psychiatric patients. population attitudes, habits and knowledge on antibiotic use before 99 36 and after educational activities delivered through public campaigns. 100 37 Time series analysis of antibiotic outpatient’s consumption through 101 38 Highlights of montelukast in Children. the period of five years was also conducted. 102 39 updated analysis of the related suicide Results: Improvement in cognitive (91.08 to 95.03%) affective 103 40 behaviours in the who database. (17.76 to 11.2%), and behavioural (17.71 to 8.14%) component 104 41 January 2015. is observed during the period of five years. The willingness to self- 105 42 A. Aldea-Perona1; M. García-Sáiz1; and E. Sanz-Álvarez1,2,3 medicate was lowering over the years from 26% in 2009 to 13.6% 106 43 1Hospital Universitario de Canarias, Tenerife, Spain; 2University in 2014. After the educational measures among the population and 107 44 of La Laguna, Tenerife, Spain; and 3WHO Uppsala Monitoring physicians were implemented, the reduction of outpatient antimicro- 108 45 Centre Signal Review Panel, Uppsala, Sweden bial drug use was noted in Primorsko-goranska County from 7.91 109 46 Introduction: At present, there are divergent opinions on the associa- DDD/inhabitant in 2008 to 7.37 DDD/inhabitant in 2013. 110 47 tion of suicide behaviour and the use of montelukast in asthmatic Conclusion: Educational measures through the public campaign 111 48 or allergic patients. significantly improved knowledge of the population and have had a 112 49 Material and Methods: The BCPNN method was used to analyse substantial positive impact on more appropriate antibiotic consump- 113 50 the ICSR of the association montelukast-suicide behaviours, up to tion in outpatient setting. 114 51 January 2015, in order to evaluate the safety concerns that have 115 52 been raised regarding the increased risk of completed, ideation and 116 53 117 attempt suicide with its use. Biologic agents in Rheumatic diseases – a 54 Results: The most frequent fatal cases reported with Psychiatric dis- 118 55 real life experience 119 orders and montelukast were (Nfatal/Ncomb): 183/183 completed 1 1 1 1,2 56 M. Stanić ; N. Skočibušić ; T. Zekić ; S. Novak ; and V. 120 suicide, 26/1083 depression, 10/832 insomnia, 10/815 anxiety. The 1,2 57 Vlahović -Palčevski 121 ICSR of suicidal ideation, aggression, suicide attempt or depression 1 58 University Hospital Center Rijeka, Rijeka, Croatia; and 122 have positive dechallenge in 52 %, 44%, 22% and 48%, of the 2University of Rijeka Medical Faculty, Rijeka, Croatia 59 cases respectively. Positive rechallenge were reported in 3 cases of 123 Introduction: Since biologic-agents have recently become part of 60 suicide ideation. 124 regular treatment protocols for rheumatic disorders the aim of this 61 In the global WHO Database there were 6,722 ICSR for the 125 study was to evaluate their use, efficacy and safety at the University 62 “Suicidal and self-injurious behaviours” HLGT for all drugs in 126 Hospital Centre Rijeka in Croatia. 63 pediatric population. Out of them 10% (674) corresponds to 127 64 128

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1 Patients and Methods: A total of 108 patients diagnosed with rheu- Conclusion: It is valid to use PPI to provide and maintain a gas- 65 2 matoid arthritis (RA) (50), ankylosing spondilits (AS 33), psoriatic tric acid suppression at planned duration after investigational drug 66 3 arthritis (PsA 16), treated with biologicals (TNFα inhibitors – adali- administration when special considerations are needed regarding a 67 4 mumab/infliksimab/golimumab/etanercept, tocilizumab, rituksimab) gastric acid environment. Although the dose of acid reducers and the 68 5 were evaluated in a retrospective study conducted in eight-year timing of the administration need further investigation, our results 69 6 period. indicate the future possibility of conducting clinical studies for a 70 7 Results: Average treatment period for the first-line biological was 56, special range of gastric acidity with carefully chosen agents. 71 8 41, 36, 36, 28, 20 months for etanercept, adalimumab, infliksimab, 72 9 rituksimab, tocilizumab and golimumab respectively. In patients 73 10 with RA, first-line TNFα inhibitors were prescribed in 53% cases, Interaction between Tramadol and 74 11 followed by etanercept and tocilizumab in 18% and rituksimab SSRI’s: do we care? 75 12 in10%. For AS and PsA, TNFα inhibitors were more frequently first P.E. Spies1; R. Willems2; H. Pot3; J.M. Bos4; and C. Kramers4,5 76 13 choice biological when compared to etanercept (AS 79% and 21% 1Rijnstate hospital, Arnhem, The Netherlands; 2Erasmus medical 77 14 vs. PsA63% and 37%). The longest duration of biologic therapy was centre, Rotterdam, The Netherlands; 3Meander medical centre, 78 15 in AS patients (47 months). Regardless of diagnosis, 31% patients Amersfoort, The Netherlands; 4Canisius Wilhelmina hospital, 79 16 required switching to another biological due to non efficacy (94, Nijmegen, The Netherlands; and 5Radboud university medical 80 17 1%). TNFα inhibitors were switched in 73% cases and etanercept in centre, Nijmegen, The Netherlands 81 18 27% patients. Seven patients discontinued treatment due to complete Introduction: The combination of a selective serotonin reuptake 82 19 remission, serious infection, chemotherapy, cerebrovascular insult, inhibitor (SSRI) with tramadol can result in serotonin syndrome, 83 20 newly diagnosed psychiatric disorder, moving to another city and characterized by neuromuscular excitation, autonomic nervous sys- 84 21 private reason. There were 21 adverse drug reactions: infections (16), tem excitation, and altered mental state. The serotonin syndrome 85 22 leucopenia and anemia (4) and pharyngeal carcinoma (1). can be mild but also life-threatening and is more easily prevented 86 23 Conclusion: Six biologic agents with different mechanism of action than treated. Most overview articles consider awareness of the sero- 87 24 (TNFα inhibitors (4), anti-CD20 (1) and IL6 inhibitor (1)) are used tonin syndrome the most important step to prevent it, yet research 88 25 in treatment of RA. For AS and PsA, four TNFα inhibitors were used among GP’s showed that a mere 15% was aware of this potentially 89 26 what is in accordance with Croatian clinical practice guidelines. More dangerous syndrome. We aimed to investigate whether prescribers 90 27 frequent switching between different TNFα inhibitors is consistent in a general hospital were aware of this risk and if it influenced their 81 28 with similar reports. prescriptions. 92 29 Material and Methods: A questionnaire was sent to 185 physicians 93 30 and 9 physician assistants in a general teaching hospital with over 94 31 Intragastric PH transition induced by 650 beds in the Netherlands. The questionnaire presented four cases, 95 32 Rabeprazole: investigation of clinical two of whom used an SSRI among other medications, and asked 96 33 study design the respondent to prescribe an opioid in each case. The respondent 97 34 M. Shiramoto1; E. Chung1; H. Uchimaru1; T. Eto2; M. Inoue1; H. was not made aware of the focus of the research. In addition, we 98 35 Tachiki3; and S. Irie1 explored actual prescription rates of tramadol in admitted patients 99 36 1Hakata Clinic, Souseikai Global Clinical Research Center, who used or did not use an SSRI by using the database of the hospital 100 37 Fukuoka, Japan; 2PS Clinic, Souseikai Global Clinical Research pharmacy. 101 38 Center, Fukuoka, Japan; and 3Research & Development Division, Results: Eighty-four questionnaires were available for analysis 102 39 Towa Pharmaceutical Co., LTD., Kyoto, Japan (response rate 46%). About one-third of respondents prescribed 103 40 Background: Gastric pH is known to vary depending upon diverse tramadol and indicated they were aware of the interaction with 104 41 populations and may affect the solubility, dissolution or absorption SSRI’s. About one-fifth deliberately avoided tramadol because an 105 42 of a drug. In drug development, if the investigational drug increases interaction with SSRI’s was identified. However, there was no differ- 106 43 gastric pH, the effects on other drugs sensitive to this should be pre- ence in actual tramadol prescriptions: 23.8% of SSRI-users received 107 44 dicted and considered in vivo studies for further evaluation. However, tramadol, versus 24.6% of non-SSRI-users. 108 45 since it is difficult to conduct a study with healthy volunteers who Conclusions: A small part of prescribers in a general hospital is 109 46 have suppressed gastric acid secretion, we evaluated the study design aware of the interaction between tramadol and SSRI’s, yet this does 110 47 using Proton Pump Inhibitor (PPIs). not translate to a difference in tramadol prescriptions in clinical prac- 111 48 Materials and Methods: Eighteen healthy male volunteers who pro- tice. Hospital pharmacies may play an important role in signaling the 112 49 vided written informed consent participated. This study was an open- interaction and advising prescribers. 113 50 label, 3-period, 2-part, crossover study. Part 1 was the control period, 114 51 and Part 2 was for effects of food and Rabeprazole determination. 115 52 116 The 24 hour intragastric pH was monitored starting at 17:00 for each Noninvasive retinal and cutaneous 53 period. Rabeprazole (20 mg) was administered orally as PPI at 19:30 117 54 Microcirculation imaging in sickle cell 118 after dinner and at 06:00 the next morning. Moreover, we evaluated disease patients and Healthy Volunteers 55 the difference in intragastric pH transitions among the three differ- 119 56 W. Birkhoff; J. de Vries; T. Ruijs; M. de Kam; M. Moerland; and 120 ent genotypes of CYP2C19: homoEM (EM: Extensive Metabolizer), J. Burggraaf 57 heteroEM, and PM (Poor Metabolizer). 121 58 Centre for Human Drug Research, Leiden, The Netherlands 122 Results: Rabeprazole increased the intragastric pH (pH > 5.5) and Validated methodology to assess microvascular function in sickle cell 59 maintained this condition at the target time between 09:00 and 13:00 123 60 disease (SCD) patients is not readily available, but could be of great 124 the next day. Food did not affect the results considerably, but the benefit in clinical research. We explored the feasibility and robust- 61 intragastric pH increased slightly in the group without food after 125 62 ness of two quantitative methods for microvascular function: laser- 126 Rabeprazole. Furthermore, Rabeprazole had a tendency to increase speckle contrast imaging (LSCI) and non-invasive retinal function 63 the intragastric pH in CYP2C19 PM compare to CYP2C19 homoEM. 127 64 imaging (RFI). 128

2015 e5 Clinical Therapeutics

1 Microvascular function was assessed in moderate to severe hypertension (16.4%) and other toxicities (30.3%). CYP3A4 65 2 SCD patients, male/female, aged 18-65 (n = 6), healthy volunteers rs4646437(G> A) was not significantly associated to any toxicity 66 3 matched for age, BMI, smoking behavior and skin color (n = 6) and endpoint in the multivariate analysis . Median PFS was 20 months 67 4 unmatched healthy volunteers (HV; n = 12). Measurements were (follow-up 45) and OS was 31 months (follow-up 55). There were 68 5 conducted twice on two study days separated by one week. LCSI no differences in PFS and OS between CYP3A4 rs4646437 wild type 69 6 was performed before, during and after 5 minutes brachial artery and A allele carrier patients. 70 7 occlusion and after inspiratory breath holding (IBH) of 20 seconds, Conclusions: SNP CYP3A4 rs4646437(G> A) is not associated 71 8 endpoints included basal flow, flow upon occlusion-reperfusion and with treatment outcome in our cohort of clear cell mRCC 72 9 flow during an IBH (measured in arbitrary units (AU)). RFI was patients. 73 10 performed after LSCI for assessment of arterial and venous retinal 74 11 blood flow (measured in mm/sec). Variability of these measurements 75 12 was calculated between and within subjects, and contrast between Pharmacokinetics and circulating 76 13 groups was assessed with a mixed model analysis of variance: LSCI Microrna profiles of extended release 77 14 basal flow, LSCI maximal flow, RFI arterial flow and RFI venous flow Hydromorphone in healthy subjects 78 15 showed excellent intra subject repeatability between days (CVC of K. To yama1; N. Kiyosawa1; H. Ishizuka1; T. Sambe2,3; 79 16 7.6%, 7.6%, 7.9% and 9.8% respectively) and between measure- S. Kobayashi3; and N. Uchida2,3 80 17 ments (CVC of 7.6%, 4.9%, 7.0% and 7.3% respectively). 1Daiichi Sankyo Co., Ltd., Tokyo, Japan; 2Showa University, 81 18 There were significant differences between SCD patients and Tokyo, Japan; and 3Showa University Clinical Research Institute 82 19 matched HV in LSCI basal flow AU (35.31 vs. 25.25; P < 0.0001), for Clinical Pharmacology and Therapeutics, Tokyo, Japan 83 20 LSCI maximal flow AU (96.16 vs. 75.16; P < 0.0001), LSCI Delta Background: Hydromorphone is a semisynthetic opioid analgesic 84 21 flow during an IBH (10 vs. 5; P ≤ 0.0001), RFI arterial flow mm/sec which has been used extensively as an effective alternative to mor- 85 22 (4.013 vs. 3.532; P < 0.007) and RFI venous flow mm/sec (3.054 vs phine for the relief of acute and chronic pain. However, currently, 86 23 2.737; P = 0.0310). no hydromorphone formulation has been approved in Japan. A new 87 24 The relatively low variability for most LCSI and RFI readout hydrophilic matrix extended-release (ER) tablet has been developed 88 25 measures and the discriminating power between SCD patients and to deliver hydromorphone over an extended period resulting in sus- 89 26 matched healthy volunteers demonstrate the feasibility of both tech- tained plasma concentrations. The objective of th is study was to 90 27 niques to assess the microcirculation in clinical research. assess the pharmacokinetics and safety of hydromorphone to healthy 81 28 Japanese subjects. In addition, circulating microRNAs (miRNAs) 92 29 were evaluated to explore candidate biomarkers for pharmacody- 93 30 Association analysis of CYP3A4 namics and safety of hydromorphone. 94 31 RS4646437(G> A) with sunitinib response in Material and Methods: Healthy male subjects participated in an 95 32 renal Cancer open-label study to receive a single oral dose of the ER hydromor- 96 33 A. Belaustegui1; M. Diekstra2; J. Swen2; B. Sanjose1; I. Bilbao1; phone tablet. The plasma and urinary concentrations were measured 97 34 G. Ros1; M.A. Gil1; A. de Basagoiti1; M. de Miguel1; and by LC-MS/MS. Plasma miRNA profiling was performed with an 98 35 H.J. Guchelaar2 Exiqon Serum/Plasma focus PCR panel (179 miRNAs). Safety was 99 36 1Hospital Universitario Cruces. Barakaldo, Bizkaia, Spain; and assessed by clinical evaluation and laboratory measurements. 100 37 2Leids Universitair Medisch Centrum, Leiden, The Netherlands Results: The median plasma hydromorphone concentration peaked 101 38 Introduction: Sunitinib is a widely prescribed drug in metastatic rather late. AUC and C max increased almost dose-proportionally. 102 39 renal cell carcinoma (mRCC) with a large inter-individual variabil- The degree of fluctuation in the plasma concentration for the ER 103 40 ity in response. Identification of genetic biomarkers to predict suni- tablet was low and certain levels of plasma concentrations were 104 41 tinib treatment outcome could improve clinical practice. Recently, maintained after 24 h of ER dosing. The cumulative urinary excre- 105 42 106 rs4646437(G> A) in CYP3A4 was suggested to be related to suni- tion amounts of hydromorphone and hydromorphone-3-glucuronide 43 tinib induced toxicity. Therefore, we aimed to investigate whether were 3% and 30% of the dose, respectively. A number of miRNAs 107 44 there was a relationship between this single nucleotide polymor- showed temporal changes in their expression levels, most of which 108 45 phism (SNP) and sunitinib treatment response in a cohort of mRCC are likely to reflect the circadian rhythm. A limited number of miR- 109 46 patients. NAs showed up-regulation. In particular, miR-28, miR-551 and 110 47 Material and Methods: An observational retrospective multicentre let-7d showed relatively unique up-regulation. All doses of hydro- 111 48 study was performed. Germ line DNA and clinical information from morphone were well-tolerated. 112 49 medical records of clear cell mRCC patients, treated with sunitinib Conclusions: A once daily dose of the new ER formulation of hydro- 113 50 was obtained. Genotyping analysis was performed by real-time PCR morphone would provide a suitable efficacy in patients from the 114 51 with Taqman® probes on LightCycler480® platform. Toxicity was pharmacokinetic profiles. A number of miRNA elicited differential 115 52 evaluated during the first 4 cycles of treatment according to CTCAE regulations in the plasma, which may potentially contain novel bio- 116 53 (version 4.0). The association of the SNP with leukopenia, throm- markers to evaluate pharmacodynamics and safety. 117 54 bocytopenia, hand-foot syndrome (HFS), mucositis, hypertension 118 55 and any other toxicity above grade 2 was tested with logistic regres- 119 56 120 sion. Progression free survival (PFS) and overall survival (OS) were Particularities of the Pharmacological 57 estimated using Kaplan-Meier. Cox-regression model was used for 121 58 management of dilated Cardiomyopathy 122 multivariate association analysis of the SNP with survival. in Cluj-Napoca County Hospital 59 Results: Two hundred one patients were included (67.7% males). 123 C. Pop; E. Buzdugan; O. Vostinaru; I. Cazacu; F. Loghin; and 60 Median age, at start of treatment, was 61 years old (range: 34-84). 124 C. Mogosan 61 Dose reductions after cycle 1, 2 or 3 occurred in 33.3% of patients 125 University of Medicine and Pharmacy “Iuliu Hatieganu” 62 (79% due to toxicity). Observed grade 3-4 toxicities were: thrombo- 126 Cluj-Napoca, Romania 63 cytopenia (10%) leukopenia (3%), mucositis (1.5%), HFS (5.5%), 127 64 128

e6 Volume XX Number XX Challenges of Generic Imatinib Therapy for Croatian Patients With Gastrontestinal St Romal Tumors (GIST)

1 Introduction: Dilated cardiomyopathy (DCM) remains an important Pharmacokinetic Issues in Obese Patients 65 2 cause of systolic heart failure and the most common cause of heart S. Engeli1; M. May2; and J. Jordan1 66 3 failure in people referred for cardiac transplantation. Currently, there 1Institute of Clinical Pharmacology, Hannover Medical School, 67 4 are no official guidelines for the management of DCM, only evidence- Hannover, Germany; and 2Clinical Research Center Hannover, 68 5 based recommendations, thus particularities can occur in each clinic. Hannover Medical School, Hannover, Germany 69 6 The objective of the present study was to analyze the pharmacological Introduction: Obesity is associated with several pathophysiological 70 7 management of DCM patients in a County Hospital. changes that may interfere with pharmacokinetic properties of drugs 71 8 Materials and Method: The present work is a retrospective non- including increased plasma volume, fatty liver disease, and changes 72 9 interventional study. Patient selection and data collection were in glomerular filtration rate (GFR). Drastic weight changes with 73 10 performed using the County Hospital database. We analyzed demo- bariatric surgery further complicate the issue. Correct drug dosing 74 11 graphic and clinical data for patients hospitalized between January in obese patients, particularly following bariatric surgery, therefore 75 12 2010 and December 2012, primarily diagnosed with DCM, and hav- appears a difficult task. 76 13 ing a left ventricular ejection fraction (LVEF) < 40%. Material and Methods: We reviewed and summarized relevant litera- 77 14 Results: A total of 85 patient charts were analyzed (75.3% male, ture and available information on drug-disease interaction and phar- 78 15 mean age 66.3 years). The main drug classes used for the manage- macokinetic alterations associated with obesity and bariatric surgery. 79 16 ment of DCM patients were: beta blockers (77.65%), angiotensin- Results: Adipose tissue accumulation, changes in regional blood 80 17 converting enzyme inhibitors (ACE-I) (71.76%), diuretics (58.82%), flow, and changes in plasma protein binding capacities change the 81 18 antagonists (49.41%), coumarins (45.88%) and statins volume of distribution of drugs in obese patients. Additionally, 82 19 (42.35%). Comparing the differences and similarities of the therapy cytochrome P450 enzyme activities may be changed, although not 83 20 of DCM patients with NYHA class I to those with NYHA class in a consistent manner. For example, CYP3A4 activity appears to be 84 21 IV, ACE-I use was relatively similar (57.14% to 59.1%), diuretics decreased in obesity, but 1 year after bariatric surgery, metabolism 85 22 use increased (42.85% to 81.81%) and beta blockers use decreased of CYP3A4-dependent drugs is enhanced despite the loss of intesti- 86 23 (42.85% to 31.81%). The use of beta blockers was associated with nal CYP3A4 activity through surgery. GFR is transiently increased 87 24 an improvement of LVEF within 6 months from a median of 30% to in early obesity and then tends to decline secondary to glomerular 88 25 48%, in 27.37% of the patients. damage that develops with longstanding obesity. Several examples 89 26 Conclusion: Despite the lack of official guidelines, DCM patients for dose adjustment suggestions were identified in the literature, 90 27 received optimal treatment leading to the improvement of LVEF. many not based on solid evidence. Pharmacokinetic consequences 81 28 Beta blockers, ACE-I and diuretics were the most frequently used of bariatric surgery and implications for drug therapy are divergent 92 29 drugs for the management of DCM patients, while cardiac glycosides and individually influenced by type of surgery, drug properties and 93 30 angiotensin II receptor blockers and calcium channel blockers were potential intestinal adaptions after surgery. 94 31 less frequently used. Conclusions: We identified a tremendous knowledge gap caused by 95 32 the lack of appropriate studies regarding dose adjustments in obesity 96 33 and after bariatric surgery. The lack of knowledge poses a safety 97 34 Correlation between diabetic cataract, concern in massively obese subjects, particularly for drugs with a 98 35 HBA1C and Gurakhu: a clinical study in small therapeutic window. 99 36 Chhattisgarh State 100 37 A. Bhattacharya; Sanjay Gupta; and S.H. Bodakhe 101 38 GGV Central University, Bilaspur, Chhattisgarh, India Predictive ability of different 102 39 Introduction: In diabetes mellitus, higher amounts of glycated hemo- analytical parameters in Mycophenolate 103 40 globin, indicating poorer control of blood glucose levels, have been Pharmacokinetics and dosing 104 41 105 associated with cardiovascular disease, nephropathy, and retinopa- B.M. García Palop; M.J. De Dios García; A. Blanco Grau; 42 106 thy. Guraku’s basic components are nicotine and jaggery; jaggery is I. Comas Reixach; and J.B. Montoro Ronsano 43 107 made up of sugarcane so can have a diabetogenic potential which is Vall d'Hebron University Hospital, Barcelona, Spain 44 108 exacerbated in presence of nicotine. This work had done with the aim Background: Mycophenolate (MPA), antimetabolite inmunosup- 45 109 to find correlation between Diabetic cataract, HbA1c and Guraku. pressant of choice in solid organ transplant regimens, is available in 46 110 Material and Methods: A cross sectional observational study of total two compounds (mofetil and sodium) and displays large between- 47 111 75 subjects had been performed. Data was collected from the pre- subject pharmacokinetic (PK) variability. The aim of this study was to 48 112 scriptions, medical history and self designed questionnaire. The sub- identify and model the different factors influencing MPA variability. 49 113 jects were enrolled according to the inclusion and exclusion criteria. Methods: Patients treated with oral mycophenolate (mofetil or 50 114 Results: In the study it was found that people consuming Guraku sodium) in our institution and having a record of drug serum levels 51 115 had a high level of HbA1c thus are more prone to the development were included in this observational, cross-over study over a period 52 116 of diabetic cataract. Male subjects (57%) are the more than female of six years (2004-2010). Both biodemographic (age, sex, weight, 53 117 subjects (43%). Most of the subjects belong to the lower socioeco- height, ethnicity) and analytical data (creatinine, total and direct 54 118 nomical class and not very educated. Average blood glucose (29%), bilirubin) were collected. Renal function was assessed by CKD-EPI 55 119 Subjects with high level of Hb1Ac (40%) and subjects with high level formula. The influence of these variables on mycophenolate phar- 56 120 of Glucose tolerance value (30%) in diabetic cataract were observed. macokinetics was evaluated following a multiple linear regression 57 121 Conclusion: It could be concluded that this type of study could model. 58 122 be useful in identifying number of subjects suffering from diabetic Results: Data from 136 patients, treated with mycophenolate mofetil 59 123 cataract whose condition get worse by use of nicotine product like (64%) or sodium (36%), were included; mean age 53 years, 67% 60 124 Guraku and preventive measure to be taken in prevention of this type men. Dose values MPA/kg and minimum plasma drug concentra- 61 125 of diabetic complication. tion (C ), in addition to serum creatinine and bilirubin - total 62 trough 126 Key words: Diabetic cataract, HbA1c, Guraku, Diabetogenic poten- and direct - were [mean (SD)] 11 mg/kg (3.6), 2.43 mg/mL (1.61), 63 127 tial 1.69 mg/dL (3.10), 0.61 mg/dL (0.28), 0.28 mg/dL (0.10), 64 128

2015 e7 Clinical Therapeutics

1 respectively. Mean renal function was 58.8 mL/min/1.73m2 (23.2), 1University Medical Center Groningen, Groningen, The 65 2 according CKD-EPI formula. The regression analysis showed that Netherlands; 2University of Maastricht, Maastricht, The 66 3 4 3 19.4% of Ctrough variation can be explained by the different drug Netherlands; Ghent University, Ghent, Belgium; VU University 67 5 4 formulation (P = 0.018) and the individual clearance pattern of each Medical Center, Amsterdam, The Netherlands; MasOutreach, 68 6 5 patient - renal (P = 0.001) and hepatic function (P = 0.033). Leeuwarden, The Netherlands; and iChoice4U, Groningen, The 69 6 Conclusions: MPA formulation, as well as renal (CKD-EPI) and Netherlands 70 7 hepatic function (total bilirubin), were the covariates identified as Introduction: “Pscribe” is a problem-based, case-oriented and multi- 71

8 influencing MPA troughC . Therefore, individualisation of MPA treat- functional pharmacotherapy e-learning web-application based on the 72 9 ment using a forecasting model to assess target concentration that WHO-6Step patient-treatment-model. Aim of this study is: 1) to test 73 10 contemplates these factors must be considered in preference to giving the data-tracking module (DaTM) of Pscribe as a valid instrument 74 11 a standard dose. that can be used to automatically register and map data during the 75 12 drug-choice process (tDCP), 2) to compare tDCP of bachelor medical 76 13 students and experts. 77 14 Comparative safety profile of Amoxicillin Methods: DaTM automatically registers online 26 variables related 78 15 to drug-choice behaviour including: the quality of drug-therapy 79 alone and in association with n n 16 clavulanic Acid in pediatrics: data from choice (QDTC), the duration of every taken step (DoEStep ) in the 80 17 spontaneous reporting in Italy 6Step route and the number of consultations on drug information 81 18 M. Donati; G. Raspadori; M. Melis; C. Biagi; A. Vaccheri; and [NoCoDI] during tDCP. 1) Its technical reliability was assessed with 82 19 D. Motola the help of predefined paper protocols; all input values were com- 83 20 University of Bologna, via Irnerio 48, 40126, Bologna, Italy pared with output values, 2) We compared 85 bachelor students in 84 21 Background or Introduction: Amoxicillin alone and with clavulanic four groups (n = 18 – 25) with one expert group (n = 5) solving 85 22 acid are among the most prescribing antibacterial agents in Italy. the same patient-case problems. Data were collected, analysed and 86 23 These drugs are generally well tolerated and usually prescribed by visualised using DaTM, Excel, SPSS and MATLAB. 87 24 paediatrics, although published studies indicate that they are fre- Results: 1) Input values of all tested 26 variables are 100% matching 88 25 quently associated with adverse drug reactions (ADRs), in particular with the output values. The online time-delay (~3 seconds) spend 89 n is corrected, 2) The student groups differed 26 cutaneous and gastrointestinal ones. We analyzed the Italian database in each registered step 90 significantly (P 0.05) from the expert group in the QDTC scores 27 of spontaneous reporting of suspected ADRs in order to compare the < 81 and duration of the relevant drug-treatment step DoEStep3.2, and 28 safety profile of amoxicillin and amoxicillin/clavulanic acid (amoxi- 92 (P 0.01) in [NoCoDI]. We could perform pattern analysis of how 29 clav) in pediatrics. < 93 participants per group went through the 6Step route, visualized by a 30 Material and Methods: Reports of suspected ADRs due to amoxi- 94 matrix method and yielded various step-patterns. 31 cillin and amoxi-clav in pediatric patients, until 1 September 2014, 95 Conclusions: 1) Pscribe is a valid instrument to automatically register 32 were extracted. ADRs were coded using MedDRA terminology. To 96 and map data during tDCP, 2) QDTC, DoEStep3.2 and NoCoDI may 33 evaluate the correlation between drug use and occurrence of ADRs 97 represent good variables to discriminate and reflect differences in 34 a disproportionality analysis through Reporting Odds Ratio (ROR) 98 knowledge and reasoning skills between students and experts dur- 35 was performed. 99 ing tDCP. Combining these data with analysis of step patterns will 36 Results: We collected 3.345 reports associated with amoxicillin and 100 provide insight in the way optimal drug choices are made. 37 amoxicillin/clavulanic acid, 1.188 (35.5%) related to amoxicillin and 101 38 2.157 (64.5%) to amoxicillin with clavulanic acid. The percentages 102 39 of serious ADRs were 12% for amoxicillin and 16% for amoxi-clav. 103 40 The percentage of skin reactions was higher for amoxicillin (75%) Cardioprotective properties of 104 41 than for amoxicillin/clavulanic acid (67%) and for gastrointestinal polyphenol concentrate in Rat model of 105 42 reactions was higher for amoxicillin/clavulanic acid (16%) than for Doxorubicin-induced Cardiomyopathy 106 43 amoxicillin (10%). For amoxicillin, significant disproportionality Z. Shulgau; A. Gulyayev; B. Yermekbayeva; G. Adilgozhina; 107 44 was observed only for cutaneous ADR like dermatitis (ROR, 2.31; V. Tritek; and T. Nurgozhin 108 45 95% CI, 1.26–4.25), rash (1.30; 1.08–1.57), erythematous rash PI “Center for Life Sciences”, Nazarbayev University, Astana, 109 46 (1.70; 1.18–2.45). For amoxicillin/clavulanic acid was observed only Kazakhstan 110 47 for gastrointestinal ADR: diarrhoea (1.56; 1.15–2.12), abdominal Purpose: Present study aimed to investigate possible cardioprotec- 111 48 pain (2.11; 1.14–3.93) and sickness (1.69; 1.20–2.38). tive properties of polyphenol concentrates obtained from Cabernet 112 49 Conclusions: Our analysis shows a different safety profile for amoxi- Sauvignon type of Kazakhstani grapes using rat model doxorubicin- 113 50 cillin and amoxi-clav in paediatrics: the first is associated with an induced cardiomyopathy. 114 51 higher risk of skin reactions while the amoxi-clav with gastroin- Methods: Study was conducted on 20 white outbred female rats 115 52 testinal ones. Nevertheless, data did not reveal an increased risk of weighing 160±20 g. that were divided into three groups: two 116 53 liver damage from clavulanic acid than amoxicillin alone, as widely groups with cardiomyopathy (14 rats) and one intact group (6 rats). 117 54 reported in literature. Cardiomyopathy was obtained by i.p. administration of doxoru- 118 55 bicin (8.0 mg/kg). The experimental group (7 rats) was receiving 119 56 intragastrically 0.5 ml of polyphenols concentrate during the next 120 57 121 Pscribe: a Pharmacotherapy E-learning 7 days after injection of doxorubicin. The control group of animals 58 with cardiomyopathy (7 rats) was not treated. Activity of aspartate 122 59 Web-application enabling registration 123 and mapping of the rational drug-choice aminotransferase (AST) was determined in plasma. An oxidative 60 status in rats’ blood plasma was analyzed with 4 FRAS (Evolvo 124 61 process of students and experts 125 1,6 1 2 srl, Italy) using d-ROMs Test, which indicates the amount of free 62 A.B.D. van Doorn ; A.R. den Otter ; B.J.A. Janssen ; 126 1 1,6 5 1 radicals, and PAT Test, which characterizes total antioxidant activ- 63 L.J. Middel ; G.K. Bijl ; P.P. Bijl ; I. de Waard-Siebinga ; 127 3 4 1 ity of blood plasma. 64 R. van der Stichele ; Th.P.G.M. de Vries ; and R.H. Henning 128

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1 Results: The AST content, a measure of cytolysis, was higher for 22% Background: Five-oxoproline is a product of disordered glutathione 65 2 in animals with doxorubicin cardiomyopathy than in the intact ani- metabolism in the gamma glutamyl cycle: glutathione deficiency 66 3 mals. Administration of polyphenols restored the AST content degree removes the feedback inhibition resulting in the formation of γ -glu- 67 4 to normal values. The d-ROMs test showed an activation of oxida- tamylcysteine and elevated concentrations of γ -glutamylcysteine 68 5 tive stress in control group compared to the intact animals by 24%, leading to the formation of 5-oxoproline, which is degraded by 69 6 whereas the administration of polyphenols decreases oxidative stress 5-oxoprolinase. Both paracetamol and flucloxacillin interact with 70 7 activity by 12%. In comparison with intact animals, rats with cardio- the gamma glutamyl cyclus. Paracetamol depletes glutathione which 71 8 myopathy had a decrease in antioxidant potential by 28% according leads to the accumulation of γ –glutamylcysteine that is a precursor 72 9 to the PAT Test. However, the treated with polyphenols group had 9% for 5-oxoproline and flucloxacillin inhibits 5-oxoprolinase which 73 10 higher total antioxidant activity than the control group. also leads to accumulation of 5-oxoproline. The accumulation of 74 11 Conclusion: A concentrate of polyphenols obtained from Cabernet 5-oxoproline, an acid residue, may lead to a high anion gap and a 75 12 Sauvignon prevents reduction of the total antioxidant activity of metabolic acidosis. Although a few cases of this drug-drug interaction 76 13 plasma, limits the development of oxidative stress, and prevents cyto- are published, it is still not included in the summary of product char- 77 14 lytic processes in rats with doxorubicin cardiomyopathy. acteristics of paracetamol and flucloxacillin or included in medication 78 15 safety monitoring systems in hospitals and pharmacies. 79 16 Material and Methods: We analyzed all submitted reports to the 80 17 Phase i clinical trialto evaluate Netherlands’ Pharmacovigilance Centre Lareb till 31 December 2014 81 18 the pharmacokinetics, safety, and on this drug-drug interaction. 82 19 tolerability of one intramuscular Results: Lareb received 3 reports of metabolic acidosis where both 83 20 injection of risperidone ISM® at paracetamol and flucloxacillin, used in therapeutic doses, were 84 21 different dose strengths in subjects marked as suspected and interacting drugs. The cases concern 3 85 22 with Schizophrenia or Schizoaffective females of older age (67, 72 and 78 years). The aberrant mechanism 86 23 disorder (PRISMA-1) of the 72 year old female was treated with acetyl cysteine; she died. 87 24 J. Llaudó; I. Ayani; M. Monreal; J. Martínez-González; and The other 2 women were treated with sodium bicarbonate and recov- 88 25 I. Gutierro ered. We could not confirm a relationship between the treatment and 89 26 Laboratorios Farmacéuticos ROVI, S.A., Madrid the outcome of the interaction. 90 27 Introduction: Risperidone ISM is a new long acting intramuscu- Conclusions: Our reported cases contribute to the suspicion of a 81 28 lar injection of risperidone, intended for a 4-weekly administra- relationship between metabolic acidosis and concomitantly used par- 92 29 tion, without oral supplementation. A clinical trial was conducted acetamol and flucloxacillin. This drug interaction should be included 93 30 to characterize the pharmacokinetics and to evaluate the safety of in the summary of drug characteristics and included in medication 94 31 Risperidone ISM® in subjects with schizophrenia or schizoaffective monitoring systems in health institutions. 95 32 disorder (ClinicalTrials.gov identifier: NCT01788774). 96 33 Material and Method: A total of 36 subjects were randomized 97 34 (1:1:1) to receive a single IM injection of Risperidone ISM®: 13 (50 Evaluation of acute Cardiovascular 98 35 mg), 12 (75 mg) and 11 (100 mg). Blood samples were collected effects of immediate-release 99 36 through 75 days post-dose to measure the plasma concentrations of Methylphenidate in children and 100 37 risperidone and 9-OH-risperidone. adolescents with attention deficit 101 38 Results: A total of 36 subjects received a single IM injection of Hyperactivity disorder 102 39 Risperidone ISM®. The mean plasma concentration of the active M. Lamberti; D. Italiano; L. Guerriero; G. D’Amico; 103 40 104 moiety (risperidone + 9-OH-risperidone) in the 50 mg, 75 mg, and R. Siracusano; M. Ingrassia; E. Germanò; M.P. Calabrò; 41 100 mg group, respectively, was 21.4 ng/mL, 24.6 ng/mL, and 29.6 A. Gagliano; and E. Spina 105 42 ng/mL (24 hours after injection); 22.8 ng/mL, 24.5 ng/mL, and 31.4 University of Messina. Messina, Italy 106 43 ng/mL (48 hours after injection); and 12.2ng/mL, 17.3 ng/mL, and Introduction: Attention-Deficit Hyperactivity Disorder (ADHD) is 107 44 20.0 ng/ (Day 30 after injection). a frequent condition in children and often extends into adulthood. 108 45 Overall, 34 subjects (94.4%) experienced at least 1 Treatment Immediate release methylphenidate (IR-MPH) has raised concerns 109 46 Emergent Adverse Event (TEAE) during the study. The percent- about potential cardiovascular adverse effects within a few hours 110 47 age of subjects reporting at least 1 TEAE was similar across the 3 after administration. This study was carried out to investigate acute 111 48 dose groups (92.3%, 100%, and 90.9% in the 50, 75 and 100 mg effects of IR-MPH on ECG in a pediatric population. 112 49 group, respectively). Two subjects experienced an SAE and no deaths Methods: A total of 54 consecutive patients with ADHD (51 males 113 50 114 occurred during the study. There were no EPS-related SAEs and no and 3 females; mean age = 12.14+2.6 years, range 6-19 years), 51 subjects experienced significant change of any C-SSRS parameter. receiving a new prescription of methylphenidate (MPH), under- 115 52 Conclusions: Risperidone ISM® provided a sustained release of ris- went a standard ECG 2 hours before and after the administration of 116 53 peridone that achieved monthly therapeutic plasma levels within the IR-MPH 10 mg per os. Basal and post-treatment ECG parameters, 117 54 first day without oral supplementation. Risperidone ISM® was found including mean QT (QTc), QT dispersion (QTd) interval duration, 118 55 to be safe and well tolerated. T peak – T end (TpTe) intervals and TpTe/QT ratio were compared. 119 56 Results: Significant modifications of both QTc and QTd values were 120 57 not found after drug administration. QTd fluctuated slightly from 121 58 122 Metabolic acidosis with a high anion: 25.7 ± 9.3 ms to 25.1 ± 8.4 ms; QTc moved from 407.6 ± 12.4 ms 59 to 409.8 ± 12.7 ms. A significant variation in blood pressure (BP) 123 60 a drug-drug interaction between 124 Paracetamol and Flucloxacillin (Systolic BP 105.4 ± 10.3 vs 109.6 ± 11.5; P < 0.05. Diastolic BP 61 59.2 ± 7.1 vs 63.1 ± 7.9; P 0.05) was observed, but all the data 125 N.T. Jessurun; F. van Hunsel; and E. van Puijenbroek < 62 were within normal range. Heart rate (HR) moved from 80.5 ± 15.5 126 Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, 63 bpm to 87.7 ± 18.8 bpm. No change in TpTe values was found but 127 64 The Netherlands 128

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1 a statistically significant increase in TpTe/QTc intervals was found Results: A total of 25 patients (13 females and 12 males, mean 65 2 with respect to basal values (0.207 ± 0.02 ms vs 0.214 ± 0.02 ms; age 41.2 ± 12.8 years) concluded the study. Mean olanzapine dose 66 3 P < 0.01). was 12.2 ± 5.4 mg/day. The mean olanzapine serum concentrations 67 4 Conclusions: The findings of this study show no significant changes decreased from 27.7 ± 14.4 ng/mL during treatment with the branded 68 5 in ECG parameters. Our data suggest a relative cardiovascular safety formulation, to 22.6 ± 12.3 ng/mL after the switching to the generic 69 6 of IR-MPH in childhood, even if stimulants may exert a cardiovascu- formulation (P < 0.01). The log-transformed ratio of generic/brand- 70 7 lar effect on BP and HR. TpTe values can be an additional parameter name olanzapine serum concentration at steady-state was 0.81 (90% 71 8 to evaluate borderline cases. CI: 0.72–0.91). Total PANSS scores did not significantly change after 72 9 switching from branded to generic formulation (49.6 ± 8.3 vs 48.6 73 10 ± 9.5, P = 0.777). No patient exhibited disease relapse or required 74 11 The effect of Dexmedetomidine and dose adjustment after switching. 75 12 Dexketoprofen on Rat siatic nervous Conclusions: Significantly lower serum olanzapine concentrations 76 were found after switching from branded to generic olanzapine. 13 S. Bagci Taylan; and H. Barıskaner 77 Although these modifications did not significantly impair schizophre- 14 Selcuk University Faculty of Medicine, Konya, Turkey 78 15 nia symptoms control, it cannot be excluded that a longer exposure 79 Background: Dexmedetomidine (DXM), is a selective α -adreno- 2 to lower olanzapine serum concentrations may result in relapse of 16 receptor agonist agent that used because of its sedative, anxiolytic 80 schizophrenic symptoms. Generic substitution should be considered 17 and analgesic effect. Dexketoprofen (DXT), which used for analgesic 81 as an indication for therapeutic drug monitoring in psychiatry. 18 properties, is a non-selective nonsteroidal anti-inflammatory drug. 82 19 In this study, we aimed to investigate and compare DXM and DXT 83 20 effects on the peripheral nerve transmission. 84 21 Material and Methods: Isolated rat sciatic nerves which were trans- The CYP 2C19*2 and CYP2C19*17 85 22 ferred to the nerve chamber includes Krebs solution, were stimu- Polymorphisms play a vital role in 86 23 lated by standard square wave pulse protocols. The compound platelet responsiveness to clopidogrel 87 24 action potentials (CAPs) were recorded from stimulated nerves with after percutaneous coronary 88 25 89 electrophysiological methods. DXM (n = 8) and DXT (n = 8) were intervention: a Pharmacogenomic study 26 administered in the nerve chamber with cumulative concentrations F. Saydam1; I. Degirmenci2; A. Birdane2; M. Ozdemir2; T. Ulus2; 90 27 (10-9 to 10-5 M) and CAPs were recorded for 5th and 10th minutes. C. Ozbayer2; E. Colak2; N. Ata2; and H.V. Gunes1 81 28 The area under a CAP waveform, maximum depolarization values, 1Recep Tayyip Erdogan University Faculty of Medicine, Rize, 92 29 maximum derivatives, latency periods and conduction velocity of the Turkey; and 2Eskisehir Osmangazi University Faculty of Medicine, 93 30 CAPs were calculated. Eskisehir, Turkey 94 31 Results: In this in vitro study, both of DXM and DXT, significantly Background: Clopidogrel inhibits platelet activation and aggrega- 95 32 depressed all CAPs parameters in a dose dependent and reversible tion by blocking the P2Y12 receptor. Dual antiplatelet therapy with 96 33 97 manner (P < 0.05). The significantly differences were found between clopidogrel and aspirin is recommended treatment by current guide- 34 98 DXM and DXT in terms of the nerves transmission inhibition (P > lines for patients undergoing percutaneous interventions. Recurrent 35 0.05). ischemic cardiac events after this treatment showed the lack of plate- 99 36 Conclusions: Higher doses of DXM were found to suppress the let responsiveness to clopidogrel and defined as clopidogrel resist- 100 37 transmission of fast conducting fibers, but DXT was found to sup- ance. Several mechanisms have been implicated in the development of 101 38 press the time-dependent effects on the slow conducting fibers, the clopidogrel resistance, but genetic variations have a most pronounced 102 39 dose-dependent effect on medium and fast conducting fibers. effect. Therefore, we aimed to investigate the most noticeable vari- 103 40 ations in the genes involved in clopidogrel pharmacokinetics and 104 41 pharmacodynamics. 105 42 106 Generic olanzapine substitution in Material and Methods: Three hundred forty-seven Turkish patients 43 underwent elective or emergency percutaneous coronary interven- 107 44 patients with Schizophrenia: assessment 108 of serum concentrations and tions with stent implantation are included in our study. Platelet reac- 45 tivity (PRU) and % inhibition were measured with VerifyNow P2Y12 109 46 therapeutic response after switching 110 D. Italiano; A. Bruno; V. Santoro; G. Lanza; M.R. Muscatello; assay in blood samples collected from patients that took a standard 47 dose of clopidogrel (75 mg/day) for at least 7 days. The variations in 111 48 R. Zoccali; and E. Spina 112 University of Messina, Messina, Italy the CYP2C19, CYP3A4, CYP2B6, ABCB1, ITGB3 and PON1 genes 49 are genotyped using the Sequenom MassARRAY system. 113 50 Introduction: Several reports of loss of efficacy or adverse effects 114 have been described after generic substitution of antipsychotics. To Results: When grouped the patients with PRU values > 208 as resist- 51 ant to clopidogrel, it was determined that 104 (30%) patients were 115 52 date, studies comparing serum drug levels in patients switched to 116 generic antipsychotics in a standard clinical setting are lacking. The resistant and 243 (70%) patients were nonresistant. A significant 53 association was found between CYP2C19*2 (G636A) polymorphism 117 54 aim of this study was to investigate if switching to generic olanzapine 2 118 in patients affected by schizophrenia is associated with differences in and clopidogrel resistance (χ = 25.09, P < 0.001). A allele frequency 55 of this polymorphism was high in patients with resistance, its odds 119 56 its serum concentrations and therapeutic response. 120 ratio was 2.92 compared to G allele (P < 0.001, 95% CI, 1.91-4.46). 57 Methods: Pre- and post-switching serum olanzapine concentrations 121 PRU values of CT genotypes were lower (P = 0.029) and % inhibi- 58 were compared in schizophrenic outpatients who were switched from 122 a chronic treatment with branded olanzapine to the same dose of tion values of CT genotypes were higher (P = 0.008) compared to 59 CC genotypes for CYP2C19*17 (C806T) polymorphism. None of 123 60 its generic alternative. The Positive and Negative Syndrome Scale 124 (PANSS) was concurrently administered to assess modifications in the other genetic variations was found to be statistically associated 61 with clopidogrel resistance and antiplatelet response. 125 62 schizophrenia symptom control. 126 63 127 64 128

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1 Conclusions: Our findings suggest that CYP2C19*2 polymorphism explores their role on oxidative stress markers, inflammatory media- 65 2 is associated with clopidogrel resistance and CYP2C19*17 poly- tors, as well as apoptosis on HCT-116 and Caco-2 CRC cell lines. 66 3 morphism enhances antiplatelet activity of clopidogrel. According Materials and Methods: Drug interaction was evaluated using 67 4 to genotype status of these two polymorphisms, clopidogrel-treated isobologram equation and the expression of pro-inflammatory 68 5 patients can be protected from stent thrombosis. cytokines was determined by RT-PCR. Protein levels of BAX and 69 6 Bcl-2 was determined using western blotting and matrix metallo- 70 7 proteinases-2 and -9 by zymography. Caspase-3 activity, malondi- 71 8 Toxic tobramycin levels after aldehyde (MDA), glutathione (GSH) and nitric oxide contents were 72 9 Tobramycin intake via selective measured spectrophotometrically. 73 10 decontamination of the digestive tract Results: Metformin enhances CRC cell death induced by 5-ASA, this 74 11 (SDD) manifested a significant activation of apoptotic machinery, caspase-3 75 activity and the BAX/Bcl-2 protein ratio. In addition, the combina- 12 S. Wassenaar; Z. Brkic; D. Dos Reis Miranda; N. Hunfeld; and 76 tion resulted in an exaggerated increase in MDA and decrease in 13 B.C.P. Koch 77 intracellular GSH levels indicating an increase in oxidative stress and 14 Erasmus MC, Rotterdam, The Netherlands 78 apoptosis. Moreover, metformin also enhanced the anti-inflammatory 15 Background: Intensive Care Unit (ICU) patients in our hospital are 79 effect of 5-ASA by significantly decreasing COX-2, IL-6, IL-1 , and 16 treated for selective decontamination of the digestive tract (SDD). In α 80 TNF- and its receptors, TNF-R1 and TNF-R2. A significant reduc- 17 SDD tobramycin is given as mouth paste and oral suspension, dosing α 81 tion in MMP-2 and MMP-9 enzyme activity was also observed upon 18 4–8 times a day 80 mg. High trough blood levels of tobramycin can 82 treatment with the combination indicating a decrease in invasiveness. 19 lead to nephrotoxicity and ototoxicity. However, in SDD, tobramycin 83 Conclusion: Metformin potentiates the antitumor effect of 5-ASA 20 suspension is given orally and aminoglycosides are not absorbed via 84 on CRC cells by inhibiting inflammation-mediated tumor progres- 21 the gut. Therefore, SDD will, generally, not lead to systemic expo- 85 sion suggesting their potential use as an adjuvant treatment in CRC. 22 sure. However, we describe a patient with Graft Versus Host Disease 86 23 (GVHD) who developed toxic tobramycin levels. 87 24 Methods: In this case report, we describe a 34 year old male patient 88 25 with Acute Myeloid Leukemia. After allogenic stem cell transplan- Training of various participants 89 26 tation he developed GVHD of the intestines, amongst all lead- cooperating in medicines development. 90 27 ing to severe diarrhea. Previously, several ICU patients with SDD the Pharmatrain concept 81 28 and GVHD developed systemic tobramycin exposure. Therefore, S. Kerpel-Fronius 92 29 tobramycin levels were measured by means of EMIT Immunoassay Semmelweis University, Budapest, Hungary 93 30 (Architect, Abbott). The participation in global clinical drug trials of innovative agents 94 31 Results: After use of 8 times a day 80 mg tobramycin orally for as well as the need for local production and evaluation of follow-on 95 32 96 30 days, his tobramycin trough level was 3.5 mg/L (reference < 0.5 generic and biosimilar medicines necessitates intensive training of 33 97 mg/L). His creatinine was 102 μ mol/L and urea was 23.1 mmol/L specialists working both in the pharmaceutical industry and at the 34 98 (increase > 20% last 4 days). Tobramycin was stopped and levels clinical investigation sites. In Hungary clinical pharmacology is a 35 dropped to 0.87 mg/L after 2 days and 0.22 mg/L after 4 days. secondary specialization built on top of a clinical specialty. For per- 99 36 Tobramycin was started again in a regimen of 4 times a day 80 mg forming a phase I drug trial the responsible clinical investigator needs 100 37 tobramycin orally, under daily monitoring of tobramycin levels. to have a clinical pharmacology board examination. Accordingly, in 101 38 Creatinine and urea recovered. High tobramycin levels were con- their training the teaching of medicine development and drug regu- 102 39 tributed to systemic leakage of tobramycin via the intestines. latory science occupies a central role. For performing other phases 103 40 Conclusion: In SDD, tobramycin is normally not absorbed. However, of drug trials clinical investigators need a GCP certificate. Recently 104 41 in severe intestine GVHD, systemic absorption of tobramycin can for training the increasing number of non-medically qualified sci- 105 42 occur. In this patient toxic tobramycin levels were combined with entists working in medicines development a harmonized European 106 43 impaired renal function. In patients with GVHD of the intestines educational curriculum leading to clearly defined learning outcomes 107 44 and frequent administration of tobramycin-containing SDD frequent has been developed within the Innovative Medicine Initiative- 108 45 monitoring of tobramycin levels is recommended. PharmaTrain (IMI-PhT) program. As part of this project, a regional 109 46 university training network, the Cooperative European Medicine 110 47 Development Course (CEMDC), was organized in Central-Eastern 111 48 Europe which is coordinated by the Semmelweis University. Finally, 112 49 Metformin promotes the inhibitory 113 effect of 5-Aminosalicylic Acid on the introduction of the Clinical Investigators Course (CLIC) devel- 50 oped jointly by PharmaTrain and the European Clinical Research 114 51 inflammation-mediated proliferation 115 and progression of colorectal Cancer Infrastructures Network (ECRIN) is in progress at several European 52 Universities with the aim to increase the competency of clinical 116 53 cell lines 117 1 1 1 2 investigators. The different educational programs available now are 54 M. Magdy ; M.A. Galal ; A.A. Ain-Shoka ; and S.A. Shouman 118 1Faculty of Pharmacy, Cairo, Egypt; and 2National Cancer essential to increase the quality of medicines development in general 55 and the competitiveness of the European pharmaceutical research. 119 56 Institute, Cairo, Egypt 120 57 Introduction: The link between inflammation and cancer has been 121 58 suggested and confirmed by the use of anti-inflammatory therapies 122 59 in cancer prevention and treatment. Five-aminosalicylic acid (5-ASA) Lichenoid reactions associated with 123 60 was shown to decrease the growth and survival of colorectal cancer TNF-α inhibitors identified through 124 61 (CRC) cells. Metformin, an oral anti-diabetic drug, decreased the spontaneous reporting system 125 1 1 2 2 62 incidence of colorectal adenomas in diabetic patients with previ- L. Ghiglione ; A. Peláez ; N. García-Doladé ; and G. Cereza 126 1 63 ous CRC and induced apoptosis in several cancer cell lines. This Clinical Pharmacology Service. Vall d’Hebron Hospital, 127 2 64 study addresses the combinatory effect of 5-ASA and Metformin and Barcelona, Spain; and Fundació Institut Català de Farmacologia, 128

2015 e11 Clinical Therapeutics

1 Barcelona, Spain AUC0-∞, apparent oral clearance (CL/F), and t1/2 were not significantly 65 2 Introduction: Lichenoid reactions (LR) are an uncommon mucocu- different among three genotypes. 66 3 taneous inflammatory disease. As adverse drug reactions (ADRs) Conclusions: Our study showed that CYP2D6 genetic polymor- 67 4 have been attributed to several drugs, including tumour necrosis fac- phism did not play an important role on the pharmacokinetics of 68 5 tor alpha inhibitors (TNF-α inhibitors). The aim of the study is to clomiphene. 69 6 describe the main characteristics of LR attributed to TNF-α inhibitors 70 7 received by the Spanish Pharmacovigilance System (SPvS). 71 8 Material and Methods: Spontaneously reported cases describing LR CYP3A5 Polymorphism affects the increase 72 9 (“lichen planus”, “oral lichen planus”, “keratosis lichenoid”, and in CYP3A activity after living Kidney 73 10 “pityriasis lichenoides”) associated with TNF-α inhibitors (etaner- transplantation in patients with end 74 11 cept, infliximab, adalimumab, certolizumab-pegol and golimumab) stage renal disease 75 12 received by the SPvS between 1983 and 2014 were selected. The Y. Suzuki1; T. Fujioka1; F. Sato2; K. Matsumoto3; N. Muraya1; 76 13 variables studied were age and sex of the patient, suspect drugs, R. Tanaka1; Y. Sato1; K. Ohno3; H. Mimata2; S. Kishino3; and 77 14 indication, induction period, seriousness and outcome of LR, previ- H. Itoh1 78 15 ous knowledge of the drug-reaction association, rechallenge, and the 1Oita University Hospital, Oita, Japan; 2Oita University, Oita, 79 16 existence of alternative causes. Japan; and 3Meiji Pharmaceutical University, Tokyo, Japan 80 17 Results: During the period of study, the SpvS received 3,864 spon- Background: Several previous studies have shown that renal failure 81 18 taneous reports of ADRs to TNF-α inhibitors; 211 (31.3%) of them decreases not only renal elimination but also metabolic clearance of 82 19 described dermatological ADRs and only 9 were LR; lichen planus drugs, particularly those metabolized by cytochrome P450 (CYP)3A. 83 20 (3 cases), oral lichen planus (1), keratosis lichenoid (4) and pityriasis We have previously reported that CYP3A activity increases in patients 84 21 lichenoides (1). Six cases were associated with infliximab, 2 with with end stage renal disease (ESRD) after kidney transplantation, 85 22 adalimumab and 1 with etanercept. The median age of the patients with wide interindividual variability in the degree of increase. The 86 23 was 49 years (min. 29 –max. 73); 5 were men and 4 women. Eight aim of this study was to evaluate the influence of CYP3A5 polymor- 87 24 reports described serious LR. The induction period was between 30 phism on the increase in CYP3A activity after living kidney transplan- 88 25 days and 2 years. The outcome after withdrawal of the suspect drug 89 tation, by measuring plasma concentration of 4β -hydroxycholesterol. 26 was recovery in 4 cases; not recovery in 2 cases and unknown in 3 Material and Methods: This prospective study recruited 20 patients 90 27 cases. Five reports described previously unknown or poorly known with ESRD who underwent the first living kidney allograft transplan- 81 28 drug-induced LR; in one case alternative explanations were excluded. tation, comprising 12 patients with CYP3A5*1 allele (CYP3A5*1/*1 92 29 Conclusions: The SPvS has received spontaneous reports of LR or *1/*3) and 8 patients without CYP3A5*1 allele (CYP3A5*3/*3). 93 30 associated with TNF-α inhibitors. Despite the difficulty to exclude Morning blood samples were collected before and 7, 14, 30, 90 and 94 31 alternative causes, temporal sequence and improvement after drug 180 days after living kidney transplantation. Plasma concentration 95 32 withdrawal suggests a causal relationship. It would be appropriate 96 of 4β -hydroxycholesterol was measured using GC-MS. 33 to include LR in the product information. Results: No significant difference in creatinine clearance over time 97 34 was observed between patients with CYP3A5*1 allele and patients 98 35 without CYP3A5*1 allele, suggesting that the degrees of recovery 99 36 Lack of association between in renal function after living kidney transplantation are similar in 100 37 101 CYP2D6 Genetic polymorphism and the two groups. However, plasma concentrations of 4β -hydroxy- 38 pharmacokinetics of clomiphene cholesterol on days 90 after living kidney transplantation were sig- 102 39 Y.H. Kim; J.Y. Byeon; H.J. Lee; S.H. Kim; Y.S. Lee; Y.J. Lee; and nificantly higher in the presence of CYP3A5*1 allele than in the 103 40 S.Y. Lee absence of CYP3A5*1 allele. Areas under the plasma concentration 104 41 105 School of Pharmacy, Sungkyunkwan University, Suwon, Republic of 4β -hydroxycholesterol–time curves from before to 180 days after 42 of Korea living kidney transplantation were significantly higher in patients 106 43 Introduction: Clomiphene citrate is a selective estrogen receptor with CYP3A5*1 allele than in patients without CYP3A5*1 allele. 107 44 modulator that enhances the release of gonadotropin-releasing hor- Conclusions: These findings suggest that CYP3A activity may 108 45 mone and widely prescribed for ovulation induction. As clomiphene increase markedly associated with recovery of renal function in 109 46 shares triphenylethylene structure with other selective estrogen recep- patients with CYP3A5*1 allele, and that decreased CYP3A activity 110 47 tor such as tamoxifen, it is suggested that CYP2D6 is involved in the associated with renal failure may be caused by decrease in CYP3A5 111 48 clomiphene metabolism. CYP2D6 is highly polymorphic enzyme and activity. 112 49 plays an important role in variability of drug response. Therefore, 113 50 the aim of the study was to investigate the role of CYP2D6 genetic 114 51 115 polymorphism on the pharmacokinetics of clomiphene. Evaluation of Websites on Human 52 Material and Methods: Twenty two healthy Korean subjects were 116 53 Pharmacology 117 volunteered and divided into three different groups according to 1 1 2 54 M. Tannhauser ; C.L. Tannhauser ; and H.M.T. Barros 118 CYP2D6 genotype: CYP2D6*wt/*wt (*wt = *1 or *2, n = 8), 1 2 55 Encrementare, Porto Alegre, Brazil; and Pharmacosciences Dept, 119 CYP2D6*wt/*10 (n = 8) and CYP2D6*10/*10 (n = 6). After over- UFCSPA, Brazil 56 night fasting, each subject received a single oral dose of 50 mg clo- 120 57 Introduction: Popular health internet sites offer information that 121 miphene. Blood samples were collected up to 168 hours after drug may affect consumer’s choice of treatment, however, may also con- 58 intake, and plasma concentrations of clomiphene were determined 122 59 tain inaccurate information. To enable consumers, it is imperative 123 by using liquid chromatography-tandem mass spectrometry system. to evaluate content of health websites including the meta-criteria: 60 Results: Although C of clomiphene in CYP2D6*10/10 group was 124 61 max relevance, accessibility, selection, validity, interchange, site transpar- 125 1.4-fold higher than that in CYP2D6*wt/*wt group (P = 0.0185), 62 ency, links, quality, assurance and safeguards. Our objective is to 126 63 127 64 128

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1 nominate and describe the top websites on applied pharmacology Microscopic examination shows Degradation rate in the CG com- 65 2 and provide a general view of governmental and non-governmental pared to NCG, VG and EXT400 was significant (P < 0.05). This 66 3 sites on pharmaceuticals applied to human health. difference between the other groups wasn’t significantly from each 67 4 Material and Methods: The search engine was Google and search other. MPO activity assessments show there are no significant dif- 68 5 terms were “pharmaceuticals” OR “pharmacology” OR “medicines” ferences between the extract groups with NG and SULFG, but there 69 6 OR “drugs” AND “human health”, in English or Portuguese. For are significantly with VG and NGV (P < 0.05). 70 7 each website search, the first 50 results were evaluated. Sites of non- Conclusions: The anti-inflammatory effect of P. graveolens is signifi- 71 8 web material, aiming commerce, restricted to health professionals or cant on colitis specially the dose of 100 mg/kg is recommended due to 72 9 by payment were excluded. Quality assessment of retrieved websites provide better effects than the others, so the results are encouraging 73 10 was performed with a tool adapted from HON, HITI and American and warrant clinical trials for further confirmation. 74 11 Medical Association (J Health Inform, 2009, 1:27–33). 75 12 Results: Top sites were defined as those that presented all of the nine 76 13 evaluation meta-criteria. There were 40 websites with relevant and A survey of Hematological and 77 14 accurate information on evidence for drug use for human health that Biological abnormalities in dress 78 15 are easy-to-use, disclose information about sponsorship, purpose/ Syndrome 79 16 scope, audience and intended use, currency, source/credentials and N. Fathallah1; R. Slim1; S. Larif1; H. Ben romdhane1; 80 17 link to sources. There were 7 sites from worldwide organizations (ex: A. Aounallah2; N. Ghariani2; and C. Ben Salem1 81 18 WHO, UNESCO, CIOMS); 13 sites from the Americas; 10 sites from 1Faculty of Medicine of Sousse, Tunisia; and 2Farhat Hached 82 19 Europe; 4 sites from Africa; 3 sites from Asia; 4 sites from Oceania. University Hospital of Sousse, Tunisia 83 20 Conclusions: To be useful for consumer’s choice of pharmacological Background: DRESS syndrome is a rare hypersensitivity syndrome 84 21 treatment it is necessary to evaluate the quality of the communication associated with high variability on its hematological and biological 85 22 of knowledge provided in internet sites. The great amount of sites test findings. The aim of this study was to detail, from a patient serial, 86 23 disclosed using search tools result in few that provide evidence of the hematological abnormalities as well as the biological disturbances 87 24 effectiveness of treatment for consumer’s information. In the mean- that may occur with DRESS. 88 25 time, it is extremely important to ensure publicity of the top websites. Materials and Methods: All cases of DRESS reported to our phar- 89 26 macovigilance center from January 2009 to December 2014 were 90 27 retained. Hemograms, liver level tests, LDH and CPK were detailed. 81 28 The anti-inflammatory effect of Results: Twenty-four cases concerned 7 women and 17 men. Median 92 29 pelargonium graveolens methanolic of age was 46.75 years old. The most involved drugs were: anticon- 93 30 extract in acetic acid-induced ulcerative vulsivants in 30% of cases, salazopyrine in 20% and allopurinol in 94 31 colitis in Rat model 16%. Seventy-five percent had eosinophilia exceeding 0.5 g/L and 95 32 B. Ghanizadeh1; H. Shafaroodi1; J. Asgarpanah2; and Z.N. Sharifi3 33% had eosinophilia exceeding 1 g/L. Leukocytosis was present in 96 33 1Department of Pharmacology & Toxicology, Faculty 54% of cases. Lymphocytopenia in 16% and lymphocytosis in 33% 97 34 of Pharmacy, Pharmaceutical Sciences Branch, Islamic of patients. Neutropenia was found in 12 % of cases. Fifty percent 98 35 Azad University, Tehran - Iran (IAUPS); 2Department of had cytolysis and 50% of them were exceeding 4 folds normal range 99 36 Pharmacognosy, Faculty of Pharmacy, Pharmaceutical Sciences whereas cholestasis was present in only 12% of cases. LDH and 100 37 101 Branch, Islamic Azad University, Tehran - Iran (IAUPS); and CPK values > 2 folds upper normal range limit was present in 29% 38 3Department of Anatomy, Tehran Medical Branch, Islamic Azad of cases. Almost 50% of them had values upper of 10 folds normal 102 39 University, Tehran, Iran range. 103 40 Background: IBD refers to two different, inflammatory conditions, Conclusions: Eosinophilia was the most frequently occurring 104 41 Crohn’s disease and ulcerative colitis. There are limited drug classes hematological abnormality in our survey. Other hematological 105 42 for Treatments of IBD. As regards, more effective and less harm- abnormalities observed were leukocytosis and neutropenia. Hepatic 106 43 ful compound for treatment appears to be essential, we investigate involvement in the form of hepatocellular injury was the most com- 107 44 the efficacy of Pelargonium graveolens on colitis, which has anti- mon visceral abnormality and it was present in 4 cases with sul- 108 45 inflammatory ingredients. fasalazine and in 3 cases with allopurinol. Liver injury may be a 109 46 Methods: After P. graveolens was extracted, rats were divided into pro-drome of DRESS and patients with hepatocellular injury are 110 47 groups Such as: the normal group (N.G) and the negative control relatively young in our survey (mean age of 36.3). Elevated LDH 111 48 group (NCG.), that received only normal saline; EXT100, EXT200 and CPK was observed most often with sulfasalazine. There is an 112 49 and EXT400 groups, which received 100, 200 and400 mg/kg/day of evidence of great frequency of haematological abnormalities that 113 50 extract (p.o); the vehicle group (VG), which received vehicle orally; occur during DRESS. 114 51 the Positive control group (SULF.G), which received Sulfasalazine 115 52 (500 mg/kg/day, orally). Rats were given compounds for 72, 48, 24 116 53 and 2 hours before colitis induction as well as 24h thereafter. For 117 54 Fenofibrate-induced photosensitivity 118 induce colitis, 1ml of acetic acid 4.5% were instilled intra-colonially associated with lingual and oral Mucosa 55 to each group. NS (1 mL) was administered to normal group. Twenty- 119 56 Hyperpigmentation 120 four hours after the last gavage, colons were removed for assessed 1 1 1 2 2 57 N. Fathallah ; S. Larif ; R. Slim ; L. Boussffara ; N. Ghariani ; 121 its macroscopic and microscopic changes and myeloperoxidase 2 1 58 R. Nouira ; and C. Ben Salem 122 activities. 1Faculty of Medicine of Sousse, Tunisia; and 2Farhat Hached 59 Results: Forty-eight hours after colitis was induced, the macro- 123 University Hospital of Sousse, Tunisia 60 scopic scores and DAI show inflammation in NCG and VG and the 124 Introduction: Fenofibrate is a lipid regulating agent approved in the 61 results of two groups weren’t significant difference together but other 125 treatment of hyperlipidemia. Cutaneous adverse reactions attributed 62 groups were significantly different with these two groups. Whereas, 126 63 to the drug are rare including acute hypersensitivity reactions, pruri- 127 among other groups, there was no significant difference (P < 0.05). 64 tus and skin ulcer. Although photosensitivity induced by fenofibrate 128

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1 was reported in rare cases in the literature, there are no reports of more severe. Patch tests on lesional skin may be a safe alternative to 65 2 fenofibrate-induced photosensitivity associated with lingual and oral identify the incriminated drug in GBFDE. 66 3 mucosa pigmentation. Herein, we report the first case, to the best of Conclusion: Clinicians should be aware of the risk of GBFDE. Patch 67 4 our knowledge, of a patient who developed gingival, labial, lingual test may be a useful tool in identifying GBFDE. 68 5 pigmentation associated with photosensitivity after fenofibrate therapy. 69 6 Case report: A 43-year-old woman presented with skin eruption 70 7 affecting the sun-exposed areas. Her medical history was unremark- Hypersensitivity to Amoxicillin after 71 8 able except for hyperlipidemia treated with fenofibrate (200 mg daily) allopurinol-induced hypersensitivity 72 9 started three months earlier. Physical examination revealed numerous syndrome: a co-sensitization to 73 10 variously sized hyperpigmentated plaques over the sun exposed areas. unrelated drugs 74 11 Inspection of the oral mucosa revealed hyperpigmentated macules. N. Fathallah1; R. Slim1; S. Larif1; A. Aounallah2; N. Ghariani2; 75 12 Laboratory investigation was in normal ranges except for triglycer- R. Nouira2; and C. Ben Salem1 76 13 ides. Serum levels of adrenocorticotropic hormone and cortisol were 1Faculty of Medicine of Sousse, Tunisia; and 2Farhat Hached 77 14 also in normal ranges. Histologic examination revealed a non-specific University Hospital of Sousse, Tunisia 78 15 lymphoplasmacytic infiltrate. Introduction: Allopurinol hypersensitivity syndrome is a rare but 79 16 Discussion: Diagnosis of drug-induced photosensitivity is often chal- severe adverse drug reaction. Although cross-reactivity reactions are 80 17 lenging. It is based primarily on the history of drug intake and the reported with chemically related drugs, drug hypersensitivity after a 81 18 clinical appearance of the eruption, primarily affecting sun-exposed history of DRESS syndrome induced by chemically unrelated drugs is 82 19 areas of the skin. Among the class of fenofibric acid, this photosen- exceptional. Herein, we point out a possible co-sensitization to chem- 83 20 sitizing capacity of fenofibrate is mainly determined by the photo ically and antigenically unrelated drugs: amoxicillin and allopurinol. 84 21 excited chemical structure, the benzophenone moiety. Our revue of Case description: A 76-year-old female with a 10-year history of 85 22 literature did not reveal any case of fibric acid-induced mucosal pig- hypertension and a six-year history of chronic renal failure was 86 23 mentation and our patient is the first case of fenofibrate-induced oral initiated on allopurinol for the treatment of hyperuricemia. Three 87 24 pigmentation. The suggested mechanism of fenofibrate-induced oral weeks later, the patient developed generalized exanthema with fever 88 25 pigmentation in our patient can be related to a direct effect of the and cervical lymphadenopathy. Biochemical investigation revealed 89 26 drug in melanin secretion. hypereosinophilia with cytolysis. 90 27 Conclusion: Fenofibrate-photo-induced hypersensitivity is a known Allopurinol-induced hypersensitivity syndrome was suspected 81 28 adverse effect of the drug. Besides, clinicians should be aware of the and the drug was withdrawn. All symptoms were relieved after two 92 29 possibility of oral hyperpigmentation related to fenofibrate. weeks. Four months later, the patient exhibited an extensive pruritic 93 30 skin rash associated with fever and hypereosinophilia, 2 days after 94 31 amoxicillin intake for respiratory tract infection. Symptoms disap- 95 32 Generalized bullous fixed Drug eruption: peared few days after amoxicillin withdrawal. We noted that our 96 33 a case series patient was previously exposed to amoxicillin without any history of 97 34 H. Ben Romdhane1; S. Larif1; R. Slim1; N. Fathallah1; hypersensitivity to the drug or to other beta-lactam drugs. 98 35 C. Belajouza2; N. Ghariani2; and C. Ben Salem1 Discussion: Allopurinol hypersensitivity syndrome is a severe adverse 99 36 1Faculty of Medicine of Sousse, Tunisia; and 2Farhat Hached reaction characterized by rash, fever, internal organ involvement occur- 100 37 University Hospital of Sousse, Tunisia ring 2 to 6 weeks after drug initiation. It is more frequently associated 101 38 Introduction: Generalized bullous fixed drug eruption (GBFDE) is with chronic renal insufficiency in relation to the accumulation of 102 39 a rare and severe form of fixed drug eruption (FDE) that may be allopurinol’s metabolite leading to tissue damage. Hypersensitivity to 103 40 misdiagnosed with other forms of bullous drug eruptions (BDE). amoxicillin after allopurinol-related DRESS, two drugs without any 104 41 Herein, we report three cases of GBFDE. chemical or antigenic similarity, are rare and are due at least in part, to 105 42 Case Reports: Case 1: An 89-year-old man developed an indurated the administration of amoxicillin during the period of immunological 106 43 edematous plaque on his arm 1 day after acetaminophen ingestion. depression following the hypersensitivity to allopurinol. 107 44 There was an extension of the lesion with occurrence of flaccid vesi- Conclusion: Clinicians should be cautious when prescribing amoxi- 108 45 cles. There was a previous history of recurrent reaction in the same cillin to a patient with a previous history of hypersensitivity syndrome 109 46 sites. The rash resolved after acetaminophen withdrawal. Case 2: to allopurinol. 110 47 A 48-year-old woman presented with well-defined bullous lesions 111 48 and ovular patches spread diffusely over her arms, trunk and face, 112 49 which appeared 1 day after the consumption of mefenamic acid. 113 50 Hypersensitivity to penicillins diagnosed 114 The diagnosis of GBFDE was considered especially with a reported with delayed reading prick tests 51 history of a previous reaction occurring in the same site. A patch 115 52 S. Larif; N. Fathallah; R. Slim; H. Zayani; and C. Ben Salem 116 test with mefenamic acid revealed a positive reaction. Case 3: A Faculty of Medicine of Sousse, Tunisia 53 51-year-old man developed well-limited bullous lesions located on 117 54 Background: Penicillins are widely prescribed class of antibiotics 118 the trunk, arms and scrotum, 24h after mefenamic acid intake. He because of their activity spectrum and cost effectiveness. Nevertheless 55 reported two other previous episodes occurring in the same site. The 119 56 they can be prohibited because of allergic reactions. In these cases, 120 role of mefenamic acid was confirmed by a patch test on a residual skin tests can be useful and have to be applied according to the 57 pigmented lesion. 121 58 pathomechanism of the allergy-induced by the drug. In immediate 122 Discussion: Differential diagnosis to GBFDE is BDE such as Stevens- beta-lactam drug allergy, an Ig E-mediated reaction can be demon- 59 Johnson syndrome and toxic epidermal necrolysis. A history of 123 60 strated by a positive skin prick test with a reading at 20 mn. Herein, 124 hyperpigmented and bullous lesions occurring at the same sites we report a case of hypersensitivity to penicillin diagnosed with a 61 related to drug consumption may be helpful in diagnosing GBEDE. 125 62 delayed reading prick tests. 126 Positive rechallenge with the suspected drug is useful with FDE but Case Report: A 27 year old female with an unconfirmed history of 63 it may be dangerous with GBFDE as lesions may be extensive and 127 64 anaphylaxis reaction to beta-lactamins in the age of 3 years is pre- 128

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1 sented to our department in order to confirm this allergy. Clinical Introduction: Drug Rash with Eosinophilia and Systemic Symptoms 65 2 investigation included a skin Prick test to co-amoxicillin, oxacillin, (DRESS) is a severe drug-induced hypersensitivity syndrome associ- 66 3 ampicillin and cefotaxim. The reading at 20 mn and 30 mn was nega- ated with multisystem involvement. It may occur in both adults and 67 4 tive. We have proposed for our patient intradermal test (IDT) but children. However, it is poorly known by pediatricians and rarely 68 5 she refused. Forty-eight hours later, warm pruritic and erythematous reported in children. We report two cases of DRESS syndrome- 69 6 nodules appeared in the area of the co-amoxicillin and ampicillin induced by anticonvulsivants occurring in children. 70 7 prick tests. Case Reports: Case 1: A 9-year-old boy with a medical history of 71 8 Conclusion: Skin prick tests are the safest and easiest tests for partial seizures treated by carbamazepine presenting with three days 72 9 detecting immediate drug reactions. The result is evaluated after15- history of generalized erythema and facial edema associated with 73 10 20 mn. If negative, IDT can be performed. We present evidence fever, lymph node enlargements and hypereosinophilia, one week 74 11 that prick skin tests should be evaluated certainly after 20 mn but after CBZ initiation. Case 2: A 7 year-old boy presented a generalized 75 12 even after 24 and 48 hours. Both patients and clinicians should be exanthema with fever, hypereosinophilia and cytolysis three weeks 76 13 aware of the risk of switching from negative to positive reactions after lamotrigine initiation for the treatment of partial seizures. 77 14 after prick skin tests. Discussion: DRESS-syndrome is a rare drug-induced hypersensitiv- 78 15 ity reaction. Compared to adults, fewer cases involving children are 79 16 reported in the literature. Nevertheless, it is considered to be a pedi- 80 17 Nummular eczema secondary to atric emergency owing to its potential life-threatening consequences. 81 18 interferon BETA-1B therapy in a patient In children, DRESS syndrome may mimic infectious, neoplastic and 82 19 with multiple Sclerosis immunologic conditions. This may delay the diagnosis and the 83 20 S. Larif1; N. Fathallah1; R. Slim1; H. Zayani1; N. Ghariani2; and prompt management. DRESS syndrome is characterized by diffuse 84 21 C. Ben salem1 maculopapular rash, lymphadenopathy, multivisceral involvement, 85 22 1Faculty of Medicine of Sousse, Tunisia; and 2Farhat Hached eosinophilia and/or atypical lymphocytes. The pathophysiology of 86 23 University Hospital of Sousse, Tunisia DRESS syndrome remains unclear. It has been recently classified 87 24 Introduction: Interferon beta-1b is an immunomodulatory drug with under a delayed type IVb hypersensitivity reaction where T-helper 88 25 proven efficacy in the treatment of multiple sclerosis (MS). Herein, type 2 cells play a significant role. Early recognition of the syndrome 89 26 we report an unusual case of nummular eczema following exposure and withdrawal of the culprit drug may be the key step to preventing 90 27 to interferon beta-1b in a middle-aged woman with MS. mortality or substantial organ damage. 81 28 Case Description: A woman in her 40S was diagnosed with the Conclusion: In children, increase in awareness enables early recog- 92 29 relapsing remitting form of MS. Four months after the first dose nition of anticonvulsant-induced DRESS syndrome so as to reduce 93 30 of interferon beta-1b (8 million units, one time weekly), the patient morbidity and mortality. 94 31 was seen in the dermatology clinic for evaluation of pruritus and 95 32 multiple eczema-like lesions on the legs and bottom. Physical exami- 96 33 nation findings revealed erythematous nummular patches on the legs Pharmacogenetic tests: new tools for 97 34 and bottom with linear excoriations (Figure 1). Involved skin biopsy old questions in adverse Drug reactions? 98 35 revealed a mild epidermal hyperplasia with spongiosis and lympho- N. Fathallah; R. Slim; S. Larif; and C. Ben Salem 99 36 cyte exocytosis, overlying parakeratosis and a perivascular lympho- Department of clinical Pharmacology, Matebolic biophysics, 100 37 cytic dermal infiltrate including rare eosinophils. Interferon beta-1b professional toxicology and applied Environmental Laboratory 101 38 was withdrawn, and the patient received 0.05% betamethasone LR12ES02, Faculty of Medicine of Sousse, Sousse University, 102 39 dipropionate ointment. There was an improvement of the lesions. Tunisia 103 40 Two months later, interferon was readministrated and few days later Background: The interindividual variability to the standard dose of 104 41 the patient noted an aggravation of the previous lesions with develop- certain drugs remains a major problem in clinical practice. It mani- 105 42 ment of new lesions. Interferon was definitely stopped. fests either by a therapeutic insufficiency or the occurrence of side 106 43 Discussion: In our case, the pathogenic role of the interferon beta-1b effects that are a considerable cause of morbidity and mortality. The 107 44 seems likely, because the lesions occurred during the course of treat- variability is related mainly to genetic factors. Pharmacogenetics 108 45 ment, regressed after withdrawing the treatment, reappeared after the is a recognized discipline within pharmacology that involves test- 109 46 reintroduction of interferon, and other evident etiologies of eczema ing relevant human genes, whose products are involved with the 110 47 were absent. Skin manifestations resulting from treatment with inter- inter-individual variability of a drug’s pharmacokinetics, pharma- 111 48 feron beta-1b consist principally of injection-site reaction with lesions codynamics and human leukocyte antigen profile. The promise of 112 49 varying from sclerotic dermal plaques to erythematous plaques to pharmacogenetics is to improve the therapeutic efficacy of drugs 113 50 cutaneous ulcers. The etiology of nummular eczema is multifactorial, while reducing the incidence and severity of adverse drug effects, 114 51 involving allergic, environmental, emotional, and nutritional factors. and drive the optimum drug selection for therapy. The aim of this 115 52 Drugs such as isotretinoin, interferon alfa-2b and ribavirin are rarely overview is to provide the situation today of using pharmacogenetic 116 53 reported to be a trigger factor. testing in elucidating adverse drug reactions. 117 54 Conclusion: Physicians should be aware of this side effect induced Methods: Literature review using Pubmed system is conducted and 118 55 by interferon beta-1b. articles concerning pharmacogenetics and adverse drug reactions are 119 56 selected from 2000 to 2014. 120 57 Results: Most adverse drug reactions are type A reactions and repre- 121 58 sent major causes of hospitalization, in some cases leading to death. 122 59 Anticonvulsivant-induced dress 123 syndrome in Children: two cases Pharmacogenetic tests seem to have an important role in minimizing 60 adverse drug reactions. However, the use of these tests faces substan- 124 N. Fathallah1; A. Mlika2; R. Slim1; S. Larif1; H. Zayani1; 61 tial challenges and it is not usually used. In our overview, we provide 125 L. Boughammoura2; and C. Ben Salem1 62 a list of the most implicated drugs in adverse drug reactions that are 126 1Faculty of Medicine of Sousse, Tunisia; and 2Farhat Hached 63 metabolized by enzymes with variant alleles associated with a poor 127 64 University Hospital of Sousse, Tunisia 128

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1 metabolism profile. Our findings reveal that pharmacogenetic test, for to 103 volunteers participated in each study, depending on the pro- 65 2 some polymorphisms, may be considerably efficacious in preventing tocol design (it is possible to hospitalize 45 volunteers in one time). 66 3 adverse effects. Results and discussion: The strict control over BE studies conducted 67 4 Conclusion: Most of side effects can be avoided if pharmacoge- by the Quality Department in accordance with SOPs. The results 68 5 netic tests become routinely applicable. Although differences in revealed some defects of a general type: improper preparation of 69 6 drug response are increasingly recognized, there is an urgent need to protocols (31%), lack of protection of the subjects (19%), lack of 70 7 translate the knowledge in this area into clinical recommendations. definition of responsibilities of the researcher (28%), the allocation 71 8 Pharmacogenetic tests may be a safe and reproducible tool in the of responsibilities between the sponsor and the organizers of clinical 72 9 prevention of adverse drug reaction. studies (24%). Using of Yaroslavl bioanalytical laboratory, which is 73 10 working according GLP rules, avoid the errors in the pharmacoki- 74 11 netic part of the study, incorrect statistical analysis. We are faced with 75 12 Hypolipidemia and Antidiabetic effect the following problems: the prevalence of non-compliance patients 76 13 of aqueous extract of Mesocarp - 4%, the high prevalence of adverse events in some studies up to 77 14 layer (spongy layer) of cocos 78%, different problems during bioanalytical part - 5%, the prob- 78 15 nucifera nut in white albino rats lems associated with the final report on the study - in 2%. The center 79 16 and medicinal evaluation of the has the experience of using the pharmocogenetics in BE studies to 80 17 extract using Phytochemical analysis, reduce sample size (CYP2C9, CYP2C19, CYP2D6). 81 18 Gas Chromatography and Mass Conclusions: Some mistakes in planning of BE studies leads to 82 19 Sectrophotometer (GC-MS) decreasing of drug efficacy and safety, loss of confidence in generics 83 and the rising of drug therapy cost in future. 20 S.S. Onasanya1; R.O. Tijani1; and O.A. Jokotaga2 84 21 1Moshood Abiola Polytechnic, Ojere, Abeokuta, Ogun State, 85 22 Nigeria; and 2Abraham Adesanya Polytechnic, Ijebu igbo, Nigeria 86 23 Background: This study investigated the effect of the aqueous extract Coadministration of Fluvoxamine 87 24 of the mesocarp layer of Cocos Nucifera on blood sugar level and and Tolperisone in relation to CYP2D6 88 25 lipid profile in normal and Streptozocin- induced diabetes rats and in genotype 89 26 rats fed on a high fat diets {HFD} after which Phytochemical analysis Y.H. Kim; S.H. Kim; J.Y. Byeon; H.J. Lee; Y. Lee; Y.J. Lee; and 90 27 and Gas chromatography-Mass Spectrophotometric evaluation of S.Y. Lee 81 28 the extract was done. School of Pharmacy, Sungkyunkwan University, Suwon, Republic 92 29 Methods and Results: Mice treated with filtered and evaporated of Korea 93 30 aqueous extract (spongy layer) of Cocos nucifera (AECN) (10mg/ Introduction: Tolperisone, a piperidine derivate, is used to relieve 94 31 kg, 30mg/kg, 90mg/kg p.o) and mice treated with glibenclamide spasticity of neurological origin and muscle spasm. CYP2D6 was 95 32 (10mg per kg) significantly reduced the Streptozocin (STZ) – induced identified as the key enzyme in the metabolism of tolperisone and 96 33 increase in blood sugar (Bg), Total Cholesterol (Tc), and Serum CYP1A2 and CYP2C19 were also involved in the metabolism of 97 34 Triglyceride level (Tg). AECN at 90mg/kg manifested an hypolipi- tolperisone. Fluvoxamine is an antidepressants and known as one 98 35 demic effects but effectively lowers the elevated plasma BG level in of CYP2C19 inhibitors. As CYP2D6 is very high polymorphic and 99 36 oral glucose tolerance test, while Glibenclamide showed a significant causes large interindividual differences in drug response, we investi- 100 37 reduction in TC, BG, TG in Normoglycemic rats. The histopatho- gated the effects fluvoxamine, a CYP2C19 inhibitor, on the pharma- 101 38 logical analysis of Pancreas and the Plasma insulin level revealed cokinetic parameters of tolperisone. 102 39 beneficial effects of AECN in protecting beta cells integrity. In mice Material and Methods: Thirty healthy Korean subjects were vol- 103 40 treated with AECN (10mg/kg, 30mg/kg, 90mg/kg), and mice that are unteered and divided into three different groups according to 104 41 105 treated with fenofibrate 200mg/kg, the {HFD} associated rise in TC, CYP2D6 genotype: CYP2D6*wt/*wt (*wt = *1 or *2, n = 10), 42 106 TG were significantly reduced. The hypocholesterolemic effects of CYP2D6*wt/*10 (n = 10), and CYP2D6*10/*10 (n = 10). All 43 AECN appears more at 90mg/kg with significant decrease in VLDL subjects received a single oral dose of 150 mg tolperisone in the 107 44 and LDL Cholesterol and an elevation of HDL Cholesterol. The control phase after overnight fasting. Before study day (day 6), a 50 108 45 Phytochemical Screening and GC-MS analysis of AECN revealed mg oral dose of fluvoxamine was administered once a day for five 109 46 that AECN contained alpha, beta amyrin, and Pyrazine. days. On day 6, subjects received a single oral dose of tolperisone 110 47 Conclusion: These findings reflect the potential antihyperglycemic one hour after the administration of fluvoxamine. Blood samples 111 48 and hypolipidemic effects of AECN and suggest that alpha, beta were collected up to 12 hours after drug administration, and plasma 112 49 amyrin or Pyrazine) could be a lead compound for drug development concentrations of tolperisone were determined by using liquid chro- 113 50 effective in diabetes and atherosclerosis. matography-tandem mass spectrometry system. 114 51 Results: C and AUC of tolperisone was significantly different in 115 52 max inf 116 each group between control phase and study day (P < 0.01). On study 53 day, C increased by 3.6-fold, 2.0-fold, and 5.0-fold, respectively 117 54 Analysis of bioequivalence studies: max 118 problems, ways of solution in the CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 55 group, compared to control phase. Also, apparent oral clearance 119 56 Research objective: The investigation of drugs bioequivalence is the 120 main requirement of medical and biological control of generics in (CL/F) of tolperisone on study day decreased by 74.2%, 72.0%, 57 and 86.2%, respectively in CYP2D6*wt/*wt, CYP2D6*wt/*10, and 121 58 Russia. 122 Materials and Methods: On the basis of Yaroslavl Clinical hospital CYP2D6*10/*10 group, compared to control phase 59 Conclusions: Significant differences in the pharmacokinetics of tol- 123 60 № 2 103 bioequivalence studies (BE) were conducted at the period of 124 2011 – 2015, including 12% with replicative design. Among these perisone were observed after coadministration of fluvoxamine in 61 relation to CYP2D6 genotype. 125 62 studies 21 were foreign and 82 – domestic. Volunteers of both sexes 126 63 were involved in BE studies in the amount of 1437 people. From 18 127 64 128

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1 Coadministration of duloxetine and CYP2C19PM (CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3, 65 2 tolperisone in relation to CYP2C19 n = 7). In the control phase, all subjects received a single 150 mg oral 66 3 genotype in Korean subjects dose of tolperisone after overnight fasting. After administration of 67 4 Y.H. Kim; S.H. Kim; J.Y. Byeon; H.J. Lee; Y. Lee; Y.J. Lee; and 30 mg duloxetine twice in a day for consecutive three days, 150 mg 68 5 S.Y. Lee oral dose of tolperisone was administered one hour after administra- 69 6 School of Pharmacy, Sungkyunkwan University, Suwon, Republic tion of a single 30 mg oral dose of duloxetine in test phase. Blood 70 7 of Korea samples were collected up to 12 hours after drug administration, and 71 8 Introduction: Tolperisone is a centrally acting muscle relaxant is plasma concentrations of tolperisone were determined by using liquid 72 9 prescribed for the treatment of muscle spasm. Tolperisone is pre- chromatography-tandem mass spectrometry system. 73

10 dominantly biotransformed by CYP2D6, and to a lesser extent Results: Cmax of test phase increased by 1.93-fold, 1.80-fold, 74 11 by CYP2C19 and CYP1A2. Duloxetine is a potent dual reuptake and 1.57-fold, respectively in CYP2C19EM, CYP2C19IM, and 75 12 inhibitor of serotonin and norepinephrine and acts as an inhibitor CYP2C19PM group, compared to control phase (P = 0.045, P = 76

13 of CYP2D6. As CYP2C19 is one of the most important polymorphic 0.027, and P = 0.031, respectively). AUC0-∞ of test phase was sig- 77 14 CYPs, the aim of study was to determine pharmacokinetic changes nificantly higher in CYP2C19EM and CYP2C19IM group than that 78 15 of tolperisone after coadministration of duloxetine according to of control phase (P = 0.034 and P = 0.005, respectively), but there 79 16 CYP2C19 genotype. was no significant difference in CYP2C19PM group between control 80 17 Material and Methods: Twenty four healthy Korean subjects phase and test phase (P = 0.124). 81 18 were volunteered and classified into three different groups in rela- Conclusions: Coadministration of tolperisone and duloxetine has 82 19 tion to CYP2C19 genotype: CYP2C19EM (CYP2C19*1/*1, significant effects on the pharmacokinetics of tolperisone according 83 20 n = 9), CYP2C19IM (CYP2C19*1/*2 or CYP2C19*1/*3, n = 8) and to CYP2C19 genotype. 84 21 85 22 86 23 87 24 88 25 89 26 90 27 81 28 92 29 93 30 94 31 95 32 96 33 97 34 98 35 99 36 100 37 101 38 102 39 103 40 104 41 105 42 106 43 107 44 108 45 109 46 110 47 111 48 112 49 113 50 114 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

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1 An Educational Intervention To Improve interventions was randomly assigned. Primary endpoint was the 65 2 Nurses Reporting of Adverse Drug change in acetaminophen exposure defined as the difference in area 66

3 Reactions under the plasma concentration-time curve (Δ AUC0-8 hours) using non- 67 4 S. Marquez1; M.T. Herdeiro1,2; and I. Ribeiro-Vaz2 compartmental analysis. Changes in UGT1A1-mediated metabolism 68 5 1University of Aveiro, Aveiro, Portugal; and 2Northern were investigated by comparing baseline unconjugated (indirect) bili- 69 6 Pharmacovigilance Centre, Porto, Portugal rubin concentrations between the interventions. 70 7 Introduction: Adverse drug reactions (ADR) are an important cause Results: Short-term fasting increased acetaminophen exposure 71

8 of mortality and morbidity leading to additional costs with health. by 28.2% (Δ AUC0-8 hours,P = 0.021) and increased unconjugated 72 9 Drug safety data before commercialization is limited and incom- bilirubin from 8.5 µmol/L (range, 3–21 µmol/L) to 21.5 µmol/L 73 10 plete, which is the reason why pharmacovigilance is important. ADR (range, 10–56 µmol/L) (P = 0.008) in comparison with control. 74 11 reporting system is efficient in drug safety monitoring. Nurses can Short-term high-fat diet did not affect acetaminophen exposure 75

12 have an important role in ADR reporting due to their daily activities (Δ AUC0-8 hours= 0.15%, P = 0.374), but decreased unconjugated 76 13 of drugs administration (including vaccines). However, among these bilirubin from 8.5 µmol/L to 4.0 µmol/L (range, 2–10 µmol/L) 77 14 professionals, there a high rate of underreporting. Based on the rea- (P = 0.013) when compared to the control intervention. 78 15 sons proposed by Inman for underreporting ADR, it was concluded Conclusions: Fasting increases acetaminophen exposure and 79 16 that the main obstacles to ADR reporting among nurses were indiffer- decreases nontoxic UGT1A1-mediated metabolism in healthy sub- 80 17 ence (the belief that a single case cannot contribute to medical knowl- jects. This may lead to increased hepatotoxicity. A high-fat diet did 81 18 edge) and the lack of knowledge about the pharmacovigilance system. not alter acetaminophen exposure but increased UGT1A1-mediated 82 19 The aim of this study is to evaluate the quantitative and qualitative metabolism. 83 20 increase of ADR reports by nurses after an educational intervention. 84 21 Methods: A quasiexperimental study was performed in nurses 85 22 working in primary care in Braga district, Portugal. One hundred The value of computer assisted 86 23 thirteen individuals were placed in the intervention group while the medication review in hospitalised 87 24 control group included 590 nurses. Two educational interventions patients 88 25 were performed to nurses working in primary care in ACES Cavado H. van der Kuy1; and K. Hurkens2 89 26 II (intervention group) that focused on the problem of adverse drug 1Orbis Medical Centre, Sittard-Geleen, The Netherlands; and 90 27 reaction, the impact on public health and spontaneous reporting. 2Academic Medical Centre, Amsterdam, The Netherlands 91 28 Statistical analysis were based on absolute and relative frequencies. Introduction: Polypharmacy is one of the main risk factors for 92 29 Results: Between January 2013 and September 2014 the Northern adverse drug events, drug–drug interactions and undertreatment. 93 30 Pharmacovigilance Centre received 8 reports/100 nurses from the This makes medication management in the hospital a challenging 94 31 intervention group and 5 reports/100 nurses from control group. responsibility. A medication review is used to optimise therapy in a 95 32 Conclusions: The educational intervention increased 1.6 times the structured way. It is done manually and therefore prone to mistakes. 96 33 number of reports during the study period. The second intervention The aim of this study was to evaluate the additional value of our 97 34 had more impact than the first one. CDSS to manual medication reviews compared with manual medica- 98 35 There was no significant increase in the quality of ADR reports tion review alone on medication errors in the hospital. 99 36 in the intervention group. In the second intervention the number of Methods: During 4 months data were gathered by observation of 100 37 reports increased only at the intervention day. the medication reviews during the weekly grand rounds at an inter- 101 38 nal and orthopaedic ward and electronic extractions were made all 102 39 patients. The e-data were analysed by a Clinical Decision Support 103 40 The Influence of Nutritional Status On System (CDSS). After data collection, notifications obtained during 104 41 Acetaminophen Metabolism In Healthy the grand rounds and from the CDSS were analysed. 105 42 Subjects Results: In total 332 patients were reviewed, 219 (mean number 106 43 107 R. Achterbergh; L.A. Lammers; L. Kuijsten; H.J. Klümpen; of drugs = 9) at the internal ward (242 alerts from which 133 from 44 108 R.A.A. Mathôt; and J.A. Romijn cdss) and 113 (mean number of drugs = 10)at the orthopaedic ward 45 109 Academic Medical Center, University of Amsterdam, Amsterdam, (61 alerts from which 44 from cdss). Mean age on both wards was 46 110 The Netherlands 67 years. Further data is shown in table. 47 111 Background: Animal studies have shown that fasting and obesity 48 112 are predisposing factors for acetaminophen-induced hepatotoxicity. 49 Type of error Total Value CDSS 113 Fasting can decrease nontoxic clearance of acetaminophen by UDP- 50 114 glucuronosyltransferases (UGT1A1, UGT1A6) and sulfotranserases Yes (%) 51 115 resulting in increased formation of the toxic metabolite N-acetyl-p- Indication without medication 59 (100) 32(54.2) 52 116 benzoquinone imine (NAPQI), whereas obesity can increase NAPQI- Medication without indication 48 (100) 0 (0) 53 Contraindications/interactions/side effects 102 (100) 88 (86,.3) 117 formation by induction of hepatic CYP2E1. We investigated the effect 54 Dosage problem 34 (100) 30 (68.2) 118 of short-term fasting and a short-term high-fat diet on acetaminophen Double medication 6 (100) 3 (50) 55 119 metabolism in healthy subjects. Furthermore, changes in UGT1A1- Wrong medication 10 (100) 0 (0) 56 120 mediated metabolism were studied by using unconjugated bilirubin, Therapeutic drug monitoring 34 (100) 24 (70,6) 57 Total 303 (100) 177 (58.4) 121 metabolised by UGT1A1, as a proxy. 58 122 Materials and Methods: Nine healthy male subjects were enrolled 59 Conclusions: The CDSS is a relevant addition to the manual per- 123 in a crossover intervention study. Subjects received a single oral 60 formed medication reviews in the hospital. An accurate CDSS is 124 administration of 1000mg acetaminophen after an overnight fast 61 imperative to assist the physician in performing medication reviews. 125 following 3 interventions: (1) regular diet (control), (2) 36 hours 62 Future developments include adding medical history to the clini- 126 of starvation and (3) 3 days of a high-fat diet consisting of 500 mL 63 cal rules, fine-tuning the CDSS and determine relevance on patient 127 of cream supplemented to their regular diet. The sequence of the 64 outcome. 128

2015 e1 Clinical Therapeutics

1 Characterization of The Structure of respectively, in Japanese cancer patients. The plasma concentration of 65 2 Human Serum Albumin In Patients With fentanyl normalized with theoretical absorption rate was significantly 66 3 End Stage Renal Disease After Kidney higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. 67 4 Transplantation The median and the interquartile range of serum 4β -hydroxycholesterol 68 5 R. Tanaka1; Y. Suzuki1; T. Imafuku2; F. Sato3; Y. Ishima2; Y. Sato1; concentration were 41.1 and 27.6 to 61.4 ng/mL, respectively. The 69 6 H. Watanabe2; T. Maruyama2; H. Mimata3; and H. Itoh1 serum concentration of 4β -hydroxycholesterol was significantly lower 70 7 1Oita University Hospital, Oita, Japan; 2Graduate School of in the CYP3A5*3/*3 group than in the *1 allele carrier group. The con- 71 8 Pharmaceutical Sciences, Kumamoto University, Kumamoto, centration of plasma fentanyl normalized with the theoretical absorp- 72 9 Japan; and 3Faculty of Medicine, Oita University, Oita, Japan tion rate was not correlated with that of serum 4β -hydroxycholesterol. 73 10 Introduction: The degree of oxidized cystein (Cys) 34 in human serum Conclusion: CYP3A5*3 affected the blood exposures of fenta- 74 11 albumin (HSA) is a sensitive biomarker for diagnosis of the oxidative nyl and serum concentration of 4β -hydroxycholesterol in cancer 75 12 stress in various diseases. Although previous report suggested that patients. However, the blood exposure of fentanyl was not able to 76 13 the oxidation of Cys 34 in HSA was significantly increased with the explain using the serum concentration of 4β -hydroxycholesterol. 77 14 progression of end stage renal disease (ESRD), a representative oxida- Nonmetabolic factors may affect the plasma exposure of fentanyl 78 15 tive stress-associated disease, little is known regarding its variation in in cancer patients. 79 16 ESRD patients after kidney transplantation. The purpose of this study 80 17 was to assess whether improvement of renal function after kidney 81 18 transplantation had an impact on the redox state of Cys 34 in HSA. Effect of Cyp2d6 Genetic Polymorphism 82 19 Material and Methods: Eighteen patients with ESRD who were on The Pharmacokinetics of Multiple- 83 20 scheduled to undergo the first kidney allograft transplantation were Dose Metoclopramide 84 21 enrolled. Plasma sample was collected from the ESRD patients before J.Y. Byeon; S.H. Kim; Y.H. Kim; H.J. Lee; Y. Lee; Y.J. Lee; 85 22 and 7, 14, 30, 60, 90, 180 and 360 days after kidney transplanta- D.H. Kim; H.J. Lim; C.G. Jang; and S.Y. Lee 86 23 tion. Structual heterogeneity of HSA was analysed using electrospray Sungkyunkwan University, Suwon, Republic of Korea 87 24 ionization time-of-flight mass spectrometer (ESI-TOFMS). Introduction: Metoclopramide is indicated for the treatment of 88 25 Results and Discussion: Since creatinine clearance increased signifi- heartburn caused by gastroesophageal reflux and is commonly used 89 26 cantly from day 7 after kidney transplantation compared to before to treat nausea and vomiting. Metoclopramide is mainly metabolized 90 27 kidney transplantation and remained almost stable thereafter, it was by CYP2D6, and to some extent by CYP3A. Metoclopramide is also 81 28 suggested that these allograft transplantations were successful. Two known for potent inhibitor of CYP2D6. CYP2D6 is highly polymor- 92 29 major peaks, corresponding to the cysteinylation of Cys 34 (Cys-Cys phic and the polymorphism of CYP2D6 significantly affects the phar- 93 30 34-HSA) and reduced Cys 34-HSA in plasma samples obtained from macokinetics of drugs in clinical use, such as codeine, risperidone, 94 31 these patients before kidney transplantation, were identified by ESI- and fluoxetine. Therefore, we investigated the effect of CYP2D6 95 32 TOFMS. A significant decrease in the ratio of Cys-Cys 34-HSA and genetic polymorphism on the pharmacokinetics of metoclopramide 96 33 reduced Cys 34-HSA was observed from day 7 after kidney trans- after multiple-dose. 97 34 plantation compared to before. In addition, the gradual decrease of Material and Methods: Forty one healthy Korean subjects were 98 35 its ratio was confirmed until 360 day after kidney transplantation. recruited and classified into three different groups according to 99 36 100 Conclusion: These results suggested that the redox state of Cys 34 in CYP2D6 genotype: CYP2D6*wt/*wt (*wt= *1 or *2, n = 11), 37 101 HSA was improved by the restoration of renal function after kidney CYP2D6*wt/*10 (n = 15), and CYP2D6*10/*10 (n = 15). After 38 transplantation. overnight fasting, each subject received a single oral dose of 10 mg 102 39 metoclopramide. Blood samples were collected up to 24 hours after 103 40 drug ingestion, and plasma concentrations of metoclopramide were 104 41 Relationships Between Plasma determined by using validated liquid chromatography-tandem mass 105 42 Concentrations of Fentanyl and 4beta- spectrometry system. 106 43 Hydroxycholesterol In Cancer Patients Results: After multiple-dose metoclopramide, C and AUC 107 44 max 0-24 108 T. Ishida; T. Naito; H. Sato; K. Ohnishi; and J. Kawakami of metoclopramide in CYP2D6*10/*10 group were signifi- 45 109 Hamamatsu University School of Medicine, Hamamatsu, cantly higher than those in CYP2D6*wt/*wt group (P = 0.014 46 110 Shizuoka, Japan and P = 0.007, respectively). Also, apparent oral clearance 47 111 Background and Introduction: Transdermal fentanyl possesses a (CL/F) in CYP2D6*10/*10 group was 24.6% lower than that in 48 112 large pharmacokinetic variation in cancer patients. Genetic polymor- CYP2D6*wt/*wt group (P = 0.018). There were no significant dif- 49 113 phism of cytochrome P450 (CYP) 3A5 influences the plasma exposure ferences in t and t among 3 different groups. 50 max 1/2 114 of fentanyl. Recently, the serum concentration of 4 -hydroxycholes- Conclusions: The present study showed that CYP2D6 genetic 51 β 115 terol has been reported as an endogenous marker of CYP3A4/5 in polymorphism had significant effects on the pharmacokinetics of 52 116 humans. The aim of this study was to evaluate the concentrations of multiple-dose metoclopramide. 53 117 plasma fentanyl and serum 4 -hydroxycholesterol based on CYP3A5 54 β 118 genetic polymorphisms in cancer patients. 55 119 Material and Methods: Forty Japanese cancer patients treated with 56 Influence of Cyp2d6 Genetic 120 transdermal fentanyl were enrolled in this study. Blood samples were 57 Polymorphism on The Pharmacokinetic 121 obtained at day 8 or later after starting the medication. The concen- 58 Parameters of Risperidone and Its Active 122 trations of plasma fentanyl and serum 4 -hydroxycholesterol were 59 β Metabolites 123 measured using LC-MS/MS. The relationships between the concen- 60 J.Y. Byeon; S.H. Kim; Y.H. Kim; H.J. Lee; Y. Lee; Y.J. Lee; 124 trations of plasma fentanyl and serum 4 -hydroxycholesterol, and 61 β D.H. Kim; H.J. Lim; and S.Y. Lee 125 CYP3A5 genotype were evaluated. 62 Sungkyunkwan University, Suwon, Republic of Korea 126 Results: The medians of theoretical absorption rate and plasma 63 Introduction: Risperidone is an antipsychotic drug that is used to 127 concentration of fentanyl were 0.64 g/h/kg and 1.74 ng/mL, 64 μ treat schizophrenia and symptoms of bipolar disorder. Risperidone 128

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1 is mainly metabolized to its active metabolite, 9-hydroxyrisperidone, C-Peptide Clearance: Potential Marker of 65 2 by CYP2D6. CYP2D6 is subject to genetic polymorphism and shows Endogenous Insulin Secretion for Pkpd 66 3 interindividual variability in metabolic capacity. Therefore, we inves- Studies of Insulin In Neonates 67 4 tigated the influence of CYP2D6 genetic polymorphism on the phar- E.R. Salis1; M.K. Soelbeck2; D.M. Reith1; B.J. Wheeler1; 68 5 macokinetic parameters of risperidone and 9-hydroxyrisperidone. R.S. Broadbent1; and N.J. Medlicott1 69 6 Material and Methods: Thirty-seven healthy Korean subjects 1University of Otago, Dunedin, New Zealand; and 2University of 70 7 were recruited and divided into three different groups according to Copenhagen, Copenhagen, Denmark 71 8 CYP2D6 genotype: CYP2D6*wt/*wt (*wt = *1 or *2, n = 11), Background: Insulin and C-peptide are secreted in equimolar 72 9 CYP2D6*wt/*10 (n = 16) and CYP2D6*10/*10 (n = 10). After amounts from the pancreas [1]. However, since C-peptide is not 73 10 overnight fasting, every subject ingested a single oral dose of 2 mg hepatically cleared, it may be possible to estimate insulin secretion 74 11 risperidone. Blood samples were collected up to 48 hours after from the urinary C-peptide excretion rate [1]. This may give a non- 75 12 administration, and plasma concentrations of risperidone and its invasive way of measuring insulin production in neonates [2]. 76 13 active metabolite were simultaneously determined by using liquid Aims: To measure urinary C-peptide concentrations, then calculate 77 14 chromatography-tandem mass spectrometry system. C-peptide clearance (Cl) and excretion rate (UER) in neonates. In 78

15 Results: Cmax and AUC0-∞ of risperidone in CYP2D6*10/*10 addition, the effect of gestational age (GA) and blood glucose levels 79 16 group was 1.91-fold and 3.62-fold higher respectively than those (BGL) on C-peptide UER were investigated. 80

17 in CYP2D6*wt/*wt group. t1/2 of risperidone was 1.87-fold pro- Materials and Method: Insulin concentrations in plasma, and 81 18 longed in CYP2D6*10/*10 genotype than that in CYP2D6*wt/*wt C-peptide concentrations were measured in plasma and urine, in 82

19 group. Also, Cmax of 9-hydroxyrisperidone in CYP2D6*10/*10 was 20 neonates. Chemiluminescent immunoassays (IV2-004, Invitron, 83 20 significantly higher than that in CYP2D6*wt/*wt (P < 0.001) and Monmouth, UK) were used for insulin and C-peptide measurements, 84

21 t1/2 was significantly different among three CYP2D6 genotype groups with urine diluted to 40% with bovine serum albumin (BSA) 1% 85 22 (P = 0.003). in phosphate buffered saline (PBS). Standard addition and direct 86 23 Conclusions: CYP2D6 genetic polymorphism plays an important measurement from the standard curve were compared for meas- 87 24 role in the metabolism of risperidone and affects the pharmacokinet- urement of urinary C-peptide. Urine volume and time of collection 88 25 ics of risperidone and its active metabolite. were recorded and used to calculate UER and Cl. 89 26 Results: The mean Cl of C-peptide was 0.309 ± 0.329 mL/min/kg, 90 27 and UER was 0.0329 ± 0.0342 pmol/min/kg. Correlations between 81 28 Cyp2d6*10 Allele Has Significant Effects Cl or UER and GA were not significant (P > 0.05). No significant cor- 92 29 on The Pharmacokinetics of Tramadol relation was shown between Cl or UER and BGL (P > 0.05). Direct 93 30 and Its Metabolite measurement from kit standards produced a more precise method 94 31 J.Y. Byeon; S.H. Kim; Y.H. Kim; H.J. Lee; Y. Lee; Y.J. Lee; for determining C-peptide concentration and was simpler than the 95 32 D.H. Kim; H.J. Lim; and S.Y. Lee standard addition method. 96 33 Sungkyunkwan University, Suwon, Republic of Korea Conclusions: Both Cl and UER were highly variable in neonates 97 34 Introduction: Tramadol is a centrally acting analgesic used to treat but were not correlated with GA. Additionally, BGL did not appear 98 35 moderate to severe pain. Tramadol exerts its activity by binding to to affect C-peptide UER and Cl, although sample size in this study 99 36 100 the μ -opioid receptor and inhibiting the reuptake of serotonin and was small. Since GA and BGL did not appear to affect Cl and UER, 37 norepinephrine. Tramadol is metabolized to its active metabolite, urinary C-peptide may provide a noninvasive method of measuring 101 38 Ο-desmethyltramadol, by CYP2D6. About 20 to 30% of drugs in insulin production in neonates. 102 39 clinical use are metabolized by CYP2D6 and CYP2D6 genetic pol- 103 40 ymorphism have been associated with altered enzyme activity. As 104 41 CYP2D6*10 allele is the most common allele in the Asian popula- Pharmacokinetics of Tolterodine And Its 105 42 tion, we investigated the effect of CYP2D6*10 allele on the pharma- Active Metabolite After Multiple Doses In 106 43 cokinetics of tramadol and its active metabolite. Relation To Cyp2d6 Genotype 107 44 108 Material and Methods: Forty-four healthy Korean subjects S.H. Kim; J.Y. Byeon; Y.H. Kim; H.J. Lee; Y. Lee; Y.J. Lee; 45 109 were recruited and divided into 3 different groups according to D.H. Kim; H.J. Lim; C.G. Jang; and S.Y. Lee 46 110 CYP2D6 genotype: CYP2D6*wt/*wt (*w t= *1 or *2, n = 15), Sungkyunkwan University, Suwon, Republic of Korea 47 111 CYP2D6*wt/*10 (n = 14) and CYP2D6*10/*10 (n = 15). After Introduction: Tolterodine is an antimuscarinic drug and is prescribed 48 112 overnight fasting, each subject received a single oral dose of 100 mg to treat overactive bladder to relieve urinary difficulties. Tolterodine 49 113 tramadol. Blood samples were collected up to 30 hours after drug is predominantly metabolized by CYP2D6 and the metabolism 50 114 intake, and plasma concentrations of tramadol and its metabolite of tolterodine involves the formation of pharmacologically active 51 115 were determined by using validated liquid chromatography-tandem 5-hydroxymethyl tolterodine. As CYP2D6 is highly polymorphic, 52 116 mass spectrometry system. we investigated the effects of CYP2D6 genetic polymorphism on the 53 117 Results: Although C of tramadol was not significantly different pharmacokinetic parameters of tolterodine and its active metabolite 54 max 118 among 3 different groups, AUC of tramadol in CYP2D6*10/*10 after multiple doses. 55 0-∞ 119 group was 1.56-fold higher than that in CYP2D6*wt/*wt Material and Methods: Forty-six healthy Korean subjects 56 120 group (P < 0.001) and apparent oral clearance (CL/F) of trama- were recruited and divided into 4 different groups according 57 121 dol in CYP2D6*10/*10 group was 32.9% lower, compared to to CYP2D6 genotype: CYP2D6*wt/*wt (*wt *1 or *2, n 58 = = 122 CYP2D6*wt/*wt group. In terms of its active metabolite, C and 14), CYP2D6*wt/*10 (n 14), CYP2D6*10/*10 (n 15), and 59 max = = 123 AUC in CYP2D6*10/*10 group were significantly higher than CYP2D6*5/*10 (n 3). After overnight fasting, every subject 60 0-∞ = 124 those in CYP2D6*wt/*wt group (both, P < 0.001). received a single oral dose of 2 mg tolterodine. Blood samples were 61 125 Conclusions: CYP2D6*10 allele has significant effects on the plasma collected up to 24 hours after drug ingestion, and plasma concentra- 62 126 exposure of tramadol and its active metabolite. tions of tolterodine and its active metabolite were simultaneously 63 127 64 128

2015 e3 Clinical Therapeutics

1 determined by using liquid chromatography-tandem mass spectrom- Introduction: Tolperisone is used to the treat painful reflex muscle 65 2 etry system. spasm or spasticity. CYP2D6 plays an important role in the metabo- 66

3 Results: There were significant differences in Cmax and AUC0-24 lism of tolperisone and CYP2C19 also contributes to the metabolism 67 4 among four different groups (both, P < 0.001) and Cmax and AUC0-24 of tolperisone. Fluoxetine is one of the widely prescribed antide- 68 5 of tolterodine in CYP2D6*10/*10 and CYP2D6*5/*10 group pressant and is known for CYP2D6 inhibitor. CYP2C19 is highly 69 6 were significantly higher than those inCYP2D6*wt/*wt group. polymorphic and involved in the metabolism of a lot of drugs, such 70 7 Apparent oral clearance (CL/F) of tolterodine was 94.4% lower as proton pump inhibitors and clopidogrel. In this study, we investi- 71 8 in CYP2D6*5/*10 group than that in CYP2D6*wt/*wt group. In gated the effect of fluoxetine on the pharmacokinetic parameters of 72

9 respect to its active metabolite, Cmax and AUC0-24 had significant tolperisone in relation to CYP2C19 genetic polymorphism. 73 10 changes among 4 different groups (P = 0.026 and P = 0.039, respec- Material and Methods: Twenty-five healthy Korean subjects 74 11 tively). were volunteered and classified into 3 different groups according 75 12 Conclusions: CYP2D6 genetic polymorphism has significant effects to CYP2C19 genotype: CYP2C19EM (CYP2C19*1/*1, n = 10), 76 13 on the pharmacokinetics of tolterodine and its active metabolite. It is CYP2C19IM (CYP2C19*1/*2 or CYP2C19*1/*3, n = 11) and 77 14 recommended that physicians optimize dose of tolterodine accord- CYP2C19PM (CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3, 78 15 ing to CYP2D6 genotype and keep monitoring the adverse effects of n = 4). In the control phase, a single 150 mg oral dose of tolperisone 79 16 tolterodine, especially in CYP2D6 poor metabolizers. was administered to every subject. During the test phase, each subject 80 17 received a single 20 mg oral dose of fluoxetine in the morning for 5 81 18 consecutive days. On day 6, a single 150 mg oral dose of tolperisone 82 19 Effect of Paroxetine on The and a single 20 mg oral dose of fluoxetine were coadministered. 83 20 Pharmacokinetics of Atomoxetine In Blood samples were obtained up to 12 hours after drug intake, and 84 21 Different Cyp2d6 Genotype plasma concentrations of tolperisone were determined by using liquid 85 22 S.H. Kim; J.Y. Byeon; Y.H. Kim; H.J. Lee; Y. Lee; Y.J. Lee; chromatography-tandem mass spectrometry system. 86 23 Results: C and AUC of tolperisone in each group were signifi- 87 D.H. Kim; H.J. Lim; and S.Y. Lee max 0-∞ 24 Sungkyunkwan University, Suwon, Republic of Korea cantly higher in the test phase than those in control phase (all, P < 88 25 0.001). Although t and t were not significant different between 89 Introduction: Atomoxetine is a norepinephrine reuptake inhibitor max 1/2 26 that is prescribed for the treatment of attention deficit hyperactivity control phase and test phase in each group, apparent oral clear- 90 27 disorder (ADHD). Atomoxetine is mainly metabolized to 4-hydroxy- ance (CL/F) of tolperisone was significantly different between con- 81 28 atomoxetine by CYP2D6. Paroxetine is an antidepressant drug that trol phase and test phase; 85.5%, 60.9%, 35.3% was decreased in 92 29 belongs to selective serotonin reuptake inhibitor and is also known CYP2C19EM, CYP2C19IM, and CYP2C19PM group, respectively. 93 30 for potent CYP2D6 inhibitor. Therefore, the aim of this study was Conclusions: Coadministration of fluoxetine had significant effects on 94 31 to determine the effect of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics of tolperisone according to CYP2C19 genotype. 95 32 the pharmacokinetics of atomoxetine in different CYP2D6 genotype. 96 33 Material and Methods: Forty-five healthy Korean subjects were 97 34 volunteered and divided into 3 different groups according to Drug-Drug Interaction Between 98 35 99 CYP2D6 genotype: CYP2D6*wt/*wt (*wt = *1 or *2, n = 16), Meloxicam and Amiodarone 36 100 CYP2D6*wt/*10 (n = 15) and CYP2D6*10/*10 (n = 14). In the H.J. Lee; Y.H. Kim; S.H. Kim; J.Y. Byeon; Y. Lee; and Y.J. Lee 37 control phase, each subject received a single oral dose of 20 mg atom- Sungkyunkwan University, Suwon, Republic of Korea 101 38 oxetine after overnight fasting. In the test phase, each subject ingested Introduction: Meloxicam is a nonsteroidal anti-inflammatory 102 39 a single oral dose of 20 mg paroxetine at 8 A.M. for consecutive seven drug (NSAID) and is used to relive pain and tenderness cause by 103 40 days. At the study day, 20 mg atomoxetine was administered to every osteoarthritis. CYP2C9 and CYP3A4 are predominantly involved 104 41 subject with 20 mg paroxetine. Blood samples were collected up to in the metabolism of meloxicam and 5’-carboxymeloxicam is a 105 42 24 hours after drug intake, and plasma concentrations of atomox- major metabolite. Amiodarone is an antiarrhythmic agent and is 106 43 etine were determined by using liquid chromatography-tandem mass prescribed for treatment and prevention of ventricular arrhythmias. 107 44 spectrometry system. Amiodarone is known for a moderate CYP2C9 inhibitor. Therefore, 108 45 109 Results: Cmax of atomoxetine in each group was 2.3-fold, 1.7- we determined the effect of amiodarone on the pharmacokinetics of 46 fold, and 1.5-fold higher respectively in the test phase than that in meloxicam in CYP2C9*1/*1 subject, in order to minimize the effects 110 47 111 control phase (all, P < 0.001). t of atomoxetine in each group of CYP2C9 genetic polymorphism. 48 1/2 112 prolonged in the test phase (all, P < 0.001) and apparent oral clear- Material and Methods: Fourteen healthy Korean subjects genotype 49 ance (CL/F) of atomoxetine was significantly decreased in the test as CYP2C9*1/*1 were recruited. In control phase, each subject 113 50 phase; 91%, 79.3%, 70.3% was decreased in CYP2D6*wt/*wt, ingested oral dose of 15 mg meloxicam after overnight fasting. An 114 51 CYP2D6*wt/*10, and CYP2D6*10/*10 group. oral dose of 600 mg oral dose of amiodarone was administered once a 115 52 Conclusions: Present study showed that paroxetine, a potent day for 5 consecutive days and on study day meloxicam was adminis- 116 53 CYP2D6 inhibitor, had significant effects on the pharmacokinetics tered 1 hour after sixth administration of amiodarone. Blood samples 117 54 of atomoxetine according to CYP2D6 genotype. were collected up to 72 and 144 hours, respectively in control phase 118 55 and amiodarone phase, and plasma concentrations of meloxicam and 119 56 its major metabolite were simultaneously determined by using liquid 120 57 121 Cyp2c19 Genetic Polymorphism chromatography-tandem mass spectrometry system. 58 Results: C of 5’-carboxymeloxicam in amiodarone phase was sig- 122 Has Significant Effects on The max 59 nificant lower than that in control phase (6.3 ± 1.6 ng/mL versus 3.5 123 60 Pharmacokinetics of Tolperisone After 124 ± 1.0 ng/mL, P < 0.0001). Also, AUC of meloxicam in amiodarone 61 Administration of Fluoxetine 0-∞ 125 S.H. Kim; J.Y. Byeon; Y.H. Kim; H.J. Lee; Y. Lee; Y.J. Lee; phase was 1.43-fold higher (P < 0.0001) than that in control phase 62 and apparent oral clearance (CL/F) of meloxicam in amiodarone 126 63 D.H. Kim; H.J. Lim; and S.Y. Lee 127 phase decreased by 30.6%, compared to control phase (P < 0.0001). 64 Sungkyunkwan University, Suwon, Republic of Korea 128

e4 Volume XX Number XX An Educational Intervention To Improve Nurses Reporting of Adverse Drug Reactions

1 Conclusions: There were significant drug–drug interaction between will be needed to establish clear relationship between MRP2 C24T 65 2 meloxicam and amiodarone, a moderate CYP2C9 inhibitor. allele and the pharmacokinetics of . 66 3 67 4 68 5 Smoking Has Significant Effects on Lack of Association Between Oct2 69 6 The Pharmacokinetic Parameters of C602t Genetic Variant and The 70 7 Tolperisone Pharmacokinetics of Lamivudine In Healty 71 8 H.J. Lee; Y.H. Kim; S.H. Kim; J.Y. Byeon; Y. Lee; and Y.J. Lee Korean Subjects 72 9 Sungkyunkwan University, Suwon, Republic of Korea Y. Lee; J.Y. Byeon; Y.H. Kim; S.H. Kim; H.J. Lee; and Y.J. Lee 73 10 Introduction: Tolperisone is a muscle relaxant and has been author- Sungkyunkwan University, Suwon, Republic of Korea 74 11 ised in several countries for the treatment of muscle spasm and Introduction: Lamivudine is an analogue of cytidine and prescribed 75 12 spasticity. In the metabolism of tolperisone, CYP2D6, CYP2C19, for the treatment of chronic hepatitis B. Lamivudine is in a class 76 13 and CYP1A2 are involved. CYP1A2 activity is largely determined of medications called nucleoside reverse transcriptase inhibitors 77 14 by smoking behaviour as smoking is a potent inducer of CYP1A2. (NRTIs). The renal excretion of lamivudine is mostly mediated by 78 15 Therefore, we investigated the effects of smoking on the pharmacoki- OCT2, an influx transporter encoded by SLC22A2 gene. The aim 79 16 netics of tolperisone in healthy Korean subjects. of the present study was to investigate the effects of OCT2 C602T 80 17 Material and Methods: One hundred healthy Korean subjects variant on the pharmacokinetics of lamivudine. 81 18 82 were volunteered and divided into 2 groups: Smokers (n = 50) and Material and Methods: Nineteen Korean subjects were volunteered 19 83 Nonsmokers (n = 50). After overnight fasting, a single 150-mg oral and divided into 2 different groups according to OCT2 C602T: 20 84 dose of tolperisone was administered to every subject. Blood samples c.602CC (CC type, n = 12) and c.602CT (CT type, n = 7). After over- 21 were collected up to 12 hours after drug ingestion, and plasma con- night fasting, a single 100-mg oral dose of lamivudine was adminis- 85 22 centrations of tolperisone were determined by using validated liquid tered to every subject. Blood samples were collected up to 24 hours 86 23 chromatography-tandem mass spectrometry system. after drug administration, and plasma concentrations of lamivudine 87 24 Results: As expected, C in non-smoking group was 1.58-fold were determined by using validated liquid chromatography–tandem 88 25 max 89 higher than that in smoking group (P = 0.019). AUC0-∞ in non- mass spectrometry system. 26 smoking group was significantly higher than that in smokers (188.5 Results: C and AUC values of lamivudine were not significantly 90 27 max 81 ± 198.2 versus 122.9 ± 140.2, P = 0.0323). Also, apparent oral different between CC type and CT type. Cmax of lamivudine in CC 28 clearance (CL/F) of tolperisone decreased by 33% in nonsmoking type and CT type was 1150.0 ± 191.4 ng/mL and 1255.6 ± 249.8 ng/ 92 29 93 group, compared to smoking group (P = 0.021). mL, respectively. AUCinf of lamivudine in each genotype group was 30 Conclusions: Smoking, which is a potent inducer of CYP1A2, has 4429.4 ± 427.5 nghr/mL and 4297.4 ± 1047.9 ng/hr/mL, respec- 94 31 significant impacts on the pharmacokinetic parameters of tolperisone. tively. Also, apparent oral clearance (CL/F) and elimination half-life 95 32 96 (t1/2) of lamivudine were not also significantly different between 2 33 genotype groups. 97 34 Conclusions: In conclusion, there were no significant changes in the 98 35 Influence of Mrp2 C24t Genetic Variant 99 on The Pharmacokinetics of Valsartan pharmacokinetics of lamivudine in relation to OCT2 C602T genetic 36 variant. 100 37 H.J. Lee; Y.H. Kim; S.H. Kim; J.Y. Byeon; Y. Lee; and Y.J. Lee 101 38 Sungkyunkwan University, Suwon, Republic of Korea 102 39 Introduction: Valsartan is an angiotensin-receptor blocker (ARB) 103 40 and is widely prescribed for the treatment of hypertension. Valsartan Effect of Diltiazem, A Moderate Cyp3a4 104 41 is predominantly excreted into the bile in unchanged form. It is Inhibitor, on The Pharmacokinetic 105 42 reported that valsartan is a substrate of MRP2, an efflux transporter Parameters of Tamsulosin 106 43 encoded by ABCC2 gene. Several SNPs in the gene are involved Y. Lee; J.Y. Byeon; Y.H. Kim; S.H. Kim; H.J. Lee; and Y.J. Lee 107 44 in the interindividual variation of drug response. C24T SNP in the Sungkyunkwan University, Suwon, Republic of Korea 108 45 MRP2 occurs with a relatively high allelic frequency. Therefore, we Introduction: Tamsulosin is selective α 1-adrenoceptor antagonist 109 46 investigated the effect of MRP2 C24T genetic variant on the phar- that is used to treat symptoms of benign prostatic hyperplasia (BPH). 110 47 macokinetics of valsartan. CYP2D6 and CYP3A4 are involved in the metabolism of tamsulo- 111 48 Material and Methods: Eleven healthy Korean subjects were volun- sin. Diltiazem is one of calcium channel blockers used to treat high 112 49 teered and divided into 2 groups according to MRP2 C24T allele: blood pressure and to control angina and it is known for a moderate 113 50 24CC type (n = 6) and 24TT type (n = 5). After overnight fasting, CYP3A4 inhibitor. We investigated the effects of coadministration 114 51 each subject received a single 80 mg oral dose of valsartan. Blood of diltiazem on the pharmacokinetics of tamsulosin. 115 52 samples were collected up to 24 hours after drug administration, Material and Methods: Ten healthy Korean subjects genotyped as 116 53 and plasma concentrations of valsartan were determined by using CYP2D6*wt/*wt (*wt = *1 or *2) were volunteered. After overnight 117 54 high-performance liquid chromatography. fasting, each subject received a single 0.2-mg oral dose of tamsulo- 118 55 Results: Cmax and AUCinf of valsartan in TT type (3.2 ± 2.0 ng/mL sin in control phase. In the diltiazem phase, all subjects received 60 119 56 and 20.1 ± 13.8 ng/hr/mL, respectively) were higher than those in mg diltiazem 3 times a day for 4 days. On study day, 0.2 mg oral 120 57 CC type (2.2 ± 0.8 ng/mL and 11.0 ± 3.6 ng/hr/mL, respectively). dose of tamsulosin was administered to each subject 1 hour after 121 58 Oral clearance (CL/F) of valsartan in TT type was lower than that in the administration of diltiazem. Blood samples were collected up to 122 59 CC type (6.4 ± 5.0 L/hr versus 8.7 ± 5.3 L/hr). However, all of these 48 hours after drug intake, and plasma concentrations of tamsulo- 123 60 differences were not significant, maybe due to relatively small number sin were determined by using liquid chromatography–tandem mass 124 61 of subjects in each group. spectrometry system. 125 62 Conclusions: Our study showed that ABCC2 C24T did not have Results: Cmax and AUC0-∞ of tamsulosin in diltiazem phase were 126 63 significant effects on the pharmacokinetics of valsartan. Further study both 1.71-fold increased than those in the control phase (both, 127 64 128

2015 e5 Clinical Therapeutics

1 P < 0.0001). Apparent oral clearance (CL/F) of tamsulosin in Pharmacokinetics of Ceftriaxone 65 2 diltiazem phase decreased by 41.9%, compared to control phase Included In Cellular Transport System 66 3 (P < 0.0001). T. Nurgozhin1; A. Gulyayev1; S. Lokhvytsky2; B. Yermekbayeva1; 67 4 Conclusions: In conclusion, there were significant differences in the S. Sergazy1; Z. Shulgau1; and K. Berikkhanova1 68 5 pharmacokinetics of tamsulosin after administration of diltiazem, 1PI “Center for Life Sciences”, Nazarbayev University, Astana, 69 6 leading to an increase in the plasma exposure of tamsulosin. Kazakhstan; and 2Karaganda State Medical University, Karaganda, 70 7 Kazakhstan 71 8 Autologous blood cells can be used to implement targeted drug deliv- 72 9 Cyp2d6 Genetic Variant Has Significant ery. However the pharmacokinetics of a drug substance placed in the 73 10 Effects On The Pharmacokinetics Of blood cells can vary. The use of antibiotics as objects for inclusion in 74 11 Metoclopramide the red blood cells is widely spread. Pharmacokinetics of ceftriaxone 75 12 Y. Lee; J.Y. Byeon; Y.H. Kim; S.H. Kim; H.J. Lee; and Y.J. Lee included in cellular transport systems had been described after a sin- 76 13 Sungkyunkwan University, Suwon, Republic of Korea gle intravenous administration of the drug to 28 patients (age 28–54 77 14 Introduction: Metoclopramide is in a class of medications known years, 11 men, 17 women) who were in the clinic of surgical diseases 78 15 as dopamine-receptor antagonist and relives symptoms such as of the Karaganda Medical University. This cohort was divided into 3 79 16 nausea, vomiting, and heartburn. Metoclopramide is mainly groups: 1 - intravenous administration of ceftriaxone in free form (8 80 17 metabolized via monodeethylation, which is mainly mediated by patients); 2 - administration of ceftriaxone inserted into autologous red 81 18 CYP2D6. As CYP2D6 is highly polymorphic and exhibits interin- blood cells (13 patients); 3 - administration of ceftriaxone inserted into 82 19 dividual differences in enzyme activity, we investigated the effects autologous leukocytes (7 patients). The dose of ceftriaxone injected 83 20 of CYP2D6 genetic variants on the pharmacokinetics of metoclo- into transport system was 1000 mg. Also the equivalent dose was used 84 21 pramide. for a free form injection of ceftriaxon. The concentration of ceftriaxone 85 22 Material and Methods: Twenty-eight Korean subjects were selected in the blood serum was measured by HPLC with UV detection using 86 23 and classified into 3 different groups in relation to CYP2D6 gen- Agilent 1290 chromatograph. The table below demonstrates how the 87 24 88 otype: CYP2D6*1/*1 (n = 10), CYP2D6*10/*10 (n = 10) and cellular transport system significantly alters the pharmacokinetics of 25 89 CYP2D6*5/*10 (n = 8). After overnight fasting, each subject the antibiotic incorporated into the transport system. 26 ingested a single 1- mg oral dose of metoclopramide. Blood sam- 90 27 ples were collected up to 24 hours after drug ingestion, and liquid Table – Pharmacokinetic parameters of the ceftriaxone after intravenous 81 28 chromatography-tandem mass spectrometry system was used to administration 92 29 determine plasma concentrations of metoclopramide. 93 30 Method of administration (mean values) 94 Results: Cmax of metoclopramide in CYP2D6*10/*10 and 31 CYP2D6*5/*10 groups were 1.8- and 1.9-fold higher than that in 95 32 Pharmacokinetics constants Group 1 Group 2 Group 3 96 CYP2D6*1/*1 group (both, P < 0.0001). AUCinf of metoclopramide 33 in CYP2D6*10/*10 and CYP2D6*5/*10 groups were 2.4- and 2.5- 97 34 Half-elimination period, min 181.9 620.4 822.1 98 fold higher than that in CYP2D6*1/*1 group (149.6 ± 48.2 ng•hr/ Elimination constant 0.004 0.001 0.001 35 99 mL, both P < 0.0001). Oral clearance (CL/F) of metoclopramide in Distribution volume, ml 6.0 8.3 8.8 36 CYP2D6*10/*10 and CYP2D6*5/*10 groups were 59% and 62% Clearance, ml/min 0.02 0.009 0.006 100 37 Area under curve 43687.0 107542.1 166068.4 101 lower than that in CYP2D6*1/*1 group (both, P < 0.0001). 38 Conclusions: In conclusion, CYP2D6 genetic variant has significant 102 39 impacts on the pharmacokinetic parameters of metoclopramide. There was no significant difference between the pharmacokinetic 103 40 parameters of ceftriaxone in the composition of erythrocyte com- 104 41 pared to leukocyte cell systems. However, the main difference of 105 42 pharmacokinetics parameters between antibiotic in free form and 106 43 Hemodynamic Adrenergic ceftriaxone included into transport system were: increased half- 107 44 Stimulation Can Be Attenuated By elimination period, distribution volume and increased area under 108 45 (-)-Epigallocatechin-3-O-Gallate (Egcg) the curve whereas elimination constant and clearance were decreased. 109 46 K.-W. Oh; E.-H. Oh; and J.-M. Hong 110 47 Chungbuk National University, Cheongju, Republic of Korea 111 48 We previously reported that (-)-epigallocatechin-3-O-gallate (EGCG) Determination of Methylphenidate In 112 49 could counter the caffeine-induced stimulant effects of the central Human Plasma By A Validated Lc-Ms/Ms 113 50 nervous systems, by inhibition of catecholamine release. In these Method 114 51 experiments, EGCG reduced hemodynamic adrenergic stimulation L. Kasabova; and D. Svinarov 115 52 induced by adrenergic agonists in rats. In addition, caffeine tablets Alexander University Hospital, Faculty of Medicine, Medical 116 53 (200 mg) were orally administered to healthy men aged between University, Sofia, Bulgaria 117 54 25 and 35 years 30 minutes after the oral administration of 100 Background: Development and validation of LC-MS/MS determina- 118 55 mg and 200 mg EGCG. The mean BP and HR were measured 30 tion of methylphenidate (MPD) was performed with the aim to be 119 56 minutes after caffeine administration. The increase in BP induced by applied in the course of a bioequivalence study. 120

57 caffeine was inhibited when coadministrated with EGCG. We found Methods: MPD and methylphenidate-d9 (MPD-d9, internal stand- 121 58 that caffeine slightly decreased the HR in the volunteers. Moreover, ard) were extracted from human plasma with 1-chlorobutane. 122 59 EGCG enhanced HR reduction. In addition, caffeine increased Chromatographic separation was performed on C18 analytical 123 60 blood catecholamines (noradrenaline, adrenaline and dopamine) column with mobile phase consisting of 65% aqueous methanol 124 61 levels but EGCG inhibited the increase in noradrenaline, adrenaline and 0.2% formic acid. Positive electrospray ionization and selected 125 62 and dopamine levels induced by caffeine. These results suggest that reaction monitoring were used to follow the predominant transi- 126 63 hemodynamic adrenergic stimulation can be attenuated by (-)-epi- tions: collision energy 20, m/z 234→ 84 for MPD, and m/z 243→ 93 127

64 gallocatechin-3-O-gallate (EGCG) in humans. for MPD-d9. Raw data of mass chromatograms were collected and 128

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1 processed by specialized software, and weighted (1/X) linear regression was assessed in elderly and patient with RI, only severe RI could produce 65 2 was performed to determine the concentration of MPD. Validation accumulation of bemiparin. Aggregation of data of clinical trials (CT) 66 3 strategy was strictly adhered to current industrial guidance. is useful for identifying subgroups at higher risk of adverse reactions. 67 4 Results: Selectivity was assessed with 8 individual sources of human Material and Methods: CT were aggregated if bemiparin was used 68 5 plasma and confirmed with matrix effect (ME) averaging 106 to for more than 3 weeks. RI was defined according to creatinine clear- 69

6 109% for MPD, 106 to 107% for MPD-d9, and relative ME of 100 ance and Cockcroft-Gault equation: mild (≥ 50 y ≤ 80 mL/min); 70 7 to 102% for MPD. Accuracy ranged from −3.4 to 12.6% within runs moderate (≥ 30 y < 50 mL/min) and severe < 30 mL/min). Elderly 71 8 and from −0.8 to 10.6% between runs. Precision was up to 4.3% were > 65 years. Bleeding Rate (BR) and relative risk reduction (RRR) 72 9 within-runs, and up to 6.5% between-runs. Extraction recoveries with confidence interval (CI) at 95% was calculated for bemiparin 73

10 averaged 60-65% for MPD and 68-79% for MPD-d9. Linearity was and placebo. 74 2 11 assured in the range 0.1 ÷ 99.0 µg /L, R > 0.99. Freeze-thaw stability Results: Six CT fulfilled selection criteria; 782 patients were treated 75 12 was determined for 3 cycles each lasting 24 hours, postpreparative with bemiparin and 649 with placebo; 277 (17.8%) and 242 (15.6%) 76 13 stability was documented for 24 hours at 10oC, short-term stability were elderly in bemiparin and placebo, respectively; median treat- 77 14 at 4 to 8oC was proven for 18 hours in the dark and for 2 hours at ment with bemiparin was 56.69 (SD 34.02) days, and placebo 36.05 78 15 daylight; stock solution stability and long term stability in plasma (SD 36.81). Regarding RI classification, 264 (23.6%)/235 (39.2%) 79 16 were documented for 66 days at −20oC. With run time of 1 minute, had mild, 51(7.1%)/59 (9.8%) moderate and 7(1%)/1 (0.2%) had 80 17 a throughput of over 400 samples per working day was achieved. severe RI in bemiparin and placebo. BR in RI was in mild 3.4% 81 18 Conclusion: The method was validated according to current indus- and 3.4% in bemiparin and placebo (RRR = 0; 95% CI, −1.55 to 82 19 trial requirements and allows the accurate and precise determination 0.61; P = 0.598); in moderate was 3.9% in bemiparin, no bleeding 83 20 of MPD in human plasma. events occur in placebo; no bleeding events occurred in severe RI. 84 21 BR in subjects with normal renal function was 2.3% and 4.3% in 85 22 bemiparin and placebo (P = 0.097; RRR = 0.47; 95% CI, −0.22 to 86 23 Hospital Deaths Induced By Drugs In A 0.77). BR in elderly was 3.4% and 1.9% (P < 0.216 in bemiparin 87 24 University Hospital During One Year and placebo;RRR = −0.75; 95% CI, −4.06 to 0.39); in adult were 88 25 O. Lapatto-Reiniluoto; J.T. Backman; M. Niemi; and 2.1% and 4.4% (RRR = 0.53; 95% CI , −0.02 to 0.78; P < 0.039 89 26 P.J. Neuvonen in bemiparin and placebo). 90 27 Helsinki University, Helsinki University Hospital, Helsinki, Conclusion: Aggregated data of CT do not showed an increase of 81 28 Finland bleeding in mild and moderate RI and in elderly, after receiving bemi- 92 29 Introduction: We studied the incidence of fatal adverse drug reac- parin in comparison with placebo. 93 30 tions (ADR) in a tertiary hospital in order to find out which drugs 94 31 are involved and whether there are changes compared to 12 years 95 32 earlier published data from the same hospital. Pediatrician! Do you know DRESS 96 33 Methods: All 1708 death cases in the Helsinki University Central syndrome? 97 34 Hospital during the year 2012 were retrospectively evaluated. All R. Slim; N. Fathallah; S. Larif; H. Ben Romdhane; A. Aounallah; 98 35 suspected drug-related deaths, excluding suicides, were scrutinized N. Guariani; and C. Ben Salem 99 36 by an expert panel using the WHO ADR probability classification. 1Faculty of Medicine of Sousse, Tunisia; and 2Farhat Hached 100 37 Results: Of all death cases, 52 (3.0%) were classified as certainly University Hospital, Sousse, Tunisia 101 38 or probably drug-related and 24 (1.4%) as possibly drug-related. Introduction: Drug rash with eosinophilia and systemic symptoms 102 39 Together, these correspond to 0.02% of all hospital admissions (DRESS) syndrome, also known as drug induced hypersensitivity 103 40 (394 338 admissions). The most commonly involved drugs in certain syndrome (DIHS), is a severe and potentially life-threatening disease 104 41 or probable cases were cytostatics (18 cases, 1.1% of all cases) and with mortality rates of up to 10%. The most commonly implicated 105 42 antithrombotics (17, 1.0%). Twelve years earlier, these caused 27 drugs are anticonvulsants, sulfonamides and allopurinol. 106 43 (1.8%) and 22 (1.5%) cases, respectively. Nonsteroidal anti-inflam- DRESS syndrome appears mostly in adults, but it is rarely 107 44 matory drugs (NSAIDs) and glucocorticoids caused less (2 and 0 reported in children. 108 45 109 cases) fatal ADRs than earlier (12 and 4 cases, P = 0.048 and P = Methods: We report 5 cases of DRESS syndrome in pediatric popula- 46 0.005, respectively). Most of the ADRs leading to death were present tion notified to the Pharmacovigilance Unit of Sousse. Observations 110 47 already in admission and affected seriously ill or elderly patients. were classified as definitive DRESS cases according to the RegiSCAR 111 48 Hospital-born fatal ADRs occurred in 0.003% of patients. scoring system and imputability was established according to 112 49 Conclusions: The current incidence of fatal ADRs (3.0% of all Naranjo probability scale. 113 50 deaths) seems to be less than that (5.0%) observed 12 years ear- Results: Our patients ranged from 6 to 16 years old at the time 114 51 lier in the same hospital. Despite declining trends, cytostatics and of presentation. Symptoms onset ranged from 8 days to 5 weeks 115 52 antithrombotics are still the leading causes. NSAIDs and glucocorti- from the start of the inciting drug. All patients had fever and gen- 116 53 coids seem to cause fatal ADRs less often than previously. Improved eralized maculopapular pruritic eruption. Two patients had facial 117 54 awareness, prevention and treatment of ADRs as well as safer medi- edema and oral mucositis. Most patients had lymphadenopathy (3/5). 118 55 cines may explain these declining trends. All patients had significant eosinophilia. Three patients had hepatic 119 56 cytolysis. Differential diagnosis for DRESS syndrome such as infec- 120 57 tious diseases and connective tissue disorders were ruled out through 121 58 122 Aggregated Data of Clinical Trials: viral and bacterial examinations. Incriminated drugs were: carbamaz- 59 epine (2 cases), lamotrigine (1 case), and sulfasalazine (2 case). After 123 60 Bemiparin Bleeding Risk In Elderly And 124 Patients With Renal Impairment culprit-drug withdrawal, outcomes were favorable for all patients. 61 Conclusion: The knowledge of DRESS syndrome clinical symptoms 125 I. Ayani; and J. Martínez-Gonzalez 62 in children is essential for clinicians. It is especially important that 126 Medical Department, Laboratorios Farmacéuticos Rovi 63 pediatricians should be able to take this life-threatening syndrome 127 Introduction: Bleeding in elderly and patients with renal impairment 64 into consideration for differential diagnosis. Early diagnosis and 128 (RI) are a safety concern with LMWH. The antiXa activity of bemiparin

2015 e7 Clinical Therapeutics

1 immediate cessation of the suspected drug is primordial to prevent education program on pain management, anticoagulants, fluid and 65 2 potentially fatal outcomes. electrolyte management and antibiotics for prescribing physicians 66 3 on surgical departments of large community hospitals. In addition a 67 4 weekly structured medication review is performed by hospital phar- 68 5 Ethnic norwegian doctors and diabetic macists on high risk surgical patients and discussed with the physician 69 6 pakistani women in oslo - what is the (assistant) on the ward. Risk assessment is based on pain medication, 70 7 patients' need for information? anticoagulant therapy and comorbidities (for example, heart and 71 renal failure). The aim of this intervention is to educate and support 8 E.-L. Toverud; W. Abuelmagd; K. Mahmood; N. Taghizadeh; 72 the prescribing physician on high risk patients, aimed at qualitatively 9 M. Jakovljevic; and H. Håkonsen 73 improved prescribing. Also an economic evaluation was performed. 10 School of Pharmacy, University Of Oslo, Oslo, Norway 74 Results: A total of 13,264 admissions of surgical patients were 11 Background: The Pakistanis constitute a big immigrant population 75 included (6780 admissions in the usual care group vs 6484 admis- 12 in Oslo with a high prevalence of diabetes. The aim of the project 76 sions in the intervention group). Results of the study show that this 13 was to study challenges Norwegian GPs experience with non-western 77 intervention leads to a significant reduction of preventable serious 14 immigrants, and what knowledge diabetic Pakistani women have 78 adverse events (disability, death, increases hospital stay and readmis- 15 about their disease, and their need for information. 79 sion) due to prescription errors (106 events versus 73 events, P 16 Material and Methods: The material was 22 ethnic Norwegian GPs = 80 17 with many immigrant patients, and 125 diabetic Pakistani women 0.029). The pharmaco economic analysis shows that the intervention 81 18 (29–80 y old), recruited through mosques and female networks. All does not incur higher costs due to time spent by involved health-care 82 19 participants were interviewed personally with structured question- providers (€ 6.04 vs € 6.18 per admission, P = 0.272). 83 20 naires; the women in their homes. Approval was obtained from the Conclusion: This large study shows that education and support of 84 21 Norwegian Social science data services. the prescribing physician on high risk patients on surgical depart- 85 22 Results: The main obstacle for the GPs was language. Consequently ments by the hospital pharmacist leads to a significant clinical rel- 86 23 it was difficult to diagnose and to explain drug treatment. The main evant benefit for patients. 87 24 chronic disease was diabetes. The doctors could see from blood levels 88 25 how drug adherence decreased during Ramadan. The language was 89 26 the main challenge also for the patients, even with an average stay Analgesic Drug Consumption Increases 90 27 of 30 years in Norway. Seventy percent had to be interviewed in After Carpal Tunnel Surgery: A 81 28 Urdu; 27% were illiterates. Almost 40% reported poor/very poor Pharmacoepidemiological Study 92 29 health status. Above half did not know their type of diabetes. The Investigating Postoperative Pain 93 30 treatment was tablets for 70%, insulin for 4% and both medication A. Palmaro1,2; R. Fuzier1,2; I. Serres1,2; R. Bourrel3; and 94 31 forms for 24%. Twenty-five percent altered their medication intake M. Lapeyre-Mestre1,2 95 32 during Ramadan. Macrovascular diseases were widely spread among 1Medical and Clinical Pharmacology Unit, CHU Toulouse 96 33 all ages. Number of meals per day was too low according to guide- University Hospital, Toulouse, France; 2Pharmacoepidemiology 97 34 lines. Two third admitted high calorie intakes between meals. Physical Research Unit, INSERM 1027, University of Toulouse, Toulouse, 98 35 activity was reported by 46%. The majority could only benefit from France; and 3National health insurance fund for workers. 99 36 oral information, and in Urdu. Most participants primarily missed Toulouse, France 100 37 information about the drugs they were using. Background or Introduction: The aim of this pharmacoepidemio- 101 38 Conclusion: The study shows how cultural and religious barriers logical study was to investigate analgesic drug consumption before 102 39 prevent Norwegian doctors to have a good communication with and after surgery as a surrogate of chronic postoperative pain. 103 40 non-Western patients and also how difficult it is for diabetic Pakistani Material and Methods: A retrospective cohort study of French ben- 104 41 women to get the right information about their disease. eficiaries from the main health insurance scheme in Midi-Pyrenees 105 42 area was designed using data from the SNIIRAM (Système National 106 43 d'Information Inter-Régime de l'Assurance Maladie). All patients 107 44 108 Effect of Medication Review And undergoing carpel tunnel surgery between 1 January 2010 and 30 45 June 2010 were identified. Definition of increase in antineuropathic 109 46 Physician Training Programme On Drug 110 Related Events In High Risk Surgical drugs (carbamazepine, gabapentine, prégabaline, clomipramine, ami- 47 triptyline, duloxetine, clonazepam) or opioids (ATC code N02A) was 111 48 Patients (P-Review Study) 112 1 2 3 3 based on the comparison of the accumulated Defined Daily Doses 49 J.M. Bos ; P.M.L.A. van den Bemt ; H. Pot ; J.E. Nagtegaal ; 113 4 5 5 1,5 (DDDs) received by months between pre (2 mo before) and late 50 A. Wieringa ; P. de Smet ; G.J. van der Wilt ; and C. Kramers 114 1 postoperative period (2–12 mo after surgery). A multivariate logistic 51 Canisius Wilhelmina hospital, Nijmegen, The Netherlands; 115 2 3 regression model was used to identify factors associated with increase 52 Erasmus Medical Centre, Rotterdam, The Netherlands; Meander 116 4 in either antineuropathic or opioid analgesic drug consumption. 53 medical centre, Amersfoort, The Netherlands; Isala hospitals, 117 5 Results: Among the 3495 patients included, 3082 received at least one 54 Zwolle, The Netherlands; and Radboud University Medical 118 analgesic during the late postoperative period (29%, n = 1003 for opi- 55 Centre, Nijmegen, The Netherlands 119 Background: Prescription errors in the hospital can lead to prevent- oids and 14%; n = 499 for antineuropathics). Consumption of opioid 56 analgesics was increased in the late postoperative period in 22% of the 120 57 able harm to patients. These events are often caused by NSAIDs, anti- 121 patients (n = 752) (10% (n = 359) for antineuropathics). History of 58 coagulants, diuretics, antibiotics and opioids. Especially patients on 122 surgical departments are at risk, since patients with complex co-mor- diabetes, rheumatoid arthritis and psychiatric disorders were associated 59 with an increase in opioid use, whereas hospitalisation (versus ambula- 123 60 bidities in complex situations are treated by physicians who have had 124 no specific additional training on prescribing. The hospital pharmacist tory surgery), high level of preoperative pain and psychiatric disorders 61 were found to be associated with an increase in antineuropathic drug use. 125 62 has an important role to safeguard patients for medication errors. 126 Material and Methods: The P-REVIEW study is an open interven- Conclusions: This study revealed that around 1 out of 3 patients 63 undergoing carpal tunnel surgery had persistent and even increased 127 64 tion study with a before after design that introduces a structured 128

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1 use of opioids and antineuropathics drugs more than two months Introduction: In the era of rising antibiotic resistance rates, treatment 65 2 after surgery, in relation with possible chronic postoperative pain. of complicated urinary tract infections (cUTIs) caused by bacterial 66 3 Considering the incidence of carpal tunnel syndrome, the risks associ- strains producing extended spectrum beta lactamases (ESBL) repre- 67 4 ated with persistent opioid use in this population should be further sents a major therapeutic problem. Hence, there is a growing interest 68 5 monitored. in the investigation of older antibiotics like fosfomycin, especially 69 6 due to its rapid bactericidal activity, oral route of administration, 70 7 low resistance rates and low cost. 71 8 Thomboprophylaxis In Multiple Myeloma Material and Methods: One hundred forty-five urinary isolates of 72 9 Patients Treated With Lenalidomide or ESBL producing E. coli and K. pneumoniae from ambulatory patients 73 10 Thalidomide were prospectively in vitro tested to fosfomycin and other routinely 74 11 A. Palmaro1; F. Despas1; and M. Lapeyre-Mestre1,2 used antibiotics. Those patients with isolates sensitive to fosfomycin 75 12 1Medical and Clinical Pharmacology Unit, CHU and fulfilling inclusion and exclusion criteria then received on average 76 13 Toulouse University Hospital, Toulouse, France; and 3.7 doses of fosfomycin. Fosfomycin was administered orally, every 77 14 2Pharmacoepidemiology Research Unit, INSERM 1027, 2 days. Patients on average had 2.3 complicating factors (most com- 78 15 University of Toulouse, Toulouse, France monly recurrent UTIs, diabetes mellitus and chronic kidney disease). 79 16 Background: Immunomoduladory drugs IMiDs (lenalidomide and Microbiological cure was evaluated 7 to 9 days after completion of 80 17 thalidomide) have contributed to improve patients’ survival in mul- treatment by means of urinary culture. 81 18 tiple myeloma. However, they increase the risk of thromboembolic Results: All E. coli ESBL isolates (n = 81) were in vitro sensitive to 82 19 events and often require a concomitant thromboprophylaxis based fosfomycin, which was statistically different from all other tested 83 20 on treatment received and level of risk. Strategy of prophylaxis is still orally administered antibiotics, P < 0.001 (nitrofurantoin 73%, cef- 84 21 debated, while international guidelines tend to recommend either tibuten 66%, amoxicillin clavulanate 51%, trimethoprim sulfameth- 85 22 aspirin or low weight molecular heparin (LWMH). The aim of this oxazole 20%, ciprofloxacin 11%). Thirty-three of 64 K. pneumoniae 86 23 study was to describe strategy of thromboprophylaxis in a cohort ESBL isolates were in vitro sensitive to fosfomycin (52%), which was 87 24 of multiple myeloma patients during their first imid-based regimen. statistically different from trimethoprim sulfamethoxazole (32%) 88 25 Material and Methods: A retrospective cohort study of French ben- and ciprofloxacin (11%), P < 0.05, and similar to ceftibuten (55%) 89 26 eficiaries from the main health insurance scheme database -SNIIRAM and amoxicillin clavulanate (39%). Eradication of ESBL strain was 90 27 (Système National d'Information Inter-Régime de l'Assurance achieved in 29 of the 44 patients with cUTIs (66%), while clinical 81 28 Maladie) was designed in the Midi-Pyrénées area (South West France, improvement was achieved in all patients, at least temporarily. 92 29 2.8 million inhabitants). Multiple myeloma patients were identified Conclusions: In vitro sensitivity of E. coli ESBL to fosfomycin 93 30 through hospital diagnosis or long-term conditions. Beneficiaries with is excellent while that of K. pneumoniae ESBL is much lower. 94 31 at least 1 dispensing record for lenalidomide or thalidomide in hos- Fosfomycin administered orally in several doses represents a poten- 95 32 pital pharmacy from January 2010 to March 2014 were included. tially attractive oral therapeutic option for cUTIs caused by ESBL 96 33 Patients’ characteristics, previous and current treatment line together producing strains. 97 34 with thromboprophylatic drugs were described. 98 35 Results: Among the 271 multiple myeloma patients (62% male, 99 36 100 60% > 65 y) starting an imid-based regimen: 21% (n = 58) received Randomized Pragmatic Clinical Trial On 37 101 thalidomide alone or thalidomide- (T-TD), 14% (n = The Duration Of Antimicrobial Treatment 38 102 38) bortezomib-thalidomide-dexamethasone (VTD), 25% (n = 68) For Enterobacteriaceae Bacteremia In 39 103 melphalan-prednisone-thalidomide (MPT) and 40% (n = 107) had Adult Patients (Shorten Study) 40 lenalidomide-dexamethasone (RD) therapy. Forty-eight percent were C. Rosso-Fernández1; B. Solano1; L. Lavín-Alconero1; Y. Borrego2; 104 41 at first-line therapy, 42% in second-line therapy and 10% in third-line J.M. Cisneros1; A. Valiente4; C. Natera5; and J. Molina1 105 42 1 106 therapy. Around 85% (n = 230) of the patients received > 1 drug for Hospital UniversitarioVirgen del Rocío, Seville, Spain; 43 thromboprophylaxis after starting their imid regimen: 63% aspirin 2Hospitales Universitarios Virgen Macarena y Virgen del Rocío, 107 44 4 108 (n = 198), 36% unfractionated heparin or LWMH (n = 98), 15% Seville, Spain; Hospital Universitario Virgen Macarena, Seville, 45 5 109 vitamin K antagonists (n = 42). No prophylaxis was retrieved for Spain; and Hospital Universitario Reina Sofía, Córdoba, Spain 46 110 15% of the patients (n = 41). Further analyses are currently imple- Background: The antimicrobiAQ2al crisis is a major problem as 47 mented to describe thromboprophylaxis in high risk cases: radio- resistant bacteria infections have increased and the availability of 111 48 therapy, previous thromboembolism, current use of biphosphonates, effective antibiotics have been reduced. Gram-negative bacilli are 112 49 or hormonal treatments. responsible for frequent and potentially severe bloodstream infec- 113 50 Conclusions: These preliminary results revealed a great variability in tions, among which up to 47% can be produced by Enterobacteria 114 51 the implementation of thromboprophylaxis strategy in real-life, even (EB).The optimal duration of antibiotic treatment in this clinical 115 52 in high risk treatment lines with chemotherapy or dexamethasone in setting is unknown, as no clinical trials (CT) have been designed to 116 53 which thromboprophylaxis should be systematically applied. answer this question. Moreover, the role of biomarkers such as pro- 117 54 calcitonine (PCT) in this setting has not been established. 118 55 Material and Methods: SHORTEN study is a randomized, multi- 119 56 centric, open-label and phase IV trial designed to prove that a 7-day 120 57 Prospective clinical study of fosfomycin 121 efficacy in the treatment of complicated course with any authorized antibiotic for uncomplicated EB bacte- 58 remia according to clinical practice guidelines, is more efficient and 122 59 urinary tract infections caused by e. Coli 123 and k. Pneumoniae producing extended equally safe than a 14-day scheme. Two hundred thirty-eight patients 60 will be randomized in 1:1 ratio to experimental/control arm and 124 61 spectrum beta lactamases 125 1 1,2 followed up to 28 days to evaluate clinical and microbiological cure 62 L. Bielen ; and R. Likic 126 1 and safety of both arms. The optimal cut-off of PCT level for safely 63 University of Zagreb School of Medicine, Zagreb, Croatia; and 127 2 interrupting antibiotic treatment was included as secondary objective. 64 University Clinical Hospital Center Zagreb, Croatia 128

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1 Results: The study is publicly funded (PI-0161-2013) and is being preclinical studies were found that Cytaphat has hepatoprotective, 65 2 conducted in 3 public hospitals. It has been approved by Spanish antioxidant, membrane stabilizing and choleretic activity. Cytaphat 66 3 Medicines Agency and central Ethical Review Board and for the 3 accelerates regeneration of liver tissue after resection. Phase 1 clini- 67 4 local Ethic Committees on which is developed. Severity and frequent cal trial on healthy volunteers allowed to determine that the optimal 68 5 complications of this infection are cause of a specific surveillance tolerated dose of Cytaphat was 200 mg/kg. Side effects with high 69 6 regarding pharmacovigilance applicable in CT as there are several doses (100–200 mg/kg) are tachycardia and increased blood pressure. 70 7 drugs included as IMP. The study organization and coordination Currently Cytaphat passes Phase 2 clinical trials in Kazakhstan as 71 8 requires a multidisciplinary group in order to cover with all the hepatoprotector for the treatment of acute toxic hepatitis. 72 9 requirements and to obtain real data. There are 142 patients with an acute toxic hepatopathy which were 73 10 Conclusion: The use of drugs from the own hospital provision and participating in phase 2 clinical trial. Patients were divided into 3 groups: 74 11 the similarities of procedures to daily practice makes this study an 1 – patients were taking Essentiale (200 ml of 5% glucose + 10 ml of 75 12 example of real pragmatic trial supported for noncommercial clinical Essentiale) i/v once per day for 3 days; 2 – patients were taking Cytaphat 76 13 research unit in order to accomplish with ethic and legal requirements. (10 mg/kg + 200 ml of 5% glucose) i/v once per day for 3 days; 3 – patients 77 14 were taking placebo. The method of clinical trials was double-blind. 78 15 The table shows that Cytaphat has significantly better positive 79 16 Anti-Tnf But Not Ustekinumab Induced effect compare to placebo. 80 17 Paradoxical Psoriasiform Lesions In 81 18 Patients With Psoriasis: Association With Table – Dynamics of indicators characterizing the level of cytolysis 82 19 83 Genetic Polymorphisms Studying Group 1 Group 2 Group 3 20 T. Cabaleiro1,2; R. Prieto-Pérez1; R. Navarro3; G. Solano3; parameters Essentiale Cytaphat Placebo 84 21 M. Roman1; D. Ochoa1; E. Daudén3; and F. Abad-Santos1,2 ALT, nmol · sec/l Before treatment 542.2 ± 38.2 458.6 ± 27.4 418.5 ± 30.7 85 22 1Clinical Pharmacology Service, Hospital Universitario de la After treatment 232.2 ± 20.8 248.9 ± 35.8 354.7 ± 25.0 86 23 AST, nmol · sec/l Before treatment 298.2 ± 36.1 347.5 ± 40.2 322.6 ± 18.4 87 Princesa, Instituto Teófilo Hernando, Instituto de Investigación After treatment 154.7 ± 19.6 109.1 ± 8.7 297.1 ± 33.6 24 2 88 Sanitaria Princesa (IP), Madrid, Spain; Centro de Investigación Total bilirubin, Before treatment 54.3 ± 6.1 38.8 ± 2.1 40.1 ± 6.2 25 Biomédica en Red de Enfermedades Hepáticas y Digestivas µmol/l 89 26 (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; and After treatment 18.6 ± 2.4 19.8 ± 1.7 34.5 ± 3.7 90 27 3Dermatology Service, Hospital Universitario de la Princesa, 81 28 Instituto Teófilo Hernando, Instituto de Investigación Sanitaria The average time of the elimination of toxic hepatopathy using 92 29 Princesa (IP), 28006 Madrid, Spain Cytaphat was 2.8 days, using Essentiale – 7.2 days and placebo – 10.6 93 30 Background: Biological drugs are effective in several chronic inflam- days. Cytaphat has showed high efficiency compare to placebo and com- 94 31 matory diseases such as psoriasis. Paradoxically, psoriasiform lesions parative drug Essentiale. Results indicate the presence of hepatoprotective 95 32 activity of Cytaphat for the treatment of acute toxic hepatopathy. 96 have been described following anti-TNFα therapy. We aimed to study 33 the association between the development of these lesions and genetic 97 34 polymorphisms. 98 35 Material and Methods: One hundred eighty psoriasis patients (107 Inhibition of Acute Vascular 99 36 100 men and 73 women) treated with anti-TNFα drugs and ustekinumab Inflammation By Nicotinamide Adenine 37 were genotyped through the Illumina Veracode genotyping platform Dinucleotide (Nad)-Containing Drug 101 38 for different genes previously associated with psoriasis or other auto- In Early Form Of Atherosclerosis In 102 39 immune diseases or to response to biological drugs. Experiments 103 40 104 Results: Among 180 patients, 25 (11 men and 14 women) developed N. Gongadze1; T. Kezeli2; G. Sukoyan3; Z. Chapichadze4; 41 105 a psoriasiform lesion, mostly a psoriasis guttata (88%). These lesions N. Dolidze1; S. Jibuti4; M. Mirziashvili1; M. Chipashvili2; 42 106 were developed 9.20 ± 13.52 months after initiating treatment in A. Isakadze1; and T. Makharadze1 43 107 9.8% patients treated with adalimumab, 21.4% with etanercept, 1Tbilisi State Medical University, Tbilisi, Georgia; 44 108 7.7% with infliximab, and 0% with ustekinumab. Gender, pso- 2Iv. Javakhishvili Tbilisi State University, Tbilisi, Georgia; 45 109 riasis type and PASI75 were not associated with the development 3Research Laboratory, Biotechpharm CE, Tbilisi, Georgia; and 46 110 of psoriasiform lesions. After a multivariate logistic regression, 5 4LEPL State Regulation Agency For Medical Activities, Tbilisi, 47 111 SNPs were associated to the development of a psoriasiform lesion: Georgia 48 112 rs11209026 in IL23R, rs3087243 in CTLA4, rs651630 in SLC12A8, Introduction: The aim of the present study was to evaluate the effect 49 113 and rs1800453 in TAP1, and rs96844 in MAP3K1. of reduced form of NAD-containing drug, Nadcin®, on cardiovascular 50 114 Conclusions: Genetic polymorphisms are associated with the devel- benefit by inhibiting vascular inflammation and decreases of redox- 51 115 opment of psoriasiform lesions in patients with psoriasis after anti- potential level in early form of experimental atherosclerosis. 52 116 TNFα drugs. This adverse reaction was not induced by ustekinumab. Materials and Methods: Forty-one male rabbits were included in this 53 117 study. The animals were randomized into 3 groups: I (control) - rabbits 54 118 fed normal diet for 12 weeks; II - rabbits fed 1% cholesterol enriched 55 119 diet (CED) for 12 weeks; III - rabbits fed with CED for 6 weeks, and 56 Cytisin Amidophosphate – Promising Role 120 then continued on CED and treated with 10 mg/kg/day orally Nadcin® 57 for The Liver Treatment 121 for the next 6 weeks. Blood and aortic tissue samples were collected at 58 A. Gulyayev; Z. Shulgau; B. Yermekbayeva; S. Sergazy; and 122 the start of the study, at 6 weeks, and at the end of treatment course to 59 T. Nurgozhin 123 measure serum lipids profile, C-reactive protein (CRP), tumor necrosis 60 PI “Center for Life Sciences”, Nazarbayev University, Astana, 124 factor (TNF ), intercellular adhesion vascular molecule (ICAM-1) and 61 Kazakhstan α 125 vascular cell adhesion molecule-1 (VCAM-1) with ELISA-tests. 62 This study was carried out to investigate hepatoprotective effect of 126 Results: In group II significant progression of atherosclerosis was devel- 63 “Cytaphat” drug, which is a semisynthetic derivative of the alkaloid 127 oped. Compared with the control, levels of blood lipids, TNF- , CRP, 64 cytisine – 0,0-dimethyl-N-(methylcytisinyl)-phosphate. During the α 128

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1 VCAM-1 and ICAM-1 increased markedly, while the redox-potential Conclusions: New-developed KP insulin has the same ability to 65 2 NAD/NADH decreased in both in blood and in aortic tissues. Nadcin® inhibit binding of [125I] insulin to IR and induces at the similar level 66 3 caused a significant reduction (P < 0.05) in serum level of total choles- as human insulin standard the intracellular signalling. The structural 67 4 terol, triglycerides, CRP and TNFα and a significant increase (P < 0.05) differences between KP and IRS-1 are so essential to generate the 68 5 in serum high density lipoproteins. There was a significant reduction differences at the molecular activity. 69 6 (P < 0.05) in aortic markers of inflammation, VCAM-1 by 23% and Supported by European Regional Development Found, 70 7 ICAM-1 by 45% versus to untreated control group that correlated with POIG.01.01.02-00-007/08. 71 8 the reduction in aortic intima-media thickness, P < 0.002. 72 9 Conclusion: These results suggest that NAD-containing drug can 73 10 cause the reduction in lipids profile disorders and vascular inflam- Drug Interaction With Milk and The 74 11 mation markers throughout increasing the redox-potential (NAD/ Relevance of Acidifying/Alkalizing 75 12 NADH) levels in blood and in aortic tissue, therefore be beneficial Nature of Food 76 13 in preventing atherosclerosis and reducing risk factors for cardio- A. Reis1,2; and J. Joaquim2 77 14 vascular diseases. 1Farmácia Peixinho, Aveiro, Portugal; and 2Instituto Politécnico 78 15 de Coimbra, Coimbra Health School – ESTESC, Farmácia, 79 16 Coimbra, Portugal 80 17 In Vitro Evaluation of Pharmacological Background: An interaction is a clinical event in which the effects 81 18 Properties of A New-Developed Short of a drug are affected by presence of another drug, herbal, food, 82 19 Acting Insulin Analogue drink or some chemical agent. The drug–food interactions can cause 83 20 M. Bogiel1; M. Pawlowska1; J. Antonik2; J. Smagur2; and changes in bioavailability and excretion of the drug may lead to 84 21 P. Borowicz1 treatment failure or may have beneficial effects. The aim of this study 85 22 1Institute of Biotechnology and Antibiotics, Warsaw, Poland; and is to explore the milk interactions with certain medicines to inform 86 23 2BioCentrum Ltd., Cracow, Poland healthcare professionals and patients. 87 24 Introduction: Short acting insulin analogues are the essential drugs of Material and Methods: This study is classified as a secondary study, 88 25 an intensive antidiabetic therapy. The analogues administered before a systematic review of the literature without meta-analysis. The infor- 89 26 meals together with the basal long acting insulins allow to achieve mation was collected from electronic databases such as PubMed, 90 27 pharmacokinetic profile that most closely mimics physiological secre- Google academic and b-on, with the aid of computer software. The 81 28 tion of endogenous insulin. research was carried out with keywords like “drug Interactions”, 92 29 The objective of the study was to assess pharmacodynamic “milk and drugs”, “interaction between the drug and milk”, among 93 30 activity in vitro and describe molecular mechanism of action of others. We selected studies published in the last 25 years and at the 94 31 the B28Lys-B29Pro human insulin (KP) in comparison to EU end were obtained 20 references relevant to the development of this 95 32 Pharmacopeia human insulin standard (HIS) and insulin growth article. 96 33 factor-1 (IGF-1). Results: The milk interferes with the absorption of various antibiot- 97 34 Material and Methods: ELISA tests were adapted to analyze the ics such as tetracycline’s (decreasing absorption) and few quinolones, 98 35 (auto)phosphorylation/dephosphorylation of insulin receptor (IR), propranolol, mercaptopurine (reduce bioavailability), nonsteroidal 99 36 IGF-1 receptor, insulin receptor substrate-1 protein (IRS-1) and acti- anti-inflammatory drugs, digitalis, amiloride, omeprazole, spirono- 100 37 vation of kinases (Akt1, p44MAPK). Tests were performed on human lactone and ranitidine. The main effects of these interactions are 101 38 breast adenocarcinoma cell line (MCF7). Radioligand binding assay decreased bioavailability of drugs, increase/decrease the excretion of 102 39 were used to assess the affinity of the tested compounds for the ago- drugs, depletion of absorption of nutrients, among others. 103 40 nist site of IR on membrane homogenates of the rat liver cells. Kd Conclusion: As already known drug–food interactions can influence 104 41 105 (equilibrium dissociation constant) in phosphorylation assays, t1/2 the safety and efficiency of drug therapy. The interactions between 42 (half-life of reaction) in dephosphorylation assays and IC50 (half- milk and drugs are mostly pharmacokinetic interactions, since the 106 43 maximal inhibitory concentration) for binding assay were statistically milk affects the absorption and excretion of drugs and are classified 107 44 analyzed for each tested pair using sum-of-squares F test. as moderate in severity because can occur a failure in the treatment 108 45 Results: and need for additional treatment. To avoid them just that medicines 109 46 and milk are taken at different times. Also, having knowledge about 110 47 medicines and which foods affect its therapeutic action is of utmost 111 Parameter Tested compound 48 importance. 112 49 Metabolic activity [unit] KP HIS IGF-1 113 50 114 (auto)phosphorylation IR Kd [nM] 1.34 2.11 216.50* 51 115 IGF-1R 50.87 82.92 3.91* 52 Characterization of Target Topical 116 53 IRS-1 3.52 3.84 0.90* Ocular Delivery form of Levofloxacin 117 1 1 2 2 54 Akt1 5.71 8.87 1.65* N. Gongadze ; M. Dvali ; G. Sukoyan ; E. Tsivtsivadze ; 118 T. Kezeli3; Z. Chapichadze4; I. Margvelashvili5; N. Dolidze3; and 55 p44MAPK 130.50 120.00 4.02* 119 4 56 S. Jibuti 120 dephosphorylation IR t [min] 5.61 3.20* 5.78 1/2 1Tbilisi State Medical University, Tbilisi, Georgia; 2Research 57 IGF-1R 1.26 1.16 11.79* 121 3 58 Laboratory, Biotechpharm CE, Tbilisi, Georgia; Iv. Javakhishvili 122 IRS-1 9.88 11.49 12.49 4 59 Tbilisi State University, Tbilisi, Georgia; LEPL State Regulation 123 5 60 binding IR IC50 [µM] 0.055 0.052 n.a. Agency for Medical Activies; and Association of Pharmaceutical 124 61 n.a. – not applicable Companies Representatives in Georgia 125 * - statistically significant differences (P < 0.05) detected between KP and tested Introduction: In the present work we developed and optimized levo- 62 compound 126 63 floxacin loaded PLGA nanodispersions for enhanced ocular delivery 127 64 of levofloxacin. 128

2015 e11 Clinical Therapeutics

1 Materials and Methods: The optimized nanodispersions were pre- at least 1000 times lower than the mean Cmax and AUC reported 65 2 pared by double emulsification solvent evaporation method using after therapeutic 400 mg oral doses of levofloxacin. Prevent ocular 66 3 high pressure homogenizer. Particle size of nanodispersion was drainage of levofloxacin in nanodisperssion form enhanced ocular 67 4 found to be dependent on PLGA concentration, PLGA:drug ratio, bioavailability by 3.7-fold. The antibacterial activities of the nano- 68 5 PVA concentration and Water:Oil phase volume ratio whereas drug suspension were performed against S. aureus and P. aeroginosa. 69 6 encapsulation was related to PLGA concentration and PLGA:drug The levofloxacin-loaded PLGA nanosuspensions showed uniform 70 7 ratio. Encapsulation efficiency of optimized nanodispersion was 78% in vitro corneal permeability across isolated goat cornea, indicating 71 8 with a mean particle size of around 178 ± 12 nm which makes them the suitability of the nanosuspension formulation in the ophthalmic 72 9 a suitable candidate for ocular administration. The plasma half-life delivery of levofloxacin. 73 10 of levofloxacin was estimated to be 13 hours. Drug release kinetic Conclusion: The optimised nano-suspension was found to be more 74 11 studies of a sustained release profile of levofloxacin from nanodisper- active against S. aureus and P. aeruginosa compared to the marketed 75 12 sions was studied. eye drops. 76 13 Results: Plasma concentrations of levofloxacin were measured in 21 77 14 male and female adult subjects receiving bilateral topical ocular doses 78 15 of levofloxacin solution every 8 hours for a total of 13 doses. Biphasic Citizen Perception Regarding Drug 79 16 extended-release profile was produced in vitro. The mean steady- Information And Safety 80 17 state Cmax and AUC were 2.87 ± 0.23 ng/mL and 44.5 ng·hr/mL, C. Gurruchaga; G. Manso; F.J. Jimeno; L. Ordoñez; and 81 18 respectively. These systemic exposure values were at least 1000 times E. Salgueiro 82 19 lower than the mean Cmax and AUC reported after therapeutic 400 University of Oviedo 83 20 mg oral doses of levofloxacin. Prevent ocular drainage of levofloxacin Introduction: To ascertain public opinion on drug information aimed 84 21 in nanodispersion form enhanced ocular bioavailability by 3.7-fold. at citizens enclosed in the package leaflet information and public 85 22 The antibacterial activities of the nanosuspension were performed perception of some safety aspects of medicines. 86 23 against S. aureus and P. aeruginosa. The levofloxacin-loaded PLGA Methods: Descriptive, cross-sectional study by means of a voluntary, 87 24 nanosuspensions showed uniform in vitro corneal permeability across anonymous survey aimed at citizens from May to December 2014 88 25 isolated goat cornea, indicating the suitability of the nanosuspension in Asturias, Northern Spain. An initial pilot study was performed to 89 26 formulation in the ophthalmic delivery of levofloxacin. analyse the validity and feasibility of the survey. Surveys were filled 90 27 Conclusion: The optimised nano-suspension was found to be more out by the researcher according to the answers provided or self-com- 81 28 active against S. aureus and P. aeruginosa compared to the marketed pleted. Considering the characteristics of the surveyed population, we 92 29 eye drops. analysed the reading comprehension difficulty of the package leaflet 93 30 information as well as the public perception of drug safety. 94 31 Results: A total of 223 (84.5%) of those surveyed claimed to read the 95 32 Characterization of Target Topical medicine information leaflet: always read 166 (62.9%) (women 105 96 33 Ocular Delivery form of Levofloxacin [39.8%], men 61 [23.1%]) and sometimes 57 (21.6%) (women 38 97 34 Nikoloz N. Gongadze1; Merab M. Dvali1; Galina G. Sukoyan2; [14.4%], men 19 [7.2%]). Regarding educational level, 109 (41.3%) 98 35 Edisher E. Tsivtsivadze2; Tamara T. Kezeli3; Zaza Z. of those surveyed with higher or secondary education and 46 (17.4%) 99 36 Chapichadze4; Irakli I. Margvelashvili5; Nino N. Dolidze3; and with primary studies, always read the information. Of those inter- 100 37 Shota S. Jibuti4 viewed, 196 (74.2%) perceived prescribed medicines to be safer. Only 101 38 1Tbilisi State Medical University, Tbilisi, Georgia; 2Research 37 (14.0%) consider that both prescription and over-the-counter 102 39 Laboratory, Biotechpharm CE, Tbilisi, Georgia; 3Iv. Javakhishvili medicines are safe. In total 110 (41.7%) claimed to have had some 103 40 Tbilisi State University, Tbilisi, Georgia; 4LEPL State Regulation adverse drug reaction (78.2% of them reported it to their doctor, 104 41 Agency For Medical Activies; and 5Association of Pharmaceutical 0.9% to the pharmacist, and 1.8% to both). Other medicine-related 105 42 Companies Representatives in Georgia problems were experienced by 36 (13.6%) of those surveyed. 106 43 Introduction: In the present work we developed and optimized levo- Conclusions: Women claimed to read the package leaflet information 107 44 floxacin loaded PLGA nanodispersions for enhanced ocular delivery more than men and also recognized a greater difficult in understand- 108 45 of levofloxacin. ing. Although understanding the information leaflet is directly related 109 46 Materials and Methods: The optimized nanodispersions were pre- with educational level, a high percentage of interviewees with higher 110 47 pared by double emulsification solvent evaporation method using or secondary education claimed to occasionally have comprehension 111 48 high pressure homogenizer. Particle size of nanodispersion was difficulty. Prescription medicines are perceived as safer. Most of the 112 49 found to be dependent on PLGA concentration, PLGA:drug ratio, citizens that suffered an adverse drug reaction claimed to report it 113 50 PVA concentration and Water:Oil phase volume ratio whereas drug to their doctor. 114 51 encapsulation was related to PLGA concentration and PLGA:drug 115 52 ratio. Encapsulation efficiency of optimized nanodispersion was 78% 116 53 with a mean particle size of around 178 ± 12 nm which makes them 117 54 The Prevalence of Enos and Agtr2 Gene 118 a suitable candidate for ocular administration. The plasma half-life Polymorphism In Patient With Coronary 55 of levofloxacin was estimated to be 13 hours. Drug release kinetic 119 56 Artery Desease 120 studies of a sustained release profile of levofloxacin from nanodisper- 1 1 1 1 57 A. Khokhlov ; A. Miroshnikov ; N. Pozdnyakov ; D. Komarov ; 121 sions was studied. 2 58 and I. Dryagencova 122 Results: Plasma concentrations of levofloxacin were measured in 1Yaroslavl Medical State University, Yaroslavl, Russia; and 59 21 male and female adult subjects receiving bilateral topical ocu- 123 2Clinical Hospital of Russian Railways, Yaroslavl, Russia 60 lar doses of levofloxacin solution every 8 hours for a total of 13 124 Background: The aim is to study the prevalence of polymorphisms 61 doses. Biphasic extended-release profile was produced in vitro. The 125 894G> T eNOS gene and 1675 G> A AGTR2 gene in patients with 62 mean steady-state Cmax and AUC were 2.87 ± 0.23 ng/mL and 126 coronary artery disease in the form of stable angina (SA), unstable 63 44.5 ng·hr/mL, respectively. These systemic exposure values were 127 64 angina (UA) and acute myocardial infarction (AMI). 128

e12 Volume XX Number XX An Educational Intervention To Improve Nurses Reporting of Adverse Drug Reactions

1 Material and Methods: The study involved 100 patients, of both preventing the potential risks of analgesics represents an important 65 2 sexes, aged 36 to 86 years (63.7 ± 11.4). Determination of gene poly- step in minimizing their negative effects on patients. 66 3 morphisms was performed by polymerase chain reaction. Statistical 67 4 processing was performed by using the Statistica 10.0 68 5 Results: In the AMI group distribution of alleles of eNOS gene was Drugs of Abuse, Pharmacology 69 6 GG-81.25% (P < 0.05), GT-18.75%, TT-0% (P < 0.05); AGTR2 Curriculum And Learning Styles of 70 7 alleles were GG-50%, GA-18.75%, AA-31.25%. In the SA group Medical Students 71 8 distribution of alleles of eNOS gene was GG-46.8%, GT-48.9%, H.M.T. Barros1; C.L. Tannhauser1,2; and M. Tannhauser2 72 9 TT-4.3% (P < 0.05); AGTR2 alleles were GG-34%, GA-39.8%, 1Ligue 132, Pharmacosciences Dept, UFCSPA, Brazil; and 73 10 AA-36.2%. In the UA group distribution of alleles of eNOS gene was 2Encrementare, Porto Alegre, Brazil 74 11 GG-56.8%, GT-37.8%, TT-5.4% (P < 0.05); AGTR2 alleles were Introduction: Drug abuse (tobacco, alcohol and illicit drugs) can 75 12 GG-40.5%, GA-19%, AA-40.5%. In postinfarction cardiosclerosis worsen several health disorders; are among the twenty most common 76 13 group distribution of alleles of eNOS gene was GG-60% (P < 0.05), burden to health problems worldwide. Medical student education 77 14 GT-31.4%, TT-8.6% (P < 0.05); AGTR2 alleles were GG-42.9%, should provide detailed knowledge of these issues together with skills 78 15 GA-17.1%, AA-40%. Furthermore it is elicited that the genotype needed to detect/counsel patients with unhealthy drug use patterns. 79 16 AA and GA AGTR2 gene influences on debut of angina. In the case Time to include subjects in the clinical pharmacology curriculum to 80 17 of AA genotype the age of the debut of angina was 53 (P < 0.05), medical students is limited. Online educational strategies are often 81 18 GA-60.5 (P < 0.05) and GG-54. sought. It is necessary to evaluate the educational outcomes. This 82 19 Conclusions study was designed to develop and evaluate an online module on 83 20 1. The high prevalence is elicited in mutant alleles of eNOS and drug abuse to teach medical students about pharmacology of drugs 84 21 AGTR2. and brief intervention of drug use problems. 85 22 2. The high prevalence is elicited in homozygous mutation of the Material and Methods: Eighty-nine medical students of UFCSPA 86 23 allele A of AGTR2 gene in the structure of patients with coronary were taking the Pharmacology Course in 2014. Drug abuse is not 87 24 artery disease, particularly in post infarction cardio sclerosis patients. part of their curricular medical program and an online training 88 25 3. The influence of the mutant allele A AGTR2 is detected on was offered as additional set of studies for volunteer enrolment. 89 26 debut of angina. Information (written and videos, exercises, reading recommenda- 90 27 tions) on drugs of abuse and health, mechanisms of action, biological 81 28 effects of drugs, methods of drug screening, brief interventions and 92 29 Potential Drug-Drug Interactions from treatment protocols for drug abuse and dependence were presented 93 30 Analgesic Prescriptions In Romania online. After the course, all students, volunteering or not, completed 94 31 I. Cazacu; C. Pop; C. Bucsa; C. Mogosan; and F. Loghin an evaluation and the Kolb Learning Style Inventory (KLSI). 95 32 Iuliu Hatieganu University of Medicine and Pharmacy, Results: Seventy students enrolled and completed the online train- 96 33 Cluj-Napoca, Romania ing with success. The range time for completion was 5 to 20 hours. 97 34 Introduction: Analgesics are among the most frequently used drugs The mean knowledge score after completing the online training was 98 35 worldwide, being dispensed both with and without prescription. The 90/100. All medical students who completed the online Training 99 36 present study aims to detect potential drug–drug interactions (DDIs) described satisfaction. A difference in KLSI was detected between 100 37 of analgesics by analyzing prescriptions covered by the healthcare students who had/had not volunteered to the online training. 101 38 system and dispensed in a Romanian community pharmacy. Conclusions: The online training on drugs of abuse resulted in sig- 102 39 Methods: We included in the analysis analgesics medical prescrip- nificant changes in knowledge. This online format could be incorpo- 103 40 tions issued during one month. We recorded patients’ demographics rated into the medical school curriculum, with students learning the 104 41 and medications and we used Thomson Micromedex® 2.0 database material at their own pace and in their available time. 105 42 to detect DDIs. 106 43 Results: We selected 238 prescriptions corresponding to a num- 107 44 108 ber of 236 patients (female/male ratio = 2.3, mean age: 60.3 y). Biocomparison of THREE formulations of 45 A total number of 291 analgesics were prescribed and dispensed: 109 46 the S1P1 receptor modulator ponesimod 110 nonsteroidal anti-inflammatory drugs (NSAIDs, 67%), opioid anal- in healthy subjects 47 gesics (17.5%) and anticonvulsants (15.5%). Diclofenac (15.5%) and 111 P.-E. Juif; M. Hoch; D. D’Ambrosio; and J. Dingemanse 48 gabapentin (15.1%) were the most widely prescribed for analgesic 112 Actelion Pharmaceuticals Ltd, Allschwil, Switzerland 49 action, followed by dexketoprofen (13.4%), etoricoxib (12.7 %) 113 Background: Ponesimod is a potent, orally active, selective, revers- 50 and tramadol alone or in combination with paracetamol (7.6%). 114 ible sphingosine-1-phosphate receptor 1 (S1P ) modulator. Single- 51 We detected 104 potential DDIs in which NSAIDs associated with 1 115 dose administration of ponesimod leads to a reduction of circulating 52 cardiovascular medications (diuretics 25%, angiotensin-converting 116 lymphocytes reflecting their sequestration within lymphoid organs. 53 enzyme inhibitors 22%, beta-blockers 19%) or methotrexate (14%) 117 Modulation of the S1P receptor has been described to be an effective 54 were most commonly involved. Eighteen major potential DDIs 1 118 treatment of autoimmune diseases (eg, multiple sclerosis). The aim 55 (17.3%) were found and 7 prescriptions (3%) contained 2 NSAIDs 119 of these studies was to compare the relative bioavailability of two 56 used concurrently. 120 polymorphic forms of ponesimod in capsules (Form A vs. C, Study 57 Discussion and Conclusions: Our study showed that on reimbursed 121 1) and of a capsule vs. a tablet formulation (both of polymorphic 58 prescriptions NSAIDs were the leading analgesics involved in poten- 122 Form C, Study 2). 59 tial DDIs. The main potential risk when combining NSAIDs with 123 Methods: Two open-label, randomized, two-way crossover studies 60 other drug classes were decreased efficacy of antihypertensive drugs 124 in healthy subjects were performed. In Study 1, 12 male and female 61 and increased methotrexate toxicity. Diclofenac, recently associ- 125 (ratio 1:1) subjects received a single dose of ponesimod (20 mg) of 62 ated with safety issues concerning the cardiovascular risk similar 126 polymorphic Form A and C in capsules. In Study 2, 14 male sub- 63 to coxibs, was the most prescribed NSAID. Acknowledging and 127 64 jects received a single administration of ponesimod (Form C, 40 mg) 128

2015 e13 Clinical Therapeutics

1 either in a capsule or a tablet formulation. Pharmacokinetic and Introduction: Intraoperative fluorescence imaging of primary tumor 65 2 safety (clinical laboratory, vital signs, and electrocardiogram) vari- and metastases potentially results in better patient outcomes. OTL38 66 3 ables were assessed. is an imaging agent that specifically binds to the folate receptorα 67 4 Results: When comparing the exposure to ponesimod following (FRa) which is overexpressed by various carcinomas. FRa-positive 68

5 the formulations in Study 1, the geometric mean ratios for AUC0-∞, cells retain the agent, making them detectable with near-infrared 69 6 AUC0-t, t1/2, and Cmax and the responding 90% CIs were all within (NIR) fluorescence. In this first-in-human study OTL38 was investi- 70 7 the 0.80 to 1.25 interval. In Study 2, a more rapid absorption of gated in healthy volunteers and ovarian cancer patients. 71 8 ponesimod was observed with the tablet compared to the cap- Material and Methods: Four different iv doses were studied in 72 9 sule formulation. There was no marked difference in the nature, healthy volunteers in a single ascending dose, randomized, placebo- 73 10 severity, and incidence of adverse events reported for the different controlled study in which tolerability, pharmacodynamics (PD; 74 11 formulations in Study 1 and Study 2. However, a dose relationship defined as fluorescent signal in the skin) and pharmacokinetics (PK) 75 12 regarding the number of adverse events reported was observed. were assessed. The optimal doses were subsequently explored in in 76 13 Conclusions: The 2 polymorphic forms of ponesimod and the tablet 5 patients thus far, with an emphasis on tolerability, number of sus- 77 14 versus capsule formulation were similar in terms of PK, except the pected lesions detected with fluorescence and concordance between 78 15 more rapid absorption of the tablet formulation. At the same dose fluorescence and FRa-status on histopathology. 79 16 strength safety and tolerability were similar. Results: Low dose OTL38 was without any clinically significant 80 17 adverse effects, but at the highest doses levels hypersensitivity reac- 81 18 tions were observed. The plasma concentration-time profile showed 82 19 Pharmacotherapeutic decisions in case bi-phasic elimination (elimination half-life: 26–160min) and a pos- 83 20 reports, can we learn from them? sible non-linear increase in AUC. In OTL38-treated volunteers a 84 21 R.J. van Unen; T. Schutte; J. Tichelaar; Th.P.G.M. de Vries; dose-dependent fluorescent signal was observed in the skin, show- 85 22 M.C. Richir; and M.A. van Agtmael ing distribution and clearance of OTL38 in tissue at a lower rate 86 23 VU University Medical Center, Amsterdam, the Netherlands; compared to blood. These data allowed definition of the optimal 87 24 and RECIPE (Research & Expertise Center in Pharmacotherapy doses and time window for intra-operative imaging. Preliminary 88 25 Education), Amsterdam, the Netherlands analysis of the study in patients shows accumulation of OTL38 in 89 26 *contributed equally FRa positive tumor and successful intra-operative NIR fluorescence 90 27 Background: Reading case reports is a method to train clinical reason- imaging with detection of multiple lesions not identified by inspec- 81 28 ing in general, however they seem to be focused at diagnostics rather tion/palpation. 92 29 than therapeutics. Doctors in training indicate they experience a deficit Conclusions: Low doses of OTL38, the first tumor-specific agent 93 30 in education in pharmacotherapeutic reasoning. To determine the edu- that fluoresces the NIR spectrum, were successfully used for intra- 94 31 cational value of case reports in therapeutic reasoning, we analyzed to operative fluorescence imaging of FRa-positive tumors. The prelimi- 95 32 what degree pharmacotherapeutic reasoning was discussed. nary data suggest that our approach using healthy volunteers and PK/ 96 33 Methods: Review of clinical cases published in 2 high impact medical PD modelling appear to be extremely useful in the development of 97 34 journals (BMJ and Lancet). For every drug therapy started in these tumor-specific imaging agents. 98 35 case reports, information regarding the choice and argumentation 99 36 was assessed. We used a score form based on the WHO 6-step, a 100 37 method used in medical schools to train students therapeutic reason- Severe Dermatologic Reactions 101 38 ing in a step-by-step approach. Associated With Drugs Identified In The 102 39 Results: PubMed database was searched for articles classified as case Hospital Universitario De La Princesa 103 40 report and published in the first half year of 2014. We identified 58 S. Valdez; A. Rivas; E. Gonzalez; F. Abad-Santos; and D. Ochoa 104 41 articles, 44 of which we qualified as clinical case report. In 24 of Clinical Pharmacology Service, Hospital Universitario de la 105 42 these reports a total of 43 drugs were started. The drug name was Princesa, Instituto Teófilo Hernando, Instituto de Investigación 106 43 107 mentioned in 65% and in < 10% general drug information (contrain- Sanitaria Princesa (IP), Madrid, Spain 44 108 dications, adverse effects and interactions) was given. In < 3% the Background: Cutaneous adverse drug reactions (CADR) represent 45 presence/absence of contraindications/interactions and suitability for a heterogeneous field including various clinical patterns without 109 46 the patient was discussed. specific features suggesting drug causality. Serious reactions (fatal 110 47 Conclusions: Although case reports could play a role in developing outcome, sequelae) represent 2% of CADR: bullous reactions 111 48 clinical reasoning skills, this opportunity is not fully utilized for phar- Stevens-Johnson Syndrome, toxic epidermal necrolysis (SJS/TEN), 112 49 macotherapeutic reasoning. We emphasize that pharmacotherapeutic DRESS (drug reaction with eosinophilia and systemic symptoms), 113 50 reasoning is complex and hard to fully assess. However, even using a and acute generalized exanthematous pustulosis (AGEP). 114 51 “simple” score form, we showed that drug choices were frequently Objective: To identify serious cases of (CADR) and the main sus- 115 52 not described completely and argumentation for these choices was pected drugs. 116 53 hardly mentioned. We propose a more detailed description of phar- Materials and Methods: Retrospective observational, between 117 54 macotherapeutic reasoning in case reports, e.g. by using some steps 2008 and 2014 at the Clinical Pharmacology Service of Hospital 118 55 of the WHO-6-step method. Universitario de la Princesa (Madrid) have identified 28 cases of 119 56 severe skin reactions induced by drugs. 120 57 Results: Twenty-eight (CADR), 18 women and 10 men, mean age 121 58 122 A novel tumor-specific imaging agent for 43.1 years, (35.7%) in dermatology services, UCI, internal medicine. 59 The main identified toxicodermia was AGEP (35.71%), followed 123 60 fluorescence guided surgery: 124 a translational study by DRESS syndrome and SJS / TEN (25%), erythema multiforme 61 (7.14%), leukocytoclastic vasculitis and linear IgA bullous dermatitis 125 C.E.S. Hoogstins1,2; Q.R.J.G. Tummers1,2; A.F. Cohen1; 62 (3.57%). Main identified drug was phenytoin (28.75%), followed by 126 C.J.H. van de Velde2; A.L. Vahrmeijer2; and J. Burggraaf1 63 amoxicillin/clavulanate (14.28%), carbapenems, antiretroviral treat- 127 1Centre for Human Drug Research, Leiden, the Netherlands; and 64 ment, piperacillin/tazobactam and magnesium metamizol (7.14%), 128 2Leiden University Medical Centre, Leiden, the Netherlands

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1 and allopurinol, tramadol, NSAIDs, vancomycin, clindamycin, Adequate cardiovascular therapy that includes usage of agents act- 65 2 ranitidine, and simvastatin a (3.57%). Mortality rate was: 28.57% ing on renin-angiotensin system (RAS), (ATC, C09) results in the 66 3 (n = 8), of which 4 by SJS/TEN, 2 by DRESS, and 2 by AGEP total reduction of cardiovascular morbidity and mortality. It is important 67 4 of 8 patients. to establish measures for higher usage of cheaper generics which 68 5 Conclusions: Serious toxicodermies in the Hospital de la Princesa will lead to the reduction of the healthcare costs. The aim of our 69 6 have a low frequency but are associated with high mortality, study was to identify and analyse changes in the usage of original 70 7 risk of complications and sequelae; Very similar to that found in and generics drugs in RAS subgroup agents in Croatia from 2000 to 71 8 other studies, the most frequent is acute generalized exanthematous 2013 and to identify the rate of the generic drugs usage as well as the 72 9 pustulosis. average price for 1 DDD. 73 10 Data on the consumption have been obtained from the database 74 11 IMS (International Medical Statistics) for Croatia. According to the 75 12 Targeted Exome Resequencing: Adme World Health Organization Collaborating Centre for Drugs Statistics 76 13 Pharmacogenetics In Human Liver Methodology annual volumes of drugs are presented in defined daily 77 14 K. Klein1,2; S. Fehr3; R. Tremmel1,2; E. Schaeffeler1,2; S. Winter1,2; doses/1000 inhabitants/day (DDD/1000), while drug costs data are 78 15 M. Schwab1,2,4; S. Biskup3; and U.M. Zanger1,2 presented in Euro per DDD. 79 16 1Dr. Margarete Fischer-Bosch Institut für Klinische The usage of original drugs increased from 5.86 DDD/1000/day 80 17 Pharmakologie, Stuttgart, Germany; 2University of Tuebingen, to 63.56 during the investigated period and generics increased from 81 18 Tuebingen, Germany; 3CeGaT GmbH, Tuebingen, Germany; 52.70 to 136.32. Consumption share of generics decreased from 90% 82 19 and 4University Hospital Tuebingen Department of Clinical in 2000 to 56% in 2006, and then we had constant increase to 68% 83 20 Pharmacology, Tuebingen, Germany in 2013. Average price of 1 DDD for both original and generic drugs 84 21 High-throughput approaches including Next-Generation Sequencing in C09 subgroup decreased in total from 0.31 EUR/DDD in 2000 to 85 22 (NGS) offer the opportunity to analyze a large number of genes to 0.16 EUR/DDD in 2013, which is decrease of 48.91% (39.42% for 86 23 detect known and novel single nucleotide variants (SNVs) and copy originals, and 55.57% for generics). 87 24 number variations (CNVs). We have developed a panel-based tar- The national healthcare policy promoting generics resulted in 88 25 geted NGS pipeline for comprehensive sequence analysis of 341 their increase of usage up to 2013, but due to the introduction of 89 26 genes involved in absorption, distribution, metabolism and excretion new INNs in subgroup (Angiotensin II antagonists, plain and com- 90 27 (ADME) of xenobiotics and endogenous substances. binations) it was less obvious than expected. The price trend showed 81 28 DNA enrichment for NGS was specifically designed for optimal price decrease in originals and generics as a result of price reduction 92 29 capturing of all exonic, exon/intron boundaries, 5’ and 3’UTRs of the policy introduced by Croatian National Insurance Company, but it is 93 30 selected target genes with a total target size of 1.17 Mbases. A set of necessary to introduce new measures for further generic promotion. 94 31 150 extensively characterized Caucasian liver samples was analyzed. 95 32 Variants were compared to available SNV data in databases (dbSNP, 96 33 DGV). Validation was performed using Illumina HumanHAP300 Micro Rna-Dependent Regulation of The 97 34 SNP arrays and other genotyping methods. The impact of SNVs/ Farnesoid X Receptor 98 35 CNVs on gene expression (Illumina Human WG6v2) was assessed. R. Krattinger1; A. Boström2; H.B. Schiöth2; J. Mwinyi1,2; and 99 36 Resequencing revealed more than 2 GB mappable reads contain- G.A. Kullak-Ublick1 100 37 ing about 29,500 variant positions with a mean coverage of about 1University Hospital Zurich, Zurich, Switzerland; and 2University 101 38 140-fold. About 40% of observed SNVs were not yet listed in dbSNP of Uppsala, Uppsala, Sweden 102 39 database and one third of them were rare in our sample collection. Background: The transcription factor farnesoid X receptor (FXR) 103 40 Association analysis of SNVs with expression data was performed plays an important role in the regulation of bile acid and lipid homeo- 104 41 gene family-wise. For example, within 11 genes of human CYP fami- stasis and has the potential to enfold protective effects against dif- 105 42 lies 1, 2 and 3, a total of 3 CNVs and 226 SNVs could be detected. Of ferent cancer forms, such as hepatocellular or colon carcinoma. The 106 43 these, 18 were not listed in dbSNP database, including ten missense short non-coding microRNA miR-192 is, like FXR, mainly expressed 107 44 mutations found as single observations. Their functional prediction in the liver and colon, plays a crucial role in the pathogenesis of 108 45 (SIFT/PolyPhen) revealed deleterious effect for CYP1A1 (R98W, colon carcinoma and serves as a reliable serum biomarker for cancer- 109 46 H60L), CYP2C8 (R124W, L268Q), CYP2C9 (S115R, Q324*), and associated or drug-induced liver injury. In this study we investigated 110 47 CYP2E1 (I383M). Association analysis of SNVs/CNVs with expres- to what extent FXR is regulated by miR-192-3p. 111 48 sion data will be presented. Material and Methods: Two putative binding sites for miR-192-3p 112 49 Our targeted NGS approach on an ADME gene panel with its cus- within the FXR-3’UTR were predicted in silico and tested in vitro by 113 50 tom bioinformatics pipeline is a highly efficient and sensitive method performing Luciferase reporter assays. The NR1H4-3’UTR was sub- 114 51 for comprehensive pharmacogenomic studies. Moreover it provides cloned into pmirGlo reporter vector in wild-type and mutated form and 115 52 high coverage to detect rare known and novel variations. co-transfected into Huh-7 cells together with miR-192-3p. To study 116 53 The study was supported by the German BMBF (VLN grant the endogenous miR-192-3p-dependent expression of FXR and FXR- 117 54 0315755) and by the Robert Bosch Foundation, Stuttgart, Germany. regulated target genes Huh-7 cells were treated for 48 hours and 72 hours 118 55 with miRNA mimic or negative control. MRNA and protein expression 119 56 were measured using TaqMan technology and western blot analysis. FXR 120 57 and miR-192 expression levels obtained in colon cancer tissue samples 121 58 Agents Acting On Renin-Angiotensin 122 System: The Impact of Generics And Price from 65 patients were correlated using Pearson’s correlation analysis. 59 Results: MiR-192-3p binds specifically to the FXR-3’UTR and sig- 123 60 Trends In Croatia 124 1 2 2 2,3 nificantly decreases luciferase activity. Transfection of Huh-7 cells 61 M. Kucan ; J. Mrsic-Pelcic ; D. Mance ; and D. Vitezic 125 1 2 with miR-192-3p led to a significant decrease in FXR mRNA and 62 JGL d.d., Rijeka, Croatia; University of Rijeka Medical School, 126 3 protein levels as well as mRNA levels of the FXR-inducible bile acid 63 Rijeka, Croatia; and University Hospital Centre Rijeka, Rijeka, 127 transporters OSTα -OSTβ and OATP1B3. Significant inverse cor- 64 Croatia 128

2015 e15 Clinical Therapeutics

1 relations of miR-192 and FXR expression were observed in colon Microrna Dependent Regulation of The 65 2 cancer-derived samples. Hepatic Uptake Transporter Oatp1b3 - The 66 3 Conclusions: MiR-192-3p negatively regulates the expression of FXR, Role Of Mir-509 And Mir-656-3p 67 4 thereby significantly decreasing the expression of the FXR-inducible G.A. Kullak-Ublick1; R. Krattinger1; T. Claro DaSilva1; 68 5 target genes OSTα /β and OATP1B3. Because of the role of miR-192 in A. Boström2; N. Dutler1; H.B. Schiöth2; and J. Mwinyi1,2 69 6 cancerogenesis, this miRNA-dependent mechanism of FXR regulation 1University Hospital Zurich, Zurich, Switzerland; and 2University 70 7 could affect the expression of FXR target genes in liver and colon cancer. of Uppsala, Uppsala, Sweden 71 8 Background: The hepatic uptake transporter OATP1B3 mediates the 72 9 uptake of endogenous and xenobiotic compounds from portal venous 73 10 Influence of Formulation Change and blood into the liver. Substrates of OATP1B3 include bile acids, hormones 74 11 Cyp2c19 Genotypes On Pharmacokinetics as well as different therapeutics such as statins, antidiabetics and anti-can- 75 12 of Single-Dose Rabeprazole In Healthy cer drugs. In the current study we investigated to which extent the micro- 76 13 Chinese Adults By Lc-Ms/Ms RNAs miR-509 and miR-656-3p regulate the expression of OATP1B3. 77 14 Z. Wang1#; Y.Q. Du2#; S.H. Wan1#; N.P. Zhao1; J. Zhou1; Material and Methods: The SLCO1B3 3‘-UTR was subcloned into 78 15 S.X. Tang1; X. Kang1; T.T. Cai1; W.Y. Yang1; L. Zhang1; S. Gao1; pmiRGLO luciferase vector both as wildtype sequence as well as with 79 16 and Z.S. Li2 targeted mutations within the bioinformatically predicted consensus 80 17 1Department of Pharmacy, Changhai Hospital, Second Military sequence for miR-509-3p or miR-656-3p. Reporter vectors were co- 81 18 Medical University, Shanghai, 200433, China; and 2Department transfected with either mimics corresponding to both microRNAs 82 19 of Gastroenterology, The First Affiliated Hospital, Second Military or with negative control, and luciferase gene reporter activities were 83 20 Medical University, Shanghai, 200433, China compared. SLCO1B3 mRNA and protein were detected by real-time 84 21 #Co-first authors with the same contribution; *Co-corresponding PCR and western blot analysis in extracts derived from Huh7 cells 85 22 authors treated with miR-509-3p, miR-509-5p and miR-656 mimics. The 86 23 Background: Rabeprazole is a new type of proton pump inhibitor. Its expression of miR-509-3p, miR-509-5p, miR-656 and SLCO1B3 87 24 oral enteric-coated formulations have been widely used. Compared mRNA was correlated in cholangiocarcinoma probes performing 88 25 with omeprazole and lansoprazole, pharmacokinetics of rabeprazole Pearson’s correlation analyses. 89 26 was reported to be less affected by Cytochrome P450 2C19 (CYP2C19) Results: Luciferase activity was significantly decreased in co- 90 27 genotypes, for rabeprazole being not mainly metabolized by enzymatic transfection experiments with miR-509-3p or miR-656 mimic and 81 28 process. An new injection formulation of rabeprazole has just been reconstituted in cases where the binding sites for these microRNAs 92 29 approved in China. However, the pharmacokinetic characteristics of were artificially mutated. MiR-509 and miR-656-3p mimic were 93 30 this new formulation are seldom reported, and whether there are differ- associated with decreased levels of SLCO1B3 mRNA in Huh7 cells, 94 31 ences in the effect of CYP2C19 between the two dosage formulations thereby leading to significantly suppressed levels of OATP1B3 pro- 95 32 of rabeprazole is undefined. We carried out the following research to tein in these cells as compared to mock transfected cells. Significant 96 33 compare the pharmacokinetics between the oral and injection formula- inverse correlations were detected in cholangiocarcinoma between 97 34 tion of rabeprazole in relation to CYP2C19 genotypes. SLCO1B3 mRNA and miR-509-5p. 98 35 Material and Methods: A sensitive and efficient LC-MS/MS method Conclusion: MiR-509 and miR-656 markedly decrease SLCO1B3 99 36 was developed to assay plasma concentration of rabeprazole sam- expression in vitro. The suppressive effect of miR-509-5p on 100 37 ples. Twenty healthy volunteers were enrolled and given single dose SLCO1B3 is supported by correlation data in vivo obtained in chol- 101 38 (20mg) of enteric-coated tablet and rabeprazole for injection in a angiocarcinomas. 102 39 crossover manner, and CYP2C19 genotypes were detected before 103 40 dosing. Pharmacokinetic parameters were calculated with software 104 41 and compared with each others. Sense And Nonsense of Treatment of 105 42 106 Results: In injection group, plasma half-time (t1/2) was 1.20 ± 0.5h, Comorbid Diseases In Terminally Ill 43 the area under plasma concentration-time curve (AUC) was 1410.34 Patients 107 44 108 ± 395.69 μ g/h/L, and clearance (CL) was 15.25 ± 4.25 L/h. In oral E.C.T. Geijteman1; T. van Gelder2; and L. van Zuylen1 45 109 group, time to peak concentration was 3.95 ± 1.01 h, peak concentra- 1Erasmus MC Cancer Institute, Erasmus University Medical 46 110 tion (C ) was 485.65 ± 193.81 h, t was 1.23 ± 0.58 h, AUC was Center, Rotterdam, the Netherlands; and 2Erasmus University 47 max 1/2 111 1089.05 ± 405.20 μ g/h/L, and CL was 20.72 ± 7.24 L/h. Absolute Medical Center, Rotterdam, the Netherlands 48 112 bioavailability (AB) of rabeprazole was about 69%. Relative values Background: Pharmacotherapy is the appropriate use of drugs to 49 113 of AUC after oral and intravenous administration of rabeprazole prevent and treat diseases and to relieve symptoms. In the final phase 50 114 in the 3 CYP2C19 genotype (HomEM:HetEM:PM) groups were of life, treatment goals change, and drugs should be reconsidered. 51 115 1:1.02:1.98 and 1:1.01:1.84 respectively. Case: A 69-year-old woman was diagnosed with metastatic pancreatic 52 116 Conclusions: AB of oral rabeprazole in Chinese population was cancer. She had a history of type 2 diabetes mellitus, diagnosed 7 years 53 117 higher than reported in other populations. Pharmacokinetic proper- earlier. Initially, her diabetes remained under control by metformin 54 118 ties of rabeprazole given either intravenously or orally were depended and by strictly adhering to a healthy lifestyle. For example, she had 55 119 on the CYP2C19 status in Chinese population. Race difference stopped eating her beloved ice cream. She was treated with palliative 56 120 and genetic polymorphism might be the reason of the difference in chemotherapy, including dexamethasone to reduce associated nausea. 57 121 reported bioavailability. During the first cycles blood glucose levels rose to 16 mmol/l, for 58 122 59 123 60 124 61 125 62 126 63 127 64 128

e16 Volume XX Number XX An Educational Intervention To Improve Nurses Reporting of Adverse Drug Reactions

1 which she received short-acting insulin. At home, glucose levels were Conclusions: In terminally ill patients, physicians must adapt drug 65 2 occasionally slightly above target values. Under these circumstances she treatments to new objectives. This case illustrates that such manage- 66 3 stopped eating. The physician told her that higher glucose levels were ment may improve quality of life and potentially reduce unnecessary 67 4 not a problem when they gave her no symptoms. This information and costly pharmacotherapy. 68 5 was very disconcerting to her because she had always been told that it In our current research project Medication management in the 69 6 was extremely importance that glucose levels would not exceed target last phase of life we gain insight into current practices of pharmaco- 70 7 values. The physician repeated that higher levels were unlikely to be therapy in the last three months of life. The project is expected to be 71 8 harmful, especially in the absence of symptoms. He emphasized that completed in the summer of 2015. 72 9 she was not being abandoned. In contrast, her caregivers were applying 73 10 tailored therapy. The patient appreciated this explanation, and despite 74 11 her nausea, she was keen to eat ice cream again. 75 12 76 13 77 14 78 15 79 16 80 17 81 18 82 19 83 20 84 21 85 22 86 23 87 24 88 25 89 26 90 27 81 28 92 29 93 30 94 31 95 32 96 33 97 34 98 35 99 36 100 37 101 38 102 39 103 40 104 41 105 42 106 43 107 44 108 45 109 46 110 47 111 48 112 49 113 50 114 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

2015 e17 Clinical Therapeutics/Volume XX, Number XX, 2015

1 Measuring Drug use: differences between Treatment personalisation for Breast 65 2 medical records and Healthcare Cancer: estrogen receptor splicing 66 3 Utilisation Databases variants in peripheral Blood Leukocytes 67 4 P. Ferrer1; M. Sabaté1,2,3; E. Ballarín1,2,3; M. Rottenkolber4; as New promising biomarkers 68 5 S. Schmiedl5,6; J. Amelio7; F. De Abajo8,9; A Ruigómez10; M. Gil11; L. Bertolaso1; E. Pezzolo1,2; F. Pasini1; C. Barile1; Y. Modena1; 69 6 C. Huerta11; H. Gardarsdottir12; A. Afonso12; O. Klungel12; D. Menon1; A. Bononi1; G. Crepaldi1; and M. Gusella1 70 7 M. De Groot12; R. Schlinger13; R. Reynolds14; L. Ibáñez1,2,3; and on 1Azienda ULSS 18, Rovigo, Italy; and 2University of Padua, Italy 71 8 behalf of PROTECT project Work Package 2 Background: Estrogen receptor alpha (ERα )-positive breast cancer 72 9 1Foundation Catalan Institute of Pharmacology, Barcelona, Spain; is the most frequent tumour in women and tamoxifen (TAM), an 73 2 3 10 University Hospital Vall d’Hebron, Barcelona, Spain; Universitat ERα competitive antagonist, is diffusely used for its treatment and 74 11 Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain; prevention. Unfortunately, a significant percentage of patients do 75 12 4Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany; not benefit the treatment because of intrinsic and acquired resist- 76 5 13 Philipp Klee-Institute for Clinical Pharmacology, HELIOS Clinic ance. ERα is activated by estrogen binding and regulates its own 77 14 Wuppertal, Wuppertal, Germany; 6Witten/Herdecke University, and estrogen-sensitive genes (ESG, e.g., MGP) expression. Recently, 78 7 15 Witten, Germany; Center for Observational Research, Amgen, ERα splice variants (ESV) have been detected in healthy and tumour 79 16 ltd, Uxbridge, Middlesex, United Kingdom; 8Faculty of Medicine tissues, with pharmacological characteristics partially different from 80 9 17 and Life Sciences, University of Alcalá, Madrid, Spain; University the complete form (ERα 66), and emerging data suggest that they may 81 18 Hospital Príncipe de Asturias, Madrid, Spain; 10CEIFE- modulate TAM efficacy. 82 19 Centro Español de Investigación Farmacoepidemiológica, Our study aimed to investigate the effect of TAM on ESV and 83 20 Madrid, Spain; 11BIFAP-Base de datos para la investigación ESG expression in vivo, using peripheral blood leukocytes as sur- 84 21 farmacoepidemiológica en atención primaria, Ministry of rogate tissue. 85 22 Health, Social Welfare and Equality, Madrid, Spain; 12Division Methods: Thirty-four women taking TAM as adjuvant therapy and 86 23 of Pharmacoepidemiology and Clinical Pharmacology, Utrecht 100 aged-matched healthy women were enrolled for this pilot study. 87 24 University, Utrecht, Netherlands; 13Novartis, Basel, Switzerland; Leukocytes from peripheral blood were collected to extract RNA. 88 25 and 14Pfizer Limited, United States of America The expression of ESV and ESG were quantified by Taqman probes 89 26 Introduction: Drug use retrieved from healthcare databases has and SYBR-Green dye, respectively. T Student’s test and correlation 90 27 a key role in drug utilization studies and pharmacoepidemiology. analysis were performed. 91 28 Our aim is to compare and analyse the differences and level of Results: Our data showed that ERα 36 and ERα 66 were the most 92 29 agreement in prevalence of drug use between healthcare utiliza- expressed isoforms in leukocytes. Their levels were largely variable among 93 30 tion (HCU) and medical records (MRs) databases, expressed in patients and inversely correlated (P < 0.0001). TAM was associated with 94 31 number of users. reduced levels of ERα exon 5 deleted variant (P = 0.01) and on average 95 32 Methods: One-year period prevalence rates (PPRs) in 2008, doubled levels of the ERα missing exon-7 isoform (P = 0.06), compared 96 33 expressed as number of users/1,000 people (MRs) and DDD/1,000 to controls. In patients, MGP expression levels were significantly down- 97 34 inhabitants/day (DIDs) transformed into number of apparent users regulated compared to subjects with no anti-estrogenic treatment (P < 98 35 (HCU) were calculated for the following medicines (Anatomic 0.0001) and correlated with ERα 36 levels (R = 0.37, P = 0.03). 99 36 Therapeutic Chemical [ATC] code): calcium channel blockers Conclusions: Leukocytes may be used to study the expression pro- 100 37 (C08C, C08D), antiepileptic drugs (N03A), macrolides (J01FA), files of ERα variants and sensitive genes, in patients taking TAM. 101 38 benzodiazepines (N05BA, N05CD, N05CF), and antidepressants TAM significantly affected 5- and 7-exon deleted isoforms and down- 102 39 (N06AA, N06AB). Data were available for the Netherlands (2 MRs, regulated MGP gene. The ERα 36 isoform, that does not bind TAM, 103 40 1 HCU), Spain (1 MR, 1 HCU) and United Kingdom (2MRs, 1 stimulated MGP transcription when ERα 66 was inhibited by the 104 41 HCU). Percentage differences, Pearson correlation coefficients and drug, suggesting a role in treatment resistance. 105 42 level of agreement with Bland Altman statistics were calculated. Funded by LILT (Italy) 106 43 Data were aggregated by ATC level: ATC level 3 (N03A, C08C, 107 44 C08D) and ATC level 4 (J01FA, N05BA, N05CD, N05CF, N06AA, 108 45 N06AB). CD147, The Ancillary protein of MCT4, 109 46 Results: Percentage differences between PPRs [median (interquartile as marker for prognosis and clinical 110 47 range)] fluctuated from −34.4% (38.2%) at ATC level 3 to −65.2 outcome in primary clear cell renal cell 111 48 (49.2%) at ATC level 4; and from −96.0% (1.6%) for macrolides Carcinoma and Metastasis 112 49 113 to 28.2% (54.4%) for calcium channel blockers. The correlation P. Fisel1,2; V. Stühler3; S. Winter1,2; S. Rausch3; J. Hennenlotter3; 50 114 coefficients were r = 0.88 (P < 0.001) and r = 0.51 (P = 0.008) A.T. Nies1,2; A. Stenzl3; M. Scharpf4; F. Fend4; S. Kruck3; 51 115 at ATC level 3 and 4, respectively. The level of agreement showed J. Bedke3; M. Schwab1,2,5; and E. Schaeffeler1,2 52 116 a deviation of −2.2/1000 users (limits of agreement [LA] −19.7 to 1Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 53 117 6.4) and −28.9/1000 users (LA −84.3 to 26.6) at ATC level 3 and Stuttgart, Germany; 2University of Tuebingen, Tuebingen, 54 118 4, respectively. Germany; 3University Hospital Tuebingen, Department of 55 119 Conclusions: The study suggests that the level of agreement between Urology, Tuebingen, Germany; 4University Hospital Tuebingen, 56 120 users and DIDs were high the more aggregated data is presented. Institute of Pathology and Neuropathology, Tuebingen, Germany; 57 121 The wide LA might reflect not only the low number of groups of and 5University Hospital Tuebingen, Department of Clinical 58 122 medicines studied, but also systematic bias in the measurement of Pharmacology, Tuebingen, Germany 59 DIDs and one-year PPRs. 123 60 124 61 125 62 126 63 127 64 128

2015 e1 Clinical Therapeutics

1 Cluster of differentiation 147 (CD147, or EMMPRIN/basigin), is a half -cycle corrections) were utilized for the model. Robustness of 65 2 transmembrane glycoprotein mediating oncogenic processes partly th e model parameters was explored by one-way and probabilistic 66 3 attributed to its role as obligatory binding partner for proteins sensitivity analysis. 67 4 involved in carcinogenesis, e.g., the monocarboxylate transporters Results: Analysis of the registries showed significant decrease 68 5 MCT1 and MCT4. Just as previously demonstrated for MCT4, of incidence of diseases associated with S. pneumonia in children 69 6 CD147 is proposed to be associated with tumor progression and that received the PCV-13. Moreover, the introduction of PCV-13 70 7 metastasis in clear cell renal cell carcinoma (ccRCC) and therefore decreased the under 1-age mortality due to pneumonia by half 71 8 might represent a promising target for therapeutic intervention and (95% CI, P = 0.001). As a result of 5 year stimulation of the 72 9 a marker for prognosis and patient outcome. For more objective model, the CER of PCV -13 was estimated as 8432 tenge/LYG or 73 10 and reproducible quantification of biomarker expression, use of 8574 tenge/QALY, whereas CER for no PCV-13 was estimated 74 11 the automated image analysis software Definiens Tissue Studio as 7441 tenge/LYG or 7605 tenge/QALY. ICER was estimated as 75 12 might represent an attractive alternative to conventional visual 122 070 tenge/QALY, which is within the cost-effectiveness threshold 76 13 evaluation. values recommended by WHO. 77 14 CD147 protein expression was assessed in two independent Conclusions: The introduction of PCV-13 seems to be a cost-effective 78 15 cohorts of 207 and 64 ccRCC patients, respectively, and in 13 dis- programme in Kazakhstan. These findings may better inform deci- 79 16 tant metastases derived from primary ccRCC, by immunohisto- sion makers regarding formulary inclusion and reimbursement in the 80 17 chemical staining of TMAs and subsequent automatic evaluation vaccine programmes in Kazakhstan. 81 18 using Definiens Tissue Studio. Obtained results were correlated 82 19 with a semi-quantitative score derived from visual evaluation. 83 20 Additionally, CD147 protein expression levels were associated Cultural determinants of the 84 21 with patients’ clinicopathological parameters and outcome data. differences of use of Antidepressants in 85 22 The prognostic relevance was compared to that of MCT4 protein 5 European settings 86 23 expression. A. Gómez1,2; P. Ferrer3; M. Sabaté1,3; E. Ballarín1,3; U. Moretti4; 87 24 CD147 protein expression levels generated with Definiens Tissue M. Andretta5; A. Coma6; and L. Ibáñez1,3 88 25 Studio correlated significantly with levels derived with the semi- 1University Hospital Vall d’Hebron, Barcelona, Spain; 2Universitat 89 26 quantitative score (P 0.0001, r 0.85). Furthermore, CD147 90 < S = Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain; 27 expression was significantly associated with clinicopathological 3Foundation Catalan Institute of Pharmacology, Barcelona, 81 28 parameters and cancer-related death. Metastatic tissue showed high Spain; 4Centro Farmacovigilanza Regione Veneto, Verona, Italy; 92 29 CD147 expression as well. The comparison of prognostic relevance 5Servizio Farmaceutico Territoriale Veneto, Verona, Italy; and 93 30 of CD147 and MCT4 protein expression however, showed a higher 6Centre Regional Barcelona. Servei Català de la Salut (CatSalut), 94 31 significance for MCT4 protein expression. Barcelona, Spain 95 32 We could proof that software-based evaluation of protein expres- Background: Little is known about how culture could influence in 96 33 sion using Definiens Tissue Studio is a feasible alternative to visual drug consumption. The aim of this study was to describe the use of 97 34 semi-quantitative scoring. In addition, we confirmed an association antidepressants (AD) in 5 European settings and to elucidate if its 98 35 of CD147 protein expression with ccRCC progression and outcome, use was related to cultural differences. 99 36 but its prognostic significance could not surpass that of MCT4. The Material and Methods: Data on AD (Anatomical Therapeutic 100 37 potential for CD147 as therapeutic target however, especially for Chemical classification code: N06A) consumption were retrieved 101 38 metastatic ccRCC, remains. from the national drug consumption databases of Catalonia, 102 39 Denmark, Norway, Sweden and Veneto during the study period 103 40 2007-2011. Defined Daily Doses (DDD) and DDD/1000inhabitants/ 104 41 Evaluation of health outcomes and day (DID) were calculated and stratified by sex and age. Spearman 105 42 cost-effectiveness of 13-valent correlation coefficient was used to calculate correlations between 106 43 Pneumococcal Conjugate Vaccination the total AD use and the Hoftede’s country scores for the six cultural 107 44 for infants in Kazakhstan dimensions (power distance, masculinity, indulgence, uncertainty 108 45 C.R. Bektur; and T.S. Nurgozhin avoidance, individualism) adjusted by pharmaceutical expenditure 109 46 Center for Life Sciences, Nazarbayev University, Astana, and general practitioners by 1000 inhabitants. Data were retrieved 110 47 Kazakhstan from the Hofstede Centre and OECD (Organization for Economic 111 48 Introduction: S. pneumoniae is one of the leading causes of serious Co-operation and Development) WebPages. 112 49 illness, including pneumonia, in children and adults. PCV vaccination Results: In 2011, Denmark showed the highest consumption (83.81 113 50 showed high effectiveness in prevention of pneumococcal disease DID) and Veneto the lowest one (34.92 DID). An increase in AD use 114 51 and decrease of pneumonia-associated infant mortality. Present study was observed for all the countries during the study period, the lowest 115 52 evaluates the health benefits and cost-effectiveness of 13-valent pneu- increase was observed in Norway, 3.5%, and the highest in Catalonia 116 53 mococcal conjugate vaccine (PCV-13) programme for Kazakhstani and Denmark, 18.2%% and 18.1%, respectively. Women and the 117 54 infants from the perspective of Ministry of Health. elderly consumed the most in all the countries. We found a strong 118 55 Material and Methods: A Markov model was constructed to esti- correlation for two cultural dimensions: masculinity and indulgence, 119 56 120 mate the effects and directs costs of PCV-13 programme compared in all the years (r > 0.7). The values for power distance were r = 0.9 57 121 to other PCV programmes for infants initiated in Kazakhstan. (2007), r = 0.78 (2008) and r = 0.77 (2011). For the uncertainty 58 Treatment efficacy and transition probabilities were synthesized avoidance and individualism dimensions we found a strong correla- 122 59 123 from local registries. The characteristics of patient cohort and treat- tion only in 2007 (r = 0.86). 60 ment costs (vaccine cost, monitoring, adverse effects management) in Conclusions: AD consumption increased over the study period. The 124 61 year 2014 Kazakhstani tenge (KZT) were estimated from republican results of the correlations suggest that Hofstede cultural dimensions 125 62 official sources. Annual 3% discounting rate and 1 year cycles (with may play a role in explaining the use of AD across countries. 126 63 127 64 128

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1 Pharmacoeconomic analysis comparing 300 mg/m2/die of 5-fluorouracil protracted venous infusion and 56 65 2 Clopidogrel Desensitization Protocol Gy radiation, followed by surgical resection. Response was directly 66 3 versus ticagrelor for Antithrombotic evaluated on surgical specimens and scored according to tumor 67 4 treatment in Coronary Artery residual mass as in TNM classification. PT0-2 were defined as major 68 5 Disease Patients with Clopidogrel response. Genomic DNA was extracted from peripheral blood lym- 69 6 Hypersensitivity after PCI phocytes and ERCC1, XPD, XPC, XPA, XRCC1, XRCC3, UMPS, 70 7 I. Cegec1; I. Francetic1,2; V. Erdeljic Turk1; K. Makar Ausperger1; MTHFR and TYMS polymorphisms were analyzed by PCR-RFLP. 71 8 M. Aumiler Radacic1; I. Kraljickovic1; I. Cacic1; and R. Likic1,2 Genotypes were associated with tumor outcomes to CRT using Chi 72 9 1University Hospital Rebro, Zagreb, Croatia; and 2University of square test and the MDR method. 73 10 Zagreb School of Medicine, Zagreb, Croatia Results: patients’ response to CRT was as follows: pT0 in 25.7%, 74 11 Background: Antithrombotic treatment for CAD patients undergo- pT1-2 in 34.3% and pT3-4 in 40%. Chi square test found no signifi- 75 12 ing PCI includes dual antiplatelet therapy comprising oral loading cant relationship between genotypes and local pathological response. 76 13 doses of 150–300 mg of acetylsalicylic acid and 300–600 mg of Using the MDR method, we showed a significant association between 77 14 clopidogrel, followed by daily doses of 75–100 mg and 75 mg orally the combination of XPC/TYMS/XRCC3 genetic variants and major 78 15 of each drug respectively. According to the literature about 6% of response (P = 0.0001) that was correctly predicted in 81.8% of 79 16 patients develop an allergic reaction to clopidogrel. In those cases it is patients (VPP, 80.7%; 95% CI, 62.1–91.5; VPN, 86.4%; 95% CI, 80 17 recommended to switch therapy to a newer generation P2Y12 platelet 73.3–93.6; sensibility, 77.8%; specificity, 88.4%). 81 18 receptor blocker: prasugrel or ticagrelor, due to their quicker onset Conclusions: MDR proved to be an easy and valid method to detect 82 19 of action and more potent platelet aggregation inhibition. Our aim genetic combinations identifying rectal cancer patients with a high 83 20 was to compare the annual cost of newer antiplatelet drugs versus probability of chemoradiotherapy response. 84 21 outpatient oral clopidogrel desensitization procedure followed by Funded by LILT (Italy). 85 22 clopidogrel therapy. 86 23 Material and Methods: We calculated the yearly price of ticagrelor 87 24 therapy for one patient by using the publicly available prices of DDD Is it effective and safe to plus 88 25 in Croatia (ESC guidelines for antithrombotic treatment in CAD traditional Chinese medicine injection 89 26 patients undergoing PCI) to be 813.4€ (prasugrel is not reimbursed for patients in acute phase of stroke?–a 90 27 in Croatia), while one year of clopidogrel therapy including the cost meta analysis** 81 28 of outpatient oral clopidogrel desensitization procedure (3 half-day Z. Wang1,#; X.D. Hu2,#; S.H. Wan2; J.F. He3; S.X. Tang1; B. Wang1; 92 29 clinical visits) amounted to 289.51€ . S. Gao1,*; and F. Yu2,* 93 30 Results: Approximately 6529 patients undergo PCI procedures in 1Department of Pharmacy, Changhai Hospital, Second Military 94 31 Croatia per year and 6% of them develop allergy to clopidogrel. Medical University, Shanghai, 200433, China; 2School of 95 32 Yearly savings would amount to 205,244.38€ if those patients would Pharmacy, China Pharmaceutical University, Nanjing, 211198, 96 33 stay on clopidogrel after successfully (90%) completing oral clopi- China; and 3School of Pharmacy, Anhui University of Chinese 97 34 dogrel desensitization rather than be started on ticagrelor. Medicine, Hefei, 230031, China. 98 35 Conclusions: Since annual therapy with clopidogrel, even with #Co-first authors with the same contribution; *Co-corresponding 99 36 desensitization, is 2.8 times cheaper than ticagrelor treatment, we authors; **This study was funded by “1255” discipline promotion 100 37 believe that it would be more cost effective for patients with clopi- plan of Changhai Hospital (No. CH125520400). 101 38 dogrel allergy who cannot afford copayment for a newer generation Introduction: Traditional Chinese medicine injection (TCMI) has 102 39 platelet aggregation inhibitor. been widely used in China. However, adverse reactions reports about 103 40 TCMI are also gradually increasing, and the efficacy and safety of 104 41 TCMI are very controversial. The aim of this study is to assess the 105 42 Genetic biomarkers for predicting efficacy and safety of TCMI for acute phase of stroke. 106 43 Patological response in Material and Methods: A meta-analysis method was used to review 107 44 Chemoradiotherapy treated rectal the reported clinical trials systematically. The protocol was based 108 45 Cancer Patients on classic medication therapy including antiplatelet agents, antico- 109 46 110 E. Pezzolo1,2; L. Bertolaso1; Y. Modena1; D. Menon1; C. Capirci1; agulants, fibrinogen-depleting agents and neuroprotective agents. 47 111 F. Pasini1; P. Giusti2; and M. Gusella1 In the observation group, TCMI were used together in the acute 48 112 1Azienda ULSS 18, Rovigo, Italy; and 2University of Padova, phase of stroke. Four investigators independently identified the 49 113 Padova, Italy relevant articles from 4 foreign language databases and 3 Chinese 50 114 Background: neo-adjuvant 5-fluorouracil-based chemoradiotherapy databases from the inception to 2 July 2014. The pooled RR 51 115 (CRT) for locally advanced rectal adenocarcinoma is effective in (Relative Risk), RD (risk difference) and MD (mean differences) 52 116 downstaging more than half of patients before surgery. Interindividual with 95% confidence intervals (CIs) were calculated by Revman 53 117 variations in DNA repair and metabolism of pyrimidine nucleotides 5.2.7 software. 54 118 and folates may be important mechanisms of resistance to radio and Results: According to the inclusion criteria, ultimately 77/943 stud- 55 119 chemotherapy and often their associations with anticancer treatment ies on 14 TCMI with 7449 patients were defined. The meta-analysis 56 120 cannot be revealed by classical statistics, due to epistasis. showed that TCMI was unable to reduce all-cause mortality of acute 57 121 The Multifactor Dimensionality Reduction (MDR) method was period stroke case (RD, −0.04; 95% CI, −0.08 to 0.01; P = 0.10), the 58 122 designed to identify and model gene to gene interactions. The aim of deterioration was on good control after adding TCMI (RD, −0.06; 59 123 our study was to verify if genetic variants in DNA repair and pyrimi- 95% CI, −0.08 to −0.04; P < 0.00001). The TCMI combined therapy 60 124 dine/folate metabolism are associated with rectal cancer response to could improve the neurological deficit of acute phase stroke accord- 61 125 CRT, comparing different statistical approaches. ing to the total efficient rate and neurological deficit score improve- 62 126 Material and Methods: Seventy patients with stage II and III rec- ment (RR, 1.25; 95% CI, 1.22 to 1.27; P < 0.00001; and MD, 4.15; 63 127 tal cancer were enrolled and treated for 5 weeks with concurrent 95% CI, 2.31 to 5.98; P < 0.00001, respectively). TCMI seemed to 64 128

2015 e3 Clinical Therapeutics

1 be a relatively safe therapy in acute phase (RD, 0.02; 95% CI, −0.01 Results: Integration of pharmacovigilance in the national 65 2 to 0.06; P = 0.19). TB-program has been carried out in 2014. Total amount of ADRs 66 3 Conclusions: TCMI might be beneficial to improve the neurological included to national data base are 81 cases by 2014, 37 cases out of 67 4 deficit of acute phase stroke, and relatively safe if be used rationally. them due to anti-TB drugs. The most of medication complications 68 5 However, parts of reported TCM trials were limited in methodology were on drugs: cycloserine, protionamide, pyrazinamide. Side effects 69 6 quality, which may affect the credibility of this research to a certain were from the central nervous system and the gastrointestinal tract, 70 7 extent. which clinically come out in hypersensitivity reactions (56%), con- 71 8 vulsions (7%), headache, dizziness (14%), nausea, vomiting (21%) 72 9 and diarrhea (2%). TB patients are male (57%), but the ADR is 73 10 A Prospective study of QTC prolongation more frequently in women. The average age of patients was 30 years. 74 11 due to Erytrhomycin used as Prokinetic Conclusion: The integration of pharmacovigilance in the national 75 12 agent in Icu Patients TB-program has contributed to increasing the number of spontaneous 76 reports of ADR for TB-drugs and prescribed drugs more efficiently, taking 13 R.B. Fiets1; J.M. Bos2; R. Donders1; M. Bruns2; E.J. Lamfers2; 77 into account the available data and thereby minimize the risk of ADR. 14 J.A. Schouten2; and C. Kramers1,2 78 15 1Radboud University Medical Center, Nijmegen, the Netherlands; 79 16 and 2Canisius Wilhelmina Hospital, Nijmegen, The Netherlands 80 17 Background: High dose erythromycin used as antibiotic prolongs Impact of the CYP3A4 metabolic 81 18 QTc. Low dose erythromycin is frequently used as a prokinetic agent, activity and CYP2C19 Polymorphisms on 82 19 especially in patients at the ICU. It is unknown whether low dose Antiplatelet effects of clopidogrel in 83 20 erythromycin prolongs QTc and put patients at risk for torsades Russian Patients with acute Coronary 84 21 des pointes. Syndrome undergoing coronary stent 85 22 Methods: In this prospective study we included patients at the ICU implantation 86 23 treated with erythromycin in a dose of 200 mg bd. Electrocardiogram K.B. Mirzaev1; D.A. Sychev1; D.A. Andreev2; R.E. Kazakov3; and 87 24 was registered before, 15 minutes and 24 hours after start of eryth- V.V. Smirnov3 88 25 romycin. No new QTc medication should be started during study. 1Russian Medical Academy of Postgraduate Education, Moscow, 89 26 QTc was measured by 2 investigators. Electrolytes, renal function Russian Federation; 2I.M. Sechenov First Moscow State Medical 90 27 and hepatic function was measured in all patients. University, Moscow, Russian Federation; and 3Scientific Center 81 28 Results: In a total of 51 patient, 3 ECGs were recorded and no on Expertise of Medical Application Products, Moscow, Russian 92 29 change was made in QTc prolonging medication. In these 51 patients Federation 93 30 94 QTc increased significantly from 430 ms at baseline to 439 ms (p= Introduction: Dual antiplatelet therapy, involving aspirin and clopi- 31 95 0.03) after 15 minutes and 444 ms (p = 0.01) after 24 hours. After dogrel, is recommended in patients undergoing coronary stenting to 32 15 minutes and 24 hours upper limit of 95% confidence interval avoid the occurrence of stent thrombosis and others ischaemic events. 96 33 for prolongation of QTc was well above 10 ms. In 4 patients QTc The presence of CYP2C19*2 polymorphism and CYP3A4 low meta- 97 34 increased to more than 500 ms and in 2 patients QT was already bolic activity can reduce the formation of the active metabolite of 98 35 above 500 ms. No QTc related arrhythmias were seen. clopidogrel, resulting in less platelet inhibition. High residual platelet 99 36 Conclusion: Erythromycin in a dose of 200 mg bd prolongs QTc and reactivity is associated with an increased risk of a cardiovascular 100 37 ECG should be controlled when this is prescribed. event after coronary stenting. The aim of our study was to evaluate 101 38 the impact of the CYP3A4 metabolic activity and CYP2C19 poly- 102 39 morphisms on platelet reactivity during dual antiplatelet therapy. 103 40 Material and Methods: We determined the CYP2C19 genotypes 104 41 Pharmacovigilance in Kyrgyz 105 Tuberculosis Public Program: current (Real-time PCR) and CYP3A4 metabolic activity (6b-hydroxycor- 42 tisol/cortisol (6-OHC/FC) in urine were determined by high-perfor- 106 43 situation 107 1 1,2 3 mance liquid chromatography) of 81 subjects with acute coronary 44 G.A. Kulushova ; A.Z. Zurdinov ; and S.R. Moldoisaeva 108 1 syndromes (ACS) undergoing coronary stent implantation (62 male 45 Department of Drug Supply and Medical Equipment under the 109 2 patients, mean age 64 years) receiving clopidogrel and evaluated the 46 Ministry of Health, Bishkek, Kyrgyzstan; Kyrgyz State Medical 110 3 effect of these factors on on-treatment platelet aggregation using the 47 Academy, Bishkek, Kyrgyzstan; and Ministry of Health, Bishkek, 111 Kyrgyzstan VerifyNow P2Y12 assay. The SPSS 20.0 software was used for all 48 statistical analyses. A P value of 0.05 was regarded as significant. 112 Introduction: Tuberculosis (ТВ) remains a major public health prob- < 49 Results: The distribution of the CYP2C19 genotypes were 84,0 % in 113 50 lem globally. The problem has been exacerbated in connection with 114 the increasing of multiresistances of M. tuberculosis to the drugs extensive metabolizers (EM;CYP2C19*1/*1), 16,0 % in intermediate 51 metabolizers (IM;*1/*2), and poor metabolizers (PM;*2/*2) were 115 52 used and the occurrence of serious adverse drug reactions (ADR). 116 Difficulties in identifying drugs, the use of which has led to the ADRs, not found. The mean platelet reactivity unit (PRU) was significantly 53 higher in patients with CYP2C19*2 the compared to non-carriers: 117 54 particularly severe events affect on the adherence of patients to the 118 190.8 ± 48.2 in IM versus 166.0 ± 50.8 in EM (P = 0.007) and 55 prescribed treatment regimen. Low compliance of patients due to 119 ADRs, and as a result, stop taking anti-TB drugs is a big risk for the frequency of clopidogrel resistance (PRU > 208) was 53.8 and 56 16.2 correspondingly. The index of urinary 6-OHC/FC (marker of 120 57 patients and serious threat to society. Objective of this work is to 121 CYP3A4 activity) ratios were 3.4 ± 2.8 in PRU > 208 and 3.2 ± 3.0 58 assessment the frequency and severity of side effects anti-TB drugs. 122 in PRU > 208 groups (P = 0.8) and not found statistically significant 59 And also demonstrate the importance of integration of pharmacovigi- 123 correlation between PRU and 6-OHC/FC ratios (P = 0.84). 60 lance in the national TB- programs. 124 Methods: The method of spontaneous reports of suspected ADR Conclusions: Clopidogrel treated patients with the CYP2C19*2 pol- 61 ymorphism have significantly increased platelet reactivity compared 125 62 of drugs was used. The study included all patients hospitalized and 126 treated with anti-TB drugs. Statistical analysis was performed using to non-carriers. The ratio of urinary 6-OHC/FC was not influence 63 on on-treatment platelet aggregation. 127 64 MS Excel 2010. 128

e4 Volume XX Number XX Measuring Drug use: differences between medical records and Healthcare Utilisation Databases

1 Acute Levodopa challenge for a feedback letter to the reporter and a summary for the pharmacovig- 65 2 Diagnostic and Therapeutic purposes in ilance-databases of the European Medicines Agency and WHO. This 66 3 elderly patients with Newly diagnosed student-assessment was then verified by Lareb staff, who evaluated 67 4 Parkinsonian Syndrome student-handling it in an e-questionnaire. 68 5 B. Pozuelo Moyano; J. Horvath; and F. Herrmann Results: From May to December 2014, 89 different ADR-reports 69 6 Hôpitaux Universitaires de Genève, Switzerland selected by Lareb staff were handled, with the top 3 reported ADRs 70 7 Background: Clinical response to acute levodopa challenge can pre- being; palpitations, urinary retention and agitation. Thirty-five stu- 71 8 dict the efficacy of this drug in the long-term treatment of Parkinson dents and 3 Lareb staff members participated. Lareb staff rated the 72 9 disease (PD). Furthermore, a good response supports the diagnosis of student assessments (very) useful (> 92%), scientifically substantiated 73 10 idiopathic PD. However, in elderly patients who usually suffer from (> 88%), complete (not lacking information) and without inaccura- 74 11 many comorbidities, side effects of a single levodopa dose may limit cies (both > 92%). Altogether the student-assessments were rated 75 12 the tolerance and usability of this test. mean 8.3 (1–10; min-max). Compared to self-handling, Lareb staff 76 13 Objective: 1. To assess the feasibility of acute levodopa challenge in indicated student-assessment cost less time in 33% assessments, neu- 77 14 elderly patients with newly diagnosed parkinsonian syndrome in a tral in 55%, and cost extra time in 11%. 78 15 university hospital setting. 2. To assess the predictive value of acute Conclusion: The Student-run pharmacovigilance program is a 79 16 levodopa test for the efficacy of chronic dopaminergic treatment. win-win venture. It offers students a valuable “pharmacovigilance 80 17 3. To correlate the result of acute levodopa test with the dopamine experience”, creates awareness in future doctors with the potential 81 18 transporter uptake ratio quantified by a DaTSCAN. to increase ADR-reporting, and didn’t cost Lareb staff extra time 82 19 Methods: Candidates for the study will be selected via neurological overall. The learner effects need to be investigated in future studies. 83 20 consultation, performed by a movement disorders specialist, among 84 21 patients hospitalized in geriatric wards. Unstable cardiovascular or 85 22 mental condition, severe infection or ongoing dopaminergic or dopa- In search of the suspicious link: 86 23 mine receptor blocking treatment will constitute exclusion criteria. Smokeless Tobacco use and oral 87 24 MDS-UPDRS 3 subscale (with video recording) will be performed Mucositis in Head and Neck Cancer 88 25 for the assessment of parkinsonian motor signs before («time 1») Patients 89 26 and 1 hour after acute levodopa administration («time 2») as well S. Begum1; and S. Mukhopadhyay2 90 27 on stable chronic levodopa therapy at 2 months («time 3»). The first 1RG Kar Medical College, Kolkata, India; and 2Christian Medical 81 28 acute levodopa dose will be calculated by the body weight and the College, Ludhiana, India 92 29 chronic therapeutic dose will be titrated individually and progres- Introduction: Smoking of tobacco is implicated as one of the major 93 30 sively according to efficacy and tolerance to achieve the best clinical risk factors for development of oral mucositis (OM). Tobacco in 94 31 response. Cognitive state (Mini Mental State and Neecham Scale) other smokeless forms is a major form of addiction in many countries. 95 32 and arterial blood pressure in lying and standing position (Schellong However, the association of smokeless tobacco with oral mucositis 96 33 test) will be assessed at baseline and Neecham Scale and Schellong has hardly studied. The present study aims at finding the association, 97 34 test at each evaluation time. Any other adverse effect will be searched if any, with different types of tobacco use with OM. 98 35 and noted (nausea, dizziness, vomiting etc.) DaTSCAN will be per- Materials and Methods: In this cross-sectional study, head and neck 99 36 formed during the hospital stay and striatal uptake of radioligand cancer patients receiving radiation, chemotherapy or concurrent 100 37 quantified. Statistical analyses will consist in computing Poisson 95% chemo-radiation who developed oral mucositis over a study period 101 38 confidence intervals for the incidence of side effects predicting efficacy of three months were enrolled. History of different forms of tobacco 102 39 using logistic and linear regression models and the association with use, alcohol, oral hygiene and other risk factors were noted along 103 40 DaTSCAN with Pearson correlation coefficient. with other demographic variables and analyzed. 104 41 Results: Out of total 20 enrolled patients of OM, data of 18 consent- 105 42 ing patients were analyzed. Smokeless tobacco addiction in any form 106 43 107 Learning by doing in the student-run was found in 59% patients (n = 10) compared to 16.7% patients 44 108 Pharmacovigilance Program (n = 3) who had no history of tobacco addiction (P = 0.01). Similar 45 109 T. Schutte1,2; J. Tichelaar1,2; M.O. Reumerman1; R. van Eekeren3,4; numbers of smokers were detected to have OM. Poor dental hygiene 46 110 L. Rolfes3,4; M.C. Richir1,2; E. van Puijenbroek3,4; was noted in 72% patients. 47 111 and M.A. van Agtmael1,2 48 Prevalence of Oral mucositis and different addictions 112 1VU University Medical Center, Amsterdam, the Netherlands; 49 25 113 2RECIPE (Research & Expertise Center In Pharmacotherapy 50 114 Education), Amsterdam, the Netherlands; 3The Netherlands 20 18 51 115 Pharmacovigilance Centre Lareb (Lareb); and 4University of 15 52 10 10 116 Groningen, Groningen, The Netherlands 10 53 7 117 Background: Medication safety is an important topic in healthcare 6 54 Number of patients 118 nowadays. Pharmacovigilance, the monitoring of drug safety after 5 3 55 119 approval for marketing, depends mainly on the quality and quan- 0 56 120 tity of reported adverse drug reactions (ADR). To increase pharma- Total patient Smoker Smokeless t No tobacco Smoking + Alcohol 57 Smokeless t 121 covigilance awareness among medical students, we developed and Addiction types and total patients 58 122 evaluated a Student-run Pharmacovigilance program, together with 59 123 pharmacovigilance centre Lareb. 60 Similar numbers of smokers were detected to have OM. Poor 124 Method: A pilot study was performed in which teams of (1st-4th 61 dental hygiene were noted in 72% patients. 125 year) medical students assessed real ADR-reports from patients/ 62 Conclusions: Smokeless tobacco, like its smoking counterpart, was 126 healthcare professionals reported to Lareb. After assessment on cau- 63 found to being associated significantly with oral mucositis among 127 sality, students searched for a pharmacological explanation and wrote 64 the head neck cancer patients receiving radiation or chemotherapy. 128

2015 e5 Clinical Therapeutics

1 However, larger longitudinal study is recommended to find out ADD (n = 88), the patients with AMI and ADD without agomelatine 65 2 whether it is a mere association or a significant risk factor. therapy (n = 58) and the patients with AMI and ADD with agomela- 66 3 tine therapy (n = 50). We studied coagulation and vascular-platelet 67 4 hemostasis on the first 24 hours of hospitalization and in the dynam- 68 5 Characterization of Blood Glucose ics of the disease on the 14th day of hospitalization. 69 6 & Glycosuria following IV Trehalose Results: Activity of blood coagulation is more pronounced in 70 7 (Cabaletta) administration for OPMD patients with AMI and ADD in comparison with patients without 71 ADD. Despite ongoing antiplatelet therapy of patients with AMI and 8 H. Vornovitzki1; S. Blotnick1; I. Gliko-Kabir2; Z. Argov2; and 72 ADD observed a high level of platelet activation on the first day of 9 Y. Caraco1 73 hospitalization and in the dynamics of the disease on the 14th day in 10 1Clinical Pharmacology Unit, Hadassah University Hospital, 74 comparison with patients without ADD. Patients with AMI and ADD 11 Jerusalem, Israel; and 2Bioblast-Pharma Ltd., Tel-Aviv, Israel 75 with agomelatine therapy in addition to standard antiplatelet therapy 12 Background: Trehalose is a naturally occurring disaccharide that 76 in the dynamics of the disease on the 14th day of hospitalization a 13 is currently being evaluated for the treatment of Oculopharyngeal 77 clear decrease in platelet aggregation compared to the 1st and days 14 Muscular Dystrophy (OPMD) and spinocerebellar ataxia 3. 78 of hospitalization. After 14th day from the start agomelatine therapy 15 Objective: The purpose of this sub-study (part of OPMD phase 2 79 a tendency to reduce the severity of ADD. 16 therapy trial) was to evaluate the extent of increase in blood glucose 80 Conclusions: We registered a positive response to receiving 17 and the extent and duration of glycosuria associated with the intra- 81 antithrombotic therapy in patients with AMI in combination with 18 venous administration of Trehalose. 82 ADD on the background of early treatment with agomelatine. This 19 Methods: Fourteen OPMD patients received weekly intravenous 83 can have a favorable effect on the course and prognosis of patients 20 30 gr trehalose over a period of approximately 80 minutes. Just 84 with AMI and ADD. 21 prior to and following the administration of the 3rd dose, blood 85 22 were taken periodically over 5 hours for the evaluation of plasma 86 23 concentration of trehalose using a validated high performance liquid 87 24 chromatographic tandem mass spectrometry. On a different dosing Double-blind, placebo and active 88 25 day, plasma and urine samples were taken periodically over 8 hours comparator-controlled study in Healthy 89 26 for the evaluation of glucose concentration using hexokinase enzyme Males followed by an open-label study 90 27 method on a chemistry analyzer. in Healty Males and Females, to asses the 81 28 Results: Plasma concentration of trehalose exhibited more than safety, Pharmacokinetics and –dynamics 92 29 2-fold variation with AUC ranging from 2698 to 6103 µg*h/mL. A of 2B3-201 93 0→5 30 mild rise in plasma glucose was noted in 11 patients reaching a peak of K.M.S. Kanhai1; R.G.J.A. Zuiker1; W. Gladdines2; J. Stevens1; 94 31 (mean ± SD) 11.28 ± 7.27 mg% within 1-2 hours following Trehalose I. Stavrakaki2; and G.J. Groeneveld1 95 32 infusion. The rise in blood glucose was transient and it reverted 1Centre for Human Drug Research, Leiden, the Netherlands; and 96 33 back to pre-Trehalose concentrations within 1-4 hours (2.10 ± 2Former BBB therapeutics, Leiden, the Netherlands 97 34 1.29 hours). Some degree of glycosuria was noted in all patients. Background: Intravenous methylprednisolone (MP) has for long been 98 35 Maximal glucose urinary concentration varied ranging from 42 mg% the mainstay of relapse treatment in MS. However, it is inconvenient 99 36 and up to 1031 mg% (358 ± 341 mg%). Peak glycosuria was noted and its side effects are undesirable. Both the dose and the dosing fre- 100 37 within 1-3 hours and it was evident only in 1 patient in the urine quency can be reduced by incorporating MP in (PEGylated) liposomes, 101 38 sample taken after 8 hours. creating a slow-release formulation with reduced systemic toxicity, but 102 39 Conclusions: The intravenous administration of 30 gr trehalose similar peripheral efficacy. By adding glutathione to the PEGylated 103 40 (Cabaletta) is associated with a subtle rise in blood glucose concen- liposomes (2B3-201), enhanced delivery of MP into the brain is 104 41 tration and transient glycosuria. The presence of urinary glucose achieved. Preclinical studies in animal models of MS showed that 2B3- 105 42 represents most probably in-situ renal activity of trehalase. 201 had fewer side effects and a superior efficacy compared to free MP. 106 43 Methods: In this double-blind, 3-way cross over study, 18 healthy 107 44 males in 3 cohorts, received an ascending doses of 2B3-201, active 108 45 comparator (MP) or placebo. MP plasma concentrations, standard 109 46 Influence Agomelatine Therapy on 110 Hemostasis of patients with acute safety parameters, lymphocyte counts, ACTH and fasting glucose 47 were determined. Neurocognitive tests were performed. Part 2 of the 111 48 Myocardial infarction 112 1 1 1 study was an open-label infusion of 2B3-201 to assess PK in women 49 M.S. Chernyaeva ; N.Y. Shimohina ; M.M. Petrova ; 113 1,2 1 and the influence of anti-histaminics on side effects. 50 A.A. Savchenko ; and D.S. Kaskaeva 114 1 Results: 2B3-201 was shown to have a plasma half-life of 23 h, com- 51 Krasnoyarsk State Medical University named of professor V.F. 115 2 pared to a half-life of 3 h for free MP. 2B3-201 (150, 300 or 450 mg) 52 Voyno-Yasenetsky, Krasnoyarsk, Russia; and Research Institute 116 of Medical Problems of the North, Krasnoyarsk, Russia resulted in a similar reduction in the lymphocyte count as 1000 mg 53 of free MP. This effect was sustained considerably longer after 450 117 54 Introduction: The problem the treatment of depression in patients 118 mg 2B3-201 administration to > 74 h. Similar patterns were observed 55 with acute myocardial infarction (AMI) is determined by the grow- 119 ing prevalence of anxiety and depressive disorders (ADD) among for a decline in ACTH and a rise in fasting glucose. No signs of CNS 56 side effects or serious AEs were observed. The AEs were generally 120 57 patients. ADD has a negative impact and prognosis of AMI. Some 121 studies have confirmed the high therapeutic efficacy and tolerability mild and self-limiting. Results of part 2 are not final yet and will be 58 presented at the EACPT meeting. 122 59 standard doses of agomelatine for the treatment of mild and moder- 123 ate severity depressive disorders in cardiology practice in Russia in Conclusions: 2B3-201 at doses up to 450 mg was considered safe. 60 2B3-201 shows a long plasma half-life (23h) and immunosuppressive 124 61 combination with preparations for the treatment of AMI. 125 Material and Methods: The study included 196 patients of both effects. This supports development of 2B3-201 as a safe treatment 62 of acute relapses in MS. 126 63 sexes (mean age 64.2 ± 0.8 years). The patients with AMI without 127 64 128

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1 Pharmacokinetics and Pharmacodynamic was fairly constant within each patient. There was no rise in peak 65 2 dosage adaptation of cefaclor in anti-Xa activity on day 3 and 5 after consecutive administration. 66 3 systemic infections Conclusions: Prophylactic dosages of nadroparin showed no accu- 67 2 4 A. Tomas; O. Horvat; M.P. Kusturica; N. Pavlović ; B. Milijašević ; mulation in patients with a GFR between 30–50 mL/min/1.73 m . 68 5 Z. Tomić ; and A. Sabo Dose reduction in this group could lead to suboptimal thrombo- 69 6 Medical faculty, University of Novi Sad, Serbia prophylaxis. Due to underrepresentation of patients with GFR < 30 70 2 7 Background: Cefaclor was one of the commonly used antimicrobi- mL/min/1.73 m (n = 2) we cannot give recommendations for this 71 8 als in Serbia, but due to fast development of resistance, other oral group. 72 9 cephalosporins rapidly upstaged cefaclor and cefaclor was removed 73 10 from the list of the drugs reimbursed by the National Health 74 11 Insurance Fund. Use of recommended dosing regimen (250-500mg/8- Possibilities of optimization of 75 12 12h) is likely to result in sub-therapeutic concentrations for a wide statin Therapy based on genotyping 76 13 portion of dosing interval due to short half-life of cefaclor, which SLCO1B1 and CYP2C9 at patients with 77 14 may facilitate development of resistance. The aim of this study was Cardiovascular disease 78 15 to determine adequate dosing interval for cefaclor in treatment of sys- A.M. Sirotkina; A.A. Khokhlov; E.A. Voronina; and D.A. Sychev 79 16 temic infections using Pharmacokinetic (PK) and pharmacodznamic 1Yaroslavl State Medical University, Yaroslavl, Russia; and 80 17 (PD) parameters with special regard to postantibiotic effect (PAE). 2Russian Medical Academy of Postgraduate Education, Moscow, 81 18 Material and Methods: PK profile of cefaclor in healthy volunteers Russia 82 19 and PK/PD indices relating to efficacy of cephalosporins were deter- Introduction: The individual mode of drugs dispensing on the 83 20 mined, as well as minimum inhibitory concentration (MIC) and PAE basis of genotyping can promote more effective and safe therapy. 84 21 85 of cefaclor on 4 susceptible bacteria. Frequency of detection of gene polymorphism of SLCO1B1(TC + 22 86 Results: Cmax of 23.142 ± 5.67 µg/mL was measured after 40-60 CC) in Russia is between 30 and 45%. Identification of carriers 23 87 minutes. Tmax was 0.72 ± 0.13 hours. Calculated AUC(0-t) was 29.148 pathological C-allele allows personalized approach to drugs selec- 24 ± 9.27 µg/mL/h. MICs were in range of 1-2 µg/mL. Cefaclor induced tion and the mode of its dispensing. The isoenzyme of cytochrome 88 25 PAE of 1-2h. There was inconsistency between standard dosing regi- P-450 (CYP2C9) is responsible for a metabolism of many drugs. 89 26 men and PK/PD parameters. Main PK/PD index relating to efficacy Genetic variability of CYP2C9*2/*3 in addition to SLCO1B1 can 90 27 of cephalosporins (%t> MIC) for the 750mg dose was 33.5–42.1%. affect on pharmacokinetics of drugs. The aim was to determine the 81 28 PK/PD breakpoints for cefaclor were between 0.3-1µg/mL. Even the frequency of polymorphism of SLCO1B1, frequency of polymor- 92 29 maximum doze with standard dosing intervals is not appropriate for phisms of CYP2C9*2/*3 in carriers of C allele of the gene SLCO1B1 93 30 eradication of susceptible organisms. Short PAE can’t compensate in group of patients with dyslipidemia, to identify the prevalence of 94 31 for sub-inhibitory concentrations at the half of the dosing interval. polymorphisms of several genes of one patient. 95 32 Conclusions: In reference to PK/PD parameters cefaclor should be Material and Methods: DNA of 604 patients at the age of 52.2 ± 96 33 administered every 6h for the doses of 500mg and 750mg, and every 11.9 years (353 men, 251 women) with a dyslipidemia were analysed. 97 34 4-4.5h for the 250mg dose in order to maximize its therapeutic effi- Results: Polymorphism of SLCO1B1(TC/CC) was detected in 98 35 99 cacy and minimize development of resistance. DNA of 202 patients (33.4%). ТС: 177 (29.3%). СС: 25 (4.1%). 36 100 This work was supported by the Ministry of Science and Carriers of C allele had SLCO1B1 genotyping of CУP2C9*2/*3. 37 101 Technological development, Republic of Serbia, project No III 41012. Polymorphism of CУP2C9*2(СТ/ТТ) was detected in DNA of 17 38 102 patients (15%). СТ: 13 (11.5%), ТТ: 4 (3.5%). Polymorphism of 39 103 CУP2C9*3(АС) in DNA of 15 patients (13.3%). The structure of 40 No Accumulation of a high Prophylactic occurrence of polymorphism of the studied genes was analysed: 104 41 105 Nadroparin dosage in Patients with 1 patient had polymorphisms of SLCO1B1(СС) + CУP2C9*2(ТТ), 42 106 moderate renal insufficiency assessed by 2 patient – heterozygote of SLCO1B1(ТС+СС) and CУP2C9*2/*3 43 107 peak Anti-XA activity (АС +СТ). 44 108 F. Atiq; P.M.L.A. van den Bemt; F.W.G. Leebeek; T. van Gelder; Conclusions: In the studied population of patients with dyslipidemia 45 109 and J. Versmissen a significant number of polymorphism of SLCO1B1 was founded, 46 110 Erasmus Medical Center, Rotterdam, The Netherlands that may interfere a profile of safety of statins. Prevalence of poly- 47 111 Introduction: Low-molecular weight heparins (LMWHs) have been morphism of CYP2C9*2/*3 is also important. Early detection of 48 112 shown to accumulate in patients with renal insufficiency, especially polymorphisms in several genes involved in the biotransformation 49 113 in therapeutic dosages. However, no appropriate studies have been of drugs in DNA of one patient with polymorbidity pathology can 50 114 conducted for prophylactic dosages of nadroparin. As a consequence, predict the risk of adverse side effects. 51 115 dose reduction is often recommended especially in high prophylactic 52 116 dosages. We assessed accumulation of a high prophylactic dosage of 53 117 nadroparin in patients with renal insufficiency. 54 Does Polypharmacy in Elderly Patients 118 Materials and Methods: We conducted a prospective cohort study 55 with heart failure influence Mortality 119 and measured peak anti-Xa activity 4 hours after subcutaneous 56 and Hospitalisation? 120 nadroparin injection on day 1, 3, 5 and if possible day 10 in adults 57 M. Eijsink; M. Zeeman; J. van Wijngaarden; E. Badings; and 121 with and without renal insufficiency defined as a glomerular filtration 58 E. van’t Riet 122 rate (GFR) below or above 50 mL/min/1.73 m2. Patients with a GFR 59 Deventer Hospital, Deventer, The Netherlands 123 below 10 ml/min/1.73 m2 were excluded. 60 Background: The incidence of heart failure among the elderly is 124 Results: We included 14 patients in each group. In the group with renal 61 increasing. Ageing is often accompanied with comorbidity and there- 125 failure 12 patients had a GFR between 30 and 50 mL/min/1.73 m2. 62 fore patients often face polypharmacy. Whether polypharmacy is 126 Peak anti-Xa activity showed a high interindividual variability, but 63 related to any adverse outcome is unknown. We performed a study 127 64 128

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1 to identify the incidence, extent and effects of polypharmacy among higher costs of care were recorded in mAb-treated group in other 65 2 the elderly with heart failure. domains, such as hospital admission. More selective reimbursement 66 3 Material and Methods: In this retrospective cohort study of an out- criteria should be applied in order to decrease costs related to effec- 67 4 patient heart failure clinic, 114 elderly patients (> 65 years) with tiveness of targeted oncology agents. 68 5 heart failure with a reduced ejection fraction (< 40%) were analysed. 69 6 During a one year follow-up all adverse events were recorded. The 70 7 relationship between the amount of prescriptions and adverse out- Coenzyme Q10 levels in Patients on 71 8 comes was analysed. low dose statins in relation to their 72 9 Results: Of all heart failure patients 85% had polypharmacy (i.e. Therapeutic and adverse effects 73 10 ≥ 5 prescriptions). In 35% of all patients an adverse event occurred, K. Zagorodnikova 74 11 either death (10%) or hospitalisation (90%). Statistical analysis North-western State Medical University n.a.I.I.Mechnikov, 75 12 showed that patients with 10 or more prescriptions had a higher risk Saint-Petersburg, Russia 76 13 of developing an event compared to patients with 6 or less prescrip- Background: Ubiquinone (Q10) has been related to statin-induced 77 14 tions. This risk was no longer significant when corrected for known myopathy and was shown to decrease during treatment. In our pro- 78 15 predictors of adverse outcome in heart failure, such as NT-proBNP, spective study we evaluated these effects in patients on low-dose 79 16 anemia, COPD or NYHA-classification. statin treatment. 80 17 Conclusion: Polypharmacy occurs in a large majority (85%) of Material and Methods: Eighty-two patients with dyslipidemia were 81 18 elderly patients with heart failure. Patients with 10 or more pre- prospectively recruited. All received initial simvastatin (same brand 82 19 scriptions have a higher risk of developing an event within one name) 20 mg/day and were followed up every 2 weeks of treatment 83 20 year. However, when corrected for NT-proBNP, anemia, COPD and during 1 or 2 months. The following parameters were analysed at 84 21 HYHA-classification, this effect was not statistically significant. In each visit: total cholesterol, LDL, HDL, creatine kinase (CK) and 85 22 our heart failure population, the severity of heart failure seems to be total Q10 (HPLC). Daily cholesterol intake was calculated based on 86 23 more important to predict an adverse event. reported diet, muscular pain symptoms were recorded. 87 24 Key words: polypharmacy, elderly, heart failure. Results: Total Q10 levels were evaluated in 30 patients. Cholesterol 88 25 intake was stable over the time of observation. Mean initial Q10 levels 89 26 were 350 ± 180 ng/mL. Significant decrease was observed after first two 90 27 81 Real-life costs and cost-effectiveness weeks of treatment (270 ± 160 ng/mL, P < 0.05), and was more pro- 28 92 of different treatment protocols of found at week 4 (260 ± 120 ng/mL, P < 0.005), while at week 6 tended 29 metastatic colorectal Cancer in Five-Year to increase and was not significantly different from initial values (280 ± 93 30 Period 150 ng/mL). Initial Q10 levels did not correlate with baseline LDL values, 94 31 A. Kovacevic1; V. Dragojevic-Simic1; D. Tarabar1; N. Rancic1; but tended to correlate with LDL levels on the 2nd week of treatment 95 32 1 1 2 96 N. Jacimovic ; J. Katic ; and M. Jakovljevic (Spearman r = 0.5, P = 0.06). Second week Q10 levels correlated with 33 1 2 97 Military Medical Academy, Belgrade, Serbia; and Faculty of corresponding LDL (Spearman r = 0.52, P < 0.05), there was no cor- 34 Medical Sciences, University of Kragujevac, Kragujevac, Serbia relation of Q10 and LDL levels at weeks 4 and 6. Despite no muscular 98 35 Background and Introduction: Aim of this study was to define and symptoms reported, we observed increase in CK levels at weeks 2 (113 ± 99 36 100 quantify structure of real-life costs of oncology treatment in patients with 69 U/L vs 92 ± 43 U/L, P = 0.008), and 4 (123 ± 92 U/L, P < 0.005). 37 metastatic colorectal cancer (mCRC), during five-year survival period. No significant correlation between Q10 and CK levels was observed. 101 38 Material and Methods: Retrospective randomized case series and Conclusions: Significant decrease in Q10 levels and increased CK 102 39 cost analysis study of mCRC treatment protocols has been done, was observed even with low-dose statin treatment. As expected, Q10 103 40 using hard copies of patients’ files from the university hospital. levels were in good correlation with statin effects expressed in LDL 104 41 Sixty-two patients with mCRC with clinical, histological, imaging decrease. Correlation of Q10 and CK levels, however, were not so 105 42 and laboratory conformation were randomly selected and divided obvious, although the sample size was small. 106 43 based on cytotoxic protocols used (conventional chemotherapy vs. 107 44 chemotherapy with monoclonal antibodies (mAbs - 108 45 or ) added. Costs comprised pharmaceuticals, laboratory 109 46 The vascular functional remodelling 110 analyses, physicians’ services and hospital admission, were presented Age-related between the Thoracic and 47 as mean ± standard deviation (95% CI for mean) and percentage. 111 48 Abdominal Aorta is Heterogeneous 112 Long-term survival estimates were calculated using the Kaplan-Meier 1 1,2 2 1 1 49 T. Pérez ; A. Ruiz ; L. Manuel ; C. Castillo ; and A. Alatorre 113 method and for calculation of incremental cost-effectiveness ratio 1 2 50 Escuela Superior de Medicina, IPN, México; D.F.; and Unidad 114 (ICER) between two groups, estimated survival in five-year period de Alta Especialidad Centro Médico Siglo XXI, México, D.F. 51 and average costs of treatment of each group were used. 115 52 Vascular beds undergo continuous functional remodelling of the ele- 116 Results: Total direct medical costs reached € 5,137 (€ 3,758–€ 6,517) ments of the vascular wall and adaptative changes that observed in 53 (pharmaceutical costs share amounted 82% of total costs) and 117 54 this process. Functional remodelling is heterogeneous. The aorta is 118 € 22,113 (€ 16,201–€ 28,025) (pharmaceutical costs 93.24%) for con- 55 considered that structural and functionally homogenous along their 119 ventional treatment and with mAbs added, respectively. Statistically different segments. However, the magnitude of mechanical stress is 56 insignificant difference in terms of overall survival between the two 120 57 not uniform between aorta segments. In this way, was tested that 121 treatment groups was shown (P = 0.993), but in terms of five-year whether functional remodelling age-related is the character heterog- 58 survival period, mAbs-based treatment group showed six months 122 59 enous on thoracic and abdominal aorta of rat. 123 longer survival on average. ICER of € 32,108 per life year gained 60 Methods and Results: We studied In vitro experiments that func- 124 attributable to mAbs treatment exceeds by three-fold informal will- tional remodelling is heterogeneous in endothelium intact thoracic and 61 ingness to pay threshold of Serbia. 125 62 abdominal aortic rings from rats of 3 and 6 month-old. The concentra- 126 Conclusions: Costs for mCRC were driven by targeted biologicals, tion response curves to Ach, Phe and AngII were similar in thoracic 63 with rather modest impact on survival period. Also, significantly 127 64 rings (Fig. 1B-C-D). In abdominal rings the relaxation induced by Ach 128

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1 was impaired (Fig. 1E) and this was related with reduction on functional and appropriate clinical management of these serious life-threatening 65 2 endothelium cell (Fig. 1A) also the contraction curves to Phe (did not AEs may optimize clinical outcomes reducing morbidity and mortal- 66 3 to AngII) it was lower in rats of 6mo old (Fig. 1F-G). The reduction of ity in cancer patients. 67 4 relaxation with LNAME in abdominal rings of 3mo old was to simi- 68 5 lar that rings of 6mo old without LNAME (Fig. 2B). The endothelial 69 6 influence on Phe induced contractions in young rats were completely Anti-EGFR monoclonal antibodies and 70 7 blocked by LNAME in the aorta with any differences between groups. risk of severe Haematological adverse 71 8 Conclusion: events in Cancer Patients: a systematic 72 9 – The decrease of NO in response to agonist is counteract with review and meta-analysis 73 10 the apparently desensitization of contractile response by Phe at M. Miroddi1; P. Pellegrino2; C. Sterrantino1; L. Caridi1; A. Rollo3; 74 11 abdominal level. C. Perrotta2; G. Calapai1; S. Radice2; and E. Clementi2,4 75 12 – The increased of sensitivity to Phe in thoracic and abdominal 1Policlinico “G. Martino”, University of Messina, Messina, Italy; 76 13 rings with LNAME to confirm the critical role of endothelium in 2University Hospital “Luigi Sacco”, University of Milan, Milan, 77 14 the regulation of smooth muscle tone by releasing NO under basal Italy; 3University of Verona, Verona, Italy; and 4Scientific Institute, 78 15 conditions. IRCCS E. Medea, Lecco, Italy 79 16 – We demonstrated relevant changes heterogeneous age-related Background: Cetuximab and have been proven to 80 17 in the functional remodelling that impact importantly the abdominal be effective in several randomised clinical trials (RCTs) and are now 81 18 aorta without changes of thoracic aorta. This heterogeneous remodel- widely used in oncology. The occurrence of severe haematological 82 19 ling could be explain, at least part, for differences between mechani- adverse events (AEs) is a common finding in patients receiving chemo- 83 20 cal stress that have influence along by aorta. therapeutic agents. This makes it difficult to discern between the 84 21 effects of these monoclonal antibodies (MoAbs) and the effects of the 85 22 backbone regimen. A possible way to tackle this issue is to summarise 86 23 Anti-EGFR monoclonal antibodies the growing amount of evidences from RCTs comparing these MoAbs 87 24 increase the risk of Pulmonary Embolism plus backbone therapy with backbone therapy alone. 88 25 in Cancer Patients. a systematic review Methods: PubMed, Embase, Web of Science and CENTRAL data- 89 26 and meta-analysis bases were searched for articles published until 1st October 2014. 90 27 M. Miroddi1; C. Sterrantino1; V. Conti2; A. Rollo3; and Eligible studies included prospective randomized phase II and III 81 28 G. Calapai1 trials comparing anti-EGFR containing regimens with the same 92 29 1Policlinico “G. Martino”, University of Messina, Messina, Italy; regimens without anti-EGFR to treat cancer. Data on haematologi- 93 30 2Regional Centre for Pharmacovigilance, Lombardy, Milan, Italy; cal toxicities were extracted. Cochrane Risk of Bias assessment was 94 31 and 3University of Verona, Verona, Italy performed. Statistical analyses calculated the summary incidence of 95 32 Background: Cancer patients have a thrombophilic condition predis- AEs, relative risks (RRs) and 95% confidence intervals (CIs) by using 96 33 posing to thromboembolic events such as pulmonary embolism (PE); either random effects or fixed effect models on the basis of the het- 97 34 in addition, drug-exposure can increase this risk. Anti-Epidermal erogeneity of the included studies. 98 35 Monoclonal Antibodies (anti-EGFR Results: A total population of 19,143 patients from 32 ran- 99 36 MoAbs), Cetuximab and Panitumumab, are beneficial in the treat- domised clinical trials was analysed. No significant increase in the 100 37 ment of various malignancies, but are burdened by severe and life- risk of severe neutropaenia or thrombocytopaenia was found, but 101 38 threatening harms including PE. We conducted a systematic review we observed a statistically significant risk increase (RR, 1.73; CI, 102 39 and meta-analysis in order to determine the incidence and the risk of 1.16 –2.57) for anaemia in colorectal cancer patients, with an inci- 103 40 PE associated with Cetuximab and Panitumumab. dence of 3.3% (95% CI, 1.5–5.1%) in the experimental arm and 104 41 Material and Methods: Medline, Embase, Web of Science, 1.6% (95% CI, 0.5–2.7%) in the control arm. 105 42 CENTRAL databases were searched for articles published until Conclusions: We present the first systematised evidence suggesting 106 43 October 2014. Eligible studies were randomized phase II and III that Panitumumab treatment is not associated with a significant 107 44 trials comparing anti-EGFR MoAbs containing regimens with the increase in the risk of neutropaenia. Our analysis also indicates the 108 45 same regimens without anti-EGFR to treat cancer. Pooled estimates absence of an increased risk of any haematological toxicity following 109 46 of summary incidence of severe and life-threatening AEs, RRs and the administration of anti-EGFR MoAbs, with the only exception of 110 47 95% confidence intervals (CIs) were calculated using random effects anaemia among colorectal cancer patients. 111 48 model. Heterogeneity among studies was however investigated visu- 112 49 ally and using I-squared statistics. We re-expressed RR in Number 113 50 Needed to Treat to Harm (NNTH). Subgroup analysis according to 114 51 Anti-EGFR monoclonal Antibodies 115 anti-EGFR agent was performed. Study quality was assessed using increase the risk of severe 52 Cochrane Risk of Bias Tool. 116 53 Gastrointestinal adverse events in 117 Results: Bibliographic search provided 6,777 records, after a selec- Cancer Patients: a systematic review and 54 tion process 6 articles were eligible. A total number of 6,773 patients 118 55 meta-analysis 119 were considered in our analysis. Patients receiving anti-EGFR MoAbs 1 1 2 1 2 56 C. Sterrantino ; M. Miroddi ; V. Conti ; L. Caridi ; M. Venegoni ; 120 had a significantly increased risk of severe PE (RR, 1.56; 95%, CI 1 57 and G. Calapai 121 1.20–2.04) and an incidence of 4.3% (95% CI, 2.7–6.0%) vs 2.7% 1 58 Policlinico “G. Martino”, University of Messina, Messina, Italy; 122 (95% CI, 1.6–3.8%). NNTH was 63 (95% CI, 35–173). Statistical and 2Regional Centre for Pharmacovigilance, Lombardy, Milan, 59 heterogeneity was irrelevant (I² 0%). Subgroups analyses revealed 123 = Italy 60 no differences between Cetuximab and Panitumumab. Visual inspec- 124 Background: Cetuximab and Panitumumab have been proven to 61 tion of funnel-plot indicates no publication bias. 125 be effective in several randomised clinical trials (RCTs) and are now 62 Conclusions: The addition of anti-EGFR MoAbs to backbone ther- 126 widely used in oncology. The risk of severe gastrointestinal adverse 63 apy increased the risk of PE by the 56%. Prevention, early recognition 127 64 events (AEs) seems to be increased by the addition of these agents. 128

2015 e9 Clinical Therapeutics

1 Diarrhea and mucositis are two of the most common AEs in patients observed in 8 (16%) of all patients, none in NRF, 3(45%) in NTRF 65 2 receiving chemotherapy, thus it is difficult to discern between the and 5 (25%) in RR groups. In 19 (39%) of cases, all NTRF, recom- 66 3 gastrointestinal effects of these monoclonal antibodies and the effects mended dosing regimens were not adequately followed. Regimen 67 4 of the backbone regime. A possible approach to tackle this issue is to non-compliance correlated with higher vancomycin TL (r = −0.3; 68 5 summarise the growing amount of evidences from RCTs comparing P < 0.05). In patients with TL < 5 μ g/mL five (26%) died of the 69 6 these MoAbs plus backbone therapy with backbone therapy alone. treated infection, in contrast to no patients with vancomycin TL > 5 70 2 7 Methods: PubMed, Embase, Web of Science and CENTRAL data- μ g/mL (χ , P < 0.05). 71 8 bases were searched for articles published until 1st October 2014. Conclusions: Vancomycin concentrations were far too low to 72 9 Eligible studies included prospective randomized phase II and III be effective in most routinely treated patients. Higher concentra- 73 10 trials comparing a chemotherapeutic regimen with the same regi- tions were mainly due to dosing regimen non-compliance. Higher 74 11 men associated with an anti-EGFR monoclonal antibody. Data on frequency of infectious deaths was noted in patients with low 75 12 haematological toxicities were extracted. Study quality was assessed vancomycin levels, although there might be other confounding fac- 76 13 using Cochrane Risk of Bias Tool. Pooled estimates of summary inci- tors involved. 77 14 dence of AEs, Relative Risks (RRs) and 95% confidence intervals 78 15 (CIs) were calculated using random effects model. Heterogeneity 79 16 among studies was however investigated visually and using I-squared Effect of Cerebrolysin on the stress 80 17 statistics. response and Cytoarchitecture of 81 18 Results: A total number of 18,260 patients from 28 clinical studies medium spiny neurons of the Nucleus 82 19 were analysed. Patients receiving regimens containing anti-EGFR accumbens in Rats prenatally exposed to 83 20 MoAbs has a significantly increased risk of severe diarrhea (RR, Valproic Acid 84 21 1.68; 95% CI, 1.55 to 1.85) and mucositis (RR, 2.53; 95% CI, 1.58 M.A. Maximino-Rojas1; M.E. Bringas1,2; E. Carrillo1; C. Jarquín1; 85 22 to 4.06). Incidences are reported in Table 1. For mucositis outcome and G. Flores1 86 23 Egger’s test as well as visual inspection of funnel-plot could not 1Benemérita Universidad Autónoma of Puebla, Puebla, Mexico; 87 24 exclude presence of publication bias (P < 0.01). and 2Instituto Politécnico Nacional, México, D.F. 88 25 Conclusions: The addition of anti-EGFR MoAbs to therapeutic Autism Spectrum Disorders (ASD) is characterized by a neurodevel- 89 26 regimens is associated with an increased risk of severe diarrhea and opmental disorders in general, neuronal communication excess with 90 27 mucositis. Patient awareness, prevention, early recognition and implications for social behavior. Valproic acid (VPA) is a histone 81 28 appropriate clinical management of these severe AEs may optimize deacetylase blocker, with effects on the enzymes involved GABA syn- 92 29 clinical outcomes. thesis and degradation, which has been widely used in the treatment 93 30 Table 1. of epilepsy. In recent decades it was observed that administration of 94 31 VPA during the gestation increases the risk of ASD. Therefore, it has 95 32 Incidence (CI 95%) been proposed as a model for understanding the ASD. Cerebrolysin 96 33 is a preparation of derived from porcine brain, which has 97 34 Anti-EGFR arm Control arm shown a neurotrophic effects on the maintenance and remodeling of 98 35 neuronal cytoarchitecture. 99 36 Diarrhea 13.2% (10.1 to 16.3%) 7.2% (5.4 to 8.9%) 100 Mucositis 8.0% (5.2 to 10.8%) 3.9% (2.3 to 5.5%) To reproduce the model of autism we using a single dose of 37 500 mg/kg of VPA or Solution saline (SS) at 12.5 day of gestation in 101 38 pregnant rats Sprague-Dawley (SD) strain. For experimental purposes 102 39 we used male offspring which were administered with cerebrolysin at 103 40 Problems related to the use of old days 5–21 of postnatal age (PA). They were divided in two groups: 104 41 Vancomycin dosing regimens in routine Control and VPA; at 21PA and 70PA, we evaluated the response to 105 42 healthcare stress in a novel environment, after with Golgi- Cox staining the 106 43 107 M.A. Kostitcyna; and K.A. Zagorodnikova morphology of medium spiny neurons of the nucleus accumbens 44 108 North-Western State Medical University n.a. I.I. Mechnikov, was analyzed. 45 109 Saint-Petersburg, Russia The results suggest that in the 21PA group present changes in the 46 110 Introduction: Non-individualized vancomycin dosing regimens con- neuronal cytoarchitecture that are not observed in the 70PA group, 47 111 tained in drug information leaflets are still routinely used in most suggesting that the neurotrophic effects of cerebrolysin is not present 48 112 hospitals in Russia, while individual concentrations vary and recent the long term. 49 113 studies recommend higher concentrations of 15-20 μ g/mL to achieve 50 114 therapeutic goals. Our aim was to evaluate vancomycin concentra- 51 115 tions achieved in clinical routine. 52 Eocular Pharmacokinetics of 116 Material and Methods: Forty-eight patients who received van- 53 Ciprofloxacin eye drops assessed with 117 comycin based on clinical indications were enrolled to the study. 54 in-vivo microdialysis in a Rabbit model 118 Twenty one had normal renal function (NRF), seven – non-terminal 1 1 1 2 55 D. Schmidl ; G. Garhöfer ; R. Klaus ; A. Maier-Salamon ; 119 stage renal failure (NTRF), twenty were on renal replacement (RR). 2 1 1 56 W. Jäger ; M. Zeitlinger ; and L. Schmetterer 120 Trough levels (TL) of vancomycin were evaluated at steady state, 1 2 57 Medical University of Vienna, Vienna, Austria; and University of 121 concentrations were measured by HPLC. 58 Vienna, Vienna, Austria 122 Results: Concentrations < 5 μ g/mL were observed in 19 (40%) of 59 Background: Topical drug delivery is the most widely used drug 123 all cases, 11 (52%) of NRF patients, 1 of NTRF and 7 (35%) of 60 administration route for the treatment of ocular diseases. Studies 124 patients on RR. Concentrations of 5-10 μ g/mL were observed in 15 61 investigating the intraocular in-vivo pharmacokinetics of topically 125 (31%) of all cases, 8 (38%) in NRF, 1 in NTRF and 6 (30%) in RR 62 administered drugs are sparse due to the technically demanding 126 groups. Concentrations of 10-15 μ g/mL were observed in 6 (12%) 63 nature of the required procedures. In the present study, we set out to 127 cases, two cases in each group. Concentrations of 15-20 μ g/mL were 64 assess an in-vivo pharmacokinetic profile of the widely used topical 128

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1 antibiotic ciprofloxacin. Therefore, in-vivo microdialysis was used and administrative interventions may be required to improve quality 65 2 to assess pharmacokinetics of the anterior chamber and the vitreous of prescribing in pregnant women. 66 3 in a rabbit model after topical instillation of the drug. 67 4 Material and Methods: After approval by the animal welfare and 68 5 Ethics Review Committee, 8 female New Zealand White rabbits Diffuse Hepatic changes caused by oral 69 6 (Charles River, Germany) weighing 2.3–4.1kg were included. All contraceptives 70 7 experiments were performed under general anesthesia, A linear J. Joaquim1; A. André2; V. Justino1; T. Pires1; C. Matos1; and 71 8 microdialysis probe (30 kDa molecular weight cut off [MWCO]) M. Rocha3 72 9 was implanted in the anterior chamber and a concentric microdialy- 1Instituto Politécnico de Coimbra, Coimbra Health School – 73 10 sis probe (0.5×10 mm, 20 kDa MWCO) in the vitreous of the same ESTESC, Farmácia, Coimbra, Portugal; 2Instituto Politécnico de 74 11 eye. One single drop (30 µL) of ciprofloxacin eye drops (0.09 mg in Coimbra, Coimbra Health School – ESTESC, Imagem Médica 75 12 30 µL) was administered on the ocular surface after a run-in period e Radioterapia, Coimbra, Portugal; and 3Instituto Politécnico 76 13 of 2 hours. Microdialysis samples were collected every 30min for 6h. de Coimbra, Coimbra Health School – ESTESC, Ciências 77 14 Relative recovery was assessed by retro-dialysis to calculate absolute Complementares, Coimbra, Portugal 78 15 concentration values. Samples were analyzed using HPCL. Background: Oral contraceptives (OCs) consumption has grown and 79 16 Results: After single administration of ciprofloxacin, the maximum is one of the most consumed pharmacologic groups in the world. 80 17 free drug concentration (C ) was 0.373 ± 0.218 µg/mL in the ante- 81 max Ethinyl Estradiol (EE) is the most commonly used as a component 18 rior chamber and was reached (T ) after 116 ± 36 min. Calculated 82 max of OCs and hormonal replacement therapy (HRT). In women its 19 AUC in the anterior chamber was 78.8 ± 47.1µg min/mL. In the 83 (0-n) excessive and prolonged use may cause organ toxicity. The aim was 20 vitreous, C was 2.2 ± 2.5 ng/mL and maximum drug concentration 84 max to assess women that consume OCs, using ultrasound (US) exami- 21 was reached 106 ± 60 min after drug administration. AUC for 85 (0-n) nations in the liver and kidney, to highlight diffuse alterations and ciprofloxacin in the vitreous was 0.268 ± 0.370 µg min/mL. 22 density changes. 86 Conclusion: Microdialysis is a suitable method to assess in-vivo 23 Material and Methods: The US abdominal examinations were per- 87 pharmacokinetics in the rabbit’s eye. In the anterior chamber, the 24 formed using a GE®, LOGIQe®, with a 5 MHz probe. Were included 88 25 maximum concentration of ciprofloxacin was reached approximately 89 46 fertile women in the study group and 28 in the control group (n = 26 2h after single drug administration. In the vitreous, drug concen- 74), who agreed to participate under informed consent, aged 18-50 90 27 tration was considerably lower, although the time course of drug years. All women underwent an abdominal evaluation and the image 81 28 concentration was comparable. acquisitions were made in the right liver lobe and right kidney. To 92 29 evaluate the hepatic diffuse alterations, was used as imaging program, 93 30 ImageJ, with a region of interest, 18×18. 94 31 Choice of medications for Nausea and Results: The individuals has a mean age of 27.95 ±10.60 years and 95 32 Vomiting among Russian Gynecologists a mean of body mass index (BMI) of 22.56 kg/m2 ± 3.73. The group 96 33 97 M. Pokladova; A. Burbello; and K. Zagorodnikova using the 3rd generation pills is 56.51% (n = 26) and the 4th gen- 34 98 North-Western State Medical University n.a. I.I. Mechnikov, eration is 43.5% (n = 20) of the sample. Related to the density was 35 Saint-Petersburg, Russia observed that the third generation group have a higher density mean 99 36 Introduction: During pregnancy, many women experience nausea in relation to the other groups. It wasn’t found any relevant change 100 37 and vomiting. Frequency of medications use is high in many countries concerning to the duration of use neither to the progestin generation. 101 38 including Russia. At the same time excessive fears of medications- Conclusion: With the use of Ultra Sound and image program it was 102 39 related risks may influence choice of remedies to treat pregnant possible to confirm the variations in density between the different 103 40 patients. Official registration status may also play a role, since many groups. The excessive estrogen caught in different tissues (liver, 104 41 medications, like doxylamine, approved for treatment of nausea and uterus, ovary) can cause an abnormal growth or tissue damage. 105 42 vomiting in pregnancy in many countries, is officially contraindicated Concerning to the generation of OC, this study can conclude that 106 43 for this category of patients in Russia. In an ongoing study we aim the fourth generation of EE is safer than the third. 107 44 to analyze choice of medications to treat various diseases and states 108 45 among gynecologists in Russia. 109 46 110 Material and Methods: In an ongoing study anonymous question- The pattern of Drug consumption during 47 naires are distributed among practicing gynaecologists. The ques- 111 48 Pregnancy 112 tionnaire contains questions related to the selection and timing of 1 1 1 1 2 49 J. Moço ; J. Joaquim ; C. Matos ; T. Pires ; M. Rocha ; and 113 medications for the treatment of common diseases and states in preg- 1 50 J. Lopes 114 nant women. Currently presented data are based on 39 question- 1 51 Instituto Politécnico de Coimbra, Coimbra Health School – 115 naires and related to the treatment of nausea and vomiting. ESTESC, Farmácia, Coimbra, Portugal; and 2Instituto Politécnico 52 Results: For the treatment of nausea and vomiting most doctors - 26 116 53 de Coimbra, Coimbra Health School – ESTESC, Ciências 117 (67%) - preferred artichoke leaf extract, 16 (41%) indicated metoclo- Complementares, Coimbra, Portugal 54 pramide as a preferred option, 10 (26%) - essential phospholipids, 9 118 55 Background: Medical prescription during pregnancy has increased 119 (23%) – ademethionine, and 3 (8%) preferred homeopathic remedies. significantly/greatly in the last few years and nowadays it has become 56 Most of these medications, except metoclopramide, have major indi- 120 57 a matter of major importance. It can be proved that only a small 121 cations related to liver diseases, and not to nausea and vomiting itself, proportion of medicines are known to be secure for the fetus and 58 but their official registration status allows their use in pregnancy. 122 59 for the pregnant and the inappropriate medicine consumption may 123 Conclusions: In this pilot study we observed that gynecologists in cause severe and deep teratogenic changes/alterations. The aim of 60 Russia infrequently recommend evidenced-based medications for 124 61 this study is to determine the level of knowledge about medicines 125 nausea and vomiting in pregnancy. This may partly be explained by and their consumption during pregnancy. 62 official registration status of medications. Both, education of doctors, 126 63 Material and Methods: This is an observational study using a 127 64 questionnaire to collect primary data. The data collection occurred 128

2015 e11 Clinical Therapeutics

1 through this questionnaire filled in a sample of pregnant women, who Joint bio-equivalence tests with 65 2 participated in the study under informed consent, and was carried multivariate Gaussian random effects 66 3 out among pregnant women monitored in a Maternity in the central H. An; J. Chung; K. Yu; and I. Jang 67 4 region of Portugal. 1Seoul National University, Seoul, Korea 68 5 Results: It is expected, from preliminary data and based in other Introduction: To compare pharmacokinetics between two drugs, 69 6 similar studies that from the sample of women enquired around 80% conventional bio-equivalence test used independent model for two 70 7 had received at least a medical prescription during pregnancy, being 71 responses, log-transformed Cmax and AUC. In spite of strong cor- 8 most of these medicines (15%) harmful to the fetus. Women who suf- 72 relation between Cmax and AUC, their models were treated as inde- 9 fer from chronic disease(s) are the major medicine consumers and this pendent. We considered this correlation structure so that the two 73 10 consumption is highly related to gestational symptoms relief. About 74 linear mixed models for log-transformed Cmax and log-transformed 11 60% of the pregnant have a mild level of knowledge on of medicine AUC are jointly fitted for estimating the 90% confidence intervals 75 12 use during pregnancy; there is also a statistic relationship between of treatment effects. 76 13 age, social class, education field, qualifications, wanted or unwanted Material and Methods: The three kinds of models, independent, 77 14 pregnancy, and first pregnancy or following, the third trimester of correlated joint, and shared random effects model, were separately 78 15 pregnancy and medicine use level. performed for the data of one-sequence, two-period pharmacokinetic 79 16 Conclusions: The study concluded that the consumption of harmful interaction study of Fimarsartan with Amlodipine (Yi et al. 2011).1 80 17 medicines to the fetus is still very common being frequently associated For log-transformed C y and log-transformed AUC y of the 81 max,ss 1ij τ,ss 2ij 18 with the lack of women’s knowledge and other social demographic i-th subject in the j-th period, the model was 82 19 factors, therefore leading to fetal malformations and the use of self- 83 20 medication without control. 84 21 85 22 86 23 87 Emergency contraception - study of 24 Consumption and Knowledge of the risks 88 25 where for independent model and for correlated 89 in Student Populations joint model. When we assumed v ·v (i.e. 1), then the model 26 1 1 1 1 2 2i = β3 1i ρ = 90 M. Reis ; J. Joaquim ; C. Matos ; T. Pires ; M. Rocha ; and referred to the shared random effect model. We assessed the goodness 27 1 81 J. Lopes of fit among the three models by conditional AIC which described 28 1 92 Instituto Politécnico de Coimbra, Coimbra Health School – the best model showed the smallest conditional AIC. 29 ESTESC, Farmácia, Coimbra, Portugal; and 2Instituto Politécnico 93 30 Results: We selected the shared random effects model as the final 94 de Coimbra, Coimbra Health School – ESTESC, Ciências model, which had the smallest conditional AIC, 86.09 (independent, 31 Complementares, Coimbra, Portugal 95 32 107.47; correlated joint, 92.50). The GMRs of (with/ 96 Background: According to World Health Organization, every year without Amlodipine) and 90% CI for C and AUC were 1.096 33 max,ss τ,ss 97 there are 200 million pregnancies which 75 million are unintended. (0.746–1.610) and 1.163 (1.001–1.351), respectively. On the other 34 Emergency contraception pills (ECP) is one of the available methods 98 hands, those for the shared random effects model β =0.603 were 35 who prevent an unintended pregnancy, after an unprotected sexual 3 99 36 1.096 (0.793–1.515) and 1.163 (1.013–1.336), respectively. 100 intercourse or contraceptive failure. In Portugal, ECP is available Conclusions: In general, there exists positive correlation between 37 over-the-counter, so becomes necessary assess the knowledge and 101 Cmax and AUC so that we should consider this correlation struc- 38 the consumption in students’ populations about this subject, and 102 39 ture when we analyse pharmacokinetic parameters including bio- 103 realize the reasons to use this emergency contraceptive method. The equivalence tests. After using shared random effects model, the 90% 40 purpose of this study was to quantify the consumption, characterize 104 confidence intervals of geometric mean ratios for maxC and AUC were 41 the level of knowledge and understand the factors that induce the 105 42 both slightly decreased in comparison with using independent model. 106 use Emergency Contraception Pills (ECP). 1. S. Yi et al. (2011) Pharmacokinetic interaction of Fimasartan, a 43 Material and Methods: This is an observational study using a ques- 107 44 new angiotensin II receptor antagonist, with amlodipine in healthy 108 tionnaire to collect primary data. This questionnaire will be admin- volunteers. J Cardiovasc Pharmacol., 57, pp. 682–689. 45 istered to two different samples, one of a group of secondary school 109 46 students with a population of 680 students and another from a high 110 47 school of education in Coimbra with a population of 1814 students. 111 48 Those students agree to participate under informed consent. Effect of mavoglurant (AFQ056) on 112 49 Results: It is expected, based on several studies and preliminary data, the Pharmacokinetics of a combined 113 50 oral contraceptive containing ethinyl 114 that the majority (> 75%) of students had heard about ECP. In terms 51 of consumption, the majority should be first-time users of ECP and estradiol and Levonorgestrel in healthy 115 52 in more than half of the situations the factors that lead the use ECP Women 116 53 R. Sivasubramanian1; A. Chakraborty2; M. Rouzade-Dominguez3; 117 was failure of the contraceptive used. The results also may indicate 1 3 4 3 54 young’s main information sources are friends, TV and Internet. S. Neelakantham ; A. Jakab ; T. Mensinga ; E. Legangneux ; 118 55 R. Woessner3; and M. Ufer3 119 Conclusions: In Portugal, ECP is available as over-the-counter which 1 56 facilitates its obtainment and without effective control. It is strongly Novartis Healthcare Private Limited, Hyderabad, India; 120 57 2Novartis Corporation, East Hanover, NJ, USA; 3Novartis 121 expected to find a low level of knowledge in these populations regard- 4 58 ing health and medicines issues. Students show to have a low level Pharma AG, Basel, Switzerland; and QPS Clinical Development, 122 59 of knowledge Due to the facilitation of available over-the-counter Groningen, The Netherlands 123 60 ECP in Portugal, the knowledge among students probably is high Background: Mavoglurant (AFQ056) is a structurally novel, 124 61 and its use is correct. selective metabotropic glutamate receptor 5 (mGluR5) antagonist 125 62 currently under clinical development. It is expected to normalize 126 63 127 64 128

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1 excessive glutamatergic signaling via mGluR5 that is believed to and inter-individual variability of EC50 which were poorly estimated 65 2 be associated with a variety of neurological and psychiatric dis- at low Hill coefficients. For the multiple dose studies, the parameter 66 3 eases. Given its early stage of clinical development, treatment with estimation performance was not good. 67 4 mavoglurant currently requires the use of contraceptive measures in Conclusions: This simulation study quantitatively demonstrated 68

5 women of childbearing potential. Contraception may additionally the effect of the relative range of sampled concentrations to EC50 69 6 be required as a consequence of other medicines used concomitantly and sigmoidicity on the PD parameter estimation performance using 70 7 in the envisioned target patient populations, e.g. antidepressants, dense sampling design. This study can be useful in designing a clinical 71 8 neuroleptics and anti-epileptics, some of which exhibit teratogenic study to evaluate PK/PD relationship for new drug development or 72 9 potential. This study was conducted to compare the pharmacokinet- drug repositioning. 73

10 ics (PKs) of a combination oral contraceptive (OC) when given alone Key words: sigmoid Emax Models, NONMEM, parameter estimation 74 11 or concomitantly with mavoglurant. performance, stochastic simulation and estimation, human pharma- 75 12 Methods: This phase I, open-label, fixed-sequence, two-period study cology, PK/PD relationship. 76 13 included 30 healthy female subjects aged 18–40 years. In Period 1, a 77 14 single oral dose of an OC containing 30 μ g ethinyl estradiol (EE)/150 μ g 78 15 levonorgestrel (LNG) was administered alone. In Period 2, the OC Effect of UGT1A1 and UGT1A3 79 16 was administered with a clinically relevant multiple dose of mavo- polymorphisms on Pharmacokinetics of 80 17 glurant (100 mg b.i.d.) under steady-state conditions. Plasma con- in Korean 81 18 centrations of EE and LNG were measured up to 72 hours post H.J. Shin1; J.-E. Kim1; S.J. Lim1; J.E. Seo2; M.H. Kim1; 82 19 administration. The maximum plasma concentration (C ) and 83 max O.K. Hoon1; H.S. Kim1; Md. Hasanuzzaman1; Md. M. Parvez1; 20 the area under the concentration-time curve up to last measurable D.-H. Kim1; and J.-G. Shin1,2 84 21 concentration (AUC ) were estimated using non-compartmental 85 last 1Inje University College of Medicine, Busan, Republic of Korea; 22 methods. and 2Inje University Busan Paik Hospital, Busan, Republic of 86 23 Results: The geometric mean ratios of EE C and AUC obtained 87 max last Korea 24 with and without mavoglurant were 0.97 (90% confidence interval Introduction: Telmisartan, an angiotensin II receptor blocker, is 88 25 [CI]: 0.90–1.06) and 0.94 (90% CI: 0.86–1.03), respectively. The cor- widely used for the treatment of hypertension and cardiovascular risk 89 26 responding C and AUC for LNG were 0.81 (90% CI: 0.75–0.87) 90 max last reduction. It is mainly metabolized by UDP-glucuronyltransferases 27 and 0.68 (90% CI: 0.63–0.73), respectively. (UGTs) and UGT1A3 is predominantly involved in the glucuronida- 81 28 Conclusions: EE PK was unchanged, whereas C and AUC of 92 max last tion of telmisartan. Clinical studies showed the large inter-individual 29 LNG were reduced by 19% and 32%, respectively, when given with variation in the exposure of telmisartan when orally administered. 93 30 mavoglurant. Further evaluation regarding the impact on contracep- The purpose of present study was to examine whether telmisartan 94 31 tive efficacy is warranted. exposure could be affected by genetic polymorphisms of UGTs and 95 32 drug transporters. 96 33 Material and Methods: The blood samples were collected from 91 97 34 Parameter estimation performance for healthy volunteers who participated in two independent trials of 98 35 99 sigmoid emax models in exposure-response clinical trials and genotyping were conducted in UGTs (UGT1A1 36 Relationship and UGT1A3) and drug transporters (SLCO1B3 and SLCO2B1). 100 37 Md. Hasanuzzaman; Md. Masud Parvez; S.E. Park; J.-L. Ghim; Results: After oral administration of 80 mg telmisartan, unexpect- 101 38 102 J.-G. Shin; and D.H. Lee edly the AUCinf in UGT1A1*28 and *60 carriers was significantly 39 1 103 Inje University College of Medicine, Busan, Republic of Korea; lower compared to volunteers with UGT1A1 wild type. (P = 0.0004, 40 2 104 and Inje University Busan Paik Hospital, Busan, Republic of P = 0.0002, respectively). Subpopulation analysis revealed that 41 Korea UGT1A1*28 non-carriers among volunteers with UGT1A1*60 also 105 42 106 Introduction: Drug exposures are not often high enough to estimate showed significantly lower exposure (P = 0.0038). Heterozygotes 43 maximum effect (E ) to avoid drug toxicity, bring about difficulties of UGT1A3*2 and UGT1A3*3 also showed significantly lower 107 44 max 108 in estimating unbiased and precise PD parameter estimates or inevi- AUCinf (P < 0.0001, P = 0.0195, respectively). Furthermore, strong 45 tably simplified models such as linear model and log-linear model. linkage disequilibrium were demonstrated; a decisive SNP (V47A) 109 46 2 110 The purpose of this simulation study is to investigate the accuracy of UGT1A3*2 and UGT1A1*28 (D’ = 0.945, r = 0.705), and 47 and precision of PD parameter estimates in PK/PD analysis under UGT1A1*60 and 3 coding regions which compose UGT1A3*2 or *3 111 48 2 112 different doses and Hill coefficients in case of dense PK sampling (D’ = 1, r = 0.371). The effects of UGT1A1*28 and UGT1A1*60 49 design in human pharmacology study. alleles on the pharmacokinetics of telmisartan were attributed to their 113 50 Materials and Methods: Seven escalating doses of virtual drugs with strong linkage with UGT1A3*2 which enhances UGT1A3 expression 114 51 equal potency and efficacy but with five different Hill coefficients and UGT1A3*3. 115 52 were used in simulations of single and multiple dose scenarios with Conclusions: Present study collectively indicates that UGT1A1*60 116 53 dense sampling design. A total of 70 scenarios with 100 subjects is one of determinant genetic factors resulting in inter-individual vari- 117 54 were simulated and estimated 100 times applying one compartment ations in pharmacokinetics of telmisartan. 118 55 119 PK model with first-order absorption and sigmoid Emax model using 56 SSE (Stochastic simulation and estimation) of PSN (Perl-speaks- 120 57 NONMEM) and first order conditional estimation with interaction 121 58 An assessment of the Pharnacokinetics 122 (FOCE-I) method in NONMEM (version 7.2).The bias and precision of DW1029M in Healthy Korean Subjects 59 of the parameter estimates in each scenario were assessed using rela- 123 J.-Y. Jeon1; Y.-J. Im1; E.-Y. Kim1; H.M. Wang1; Y. Kim1; 60 tive bias and relative root mean square error. 124 C.H. Liom2; and M.-G. Kim1 61 Results: For the single dose scenarios, most PD parameters of sig- 125 1Biomedical Research Institute, Chonbuk National University 62 moid E model were accurately and precisely estimated when the 126 max Hospital, Jeonju, Republic of Korea; and 2Project Team of 63 C was attained more than 85%of EC , except for typical value 127 64 max 50 Dongwha Pharm.Co., Ltd., Seoul, Republic of Korea 128

2015 e13 Clinical Therapeutics

1 Background: DW1029M is a botanical extract consisting of Puerariae 1Inje University College of Medicine, Busan, Republic of Korea; 65 2 radix and Mori Cortex, developed by Dongwha Pharmaceutical, for and 2Inje University Busan Paik Hospital, Busan, Republic of 66 3 treatment of diabetic nephropathy. The objective of this study was Korea 67 4 to explore the pharmacokinetics and safety of DW1029M following Background: Platelet aggregation and coagulation play a key role 68 5 single oral administration in healthy Korean subject. in cardiovascular disease. However, there was limited data about 69 6 Material and methods: Healthy male subjects were enrolled in ran- the effects of environmental and clinical factors on the basal platelet 70 7 domized, open-label, single dose, crossover phase I clinical study. aggregation and coagulation factors. 71 8 During each period, subjects received 300 mg, 600 mg or 1200 mg of Material and Methods: The adenosine diphosphate (ADP)-, ara- 72 9 DW1029M. Blood samples were collected at intervals from 0–24 h chidonic acid (AA)-, thrombin receptor activating peptide (TRAP)-, 73 10 after administration. Plasma concentrations of puerarin were analyzed collagen (COL)- and rictocetin (RISTO)-induced platelet aggrega- 74 11 using a liquid chromatography/tandem mass spectrometry method. tion were measured using Multiplate® in 140 healthy Korean sub- 75

12 Results: Six healthy male subjects completed the study. The Cmax and jects aged 20-81 years. Other factors related to platelet aggregation 76 13 AUClast for Puerarin was 3.17 ng/mL and 12.40 h*ng/mL in the 300 (P-selectin and Von Willebrand factor), coagulation factors (factor I, 77 14 mg of DW1029M, respectively. The Cmax and AUClast for Puerarin factor II, factor V, factor VII, and factor X), and anticoagulant fac- 78 15 was 4.45 ng/mL and 19.81 h*ng/mL in the 600 mg of DW1029M, tors (protein C, and protein S) were assessed, and the information on 79

16 respectively. The Cmax and AUClast for Puerarin was 5.76 ng/mL and drug/disease history, family history and social habit including drink- 80 17 30.47 h*ng/mL in the 1200 mg of DW1029M, respectively. There ing and smoking was obtained through a questionnaire. 81 18 was no serious adverse event. Results: Stratified by sex, 5 agents-induced platelet aggregation were 82 19 Conclusions: The DW1029M was safe and well tolerated over single increased aging up to 40-50s and then decreased in males (P = 0.0047 83 20 dose range of 300~1200 mg. In this study, the pharmacokinetics pro- for ADP; P = 0.0004 for AA; P = 0.0069 for COL; P = 0.0241 for 84 21 file of puerarin was assessed. This pharmacokinetic study of botanical RISTO). Coagulation factors showed similar trends in males (factor 85 22 drug may helpful in the development of DW1029M. II, P = 0.0021; factor V, P = 0.0142; factor X, P = 0.0042). Females 86 23 over 50 years old seemed to have lower the 5 agents-induced platelet 87 24 HLA-B*5101 Allele and Lamotrigine-induced aggregation than those younger than 50 years old did, especially by 88 25 stevens- Johnson sydrome in Korean AA (P = 0.0322), and COL (P = 0.0274). Additionally, the subjects 89 26 E. Kim1,2; J. Ghim1,2; H. Jung2; Md. Parvez2; J. Kim3; and J. Shin1,2 with family history of ischemic cardiovascular disease (CVD) had 90 27 1Inje University Busan Paik Hospital, Busan, South Korea; lower ADP-, AA- and COL-induced platelet aggregation compared 81 28 2Inje University College of Medicine, Busan, South Korea; and with those without family history of ischemic CVD (P = 0.0284, 92 29 3Pukyong National University, Busan, South Korea P = 0.0189, and P = 0.0350). 93 30 Background: Antiepileptic drugs have been known to induce poten- Conclusions: We provided that mechanistic evidence that age, sex, 94 31 tially life-threatening cutaneous adverse drug reactions such as and family history of ischemic CVD had the impact on basal plate- 95 32 Stevens-Johnson syndrome (SJS). Despite of studies for examining the let aggregation and coagulation factors in healthy Korean subjects, 96 33 mechanism associated with HLA, the association between lamotrigine which can be risk factors for ischemic disease. 97 34 (LTG)-induced cutaneous adverse drug reactions and HLA alleles is 98 35 still unclear. We investigated HLA-B alleles in LTG-induced SJS. 99 36 Material and Methods: Five LTG-induced SJS patient were requested Dehydroevodiamine, isolated from 100 37 for evaluating the causality. All patients were treated with LTG due the evodia Rutaecarpa, present in the 101 38 to epilepsy. All recovered from SJS after stopping LTG treatment and traditional Chinese medicine Wu Chu 102 39 intensive care. HLA-B genotyping was performed in all 5 patients Yu, has pro-arrhythmic effects in-vitro 103 40 using PCR-SBT (sequence-based typing) method. and in-vivo, which disappear at higher 104 41 Results: Demographic findings (gender, age) and HLA-B genotypes concentrations 105 42 of the 5 patients listed in Table 1. Expression of HLA-B*5101 allele M. Vos1; R. Varkevisser1; I. Baburin2; A. Schramm3; 106 43 was detected in three (60%) LTG-induced SJS patients. One patient M. van der Heyden1; M. Houtman1; M. Jonsson1; H. Takanari1; 107 44 has homozygous HLA-B*5801. M. Hamburger3; and Stefan Hering2 108 45 Conclusions: The result suggests that Korean individuals with the 1UMC Utrecht, the Netherlands; 2University of Vienna, Austria; 109 46 HLA*5101 allele may be susceptible to LTG-induced SJS. Further and 3University of Basel, Suisse 110 47 investigations are necessary to confirm these findings. Background: Dehydroevodiamine (DHE), a constituent of a popular 111 48 and freely available traditional Chinese herb, was investigated to 112 49 Table 1. Demographics and HLA-B alleles in 5 LTG-induced 113 SJS patients. determine whether DHE prolongs cardiac repolarization and induces 50 pro-arrhythmia. 114 51 Patient No. gender age HLA-B alleles Methods: For in-vitro Action Potential (AP) measurements, ventricu- 115 52 lar cardiomyocytes were isolated from dogs with chronic atrioven- 116 53 1 M 57 *5101, *5504 tricular block (cAVB). The effect of DHE on ECG parameters was 117 2 F 26 *5801, *5801 54 evaluated in 8 anesthetized rabbits, while 8 anesthetized cAVB dogs 118 55 3 M 16 *2705, *4001 119 4 M 53 *4801, *5101 were used to evaluate the pro-arrhythmic potential. In all models, 56 5 F 39 *0702, *5101 dofetilide was used as a positive control. 120 57 Results: IC50 of DHE to block the delayed rectifier current (I ) was 121 58 Kr 122 250 ± 26 nM. In cAVB cells, DHE (0.01, 0.1, 1 and 10 μ M) prolonged 59 123 The effects of Environmental and AP Duration (APD) with a less severe prolongation at the highest dose: 60 bell shape curve. Early afterdepolarizations (EAD) were seen in 14%, 124 61 clinical factors on basal platelet 125 67%, 100%, and 67% of cells after DHE. Dofetilde (1μ M) increased 62 Aggregation and coagulation in Korean 126 Healthy Subjects APD and induced EADs (15/25). In rabbits, DHE dose dependently 63 affected heart rate, conduction and repolarization: QT interval 127 H-.S. Kim1,2; Y.-S. Ryu1; A.R. Kim2; G.Y. Kim1; Md. M. Parvez1; 64 increased by 12 ± 10%* and 60 ± 26%* after 0.05 and 0.5 mg/ 128 E.-Y. Kim1,2; and J.-G. Shin1,2

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1 kg/5 min DHE. The latter dose induced multiple episodes of Torsade Inorganic Mercury poisoning due to the 65 2 de Pointes arrhythmia (TdP) in 2 rabbits. Dofetilide (0.04 mg/kg) use of Beauty Cream in Hong Kong 66 3 increased repolarization beyond the increase seen with DHE; in T.T. Cheung; M.F. Tsoi; and B.M.Y. Cheung 67 4 contrast, no TdP was induced. In cAVB dogs, 0.33 mg/kg/5 min The University of Hong Kong, Hong Kong SAR, China 68 5 DHE (plasma level 1.2 μ M) increased QT duration by 48 ± 10% Introduction: Use of inorganic mercury compounds in cosmetic 69 6 (P < 0.05*) and induced TdP in 3/4 dogs, which was comparable to products is prohibited as it can cause significant nephrotoxicity. 70 7 dofetilide in the same animals. Surprisingly, a higher dose of DHE However, the public continues to have access to these illegal prod- 71 8 induced a similar increase in QT duration (51 ± 10%*) but this did ucts in Hong Kong. 72 9 not culminate in TdP (0/4), while dofetilide induced TdP in 3/4. Material and Methods: This is a retrospective study aiming to evalu- 73

10 Conclusions: DHE blocks IKr, which is responsible for prolonged ate the clinical characteristics and the treatment outcome of inorganic 74 11 repolarization and pro-arrhythmic effects. However, DHE seems to mercury poisoning due to the use of beauty cream. Cases were identi- 75 12 affect other ion currents and/or has extra cardiac effects that could fied using the electronic system of the Hong Kong Poison Information 76 13 limit its pro-arrhythmic potential and explain the self-protecting Centre from 2008-2015. Only those with proven inorganic mercury 77 14 properties observed at higher concentrations. poisoning and prior use of beauty cream were included. 78 15 Results: Seventeen patients were included in the analysis; 88.2% 79 16 were female and more than half of those were Indonesian. Most of 80 17 Inquiries about Biotechnological agents the patients were treated with dimercaptosuccinic acid chelation, 81 18 over a 15 year period: a descriptive study prednisolone or combination therapy. Baseline 24-hour urine mer- 82 19 D. Salat1; C. Aguilera1; C. Asensio1; M. Bosch1; F. Castañeda2; cury levels correlate with the severity of proteinuria (Pearson’s cor- 83 20 I. Danés1; E. Esterlich2; R. Llop1; and V. Vallano2 relation 0.587, P = 0.035). Compared to chelation therapy alone, 84 21 1Clinical Pharmacology Service, Hospital Universitari Vall combination therapy with prednisolone demonstrated statistical sig- 85 22 d’Hebron, Fundació Institut Català de Farmacologia, Barcelona, nificant reduction in urine protein levels (99.41 ± 0.11 vs. 98.73 ± 86 23 Spain; and 2Clinical Pharmacology Service, IDIBELL, Hospital 0.19; P = 0.015). 87 24 Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain Conclusions: Inorganic mercury poisoning due to the use of beauty 88 25 Background: Over the past years biotechnological agents have been cream causes minimal change disease, resulting in nephrotic syn- 89 26 increasingly used in clinical practice. We aimed to determine whether drome. Baseline 24-hour urine mercury level correlates with the 90 27 inquiries about them to a Clinical Pharmacology Consultation Service severity of proteinuria. Statistical significant reduction in proteinuria 81 28 have also become more frequent. was found in patients receiving combination therapy with dimercap- 92 29 Material and Methods: We reviewed consultations received at our tosuccinic acid and prednisolone. 93 30 94 institutions between 2000 and 2014. Information on the agent(s), Table 1. Baseline characteristics of the patients according to different 31 95 underlying condition, type of inquiry and affiliation of the inquirer treatment regimens 32 was retrieved. Data from inquiries about selected biotechnological 96 33 No DMSA and Prednisolone Prednisolone + 97 agents (monoclonal antibodies, fusion proteins or cytokine antago- Prednisolone DMSA only only DMSA 34 nists) were compared to data from the remainder. 98 35 Results: A total of 14,468 inquiries (365 about 30 different biotech- 99 36 N 3 3 2 7 100 nological agents) were received during the study period. Rituximab Age 47 (33–64) 32 (23–38) 39 (18) 29 (22-57) 37 101 (n = 72), infliximab (n= 62), adalimumab and etanercept (n = 53 Female (%) 3 (66.7%) 5 (100%) 1 (50%) 7 (100%) 38 for each) were most frequently inquired about. Up to 2003 only Cumulative dose of N/A 15004 ± 1.5 N/A 23976 ± 1.4 102 DMSA (mg) 39 4% of inquiries about a biotechnological agent were received, while 103 40 Cumulative dose of N/A N/A 2874 ± 3.0 1627 ± 3.4 104 48.8% were received after 2010. Conversely, yearly inquiries about Prednisolone (mg) 41 other agents consistently accounted for 5.4-7.6% of those of the Spot blood mercury level 80.2 ± 9.4 103.8 ± 3.9 80.6 ± 1.7 49.6 ± 1.4 105 42 whole period. A higher proportion of inquiries about biotechno- (nmol/L) 106 24 hour urine mercury 24.3 ± 1.9 514.9 ± 3.1 127.2 ± 12.0 204.2 ± 2.9 43 logical agents requested an opinion (87.7% vs. 77.7%), were made 107 44 level (nmol/day) 108 by physicians (89.9% vs. 76.9%) and from a hospital (81.6% vs. 24 hour urine protein 3.69 ± 1.61 7.70 ± 1.65 7.86 ± 1.45 10.53 ± 1.29 45 44.5%) and were made in regard to a specific case (87.4% vs. 74.5%) level (g/day) 109 46 110 [P value < 0.001 for all]. Adverse effects (n = 194) and/or agent selec- 47 111 tion (n = 173) were the most frequent reasons for making an inquiry. 48 112 One hundred (51.5%) of the inquiries about adverse effects were Assessment of changes in Levetiracetam 49 about the teratogenic potential of specific agents. Selection inquir- 113 50 serum concentrations by concomitant 114 ies were most frequently made regarding musculoskeletal (n = 57), Antiepileptic Drug use 51 dermatological (n 19), neurological (n 15) and gastrointestinal 115 = = B. Donertas; S. Yigitaslan; B. Sirmagul; D. Darici; G. Akdag; 52 (n 12) conditions. 116 = O. Ozdemir; O. Erdinc; and S. Oner 53 Conclusions: Inquiries about biotechnological agents progressively 117 University of Eskisehir Osmangazi, Eskisehir, Turkey 54 increased, while those about other agents remained fairly constant. 118 Introduction: Levetiracetam (LEV) is a newer antiepileptic drug. 55 Most of the inquiries about biotechnological agents were about mon- 119 Though its metabolism does not depend on cytochrome P450 56 oclonal antibodies, and were made by hospital physicians to request 120 isoenzymes, some studies suggested the influence of enzyme-induc- 57 information regarding adverse effects (especially in pregnancy) and 121 ing antiepileptic drugs (AED) on LEV plasma levels. In this study, 58 the appropriateness of use in specific patients. 122 59 123 60 124 61 125 62 126 63 127 64 128

2015 e15 Clinical Therapeutics

1 influence of concomitant AED use, particularly that of enzyme-induc- urapidil at discharge. A significant increase in the use of antihyper- 65 2 ing/inhibiting AED, on serum concentrations of LEV was examined. tensive drug combinations was observed comparing their prevalence 66 3 Material and Methods: LEV serum concentration measurements at the time of hospital admission and discharge, respectively (76.2% 67 4 between January-December 2014 were retrieved retrospectively from vs. 83.3%; P < 0.001). 68 5 Eskisehir Osmangazi University Hospital TDM database, including Conclusions: The results of the presented work showed the com- 69 6 patients from neurology department. One hundred ninety-two blood pliance of antihypertensive therapy with guidelines for treatment of 70 7 samples of 160 patients were analyzed. All LEV concentrations were arterial hypertension. The study indicates certain areas in which the use 71 8 measured using Cloned Enzyme Donor Immunoassay (CEDIA). of antihypertensive medications could be improved in elderly patients. 72 9 Remaining data were obtained from patients’ medical records. Only This study was supported by grants VEGA 1/0886/14 and VEGA 73 10 the highest LEV serum concentration per patient was included. The 1/0939/14. 74 11 reference range in serum for LEV was considered as 5–40 µg/mL. 75 12 Antiepileptic levels were presented as median (µg/mL) (Q25%–75%). 76 13 In the comparisons, Chi-square and Kruskal-Wallis tests were used Concentrations and Activity of 77 14 and P< 0.05 was considered as significant. Amphotericin B in Bile achieved by 78 15 Results: Patients were aged 18–87 years (40.6 ± 15.2). Of them, Lipid-Formulations 79 16 54.4% were male. Most of them (61.3%) had epilepsy. Forty-nine R. Welte1; S. Eschertzhuber2; S. Leitner-Rupprich1; M. Aigner1; 80 17 (30.6%) were on LEV monotherapy and valproic acid (22.5%) and C. Lass-Flörl1; S. Weiler1; E. Stienecke1; R. Bellmann-Weiler1; 81 18 carbamazepine (16.2%) were the most common AED co-medication. M. Joannidis1; and R. Bellmann1 82 19 Median LEV concentration was 14.3 (7.8–27.6) vs. 20.0 (11.6–32.5) 1Innsbruck Medical University, Innsbruck, Austria; and 83 20 in monotherapy and polytherapy groups, respectively (P > 0.05). 2Innsbruck General Hospital, Innsbruck, Austria 84 21 LEV concentration was within reference range in 79.6% and 77.5% Background: Amphotericin B (AMB) has a broad antifungal spec- 85 22 of the patients in monotherapy and polytherapy groups, respectively trum, but also a considerable toxicity. Its lipid-formulations are safer. 86 23 (P > 0.05). Influence of concomitant AED use on LEV concentrations As fungal cholangitis is a life-threatening disease, we assessed biliary 87 24 was evaluated in patients using only one additional AED (n = 68). AMB penetration in patients treated with lipid-formulated AMB and 88 25 Median LEV concentration was 18.0 (11.7-32.3), 18.3 (8.2-31.1), biliary AMB activity by in-vitro and ex-vivo-simulations. 89 26 21.4 (14.6-26.3) in patients using enzyme inducer (carbamazepine, Methods: Biliary and plasma AMB levels were measured by high- 90 27 phenytoin), enzyme inhibitor (valproic acid) and neutral AEDs, pressure-liquid-chromatography in two patients on liposomal AMB 81 28 respectively (P > 0.05). Of the patients, 51.1% in monotherapy and and in two on AMB colloidal dispersion. AMB kinetics in bile and 92 29 28.7% in polytherapy groups were seizure-free. plasma was determined in three of these patients. In-vitro simulation 93 30 Conclusions: Concomitant AED use, whether being enzyme inducer or was performed with isolates of Candida (C.) albicans, C. tropica- 94 31 inhibitor, resulted in no significant change in LEV serum concentration. lis, C. glabrata and C. krusei incubated in porcine bile or in RPMI 95 32 medium at relevant AMB concentrations for up to 48 hours. For 96 33 ex-vivo simulation, patient bile samples were inoculated with the 97 34 The use of Antihypertensive Medication in same Candida strains. 98 35 Hospitalised Elderly Patients Results: Biliary AMB concentrations were lower and displayed a 99 36 M. Wawruch; J. Murin; Z. Kallay; J. Luha; J. Papincak; P. Mikes; slower rise and decline than plasma levels. Growth of C. albicans 100 37 and T. Leitmann and C. tropicalis in porcine bile was similar to that in RPMI medium. 101 38 1Faculty of Medicine, Comenius University, Bratislava, Slovakia; Proliferation of C. glabrata was diminished, and C. krusei displayed 102 39 and 2Faculty of Medicine, Slovak Medical University, Bratislava, no proliferation in bile. AMB activity was lower in porcine bile than 103 40 Slovakia in medium. In most of the patient bile samples, fungal growth was 104 41 Background: Despite the importance of hypertension as a risk fac- delayed or lacking, even in the absence of AMB. AMB concentrations 105 42 tor for adverse outcomes, elderly patients have the lowest rate of of up to 1.28 mg/L had no fungicidal effect in patient bile. 106 43 adequate blood pressure control. The antihypertensive therapy in Conclusion: Biliary AMB concentrations were similar to or below 107 44 elderly patients requires special attention because of questions which the MIC values of relevant fungi. Fungal growth and AMB activity 108 45 remain still unresolved from the evidence based medicine point of were impaired by bile. Treatment of fungal cholangitis with AMB 109 46 view as well as regarding the safety aspects. The aim of the presented lipid formulations is not supported by these pharmacokinetic and 110 47 work was to evaluate the antihypertensive treatment in a sample of pharmacodynamic data. 111 48 112 hospitalised patients aged ≥ 65 years. 49 113 Methods: Patients aged ≥ 65 years with arterial hypertension treated 50 with at least one at hospital admission were 114 51 Terbinafine induced Erythema 115 included in our study (n = 1233). We analysed following patients’ 52 multiforme with Hepatitis 116 characteristics as possible factors influencing the prescription of anti- 1 1 1 2 1 53 R. Slim ; N. Fathallah ; S. larif ; A. Aounallah ; H. Zayani ; 117 hypertensive agents: socio-demographic signs (age, gender), living 2 1 54 N. Ghariani ; and C. Ben Salem 118 alone, immobilisation and comorbid conditions. 1 2 55 Faculty of Medicine of Sousse, Tunisia; and Farhat Hached 119 Results: In the evaluated group women were prevailing over men University Hospital, Sousse, Tunisia 56 (64.7% vs. 35.3%). The mean age of patients was 78.3 ± 6.7 years. 120 57 Introduction: Terbinafine is an antifungal agent that is effective for 121 In the group of patients aged ≥ 80 years a significantly lower preva- the oral treatment of dermatophytes. Herein, we report a rare case 58 lence of following antihypertensives was found: antagonists of AT 122 59 1 of terbinafine induced erythema multiforme (EM) associated with 123 receptors, dihydropyridine calcium channel blockers, betablockers hepatitis. 60 and agonists of I receptors. On the other hand, in this age group the 124 1 Case Report: A 59-year-old woman was admitted with a general- 61 highest prevalence of furosemide prescription was revealed. Patients 125 62 ized targetoid, pruritic eruption. Terbinafine for onychomycosis was 126 living alone were at higher chance (OR = 2.38) and those aged 80 63 started three weeks earlier. Clinical signs and skin biopsy were con- 127 years or more at lower chance (OR = 0.57) for administration of 64 sistent with EM. Laboratory investigations showed liver dysfunction 128

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1 with elevated liver enzyme activities. Diagnostic tests for viral and The routes used for off-label administration were intranasal, intrathe- 65 2 autoimmune hepatitis were negative. Other well established causes cal, sublingual and rectal route. The common subjects for off-label 66 3 of EM were ruled out. Terbinafine induced EM with hepatitis was research were the anticonvulsant, antiemetic, anti-shivering effects of 67 4 suspected, the antifungal was stopped and oral corticosteroid treat- midazolam and the use as an adjunct to local anesthetics. 68 5 ment was started. Patient’s condition improved dramatically and liver Conclusions: Off-label use of midazolam occurs frequently in the 69 6 tests returned to normal. RCTs. Although it is legal to prescribe drugs off-label, there may be 70 7 Discussion: EM is an acute mucocutaneous hypersensitivity reaction health risks and differences in legal liability. There is need to gener- 71 8 with variety of etiologies. It is characterized by a skin eruption, with ate evidence-based and safe scientific basis regarding every aspects 72 9 or without mucous membrane lesions. It can be induced by drug of clinical conditions during the processes of approving and labeling. 73 10 intake or several infections. Terbinafine is generally well tolerated 74 11 and the most common cutaneous adverse effects are rash, pruritus 75 12 and urticaria. In the literature a few cases of EM have been reported Reference 76 13 following exposure to this drug. It had also reported that patients 1. Stafford RS. Regulating off-label drug use- rethinking the role of 77 14 who have developed EM during terbinafine treatment suffered from a FDA. N Engl J Med. 2008;358:1427–1429. 78 15 systemic autoimmune disease and no hepatic disorder was associated 79 16 to the skin manifestation. Our case was diagnosed to be a suspected 80 17 case of drug-induced EM with hepatitis on the basis of drug history, Effects of uncontrolled diabetes on LDL 81 18 clinical presentation, improvement with dechallenge and exclusion levels of patients undergoing carotid 82 19 of other likely causes of EM and hepatitis. According to the Naranjo Endarterectomy on and off Statin 83 20 probability scale, the adverse drug reaction was considered probable. Therapy: preliminary study 84 21 Conclusion: Clinicians should be aware of the risk of EM associated 85 M. Oc1; I. Duman2; B. Oc1; M. Simsek1; H. Vatansev1; O. Arun1; 22 with terbinafine, a generally well tolerated drug. The skin involve- 86 and A. Duman1 23 ment may be also associated with liver disorder. 87 1Selcuk University Faculty of Medicine, Konya, Turkey; and 24 88 2Necmettin Erbakan University Faculty of Medicine, Konya, 25 89 Turkey 26 90 Off-Label use of Midazolam in Introduction: This preliminary study aims to assess the effects of 27 81 randomized controlled trials uncontrolled diabetes mellitus (DM) on LDL levels of atherosclerotic 28 1 2 3 2 92 I. Duman ; O. Arun ; F. Arun ; and B. Oc patients on long term statins and patients not on statins. 29 1 93 Necmettin Erbakan University Faculty of Medicine, Konya, Material and Methods: With institutional approval LDL levels of 30 2 94 Turkey; Selcuk University Faculty of Medicine, Konya, Turkey; 40 patients undergoing carotid endarterectomy due to atheroscle- 31 3 95 and Beyhekim State Hospital, Konya, Turkey rosis were retrospectively analyzed. All statin users were on statins 32 96 Introduction: Off-label use is the use of pharmaceutical drugs for for 1yr. Patients with HbA1C levels of 6.4% were considered as 33 > > 97 an unapproved indication or in an unapproved age group, dosage, uncontrolled DM (D ). All other patients were non diabetics (D-). 34 + 98 or form of administration (1). The goal of this study is to investigate Group1: D , statin user (n 9), group2: D- statin user (n 10), 35 + = = 99 the data regarding the off-label use of midazolam; a versatile benzo- group 3 D non statin user (n 8), and group 4: D- non statin user 36 + = 100 diazepine, in randomized controlled trials (RCTs). (n 13). LDL levels are given as mg/dl, Kruskal-Wallis and Mann- 37 = 101 Material and Methods: RCTs of were identified retrospectively Whitney tests were used for statistics. P 0.05 significant. 38 < = 102 through a search of PubMed from March 2012 to the past (1981) Results: Demographic data were similar. LDL levels for groups1, 39 103 using the search term ‘midazolam’. Identified articles were screened 2, 3 and 4 were 125.0 ± 8.7, 95.0 ± 7.0, 133.5 ± 10.0, and 114.0 ± 40 104 for purpose or indication of the midazolam use, on/off label use, 10.2 respectively. LDL levels of uncontrolled diabetic patients not on 41 105 age of patients, route and location of administration. On-label cri- statins were significantly higher than all other groups (P 0.05). LDL 42 < 106 teria were based on information provided by the manufacturer of levels of uncontrolled diabetic patients on statins were also higher 43 107 midazolam. than non-diabetic patients (P 0.05). LDL levels were similar in all 44 < 108 Results: A total of 1081 RCTs of midazolam were detected; 314 were non-diabetic patients (P 0.05) 45 > 109 off-label and 276 were conducted in children. Until 1989 the number Conclusions: Results of this preliminary study suggest that athero- 46 110 of RCTs per year was under 20 and from 1990 to 2011 the average of sclerotic patients with uncontrolled diabetes who are either on or 47 111 RCTs was 43.4 (31-54) per year. Most common on-label indication off statin therapy have higher LDL results compared to non-diabetic 48 112 was to provide sedation and induction of anesthesia. Common fields atherosclerotic patients. A study recruiting higher number of patients 49 113 of research were induction of anesthesia and/or anesthetic effect/ is needed to clearly assess the effects of uncontrolled diabetes on 50 114 technique, evaluation of pharmacokinetics and pharmacodynamics. LDL levels. 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

2015 e17 Clinical Therapeutics/Volume XX, Number XX, 2015

1 Biosimilars: regulatory overview Time to onset of ST-segment depression ≥ 1 mm was increased with 65 2 E. Sarkinovic; Z. Besovic; M. Drljevic; M. Sahman-Zaimovic; and 69.42 ± 13.89 sec. (P < 0.001) in amlodipine group and with 62.14 66 3 S. Mugosa ± 12.77 sec. (P < 0.001) in lercanidipine group. Additionally, diary 67 4 Agency For Medicines and Medical Devices, Podgorica, data showed reduction in episodes of angina (in amlodipine group 68 5 Montenegro from 6.07 ± 0.82 to 3.53 ± 0.65 (P < 0.001) and in lercanidipine 69 6 Introduction: The first generation of biopharmaceutical products group from 7.9 ± 0.83 to 4.54 ± 0.87 (P < 0.001)) and nitroglycerin 70 7 manufactured using recombinant technologies was launched in the tablet consumption (in amlodipine group from 3.76 ± 0.66 to 2.07 ± 71 8 1982, and the most of them are now on the way to patent expiration 0.44 (P < 0.01) and in lercanidipine group from 5.9 ± 0.74 to 3.09 ± 72 9 or have already expired. As a result, pharmaceutical companies are 0.63 (P < 0.01)). No significant differences could be found between 73 10 developing “generic” version for biopharmaceutical product, referred the pre and post treatment levels of lipid metabolism indicators and 74 11 to as biosimilars. on insulin resistance. 75 12 Active substance of biopharmaceutical product represent a collec- Conclusions: Lercanidipine and amlodipine are effective in reduc- 76 13 tion of recombinant proteins and not a single molecular entity, thus ing signs and symptoms of ischemia in patients with stable angina 77 14 active substances in two biopharmaceutical product are unlikely to and metabolic syndrome; at the same time these drugs don’t have a 78 15 be identical. Biosimiliars are only similar and not identical to the significant influence on lipid metabolism indicators and on insulin 79 16 innovator products and these small differences can have significant resistance. 80 17 impact on the safety and efficacy of the medicine. The EU Directive 81 18 2001/83/EC, as amended, stated that where a biological medicinal 82 19 product which is similar to a reference biological product does not Chemopreventive effect of 83 20 meet the conditions in the definition of generic medicinal products, copaifera reticulata oilresin on 84 21 the results of appropriate pre-clinical tests or clinical trials relating 1,2dimethylhydrazine-induced 85 22 to these conditions must be provided. The challenge is to determine preneoplastic lesions in Rat colon 86 23 the exact nature of the non-clinical and clinical program required to J.M. Senedese1,2; R.A. Furtado1; D.C. Tavares1; and J.K. Bastos1,2 87 24 gain regulatory approval. The European Medicines Agency has taken 1Universidade de Franca, Franca, São Paulo, Brazil; and 88 25 the lead in issuing guidelines, most of which are still under review. 2Faculdade de Ciências Farmacêuticas de Ribeirão Preto, 89 26 The guidelines advocate pre-clinical and clinical testing of biosimilars Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil 90 27 prior to market authorization, complemented by tailored pharma- Background: Colorectal cancer is a major cause of death; its inci- 91 28 covigilance plans. Generally, the approval process varies according dence is increasing worldwide. Experimental studies have suggested 92 29 to the products, because significant differences exist between them, that plant food components can suppress cancer development 93 30 and allow products to be assessed on a case by case basis. These through a variety of different mechanisms. Chemoprevention is 94 31 guidelines provide a valuable base from which to develop in this defined by the use of natural, synthetic, biological or chemical agents 95 32 evolving regulatory environment. that can reverse, suppress or prevent carcinogenesis. Plants produce a 96 33 Conclusion: There are still many unsolved scientific issues regarding conspicuous structural diversity of metabolites and represent the larg- 97 34 criteria, design, and analysis for the assessment of biosimilarity and/ est source of active compounds; they are perhaps the earliest source 98 35 or interchangeability of biosimilars. Detailed regulatory guidance for of drugs for human use. Copaifera reticulata, known as “copaiba”, 99 36 global harmonization is needed whenever possible. “pau-de-óleo”, belongs to the Leguminosae family and occurs in 100 37 fields and grasslands in the northern and northeastern parts of Brazil. 101 38 This studies describes the effects of C. reticulata oilresin on the 1,2 102 39 The efficiency of calcium channels dimethylhydrazine (DMH) - aberrant crypt foci (ACF) in the colon 103 40 antagonists in angina pectoris of male Wistar rats. Preneoplastic lesions of the colonic mucosa, 104 41 associated with metabolic syndrome the ACF, are one of the early morphological changes on the DMH- 105 42 106 V. Revenco; M. Abras; V. Ochisor; and G. Mihalache stimulated colonic mucosal surface in rode. 43 107 State University of Medicine and Pharmacy “Nicolae Material and Methods: The oilresin of C. retiulata was administered 44 108 Testemitanu” to rats by gavage at daily doses of 20, 40 and 80 mg/kg body weight. 45 109 Background: Evaluation of antiischemic efficiency of calcium chan- To evaluate the ACF assay, animals were acclimatized for one week 46 110 nels antagonists (lercanidipine and amlodipine), as also the meta- (week 1) and then treated with the C. reticulata oilresin five times a 47 111 bolic effect of these drugs in patients with stable angina pectoris and week for four weeks (weeks 2 to 5). The rats received sc (subcutane- 48 112 metabolic syndrome. ous) injections of DMH (40 mg/kg) on days 2 and 5 of weeks 2 and 49 113 Material and Methods: The 6-week randomized open-label trial 3, to induce ACF. Animals were euthanized at week 5; i.e., four weeks 50 114 included 66 patients (mean age 58.18 ± 1.0 years) with functional after the first DMH treatment. 51 115 classes II-III stable angina associated with metabolic syndrome. After Results: The groups treated with 40 and 80 mg/kg C. reticulata oil- 52 116 1 week wash-out period, a 2-week placebo run-in period, patients resin during and after DMH treatment presented significantly lower 53 117 entered a 6-week treatment period with 10 mg of lercanidipine or 5 numbers of ACF and aberrant crypts compared with the DMH group. 54 118 mg of amlodipine once daily. During the placebo run-in period and Conclusion: The C. reticulate oilresin significantly reduced ACF 55 119 at the end of the study, the patients underwent clinical examination, induced by DMH, suggesting that the oilresin has a protective effect 56 120 electrocardiography, exercise testing; episodes of angina per week and against colon carcinogenesis. 57 121 sub-lingual nitroglycerin tablet consumption, lipid spectrum indica- 58 122 tors and insulin resistance. 59 123 Results: Total exercise duration was increased with 72.62 ± 23.24 60 Dopaminergic challenge with 124 sec. (P 0.01) in amlodipine group and with 69.42 ± 13.89 sec. 61 < Bromocriptine in patients with severe 125 (P 0.001) in lercanidipine group. Time to onset of anginous pain 62 < Traumatic Brain Injury 126 was increased with 39.5 ± 8.12 sec. (P 0.001) in amlodipine group 63 < J.B. Celik; A. Duman; O. Arun; and I.Ö. Önal 127 and with 78.57 ± 15,.04 sec. (P 0.001) in lercanidipine group. 64 < Selcuk University Faculty of Medicine, Konya, Turkey 128

2015 e1 Clinical Therapeutics

1 Introduction: Bromocriptine Mesylate (BC) is an ergot derivative QTcF and any possible relationship between darinaparsin plasma 65 2 with potent dopamine receptor agonist activity. It is licensed to reduce concentration and change in QTcF was assessed in these studies. 66 3 plasma levels of prolactin. BC has central nervous effects, and is Material and Methods: Patients received a 1-hour IV infusion at 67 4 used in patients with Parkinson’s disease. There are few randomized 200 or 300 mg/m2 on 5-consecutive days of 21-day or 28-day cycle. 68 5 controlled trials with BC conducted in moderate traumatic brain Patients received triplicated ECG assessment and PK plasma sample 69 6 injury (TBI) with conflicting results (1). We aim to present our single were taken on Day 1 and 5 at 0, 1, 2, 4 hours after initiation of 70 7 center experience on dopaminergic challenge using off-label BC in dosing of darinaparsin in Cycle 1, on Day 2 before dosing, and on 71 8 patients with severe TBI. Day 6 at matched time with dosing time on Day 1-5. Time-matched 72 9 Material and Methods: TBI patients with Glasgow Coma Score baseline ECG was determined at −20, −22, −23, −24 hours before the 73 10 (GCS) of < 5 (GCS: worst score= 3, best score= 15) at admission to planned initiation time of dosing. All ECGs were read by a central 74 11 the ICU received 2.5mg of BC q.i.d after hemodynamic stability was ECG laboratory and overread by a cardiologist for verification of 75 12 ensured and no further neurologic improvement was observed dur- interval measurements. 76 13 ing course of management. BC was started and discontinued on the Result: ECG data were available for 26 patients; 17 Japanese patients 77 14 discretion of the ICU team. Long term cognitive tests are currently and 6 Korean patients. No subjects showed QTcF > 500 msec and 78 15 under assessment. delta QTcF > 60 msec throughout the study period. Concentration- 79 16 Results: A total of 8 patients were treated with BC. The average age dependent nor treatment-duration-independent effect on the QTcF 80 17 was 42.7yrs (78-18) (5M/3F). were not identified. There was no significant relationship between 81 18 Table 1: GCS of patients on admission, beginning of treatment, end of the plasma concentration of darinaparsin and a change in QTcF. 82 19 treatment and discharge. Conclusion: The study results suggested that darinaparsin, an 83 20 organic arsenic compound, has no significant effect on cardiovascu- 84 21 BC started Days on Days in GCS lar safety in Japanese and Korean PTCL patients. 85 GCS admission GCS start GCS end on day BC ICU discharge 22 86 23 87 1 3 4 8 28 8 37 8 24 2 5 5 5 15 7 39 5 The difference of Vkor activity and its 88 25 3 3 3 6 11 30 41 12 inhibition by warfarin between Vitamin K1 89 26 4 3 3 5 7 23 44 6 Epoxide and Vitamin K2 Epoxide 90 27 5 3 6 10 28 8 39 10 81 6 3 3 4 9 7 75 3 M. Kawano; T. Araki; and K. Yamamoto 28 7 3 4 4 24 14 38 died Gunma University Graduate School of Medicine, Japan; and 92 29 8 4 4 4 9 34 79 8 Gunma University Hospital, Japan 93 30 Conclusions: Our results show some neurologic improvement as Introduction: Vitamin K (VK) plays an important role in activation 94 31 95 assessed by GCS. More research is warranted before BC can be rec- of blood clotting factors. VK is oxidized by δ -glutamyl carboxylase to 32 ommended in TBI. synthesize clotting factors, and is then reduced by VK oxide reductase 96 33 (VKOR) to be recycled for reuse. The redox center of VKOR against 97 34 VK1 epoxide (VK1E) was reported as 132Cys-X-X-135Cys by some 98 35 in vitro studies. However, the redox center of VKOR against VK2E 99 36 Reference 100 1. Frenette AJ, et al. Efficacy and safety of dopamine agonists and its reaction type have not been identified. In this study, to clarify 37 101 in traumatic brain injury: a systematic review of randomized the difference of reuse intravital between VK1 and VK2, we assessed 38 102 controlled trials. J Neurotrauma. 2012;29:1–18. the difference of metabolism pattern of VKsE by VKOR. 39 Material and Methods: Metabolic activity of VKOR against VKsE 103 40 and inhibitory activity of warfarin (WF) to VKOR were measured 104 41 using pooled human hepatic microsome. The concentrations of pro- 105 42 Evaluation of Cardiovascular safety 106 of Darinaparsin (organic arsenic duced VK1 and VK2 were determined as an index of VKOR activ- 43 ity by UPLC/UV method. Metabolic activity was estimated using 107 44 compound) in Japanese and Korean 108 patients with peripheral T-cell Lymphoma Michaelis-Menten equation, and inhibition type and constant (Ki 45 value) were determined by Lineweaver-Burk plot and Dixon-plot. 109 Y. Kumagai1; H. Cai2; J. Barrett2; T. Shiraishi3; Y. Hayashi3; 46 Results: The clearance of VK2E was around 7-fold higher than that 110 Y. Sonehara4; and F. Nagahama4 47 of VK1E (0.054 and 0.0072 pmol/min/mg protein, VK2E vs VK1E). 111 1Kitasato University School of Medicine, Kanagawa, Japan; 48 S- and R- WF inhibited the reduction activity of VKOR against VK2E 112 2ZIOPHARM Oncology, Inc., Boston, MA, United States; 3A2 49 around 6-fold stronger than that against VK1E. Additively, VK1E 113 Healthcare Corporation, Tokyo, Japan; and 4Solasia Pharma K.K., 50 competitively inhibited reduction reaction of low concentration of 114 Tokyo, Japan 51 VK2E, while VK1E did not inhibit the metabolism of high concen- 115 Background or Introduction: Darinaparsin is an organic arsenical 52 tration of VK2E. 116 composed of dimethylated arsenic linked to glutathione, and has 53 Conclusions: Our data indicated the difference of inhibition type of 117 similar structure to one of the intermediates of the arsenic detoxifica- 54 VK1E against metabolism of low and high concentration of VK2E 118 tion pathway. Its place in the natural metabolic pathway of inorganic 55 by VKOR. VK1E and VK2E may be bound to the same site of VKOR 119 arsenic is expected to result in lower cardiotoxicity than inorganic 56 high affinity site, while VK2E, but not VK1E may be also bound to 120 arsenic. Two phase I studies of darinaparsin have been conducted 57 another low affinity site. In next study, we should clarify the detail of 121 in patients with peripheral T-cell lymphoma (PTCL) in Japan and 58 binding site of VKOR to VK2E and the difference on the interaction 122 Korea, respectively. Since use of an inorganic arsenic compound is 59 of VKsE with warfarin. 123 60 limited by cardio toxicity, the potential of darinaparsin to prolong 124 61 125 62 126 63 127 64 128

e2 Volume XX Number XX Biosimilars: regulatory overview

1 The qualities of sore throat index or lost enzyme’s activity, which can cause adverse drug reactions. 65 2 (QUASTI): first use in a clinical trial Researchers discovered a link between fluoxetine use and suicidal 66 3 testing the effects of Flurbiprofen behavior among teenagers. 67 4 8.75 Mg lozenge on patient-reported Case Presentation: A 17-years old teenager, a girl, has been tak- 68 5 qualities of throat pain ing fluoxetine for three months following neurologist's advice as 69 6 B. Schachtel1,2; S. Aspley3; A. Shephard3; G. Smith3; K. Sanner2; a treatment for mood instability with a prevalence of depressed 70 7 L. Savino2; E. Schachtel2; M. Lorton2; and T. Shea4 mood. The teenager committed suicide. After analyzing the girl’s 71 8 1Department of Epidemiology and Public Health, Yale University diary, the psychiatrist made a conclusion that the girl had been suf- 72 9 School of Medicine, New Haven, CT, USA; 2Schachtel Research fering from schizotypal personality disorder. Genotyping showed 73 10 Company, Jupiter, FL, USA; 3Reckitt Benckiser, Slough, Berkshire, the presence of heterozygous CYP2D6*4 allele (c.1846G> A) and 74 11 UK; and 4Reckitt Benckiser, Parsippany, NJ, USA heterozygous CYP2D6*10 allele (c.100C> T), which may deter- 75 12 Background: Beyond the evaluative complaint of a “sore” throat, mine decrease in CYP2D6 activity. No other genetic variants 76 13 patients with pharyngitis frequently report different qualities of (CYP2D6*3, CYP2D6*6, CYP2D6*9, CYP2D6*41) were found. 77 14 throat pain such as “burning” and “difficulty swallowing” (Schachtel Forensic chemistry research of bodily fluids pointed to presence of 78 15 et al. Arch Intern Med 1984). Optimally, treatments should not only fluoxetine in blood and urine. Quantitative measurement of fluox- 79 16 relieve throat soreness, but also reduce these other dimensions of etine concentration in blood wasn’t made because of insufficient 80 17 pain. We investigated the effects of a lozenge containing 8.75 mg of volume of blood. 81 18 the nonsteroidal anti-inflammatory drug, flurbiprofen, on 11 quali- Conclusions: Fluoxetine use may cause toxic drug accumulation thus 82 19 ties of throat pain. leading to worsening of suicidal thoughts if taken by teenagers with 83 20 Material and Methods: This randomised, double-blind, placebo-con- possible genetic determined insufficiency of CYP2D6 enzyme (poor 84 21 trolled, single-dose trial enrolled adults with recent onset moderate- metabolizer). 85 22 to-severe sore throat and pharyngitis (≥ 5 on the Tonsillo-Pharyngitis 86 23 Assessment; TPA). Patients were randomised to one flurbiprofen or 87 24 one identically-flavoured vehicle lozenge (placebo). At baseline and Substance use among medical students in 88 25 hourly for 3 hours post dose, patients used Likert scales to rate throat Greece 89 26 soreness and 10 other qualities of throat pain: sensory symptoms G. Papazisis1; A. Sarrigiannidis2; Ch. Pourzitaki1; E. Apostolidou1; 90 27 (burning, raw, dry, irritated/scratchy, tight, like a lump in the throat, G. Garyfallos2; and D. Kouvelas1 81 28 swollen), functional symptoms (difficulty swallowing, husky/hoarse 1Department of Pharmacology and Clinical Pharmacology, Faculty 92 29 voice) and an affective descriptor (agonising). These 11 scales com- of Medicine, Aristotle University of Thessaloniki, Greece; and 93 30 prise the Qualities of Sore Throat Index (QuaSTI). Mean changes in 22nd Department of Psychiatry, Faculty of Medicine, Aristotle 94 31 the QuaSTI scores for both treatment groups were compared from University of Thessaloniki, Greece 95 32 baseline to 3 hours after treatment. Introduction: Limited research exists worldwide on medical stu- 96 33 Results: A total of 122 patients with moderate/severe sore throat dents’ substance use patterns including alcohol and marijuana use. 97 34 were randomised to flurbiprofen or placebo treatment. Mean age The aim of the present study was to examine the prevalence of sub- 98 35 was 19.5 years, mean TPA score was 9.9. Compared with placebo, stance use, including marijuana, alcohol and other illicit substances 99 36 flurbiprofen-treated patients reported significantly greater reductions (i.e. cocaine, heroin, hallucinogens, and ecstasy) in a sample of medi- 100 37 in sensory, evaluative, affective and functional QuaSTI symptoms cal students in Northern Greece. 101 38 (all P < 0.05). Material and Methods: Six hundred fifty-five medical students 102 39 Conclusions: In adults with sore throat, a single dose of flurbiprofen (55.7% females) from the Aristotle University of Thessaloniki com- 103 40 8.75 mg lozenge reduced sensory, functional and affective qualities pleted an anonymous, self-administered, web-based survey. Students 104 41 of throat pain as well as throat soreness. The QuaSTI appears to be were asked to report the frequency of use (lifetime, the past year, and 105 42 a sensitive instrument for the measurement of different qualities of the past month) and the motive of the use. The CAGE questionnaire 106 43 throat pain and response to treatment. was used to determine the severity of the alcohol use. 107 44 Results: Seventy-two percent of the students reported having never 108 45 used any illegal substance and 21% reported marijuana use at least 109 46 A Case report of suicide in a teenager once in their lifetime; 20.9% of the students were nicotine smok- 110 47 with long-term use of fluoxetine ers. No gender difference regarding marijuana use (50.7% male vs 111 48 associated with CYP2D6 Polymorphism 49.3% female) was observed. Significantly more nicotine smokers 112 49 113 S.V. Asriyants1; O.V. Veselkina2; D.A. Sychev3; Y.D. Obuhova2; and alcohol users were noticed in the marijuana group than in the 50 114 A.V. Polyakov4; and V.A. Klevno2 no marijuana group. The use of other illicit substances was rare 51 115 1I.M. Sechenov First Moscow State Medical University, Moscow, in our sample (3% used inhalers, 2.3% cocaine, 2.3% ecstasy, 2% 52 116 Russian Federation; 2The Bureau of Forensic Medicine of the ketamine, 1.8% amphetamines and 1.7% mephedrone). However, 53 117 Moscow region, Moscow region, Russian Federation; 3Russian the use of marijuana was significantly positive correlated with use 54 118 medical academy of postgraduate education, Moscow, Russian of cocaine, LSD, ecstasy, ketamine, amphetamine and mephedrone. 55 119 Federation; and 4Research Centre of Medical Genetics of Conclusions: Although the relative mean Cage scores are low indicat- 56 120 the Russian Academy of Medical Sciences, Moscow, Russian ing a lack of severe alcohol related problems in our sample, there is a 57 121 Federation significantly higher mean CAGE score in students who use marijuana. 58 122 Background: CYP2D6 enzyme is responsible for the metabolism Marijuana use is also associated with polysubstance use, this result 59 123 of antidepressants, including selective serotonin reuptake inhibi- confirms previous findings in the general population. Nationwide 60 124 tors, such as fluoxetine. Genetic variations in the highly polymor- studies are needed further investigating the prevalence, the motiva- 61 125 phic CYP2D6 gene may be associated with increased, reduced, tion and the impact of this risky behaviour among this population. 62 126 63 127 64 128

2015 e3 Clinical Therapeutics

1 The importance of convenience for lyophilized to furnish the glycoalkaloidic extract. Chromatographic 65 2 patient adherence to drug treatments - analyses were performed in a HPLC equipment with a diode array 66 3 an overview of secondary Literature detector. Animals were orally (gavage) treated with the extract at 67 4 S. Vinther; M. Christensen; and H.R. Christensen doses of 15, 30 and 60 mg/kg body weight/day. In the colon car- 68 5 Bispebjerg and Frederiksberg Hospitals, University of cinogenesis protocol, two subcutaneous injection of 1,2-dimethyl- 69 6 Copenhagen, Denmark hydrazine (DMH; 40 mg/kg b.w.) were administered for two weeks; 70 7 Background: The convenience of a medication regime, i.e. dosing in the liver carcinogenesis model, a single intraperitoneal injection 71 8 complexity and frequency, is considered of great importance to of diethylnitrosamine (DEN; 200 mg/kg b.w.) was administered. 72 9 patient adherence. The aim of this review was to synthesise review- Animals were sacrificed 10 weeks after DMH or DEN injections for 73 10 level evidence on how convenience affects patient adherence. evaluating aberrant crypt foci (ACF) in colon and GST-P+ (placental 74 11 Material and Methods: A structured search of the Cochrane Library form of glutathione-S-transferase enzyme) foci in liver of Wistar rats. 75 12 and PubMed was conducted to identify English-language reviews, Results showed a significant reduction in the frequency of ACF in the 76 13 systematic as well as non-systematic, dealing with the importance group treated with SL plus DMH in comparison with those treated 77 14 of convenience for patient adherence, irrespective of disease and with DMH alone. These findings suggest that SL displayed a protec- 78 15 medicine type. The PubMed search was limited to reviews pub- tive affect against colon carcinogenesis. On the other hand, SL did 79 16 lished between January 2009 and December 2014. Reference lists not exert any in the liver. 80 17 of included reviews were screened in order to identify other relevant Financial support: São Paulo Research Foundation (FAPESP). 81 18 literature. 82 19 Results: The synthesis was based on 77 reviews with highly vari- 83 20 able methodological quality. Few reviews included a systematic Mitogenic activity and proliferative 84 21 search; no reviews performed systematic meta-analyses. The scope effect of a New-developed short acting 85 22 and focus of reviews varied considerably; nearly all reviews focused Insulin analogue 86 23 on chronic disease, but within a large number of therapeutic areas. M. Pawlowska1; M. Bogiel1; J. Antonik2; J. Smagur2; and 87 24 Most reviews that included a critical appraisal of primary original P. Borowicz1 88 25 literature stressed a lack of well-defined definitions, interventions and 1Institute of Biotechnology and Antibiotics, Warsaw, Poland; and 89 26 endpoints. With this proviso, a general finding for orally administered 2BioCentrum Ltd., Cracow, Poland 90 27 medicines was that ”regime complexity”, including the number of Introduction: Human insulin analogues with modified amino acid 81 28 daily doses and “units” per dosing, seemed to correlate negatively sequence may exert stronger proliferative effect and carcinogenic 92 29 to adherence. For parenterally administered drugs, the importance potential than insulin itself. The objective of the study was to assess 93 30 of convenience was much less clear. mitogenic activity and activation of proliferation in tumorigenic and 94 31 Conclusions: The association between convenience and adherence non-tumorigenic cell lines upon stimulation with a new-developed 95 32 has been discussed within many therapeutic areas, but only rarely short-acting B28Lys-B29Pro human insulin (KP) in comparison to 96 33 examined using a stringent scientific-methodological approach. Data EU Pharmacopeia human insulin standard (HIS) and insulin AspB10 97 34 suggest that increasing regime complexity may lower adherence to with strong mitogenic, cancerogenic activity. 98 35 orally administered drugs; this does not necessarily hold true for Material and Methods: The mitogenic activity and activation of cells 99 36 parenteral treatment. Given the overall low level of evidence, it proliferation were examined by the optimized and validated colori- 100 37 remains uncertain whether increased convenience, often at a higher metric MTS and BrdU tests on two cell lines: MCF7-human breast 101 38 cost, should be a decisive factor when choosing between otherwise adenocarcinoma and MCF10A-normal human epithelial breast cells. 102 39 equal drug treatments. MTS is a method for determining the number of viable cells based on 103 40 mitochondrial dehydrogenase activity measurements. BrdU immu- 104 41 noassay enables quantitative measurement of DNA synthesis and 105 42 Chemopreventive potential of Solanum thus cell proliferation. Nine concentrations of each items at range 106 43 Lycocarpum on colon Carcinogenesis 0.00–800 nM (MTS) or 0.00–2000 nM (BrdU) were tested. 107 44 induced in Wistar Rats Significant differences in increasing number of cells compared to 108 45 109 C.C. Munari1; F.H. Fernandes1; A.L.V. Sávio1; M.O.B. Nasciutti1; negative control and between each tested concentration in pair of 46 110 B. Anfilo1; J.K. Bastos2; and D.M.F. Salvadori1 evaluated items were performed using t-test at α = 0.05. 47 111 1Faculty of Medicine of Botucatu- UNESP, Botucatu, SP, Brazil; Results: There were no statistically significant differences between 48 112 and 2Faculty of Pharmaceutical Sciences of Ribeirão Preto – USP, KP and HIS on MCF10A cells in BrdU test. The differences in 49 113 Ribeirão Preto, São Paulo, Brazil other comparisons may be considered as an incidental effect, as 50 114 Solanum lycocarpum A. St.-Hil. (Solanaceae), popularly known as they appeared coincidentally in non-consecutive concentrations. 51 115 “fruit-of-wolf”, is a hairy shrub or small much-branched tree of the Statistically significance between KP and AspB10 in a wide range 52 116 Brazilian Cerrado. Plants belonging to the genus Solanum are known of concentrations were demonstrated in tumorigenic cells in BrdU 53 117 for their high concentration of alkaloids. Solasonine and solamargine (0.49–2000.0 nM) and non-tumorigenic cells in MTS (0.20–800.0 54 118 are two of the major glycoalkaloids found in at least 100 Solanum nM). BrdU assay on MCF10A demonstrated that AspB10 stronger 55 119 species. Studies on solamargine activities have demonstrated its abil- than KP activated proliferation, but statistically significant differences 56 120 ity to inhibit human tumor cells proliferation. The present study were not showed at each concentration. 57 121 aimed to investigate phytochemical composition and quimiopreven- Conclusions: The insulin KP induced cell proliferation similarly 58 122 tion potential of a fruit extract of S. lycocarpum glycoalkaloid (SL) on to HIS at most of tested concentrations. Lower concentrations of 59 123 colon and liver carcinogenesis in Wistar rats. Fruits of S. lycocarpum AspB10 (from 0.2 nM) stimulated proliferation more efficiently than 60 124 were collected in Ribeirão Preto – SP – Brazil. The dried powder KP. 61 125 from the fruits was submitted to acid-base extraction, suspended in Supported by European Regional Development Found, 62 126 distilled ethanol, filtered, concentrated under reduced pressure and POIG.01.01.02-00-007/08. 63 127 64 128

e4 Volume XX Number XX Biosimilars: regulatory overview

1 Undergraduate electives in clinical Material and Methods: From March 2011 to March 2014, 170 65 2 Pharmacology at the interface of patients receiving endovascular repair of their AAA were included in 66 3 Academia and industry the present study. Patients were divided according to their medication 67 4 S.C. Goulooze1; K. Franson2; A.F. Cohen1,3; and R. Rissmann1,3 included statins and subdivided according to their supra- or infra- 68 5 1Centre for Human Drug Research, Leiden, The Netherlands; renal endovascular fixation. Serum Creatinine (SCr) and Creatinine 69 6 2University of Colorado Skaggs School of Pharmacy & Clearance (CrCl) were determined preoperatively and 3 days postop- 70 7 Pharmaceutical Science, Aurora, USA; and 3Leiden University eratively. Patients with known renal disease and severe renal artery 71 8 Medical Center, Leiden, The Netherlands stenosis were excluded from the study. 72 9 Introduction: The Centre for Human Drug Research (CHDR) Results: Patients receiving an infrarenal fixation had no change 73 10 is a non-profit clinical research institute at the interface between in their renal function. However, patients with suprarenal fixation 74 11 academia and the pharmaceutical industry and offers internships not receiving statins marked a non significant deterioration in renal 75 12 to undergraduate (bio-)medical students. During these internship, function in the early postoperative period, whereas patients under 76 13 students get hands-on experience in clinical pharmacology research. statins had a statistical improvement both in SCr (preoperative 1.25 ± 77 14 The objective of the study was to assess the clinical pharmacology 0.13 vs postoperative 0.98 ± 0,12) and CrCl (preoperative 82.4 ± 78 15 research internships at the CHDR using an online survey of (former) 2.5 vs postoperative 88.7 ± 3.1). Also there was a statistically sig- 79 16 interns. Areas of interest included general perceptions of the intern- nificant difference between patients receiving and not receiving 80 17 ship and a comparison with academic research internships. statins when measuring SCr and CrCl changes (P = 0.001 and 81 18 Methods: An anonymous online Google Forms® survey with P = 0.005 respectively). 82 19 multiple choice, multiple answer and open-ended and Likert-scale Conclusions: In the present study statins improved renal function, 83 20 questions—was sent to all students that started an internship at the during the short postoperative period, in patients with suprarenal 84 21 CHDR between 2007–2014. fixation for AAA, compared to those not receiving statins. 85 22 Results: The response rate of the online survey was high (53 students, 86 23 61%). Most students gave the internship an overall rating of good 87 24 (43%) or excellent (42%), and 80.5% strongly agreed that their Impact of direct healthcare professional 88 25 training at the CHDR was helpful to their career. Many students communication on diclofenac 89 26 considered their internship at the CHDR to be (much) more broad consumption 90 27 81 (58%) and outcome-driven (50%), compared to academic research M. Stanković ; N. Turković ; L. Čizmović ; Ž. Bešović ; M. Drljević ; 28 internships. Although CHDR has a commercial setting, it was not and S. Mugoša 92 29 considered a major distraction by 98% of the interns. A Wilcoxon Agency for Medicines and Medical Devices, Podgorica, 93 30 rank-sum test revealed a significantly lower score of pre-Master Montenegro 94 31 students in both “Own knowledge of clinical research” and “Link Introduction: In July 2013, Pharmacovigilance Risk Assessment 95 32 between internship and knowledge from their study” when they were Committee of the European Medicines Agency issued the recom- 96 33 compared to Master students (both P < 0.01). mendation on new measures to minimise cardiovascular risks after 97 34 Conclusion: The clinical pharmacology research internships at the use of medicines containing diclofenac. Consequently, the Agency 98 35 CHDR are perceived by most students as having a good or excellent for Medicines and Medical Devices of Montenegro took regulatory 99 36 quality, and being helpful to their career. Pre-Master students might measure and sent letter to healthcare professionals who prescribe, 100 37 benefit from additional guidance to ensure a sufficient knowledge dispense or administer medicines containing diclofenac. Restriction 101 38 level for an effective internship. of indications, introduction of new contraindications, with respect 102 39 to prescription status of diclofenac, should reduce high consumption 103 40 of these medicines in Montenegro. 104 41 Statins perioperative use improves Material and Methods: This is a retrospective analysis of data from 105 42 renal function, in patients undergoing the Agency's reports on medicines consumption in Montenegro, in 106 43 endovascular treatment of Abdominal 2012 and 2013. Comparation was performed, taking into considera- 107 44 Aortic Aneurysms - preliminary data from tion consumption of diclofenac before and after communication with 108 45 a prospective observational study healthcare professionals initiated by the Agency. For comparative 109 46 110 Ch. Pourzitaki1; S. Tsakiliotis2; G. Tsaousi1; G. Papazisis1; and view of consumption international standard was used, in accord- 47 111 D. Kouvelas1 ance with the recommendations of the World Health Organisation 48 112 1School of Medicine, Aristotle University of Thessaloniki, Greece; - ATC/DDD methodology, number of defined daily doses per 1000 49 113 and 2Papageorgiou General Hospital, Thessaloniki, Greece inhabitants per day. 50 114 Introduction: Statins have beneficial effects on the vascular func- Results: Analysis of the Agency's report in 2012 showed that 51 115 tion, inducing an improvement of endothelial dysfunction as well diclofenac was the third most frequently used medicine with 52 116 as an increase in nitric oxide bioavailability and antioxidant effect. DDD/1000inhabitants/day-46,74. The same analysis in 2013 showed 53 117 Their anti-thrombotic effect and anti-inflammatory properties the same position on the list of most frequently used medicines, but 54 118 combined with the ability to stabilize the atherosclerotic plaques with DDD/1000 inhabitants/day-39,86. The data indicated that the 55 119 contribute to enhancement of vascular function. The endovascular total consumption was reduced by 14.72%. Outpatient consump- 56 120 repair of abdominal aortic aneurysms (AAA) can reduce systemic tion was reduced by 14.91%, while hospital was reduced by 2.78%. 57 121 ischaemia effects, however many patients develop renal impair- Conclusions: The regulatory measures, taken by the Agency, in line 58 122 ment, probably due to micro- or macroembolisation into the renal with national legislation and based on new information about safe 59 123 arteries after aortic manipulation of endovascular materials and an use of diclofenac, have resulted in decreased consumption. As the 60 124 induced inflammatory response. Based on the beneficial effects of consumption is still high, Agency is going to repeat communication 61 125 statins we conducted a prospective observational study investigating in order to fully implement regulatory decisions made in EU. 62 126 their effects on renal function of patients undergoing endovascular 63 127 aortic aneurysm repair. 64 128

2015 e5 Clinical Therapeutics

1 PK/PD Modelling of Diltiazem in healthy Methods: In order to optimize CYP450 activity while decreasing 65 2 subjects using HRV parameters cell apoptosis, we tested different culture conditions for differentia- 66 3 M. Bogiel1; M. Pawlowska1; J. Duda1; and Edmund Sieradzki2 tion by varying DMSO concentration from 0 to 2% and by adding 67 4 1Institute of Biotechnology and Antibiotics, Warsaw, Poland; and growth factors EGF and HGF. CYP activity was assessed using a 68 5 2Medical University of Warsaw, Poland cocktail approach by LC-MS/MS. Expression of several CYP450, 69 6 Introduction: Diltiazem hydrochloride, an antihypertensive calcium phase II enzymes UGT1A1 and UGT2B7 and various transporters 70 7 antagonist exhibits also frequency-dependent effects at the atrioven- was assessed with Nanostring® technology. 71 8 tricular (AV) node and is effective in slowing the rapid ventricular Results and Conclusions: Increase of DMSO concentration resulted 72 9 rate. The nature of the concentration-response relationship with in similar increase of the differentiated pattern. However, cell via- 73 10 regard to diltiazem effect on heart rate variability (HRV) parametres bility was significantly decreased when adding DMSO up to 2%. 74 11 has not been evaluteded so far. The aim of this study was to examine Considering CYP450 activity, DMSO increased significantly the 75 12 the PK/PD profile of diltiazem using HRV parameters as pharma- activity of CYP3A4, 2B6 and 1A2. The addition of growth factors 76 13 EGF and HGF was found to have a negative impact on cell differen- 77 codynamic factors with the application of a standard Emax model. 14 Material and Methods: The study was conducted on 8 healthy vol- tiation and thus CYP activity, but significantly improved cell viability. 78 15 unteers, following multiple doses of 120 mg of diltiazem MR once There was a good correlation between CYP activity and CYP expres- 79 16 daily. Diltiazem concentration was determined up to 24h by fully vali- sion (P < 0.05) except for CYP1A2. In all conditions tested, CYP 80 17 dated HPLC method. Compartmental analysis of diltiazem pharma- 2D6 showed a weak activity and expression levels were undetectable. 81 18 cokinetic was used. The temporal profile of diltiazem was described UGT1A1 and UGT2B7 transcripts were found at appreciable levels 82 19 by a one-compartment, first-elimination model. Pharmacodynamic and were influenced by DMSO concentration, as well as hepatic 83 20 effects were measured continuously (ECG Holter monitoring) up to transporters. Efflux transporters MRP2, MRP3 and MDR1 (P-gp) 84 21 24h after drug administration. Classical HRV analysis in time and levels were high, whereas BSEP, BCRP and MRP1 levels were low. 85 22 frequency domains was conducted and a few components of HRV The uptake transporter OCT1 was largely expressed and OATP1B1, 86 23 were estimated (RMS, SDNN, LF, and HF). The goodness of fit to 2B1, OCT3, OAT2 expression were found in acceptable levels. On 87 24 pharmacodynamic model interpretation took place with the help of the contrary, NTCP and OATP1B3 transcripts were undetectable. 88 25 Differentiation medium containing 1.5% showed similar viability 89 Akaike Information Criterion (AIC). Standard Emax model parameters 26 compared to MIL720 from Biopredic® used as reference, with slightly 90 (EC50, Emax, E0, ke0) were calculated. 27 Results: lower CYP450 activities. This medium was thus chosen for further 81 28 metabolism experiments on the HepaRG cell line. 92 29 93 30 Parameter Mean value (SD) 94 31 95 Pharmacokinetics In-vitro evaluation of DDI with cobicistat 32 ka[h-1] 0.3771 (0.1552) and ritonavir using heparg cell line 96 AUC [ng/mL*h] 1268 (604) 33 (0-t) F. Storelli; C. Bruggmann; F. Doffey-Lazeyras; C. Samer; 97 34 MRT[h] 5.112 (1.531) 98 Cmax[ng/mL] 115.9 (48.33) J. Desmeules; and Y. Daali 35 t [h] 3.689 (0.556) 99 max University Hospitals of Geneva, Geneva, Switzerland k [h-1] 0.2082 (0.0495) 36 el Background: Cobicistat is a new pharmacoenhancer which has 100 37 Pharmacodynamics recently been approved by the EMEA as a boosting agent for the 101 38 RMS SDNN LF HF HIV protease inhibitors atazanavir and darunavir. As opposed to rito- 102 39 Significance of 0.0275 0.0049 0.0033 ns navir, cobicistat does not show any antiviral activity. Also, previous 103 PK/PD correlation 40 inhibition studies on human hepatic microsomal fractions showed 104 41 (p value) 105 AIC 53.18 (7.53) 59.53 (6.26) 109.7 (7.7) 105.7 (10.7) a more specific inhibition of CYP3A4 of cobicistat versus ritonavir 42 k [h-1] 1.83 (2.08) 0.7092 (1.110) 3.45 (4.83) 1.808 (2.002) 106 e0 and a lack of induction potential on CYP3A4. The aim of this work E [ms];[ms2] 462.50 (443.21) 97.14 (105.91) 5101 (5922) 1898 (2742) 43 max was to investigate CYP450 inhibition/induction potential of major 107 EC50[ng/mL] 2120 (2470) 105.60 (201.33) 240.61 (501.90) 136.5 (131.0) 44 2 108 E0[ms];[ms ] 59.37 (16.40) 133.81 (23.57) 2850 (941.9) 1009 (335) CYPs by cobicistat and ritonavir in HepaRG. 45 Methods: Low density-seeded confluent HepaRG cells were dif- 109 46 110 Time delay between the plasma concentrations of diltiazem and ferentiated with 1.5% DMSO and plated in 24-well plates. At day 47 111 the response with the clockwise hysteresis loop was observed. 12 after plating, CYP activity in the presence/absence of cobicistat 48 112 Conclusions: The good fit for E model was established. Biophase and ritonavir (0-50 µM) was assessed using a cocktail approach and 49 max 113 distribution model with a tolerance to the effect is the most probable IC50 was calculated by linear regression. For induction assay, cobi- 50 114 PK/PD relationship in regards to AV effects of diltiazem. cistat or rifampicin (0-50 µM) was incubated with differentiated 51 HepaRG cells for 72 hours in a specific medium (0.5% DMSO, no 115 52 FBS). DMSO concentration was decreased to 0.5% 24 hours before 116 53 117 Evaluation of CYP450 and transporters addition of the inducers. CYP3A4 activity was assessed by incuba- 54 tion of midazolam 5 µM for 3 hours at 37°C and quantification of 118 55 expression and activity in heparg cell 119 line under different conditions 1’-hydroxymidazolam by LC-MS/MS. 56 Results: Cobicistat and ritonavir showed similar inhibition of CYP 120 F. Storelli; C. Bruggmann; F. Doffey-Lazeyras; C. Samer; 57 3A4 with IC50 of 0.107 µM and 0.105 µM respectively. IC50 values 121 J. Desmeules; and Y. Daali 58 of CYP 2B6, 1A2, 2C19 and 2C9 were lower for cobicistat than for 122 University Hospitals of Geneva, Geneva, Switzerland 59 ritonavir, thus suggesting that cobicistat may be a more potent inhibitor 123 Background: HepaRG cell line is able to differentiate to both hepat- 60 of these CYP450 than ritonavir. Considering CYP3A4 induction, cobi- 124 ocyte-like and biliary-like cells after reaching confluence. Previous 61 cistat did not seem to induce CYP 3A4. Rifampicin, which was used 125 works have shown that confluent HepaRG cells start to differentiate 62 as a positive control, showed induction of CYP 3A4 up to 1.6 fold. 126 63 when adding 2%DMSO in the culture medium. However, DMSO is 127 64 well known to induce cell death. 128

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1 Conclusions: This work has showed the suitability of the HepaRG 3D photography for Skin lesion 65 2 cell line to study inhibition drug interactions in vitro. Induction Quantification 66 3 assays however have still to be optimized to reach greater levels of G. Hogendoorn1; C. Lemoine1,2; R. Rissmann1,2; and 67 4 induction. J. Burggraaf1,2 68 5 1Centre for Human Drug Research, Leiden, The Netherlands; and 69 6 2Leiden University, Leiden, The Netherlands 70 7 Bioequivalence of Fixed-Dose Introduction: Reliable methods to quantify skin lesions are critical 71 8 Combinations of Dapagliflozin/ for the evaluation of disease severity and assessment of therapeu- 72 9 Metformin Relative to Single tic response. In dermatological trials often two dimensional digital 73 10 Components in Healthy Subjects photography is utilized which has inherent disadvantages. It appears 74 11 D.W. Boulton1; M. Chang1; S.C. Griffen2; C. Kitaura1; S. Lubin1; that high-resolution three-dimensional (3D) imaging may offer many 75 12 A. Pollack1; and F. LaCreta1 advantages such as offline 3D visualization and automatic picture 76 13 1Bristol-Myers Squibb Company, Princeton, NJ, USA; and segmentation resulting in an objective and detailed skin lesion char- 77 14 2JDRF, New York, NY, USA acterization. At present this technique is not optimally technical and 78 15 Background: In patients with type 2 diabetes (T2DM) fixed-dose analytical validated which is a pre-requisite for clinical application. 79 16 antihyperglycaemic combinations (FDCs) may provide complemen- Material and Methods: In this study we investigated the perfor- 80 17 tary efficacy, reduce tablet burden, and improve compliance. The mance and clinical use of the 3D skin-imaging LifeViz™ system 81 18 aim of this study was to assess the bioequivalence and tolerability (Quantificare, Sophia Antipolis, France) in conjunction with the 82 19 of 2 strengths of dapagliflozin (DAPA)/metformin extended-release DermaPix Software. The validation of the LifeViz Micro was con- 83 20 (MET-XR) FDCs versus their individual components (ICs) in healthy ducted with four trained operators that captured a synthetic phantom 84 21 subjects. object on three different skin backgrounds at four time points during 85 22 Material and Methods: This open-label, randomised, 2-way crosso- a period of one week. 86 23 ver, 4-arm study was conducted in 141 healthy adult Brazilian sub- Results: Coefficient of variations for volume of the 3D system were 87 24 jects. Two oral doses (5 mg DAPA/500 mg MET-XR and 10 mg 1.0%, 2.6% and 1.4% for inter-operator, skin background and inter- 88 25 DAPA/1000 mg MET-XR) were evaluated in fed and fasted states. day variability, respectively. The overall precision of the system was 89 26 Results: Under fed and fasting conditions the 5 mg DAPA/500 mg 2.7% for volume, 1.6% for diameter and 4.1% for height. In order 90 27 MET-XR FDC was bioequivalent to its ICs (Table). The 10 mg to determine accuracy of the system, a ruler was photographed and 81 28 DAPA/1000 mg MET-XR FDC was bioequivalent to its ICs only a mean error of 0.3% (range 0.0-0.8%) was observed. Preliminary 92 29 data on cutaneous lesions also show low inter-observer variability 93 in fed patients. Cmax for metformin was not bioequivalent to its ICs 30 (upper 95% CI outside 80%–125%) in fasted patients; this small and accurate images. 94 31 increase was not considered clinically meaningful as metformin is Conclusions: This validation study demonstrates that this novel 95 32 recommended to be administered with food. The safety and toler- 3D-imaging system is precise and objectively quantifies a phantom 96 33 ability of the FDCs were generally similar to their ICs; no serious object representing a skin lesion. The results support clinical use of 97 34 adverse events were reported. this technology enabling high-resolution computation. Also the accu- 98 35 Conclusions: Both DAPA/MET-XR FDCs were bioequivalent to their racy results are promising, but needs to be extended with accuracy 99 36 ICs, except 10mg DAPA/1000mg MET-XR in fasted patients, sup- assessment of absolute measurements. The preliminary clinical data 100 37 porting their use in patients with T2DM. suggest that application of this non-invasive imaging technique is 101 38 suitable to quantitatively measure characteristics of cutaneous lesions 102 39 Geometric mean and may be a promising tool in clinical trials. 103 40 point estimate of CI (90%) for the 104 41 Parameter FDC/IC (%) point estimate 105 42 Therapy adherence in elderly of 106 43 5 mg DAPA/500 mg MET-XR 107 Arm-1 (n 34) Dapagliflozin C 104.7 (96.3; 113.7) Northern Portugal 44 = max 108 asted I.C. Pinto1,3; F. Pereira2; and R. Mateos-Campos3,4 45 AUC 101.1 (98.0; 104.2) 109 0-inf 1Center for Research and Intervention in the Elderly, Health 46 Metformin C 96.7 (87.1; 107.5) 110 max School of Polytechnic Institute of Bragança, Portugal (isabel. AUC0-inf 101.7 (93.3; 110.8) 47 2 111 Arm-2 (n = 29) Dapagliflozin C 96.6 (88.0; 106.0) [email protected]); Center for Research and Intervention in the 48 max 112 Fed Elderly, Polytechnic Institute of Bragança, Portugal (fpereira@ 49 113 AUC0-inf 102.0 (98.9; 105.2) 3 Metformin C 100.9 (95.1; 107.0) ipb.pt); School of Pharmacy, University of Salamanca, Spain; and 50 max 4 114 AUC 104.6 (97.3; 112.4) INESPO - Innovation Network Spain-Portugal ([email protected]) 51 0-inf 115 10 mg DAPA/1000 mg MET-XR Introduction: The elderly population has been growing significantly, 52 Arm-3 (n 34) Dapagliflozin C 103.7 (96.2; 111.7) 116 = max leading to an increased prevalence of chronic diseases and conse- 53 Fasted 117 quent taking medication. The complex therapies of elderly can lead 54 AUC0-inf 102.7 (100.7; 104.8) 118 Metformin C 118.3 (109.8; 127.5) to therapy non-adherence, increasing several health risks. 55 max 119 AUC0-inf 112.6 (104.8; 120.9) Aim: This study aimed to estimate the prevalence of therapy adher- 56 Arm-4 (n 32) Dapagliflozin C 91.9 (80.9; 104.4) 120 = max ence and associated factors. 57 Fed 121 Material and Methods: This cross-sectional study was based on a 58 AUC0-inf 99.1 (97.0; 101.3) 122 Metformin C 107.1 (102.6; 111.8) questionnaire, with MAT scale (measure of adherence to therapy) 59 max 123 AUC 98.6 (93.2; 104.3) validated for the Portuguese population (Lima, 2001) based on 60 0-inf 124 61 125 62 126 63 127 64 128

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1 the Morisky scale, applied to 52 elderly (≥ 65 years) from northern Characterization of Uracil Catabolism 65 2 Portugal. To assess therapy adherence, those whose average adher- variability in healthy Volunteers 66 3 ence levels were ≥ 5, were called adherent. It was used descriptive D. Kummer1,2; B. Rindlisbacher1; S. Fontana3; J. Sistonen1; 67 4 statistics. The level of association between categories of variables was U. Amstutz1; and C. Largiadèr1 68 5 studied through the adjusted residuals (AdR) and the relationship 1Institute of Clinical Chemistry, Bern University Hospital, and 69 6 between adherence to the therapeutic and the number of medications University of Bern, Bern, Switzerland; 2Graduate School for 70 7 taken per day was studied using the Mann-Whitney U test, with a sig- Cellular and Biomedical Sciences, University of Bern, Bern, 71 8 nificance level of 5%. The study was approved by Ethics Committee. Switzerland; and 3Regional Blood Transfusion Service of the Swiss 72 9 Results: The sample consisted mainly of males elderly (61.5% vs. Red Cross, Bern, Switzerland 73 10 38.5%), aged between 67 and 98 years (mean 82.71), and while Uracil catabolism is crucial for the pharmacokinetics of the chemo- 74 11 48.1% was between 75–84 years old. The participants shows high therapeutic 5-fluorouracil (5-FU) since 5-FU is degraded by the same 75 12 therapy adherence (96.2%). The non-adherent elderly are related pathway. Decreased activity of the first catabolizing enzyme, dihydro- 76 13 to self-medication (AdR= 4.3), with the high level of cholesterol pyrimidine dehydrogenase (DPD), is a major predictor of 5-FU toxic- 77 14 (AdR= 2.9) and chronic pain (AdR= 2.9). The non-adherent elderly ity with known risk variants in the DPD gene (DPYD) accounting for 78 15 seem tend to take more drugs per day, although not statistically sig- ~30% of toxicities. However, not all toxicity cases can be explained 79 16 nificant (P = 0.063). by DPYD risk variants. To date, the phenotypic variability in the 80 17 Conclusions: This study shows that a large prevalence of elderly catabolism downstream of DPD by dihydropyrimidinase (DHP) and 81 18 adhered to the therapy prescribed. Self-medication, having high β -ureidopropionase (bUP), potentially contributing to 5-FU toxicity, 82 19 cholesterol and chronic pain and higher number of different drugs has not been investigated. Thus, we aimed to characterize the base- 83 20 per day seem related to non-adherence. line phenotypic variability of endogenous metabolites and metabolic 84 21 Key words: Elderly, Therapy adherence, Therapy non-adherence. ratios of 5-FU catabolism enzymes and to correlate the phenotype 85 22 with genetic variation in the DHP and bUP genes (DPYS and UPB1). 86 23 Material and Methods: Three variants in DPYS and UPB1 previ- 87 24 A Limited number of prescribed Drugs ously associated with 5-FU toxicity were genotyped in 320 healthy 88 25 89 account for the majority of clinically volunteers and their plasma uracil, dihydrouracil (UH2), β -ureidopro- 26 relevant Drug interactions pionic acid (UPA), and β -alanine (BAL) concentrations were deter- 90 27 J. Holm1,2; B. Eiermann1; E. Eliasson1,2; and B. Mannheimer1,3 mined by LC-MS/MS. 81 28 1Karolinska Institutet, Stockholm, Sweden; 2Karolinska University Results and Conclusions: High inter-individual variability in all met- 92 29 Hospital, Stockholm, Sweden; and 3Södersjukhuset, Stockholm, abolic ratios was observed. Sex-dependent differences were detected 93 30 Sweden at each enzymatic step in the uracil catabolism pathway, with lower 94 31 95 Introduction: Drug-drug interactions constitute a predictable and metabolite levels (P ≤ 0.007) in women. Moreover, lower UPA/UH2 32 in many cases avoidable cause of adverse drug reactions and thera- ratios (P < 0.001) were observed in women, suggesting that reduced 96 33 97 peutic failure. We conducted a register-based study to investigate the 5-Fluoro-UH2 catabolism may contribute to higher fluoropyrimi- 34 prevalence of prescribed combinations of interacting drugs in the dine toxicity rates observed in females. Furthermore, volunteers 98 35 99 whole Swedish population (Holm et al. Eur J Clin Pharmacol. 2014). carrying DPYS variant c.265-58T> C had lower UH2 plasma levels 36 100 Material and Methods: A retrospective, cross-sectional register (P = 0.033) and higher UPA/UH2 ratios (P = 0.036) and carriers 37 study was conducted, covering four months in 2010. Data from of the UPB1 variant c.1-80C> G showed lower BAL plasma levels 101 38 the Prescribed Drug Register on all dispensed drug prescriptions in (P = 0.004). These initial results are in agreement with the previously 102 39 Swedish pharmacies from January 1 to April 30 were linked to the observed reduced fluoropyrimidine toxicity in c.265-58C carriers 103 40 drug-drug interaction database SFINX. The analysis focused on drug and increased toxicity in carriers of c.1-80G, indicating a possible 104 41 interactions classified in the database as clinically relevant that can be functional effect related to these variants. 105 42 handled, e.g. by dose adjustments (C-interactions), and clinically rele- 106 43 vant interactions that should be avoided (D-interactions). Interactions 107 44 were categorized according to clinical consequence and drug type and Polypharmacy and potentially 108 45 prevalences of interacting drug combinations were described. The inappropriate medication in elderly of 109 46 study was approved by the Regional Ethics Committee. Northern Portugal 110 47 111 Results: About half of the population were dispensed at least one I.C. Pinto1,3; F. Pereira2; and R. Mateos-Campos3,4 48 112 drug prescription. Mean (SD) number of dispensed drugs was 3.8 1Center for Research and Intervention in the Elderly, Health 49 113 (3.4). About 2.5 million potentially interacting drug combinations School of Polytechnic Institute of Bragança, Portugal (isabel. 50 114 were identified in the study population of 9.3 million people. Among [email protected]); 2Center for Research and Intervention in the 51 115 detected interactions 38% were classified as C-interactions and 3.8% Elderly, Polytechnic Institute of Bragança, Portugal (fpereira@ 52 116 as D-interactions. About half of all C- and D-interactions were com- ipb.pt); 3School of Pharmacy, University of Salamanca, Spain; and 53 117 binations of drugs with potential to cause therapeutic failure. The 15 4INESPO - Innovation Network Spain-Portugal ([email protected]) 54 118 most prevalent combinations accounted for 80% of D-interactions. Introduction: The growing aging of population and increasing preva- 55 119 The 10 most prevalent individual drugs were involved in 94% of all lence of chronic diseases require the simultaneous use of drugs, lead 56 120 D-interactions. to the issue of polypharmacy and potentially interactions and inap- 57 121 Conclusions: A limited number of drugs and a few specific drug propriate use. 58 122 combinations account for the majority of D-interactions, i.e. clini- Aim: To characterize polymedicated elderly and related factors, iden- 59 123 cally relevant interactions that should be avoided, in Sweden. About tify potentially interactions and inappropriate medication in elderly. 60 124 half of interacting drug combinations among C- and D-interactions Material and Methods: This cross-sectional study was based on 61 125 potentially leads to treatment failure. a questionnaire applied to 69 elderly ( 65 years) from northern 62 ≥ 126 Portugal. It was considered as polymedicated seniors taking 5 63 ≥ 127 drugs. Beers list and the Delafuente classification were used to evalu- 64 128

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1 ate the therapeutic and possible interactions. It was used descriptive Conclusion: DBS technique combined with an innovative sampling 65 2 statistics and a model of binary regression, with a significance of 5%. device and a sensitive analytical method can be used as a self-test for 66 3 The study was approved by Ethics Committee. CYP and P-gp phenotyping The use of this technique can be further 67 4 Results: The sample consisted mainly of males (53.6% vs. 46.4%), enlarged to the quantification of other substances for PK studies and 68 5 aged between 66 and 99 years (mean 82.01), while 65.2% have therapeutic drug monitoring. 69 6 more than 80 years. However, most elderly are not polymedicated 70 7 (58%), on average 4.61 different drugs are administered per day 71 8 (maximum= 19), antihypertensives (36.2%) and antacids (30.04%) Therapeutic Drug monitoring for 72 9 are the most prescribed. Hypertension and depression increase the antidepressants and Antipsychotics – a 73 10 risk of polymedication eightfold (P = 0.004) and fivefold (P = 0.011) longitudinal prevalence analysis 74 11 respectively. Female gender seems increase the risk of polypharmacy S.M. Wallerstedt1; and J.D. Lindh2 75 12 threefold, although not statistically significant (P = 0.102), and 1University of Gothenburg & Sahlgrenska University Hospital, 76 13 regarding age, the older age group (> 85 years) seems reduces the Gothenburg, Sweden; and 2Karolinska Institutet & Karolinska 77 14 risk of polypharmacy in 0.6 fold, but also not statistically significant. University Hospital, Stockholm, Sweden 78 15 According with Delafuente classification, 1.4% of elderly has poten- Background: Therapeutic drug monitoring (TDM) can help cli- 79 16 tially drug interactions (Omeprazole and Iron salts). According to nicians to optimize dosing of medicines. Evidence on the use of 80 17 the list of Beers, 5.8% of seniors take drugs that classified as having this service in psychiatry mainly refers to questionnaire studies. 81 18 some indications (hydroxyzine, ). The aim of this study was to use register data to describe the 82 19 Conclusions: Regarding polypharmacy, 42% of elderly are poly- prevalence of TDM for antidepressants and antipsychotics dur- 83 20 medicated with an average of about 5 different drugs per day, anti- ing 2006-2013. 84 21 hypertensives and antacids the most prescribed. Hypertension and Material and Methods: The study population consisted of indi- 85 22 depression are highly associated with polypharmacy. We identified 86 viduals, ≥ 5 years of age, residing in the Stockholm County. The 23 one potentially drug interaction and about 6% of elderly taking drugs prevalence of TDM for each study year was calculated with the 87 24 that classified as having some indications. number of individuals in whom TDM had been performed as nomi- 88 25 Key words: Beers list, Delafuente classification, Elderly, Inappropriate nator (extracted from the TDM database at Karolinska University 89 26 medication in elderly, Medication interactions, Polypharmacy. Laboratory) and the number of treated individuals as denominator 90 27 (extracted from the Swedish Prescribed Drug Register). The preva- 81 28 lence of TDM was compared between substances according to the 92 29 Innovative approach to Blood sampling level of TDM recommendation by guidelines. 93 30 using dried Blood spots. application to Results: In 2006, 641 in 133,275 (0.48%) individuals on antide- 94 31 Pharmacokinetics and Cytochrome P450 pressants were subjected to TDM. In 2013, the corresponding figure 95 32 Phenotyping was 580 in 162,998 (0.36%). In 2013, the most frequently analysed 96 33 M. Bosilkovska1; J. Deglon2; A. Thomas2; C. Samer1; antidepressants were nortriptyline (6.2%) and clomipramine (4.5%). 97 34 J. Desmeules1; and Y. Daali1 For patients on antipsychotics, the prevalence of TDM increased 98 35 1Geneva University Hospitals, Geneva, Switzerland; and between 2006 and 2013, from 729 in 31,463 (2.3%) to 1,338 in 99 36 2University Center of Legal Medicine, Lausanne-Geneva, 32,534 (4.1%). In 2013, the most frequently analyzed antipsychotics 100 37 Switzerland were clozapine (29%) and perphenazine (22%). For both antidepres- 101 38 Background: The use of dried blood spots (DBS) has gained in popu- sants and antipsychotics, TDM was more common in men than in 102 39 larity in the last few years over conventional whole blood or plasma women. A trend to a greater prevalence was found for substances 103 40 sampling for PK or drug monitoring. In order to overcome the impact strongly recommended for TDM than for substances with a lower 104 41 105 that haematocrit has on the spreading of the applied drop of blood, level of recommendation (5.6% vs. 1.1%; P = 0.063). 42 precise knowledge of the collected volume is crucial for the determi- Conclusions: Each year, less than one in 200 patients on antide- 106 43 nation of drug/metabolites concentrations. pressants and less than one in 20 patients on antipsychotics have 107 44 Material and Methods: Although the collection of an accurate capil- their treatment personalized by means of TDM. The use of TDM is 108 45 lary volume using a volumetric micropipette is simpler than venous increasing for antipsychotics but not for antidepressants. Men are 109 46 blood collection, it still needs to be conducted by trained technicians more frequently monitored by plasma concentrations than women. 110 47 using dedicated instruments. To simplify this process a new capillary 111 48 blood collection device has been developed. The prototype integrates a 112 49 113 patented microfluidic plate (WO/2013/144743) allowing for accurate Hospitalisations by Drug interactions 50 volume control and a conventional filter paper card for blood storage. 114 51 with nsaids in elderly poly-treated 115 The concentrations and pharmacokinetic profiles of a patients: outcome research on 52 P-glycoprotein (P-gp) and six cytochrome P450 (CYP) probes and 116 53 administrative databases 117 their metabolites obtained with the new sampling device have been 1 2 1 1 1 54 C. Piccinni ; L. Lionello ; E. Raschi ; I.C. Antonazzo ; A. Koci ; 118 compared with a conventional volumetric micropipetting method in 2 2 2 1 55 P. Pagano ; M. Magnani ; M. Manzoli ; F. De Ponti ; and 119 a clinical trial including 30 volunteers who have received the Geneva 1 56 E. Poluzzi 120 cocktail for CYP and P-gp phenotyping. The quantification was done 1 57 Department of Medical and Surgical Sciences, University of 121 using a previously validated LC/MS-MS method. Bologna, Bologna, Italy; and 2Local Health Authority Bologna, 58 Results: Concentrations obtained with the new microfluidic sam- 122 59 Italy 123 pling device showed excellent correlation with conventional micro- Background: Elderly patients are highly susceptible to poly-pharmacy, 60 pipetting concentrations with slopes values close to 1 (0.91 – 1.03) 124 61 2 which may cause drug–drug interactions and relevant hospitalisations. 125 and determination coefficients R > 0.90 for all of the 13 analysed 62 These often involve NSAIDs (Non- Steroidal-Anti-Inflammatory- 126 substances. Sampling could be successfully performed by the volun- Drugs), which are inappropriately prescribed. This study aimed to 63 teers themselves with almost no previous training. 127 64 128

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1 investigate the risk of kidney injury and bleeding following various (0.07; 0.23) to 0.93 (0.82; 0.97). According to the Swedish, French, 65 2 NSAIDs interactions in the elderly poly-treated population. and German indicators of potentially inappropriate drugs, 18%, 66 3 Material and Methods: An historic cohort study based on adminis- 24%, and 22% of the patients had potentially inappropriate drug 67 4 trative databases of the Local Health Authority of Bologna (866,000 treatment. The sensitivity was 0.24 (0.18; 0.32), 0.29 (0.22; 0.37), 68 5 inhabitants) was performed. Patients with at least a NSAID prescrip- and 0.29 (0.22; 0.37), respectively. The specificity was 0.97 (0.88; 69 6 tion in the first semester of 2012 were selected among elderly ≥( 65 0.99), 0.90 (0.80; 0.95), and 0.97 (0.88; 0.99). 70 7 years) poly-treated (> 4 different drugs) subjects. Co-prescriptions Conclusions: These findings suggest that the indicators may be valua- 71 8 of NSAIDs + ACE- Inhibitors (or sartans), NSAIDs + diuretics, ble to monitor changes in drug utilization and effects of interventions, 72 9 NSAIDs + ACE-Inhibitors (or sartans) + diuretics (triple whammy), but are of limited value for identifying patients at risk of suboptimal 73 10 NSAIDs + metformin, NSAIDs + SSRIs, NSAIDs + corticosteroids drug treatment and to assess prescriber performance. 74 11 and NSAIDs + warfarin were considered as potential interactions. 75 12 Kidney injury and bleeding hospitalisations represented the outcome 76 13 measures. Kaplan-Meier curves and Cox regression model were used An in silico model of 77 14 to estimate the risk of two outcomes following interactions. Hazard aspirin-iduced inactivation of platelet 78 15 Ratios (HRs), with 95% Confidence Interval (95CI), were adjusted and Megakaryocyte Cyclooxygenase-1 79 16 for gender, age and concomitant drugs. A. Giaretta1; B. Rocca2; B. Di Camillo1; G.M. Toffolo1; and 80 17 Results: Out of 34,353 elderly poly-treated patients, 7,420 subjects C. Patrono2 81 18 received NSAIDs (60.8% female, 76.9 average age). Among these, 1Department of Information Engineering, University of Padova, 82 19 85.7% was exposed to NSAIDs + ACE-Inhibitors(or sartans), 69.9% Padova, Italy; and 2Department of Pharmacology, Catholic 83 20 to NSAIDs + diuretics, 32.8% to triple whammy, 21.6% to NSAIDs + University School of Medicine, Rome, Italy 84 21 metformin, 20.1% to NSAIDs + SSRIs, 17.1% to NSAIDs + cor- Background: Aspirin is a short-lived, irreversible inhibitor of platelet 85 22 ticosteroids and 8.2% to NSAIDs + warfarin. A significant risk of cyclooxygenase (COX)-1. We have recently reported that aspirin 86 23 kidney injury was found only for triple whammy (adjHR: 1.33; 95CI: action throughout the 24-hour dosing interval is impaired under 87 24 1.12-1.59); instead for other interactions involving antihypertensives conditions of accelerated platelet formation such as essential throm- 88 25 no risk increase was retrieved. The bleeding risk resulted statistically bocythemia (ET). An in silico model of aspirin pharmacodynamics 89 26 significant only for NSAIDs+ warfarin (2.84; 1.29-6.29), but not for might help elucidating the dynamic features of its action and person- 90 27 interactions with SSRIs or corticosteroids. alize regimens in different cardiovascular disorders. 81 28 Conclusions: In elderly poly-treated patients, concomitant prescrip- Methods: We set up a new multi-compartmental mathematical model 92 29 tion of NSAIDs + ACE-Inhibitors (or sartans)+diuretics or NSAIDs + that describes the key features of COX-1 dynamics, including: its syn- 93 30 warfarin have caused kidney injury and bleeding, respectively. Other thesis/degradation in the heterogeneous population of developing bone 94 31 NSAID interactions did not show impact on expected clinical outcomes. marrow megakaryocytes (Mk), the progressive platelet formation, 95 32 Therefore, physicians should carefully evaluate individual risk-benefit COX-1 acetylation by aspirin in both Mk and peripheral (platelet) 96 33 profile before prescribing NSAIDs to elderly poly-treated patients. compartments. The model, consisting of 7 differential equations and 97 34 24 parameters, was implemented in MATLAB. It was calibrated using 98 35 serum thromboxane (TX)B2 (proxy of COX-1 activity) recovery data 99 36 Concurrent validity of indicators of measured in 7 healthy controls and 2 ET patients during and after aspi- 100 37 prescribing quality in Older People rin withdrawal, and in 21 ET patients on different aspirin regimens. 101 38 S.M. Wallerstedt1; and B. Belfrage2 Sensitivity analysis was performed to identify the set of key parameters 102 39 1University of Gothenburg & Sahlgrenska University Hospital, which most significantly influenced COX-1 dynamics. 103 40 Gothenburg, Sweden; and 2Primary healthcare unit, Dals-Ed, Results: A good agreement (weighted absolute percentage error 104 41 105 Sweden < 18%, within the experimental variability) was obtained between 42 Background: Indicators of prescribing quality are used in research data and model prediction. The different recovery pattern observed 106 43 studies and for benchmarking. Indicators based on counts of drugs in healthy vs ET patients was reproduced by altering three key model 107 44 or presence of specified inappropriate drugs are appealing as they parameters identified by sensitivity analysis: platelet count (twofold 108 45 are easy to apply on register data. This study aimed to evaluate the increase), Mk lifetime (from 3 to 1 day) and platelet lifetime (from 7 109 46 concurrent validity of such indicators. to 5-6 days). Finally, the model explains an increased COX-1 acety- 110 47 111 Material and Methods: In 200 hip fracture patients (≥ 65 years), lation following a shorter dosing interval (100 mg twice daily) as 48 consecutively recruited to an RCT in Sahlgrenska University Hospital compared to a higher (200 mg) once-daily dose in ET patients. 112 49 in 2009, quality of drug treatment was assessed according to a gold Conclusions: Our in silico model adequately describes aspirin 113 50 standard as well as to indicators based on cut-offs of number of drugs responsiveness, as measured in controls and patients with high drug- 114 51 in the medication list and the presence of inappropriate drugs accord- target turnover, and might be a useful tool to design personalized 115 52 ing to the Swedish National Board of Health and Welfare, the French regimens in clinical conditions characterized by altered Mk and/or 116 53 consensus panel list, and the German PRISCUS list. As gold standard, platelet kinetics. 117 54 two specialist physicians independently assessed and then agreed on 118 55 the quality for each patient, after initial screening with STOPP/START. 119 56 120 Suboptimal drug treatment was defined as≥ 1 STOPP/START out- 57 Agomelatin for treatment of depressive 121 comes assessed as clinically relevant at the individual level. disorders in Russia: a cost-utility 58 Results: In all, 71% of the patients had suboptimal drug treatment 122 59 analysis 123 according to the gold standard. For different cut-offs of number of 1 2,3 1,4 60 V.I. Ignatyeva ; M.Y. Frolov ; and M.V. Avksentyeva 124 drugs in the medication list (≥ 1 to ≥ 10 drugs), 96% to 25% of the 1 61 The Russian Presidential Academy of National Economy and 125 patients were identified to have potentially suboptimal drug treat- 2 62 Public Administration, Russian Federation; Volgograd State 126 ment. The sensitivity ranged from 1.00 (95% confidence interval: 3 63 Medical University, Russian Federation; Volgograd Medical 127 0.97; 1.00) to 0.32(0.25; 0.40). The specificity ranged from 0.14 4 64 Scientific Research Center, Russian Federation; and I.M. Sechenov 128

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1 First Moscow State Medical University, Russian Federation 1Faculty of Medicine and Dentistry, Palacký University Olomouc, 65 2 Background: Economic feasibility of use in the Russian health care of Olomouc, Czech Republic; and 2University Hospital Olomouc, 66 3 agomelatin for treatment of big depressive episodes in adults in com- Olomouc, Czech Republic 67 4 parison with fluoxetine and sertraline was the purpose of the analysis. Background and Introduction: Tacrolimus and ciclosporin are sub- 68 5 Materials and Methods: The Markov model was adapted. The strates of the enzyme family CYP3A4/5 and as such are subject to a 69 6 assessment of expenses was carried out with the data of research on number of drug-drug interactions. Due to their narrow therapeutic 70 7 burden of depressive frustration, standards of financing approved in index, TDM is used to maintain an optimal therapeutic range in order 71 8 Russia in 2015 and the average registered prices of all preparations to limit toxicity while ensuring effectiveness. Some antimicrobial 72 9 of fluoxetine and a sertralin – original and generics. The period of agents, e.g. macrolides, azole antimycotics, can lead to plasma levels 73 10 modeling included 3 years. outside the optimal range, despite pre-emptive dose adjustments. 74 11 Results: Use of an agomelatin for treatment of a big depressive epi- Materials and Methods: The population included 187 renal graft 75 12 sode can be preferable alternative to use of fluoxetine and a sertralin recipients in a single transplant centre who were treated with a cal- 76 13 as additional expenses for receiving 1 additional QALY make 341.9 cineurin inhibitor for more than 3 months and had data available for 77 14 and 637.0 € respectively, that is significantly lower than the threshold their plasma levels. Risk of levels outside of target range following 78 15 value recommended by WHO. In case of comparison only of original prescription of an interacting drug and time spent outside of range 79 16 drugs strategy with use of an agomelatin was prepotent –reduction were analysed. 80 17 of expenses in comparison with other original drugs the maximum Results: Ciclosporin levels were above recommended range on aver- 81 18 utility was reached. age for 7.2% of the assessed period. For tacrolimus, levels were above 82 19 Conclusion: Use of an agomelatin for treatment of big depressive upper limit of target range on average for 6.4%. 83 20 episodes at adults in the Russia is economically expedient. The difference between tacrolimus and ciclosporin was not sta- 84 21 tistically significant (p > 0.05). 85 22 The risk of a level being above upper limit of target range was 86 23 Fenofibrate-induced Anemia and statistically significantly elevated following a prescription of an inter- 87 24 Neutropenia – a case report acting antimicrobial (17 vs. 7% for ciclosporin, P < 0.05 and 35 vs. 88 25 I. Kacirova1,2; and M. Grundmann1 12% for tacrolimus, P < 0.01). This elevated risk of levels exceeding 89 26 1Faculty of Medicine, University of Ostrava, Czech Republic; and target was present despite the fact that the dose was reduced in 75 90 27 2University Hospital Ostrava, Czech Republic % cases. The risk following dose reduction was still significantly 81 28 Introduction: Fenofibrate is used in the treatment of hyperlipidemia. increased (16% vs. 12% for tacrolimus, P < 0.02; 17% vs. 7% for 92 29 Adverse effects affect the skeletal muscle, kidneys and liver, labora- ciclosporin, P < 0.01). 93 30 tory tests could be mildly abnormal for leukocytes and hemoglobin. Conclusions: Despite pre-emptive dose adjustments, concurrent pre- 94 31 We report the first documented case of the significant fenofibrate- scription of interacting antimicrobial agents increases risk of levels 95 32 induced anemia and neutropenia. of calcineurin inhibitors exceeding the upper limit of the applicable 96 33 Methods: A 42-year-old male (BMI 48) with compensated hyper- target range. More aggressive dose reductions may be warranted if 97 34 tension suffered from hyperuricemia, diabetes mellitus type 2 and an interacting prescription is unavoidable. 98 35 pulmonary thromboembolism in anamnesis. He was treated by perin- 99 36 dopril, indapamide, metoprolol, amlodipine, allopurinol, metformin, 100 37 liraglutide, flavonoids and rivaroxaban. At May 2014, fenofibrate Modulating effect of Egonol and 101 38 200mg daily was added due to hypertriglyceridemia (6.45 mmol/L). Homoegonol on Genotoxicity induced by 102 39 Laboratory tests including lipid profile were analysed two and three different mutagens 103 40 months later. D.C. Tavares; P.F. Oliveira; J.L. Damasceno; H.D. Nicolella; and 104 41 Results: At July 2014, triglyceride level decreased to 3.78 mmol/L. P.M. Pauletti 105 42 However, significant changes occurred in white and red blood cell University of Franca, Franca, São Paulo, Brazil 106 43 9 107 count: leucocytes decreased from 7.8 to 4.3 × 10 , absolute neutro- The benzofuran nor-neolignans egonol (EG) and homoegonol (HE) 44 phil count from 4.58 to 1.26, lymphocytes increased from 27.5% to are found in all species of Styrax and considered phytochemical 108 45 51.2% and monocytes increased from 6.8% to 13.10%; hemoglobin markers for quality control of extracts of this genus. Some impor- 109 46 decreased from 149.0 to 122.0 g/L and hematocrit from 0.45 to 0.37, tant biological activities have been described for these compounds as 110 47 without any changes in clinical features. Fenofibrate was immediately antibacterial, modulation of the complement system and cytotoxic 111 48 discontinued. Three weeks after fenofibrate withdrawal the haema- activity for tumor cell lines. Previous studies conducted by our group 112 49 tological findings improved to previous normal values. with Styrax camporum extract demonstrated its modulating effect 113 50 Conclusions: We present the first case report of the significant on DNA damage induced by different mutagens. Thus, the aim of 114 51 fenofibrate-induced anemia and neutropenia. The pathogenesis of the study was to investigate whether the EG and HE are responsible 115 52 this adverse drug reaction remains unclear, however, allergic reaction by the modulating activity observed for the S. camporum extract. 116 53 following a fenofibrate prescription could be explanation. Although The study was carried out in Chinese hamster lung fibroblasts (V79 117 54 fenofibrate-induced anemia and neutropenia appears to be uncom- cells) using the micronucleus assay. The cultures were treated with 118 55 119 mon, patients receiving fenofibrate should be monitored for this EG (0.26 μ g/mL), HE (0.017 μ g/mL) alone or combined. In addition, 56 adverse drug reaction. the same concentrations were simultaneously treated with methyl 120 57 121 methanesulfonate (MMS, 44 μ g/mL), hydrogen peroxide (H2O2, 58 122 3.5 μ g/mL), camptothecin (CPT 43 μ g/mL) and etoposide (VP16 1 59 123 μ g/mL). We also included a negative (without treatment), a solvent 60 Effect of interacting Antimicrobial 124 prescription on maintenance of (dimethylsulfoxide; DMSO 0.05%) and positive control groups. The 61 cultures treated with EG plus HE showed genotoxicity. The cultures 125 62 calcineurin inhibitor Therapeutic levels 126 1 1 1 2 treated with the EG and HE alone or combined with MMS or CPT no 63 J. Strojil ; P. Anzenbacher ; K. Urbánek ; J. Orság ; 127 1 2 shown a significant effects. Regarding the combination with H2O2, 64 M. Ptáčníková ; and K. Krejčí 128

2015 e11 Clinical Therapeutics

1 the cultures treated with EG alone or combined with HE a significant The Styrax camporum Pohl is known for its wide use for the treat- 65 2 increase on the micronuclei frequencies was observed when compared ment of gastroduodenal diseases especially as regards antiulcera- 66 3 to cultures treated with H2O2 alone. Regarding the combination tive potential. In Brazil this species occurs in the cerrado of Minas 67 4 with VP16, the EG and HE alone or combined led to a reduction in Gerais, São Paulo, Mato Grosso do Sul and semi-deciduous forest 68 5 the frequency of micronuclei induced by VP16. This study allowed of the Paraná basin. S. camporum is popularly known as “benjoe- 69 6 us to better understand the mechanism of action of the S. camporum iro”, “cuia-do-brejo”, “canela-poca”, “fruta-de-pomba” and “pin- 70 7 and chemical markers and suggest modulation depends on the type duíba”. In the present study we investigate the effects of S. camporum 71 8 of mutagen used. hydroalcoholic extract on the formation of aberrant crypt foci (ACF) 72 9 Financial Support: São Paulo Research Foundation (FAPESP, Brazil, induced by 1,2-dimethylhydrazine (DMH) in rat colon. For the 73 10 grant # 2013/13903-9). experiments, male Wistar rats with four weeks of the age and 120 g 74 11 body weight (b.w.) were treated daily for gavage with different doses 75 12 of the S. camporum extract (250, 500 and 1000 mg/kg b.w.) for four 76 13 Assessment of Adverse Reactions due to weeks. The negative control group received water for gavage and a 77 14 an Iodine-based Contrast Agent subcutaneous injection of ethylenediamine tetraacetic acid (EDTA). 78 15 J. Joaquim1; C. Matos1; T. Pires1; F. Fonseca1; O. Tavares2; Also, two doses subcutaneous injection of 40 mg/kg of DMH were 79 16 L. Ramos3; and M. Rocha4 administered for two weeks, and animals were sacrificed two weeks 80 17 1Instituto Politécnico de Coimbra, Coimbra Health School – after the last injection for evaluating ACF development in colon. The 81 18 ESTESC, Farmácia, Coimbra, Portugal; 2Instituto Politécnico de results showed a significant reduction in the frequency of ACF in the 82 19 Coimbra, Coimbra Health School – ESTESC, Imagem Médica e group treated with the different doses of S. camporum extract plus 83 20 Radioterapia, Coimbra, Portugal; 3Intensive Care Unit, Centro DMH in comparison with those treated with DMH alone. Therefore, 84 21 Hospitalar e Universitário de Coimbra, Coimbra, Portugal; and these findings suggest a chemopreventive effect of the S. camporum 85 22 4Instituto Politécnico de Coimbra, Coimbra Health School – extract against the colon carcinogenesis. This protective effect may 86 23 ESTESC, Ciências Complementares, Coimbra, Portugal be related to the antioxidant activities of the extract constituents. 87 24 Introduction: Iopromide is an iodine-based contrast agent, used Financial Support: São Paulo Research Foundation (FAPESP, Brazil, 88 25 in several radiological procedures in order to obtain better image grant # 2011/21310-2). 89 26 quality. This drug is used by millions of people worldwide, and is 90 27 considered one of the safest intravenous drugs. However, its use isn't 81 28 deprived of risks. The aim of the study was to ascertain the incidence Adme-wide analysis of Copy Number 92 29 of Adverse Reactions (AR) due to iopromide along with a charac- Variation using Targeted exome 93 30 terization of the events. resequencing and their functional 94 31 Material and Method: A retrospective observational study was per- relevance in Human Liver 95 32 formed from the cases reported between September 2012 and May R. Tremmel1,2; S. Fehr3; F. Battke3; K. Klein1,2; E. Schaeffeler1,2; 96 33 2014, of adverse reactions occurred in a radiological specialized M. Schwab1,2,4; S. Biskup3; and U.M . Zanger1,2 97 34 unit. Data from reports included: date, sex, age, CT scan performed, 1Dr. Margarete Fischer-Bosch Institut für Klinische 98 35 reported symptoms and technical interventions and/or drugs used to Pharmakologie, Stuttgart, Germany; 2University of Tuebingen, 99 36 recover the patients. The inclusion criterion was the realization of Tuebingen, Germany; 3CeGaT GmbH, Tuebingen, Germany; 100 37 one CT scan with contrast agent administration. and 4University Hospital Tuebingen Department of Clinical 101 38 Results: The patients age ranged from 37 to 74 years old (mean Pharmacology, Tuebingen, Germany 102 39 103 = 57,65) and were divided into two age groups – Adults (n = 14) Copy number variants (CNVs) are involved in human disease, com- 40 104 were patients with < 65 years old and elderly (n = 9) were patients plex traits and drug efficacy and toxicity. Although several ADME 41 105 with ≥ 65 years old. Registered incidence was 0.8%, corresponding (absorption, distribution, metabolism, excretion) genes harbor CNVs 42 to 23 events from 2.870 CT scan with iopromide administration. with impact on phenotype, including expression and enzyme activ- 106 43 107 Symptoms reported were: papules (n = 17), urticaria (n = 2), ery- ity (e.g. GSTM1, CYP2A6 and CYP2D6), systematic analyses are 44 108 thema (n = 6), facial or laryngeal edema (n = 3), exanthema (n = lacking. The goal of this project is to elucidate CNVs among ADME 45 109 2), nausea or vomiting (n = 3), polypnea (n = 1), palpitations (n = genes and to assess their functional consequences in human liver. 46 110 1) and cardiopulmonary arrest (n = 1). As for the intensity, 15 were A well-documented cohort of 150 Caucasian liver samples was 47 classified as mild (65.2%), 6 moderate (26%) and 2 severe (8.7%). typed for CNVs using a combined analysis of the read coverage and 111 48 Conclusion: Iopromide shows a very favorable safety profile, and its SNP composition of a targeted exome-resequencing panel of 340 112 49 use is highly recommended. Nevertheless, healthcare professionals ADME genes (Hiseq2500, Illumina). CNV results were confirmed 113 50 must be aware of the possibility to occur an ADR. They should check using TaqMan CNV-assays (Applied Biosystems) and compared to 114 51 the patient’s history to forearm the administrations of this drug to publicly available CNV data (DGV). Quantitative phenotypes were 115 52 those that present risk factors or previous reactions to iodine-based measured using TaqMan (mRNA), Western Blot (protein content) 116 53 contrast agents. Iopromide have a lower incidence of AR (0,8%) and specific substrate assays (enzyme activity). 117 54 compared with literature for low osmolarity agents (3.13%). Systematic coverage analysis confirmed known CNVs of phase 118 55 I and II genes and detected rare CNVs in CYP2E1 (allele frequency 119 56 120 = 2%), UGT2B15 (1%) and transporters including SLC22A12/18 57 121 Styrax Camporum extract inhibits the (< 1%). In total, 5% of 118 phase I and 9% of 61 phase II genes 58 and 1% of 72 transporters harbored full gene-comprising CNVs. 122 59 formation of Preneoplastic lesions in 123 the Rat colon Positive association between CNV-type and expression was observed 60 for phase I and II genes, including CYP2D6, CYP2A6 and SULT1A1 124 P.F. Oliveira; L.F. Leandro; N.H. Ferreira; P.M. Pauletti; and 61 while for some genes, including CES1 and CYP2E1, CNV type was 125 D.C. Tavares 62 not correlated to expression. 126 63 1University of Franca, Franca, São Paulo, Brazil 127 64 128

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1 In summary, our CNV analysis using a targeted NGS approach Bioequivalence and Food effect of 65 2 revealed that numerous ADME genes harbor CNVs. The human heat-stressed and non-heat-stressed 66 3 liver cohort allowed us to study the impact of CNVs on ADME Dapagliflozin Tablets 67 4 gene expression. Although CNVs contributed to variable expression D.W. Boulton1; S. Griffen2; F. LaCreta1; X. Liu1; C. Smith3; 68 5 of CYP2A6, CYP2D6 and SULT1A1, we conclude that CYP2E1 C. Hines3; K. Volk1; and R. Tejwani1 69 6 belongs to the so-called dosage-insensitive genes, whose expression 1Bristol-Myers Squibb Company, Princeton, NJ, USA; 2JDRF, 70 7 appears to be independent of gene copy number. Further research is New York, NY, USA; and 3PPDI, Richmond, VA, USA 71 8 required to understand the underlying compensation mechanisms. Background: Stability and pharmacokinetic testing are essential 72 9 The study was supported by the Robert Bosch Foundation, to assure drug potency, safety and efficacy. Dapagliflozin, T2DM 73 10 Stuttgart, Germany medication, may convert from crystalline to amorphous forms dur- 74 11 ing storage. To assess the clinical impact of this form change, in vivo 75 12 evaluation of dapagliflozin tablets was undertaken. 76 13 Effect of food on the Pharmacokinetics Materials and Methods: Two open-label crossover, single-dose stud- 77 14 of two formulations of a New cetp ies to assess dapagliflozin pharmacokinetics from heat-stressed (HS) 78 15 inhibitor in healthy Volunteers and non-heat-stressed (NH) dapagliflozin tablets were conducted in 79 16 A.C. Kruithof1; I.M.C. Kamerling1; D. Mallikarjuna Rao2; healthy subjects. The first assessed fasted-state bioequivalence of 10 80 17 R. Kumar2; and J. Burggraaf1 mg tablets (N = 29). The second evaluated fed and fasted-state effect 81 18 1Centre for Human Drug Research, Leiden, the Netherlands; and on 2.5 mg tablets (N = 28). 82 19 2Dr Reddy’s Laboratories Ltd., Andhra Pradesh, India Results: Under fasting conditions, 90% CIs of the geometric mean 83 20 84 Background: DRL-17822 (150 mg) a new Cholesteryl Ester Transfer ratios of AUC0-inf, AUC0-t and Cmax for the HS 2.5 and 10 mg tablets 21 Protein (CETP) inhibitor, showed an increase of more than 20 fold in were within 80%–125%, indicating bioequivalence with NH tablets 85 22 bioavailability in terms of C and AUC as a result of a standard (Table). In the fed versus fasting state for the 2.5 mg tablets, AUCs 86 23 max 0-t 87 FDA high fat breakfast. To reduce this food effect, a new formulation were similar, time to Cmax was prolonged by 1.25 hours and Cmax 24 of DRL-17822 has been developed. decreased by approximately 50% for HS and NH tablets; this is not 88 25 Methods: This was a randomised, open-label, single-dose, 4-way clinically significant. No serious adverse events were reported. 89 26 cross-over study in healthy male volunteers (aged 18–45 years), Conclusions: Under fasting conditions, HS and NH 2.5 mg and 10 90 27 conducted in two parts. In each part, 12 subjects received both the mg dapagliflozin tablets are bioequivalent. The non-meaningful food 81 28 current and new formulation of 150 mg DRL-17822 in fasted and effect may support patients’ adherence to diabetes treatment through 92 29 fed state; a low fat breakfast was provided in Part A1 and a high convenience of administration irrespective of meals. 93 30 breakfast in Part B2. 94 31 Results: In both parts, the new formulation substantially increased Adjusted geometric. 95 mean ratio (%), NH vs 32 DRL-17822 exposure in fasted state, characterised by C , AUC 96 33 max 0-t Pharmacokinetic Treatment HS (90% CI) 97 and AUC0-∞, compared to the current formulation. Following high Dapagliflozin Dose Parameter comparisons [N = 25–29] 34 fat breakfast, DRL-17822 exposure was significantly less using the 98 35 99 new formulation compared to the current formulation (P < 0.01). In 2.5 mg C (ng/mL) HS-fast/NH-fast 99.8 (88.4, 112.7) 36 max 100 addition, the new formulation resulted in similar ratios fed/fasted for NH-fed/NH-fast 55.6 (49.3, 62.7) 37 AUC in following both types of breakfast while the current formu- HS-fed/HS-fast 49.9 (44.2, 56.3) 101 0-t AUC (ng·h/mL) HS-fast/NH-fast 99.0 (96.2, 101.9) 38 lation had a higher ratio after high fat breakfast compared to a low 0-t 102 39 NH-fed/NH-fast 90.3 (87.8, 92.9) 103 fat breakfast (Table 1, similar ratios were seen for C and AUC ). HS-fed/HS fast 90.3 (87.7, 93.0) 40 max 0-∞ 104 Conclusion: The new formulation had favourable pharmacokinetic AUC0-inf (ng·h/mL) HS-fast/NH-fast 97.6 (93.7, 101.6) 41 characteristics compared to the current formulation, showing a food NH-fed/NH-fast 92.5 (89.4, 95.8) 105 42 HS-fed/HS-fast 94.0 (90.2, 97.9) 106 effect of only 3-fold, which may relate in more predictable effect 10 mg C (ng/mL) HS-fast/NH-fast 101.8 (92.3, 112.2) 43 max 107 profile. HS-fed/HS-fast 55.0 (49.9, 60.6) 44 108 AUC0-t (ng·h/mL) HS-fast/NH-fast 98.8 (95.9, 101.8) 45 HS-fed/HS-fast 96.1 (93.2, 99.0) 109 Table 1. Statistical analysis results AUC0-t (ng*h/mL) for contrast fed/ AUC (ng·h/mL) HS-fast/NH-fast 99.0 (96.0, 102.1) 46 fasted new formulation vs. fed/fasted current formulation. 0-inf 110 47 HS-fed/HS-fast 97.3 (94.3, 100.4) 111 Fed state conditions P-value Back transformed 48 112

49 Second Estimate 113 50 First LSM of LSM of of the dif- 114 contrast contrast ference 90% CI Small gender differences in Drug 51 concentrations stored in a TDM 115 52 116 Lower Upper database 53 117 F. Sjöqvist; E. Eliasson; and J.D. Lindh 54 118 Low fat breakfast (Part A) 0.08 3.30 6.37 93.1% 4.4% 257.0% Karolinska University Hospital, Stockholm, Sweden 55 119 High fat breakfast (Part B) < .0001 2.82 13.48 377.6% 231.3% 588.6% Several recent reviews on pharmacological gender differences suggest 56 120 important effects on pharmacokinetics, with females having slower 57 121 drug elimination compared to men. However, the evidence referred 58 122 to is not convincing. Our department has been involved in thera- 59 References 123 peutic drug monitoring (TDM) since 1970 and presently analyzes 60 1. http://www.ncbi.nlm.nih.gov/pubmed/21347617 124 75.000 TDM samples of 100 different drugs annually. Over the years, 61 2. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ 125 the methods have been successively refined and now mostly involve 62 UCM126833.pdf 126 LC-mass spectrometry. The drug concentrations are stored in a TDM 63 127 64 128

2015 e13 Clinical Therapeutics

1 data bank (Eliasson et al. Eur. J. Clin. Pharmacol. 2013, 69, Suppl 1, Phase I, double-blind, randomized, 65 2 S25–S32) containing drug concentrations and essential clinical data. placebo-controlled clinical trial with 66 3 We have used this source to trace possible gender differences in the probiotic Nyaditum resae® in adults 67 4 dose-adjusted plasma concentrations of commonly used drugs. Men with or without latent Tuberculosis 68 5 and women did not differ in age. infection 69 6 The most frequently analyzed drugs were immunosuppressants, A. Barriocanal1,2; A.L. Arellano2,3; Y. Sanz3; A. Valderrama3; 70 7 antiepileptics, antibiotics, antivirals, antipsychotics, and antidepres- P. Cardona1,2; C. Vilaplana1,2; and E. Montané2,3 71 8 sants. 1Fundació d'Investigació en Ciències de la Salut Germans Trias 72 9 For a large number of these drugs, women achieved higher dose- i Pujol, Barcelona, Spain; 2Universitat Autònoma de Barcelona, 73 10 adjusted concentrations compared to men but after adjustment Spain; and 3Hospital Universitari Germans Trias i Pujol, 74 11 for differences in body-weight, only a small number of drugs (gen- Barcelona, Spain 75 12 tamicin, hydroxycarbazepine, isoniazid, perfenazine, and valproic Background or Introduction: Tuberculosis could be induced by an 76 13 acid) exhibited this pattern. For a majority of drugs (in particular exaggerated inflammatory response against Mycobacterium tubercu- 77 14 amikacin, ciclosporin, ganciclovir, mycophenolic acid, sertraline, and losis (Mtb) in people with Latent Tuberculosis Infection. A probiotic 78 15 tacrolimus) the opposite tendency was observed, with slightly lower containing heat-killed environmental Mycobacterium manresensis 79 16 weight- and dose-adjusted concentrations in women. (Nyaditum resae®) (NR) was developed to induce a Treg-cells- 80 17 The overall data, which will be further analyzed statistically, sug- mediated tolerance process, generating cross-immunity with Mtb. 81 18 gest that previously made claims of lower drug clearance in women To evaluate its safety and immunogenicity a phase I clinical trial 82 19 may be incorrect. If gender differences in drug elimination exist, they was conducted. 83 20 are probably negligible compared to interindividual differences due Material and Methods: A double-blind placebo-controlled, rand- 84 21 to other genetic and environmental factors. omized trial stratified by tuberculosis skin test (TST) response was 85 22 performed. Inclusion criteria: ≥ 18 years. Main exclusion criteria: 86 23 active tuberculosis, immunodeficiency and pregnancy. Primary end- 87 24 Impact of medication use on mortality in points were adverse events (AE) and immunogenicity. 88 25 Belgian community-dwelling oldest Old Volunteers received either placebo, NR low [104 Colony Forming 89 26 M. Wauters1; M. Elseviers1; B. Vaes2,3; J. Degryse2,3; O. Dalleur2; Units (CFU)] or high [105 CFU] dose vials, orally daily during 14 90 27 R. Vander Stichele1; L. Van Bortel1; and M. Azermai1 days. Four control visits including physical exploration, blood analy- 81 28 1Ghent University, Ghent, East Flanders, Belgium; 2Université sis and a volunteer's log register were performed in a 6 weeks period. 92 29 catholique de Louvain, Saint-luc Brussels, Flemish Brabant, Results: Of 76 volunteers screened, 51 were enrolled (18 received 93 30 Belgium; and 3Catholic University of Leuven, Leuven, Flemish placebo, 16 low dose NR, and 17 high dose NR). They were mainly 94 31 Brabant, Belgium female (62%) with a mean (SD) age of 31.8 years (12). No loss to 95 32 Background: High drug use in older adults is associated with adverse follow-up or discontinued intervention occurred. 96 33 outcomes. The association between medication use as a risk factor A total of 322 AE were reported in 49 volunteers (96%), and 97 34 for mortality is investigated in a Belgian community-dwelling cohort 46.3% (149) considered possibly or probably related to the treat- 98 35 99 of oldest old (80+). ment. Most of AE were gastrointestinal (82%) and mild. None of 36 Methods: Data was collected between November 2008 and July them were severe. There were no significant statistical differences 100 37 2011 of the Belfrail-med cohort. Baseline predictors included medi- when comparing safety between groups. 101 38 cation data, and personal, clinical, and functional characteristics. A statistically significant increase on the Treg response (effector 102 39 Medications were coded by the Anatomic Therapeutic Chemical CD25+CD39− and memory cells CD25+CD39+) was observed in 103 40 classification. Survival analysis included Kaplan-Meier and Cox those groups treated with NR, higher in TST positive volunteers and 104 41 regression analysis. in the high dose NR group. 105 42 106 Results: Participants’ (n = 503) mean age was 84.4 years (range Conclusions: Data support that NR administration has a good safety 43 80 – 102) and 61.2% was female. The mean medication use was 5.4 profile, and is able to induce an immunologic response through 107 44 108 (range 0 – 16). Mortality rate after 18 months was 8.9% (n = 45). increasing Treg cell population. Future clinical trials are needed to 45 The mortality group was significantly older (85.7 vs 84.3 years), assess the efficacy of NR in lowering the risk of the progression from 109 46 received more nursing care (53.3% vs 35.2%), had a higher multi- latent infection to tuberculosis. 110 47 morbidity (CIRS 4.6 vs 3.7), and used more medications (6.4 vs. 5.3). 111 48 Usage of antidepressants (Hazard Ratio 2.0, 95% CI 1.0 – 3.9), loop 112 49 diuretics (HR 2.6, 95% CI 1.4 – 4.9), verapamil/diltiazem (HR 3.5, Liver injury with dipeptidyl peptidase-4 113 50 95% CI 1.4 – 8.9), or anticholinergics (HR 2.4, 95% CI 1.3 – 4.4) (DPP-4) inhibitors (GLIPTINS): signals 114 51 were independent risk factors for mortality. Corrected for gender and emerging from the us-fda adverse event 115 52 age, loop diuretics (HR 2.8, 95% CI 1.2 – 4.3), anticholinergics (HR reporting system 116 53 117 2.05, 95% CI 1.1 – 3.8), and verapamil/diltiazem (HR 2.7, 95% CI E. Raschi; E. Poluzzi; A. Koci; I.C. Antonazzo; and F. De Ponti 54 118 1.0 – 7.1) proved risk factors for mortality in a multivariate model. Department of Medical and Surgical Sciences, University of 55 119 Conclusions: Medication use is a risk factor for mortality in the old- Bologna, Bologna, Italy 56 120 est old. Usage of loop diuretics, verapamil/diltiazem, or anticholin- Background: The recent debate on alogliptin hepatotoxicity has 57 121 ergics by the oldest old requires close follow-up and further analysis aroused interest on liver injury as a class effect of dipeptidyl peptidase-4 58 122 for comorbidities. (DPP-4) inhibitors, known as gliptins. Considering that drug-induced 59 123 60 124 61 125 62 126 63 127 64 128

e14 Volume XX Number XX Biosimilars: regulatory overview

1 liver injury (DILI) is unpredictable and clinical trials underpowered, we congestion (P = 0.048) than Desloratadine. Both H1 antihistamines 65 2 analysed the largest publicly available database of spontaneous reports, significantly reduced plasmatic level of IL-6 and TNF-α after 4 weeks 66 3 the US-FDA Adverse Event Reporting System (FAERS). of treatment. Levocetirizine reduced more significant the value of IL-6 67 4 Material and Methods: We extracted FAERS reports (up to compared to Desloratadine (P = 0.05). 68 5 December 2013) where DDP-4 inhibitors were recorded as suspect Conclusions: There were observed high plasmatic values of TNF-α 69 6 and performed a case/non case study by calculating the Reporting in patients with persistent allergic rhinitis to house dust mites. H1 70 7 Odds Ratio (ROR) with 95% CI, as a measure of disproportional- antihistamines reduce the severity of symptoms and the level of some 71 8 ity. A list of Preferred Terms (PTs) was compiled according to the pro-inflammatory mediator. 72 9 Medical Dictionary for Regulatory Activities terminology to identify 73 10 the following clinical events (i.e., cases): (a) Overall Liver Injuries 74 11 (OLI, including acute and chronic damage); (b) Acute Liver Failure Transarterial Chemoembolization to the 75 12 (ALF, a subcategory including only acute severe hepatic injuries). treatment of Hepatocellular 76 13 Non cases were all other reports without pre-specified PTs of inter- Carcinoma – preparation procedures 77 14 est. A signal was defined by statistical significant ROR (lower limit D. Ferreira1; T Pires1,2; and N. Machado2 78 15 of the 95% CI > 1). 1Instituto Politécnico de Coimbra, Coimbra Health School – 79 16 Results: During the study period, no signal of DILI emerged for ESTESC, Farmácia, Coimbra, Portugal; and 2Centro Hospitalar e 80 17 alogliptin (no ALF cases; number of OLI cases= 100; ROR = 1.73; Universitário de Coimbra,EPE Coimbra, Coimbra, Portugal 81 18 95% CI = 0.55-4.20) and linagliptin (no ALF cases; OLI cases = 18; Background: The liver is a vital organ to our organism and an 82 19 ROR = 1.20; 95% CI = 0.71-1.92). Conversely, statistically signifi- hepatocellular cancer brings several complications and problems 83 20 cant associations were found for OLI with the first-in-class DDP-4 in patient’s life quality. Nowadays, hepatocellular carcinoma is one 84 21 inhibitor sitagliptin (234; 1.33; 1.16–1.52), and also for saxagliptin of the most diagnosed in the world and the third cause of death 85 22 (38; 1.47; 1.03–2.03) and vildagliptin (22; 6.51; 3.92–10.35). related to oncologic disease. Its treatment is mostly based in cytotoxic 86 23 Conclusions: The heterogeneous marketing life, penetration and therapeutics. One of the drugs is doxorubicin, an antitumor drug 87 24 utilization of DDP-4 inhibitors may explain signals originated from belonging to anthracyclines that acts by intercalating into DNA of 88 25 FAERS, and justify population-based studies to assess actual class tumor cells. Transarterial chemoembolization (TACE) is a method 89 26 effect of gliptins. Notably, while the European label does not address that takes advantage of arterial and hepatic vascularization, which 90 27 DILI risk, the US label recommends mandatory hepatic monitoring exists near the hepatic tumors. Recently, conventional TACE has suf- 81 28 before and during alogliptin (the latest DDP-4 inhibitors receiving US fered some developments, using beads that transport the drug – tran- 92 29 approval): this mandatory recommendation may have contributed sarterial chemoembolization with drug-eluting bead. The objective of 93 30 to minimize DILI risk by excluding diabetic patients with baseline this review was to understand the different steps of the preparation 94 31 hepatic enzyme elevation. procedure of the transarterial chemoembolization with drug-eluting 95 32 beads, specifically, to doxorubicin in hepatic cancer treatment, and 96 33 its administration path. 97 34 H1 Antihistamines’ effect on Material and Methods: Was conducted a research of articles pub- 98 35 pro-inflammatory Cytokines in lished, in PubMed and Google Scholar, in English and Portuguese, 99 36 allergic rhinitis to house dust mites using key words like chemoembolization, hepatocellular carcinoma, 100 37 I.C. Bocsan; I.A. Muntean; S. Vesa; D. Deleanu; and doxorubicin and TACE-DEB. 101 38 A.D. Buzoianu Results: This method uses microspheres (TACE-DEB), which are 102 39 University of Medicine and Pharmacy, Cluj Napoca, Romania loaded with the drug in question and subsequently dropped by cath- 103 40 Background: Allergic rhinitis to house dust mites is characterized eter to the tumor site. This procedure is made in aseptic conditions, 104 41 by a chronic inflammation of nasal mucosa. H1 antihistamines from with all necessary precautions due to the nature of the drug. 105 42 second generation reduce the rhinitis’ symptoms, but may also have Conclusions: TACE-DEB with doxorubicin brings higher results and 106 43 anti-inflammatory properties. This study aims to evaluate some pro- favorable improvements in evolution of hepatocellular carcinoma. 107 44 inflammatory cytokines in patients with allergic rhinitis to house dust There are many studies ongoing to discover more things about this 108 45 mite and their evolution under treatment with H1 antihistamines. important thematic. 109 46 Material and Methods: Fifty-eight patients with persistent allergic 110 47 rhinitis to house dust mite were included in the study. They were 111 48 clinically evaluated before and after 4 week-treatment with 2nd gen- 112 49 An acenocoumarol dose algorithm in a 113 eration H1 antihistamines, Levocetirizine 5 mg/day or Desloratadine Romanian Population 50 5 mg/day. The clinical evaluation includes: symptoms scores and total 114 A.D. Buzoianu; Ş.C. Vesa; A.P. Trifa; and S. Crişan 51 symptoms score (TSS), type of sensitization. Plasmatic levels of IL-6 115 52 “Iuliu Haţieganu” University of Medicine and Pharmacy, 116 and TNF-α were determined before and after treatment. Cluj-Napoca, Romania 53 Results: A total of 20.7% of the patients were sensitized only to 117 54 Background or Introduction: A stable therapeutic dosing of vitamin 118 house dust mite, while 79.3% were polisensitized (house dust mites K antagonist such as acenocoumarol or warfarin is a difficult task 55 and pollen). Most of the patients with moderate severe forms of 119 56 due to a high inter- and intra-individual variability. This variability is 120 allergic rhinitis were polisensitized (9.8% vs 90.2%, P = 0.003). The determined by several genetic and environmental factors. Our study 57 total symptoms score was significantly higher in patients with poli- 121 58 aimed to develop an algorithm for stable acenocoumarol therapeutic 122 sensitization (P = 0.045), Plasmatic level of TNF-α was significantly 59 dose prediction in Romanian patients. 123 higher in patients with allergic rhinitis (1.92 vs 1.206, P = 0.003), 60 Material and Methods: We recruited 301 patients who necessitated 124 while IL-6 was similar to healthy volunteers. Both Levocetirizine treatment with acenocoumarol for one or two concomitant diseases: 61 and Desloratadine improved the rhinitis’ symptoms and significantly 125 62 acute deep vein thrombosis, permanent atrial fibrillation or valvular 126 reduced total symptoms score (8.62 ± 3.47 vs 2.18 ± 2.3, P = 0.000) prostheses. The patients were selected from those admitted within 63 after 4 weeks of treatment. Levocetirizine improves better the nasal 127 64 the Municipal Hospital of Cluj-Napoca and the Heart Institute 128

2015 e15 Clinical Therapeutics

1 “Niculae Stănciou” in Cluj-Napoca, Romania, between 2009 and Olanzapine, an effective and 65 2 2011. Clinical and demographic data that could influence the aceno- affordable adjuvant in prophylaxis 66 3 coumarol stable dose were recorded for each patient. Genetic analy- for chemotherapy induced nausea 67 4 sis included the genotyping the CYP2C9 gene and the -1693 G> A and vomiting on platinum based 68 5 polymorphism of the VKORC1 (vitamin K epoxide reductase) gene. chemotherapy patients 69 6 The patients were randomly divided into two groups: 200 patients S. Mukhopadhyay1; G. Kwatra2; P.A. Kingsley2; D.K. Badyal2; and 70 7 (66.4%) formed the main group designed to develop clinical and B.S. Mukhopadhyay1 71 8 genetic algorithms for acenocoumarol dose prediction, and 101 1Burdwan Medical College, Burdwan, West Bengal, India; and 72 9 patients (33.6%) formed the validation group. 2Christian Medical College, Ludhiana, Punjab, India 73 10 Results: Age and body mass index explained 18.8% (R2) of the Introduction: Chemotherapy induced nausea and vomiting (CINV) 74 11 acenocoumarol weekly dose variability in patients from the main is a great distressing complication even in modern days. Moreover, 75 12 group. When we added the genetic data to the algorithm, CYP2C9 high cost of aprepitant or other NK-1 antagonists kept this group 76 13 mutations account for 4.7% of acenocoumarol dose variability and inaccessible to many patients. Olanzapine, primarily marketed as 77 14 VKORC1 -1693 G> A polymorphism explained 19.6% of dose vari- an antipsychotic, was found to reduce breakthrough emesis in some 78 15 ation. In the validation group, clinical parameters explained 22.2% chemotherapy patients. The present study aims to evaluate the role 79 16 of the weekly acenocoumarol dose variability. Genetic variants of olanzapine in CINV in patients receiving platinum based chemo- 80 17 increased the R2 coefficient to 32.8%. therapy. 81 18 Conclusion: We created and validated an accurate algorithm for Materials and Methods: The study was a randomized, controlled, 82 19 prediction of stable therapeutic dose of acenocoumarol. assessor blinded study on 100 chemotherapy naïve consenting 83 20 patients receiving any one from cisplatin, carboplatin or oxaliplatin. 84 21 The control group (n = 50) received palonosetron and dexametha- 85 22 Vancomycin Therapeutic Drug sone in the approved therapeutic dose from the day1 of chemother- 86 23 monitoring in clinical practise apy. The test group (n = 50) received additional olanzapine 10 mg/ 87 24 88 H. Suchánková; and M. Machačová day from day1 for five consecutive days. CINV and quality of life 25 Faculty of Medicine and Dentistry, Palacký University in (QoL) were assessed. 89 26 Olomouc, Czech Republic Results: Nausea and vomiting was significantly less among the 90 27 Introduction: Vancomycin has a particular importance in treat- olanzapine treated patients. (Table 1) Though sedation was more 81 28 ment of Gram-positive bacterial infections. Recent TDM guide- in olanzapine treated patients, there was no dose limiting adverse 92 29 lines recommend monitoring of only through concentrations for event. QoL was also better among the olanzapine treated patients. 93 30 Conclusion: Olanzapine was found to be effective adjuvant in con- 94 dosage adjustment with target Cmin between 15mg/l and 20mg/l in 31 patients with invasive infections (or) where less sensitive pathogen trol of CINV. 95 32 96 is involved, and between 10mg/l and 15 mg/l in other infections. Table 1: Control of emesis. 33 This study evaluated the practice of vancomycin TDM in University 97 Result Control group Test group P value 34 Hospital in Olomouc and the influence of new recommendations 98 35 on dosing strategies. 99 Acute emesis Number Number 0.36 36 Patients and Methods: A retrospective analysis of vancomycin 100 37 (percentage) (percentage) 101 plasma levels determined in patients treated with i.v. vancomycin was Complete response (CR) 47(94) 49(98) 0.61 38 102 performed. Values with uncertain sample timing and haemodialysed Complete Control group (CC) 1(2) 1(2) > 0.99 39 patients were excluded. Each trough value was compared with the Failure 2(4) 0 0.49 103 Delayed emesis < 0.0001 40 older, and the new guidelines with regard to the type of infection and 104 41 Complete response (CR) 21(42) 48(96) < 0.0001 105 the value of MIC of the pathogen involved. Consecutively, pharma- Complete Control group (CC) 17(34) 0 < 0.0001 42 cokinetic modelling using MWPharm 3.3 software was performed Failure 12(24) 2(4) 0.007 106 43 for every patient to assess individual PK/PD indices. Overall emesis < 0.0001 107 Complete response (CR) 20(40) 47(94) < 0.0001 44 Results: A total of 250 vancomycin concentrations were included, 108 45 Complete Control group (CC) 17(34) 1(2) < 0.0001 109 which represented 143 events of monitoring performed in 74 patients. Failure 13(26) 2(4) 0.0038 46 Vancomycin was mostly used for suspected or proven sepsis (44% Rescue antiemetic use 8(16) 1(2) 0.031 110 47 111 of all patients). Pathogens with MIC > 1 mg/L were responsible for 48 24% of all infections. Clinical pharmacologist trained in TDM was Complete response (CR)- No vomiting, no nausea during the 112 49 consulted in 23.8% of all events. According to the new guidelines, defined time period. 113 50 44% patients were underdosed, and 34% overdosed. PK simulations Complete control (CC)-No vomiting, only mild nausea, but no 114 51 showed suboptimal concentrations in 34% and too high concentra- rescue medication during the defined period. 115 52 tions in 34% of the patients. 116 53 Conclusion: Dosage adjustments based only upon pre-dose con- 117 54 centrations may increase the risk of toxicity or therapeutic failure, 118 55 Antiangiogenetics-related hypertesion: 119 especially if the value is not interpreted with regard to the timing of a class-effect adverse event or therapy 56 the sampling. 120 57 response mark? an emerging topic 121 Disclosure of Interest: None declared. 1 1 1 1 58 M. Destro ; G.P. Dognini ; F. Cagnoni ; P.L. Colombelli ; and 122 2 59 S. Barni 123 60 124 61 125 62 126 63 127 64 128

e16 Volume XX Number XX Biosimilars: regulatory overview

1 1Internal Medicine Unit, Treviglio-Caravaggio Hospital, Treviglio in 2 and absent in 3 cases, dose incorrect in one case, and dose units 65 2 (BG) Italy; and 2Oncology Department, Treviglio-Caravaggio unclear in 4 cases. Decimal points were used for 26 drugs, frequency 66 3 Hospital, Treviglio (BG) Italy of dosing was unclear in 3 and absent for 8 drugs, quantity absent 67 4 Introduction: Hypertension (HTN) developing during antiangioge- in 15 cases and unclear in one, duration unclear on 11 and signature 68 5 netic (AAG) treatment in cancer patients (pts) is a well-recognised unclear on 5 forms and absent on 1. Other issues were: using brand 69 6 “class-effect” whose prevalence has recently been re-evaluated accord- names (28 drugs), abbreviations (3); date absent (5); height only 70 7 ing to new guidelines from international Societies of Hypertension provided on 1 form and weight on 4; age absent (23), unclear (6) or 71 8 and Cardiology. Its management and outcome implications have not without units (years or months: 5). The ID number was absent on 72 9 been yet completely investigated. 43 forms and only surname or first name provided on 9. For 6, more 73 10 Materials and Methods: Between March 2012 and January 2015, 41 than the expected 4 drugs were requested. 74 11 consecutive AAG-treated pts were evaluated. Clinical and instrumen- Conclusions: We identified multiple areas for improvement in sub- 75 12 tal follow-up was performed according to the ESH/ESC guidelines, mitting drug orders to Pharmacy. Our recommendations for reducing 76 13 from 1 week before starting AAG to 4 weeks after its withdrawal. patient risk were: use upper case writing, ensure full patient ID pro- 77 14 All pts underwent Home, Ambulatorial and Office blood pressure vided (patient age, ID no. and both names), note height and weight, 78 15 measurements (HBPM, ABPM, OBPM, respectively), echocardiog- and avoid abbreviations, use of brand names or decimal points. 79 16 raphy and complete laboratory examination. Further points were clarity for drug units, quantity, dose, frequency, 80 17 Results: Median age was 67yrs (mean = 66,6, range = 49-84yrs) and date of prescription. 81 18 and male/female = 27/14. Five pts, with disease progression after 82 19 one AAG, received a second AAG. The AAG employed were: beva- 83 20 cizumab (N = 18), (N = 11), sunitinib (N = 10), Mismatches in medicines reconciliation 84 21 (N = 3), (N = 2), and (N = 2). Before starting in acute medical in-patients at the chuk 85 22 AAG 33 out of 41 pts had a history of HTN (in 3 of them it was tertiary referral hospital in Rwanda 86 23 diagnosed ex novo at basal evaluation; in 7 it was uncontrolled thus E. Hakizimana1,2; E. Rutaganda1,2; J. Nyirigira1,2; 87 24 requiring an adjustment of anti-hypertensive therapy). AAG-related V. Dusabejambo1,2; and D.R.J. Singer1,2,3,4 88 25 HTN (BP > 140/90 mm Hg) was observed in 21 (61.8%) out of 34 1Centre Hospitalier Universitaire de Kigali (CHUK), Kigali, 89 26 evaluable pts (7 not evaluable). Among pts receiving AAG as sec- Rwanda; 2University of Rwanda, Kigali, Rwanda; 3Human 90 27 ond line, all the 4 evaluable developed AAG-HTN. AAG-HTN was Resources for Health Program, Rwanda; and 4Yale School of 81 28 treated according to the current guidelines and, considering both Medicine, New Haven, Connecticut, USA 92 29 first and second line of AAG, 1, 2, 3,≥ 4 antihypertensive drugs were Background: Accurate medicines reconciliation is important for con- 93 30 employed in 3, 11, 6, 5 pts respectively. tinuity of medical care and for recognizing Adverse Drug Reactions 94 31 Discussion: Despite the small number of evaluated pts, our data seem (ADRs) as a contribution to hospital admission. We assessed 95 32 to confirm that prevalence of AAG-HTN is higher than previously medicines reconciliation in the Internal Medicine Department by 96 33 reported, probably due to different criteria used to define HTN in comparing recorded information about medications and allergy on 97 34 AAG registrative studies. Moreover, as AAG-HTN presents peculiar admission with results of direct requestioning of patients or carers. 98 35 features compared to HTN in general population, a careful evalu- Methods: Data were audited prospectively for Internal Medicine in- 99 36 ation before starting AAG is essential and a tailored management patients during a continuous 8 day period in October 2014, as part 100 37 should be considered. of quality improvement for patient safety in relation to medicines. 101 38 Patients were asked to provide indications, names, and doses for 102 39 their treatment(s) on admission, including over the counter products 103 40 Patterns of medical prescriptions at the (OTC) and traditional medicines, and to report allergies. 104 41 chuk tertiary level Hospital in Rwanda Results: Results were obtained for 44 patients (19 female; mean 105 42 S. Turikumana1,2; E. Rutaganda1,2; J. Nyirigira1,2; V. age 45, range 19-88 years). There were 14 patients concordant for 106 43 Dusabejambo1,2; and D.R.J. Singer1,2,3,4 no drug history in the notes and on direct requestioning (5 female; 107 44 1Centre Hospitalier Universitaire de Kigali (CHUK), Kigali, age 51 ± 6 (SE) years). Ten (23%) of these patients had impor- 108 45 Rwanda; 2University of Rwanda, Kigali, Rwanda; 3Human tant pre-admission drugs not recorded in case notes (3 female; age 109 46 Resources for Health Program, Rwanda; and 4Yale School of 46 ± 6 years). For 24 patients recorded as being on no treatment, 110 47 Medicine, New Haven, Connecticut, USA 10 on review were found to have been on pre-admission treatment 111 48 Background: Good prescribing minimizes dispensing and other med- – one each for cloxacillin, amoxicillin, clarithromycin, artemether 112 49 ication errors. However prescriptions are commonly incomplete or and lumefantrine, paracetamol and and 4 on unknown 113 50 unclear. Consequences include toxicity from wrong medications and treatments. Notes also recorded 20 patients (11 female; mean age 114 51 increased disease severity from delayed treatment. We assessed drug 41 ± 4 years) as on pre-admission treatment. One 46 year old male 115 52 prescriptions at our Referral Hospital to identify areas for improve- did not recall pre-admission treatment with aspirin. Recording of 116 53 ment in prescribing medicines. medicines was significantly poorer in patients recorded as having no 117 54 2 118 Methods: We audited prospectively prescriptions submitted to the prior treatment (P < 0.001; χ test). 55 hospital pharmacy. Data were collected using a standard secure Conclusions: Medicines reconciliation by a combined pharmacy and 119 56 online form. internal medicine team identified that prior treatments were not iden- 120 57 Results: One hundred seventy-four drug orders were assessed in pre- tified on admission to hospital in 1 in 4 patients assessed. Absence of 121 58 scriptions for 73 patients (32 female, 34 male (gender absent for 7). prior treatment in the notes appears a strong cue for the medicines 122 59 Upper case was only used on one form and the Department name was history to be revisited. 123 60 missing on 58 forms. The drug name was unclear in one, dose unclear 124 61 125 62 126 63 127 64 128

2015 e17 Clinical Therapeutics/Volume XX, Number XX, 2015

1 Pharmacoeconomics biosimilars in chronic haloperidol use for treating psychosis (52M); lip swelling and 65 2 Oncology pruritus after 1st dose of nifedipine for hypertension (51M); recurrent 66 3 E. Janeková hypoglycaemia on metformin and glibenclamide (58F); and general- 67 4 InClinic s.r.o, Bratislava, Slovakia ized rash and pruritus on first dose carvedilol and (51M), 68 5 Background: Population growth, long life spans, an increased mor- resolving during continued treatment with the drugs. 69 6 bidity cause an increased incidence of cancer diseases. Bio-similar Conclusions: We were effective in improving ADR reporting by 70 7 drugs come to the market after the patent protection of biological many departments at this major centre and in identifying an impor- 71 8 drugs expires. In general, they reduce the price of the original drugs tant contribution of ADRs to serious morbidity at CHUB, including 72 9 by 20%. Prior to a practical use they require clinical studies that unrecognized use of traditional medicine as a cause of hospital admis- 73 10 demonstrate the quality, safety and efficacy biosimilar to that of the sions and delayed detection of serious medical conditions. 74 11 original. The price of development and production is 10 times higher 75 12 than the price of generics. 76 13 Material and Methods: For the treatment and prophylaxis of febrile Patterns of suspected adverse Drug 77 14 neutropenia the original drugs are used; such as and reactions among in-patients at King 78 15 and filgrastim biosimilars. The study compared the cost- Faisal Referral Hospital, Rwanda 79 16 effectiveness of 5 EU countries of filgrastim, pegfilgrastim and bio- E. Amendezo1,2; I. Kambutse1,2; Y. Maniraguha2; B. Habimana1,2; 80 17 similar filgrastim in different modes with cost efficiency in the Slovak F. Padua1; E. Musabeyezu1; and D.R.J. Singer1,2,3,4 81 18 Republic with a differentiating pricing policy of drugs over the years 1King Faisal Referral Hospital, Kigali, Rwanda; 2University of 82 19 2011.2012, 2013. Rwanda, Kigali, Rwanda; 3Human Resources for Health Program, 83 20 Results: The prophylaxis and therapy of febrile neutropenia with Rwanda; and 4Yale School of Medicine, New Haven, Connecticut, 84 21 biosimilar filgrastim is cost-effective when related to filgrastim and USA 85 22 pegfilgrastim. Both the international and internal analysis puts the Background: Pharmacovigilance is important for patient safety 86 23 biosimilar filgrastim to a position of a cost-effective treatment even however adverse drug reactions (ADRs) are under-reported in Sub- 87 24 in with the absence of evidence provided by a pharmacological and Saharan Africa. 88 25 therapeutical priority. Aims: We aimed to encourage ADR reporting and to assess ADR 89 26 Conclusions: The administration of an adequate treatment using patterns at our major referral hospital. 90 27 pegfilgrastin and biosimilar filgrastim is a cost difference of 289 Methods: We used WHO and Ministry of Health ADR reporting 91 28 Euros in the Slovak Republic. Savings during the administration of protocols, including causality reviews, to identify suspected harmful 92 29 the biosimilar drug for years: 2011 is 3703 thousand Euro thus, 70% responses to one or more medicines, prescribed, OTC or traditional, 93 30 of expenditure, in 2012 it was 4079 thousand. 68%. In 2013 it is known or new. 94 31 3847 thousand Euro, which is 60% of the cost for treating febrile Results: We audited ADRs prospectively over four weeks in October 95 32 neutropenia. Biosimilar drugs are the solution for oncologists as how 2014. We identified ADRs in 9 in-patients (age 25–62 years, median 96 33 to regulate the cost of oncological treatment while maintaining the 43.5 years; 4 females) from Internal Medicine, Surgery and ICU. A 97 34 effectiveness of said treatment. single drug-associated ADR was seen in five: chlorpromazine-hypo- 98 35 tension, colchicine-vomiting, cloxacillin-bronchospasm, ampho- 99 36 tericin B-severe hypomagnesemia; hypokalemia and indapamide 100 37 Pharmacogivilance at the chub National causing severe hypokalemia. Implicated drugs were stopped (and 101 38 referral hospital in Rwanda replaced if necessary), and symptomatic treatment was provided. 102 39 103 F. Mugabo1,2; N. Rutambika1; T. Walker1,2; and D.R.J. Singer1,2,3,4 Drug-illness interactions were observed in 3: lower GI bleed in a 57M 40 104 1Centre Hospitalier Universitaire de Butare (CHUB), Huye South, with proximal DVT, metastatic colon cancer, and HIV/AIDS, on war- 41 105 Rwanda; 2University of Rwanda, Kigali, Rwanda; 3Human farin for 8 months; acute gouty arthritis, hyperkalemia, and severe 42 106 Resources for Health Program, Rwanda; and 4Yale School of acute on chronic kidney injury in a 51M with dilated cardiomyopa- 43 107 Medicine, New Haven, Connecticut, USA thy and cardio-renal syndrome, on furosemide, hydrochlorothiazide, 44 108 Background: Pharmacovigilance is very important for patient safety carvedilol, losartan and spironolactone; renal failure (normal sized 45 109 as adverse drug reactions (ADR) may be serious and preventable. kidneys) after 2 weeks high dose diclofenac postoperatively in an 46 110 We aimed to encourage adverse drug reaction (ADR) reporting and ANA +ve 54F. Drug-drug interactions were suspected in 3: 57M 47 111 to assess patterns of adverse drug reactions in in-patients and out- – fluconazole interacting with new HAART (atazanavir/ritonavir/ 48 112 patients at our national referral hospital. abacavir) to cause acute liver failure; furosemide and hydrochlorothi- 49 113 Methods: We used WHO and Ministry of Health ADR reporting azide-associated hyperuricemia in 51M; elevated liver transaminases 50 114 protocols, including causality reviews, to identify suspected harmful in 41F on fluconazole and anti-TB therapy (rifampicin, isoniazid, 51 115 responses to one or more medicines, prescribed, OTC or traditional, pyrazinamide, ethambutol). 52 116 known or new. Conclusions: We raised awareness of ADR reporting at our centre. 53 117 Results: Prospective data are presented for a 1 week audit. 9 reports Key patterns for suspected ADRs included drug-drug interactions and 54 118 were received (8 patients, age range 10–58 years, median 51 years; drug-illness synergistic adverse effects. We aim next to assess impact 55 119 5 female) from: Internal Medicine, the HIV Clinic, ICU, Surgery and of ADRs on morbidity, length of hospital stay, and associated costs, 56 120 Paediatrics. 2 concerned medication errors (ciprofloxocin prescribed and how increased focus on ADR reporting may reduce preventable 57 121 – but not administered instead intended co-trimoxazole; cloxacillin morbidity and costs. 58 122 prescribed as twice the recommended dose). Two were related to 59 123 traditional medicines causing severe vomiting precipitating hospital 60 124 admission (girl of 10 also found to have severe anaemia; 31 year 61 Pharmacovigilance in Kyrgyzstan: the 125 old women with worsening post-partum oedema and severe chronic 62 current situation 126 kidney disease (creatinine 425 mol/L). Other ADRs were cloxacillin- 1,2 2 3 63 μ A.Z. Zurdinov ; G.А. Kulushova ; S.R. Moldoisaeva ; 127 induced Stevens Johnson Syndrome (14F); severe dyskinaesia from 4 64 and A.A. Zurdinova 128

2015 e1 Clinical Therapeutics

1 1Department of Drug Supply and Medical Devices under Ministry vasopressors and occurrence of MODS according to the SOFA 65 2 of Health, Bishkek Kyrgyzstan; 2Kyrgyz State Medical Academy, (sequential organ failure assessment) score. Intention to treat (ITT) 66 3 Bishkek Kyrgyzstan; 3Ministry of Health, Bishkek Kyrgyzstan; and analysis was performed. Comparisons between groups of categori- 67 4 4Kyrgyz-Russian Slavic University cal data were performed using the two-tailed Fisher’s exact test and 68 5 Introduction: Well-known that the medicines safety issues has been comparisons between groups of continuous data were performed 69 6 required increasing attention worldwide. As for Kyrgyzstan phar- using the Mann-Whitney U test. The data were analyzed using SPSS 70 7 macovigilance has been established since 2002 only. Well organized Version 15 for Windows (SPSS Inc., Chicago, IL, USA). 71 8 pharmacovigilance system is the base for rational and safely use of Results: Demographics and illness severity were similar between the 72 9 medicines and more over is the base for optimization of health facil- groups. The 28 day mortality was similar in all the groups (37.2% vs. 73 10 ity’s operation. Objective of this work is to evaluation of frequency 37.8% vs. 40.5%), as were ICU length of stay (8.7 days vs. 8.9 days 74 11 and severity of adverse drug reactions (ADRs) and highlighting the vs. 10.2 days) and duration of mechanical ventilation (4.2 vs. 4.0 75 12 importance of medicines safety issues in health system. days vs. 4.9 days). More patients in the late Ulinastatin and control 76 13 Methods: Spontaneous reporting method and retrospective analy- groups developed MODS (52.9% vs. 44.5% vs. 24.7%, P < 0.001) 77 14 sis of medical cards of hospital patients have been used. Statistical than early Ulinastatin group. There was also overall reduction in the 78 15 analysis has been done by MS Excel 2010. total vasopressors usage in both early and late Ulinastatin groups 79 16 Results: A total of 11,630 medical cards of patients in 10 hospitals over control group (54.3 % vs. 56.7% vs. 79.8%; P < 0.001). There 80 17 of country were analyzed; only 5 cases of ADR were registered, that were no increases in the overall side-effects between the groups. 81 18 is the proof of apparent lack of doctor’s activities on that direction. Conclusion: Our study found that early use of Ulinastatin (< 48 82 19 From our view it is due to the low awareness of majority medical hours) reduces the occurrence of MODS in patients with septic shock 83 20 professionals on the need to informing about ADR (91%). Also, following anastomotic failure. 84 21 another reason of low registration of ADRs is the limited knowledge 85 22 on recognition the events associated with use of medicines (72%). It 86 23 must be noted that the active implementation of pharmacovigilance Towards a more efficient and effective 87 24 has been initiated since 2013. Out of total 666 reports have been use of Psychotropic Drugs in nursing 88 25 received from the period of 2002 to 2014, 30% have been received homes: a quality improvement project in 89 26 in 2013-2014. The main parts of ADRs were due to use of antibiotics Belgium 90 27 (37%), anti-TB drugs (10.5%), vaccines (10.3%). 40.4% of reports M. Azermai1; D. De Meester2; L. Renson2; D. Pauwels2; H. Warie2; 81 28 due to use of injection medicines. and M. Petrovic1 92 29 Conclusion: The current situation of pharmacovigilance is not fully 1Ghent University, Ghent, East Flanders, Belgium; and 2Leiehome, 93 30 effective, so by nowadays there is no reliable statistical data on ADRs. Drongen, East Flanders, Belgium 94 31 The situation on pharmacovigilance has been improving since 2013 Introduction: ‘Working towards a more efficient and effective use 95 32 as a result of organizational and educational activities held, that is of psychotropic drugs' was a quality improvement project, funded 96 33 proving there is a need of further more focused and regular activities by the Belgian government. The goal was to reduce the high psycho- 97 34 at all levels of health care system. tropic drug use through education and sensitization of all actors. 98 35 Methods: This was a pilot project (2013-2014) with a pre-post 99 36 design in two residential care centers. The intervention group received 100 37 Early use of ulinastatin reduces an educational trilogy given by experts on psychotropic drugs, as 101 38 Multiorgan Dysfunction (MODS) in septic well as one-on-one professional support. The control group received 102 39 shock following anastomotic failure education-only without professional support afterwards. Drug use 103 40 A.H. Choudhuri1; R. Tyagi2; R. Tyagi2; D. Agarwal2; was recorded and coded according to the Anatomical Therapeutic 104 41 and R. Uppal1 and Chemical classification. Included psychotropics were antipsy- 105 42 1GB Pant Institute of Post Graduate Medical Education & chotics, antidepressants and benzodiazepines. Measurements were 106 43 Research, New Delhi, India; and 2Pushpanjali Hospital, Agra, done at 3 time-points: at baseline (pre), after 10 months (post) and 107 44 India after 1 year (follow-up). 108 45 109 Introduction: Anastomotic failure is a serious complication after Results: Residents’ (n = 119) had a mean age of 82 years, of which 46 major abdominal surgery resulting in septic shock and death. Early 71% were female. The mean drug use was 9 (range 1-21). Most 110 47 intervention can reduce the adverse outcomes in septic shock. commonly used drugs were central nervous system drugs (88%). At 111 48 Ulinastatin is a potentially effective intervention to attenuate the baseline (intervention group), the prevalence of psychotropic drug use 112 49 113 systemic inflammatory response induced by sepsis. was 72.3% (range 1-6). There was a significant reduction <( 0.001) 50 The aim of the present study was to compare the effects of early after the intervention, with a remaining prevalence of 60.5%. The 114 51 115 (< 48 hours) versus late (> 48 hours) use of Ulinastatin on the out- overall mean drug use decreased to 8 (range 0-20). The comparison of 52 come of septic shock following anastomotic failure after major pre versus post-measurements (intervention group) showed a strong 116 53 abdominal surgery. decrease for benzodiazepines: 50% vs. 38%, followed by antidepres- 117 54 Methods: One hundred four patients developing anastomotic fail- sants 42% vs. 36%. The decrease of antipsychotics was less strong: 118 55 ure after major abdominal surgery in two multispecialty hospitals 21% vs. 17%. In the control group (with education-only), there was 119 56 in India between October 2012 and May 2014 were included in a modest reduction of the psychotropic drug use: benzodiazepines 120 57 the study. The patients receiving Ulinastatin within 48 hours of the 58% vs. 53%, antidepressants 44% vs. 41%, and antipsychotics 121 58 122 onset of septic shock (Group A; n = 37) were compared against 30% vs. 28%. 59 those receiving Ulinastatin after 48 hours of the onset of septic Conclusion: This improvement project led to a significant decrease in 123 60 124 shock (Group B; n = 31) and control (Group C; n = 36). The pri- the use of psychotropic drugs, even after 1 year follow-up. Education 61 mary outcome was mortality at 28 days. The secondary outcomes only had a very limited effect. The person-centered approach offered 125 62 were duration of mechanical ventilation, length of ICU stay, use of by the project staff was of a great value. 126 63 127 64 128

e2 Volume XX Number XX Pharmacoeconomics biosimilars in Oncology

1 Assessment of comorbidities in patients carbapenems is well known, the available data are focused on phar- 65 2 with Symptomatic Knee osteoarthritis in macokinetic studies rather than clinical implications. 66 3 Spain: the emartro study Objective: to evaluate the clinical outcome due to interaction 67 4 S. Giménez Basallote1; J. Vergara Martín2; J.L. Llisterri Caro3; between VPA and carbapenems. 68 5 G. Rodríguez Roca4; J. Monfort Faure5; F.J. de Abajo Iglesias6; Material and Methods: An observational, retrospective and unicen- 69 6 J. Ríos Guillermo7; L. Sánchez Bellmunt8; M. Herrero Barbero8; tric study was performed. Patients whose VPA plasma levels were 70 7 and J. Vergés Milano8 closely monitored by our department and that had been simultane- 71 8 1Centro de Salud Limonar, Málaga, Spain; 2Centro de Salud ously treated with a carbapenem from 2011 to 2014 were included. 72 9 Huércal de Almería, Almería, Spain; 3Centro de Salud Ingeniero Demographic variables, VPA plasma levels, changes in prescription, 73 10 Joaquín Benlloch, Valencia, Spain; 4Centro de Salud de la Puebla electroencephalogram (EEG), and seizures were analyzed. 74 11 de Montalbán, Toledo, Spain; 5Hospital del Mar, Barcelona, Spain; Results: Of 66 patients with VPA plasmatic levels closely moni- 75 12 6Hospital Universitario Príncipe de Asturias, Madrid, Spain; tored, 9 (14%) had an interaction with a carbapenem. Of these nine, 76 13 7IDIBAPS, Hospital Clínic Barcelona, Barcelona, Spain; and 56% (5) were female, with a median age of 47 years, range 18-76. 77 14 8Bioibérica, S.A., Barcelona, Spain All of the patients were hospitalized in the intensive care unit and 78 15 Introduction: The primary outcome of the study is to assess the prev- received meropenem concomitantly to VPA. After the introduction 79 16 alence of comorbidities in symptomatic knee osteoarthritis (KOA) of meropenem, the mean decrease of the VPA plasmatic levels was 80 17 patients. Additionally, potential differentiating factors between KOA 29.3 mg/L, range from 5 to 48 mg/L. In four patients (44.4%) the 81 18 and non-osteoarthritic subjects will be assessed to detect a possible meropenem was stopped, in three (33.3%) was switched to another 82 19 prognosis effect complementary to osteoarthritis. antibiotic and in 2 (22.2%) was continued. All the patients required 83 20 Here we present the protocol of the study that is being conducted an increase of the VPA dosage. In three patients (33.3%) the drug 84 21 at the moment. interaction had clinical consequences (in one patient the VPA level 85 22 Material and Methods: It’s an observational, epidemiologic, multi- dropped 40 mg/L causing a seizure, and in the other two their EEGs 86 23 center, transversal study comparing comorbidities between subjects showed seizure activity without clinical convulsions, probably due 87 24 with and without KOA. The recruitment will be carried out by 65 to general sedation). 88 25 investigators from different Spanish’s healthcare centers. 1150 sub- Conclusions: A third of the patients treated concomitantly with 89 26 jects will be enrolled distributed in two groups: 575 KOA subjects VPA and meropenem had clinical implications such as seizures (one 90 27 selected and 575 sex and age-matched control subjects, without nei- patient) and EEGs with seizure activity (two patients). Simultaneous 81 28 ther knee pain nor osteoarthritis. The results will be analyzed using administration of both drugs should be avoided when possible. If not, 92 29 descriptive statistics. VPA plasmatic levels should be closely monitored. 93 30 Results: This study will provide new information about comorbidi- 94 31 ties in osteoarthritis which has become the leading cause of disability 95 32 in the elderly and permanent disability caused by a rheumatic disease Drug induced Pathological Gambling 96 33 (RD) and one of the most frequent reasons for consultation. In other P. Figueroa1; N. García Doladé2; and G. Cereza2 97 34 studies, it has been observed that the prevalence of comorbidities 1Clinical Pharmacology Service. Vall d’Hebron Hospital, 98 35 was significantly higher in osteoarthritis patients than controls (P Barcelona, Spain; and 2Fundació Institut Català de Farmacologia, 99 36 < 0.0001) being hypertension, diabetes mellitus, chronic obstruc- Barcelona, Spain 100 37 tive pulmonary disease, stroke and myocardial infarction the most Introduction: Pathological gambling is a severe impulse control dis- 101 38 prevalent osteoarthritis comorbidities. order. It has been associated with dopaminergic drugs prescribed 102 39 The ongoing study is in the follow-up period. to treat Parkinson’s disease (PD). In recent years, it also has been 103 40 Conclusions: Osteoarthritis is the most common RD, affecting 28% reported cases with aripiprazole. We aimed to describe the main 104 41 of those over 60 years, enduring pain, functional disability, decreased characteristics of spontaneous reports about pathological gambling 105 42 quality of life and causing significant social and economic burden. received by the Spanish Pharmacovigilance System (SPvS). 106 43 However, an important proportion of the economical costs of oste- Material and Methods: Spontaneous reports of PG received by the 107 44 oarthritis compared to non-osteoarthritic population is due to an SPvS from 1983 to 2014 were selected. The variables analyzed were 108 45 excessive use of sanitary resources which includes not only pharma- age and sex of the patients, suspect drugs and therapeutic indication, 109 46 cological treatment but also image and laboratory tests, management other concomitant adverse drug reactions (ADRs), severity and out- 110 47 of treatment adverse reactions or rehabilitation and surgical inter- come, latency period, rechallenge, underlying conditions and alter- 111 48 ventions. The knowledge of comorbidities and concomitant medica- native causes. 112 49 tions in KOA patients will provide useful information to manage the Results: Until December 2014 the SPvS database had gathered 113 50 disease more effectively and reduce its social and economic burden. 203,582 spontaneous reports of ADRs, 15 of them described patho- 114 51 logical gambling. All cases were male with a median age of 60 years 115 52 (46 to 84 years). The total number of suspect drugs was 24; all of 116 53 Valproic Acid and Carbapenems them were dopaminergic agents, mainly dopamine agonists (15). The 117 54 interaction: clinical outcomes drug most frequently reported was pramipexole (10 cases) followed 118 55 119 A.L. Arellano1,2; A. Barriocanal2,3; Y. Sanz1; and E. Montané1,2 by and ropinirole (3). All patients were treated of PD. The latency 56 120 1Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; period ranged from 1 month to 3 years. Besides pathological gam- 57 121 2Universitat Autònoma de Barcelona, Spain; and 3Fundació bling, in three cases other ADRs were described; suicidal ideation (1 58 122 d’Investigació en Ciències de la Salut Germans Trias i Pujol, case), hypersexuality, dopamine dysregulation syndrome and drug 59 123 Barcelona, Spain abuse (1) and alcoholism (1). Thirteen reports were serious (86.6%); 60 124 Background or Introduction: One of the setbacks of the valproic acid 6 patients improved after withdrawal of the suspect drug. Only one 61 125 (VPA) is the potential for pharmacological interactions. Although patient had history of previous gambling. Alternative explanations 62 126 the decrease in the VPA serum concentrations in patients receiving were excluded in 9 cases; there were no cases with a positive rechal- 63 lenge. 127 64 128

2015 e3 Clinical Therapeutics

1 Conclusions: Drug-induced pathological gambling is a serious MAPK-activated protein kinase 2 (MK2) is a cell cycle checkpoint 65 2 adverse reaction. Affected patients were treated for PD. Dopaminergic kinase involved in DNA damage response. MK2 inhibitors enhance 66 3 agents appear to be the only drugs involved, mainly pramipexole. efficacy of conventional chemotherapeutic agents, but their effective- 67 4 Prescribing physicians should warn patients and their families in ness as a single agent has not been investigated. 68 5 order to allow for early diagnosis of this condition, which would Material and Methods: The anti-cancer effectiveness of an MK2a 69 6 allow early intervention and thus avoid possible medical and social substrate-selective p38 inhibitor CMPD1 (Boehringer-Ingelheim; 70 7 complications. Davidson et. al., Biochemistry 2004; 43(37):11658-71) was deter- 71 8 mined in a panel of glioblastoma cell lines and normal cells (pri- 72 9 mary human microglia, astrocytes and neurons) using cell viability, 73 10 Brand-name to generic substitution of Annexin-V staining and cell cycle analysis. Immunofluorescence and 74 11 antiepileptic Drugs (AED) does not lead tubulin polymerization assays were conducted to study the effect of 75 12 to seizure-related hospitalization: a CMPD1 on microtubules. 76 13 Population-based case-crossover study Results: The MK2 inhibitor CMPD1 demonstrated single agent anti- 77 14 cancer efficacy with a submicro-molar IC in glioblastoma cells yet 78 E. Polard1; E. Nowak1; A. Happe1; A. Biraben2; and E. Oger1 50 15 1Pharmacoepidemiology Team CTAD-PEPI, INSERM CIC-1414, exhibited minimal toxicity on normal cells. Treatment of U87 cells 79 16 Rennes University Hospital, France; and 2Neurology Department, with CMPD1 resulted in G2/M arrest and accumulation of a poly- 80 17 Rennes University Hospital, France ploid (> 4n) population. Moreover, CMPD1 induced apoptosis and 81 18 Introduction: There are still controversies over pill substitution affected the expression of anti-apoptotic proteins in glioblastoma 82 19 among AEDs. We aimed at further estimating the association between cells. However, these observations were less evident in primary astro- 83 20 generic substitution and loss of seizure control. cytes. Interestingly, while reported to be MK2a substrate-selective 84 21 Patients and Methods: We used data from the French National p38 inhibitor, CMPD1 did not inhibit MK2 or its downstream target 85 22 Health Insurance Information System linked with the French Hospital Hsp27 at doses that are cytotoxic in U87 cells. siRNA knockdown 86 23 of MK2 did not alter the IC of CMPD1 suggesting that MK2 is not 87 Discharge Database. We identified a cohort of adult patients who 50 involved in cell death. Instead, we identified CMPD1 as a tubulin 24 filled a prescription in 2009–2011 for AEDs that had at least one 88 depolymerizing agent causing microtubule disruption in glioblastoma 25 brand-name and one generic form available on the French market. 89 cells. Furthermore, we discovered that CMPD1 reduces the expres- 26 Patients with a medical history of cancer and women who gave birth 90 sion of tubulin in U87 cells and inhibited the self-renewal capacity 27 in 2009–2011 were excluded. We designed a case-crossover study; 81 of glioblastoma cells. 28 three months were used for the case- and the control-periods. The 92 Conclusions: Collectively, we have discovered a novel microtubule 29 outcome date was defined as the date of first occurrence of hospi- 93 targeting drug candidate with selective toxicity for glioblastoma 30 talization for seizure, code G40.x or G41.x, pending being G40/ 94 therapy. We are currently developing analogues with enhanced blood- 31 G41 hospitalization-free period in the preceding year. We required 95 brain barrier permeable properties. 32 individuals to have regular dispensations of AEDs within the year 96 33 preceding the outcome date. Free patients were defined as patients 97 34 who had only brand-name dispensations before the control period. 98 35 B-G substitution was defined as a filled prescription for a generic Adverse events associated with ANTI-TNF 99 36 AED that was preceded by a filled prescription for a brand-name therapy in inflammatory bowel disease 100 37 counterpart. ORs and 95% CIs were estimated using conditional cohort group in a Croatian Tertiary 101 38 logistic regression model. Centre 102 39 1,2 1,2 1,2 103 Results: A total of 8,379 patients (mean age ± SD, 52.7 ± 18.8 years; V. Oršić Frič ; S. Mimica-Matanović ; and V. Borzan 40 sex ratio male/female, 1.27) were analyzed. Discordant pairs were 1Clinical Hospital Centre Osijek, Osijek, Croatia; and 2Faculty of 104 41 491 with B-G substitution in the control period only and 478 with Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, 105 42 B-G substitution in the case period only; OR (95% CI) 0.97 (0.86– Croatia 106 43 1.10). No statistically significant interaction was detected among Introduction: Biological therapy has significantly improved the treat- 107 44 four pre-specified subgroup analyses (gender, age strata, free or non- ment of patients with inflammatory bowel disease (IBD). Anti-Tumor 108 45 free patients and strict AED monotherapy or not). Controlling for Necrosis Factor (anti-TNF) agents infliximab (IFX) and adalimumab 109 46 non-seizure-related hospitalizations made no material difference. (ADA) are biologics most commonly used for the treatment of IBD, 110 47 Sensitivity analyses yielded similar results. but with a burden of possible severe adverse events (AEs). Our objec- 111 48 Conclusion: B-G AED substitution was not associated with an ele- tive was to present the evaluation of safety data on anti-TNF therapy 112 49 vated risk of seizure-related hospitalization. in the cohort of IBD patients in our centre. 113 50 Methods: We included patients treated with anti-TNF therapy at 114 51 the Department of Gastroenterology and Hepatology of Clinical 115 52 116 The Mapk-activated protein Kinase 2 (MK2) Hospital Centre Osijek from 2005 to 2013. Data were collected from 53 patient’s medical records and presented according to the Common 117 54 inhibitor CMPD1 is a novel microtubule 118 targeting agent for Glioblastoma Terminology Criteria for AEs. Patients with incomplete medical 55 records were excluded. 119 56 Therapy 120 1 1 2 3 3 Results: We included 60 patients treated for Crohn’s disease and 22 57 F. Gurgis ; M. Åkerfeldt ; C. Wong ; B. Heng ; G.J. Guillemin ; 121 2 1 for ulcerative colitis. Of those, 37 patients were on IFX, 25 patients 58 M. Chircop ; and L. Munoz 122 1The University of Sydney, Sydney, Australia; 2Children’s Medical on ADA, while 20 patients were treated with both medications dur- 59 ing different intervals. Median follow-up of an individual patient 123 Research Institute, Sydney, Australia; and 3Macquarie University, 60 was 36.5 months (range 1-99). At least one AE was reported for 124 Sydney, Australia 61 27 patients (47.4%) on IFX and 16 patients (35.6%) on ADA. The 125 Introduction: Glioblastoma is among the most lethal and least suc- 62 overall number of observed AEs was 67, of which 63 (94.03%) were 126 cessfully treated solid tumours. A suitable agent for brain tumour 63 mild to moderate, and 4 (5.97%) were severe. The most common 127 64 treatment must cross the blood-brain barrier and lack neurotoxicity. 128

e4 Volume XX Number XX Pharmacoeconomics biosimilars in Oncology

1 mild to moderate AEs were mild to moderate infections (upper and kidney dysfunction rises in this population. Infections need immediate 65 2 lower respiratory tract most commonly), abnormal liver enzyme tests treatment; during the further course, kidney function must be taken 66 3 and infusion reaction or local reaction at the injection site. Of severe into account. Anti-infective drugs often require dosing modifications 67 4 AEs, two cases of reactivation of tuberculosis, one case of colon car- based on an estimate of kidney function, usually the glomerular filtra- 68 5 cinoma and one hospitalization due to the febrile state was observed. tion rate (GFR). However, there is still no preferential GFR formula 69 6 Conclusion: Our data confirm that anti-TNF therapy can be con- to be used, and in acute kidney injury there is always a considerable 70 7 sidered safe, as most of the AEs were mild to moderate in severity. time delay between true kidney function and estimated GFR. 71 8 However, vigilant follow-up of patients during and after the therapy Dosing Principles: In most cases, the anti-infective therapy should 72 9 is needed for early recognition and treatment of severe AEs. start with an immediate and high loading dose. Almost any drug can 73 10 be adjusted to any kidney function in every patient. Observation of 74 11 the pharmacokinetic principles allows avoiding adverse events and 75 12 Population exposure-response modeling toxic overdose. Observation of the pharmacodynamic principles is 76 13 of oral Nepadutant administration in needed to obtain anti-infective success and to avoid ineffective under- 77 14 Colicky infants dose. Anti-infective drugs with time-dependent action should be given 78 15 P. Mazzei1; E.N. Jonsson2; S. Jönsson2; S. Bouchene2; with the target of high trough concentrations (e.g. beta lactam antibi- 79 16 M.O. Karlsson2; M. Lerro1; F. Masciopinto1; D. Zinzi1; otics, penems, vancomycin, antiviral drugs). Anti-infective drugs with 80 17 G. Poggiali1; A. Tuccio1; M. Bertolotti1; S. Scartoni1; A. Capriati1; concentration-dependent action should be given with the target of 81 18 and C.A. Maggi1 high peak concentrations (e.g. aminoglycosides, daptomycin, colistin, 82 19 1Menarini Ricerche S.p.A., Florence (Italy); and 2Pharmetheus AB, quinolones). Our group created a pharmacokinetic database, called 83 20 Uppsala (Sweden) NEPharm, that serves as a reference to obtain dosing regimens of 84 21 Introduction: Nepadutant is a potent antagonist of tachykinin NK2 anti-infective drugs in kidney dysfunction as well as renal replace- 85 22 receptors found to control the gastrointestinal hypermotility, tested ment therapy. 86 23 in clinical phase IIa studies. In NIC-03, a phase IIa multicentre, ran- Conclusion: To avoid the risk of either too low or too infrequent 87 24 domised, double-blind, placebo controlled to study the efficacy of peak concentrations, we prefer the eliminated fraction rule for dose 88 25 two oral nepadutant doses (0.1 or 0.5mg/kg) in colicky infants, a adjustment calculations. When in doubt, the peak should be the tar- 89 26 population Exposure-response (ER) analysis was performed. get. 90 27 Objectives: The study aimed to: (1) elaborate a population ER model 81 28 to illustrate the performance of the dosing regimens of oral nepadu- 92 29 tant tested in different body weight groups; (2) perform simulations Distinguishing Drug-induced Autoimmune 93 30 from the final population ER model to compare dosage regimens Hepatitis from idiopatic Autoimmune 94 31 predicting alternative doses. Hepatitis and Dili with Autoantibodies 95 32 Material and Methods: The population ER model based on observa- A. Ortega-Alonso1; A. Castiella2; M. Robles-Diaz1a; 96 33 tions of time of crying and fussing was developed in steps as the sum I. Medina-Caliz1a; C. Stephens1a; J. Sanabria1; 97 34 of three sub-models describing the response at baseline, following A. Gonzalez-Jimenez1; B. Garcia-Muñoz1; M. Garcia-Cortes1a; 98 35 placebo and following nepadutant treatments. Crying and fussing E.M. Zapata2; P. Otazua3; S. Blanco4; M. Prieto5; F. Bessone6; 99 36 7 8 9 10 100 time = Baseline + Placebo + Drug. N. Hernández ; M.C. Fernandez ; H. Hallal ; J. Primo ; 37 A continuous dependent variable, length of crying and fussing J.M. Moreno-Planas11; M. Arrese12; R.J. Andrade1; 101 38 time (min) within 2h intervals, was assembled based on records from and M.I. Lucena1 102 39 “baby’s day” diary. Modelling data were obtained at baseline and fol- 1Unidad de Hepatología y Servicio de Farmacología Clínica, 103 40 lowing 7 days placebo, nepadutant 0.1mg/kg or nepadutant 0.5mg/kg Instituto de Investigación Biomédica de Málaga (IBIMA), H U 104 41 treatment. The final analysis dataset included 9945 observations of Virgen de la Victoria, Universidad de Málaga, Málaga.; 1aCentro 105 42 crying and fussing time/2 h from 104 infants. de Investigación Biomédica en Red de Enfermedades Hepáticas 106 43 Results: The model predicted a change from baseline (CFB) and a y Digestivas (CIBERehd), Málaga, Spain; 2Hospital de Mendaro, 107 44 placebo corrected CFB for the 0.5mg/kg group of −36% and −8% Gipuzkoa, Spain; 3Hospital de Mondragón, Gipuzkoa, Spain; 108 45 respectively, resulting into a relative improvement of 29% for the 4Hospital Universitario de Basurto, Bilbao, Spain; 5Hospital 109 46 0.5mg/kg group compared to placebo. La Fe, CIBERehd, Valencia, Spain; 6Hospital Provincial 110 47 The inter-individual variability was included on the slope of the del Centenario, Rosario, Argentina; 7Hospital de Clínicas, 111 48 drug effect. Age and body weight (BW) were not significant covari- Clínica de Gastroenterología, Montevideo, Uruguay; 8Hospital 112 49 ates. Simulation analysis, predicted that 1mg/kg is expected to per- Torrecárdenas, Almería, Spain; 9Hospital Morales Meseguer, 113 50 form even better than 0.5 mg/kg. Murcia, Spain; 10Hospital de Sagunto, Valencia, Spain; 11Complejo 114 51 Conclusions: The population ER model was best described by a lin- Hospitalario Universitario de Albacete, Albacete, Spain; and 115 52 ear dose-efficacy model with a statistically significant effect of the 12Escuela de Medicina. Pontificia Universidad Católica de Chile, 116 53 higher dose group 0.5 mg/kg nepadutant. Santiago de Chile, Chile 117 54 Aim: Drug-induced liver injury (DILI) may be associated with an 118 55 autoimmune phenotype (DILI-AIH). We aimed to characterize phe- 119 56 120 Pharmacokinetics, Pharmacodynamics, notypes, outcomes and culprit drugs in idiopathic autoimmune hepa- 57 titis (AIH), DI-AIH and DILI with/without autoantibodies (AAB) in 121 58 and antimicrobials in Cancer patients 122 with Kidney Dysfunction a large cohort of DILI patients. 59 Methods: Demographic variables in 21 of 1013(2.1%) patients from 123 F. Keller 60 the Spanish-Latin DILI Registries diagnosed with DI-AIH (detectable 124 Nephrology, Medical Department 1, University Hospital, Ulm, 61 ANA/ASMA titres and high gammaglobulin levels) were compared 125 Germany 62 to 51 idiopathic AIH patients and 129 (12.7%) DILI AAB and 126 Background: Patients with cancer have a high inherent risk of infec- + 63 371 AAB−. 127 64 tious complications. In addition, the incidence of acute and chronic 128

2015 e5 Clinical Therapeutics

1 Results: DILI-AIH and AIH patients had similar age and gender Positioning the New oral 65 2 distribution, 38% males (mean 58 y) in the DILI-AIH cohort. The Anticoagulants for prevention of 66 3 DILI AAB+ were older (mean 53 years vs 49, P = 0.025) and female stroke in patients with non-valvular 67 4 predominated (57% vs 52%, P = 0.306) than DILI AAB−. Among atrial fibrilation 68 5 drugs triggering DILI-AIH and concomitant drugs in AIH patients M. Ezzeldin1; J. Sáez-Peñataro1; and X. Carné1,2 69 6 statins (19% vs 12%), NSAIDs (10% vs 12%) and antibiotics (24% 1Clinical Pharmacology Department, Hospital Clínic, Barcelona, 70 7 vs 2%) featured more frequently. Statins were also more frequent Spain; and 2Universidad de Barcelona, Barcelona, Spain 71 8 in DILI AAB+ than in AAB− (4.6% vs 3.6%). Compared to AIH, Introduction: Non-valvular atrial fibrillation (AF) is the most preva- 72 9 DILI-AIH patients were more frequently jaundiced (62% vs 31%) lent cardiac arrhythmia, being the cause of considerable morbidity 73 10 and had higher AST (23 × ULN vs 11 × ULN, P = 0.001) and ALT (i.e. stroke) and mortality. Vitamin K antagonists (VKA) have been 74 11 values (27 × ULN vs 14 × ULN, P = 0.001) at presentation. DILI the back-bone of oral anticoagulation for decades in the prevention of 75 12 AAB+ and DILI-AIH did not differ. DILI-AIH patients required less stroke in patients with moderate to high risk of stroke. In the last few 76 13 often immunosuppressant treatment than the AIH group (81% vs years, a new group of drugs, called new oral anticoagulants (NOACs) 77 14 93%), but more frequently than DILI AAB+ (81% vs 24%, P = have been introduced; acting directly on thrombin (dabigatran) or 78 15 0.00). DILI with autoimmune features responded better to treatment factor X (rivaroxaban, apixaban, edoxaban). In comparative clinical 79 16 (100% vs 92% AIH). trials of NOAC and AVK apparent advantages have been described 80 17 Conclusions: DILI-AIH and DILI AAB+ typically affects older with non-inferiority designs, like fixed-dose administration, a wide 81 18 females and less often necessitates steroid therapy than AIH cases therapeutic window and the lack of requirement for regular moni- 82 19 despite exhibiting a more severe phenotype at onset. Statins are likely toring. However, there is a need to assess their relative benefit/risk 83 20 to unmask DILI-AIH and DILI AAB+ and could be the unidentified ratio in real clinical practice conditions in order to be able to position 84 21 trigger in cases of “idiopathic” AIH suggesting a continuum across them in therapeutics. 85 22 the spectrum of drug-induced autoimmune liver disease. Objective: To review all published clinical trials of NOACs in non- 86 23 Funding: AEMPS,FIS PI12-00620,P10-CTS-6470, PI12/00378, valvular AF assessing their internal and external validity and to 87 24 AC-0073-2013,CIBERehd-ISCIII. update all the relevant literature related to their efficacy and safety 88 25 in real clinical practice conditions. 89 26 Materials and Methods: An up-to-date review and analysis of the 90 27 Individual variability in the most relevant clinical data in patients with non-valvular AF treated 81 28 Phamacokinetic of Tea Polyphenols and with VKAs and NOACs. 92 29 gene expression after oral intake of Results 93 30 94 Green Tea extrakt • Results of comparative head-to head trials with NOAC show 31 C. Scholl1; A. Lepper2; M. Steffens1; D. von Mallek1; 95 32 3 1 a trend towards dependence on the time that patients on the arm of 96 J. Brockmöller ; and J. Stingl VKA are in the therapeutic range. 33 1Federal Institute for Drugs and Medical Devices (BfArM), Bonn, 97 34 2 3 • The risks of bleeding for NOACs are greater in clinical practice 98 Germany; University of Ulm, Ulm, Germany; and University than those observed in published clinical trials. 35 Medical Centre Göttingen, Göttingen, Germany 99 36 • Treatment with NOAC (to start with or to switch on) should 100 Background: Green tea from the plant Camellia Sinensis is one of be carefully assessed in a case by case basis. 37 the most widely consumed beverages in the world. Furthermore, dry 101 38 extract of green tea is recently marketed as nutritional supplement. Conclusions: In patients with non-valvular AF at moderate/high risk 102 39 Epidemiological studies on green tea show a reduction of the can- of stroke, with good compliance and good INR, VKA must be con- 103 40 cer risk and a protective effect on the cardio-vascular system. These sidered as the treatment of choice. 104 41 effects seem to be governed particularly by green tea polyphenols, 105 42 with epigallocatechin-3-gallat (EGCG) as the main compound. 106 43 We investigate the influence of individual genetic predisposition 107 44 A Twin study of the trough plasma 108 on the pharmacokinetic of EGCG in order to gain information on steady state concentration of 45 the individual consequences of green tea consumption. 109 46 Metformin 110 Material and Methods: We carried out a clinical trial with 100 1 2 1 1 47 T.B. Stage ; P. Damkier ; R.S. Pedersen ; M.M.H. Christensen ; 111 healthy participants taking green tea extract capsules (300mg 1 1 1 48 L. Christiansen ; K. Christensen ; and K. Brosen 112 EGCG/d) for 5 days. The study protocol was approved by the Ethical 1 49 University of Southern Denmark, Odense, Denmark; and 113 Committee of the University of Ulm; participating patients gave oral 2Odense University Hospital, Odense, Denmark 50 and written consent. We determined the plasma concentration of 114 51 Background: Metformin is a glucose-lowering drug, which is used in 115 EGCG and other common green tea polyphenols on the last day of the treatment of type 2 diabetes. During the last decade the pharma- 52 study. Further, genome-wide expression profiles from participants 116 53 cogenetics of both the pharmacokinetics and –dynamics of metformin 117 before and after green tea extract treatment were analyzed. has been extensively investigated. Due to conflicting results no con- 54 Results: We determined an individual variability in the pharmacoki- 118 55 sensus has been reached regarding the impact of pharmacogenetics. 119 netics of the measured green tea polyphenols and the gene expression Thus, the aim of this study was to determine the heritability of the 56 after intake of green tea extract capsules. Several genes related to 120 57 trough concentration of metformin at steady state in twins. 121 oxidative stress and immunomodulation were significant regulated Material and Methods: We included 16 twin pairs (8 mono- and 8 58 within the study population after intake of green tea extract capsules. 122 59 dizygotic twin pairs) for this study, after contacting 524 twin pairs. 123 Here, we will present our recent results and discuss the individual They were dosed with metformin to steady state (1 g twice daily) 60 consequences of the consumption of green tea extract. 124 61 for 6 days and on day 7 the trough concentration of metformin was 125 62 determined 12 hours after the last dose. 126 63 127 64 128

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1 Results: The correlation of age and weight was higher in monozy- have the same impact according to the department? What are the 65 2 gotic twin pairs than in dizygotic twin pairs. However, the correlation feedbacks about the implementation in an oncology department? 66 3 of the trough concentration in the monozygotic twin pairs was equal Material and Methods: The experience is made on one month, all 67 4 to that of the dizygotic twin pairs. the drug conciliations have been treated retroactively (72 h) about 68 5 Conclusions: This indicates that the trough concentration of met- all entrants in a 30 beds oncology department. An exhaustive treat- 69 6 formin is not regulated to a major extent by genetic factors. ments list is establish (by crossing different sources like family, regular 70 7 doctor, pharmacy, report…) and compared to the admission’s pre- 71 8 scriptions, differences obtained are highlighted and characterized. 72 9 1964–2014: 50 Years of the declaration Following, this study conclusion is compared with existing literature 73 10 of Helsinki: a moving framework of the and results obtained by other way (other department, entry mode 74 11 ethical dilemmas in Clinical Research of patients). 75 Results: Results of conciliation in an conventional hospitalization 12 X. Carné; J.A. Arnaiz; and N. Riba 76 service versus emergencies downstream or surgery department in 13 Hospital Clínic-IDIBAPS, Barcelona, Spain 77 literature 14 Introduction: Fifty years have passed since the 18th WMA Assembly 78 15 79 adopted the original version of the Declaration of Helsinki (DoH). • On average 0.6 differences by patients (forgotten medication) 16 80 Since then it has been amended seven times (in the years 1975, 1983, versus 1.7 [0.5-3.3] (comparative board) 17 81 1989, 1996, 2000, 2008 and 2013). In the 2000 version, two notes • More than 80% of the entrants in our department are already 18 82 of clarification were added (in the years 2002 and 2004), due to hot known 19 83 debate and lack of consensus. Hospitalizations in the last 6 months (37%) 20 о 84 Material and Methods: We have compared the different versions Consultations and followed in day hospital (47%) 21 о 85 of the DoH, searching for the main changes introduced in the dif- • 16% come via emergency for a first support. 22 ferent topics in each of the new versions in relation to the previous 86 23 ones, aiming at describing the main ethical discussions of that time. Conclusion: Oncological patient regularly followed for chronic dis- 87 24 Our objective has been to draw a historical perspective of the most ease in day consultations at hospital get their chronic treatments 88 25 prevalent ethical dilemmas in relation to clinical research within the frequently reassessed, and multiple hospitalizations have solved their 89 26 scientific and bioethical community over time. acute problems. The patients’ profile is significantly different from 90 27 Results: Main changes in each version which reflect the most debated those from emergency downstream departments who are followed 81 28 topics per year were: by different actors. This explains the number of discrepancies less 92 29 important observed in relation to the literature. However this number 93 st 30 1 (1975): is not nil and encourages us to pursue our approach. 94 31 - Primacy of the individual over society 95 32 - Independence of Research Ethics Committees (RECs). 96 nd rd Off-label uses of low-dose Rituximab: a 33 2 (1983) & 3 (1989): systematic review of the Literature 97 34 - No major changes 98 M. Fernandez-Martinez1; E. Esterlich2; A. Vallano2; I. Danés1; and 35 4th(1996): 99 A. Agustí1 36 - Ethical universalism vs ethical pluralism 100 1Fundació Institut Català de Farmacologia, Clinical Pharmacology 37 - Use of placebo. 101 service, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 38 5th (2000) & footnotes to art 29 & 30 (2002, 2004): 102 and 2Clinical Pharmacology Service, Hospital Universitari de 39 - Use of placebo 103 Bellvitge, Hospitalet de Llobregat, Spain 40 - Post trial access of studied drugs 104 Background: Rituximab is frequently used in off-label indications. 41 6th(2008): 105 Recently, there has been reported that its use in low-dosage might 42 - Clinical Trials registry in a publicly accessible database 106 also be effective in approved indications such as rheumatoid arthri- 43 - Source of funding and conflicts of interest 107 tis. Therefore, our objective was to review the efficacy of low-dose 44 7th(2013): 108 courses of rituximab in off-label indications. 45 - Continuous monitoring of the risks by the researcher 109 Material and Methods: A search of Pubmed database together with 46 - Qualification of REC members 110 a reference screening was performed from January 1999 to December 47 - Use of placebo 111 2014 in order to identify all the studies that examined the effective- 48 - Post-trial provisions (access of studied drugs). 112 ness of low-dose rituximab in off-label indications. 49 113 Conclusions: The most prevalent topics in the ethical debate have Results: Among 245 publications identified, 51 (n 1049) fulfilled 50 = 114 been: General concepts in the early 70s & 80s, use of placebo and the eligibility criteria (4 clinical trials, 10 prospective cohorts, 9 ret- 51 115 post-trial provisions since early 90s onwards, and the issue of trans- rospective cohorts, 15 case-series and 13 case reports). Rituximab 52 116 parency and qualification of RECs in the late 2000s. was used in 30 off-label diseases, being kidney transplant (KT, n 53 = 117 646), immune thrombocytopenia (PTI, n 146), pemphigus (PMP, n 54 = 118 45) and autoimmune haemolytic anaemia (AIHA, n 43) the main 55 Medical reconciliation: does the service = = 119 indications. Most frequently used dosages were 500mg twice given 56 matter? 120 1-2 weeks apart for musculoskeletal system, nervous system and skin 57 C. Roessle; I. Debrix; and J.-P. Lotz 121 diseases, 100mg weekly for 4 weeks in hematological diseases and a 58 Tenon Hospital, Paris, France 122 single dose of rituximab 200mg (range 35-500mg) in KT. The over- 59 Background: The drug treatments conciliation is an interactive pro- 123 all response (OR) observed was 80.5% with a 67.9% of complete 60 cess which guarantees the continuity of care by integrating in a new 124 responses (CR). Among the most frequent diseases, the OR and CR 61 global prescription all the chronicle treatments of a patient. This 125 were 100% and 66.6% in PMP, 97.7% and 65.1% in AIHA, 82.2% 62 process minimizes prescription’s gap at criticals points of transition 126 and 81.3% for KT and 70.5% and 50% in PTI, respectively. The 63 (admission, service transfer, end of hospitalization). The interest to 127 relapse rate and follow-up -median in months (range)- were described 64 secure medical care don’t have to be proved anymore, but does it 128

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1 for AIHA [38% and 11.5 (10–36)], PMP [33% and 17 (9–38)] and Potential Gastrointestinal injury by 65 2 PTI [30.9% and 14 (3–49)]. ion-exchange resins 66 3 Conclusion: This review suggests that low-dose courses of rituximab M.C.A. Mathijsen; W. Vreuls; J.J.J.P.M. v.d. Leur; B.A.J. Veldman; 67 4 could be effective in several off-label diseases although further clinical and J.M. Bos 68 5 trials are required in order to appropriately asses its efficacy. Canisius-Wilhemina Hospital, Nijmegen, the Netherlands 69 6 Introduction: Ion-exchange resins like sodium polystyrene sulfonate 70 7 (Resonium A®; SPS), calcium polystyrene sulfonate (Sorbisterit®; 71 8 Inhibitory effects of Pomegranate CPS) and sevelamer (Renvela®) are treatments for management of 72 9 concentrated solution on the activities the electrolyte disturbances hyperkalemia and hyperphosphatemia. 73 10 of Hyaluronidase, Tyrosinase, and SPS and CPS are associated with GI adverse events (necrosis of the 74 11 Metalloproteinase 1 bowel wall, ulceration and perforation) with a high mortality rate. 75 12 S.J. Kang1,2; B.R. Choi3; S.H. Kim3; H.Y. Yi3; H.R. Park3; There is a number of predisposing factors for developing GI injury 76 13 S.J. Park1,4; C.H. Song1,4; J.H. Park5; Y.J. Lee1,2; and S.K. Ku1,4 due to SPS or CPS (postoperative state, renal failure and transplan- 77 14 1The Medical Research Center for Globalization of Herbal tation). Recently it has been suggested that sevelamer also could be 78 15 Medicine, Daegu Haany University, Gyeongsan, Republic of harmful to the bowel. 79 16 Korea; 2Department of Preventive Medicine, College of Korean Material and Methods: We matched pathology and clinical phar- 80 17 Medicine, Deagu Haany University, Gyeongsan, Republic of macy databases by searching for patients that used SPS or CPS 81 18 Korea; 3Research Institute, Health-Love Co., Ltd., Anyang, between January 2005 and July 2014 and had a bowel resection or 82 19 Republic of Korea; 4Department of Histology and Anatomy, biopsies. Cases with a possible match were reviewed by the patholo- 83 20 College of Korean Medicine, Daegu Haany University, Gyeongsan, gist. The medical history (diseases, medication) of the identified cases 84 21 Republic of Korea; and 5Department of Herbology, College of were examined and a possible causal role of ion-exchange resins in 85 22 Korean Medicine, Daegu Haany University, Gyeongsan, Republic the development of the gastrointestinal problems was determined. 86 23 of Korea Results: Nine cases were identified. Two of these cases used seve- 87 24 Background: Botanical antioxidants have attracted much attention lamer concurrently with CPS of SPS. SPS or CPS seemed to play a 88 25 as useful preventatives of skin damage. Pomegranate is consumed causal role in the development of gastrointestinal problems in three 89 26 throughout the world for its beneficial health effects, including its of the nine cases. A causal relationship between sevelamer and the 90 27 anti-oxidant and anti-inflammatory activities. development of gastrointestinal injury could not be determined in 81 28 Objectives: We investigated whether pomegranate concentrated solu- these cases, because microscopy of the bowel of these patients showed 92 29 tion (PCS) could serve as a potential functional cosmetic ingredient also SPS or CPS crystals, that could have caused the damage. 93 30 that exerts a skin-whitening effect and anti-wrinkle activity. Conclusions: A known, rare complication of ion-exchange resins 94 31 Methods: To investigate the moisturizing effect of PCS, hyaluro- is perforation of the bowel. On histological examination, distinct 95 32 nidase activity was examined in human keratinocytes (HaCaT). pathologic characteristics can be found which suggest the presence of 96 33 Elastase and pro-collagenase activities were assessed in normal ion-exchange-resin induced bowel perforation. Although less evident 97 34 human primary dermal fibroblast-neonatal (HDF-N) cells to deter- than with SPS or CPS, sevelamer is possible not such an innocent 98 35 mine their anti-wrinkle effects. Metalloproteinase 1 (MMP-1) activity bystander as thought before. Clinicians should be aware of this seri- 99 36 was also assessed following UVA irradiation. Whitening effects were ous complication when prescribing this class of drugs. 100 37 measured by a tyrosinase inhibition assay and melanin formation 101 38 test in mouse melanocytes (Melan-a). In addition, histopathologi- 102 39 cal analysis was performed to determine the number of microfolds Adverse Drug reactions as cause of 103 40 formed on the epithelial surface, mean epithelial thickness, mean Hospital admission - a study Protocol 104 41 105 number of inflammatory cells infiltrating the dermis, and collagen P. Klarskov; J.T. Andersen; H.R. Christensen; M.B. Christensen; 42 106 fiber-occupied regions within the dermis. and E. Jimenez-Solem 43 107 Results: Hyaluronan synthesis was significantly increased by PCS Bispebjerg and Frederiksberg Hospitaler, Copenhagen, Denmark 44 108 in HaCaT cells, while pro-collagenase and elastase activities were Introduction: Adverse drug reactions (ADRs) are one of the lead- 45 109 decreased in HDF-N cells. A significant decrease in UVA-induced ing causes of hospitalisation. Most ADRs are not reported to the 46 110 MMP-1 activity was also observed in PCS-treated HDF-N cells, authorities, which impairs the update of a drugs safety profile, as 47 111 compared with UVA-exposed cells. PCS effectively reduced mela- clinical trials do not mirror real life drug use. In Denmark most recent 48 112 nin production and mushroom tyrosinase activity in Melan-a cells. estimates on the rate of hospital admissions due to ADRs date back 49 113 Moreover, UVB-induced histopathological dermal sclerosis and to 1992. Since then, drug-use has increased considerably, new drugs 50 114 inflammatory signs were significantly attenuated in PCS-administered have been marketed and new indications have been registered. The 51 115 mice compared with UVB-exposed mice. aims of the present study are therefore to estimate rates of ADRs 52 116 Conclusions: Our results suggest that PCS prevents signs of aging, leading to hospitalization and to identify high-risk drugs and high- 53 117 including those related to photo-aging. These effects are associated risk patient characteristics. The findings will be corroborated in a 54 118 with enhanced hyaluronan synthesis, as well as suppressed elastase, nationwide register based study. 55 119 collagenase, MMP-1, and tyrosinase activities and melanin produc- Materials, Methods and Results: We will prospectively analyse elec- 56 120 tion. UVB-induced photo-aging, such as histopathological dermal tronic patient records of 10,000 consecutive, unplanned admissions 57 121 sclerosis and inflammatory signs, were effectively reduced upon the at a hospital in Copenhagen. For each patient an ADR assessment 58 122 addition of PCS. These results also suggest that skin aging can be will be performed using the Naranjo ADR probability scale for cau- 59 123 prevented and reduced by the antioxidant effects of PCS. sality and the Hallas criteria for preventability. Drugs, drug doses, 60 124 Key words: pomegranate concentration solution, hyaluronan, drug interactions, and patient characteristics will be registered. Based 61 125 melanin, tyrosinase, photo-aging. on our prospective analysis we will estimate the rate of ADRs and 62 126 compare them to drug consumption in the hospital’s catchment area. 63 127 Our findings will then be reanalysed in a nation-wide setting using 64 128

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1 the Danish nationwide registers. The most common drugs leading to Introduction: Medication errors are serious safety concerns that have 65 2 hospital admission will be identified and nationwide estimated rates of existed for as long as medications have been available to patients. 66 3 hospitalization will be calculated, adjusted for regional confounders. They are a widespread problem, a major cause of adverse drug events 67 4 The study has been approved by the Danish Data Protection and one of the most preventable causes of patient injury. The aim of 68 5 Agency (Id BBH-2015-005). this study was to investigate pharmacy professionals’ perception and 69 6 Conclusions: The present study will yield an updated estimate of the opinions about potential causes of dispensing errors and the strategies 70 7 rate of ADRs leading to hospital admissions and valuable information to prevent them in community pharmacies. 71 8 on high risk drugs and high risk patient characteristics. Furthermore, Material and Methods: Through a cross-sectional and descriptive- 72 9 it will identify the frequency of ADRs leading to hospitalization in a correlational study, a survey was handed to all pharmacists and phar- 73 10 post-marketing setting. macy technicians working in one of the 49 community pharmacies 74 11 of a central Portuguese region. 75 12 Results: The response rate was 90.9%. “Prescription” category 76 13 Is devolution of prescriptions assembled the largest number of causes of medication errors 77 14 contributing to community Pharmacies’ (26%). “Drugs” category was second with 23% of causes of 78 15 Financial crisis? errors. “Handwriting prescriptions” appear as the most frequent 79 16 J. Lopes1; C. Monteiro1; J. Joaquim1; and M. Rocha2 single cause of medication errors (51.5%). Besides this “source of 80 17 1Instituto Politécnico de Coimbra, Coimbra Health School – errors”, the most frequent cause was “Patient in a hurry” (47.3%); 81 18 ESTESC, Farmácia, Coimbra, Portugal; and 2Instituto Politécnico “Outdated prescriptions” (46.4%) and “Drugs with similar pack- 82 19 de Coimbra, Coimbra Health School – ESTESC, Ciências ages” (45.6%). “Prescription” category assembled the largest number 83 20 Complementares, Coimbra, Portugal of preventive methods (34%). “Professional” category was second 84 21 Introduction: Portuguese community pharmacies were already with 28%. The single prevention methods that generated the high- 85 22 affected by the global economic crisis. Pharmacies have experienced est percentage of agreement were “Check of dubious prescriptions” 86 23 successive legislative amendments, including: the implementation and “Confirmation of the respective drugs through the barcodes” 87 24 of International Non-Proprietary Name (INN) prescription, the (97%). Besides these two preventive factors, “Constant updating and 88 25 introduction of the National Code for the Electronic Prescription searching for knowledge” (96.5%), “Increased communication with 89 26 of Medicines (NCEPM) and the use of technical justifications by the medical class” (95.9%) and “Electronic prescribing” (95.3%) 90 27 physicians. Devolution of prescriptions containing errors, by the yielded the highest agreement rate. 81 28 Conference Center of Bills (CCB), represents an additional obstacle Conclusions: Community pharmacy professionals identified some 92 29 to the financial management of pharmacies. The aim of the study sources of medication errors, as well as some strategies to prevent 93 30 was to evaluate the economic impact caused by the devolution of them. Pharmacists and pharmacy technicians are key players in 94 31 prescriptions to pharmacies and to assess how the referred measures reducing the number of medication errors and in the consequent 95 32 affected the drug dispensing process. increase of patients’ safety. An appropriate educational intervention 96 33 Methodology: A longitudinal descriptive-correlational study was based on the findings of this study could improve the risk perception 97 34 performed, based on a self-administered questionnaire delivered to among pharmacy professionals. 98 35 each of the fifty pharmacies of Coimbra municipality. Software: SPSS 99 36 20.0®. Statistical tests: Friedman, Spearman’s Rho, Wilcoxon and 100 37 101 Mann-Whitney U (significance level= 0.05). Autoantibody presentation in 38 Results: The response rate was 58%. In September, the maximum Drug-Induced Liver Injury (DILI) and 102 39 103 value not paid to pharmacies was € 1,202.37. Statistically signifi- idiopathic Autoimmune Hepatitis (AIH): 40 cant differences detected between the months analyzed showed a The influence of HLA alleles 104 41 1 1 1 105 bigger impact of devolutions in September (maximum = 4.36%), C. Stephens ; A. Ortega-Alonso ; I. Medina-Cáliz ; 42 mainly due to technical justifications, but also to implementation of M. Robles-Díaz1; A. Castiella2; P. Otazua3; E. Zapata2; 106 43 NCEPM. In March, there was a reduction of the value not paid by E.M. Gomez-Moreno4; M.A. López-Nevot4; F. Ruiz-Cabello4; 107 44 5 5,6 7 1 108 CCB (maximum = € 603.09). After correction and resend of returned G. Soriano ; E. Roman ; H. Hallal ; R.J. Andrade ; and 45 prescriptions, maximum impact was 0.8%. Patient’s health was not M.I. Lucena1 109 46 affected by the errors. 1Instituto de Investigación Biomédica de Málaga (IBIMA), 110 47 Conclusions: INN prescription contributed to the reduction of Hospital Universitario Virgen de la Victoria, Universidad 111 48 returned prescriptions. Due to recent implementation, NCEPM de Málaga, CIBERehd, Málaga, Spain; 2Hosptial Mendaro, 112 49 contributed to increase devolutions. Technical justifications created Guipúzcoa, Spain; 3Hospital Mondragon, Guipúzcoa, Spain; 113 50 difficulties in drugs dispensing process and actively contributed to 4Instituto de Investigación Biosanitario de Granada, Hospital 114 51 increase the number of returned prescriptions. Values not paid by Universitario Virgen de las Nieves, Universidad de Granada, 115 52 CCB have a significant impact on financial management of pharma- Granada, Spain; 5Hospital de la Santa Creu i Sant Pau, Universitat 116 53 cies. However, pharmacies can recover the majority of this value, Autònoma de Barcelona, CIBERedh, Barcelona, Spain; 6Escola 117 54 after correction and resend of prescriptions. Electronic prescribing Universitària d’Infermeria EUI-Sant Pau, Universitat Autònoma 118 55 could be an effective measure, regarding the reduction of this impact. de Barcelona, Barcelona, Spain; and 7Hospital Morales Meseguer, 119 56 Murcia, Spain 120 57 Background: Positive autoantibody (AAB) titres are seen in a propor- 121 58 122 Medication errors in Community tion of DILI patients, resembling AIH. The underlying mechanism for 59 selective AAB occurrence in DILI is unknown, but could be associated 123 60 Pharmacy: Potencial Causes and 124 strategies for Prevention with variations in immune-associated genes. Hence, we aimed to 61 analyse HLA allele compositions in DILI with positive (AAB ) and 125 J. Lopes; J. Joaquim; C. Matos; and T. Pires + 62 negative (AAB-) AAB titres and AIH patients. 126 63 Instituto Politécnico de Coimbra, Coimbra Health School – 127 64 ESTESC, Farmácia, Coimbra, Portugal 128

2015 e9 Clinical Therapeutics

1 Material and Methods: High resolution genotyping of HLA class I Conclusion: No differences were found between groups for the main 65 2 (A, B, C) and II (DRB1, DQB1) loci were performed on 178 DILI endpoint. The study failed to demonstrate an unwitting inducement: 66 3 (drug-induced autoimmune hepatitis excluded) and 51 AIH patients the eminent scientist wasn’t really known by the study subjects. 67 4 and compared to 885 Spanish healthy controls. 68 5 Results: Fifty-one of the 178 DILI patients presented positive titres 69 6 for at least one AAB (ANA 76%, ASMA 26%, AMA 8% or LKM-1 Attentuation of Hyaluronan fragment 70 7 3%) during the DILI episode, while 127 were negative for all four induced inflammatory response in 71 8 AABs. Compared to controls, HLA alleles B*08:01 (45% vs 10%, Macrophages by Chondroitin sulphate 72 9 p4.4E-14/pc1.0E-12), C*07:01 (47% v s24%, p3.0E-04/pc0.006), E. Montell1; T. Stabler2; J. Vergés1; and V.B. Kraus2 73 10 DRB1*03:01(59% v s26%, p8.8E-07/pc2.0E-05) and DQB1*02:01 1Bioibérica, Barcelona, Spain; and 2Duke Molecular Physiology 74 11 (57% v s22%, p2.3E-08/pc3.0E-07) were significantly more frequent Inst., Durham, NC, USA 75 12 in AIH patients. The frequency of HLA-A*01:01 was increased in 76 Background: Hyaluronan (HA) fragments (< 500 kDa) are known to 13 the same population, but did not reach significance after Bonferroni’s be able to induce an inflammatory response from macrophages. We 77 14 correction (33% vs 19%, p0.02/pc0.37). There was a tendency for have previously shown that chondroitin sulphate (CS) can attenu- 78 15 higher representation of DRB1*14:01 and DQB1*05:03 in DILI ate the monosodium urate crystal mediated release of inflammatory 79 16 AAB+ compared to DILI AAB- (16% vs 4%, p0.01/pc0.28; 16% cytokines from activated macrophages in culture. 80 17 vs 5%, p0.02/pc0.3) and controls (16%vs5%, p0.002/pc0.05; 16% Materials and Methods: Mature macrophages were primed with 81 18 vs 5%, p0.004/pc0.06). No significant differences in HLA allele fre- 10 ng/mL of LPS for 24 hours with CS in various physiologically 82 19 quencies were found when stratifying the AAB+ and AAB- popula- relevant concentrations (0, 10-200 µg/mL). After 24 hours, cells were 83 20 tions into hepatocellular and cholestatic/mixed type of liver injury. incubated for 24 hours more with the previously mentioned concen- 84 21 Conclusions: The presence of HLA alleles B*08:01, C*07:01, trations of CS and with various molecular weights (sizes) (from 7.5 85 22 DRB1*03:01 and DQB1*02:01 and possibly A*01:01 appear to 6 86 kDA to 1.54 × 10 kDa) and concentrations (0, 1, 10, and 100 μ g/mL) 23 enhance the risk of AIH in Caucasians with Spanish inheritance. 87 of HA fragments. IL-1β and proIL-1β were analysed by ELISA. 24 These alleles form part of the conserved extended haplotype 8.1. Caspase-1 activity was determined by fluorometric assay. One-way 88 25 However, haplotype formations in the study cohort are currently ANOVA with Dunnett’s post-hoc test and post-hoc linear trend were 89 26 unknown. HLA alleles DRB1*14:01 and DQB1*05:03 could poten- performed using Graphpad Prism software. 90 27 tially increase the risk of positive AAB (particularly ANA) in Spanish 81 Results: As expected, HA fragments produced large increases (P < 28 DILI patients. 92 0.0001) in IL-1β release at 10 and 100 µg/mL, with a decreasing gra- 29 Funding: P10-CTS-6470, PI12/00378, AC-0073-2013, CIBERehd- 93 dient effect (P < 0.0001) seen from ULMW to MMW and no effect 30 ISCIII. seen for HMW HA. CS (100-200 µg/mL) produced a dose dependent 94 31 95 reduction in IL-1β release in cells treated with 10 µg/mL of the 3 HA 32 lower MW fragment types. While ULMW HA fragments induced a 96 33 97 Unwitting inducement to Participate in significant increase (P < 0.0001) in intracellular caspase-1 activity, 34 98 clinical trials CS had no effect on this activity. CS reduced intracellular IL-1β and 35 99 N. Riba; J. Ríos; X. Carné; and A. Trilla proIL-1β in cells treated with ULMW HA, however, the ratio between 36 Hospital Clínic-IDIBAPS, Barcelona, Catalonia, Spain the 2 was unchanged. 100 37 101 Introduction: Informed consent process is the means to guarantee Conclusions: HA fragments (≤ 289 kDa) induced an inflammatory 38 that the respect for persons (autonomy) is preserved when humans response in THP-1 macrophages which could be attenuated by CS. 102 39 are involved in research. Subjects must be given fairly the information An anti-inflammatory effect at the level of the inflammasome would 103 40 they need to decide to enter a study or not. There should neither be be expected to decrease intracellular caspase-1 activity thereby 104 41 105 pressure to participate nor undue inducement. The aim of this study decreasing the ratio of IL-1β to proIL-1β . Since we did not observe 42 (approved by the Research Ethics Committee) was to demonstrate this, it can be concluded that the anti-inflammatory effect of CS is 106 43 that some kind of unwitting inducement cannot be avoided. Our upstream of the inflammasome. 107 44 hypothesis is that the relationship between the participant and the 108 45 person who delivers the study information (usually the participant’s 109 46 doctor) can unconsciously influence the subjects’ decision. 110 47 Mitochondria: a New Chondroitin 111 Material and Methods: Subjects (healthy volunteers) attending an sulphate Therapeutic target for 48 information meeting about a clinical trial with drugs were rand- 112 49 Osteoarthritis 113 omized (1:1) in two different lecture rooms: one (control group) 1 2 2 1 50 E. Montell ; V. Calamia ; M. López-Armada ; J. Vergés ; 114 receiving the trial information from a speaker who knew the study 2 2 51 C. Ruiz-Romero ; and F.J. Blanco 115 perfectly and the second one (test group) receiving the same informa- 1 2 52 Bioibérica, Barcelona, Spain; and Universidade da Coruña, 116 tion from an eminent and internationally-known scientist working A Coruña, Spain 53 and publishing in the study field. The content of the information 117 54 Background: In a recent proteomic study, we have demonstrated that 118 was standardized before the session to minimize differences between mitochondrial dysregulation occurs in cartilage cells during osteo- 55 groups. Immediately after the session, subjects were asked to answer 119 56 arthritis (OA). In this study we have investigated the mitochondrial 120 an anonymous survey about their intention to participate in the study. activity of OA human articular chondrocytes treated with chondroi- 57 Results: A total of 156 subjects were randomised; 155 surveys were 121 58 tin sulphate (CS). 122 obtained (76 control group, 79 test group). In summary, 76 subjects Materials and Methods: OA human chondrocytes were treated 59 would agree to enter the study, 77 wouldn’t and 2 didn’t answer; 123 with CS (Bioibérica, Spain) with or without IL1β 5 ng/mL, TNFα 60 72 subjects stated that they knew the speaker before the session, 83 124 61 10 ng/mL and LPS 100 µg/mL. SPSS statistical software was used 125 didn’t. From the test group, 42 subjects would accept but only 22 to determine statistical significance by using U-Mann Whitney test 62 knew the speaker. From the control group, 34 subjects would accept 126 (P ≤ 0.05). 63 and 50 knew the speaker. 127 64 128

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1 Results: At basal condition, a 64% increase in chondrocytes Δ ψ m Combined Chondroitin sulfate and 65 2 was observed after 48 hours treatment with CS 200 µg/mL. A signifi- Glucosamine is more efficient than 66 3 cant depolarization was induced with TNFα (Δ ψ m decreased up to Celebrex in reducing serum levels 67 4 41% and 39% respectively). CS was also able to increase chondro- of COLL2-1, a cartilage degradation 68 5 cytes Δ ψ m up to 66%, partially counteracting the effect of TNFα . CS biomarker, in patients with severe OA: 69 6 significantly increased ATP production compared to basal condition results from a randomized, 70 7 (0.55 µM vs 0.65 µM). After TNFα stimulation, ATP production double-blind, multicentric clinical trial 71 8 fell to 0.40 µM; but also in this case, CS was able to inhibit TNFα Y. Henrotin1; N. Arden2; F. Berenbaum3; F.J. Blanco4; 72 9 effect increasing the ATP synthesis up to 0.62 µM. CS was able to J.R. Castillo5; P.G. Conaghan6; A.C. Hick7; M.C. Hochberg8; 73 10 reduce NO synthesis induced by IL1β , TNFα or LPS. The NO levels J. Martel-Pelletier9; J. Monfort10; I. Möller11; T. Pap12; 74 11 were reduced after cytokine stimulation up to 21%, 32% and 31% J.-P. Pelletier9; P. Richette13; A.D. Sawitzke14; P. du Souich15; 75 12 respectively. On the other hand, in presence of IL1β , ROS produc- and for the MOVES Investigation Group 76 13 tion and SOD2 activity were increased. In this case, intracellular 1University of Liège - CHU Sart-Tilman, Liège, Belgium; 77 14 ROS production as well as SOD activity decreased in CS treated 2University of Oxford, Oxford, UK; 3Sorbonne University - 78 15 chondrocytes at an average of 80%. INSERM, University of Paris, Paris, France; 4INIBIC-Complejo 79 16 Conclusions: CS improves mitochondrial activity in human OA Hospitalario Universitario A Coruña, A Coruña, Spain; 5Hospital 80 17 chondrocytes by affecting several mitochondrial processes. The Universitario Virgen del Rocío, Sevilla, Spain; 6Leeds Institute 81 18 mitochondrial membrane hyperpolarization and the increased ATP of Rheumatic and Musculoskeletal Medicine - University of 82 19 production could correlate with a greater resistance of CS treated Leeds, Leeds, UK; 7Artialis S.A., Liège, Belgium; 8University of 83 20 chondrocytes to apoptosis. Moreover, the reduction of NO and ROS Maryland School of Medicine, Baltimore, MD, USA; 9University 84 21 levels, as well as the reduction in SOD2 activity, provide evidence of of Montreal, Hospital Research Centre (CRCHUM), Montreal, 85 22 the effect of CS on oxidative stress regulation. Quebec, Canada; 10Hospital del Mar, IMIM (Hospital del Mar 86 23 Medical Research Institute), Barcelona, Spain; 11Instituto Poal 87 24 de Reumatología, Barcelona, Spain; 12Institute of Experimental 88 25 Sexual Dysfunction associated with daily Musculoskeletal Medicine, University Hospital Münster, Münster, 89 26 opioid use Germany; 13Université Paris Diderot &, Hôpital Lariboisière, 90 14 27 R.A. Ferrer1; A. Segura2; C. Puga3; P. Ortega3; R. Martín1; Paris, France; University of Utah School of Medicine, Salt Lake 81 15 28 C. Margarit1; and A.M. Peiró1 City, UT, USA; and University of Montreal, Montreal, Quebec, 92 29 1The Foundation for the Promotion of Health and Biomedical Canada 93 30 Research of the Valencian. Community (FISABIO), Spain; Background: Coll2-1 is a peptide located in the triple helical part 94 31 2Hospital General Universitario de Alicante (HGUA), Spain; of type II collagen and Coll2-1NO2 is the nitrated form. Fib3- 95 32 and 3Occupational Observatory, University Miguel Hernández 2(fragment of fibulin-3) is an extracellular glycoprotein highly 96 33 (UMH), Spain expressed in osteoarthritic cartilage. The levels of these biomarkers 97 34 Introduction: Sexual dysfunction (SD) is highly prevalent associ- have been found to be elevated in serum of osteoarthritic patients 98 35 ated to long-term treatment with opioids in chronic non-cancer pain and to vary with severity. The objective of the study was to inves- 99 36 (CNP). Furthermore, many patients do not report their symptoms, tigate soluble osteoarthritis (OA) biomarkers in the patients of the 100 37 thus causing this adverse effect to go unnoticed and without clinical double-blind Multicentre Osteoarthritis interVEntion trial with 101 38 monitoring. The purpose of this study was to investigate the occur- Sysadoa (MOVES) comparing the symptomatic efficacy and safety of 102 39 rence of male and female sexual dysfunction in our population. Chondroitin Sulfate (CS)+Glucosamine Hydrochloride (GH) versus 103 40 Material and Methods: A cross-sectional pilot study was carried out CElecoxib (CE) in knee OA patients. 104 41 105 in moderate-severe CNP patients (n = 223, 143 women, 90 men) Material and Methods: Coll2-1, Coll2-1NO2 and Fib3-2 were 42 106 treated with long-term opioids (> 12 months) in our Pain Unit, along directly measured by immunoassays (ARTIALIS SA, Liège, 43 2 years. Standardized questionnaires and medical record reviews were Belgium) in the serum of 418 subjects: 215 receiving CS (400mg) + 107 44 used to assess rates of pain diagnosis, opioid adverse effects (ADRs) GH (500mg) 3 times/day and 203 receiving CE (200mg/day) for 6 108 45 including sexual function by Female Sexual Function Index (FSFI) months. The patients were selected from the 606 patients randomized 109 46 and International Index of Erectile Function (IIEF) questionnaires in the MOVES trial which had at least one biomarker value at D0, 110 47 and drug use. D120 and D180. 111 48 Results: A prevalence of 4% of SD was found in CNP patients. In Results: Serum biomarkers values were not associated with age, sex, 112 49 total, 143 females were included (mean age 58 ± 12.3 years, VAS race, weight, height or BMI. In overall population, there were no sta- 113 50 6.2 ± 2.7, 65% married), 43% were sexually active, 81% of who tistically significant differences between CE and CS+GH groups for 114 51 reported FSD (IFSF total 15 ± 5 scores), resulting in 19% who were any of the three biomarkers at baseline, D120 and D180. However, 115 52 sexually active without impairment (IFSF total 21 ± 8 scores). In 90 there was a trend in favor of CS+GH in reducing Coll2-1 at D180 116 53 males (mean age 56 ± 10.6 years, VAS 5.7.1 ± 2.3 married 76%), IEEF (P = 0.069) and a trend in favor of CE to reduce Fib3-2 (P = 0.055). 117 54 118 scores was divided in two groups: (I) normal or mild ED> 16 scores Additionally, CS+GH induced a significantly greater decrease of 55 119 (34.17 ± 11.67); (ii) moderate or severe: IEEF < 16 scores (6.32 ± Coll2-1 in the subgroups of patients with Kellgren & Lawrence grade 56 3.67), resulting in 20 % who were sexually active without impair- III, with synovitis (at least one joint swelling or effusion event), in 120 57 ment. Drug use was: 20% analgesic, 41% tramadole, 74% opioids OMERACT-OARSI responders or in patients with WOMAC pain 121 58 and 70% some adjuvants. at baseline ≤ 369 compared to CE (P < 0.05) at D180.CE was more 122 59 Conclusions: Sexual functioning is a problem in CNP. Evidence- effective than CS + GH in reducing Fib3-2 at D180 in patients with 123 60 based interventions to support sexual activity and function in women WOMAC pain at baseline > 369 (P = 0.042). 124 61 and men with CNP are needed. Conclusions: CS + GH was more efficient than CE in reducing serum 125 62 Coll2-1, particularly in a subgroup of patients with severe OA. This 126 63 data indicates that CS+GH may down-regulate cartilage catabolism 127 64 128

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1 and are in accordance with the symptomatic benefits observed in P. Richette10; A. Sawitzke11; P. du Souich12; J.-P. Pelletier3; and 65 2 clinical trials. MOVES Investigation Group 66 3 1Departamento Farmacología Clínica del Hospital Universitario 67 4 Virgen del Rocío, Spain; 2Division of Rheumatology & Clinical 68 5 Immunology, University of Maryland School of Medicine, 69 Cilostazol in peripheral artery disease: 3 6 Cardiovascular and bleeding events in Baltimore, MD, U.S.A.; Osteoarthritis Research Unit, University 70 7 of Montreal, Hospital Research Center (CRCHUM), Montreal, 71 real-use conditions 4 8 1 2,3 2,3 4 QC, Canada; Servei de Reumatologia, Hosp. del Mar, Barcelona, 72 J. Real ; M. Giner-Soriano ; R. Morros ; G. Pera ; 5 6 9 and R. Forès4,5 Spain; Inst. POAL de Reumatologia, Barcelona, Spain; Nuffield 73 10 1IDIAP Jordi Gol, USR Lleida, Spain; 2IDIAP Jordi Gol, Department of Orthopaedics, Rheumatology and Musculoskeletal 74 11 3 Sciences, University of Oxford, Nuffield Orthopaedic Centre, 75 Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, 7 12 Spain; 4IDIAP Jordi Gol, USR Metropolitana Nord, Spain; and Windmill Road, Oxford, United Kingdom; Department of 76 13 5 Rheumatology, Faculty of Medicine Pierre & Marie Curie, 77 Institut Català de la Salut, Catalunya, Spain 8 14 Background: On 2013, the European Medicines Agency’s Committee Paris 06, AP-HP Saint-Antoine hospital, Paris, France; Leeds 78 15 Institute of Rheumatic and Musculoskeletal Medicine, University 79 on Medicinal Products for Human Use (CHMP) recommended that 9 16 the use of cilostazol should be restricted. The Spanish Agency for of Leeds, Leeds, United Kingdom; Institute of Experimental 80 17 Musculoskeletal Medicine, University Hospital Munster, Munster, 81 Medicines and Health Products (AEMPS) asked the CHMP to carry 10 18 out a review following reports of serious suspected side effects such Germany; Fédération de rhumatologie, HôpitalLariboisière, 82 19 Paris, France; 11Division of Rheumatology, University of Utah, 83 as coronary heart disease (CHD), arrhythmias and haemorrhages. 12 20 Objectives: to estimate the risk for ischemic events, arrhythmias and School of Medicine, Salt Lake City, U.S.A.; and Département 84 21 haemorrhages in patients with peripheral artery disease treated with de pharmacologie Faculté de médecineUniversité de Montréal, 85 22 cilostazol vs pentoxifylline. Montreal, QC, Canada 86 23 Material and Methods: Background: The Multicentre Osteoarthritis interVEntion trial with 87 24 Design: retrospective observational cohort study. Sysadoa (MOVES) was a phase 4, noninferiority, double-blind study 88 25 comparing the efficacy and safety of chondroitin sulfate (CS) plus 89 Population: ≥ 40 years-old individuals initiating cilostazol or pentoxi- 26 fylline for peripheral artery disease between 01/04/2009-30/09/2011, glucosamine hydrochloride (GH) with that of celecoxib (CE) in 606 90 27 not previously treated. End of follow-up: 31/12/2013. patients with knee osteoarthritis (OA) and severe knee pain. Patients 81 28 Data Sources: SIDIAP database; contains anonymized clinical infor- were randomized to receive 400 mg of CS plus 500 mg of GHtid 92 29 mation from electronic clinical records in Primary Care of 5.8 million or 200 mg of CEqd. Both treatments elicited a 50% reduction in 93 30 people from Catalonia on sociodemographic data, comorbidities, WOMAC pain (primary outcome) at 6 months, without differences 94 31 medical procedures, clinical parameters, laboratory data and phar- between them. 95 32 macy invoicing data. Diagnoses of CHD events, arrhythmias and Material and Methods: To further analyze the results obtained 96 33 haemorrhages were linked from hospital discharge database. according to different patient subsets, we sought to compare, as a 97 34 Statistical Analysis: two cohorts (cilostazol and pentoxifylline) were post-hoc analysis, the efficacy of CS+GH with that of CE on reducing 98 35 matched 1:1 using propensity-score methods to ensure comparabil- severe pain (WOMAC pain > 300) according to Kellgren-Lawrence 99 36 ity among groups and then followed-up from treatment initiation (KL) grade (2 or 3) and C-reactive protein (CRP) levels (≤ 3 vs > 3 100 37 until event, end of follow-up or death. Survival analysis was per- mg/L) in the MOVES study population, to determine whether they 101 38 formed and cumulative incidence rates of events were obtained for presented different treatment responses. 102 39 each cohort. Cox proportional-hazards regression models were per- Results: In patients with CRP > 3 mg/mL, there were no statisti- 103 40 formed to estimate hazard ratios and 95% confidence intervals (HR; cally significant differences between CS+ GH (n = 85) and CE 104 41 95% CI). (n = 81) on WOMAC pain reduction at all time points, after 1, 105 42 Results: We included 2,953 patients per cohort. They were 68.9 2, 4 and 6 months (Table 1). Equally, there were no statistically 106 43 years-old, 76.1% were men. Median follow-up were 1217 days. significant differences between CS+ GH (n = 99) and CE (n 107 44 Preliminary analysis showed no statistically significant differ- = 86) in patients with KL grade 3 at all time points (Table 2). 108 45 ences in the cumulative incidence rates between cohorts: 10.5% Consumption of rescue medication was the same in both treatment 109 46 vs 11.0% CHD events with cilostazol and pentoxifylline respec- groups for KL grade 3 and CRP > 3 mg/L (P = ns for all between- 110 47 group comparisons). An analysis for the values of interaction of 111 tively (HR= 0.97; 95% CI: 0.83–1.13), 7.1% vs 8.1% arrhythmias 48 treatment by group was made for these subsets. There was dif- 112 (HR= 0.88; 95% CI: 0.73–1.06), 0.7% cerebral haemorrhages in 49 ferences statistically significant in the interaction of treatment by 113 both cohorts (HR= 1.1; 95% CI: 0.63–2.15) and 3.6% vs 3.4% diges- 50 CRP groups (P 0.038) but not in treatment by KL group (P 114 tive haemorrhages (HR= 1.07; 95% CI: 0.81–1.40). = = 0.581). As results of the analysis KL is presented as descriptive 51 Conclusions: We found no differences between our cilostazol and 115 rather than confirmatory results. 52 pentoxifylline patients in CHD, arrhythmias and bleeding events. 116 53 Conclusions: This post-hoc analyses indicate that CS + GH has 117 54 equivalent efficacy to CE in reducing pain after 1 month in patients 118 55 with painful knee OA and KL grade 3 or with CRP > 3 mg/L. These 119 56 Combined chondroitin sulfate and data from a double-blind, randomized trial demonstrate that there 120 57 Glucosamine versus celecoxib for are no statistically significant differences between a SYSADOA and 121 58 painful Knee osteoarthritis: post-hoc a COX-2i in patients with Kellgren-Lawrence grade 3 knee osteo- 122 59 analyses by Kellgren and Lawrence grade arthritis and patients with CRP > 3 mg/L, as early as 1 month and 123 60 and C-reactive protein level from a throughout all the study period, as measured by WOMAC pain 124 61 randomized, double-blind, multicentre subscale. 125 62 clinical trial 126 1 2 3 4 63 J.R. Castgillo ; M.C. Hochberg ; J. Martel-Pelletier ; J. Monfort ; 127 5 6 7 8 9 64 I. Möller ; N. Arden ; F. Berenbaum ; P. Conaghan ; T. Pap ; 128

e12 Volume XX Number XX Pharmacoeconomics biosimilars in Oncology

1 Ocular adverse events induced by Drugs: Maracaibo, Venezuela 65 2 a review of the safety alerts issued by Background: Widespread use of HDS, their weak regulatory frame- 66 3 Health Regulatory Authorities work and unawareness of health risks, particularly liver injury, are 67 4 A. Penedones1; D. Mendes1,2; C. Alves1,2; and F. Batel Marques1,2 main causes for the growing health problem related to HDS hepato- 68 5 1AIBILI – Association for Innovation and Biomedical Research toxicity. We aim to evaluate incidence and clinical phenotype associ- 69 6 on Light and Image, CHAD – Centre for Health Technology ated with HDS-DILI. 70 7 Assessment and Drug Research, Coimbra, Portugal; and Material and Methods: Demographics, clinical and biochemical 71 8 2University of Coimbra, School of Pharmacy, Coimbra, parameters of HDS-induced DILI cases included in the Spanish and 72 9 Portugal Latin-American DILI-Registries were compared with DILI cases 73 10 Background: Drugs either used in the treatment of ocular or systemic induced by conventional medications. 74 11 pathologic conditions have the potential to cause adverse events in Results: Sixty-eight DILI cases of 1025 (7%) included were attrib- 75 12 the eye and to affect ocular functions. Ocular adverse events are the uted to herbals and dietary supplements, 26 (38%) by anabolic 76 13 fewest adverse events studied and assessed in post-marketing sur- steroid (AAS) and 42 (62%) by herbal products and other dietary 77 14 veillance. The investigation of the regulatory actions resulting from supplements (HDS). Women (57%) were more frequent among HDS- 78 15 the identification of serious ocular disorders associated with the use DILI cases, while AAS-DILI patients were all males. The mean age of 79 16 of drugs, irrespective of being locally or systemically administered, HDS-DILI was significantly higher than that of AAS-DILI cases (47 vs 80 17 during the last decade, is of utmost importance given its implication 33y) (P < 0.001), but lower than those caused by conventional drugs 81 18 for the clinical practice. (47 vs 56y) (P = 0.004). Jaundice and hospitalization were higher 82 19 Material and Methods: The websites of four health regulatory in AAS cases (92%/76%) than HDS (78%/53%) and conventional 83 20 authorities were reviewed to identify safety alerts issued on ocular drugs (68%/57%), respectively. Although hepatocellular damage pre- 84 21 adverse events. Safety alerts were included if they have been issued dominated in all groups, HDS had more hepatocellular cases than 85 22 between January 2005 and December 2014. Only safety alerts on conventional medications and AAS-DILI (86% vs 62% and 58%). 86 23 drugs with market authorization were considered for inclusion. The HDS cases presented higher ALT and AST mean values (33 87 24 Results: Thirty-eight safety alerts were included in the study. and 27xULN) compared to AAS (13 and 6× ULN) (P = 0.004, P < 88 25 “Urologicals” (n = 11; 29%), followed by “Drugs used in diabe- 0.001) and conventional medications (19 and 18× ULN) (P < 0.001, 89 26 tes”, “Antibacterials for systemic use”, “Antioneplastic agents”, P = 0.2) respectively, but lower total bilirubin values than AAS cases 90 27 and “Ophthalmologicals” were the most frequent suspected drugs (9 vs 14× ULN) (P = 0.021). HDS-DILI patients went more frequently 81 28 evaluated in the safety alerts (n = 4; 10%, each). The most frequently into acute liver failure (ALF) than DILI patients associated with 92 29 evaluated adverse events were “Visual disorders NEC” (n = 12; conventional drugs (7.3% vs 4%). No AAS cases developed ALF. 93 30 32%), including visual impairment, diplopia, and blurred vision. The Rechallenge was more frequent in HDS than conventional medication 94 31 majority (n = 25; 66%) of the safety alerts were supported by post- DILI (14% vs. 6%) (P = 0.02). 95 32 marketing spontaneous reports. The most commonly updated drug Conclusions: In comparison to conventional drugs, HDS-DILI affects 96 33 label section was the “Warnings and Precautions” section (n = 33; mainly to young women, presenting with hepatocellular injury, higher 97 34 87%), followed by the “Adverse reactions” section (n = 26; 68%). transaminase values, worst outcome leading to ALF and inadvertent 98 35 Conclusion: Ocular adverse events newly identified during this dec- re-exposition. Greater awareness and stricter regulation are required 99 36 ade come mostly from systemic drugs, some of them marketed for to prevent HDS-related severe adverse effects to the liver. 100 37 several years. Physicians should be aware of drug-induced adverse Funding: AEMPS,FISS-PI12-00620.AC-0073-2013.CIBERehd- 101 38 effects in the eye in order to avoid as soon as possible their progres- ISCIII. 102 39 sion, which can lead to visual impairment. 103 40 104 41 The efficacy and safety of 105 42 Hepatotoxicity related to Herbals and Sodium-Glucose Cotransporter 2 (SGLT2) 106 43 Dietary Supplements (HDS): a cause for Inhibitors: a systematic review and 107 44 concern meta-analysis 108 45 1,2 1 1,2 1,2 109 I. Medina-Cáliz1; M. Robles-Díaz1; C. Stephens1; C. Alves ; A. Penedones ; D. Mendes ; and F. Batel Marques 46 1 110 A. González-Jiménez1; J. Sanabria-Cabrera1; A. Ortega-Alonso1; AIBILI – Association for Innovation and Biomedical Research 47 111 M. García-Cortés1; S. Mirwani2; B. Thorpe2; on Light and Image, CHAD – Centre for Health Technology 48 112 M. Jiménez-Pérez3; M.C. Fernández4; J.M. Navarro5; E. Montané6; Assessment and Drug Research, Coimbra, Portugal; and 49 2 113 A.M. Barriocanal6; M. Prieto7; M. García-Eliz7; F. Bessone8; University of Coimbra, School of Pharmacy, Coimbra, Portugal 50 114 N. Hernández9; E. Carrera10; E. Mengual11; E. Blanco2; Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors are 51 115 M.R. Montes2; I. Bellido2; B. García-Muñoz1; R.J. Andrade1; a new class of antidiabetic drugs. The inhibition of SGLT2 receptor, 52 116 and M.I. Lucena1 located in the proximal tubule of the kidney, decreases renal glucose 53 117 1Instituto de Investigación Biomédica de Málaga (IBIMA), reabsorption and prevents the occurrence of hyperglycaemia. Due to 54 118 Hospital Universitario Virgen de la Victoria, Universidad de an insulin-independent mechanism, SGLT2 inhibitors are associated 55 119 Málaga, CIBERehd, Málaga, Spain; 2Instituto de Investigación with a low risk of hypoglycaemia. Additional beneficial effects of 56 120 Biomédica de Málaga (IBIMA), Universidad de Málaga, Spain; SGLT2 inhibitory drugs are the reduction of body weight and blood 57 121 3Hospital Regional Universitario de Málaga, Málaga, Spain; pressure. The aim of this study is to evaluate the efficacy and safety 58 122 4Hospital de Torrecárdenas, Almería, Spain; 5Hospital Costa del of the sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors), 59 123 Sol, Málaga, Spain; 6Hospital Germans Trias i Pujol, Barcelona, either as monotherapy or as add-on treatment, and to compare poten- 60 124 Spain; 7Hospital La Fe de Valencia, CIBERehd, Valencia, Spain; tial differences among these drugs. 61 125 8Hospital Provincial del Centenario, Rosario, Argentina; 9Hospital Material and Methods: Medline, Cochrane Library and clinicaltrials. 62 126 de Clínicas, Montevideo, Uruguay; 10Hospital de Especialidades gov for clinical trials (RCTs) evaluating SLGT-2 inhibitors for type 63 127 Eugenio Espejo, Quito, Ecuador; and 11Hospital Universitario de 64 128

2015 e13 Clinical Therapeutics

1 2 diabetes mellitus. Weighted mean differences (WMDs) and Odds Conclusions: This study indicated the absence of any drug-drug 65 2 ratios (ORs) were pooled using a random-effects model. interaction between DKP.TRIS 25mg and TRAM.HCl 100mg con- 66 3 Results: Canagliflozin was associated with HbA1c greater reduc- comitantly administered in healthy subjects. 67 4 tions, either when used as monotherapy (vs. placebo: WMD −0.93%, 68 5 −1.02, −0.83) or as add-on treatment (vs. placebo: WMD −0.58%, 69 6 −0.67, −0.49; vs. other antidiabetic drugs WMD −0.21%, −0.35, Pharmacovigilance in a Hospital pain 70 7 −0.06). SGLT2 inhibitors reduced body weight and systolic and dias- relief Unit 71 8 tolic blood pressure, and did not increase the risk for hypoglycemia B. Planelles1; L. Mira2; R. Ajo1; Y. Sastre3; R. Martín3; E. Cutillas2; 72 9 (OR 0.99, 0.74 to 1.32) or hypotension (OR 1.08, 0.85 to 1.37). P. Zapater3; C. Margarit3; and A.M. Peiró3 73 10 SGLT2 inhibitors increased the risk for genital infections (OR 3.64, 1Foundation for Promotion of Health and Biomedical Research 74 11 2.97 to 4.48). Only dapagliflozin was found to be associated with of Valencian Community (FISABIO), Spain; 2Occupational 75 12 urinary tract infections (OR 1.30, 1.08 to 1.56). Observatory, University Miguel Hernández (UMH), Spain; and 76 13 Conclusion: Canagliflozin seems to be slightly effective at control- 3Hospital General Universitario de Alicante (HGUA), Spain 77 14 ling HbA1c than the remaining SGLT2 inhibitors. Genitourinary Introduction: It is known that prolonged use of opioids chronic non- 78 15 infections may diminish treatment adherence to this new class. cancer related pain (NCP) can lead to a number of adverse reactions, 79 16 Nonetheless, the added therapeutic value of SGLT2 inhibitors should normally associated with gastrointestinal tract, central nervous sys- 80 17 be continuously evaluated as further RCTs will be published for the tem or dermatological effects. The aim of this study was to document 81 18 most recent drugs introduced in market. the types and severity of adverse drug reactions of chronic opioid 82 19 therapy. 83 20 Methods: A total of 650 patients NCP chronically treated with opi- 84 21 Pharmacokinetics of Dexketoprofen and oids (1350 outpatient visits) were evaluated using validated pain 85 22 tramadol given in combination: an intensity and relief scales (Visual Analogue Scale, VAS: 0-10 cm), 86 23 open-label, randomized, 3-period quality of life (EQ-VAS, 0-100%), presence of adverse events (AE 87 24 crossover study in Healthy subjects reported in model form to be filled by patients) and adverse drug reac- 88 25 P. Mazzei1; S. Milleri2; I. Paredes Lario3; L. Borràs Solé3; tions (ADR reported by physicians) and drug use, along 24 months. 89 26 L. Creus Ragasol3; A. Crea1; F. Masciopinto1; M.P. Contini1; Results: Our sample (mean age 63 ± 14 years old, 67%♀, 27 ± 6 kg/ 90 27 S. Scartoni1; M. Bertolotti1; A. Capriati1; and C.A. Maggi1 m2) shows a moderate mean pain intensity (VAS 6 cm), pain relief 81 28 1Menarini Ricerche S.p.A., Florence (Italy); 2Centro Ricerche (VAS 4 cm) and quality of life (EQ-VAS 43%). A mean of 4-5 AEs 92 29 Cliniche di Verona Srl, Verona (Italy); and 3Laboratorios Menarini were reported by each patients visit (a total of 6719 AEs, most com- 93 30 S.A., Badalona (Spain) mon were: 12% dry mouth, 10% constipation, 9% nervousness, 94 31 Introduction: Dexketoprofen trometamol (DKP.TRIS) and tramadol 7% sleepiness, 6% depression, 6% insomnia, 6% dry skin and 5% 95 32 hydrochloride (TRAM.HCl) are well known analgesics, the combi- sexual dysfunctions), being reported to Spanish Pharmacovigilance 96 33 nation of which is based on the strong rationale of their different System 140 ADRs (most common: 47% related to central nervous 97 34 98 mechanism of actions (leading to balanced analgesia from NSAID + system (CNS), 15% dermatological and 13% gastrointestinal). All 35 opioid activity) as well as different pharmacokinetics (PK) leading were predominantly mild side effects. 99 36 to the DKP.TRIS rapid onset and TRAM.HCl long lasting effect. Conclusions: In our study, a higher prevalence of CNS ADRs was 100 37 Objectives: The study investigated any effect on the pharmacokinet- found, being gastrointestinal system ADRs significantly lower than in 101 38 ics (PK) of DKP.TRIS and TRAM.HCl when concomitantly admin- previous researches. Control of adverse effects is needed to conduct a 102 39 istered in healthy subjects. proper drug prescription plan, even more, for long-term management 103 40 Material and Methods: DKP.TRIS 25 mg single dose, TRAM.HCl of chronic non-malignant pain. 104 41 100 mg single dose, and their extemporaneous combination were 105 42 administered to 30 healthy subjects (17 men) as oral tablet(s) in 106 43 107 an open, randomised, 3 period, 3 sequence, crossover study, with a Increasing needs of support on clinical 44 minimum 7-day wash out period between treatments. The study was 108 45 trials in advanced Therapies 109 conducted in accordance with Good Clinical Practice, the Declaration 1 1 1 1 2,3 46 S. Varea ; J. Pich ; A. Cruceta ; C. Encinas ; and J.A. Arnaiz 110 of Helsinki, and applicable regulatory requirements. Approval from 1 2 47 Fundació Clínic Recerca Biomedica, Barcelona, Spain; Hospital 111 the appropriate institutional review board for the participating centre Clínic i Provincial, Barcelona, Spain; and 3Universitat de 48 and written informed consent were obtained. 112 49 Barcelona, Barcelona, Spain 113 Plasma samples collected up to 48 hours post-dose were analyzed Background and Introduction: Advanced Therapies offer oppor- 50 for each enantiomer of ketoprofen, tramadol and its O-demethyl- 114 51 tunities to cover unmet needs in diseases with no current effective 115 metabolite (M1) using chiral HPLC methods. The PK properties of therapies, providing new treatment options to patients who do not 52 each analyte were compared when DKP.TRIS and TRAM.HCl were 116 53 respond to medications available in the market for their illnesses. For 117 administered as single agents and in combination. academic institutions and public hospitals the research into new treat- 54 Results: Mean Cmax [ng/mL] and AUC [ng*h/mL] of analytes for 118 55 ments with the ultimate goal of offering them to patients is essential. 119 the combination treatment were respectively: (+)TRAM: 196.9, 56 Results: The clinical trials unit of our institution has witnessed in the 120 1501.8; (-)TRAM: 177.7, 1213.6; (+)M1: 22.0, 250.5; and DKP: last five years an increase in consultations for the implementation of 57 2816.5, 3935.7. The 90% CIs of geometric mean ratio of AUC and 121 58 clinical trials with advanced therapies. They account for 13.7% of 122 Cmax of all the analytes were within the accepted bioequivalence all trials performed in our unit (10/73). In the last year (2014), 5 of 59 range (80.00-125.00%), when DKP.TRIS and TRAM.HCl were given 123 60 20 new clinical trials (25%) tested Advanced Therapies. 124 alone or in combination. Other relevant PK parameters (tmax, Vz/F Discussion: The first administration in humans of an investigational 61 CL/F, t1/2 and MRT) were not affected by the co-administration. 125 62 medicinal product, whether conventional (chemical, biological) or 126 63 advanced (cellular, tissular, gene therapy) involves compliance with 127 64 product quality, good manufacturing practice and the conduction of a 128

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1 clinical trial demonstrating, safety, and a positive risk-benefit balance. New Antiviral treatment for Chronic 65 2 The marketing authorization of these medicines is made through the Hepatitis C (HCV): learning from 66 3 EMA centralized procedure but the regulation 1394/2007 permits experience, the role of the Pharmacist in 67 4 the exemption of centralized authorization procedure allowing the improving Adherence 68 5 use of these drugs beyond the trial in specific situations: case by case S.E. Campbell Davies; V. Boccaccio; G. Muserra; and F. Reitano 69 6 approval of the Competent Authority and production and utilisation Fatebenefratelli e Oftalmico Hospital, Milan, Italy 70 7 in non-profit centers linked to the National Health System. Background: Treatment of chronic HCV is undergoing a revolu- 71 8 Conclusions: Advanced therapies account for an increasing propor- tion. Several direct acting antivirals (DAAs) have reached the mar- 72 9 tion of clinical trials conducted in our academic institution. The high ket (boceprevir, telaprevir and sofosbuvir) and many others are in 73 10 investments in the conduct of clinical trials of advanced therapies development. 74 11 should be balanced against returns beyond the trial itself: having Poor adherence is a major medical problem which leads to failure 75 12 research products available to patients with no alternative therapies. of therapy and increased healthcare cost. 76 13 The course of treatment with first generation protease inhibitors 77 14 (boceprevir, telaprevir) has been monitored in order to adopt the best 78 15 Independent Clinical Research. What may multidisciplinary approach in the management of sofosbuvir and 79 16 contribute to success? The experience other costly second generation DAAs. 80 17 at the Clinical Research Unit of Hospital Material and Methods: Between 2013 and 2014, overall 31 patients 81 18 Ramón y Cajal (27 with cirrhosis and 4 with advanced fibrosis) at the Hospital 82 19 M. Serrano Olmeda; M. Del Álamo Camuñas; E. Lorente Páramo; underwent triple therapies with either boceprevir or telaprevir in 83 20 M. Aguilar Jiménez; I. De Pablo López de Abechuco; combination with peg-interferon (PEG) and ribavirin (RBV). Medical 84 21 A. Revilla Monaj; and M.A. Gálvez Múgica prescriptions were analysed using an administrative database and the 85 22 Clinical Pharmacology. University Hospital Ramón y Cajal Italian Medicines Agency (AIFA) Monitoring Registry. 86 23 The Clinical Research Unit at Hospital Ramón y Cajal (included Results: The data showed that 52% of patients treated with first 87 24 in SCReN since 2014) has supported 48 Clinical Trials (phase I to generation protease inhibitors did not achieve sustained virological 88 25 IV) and 4 Observational Studies with independent sponsors between response (SVR) due to side effects or treatment failure. Therefore, 89 26 2010 and 2015. Of these 52 studies, 43 got public funding and only a procedural guideline between Pharmacists and Hepatologists has 90 27 9 were supported by industry. About recruitment: been endorsed to assure safe dispensing and monitoring of these new 81 28 costly agents. “Patient Information Leaflets” have been developed as 92 29 • 11 of these trials were completed in compliance with the planned a monitoring tool for patients in therapy with sofosbuvir in associa- 93 30 recruitment: tion with PEG and RBV. When sofosbuvir is dispensed at the Hospital 94 31 - 7 were sponsored by the Ramon y Cajal Hospital Foundation Pharmacy counter, a leaflet is given to each patient monthly contain- 95 32 (FIBio-HRC) and 4 by researchers. ing main information about the drug (administration, conservation, 96 33 - 9 were single-center trials and 2 multi-center trials. drug interactions, special warnings and side effects) and a compliance 97 34 - Overall, these trials resulted in 3 theses, 6 international pub- diary where the patient must fill in daily when medication is taken. 98 35 lications and 14 conference communications. The diary is checked monthly by the Doctor and the Pharmacist to 99 36 • 11 were closed without reaching the planned recruitment: survey therapy compliance. 100 37 - 5 sponsored by different Foundations and 6 by researchers. Conclusions: Pharmacist expertise can contribute to properly assess 101 38 - 7 were multi-center trials and 4 single-center trials. and respond to patients’ medication needs, thereby contributing to 102 39 • 19 ongoing trials: inter-professional management of patient care to achieve better ther- 103 40 - 11 sponsored by Foundations (10 of them sponsored by the apy adherence and clinical outcomes. 104 41 FIBio-HRC) 105 42 - 9 are single-center and 10 are multi-center trials. 106 43 - Currently 9 of this 19 trials have reached 60% of the planned Use of psychotropic drugs in older 107 44 recruitment and 6 of them have not needed to extend the patients: Prevalence and characteristics 108 45 planned recruitment timing. of patients 109 46 • 4 were transferred to CROs in recruitment phase. 110 X. Vidal1,2,3; A. Agustí1,2,3; A. San-José1,3; J. Barbé1,3; 47 • 7 failed to initiate the recruitment phase. 111 O.H. Torres3,4; F. Formiga5; A. Fernández-Moyano6; J. García7; 48 112 Conclusions: These data show that for independent clinical research, A. López-Soto8; N. Ramírez-Duque9; and on behalf of Potentially 49 113 the most successful trials were those sponsored and developed in the Inappropriate Prescription in Older Patients in Spain (PIPOPS) 50 114 own center (single-center) which generate relevant scientific publi- Investigators’ project 51 115 cations. Public-funding supported staff is a positive factor for this 1Hospital Universitari Vall d’Hebron, Barcelona, Spain; 2Fundació 52 116 successful. However, recruitment is a caveat for these studies since Institut Català de Farmacologia, Barcelona, Spain; 3Universitat 53 117 many of them were closed for lack of recruitment (21.5%) or failed Autònoma de Barcelona, Spain; 4Hospital Santa Creu i Sant Pau, 54 118 to initiate (13%) probably due to a wrong prevision. This overview Barcelona, Spain; 5Hospital Universitari de Bellvitge, Hospitalet 55 119 highlights the importance to develop good feasibility studies and to de Llobregat, Barcelona, Spain; 6Hospital San Juan De Dios del 56 120 get funding ensuring both, material and human resources, for the Aljarafe, Sevilla, Spain; 7Hospital General Juan Ramón Jiménez, 57 121 study success. Huelva, Spain; 8Hospital Clínic, Barcelona, Spain; and 9Hospital 58 122 Universitario Virgen del Rocío, Sevilla, Spain 59 123 60 124 61 125 62 126 63 127 64 128

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1 Background: Psychotropic drugs are frequently prescribed to older period 2008-2012 through ICD10 codes of cardiac ischemic events 65 2 patients. This study aimed to describe their prevalence of use and to (CIE) (AIM or unstable angina, fatal or not) and cross-checked with 66 3 compare the characteristics of patients treated with different psy- hospital discharge diagnosis; 3 controls without CIE were matched 67 4 chotropic drugs. to each case by sex, age (±5 years), area and year (±2 years) of first 68 5 Material and Methods: From a prospective and multicentric study diagnosis of OA. Data were linked with pharmacy invoicing infor- 69 6 of a cohort of patients aged 75 or older admitted to seven Spanish mation, encrypted and extracted for analysis. Exposure to NSAIDs, 70 7 hospitals for a year (March 2011 to March 2012), a sub-analysis of SYSADOAs, opioids, paracetamol and metamizole were analysed. 71 8 those treated with psychotropic drugs (antipsychotics, anxiolytics or Adjusted multivariate conditional logistic regression models were 72 9 hypnotics-sedatives and antidepressants) was performed. Information fitted to estimate odds ratio (OR) for CIE according to drug use. 73 10 on patients’ characteristics and on prescribing medicines the month Results: We studied 5663 cases and 16989 matched controls. Cases 74 11 before admission was obtained from the hospital and the primary had more morbidity and cardiovascular risk factors, but similar 75 12 care electronic medical records and from interviews with the patients characteristics for OA and joint involvement. Significantly increased 76 13 and/or relatives. risks (OR 95%CI) were observed related to the use of non-selective 77 14 Results: A total of 672 patients [median age (Q1–Q3) 82 (79–86) NSAIDs (1.10(95%CI 1.01 to 1.19)), in particular for diclofenac 78 15 years, 55.9% female] were included. 44.2% of them were treated (1.16(1.07 to 1.25) and naproxen (1.14(1.01 to 1.29), and for opioid 79 16 with anxiolytics or hypnotics-sedatives, 22.6% with antidepressants analgesics (1.13(1.04 to 1.24). SYSADOAS, paracetamol and meta- 80 17 and 10.8% with antipsychotics. A total of 12.4% were treated with mizole showed no significant associations with CIE. 81 18 a combination of anxiolytics or hypnotics-sedatives and antidepres- Conclusions: In patients with OA, non-selective NSAIDs (diclofenac, 82 19 sants. The most frequently prescribed psychotropic medicines were: naproxen) and opioid analgesics are associated to an increased risk 83 20 anxiolytics (lorazepam [17.4%] and potassium clorazepate [7.2%]), of CV events. This should be considered for the management of OA 84 21 antidepressants (citalopram [6.6%] and paroxetine [3.3%]) and patients with a high cardiovascular risk profile. 85 22 antipsychotics (haloperidol [4.7%], risperidone [3.4%] and quetia- 86 23 pine [2.3%]). Patients treated with some kind of psychotropic drug 87 24 were more frequently women, especially those treated with antide- References 88 25 pressants. In addition, those treated with antipsychotics were older, 1. National Institute for Health Care and Excellence. Osteoarthritis 89 26 and were less often visited by a GP but were more often admitted care and management in adults. National Institute for Health and 90 27 to hospital the month prior to admission. Both, those treated with Care Excellence (United Kingdom), 2014. 81 28 antipsychotics and those treated with antidepressants more often 2. http://www.nice.org.uk/guidance/cg177/resources/guidance- 92 29 lived in and were discharged to nursing home facilities. Furthermore, osteoarthritis-pdf (accessed 25th January 2015). 93 30 those treated with antipsychotics more often died during admission. 3. Bolíbar B, Fina F, Morros R et al. SIDIAP database: electronic 94 31 Conclusions: The prevalence of psychotropic medicines prescrip- clinical records in Primary Care as a source of information for 95 32 tion was high in the elderly, especially the prescription of anxiolyt- epidemiologic research. Med Clin (Barc) 2012;138:617–621. 96 33 ics or hypnotics-sedatives and antidepressants. Women were more 97 34 frequently prescribed than men, especially for antidepressants, and 98 35 patients treated with antipsychotics had worse outcomes. Metabolic risk factors affect 99 36 clinical Phenotype and outcome of 100 37 Hepatotoxicity (DILI) 101 38 102 Osteoarthritis, Drug use and risk of J. Sanabria-Cabrera1; M. Robles-Díaz1,2; I. Medina-Cáliz1,2; 39 103 Cardiac Ischaemic events: a case-control C. Stephens1,2; A. Ruíz3; A. González-Jiménez1; 40 104 study A. Ortega-Alonso1; M. García-Cortés1,2; B. García-Muñoz1; 41 1,2 2,3 3,4 5 105 C. Pontes ; R. Morros ; J.R. Marsal ; F. de Abajo ; M. Romero-Gómez2,4; M.C. Fernández5; H. Hallal6; G Soriano2,7; 42 6 7 8 9 106 J.R. Castillo ; J. Rios ; X. Carné ; and P. du Souich E. Román2,7; S. Blanco8; A. Castiella9; E.M. Zapata9; 43 1 107 Hospital de Sabadell - Institut Universitari Parc Taulí, Sabadell, J.M. Navarro10; M. Jiménez11; J.M. Moreno-Planas12; 44 2 108 Spain; Universitat Autònoma de Barcelona, Barcelona, Spain; A. Aldea13; F. Bessone14; N. Hernández15; M. Arrese3; 45 3 109 SIDIAP – Sistema d’Informació pel Desenvolupament de la R.J. Andrade1,2; and M.I. Lucena1,2 46 110 Investigació en Atenció Primària, IDIAP Jordi Gol, Barcelona, 1Instituto de Investigación Biomédica de Málaga (IBIMA), 47 4 111 Spain; Hospital Universitari Vall d’Hebron, Barcelona, Spain; Hospital Universitario Virgen de la Victoria, Universidad 48 5 112 Universidad de Alcalá - Hospital Universitario Príncipe de de Málaga; 2Centro de Investigación Biomédica en Red de 49 6 113 Asturias, Alcalá de Henares, Spain; Hospital Universitario Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, 50 7 114 Virgen del Rocío, Sevilla, Spain; IDIBAPS - Hospital Clínic Spain; 3Facultad de Medicina Pontificia. Universidad Católica de 51 8 115 de Barcelona, Barcelona, Spain; Hospital Clínic de Barcelona, Chile. Santiago, Chile; 4Hospital Universitario de Valme, Sevilla, 52 9 116 Barcelona, Spain; and Faculté de Médecine - Université de Spain; 5Hospital de Torrecárdenas, Almería, Spain; 6Hospital 53 117 Montréal, Montréal, Canada Morales Meseguer, Murcia, Spain; 7Hospital de la Santa Creu i 54 118 Background: Recent controversies on the safety profile of drugs used Sant Pau, Barcelona, Spain; 8Hospital Universitario de Basurto, 55 119 to treat osteoarthritis (OA) have led to changes in clinical guidance Bilbao, Spain; 9Hospital de Mendaro, Gipuzkoa, Spain; 10Hospital 56 120 for management (1). The objective of the study was to describe asso- Costa del Sol, Málaga, Spain; 11Hospital Regional de Málaga, 57 121 ciations between the use of different OA drug therapies and the risk Spain; 12Complejo Hospitalario Universitario de Albacete, Spain; 58 122 of cardiac ischemic events (CIE). 13Hospital Universitario de Canarias, Canarias, Spain; 14Hospital 59 123 Material and Methods: We conducted a nested case-control study Provincial del Centenario, Rosario, Argentina; and 15Hospital de 60 124 within a cohort of patients with clinically diagnosed OA (according Clínicas, Montevideo, Uruguay 61 125 to ICD10 codes in the SIDIAP database of primary care records for Background: It has been suggested that metabolic risk factors may 62 126 over 5 million people in Catalonia, Spain (2)). Study was approved play a role in drug-induced liver injury (DILI) presentation. Hence, 63 by the corresponding Ethic’s Committee. Cases were identified in the 127 64 128

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1 the aim of this study was to determine the influence of diabetes and Conclusions: This test is a useful tool to assess individually the 65 2 dyslipidemia on the clinical profile of DILI. acquired knowledge during the training period of speciality. However, 66 3 Material and Methods: Clinical profiles of 864 DILI cases included its external validation has not yet assessed. A test to certify a level 67 4 in the Spanish DILI Registry were compared according to the pres- of knowledge acquired during training on Clinical Pharmacology 68 5 ence or absence of diabetes and dyslipidemia. Patients with hepatic validated and accepted by European countries is urgently needed. 69 6 underlying diseases were excluded. 70 7 Results: Comparing patients with (n = 121) and without (n = 743) 71 8 dyslipidemia, the mean age was significantly higher in the former Rituximab as treatment of immune 72 9 group, 64 vs 52 years (P < 0.001); 38% of the patients with dyslipi- Thrombocytopenic Purpura 73 10 demia were treated with statins. Duration of treatment of DILI causa- D. Ferreira1; T. Pires1,2; and N. Machado2 74 11 tive agents and latency did not differ between the groups. Patients 1Instituto Politécnico de Coimbra, Coimbra Health School – 75 12 with dyslipidemia had significantly better outcomes (severe and fatal ESTESC, Farmácia, Coimbra, Portugal; and 2Centro Hospitalar e 76 13 cases: 3% vs 13%, P = 0.009). In the dyslipidemia group, 30% of Universitário de Coimbra, EPE Coimbra, Coimbra, Portugal 77 14 the patients had persisting liver damage after one year from DILI Background: Immune thrombocytopenia purpura (ITP) is an auto- 78 15 onset, compared to 22% in the non-dyslipidemia group. Comparing immune disease characterized by auto-antiplatelet antibody-mediated 79 16 diabetic (n = 103) with non-diabetic (n = 737) DILI patients, higher thrombocytopenia. These antibodies mediate thrombocytopenia by 80 17 mean age (66 vs 52, P < 0.001), higher mean BMI value (28 vs 25, accelerating the destruction of platelets in the peripheral blood, and 81 18 P < 0.001) longer duration of treatment (158 vs 78 days, P = 0.001) binding to megakaryocytes and impairing platelet production. In 82 19 and latency (140 vs 71 days, P = 0.002) were found in the former Europe, the annual ITP incidence is around 3 per 100,000 people. 83 20 group. No differences in severity were observed. Among the diabet- ITP tends to have a higher incidence in middle-aged females and 84 21 ics, 28% had persisting liver damage > 1 year from DILI onset versus male children. 85 22 22% of the non-diabetics. Rituximab (RTX) is a chimeric monoclonal antibody directed 86 23 Conclusions: Dyslipidemia appears to play a protective role in DILI against CD20, an antigen expressed on the surface of B-lymphocytes 87 24 severity, although persistent liver damage > 1 year from DILI onset but not present on most plasma cells. 88 25 is more frequent in patients with metabolic risk factors (diabetes The objective of this work was to better understand the treatment 89 26 and dyslipidemia). Diabetic patients presented longer treatment and of PTI, specifically with rituximab. 90 27 latency prior to DILI development. Material and Methods: Was conducted a research of articles pub- 81 28 Funding: AEMPS, FIS:PI12-00620, AC-0073-2013.CIBERehd- lished, in PubMed and Google Scholar, in English and Portuguese, 92 29 ISCIII. using key words like rituximab, immune thrombocytopenic purpura, 93 30 mechanism and treatment. 94 31 Results: The aim of this treatment is to stop ongoing bleeding and 95 32 Assessment of the Acquired Knoledge also decrease the risk of developing clinical-significant bleeding in 96 33 during the medical residency of clinical the future. There are lots of strategies in this treatment between first, 97 34 Pharmacology second and third line with steroids, intravenous immunoglobulin, 98 35 E. Montané splenectomy or immunosuppressive drugs. The decisions are guided 99 36 Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; by physicians’ personal preferences, cost considerations and various 100 37 and Universitat Autònoma de Barcelona, Spain regulatory. 101 38 Introduction: The medical residency is an important training to Conclusions: Several studies refer that the administration of RTX 102 39 become a competent specialist. Few efforts are focused on the acqui- leads to the rapid and complete depletion of circulating B cells. 103 40 sition of new knowledge and capacities as well as the evaluation of However, the mechanism of action of RTX on immune cells in ITP 104 41 learning results. Clinical Pharmacology’s residents in our service have has not yet been completely elucidated. 105 42 training on general medicine during the first year, before starting the 106 43 specific specialist period. 107 44 Material and Methods: A test with 65 binary questions was designed 108 45 Multiple adverse reactions due to 109 to assess knowledge about patient’s selection drug (10 items), phar- nervous system Drugs metabolized 46 macovigilance (15 items), drug monitoring (10), phase I clinical 110 47 through CYP2D6 111 trial (15), and clinical trials or Ethic Committee (15). The residents 1,2 1 1 3 48 A.L. Arellano ; M. Martin ; M. Monerris ; A. Llerena ; 112 answered the test before starting the residency (basal), and then annu- 1,2 49 and E. Montané 113 ally during residency (totally 5 times). For comparison of means we 1 50 Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 114 used the T test for independent data. 2 3 51 Universitat Autònoma de Barcelona, Spain; and Extremadura 115 Results: From 2008 to 2014, eight residents performed a total of 20 University Hospital and Medical School, Badajoz, Spain 52 tests. Only two of them have carried out all the 5 tests, the rest of 116 53 Background or Introduction: The CYP2D6 is a highly polymorphic 117 them have previously started the residency (2-3 test performed) or isoenzyme with more than 100 allelic variants and subvariants. It is 54 dropped out within the second year (1 test performed). The mean 118 55 involved in the metabolism of at least 25% of commonly prescribed 119 global score was 36.8 (range 16-54). The mean scores of each test drugs (such as antidepressants, antipsychotics, and analgesics). 56 were: basal 26, first year 28.7, second year 38, third year 46, and 120 57 Material and Methods: In a period of two years, a 56 year old female 121 fourth year (specialist) 48. Individual score evolution though resi- with neuropathic pain due to T2-T3 tranverse myelitis had multi- 58 dency period showed a progressive improvement (increase from basal 122 59 ple adverse drug reactions (ADR) related to nervous system drugs. 123 ranged from 12 to 33 when all tests were performed). Statistically sig- The patient had visual hallucinations due to amytriptyline (10 mg/ 60 nificant differences of means were observed when comparing before 124 61 day) and then organic psychosis related to tramadol. Tramadol was 125 starting the specific speciality training (basal and first year tests) with withdrawn by the psychiatrist and treatment with olanzapine was 62 the third and/or fourth years tests. 126 63 started. The patient presented a generalized rash with itching due to 127 64 an increase in the dose of gabapentin (2200 mg/day) that disappeared 128

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1 within 2 weeks after a reduction of half the dose. The last ADR of of these cases, the suspected drug was an anticoagulant, and in seven 65 2 the patient was symptomatic hypertension (BP up to 166/105 mm cases, the adverse event was cerebral bleeding. 66 3 Hg) due to duloxetine (30 mg/day) which was prescribed for anxiety Conclusion: The ADEM is a unique source for evaluating reporter 67 4 and depression. and ADE characteristics, in a clinical pharmacological setting, 68 5 Results: After accurately assessing each ADR, the same metabolic contributing to an increased knowledge on ADEs. Based on our expe- 69 6 pathway (CYP2D6) was seen for three of the drugs (amytriptiline, rience we strongly encourage other regions to establish an ADEM. 70 7 tramadol, and duloxetine). Gabapentin is not metabolized by the 71 8 liver. Therefore, slow metabolism of the isoenzyme was suspected 72 9 for psychosis and hypertension. Pharmacogenetic test (PGT) was Sat-Hulp Toxicovigilance program: 73 10 performed in search of polymorphisms by including: CYP2D6 (*2, Results of 30 Months 74 11 *3, *4, *5, *6, *10, *35, *41 and multiplications), CYP2C9 (*2, *3 R. Muñoz-Romo1; A.M. Borobia1; M. Quintana2; E. Ramírez1; 75 12 and *6) and CYP2C19 (*2,*3, *4, *5 and *17). The results of the M. Muñoz1; H.Y. Tong1; J. Frías1; and A.J. Carcas1 76 13 PGT analyses revealed that the patient was homocygous (wild type). 1Clinical Pharmacology Department, Hospital La Paz-Carlos III, 77 14 Conclusions: Genetic polymorphisms that could explain the ADRs IdiPAZ, Madrid (SPAIN); and 2Emergency Department, Hospital 78 15 were not found in this patient. However, further studies assessing the La Paz-Carlos III, IdiPAZ. Madrid (SPAIN) 79 16 involvement of some other gene or protein in the metabolic process Background: SAT-HULP toxicovigilance program is a validated 80 17 or transport could elucidate our preliminary suspicion. tool (R. Muñoz et al, 2013) that allows a semi-automated detec- 81 18 tion of acute intoxication for patients attending to the Emergency 82 19 Department of La Paz University Hospital. We describe the cases of 83 20 Spontaneous Adverse drug event reports acute poisoning detected by this system since its introduction in 2011. 84 21 to the Adverse Drug Event Manager Material and Methods: This is a descriptive epidemiological study 85 22 (ADEM) (April 2011-October 2013). We analyse all cases of acute poisoning 86 23 M. Lund; S. Vinther; P. Klarskov; K.M. Harboe; detected by SAT-HULP program. This system performs a daily search 87 24 and E. Jimenez-Solem for cases in the hospital’s computerized case records. The tool uses a 88 25 Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark truncated keyword list to systematically look for the reasons patients 89 26 Introduction: The “Adverse Drug Event Manager” (ADEM) is a come to the emergency department and the clinical decisions made. 90 27 service offered to health care professionals (HCPs) employed at a hos- Found cases are entered into a database for recording of type of 81 28 pital in the Capital Region of Denmark. The purpose of the ADEM poisoning episode, reasons for exposure, causative agent, signs and 92 29 is to assist HCPs report suspected adverse drug events (ADEs) to the symptoms, and treatment. 93 30 Danish health authorities, and to raise awareness of ADEs in general. Results: In the study period (30 months) 3,195 acute poisoning 94 31 In the present study, we describe the ADEs reported through the cases were identified, among 182,502 patients attending to the ED 95 32 ADEM in 2014 with respect to reporter, patient, drug and symptom (1.75%); this represents a rate of 143/100,000/year if we consider 96 33 characteristics. that the reference population is 725,006 people. The mean age was 97 34 Materials and methods: All ADE reports handled by the ADEM were 41 years (51.2% male). Abusive and/or recreational poisoning were 98 35 recorded prospectively and anonymously. For this descriptive analy- the most frequent (47.5%), followed by suicide (38.1%) and acciden- 99 36 sis, we included data from 2014, and assessed drugs and symptoms tal (14.0%) poisoning. Forty seven percent of subjects had previous 100 37 for each report made by the clinician. psychiatric pathology and 36.8% alcoholism or previous addictions. 101 38 Results: In 2014, the ADEM handled 484 ADE reports from the 81.8% had symptoms at admission. Drug abuse accounted for 51.7% 102 39 Capital Region of Denmark (1.6 million inhabitants). The median of the cases (alcohol: 86.5%). Most patients were discharge from the 103 40 number of reports per month was 37 (range 17-78). The majority of emergency department (84.1%), followed by patients admitted to 104 41 reports came from departments of internal medicine (63%), followed psychiatry unit (6.7%), internal medicine (4.9%) and intensive care 105 42 by psychiatry (14%) and surgery (7%). The most frequently reported unit (1.5%). Six patients (0.2%) died. 106 43 107 drugs were lisdexamphetamine (n = 40), dabigatran (n = 37) and Conclusions: The results after 30 months confirm that SAT-HULP 44 108 aspirin (n = 33). The most frequently reported adverse events were toxicovigilance program is a tool that provides continuous informa- 45 109 nausea (n = 42), hyponatremia (n = 40) and dyspnoea (n = 36). The tion and allows quick data management of acute poisoning. 46 proportion of ADEs with a fatal outcome was 11/484 (2.3%). In four 110 47 111 48 112 49 113 50 114 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

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1 Screening and Recruitment Procedures Results: In 3 years, 963 subjects have been registered in the course. 65 2 of Healthy Volunteers In A Phase I Among them, 779 completed the course and have already obtained 66 3 Clinical Trial Unit: Experience In 64 the certification. We had 380 students from Governmental institu- 67 4 Bioequivalence Studies tions, 274 students from different pharmaceutical companies and 68 5 B. Duque1; A.M. Borobia1,2; R. Lubomirov1; E. Ramirez1,2; CROs, and 309 individual registrations. Finally, 271 students (34.7% 69 6 P. Guerra1; N. Medrano1; H.Y. Tong2; A.J. Carcas1,2; of those completing the course) filled the anonym satisfaction survey 70 7 and J. Frías1,2 and voted on the following aspects: for 95.2% the e-learning tool is 71 8 1Pharmacology and Therapeutics Department, School of easy to use, 92.2% consider that the contents is adjusted to his/her 72 9 Medicine, Universidad Autónoma de Madrid, Spain; and 2Clinical formative needs, 93.6% said that in general the course has fulfilled 73 10 Pharmacology Department, Hospital La Paz-Carlos III, IdiPAZ, his/her expectations and for 94.8% the course has given them the 74 11 Madrid, Spain expected knowledge level. 75 12 Background: This study reports and analyses screening and recruit- Conclusions: The course has been completed (80.9%) by the most 76 13 ment procedures carried out in 64 bioequivalence (BE) studies. important target groups involved in clinical trials. Our Course is 77 14 Material and Methods: All the studies were designed and conducted being well received for the students because it is clear and concise 78 15 following the requirements of EMA for BE studies and carried out and has no time restriction to follow it. 79 16 in the Phase I Clinical Trial Unit of the Pharmacology Department 80 17 (School of Medicine, Universidad Autónoma de Madrid). For each 81 18 trial calculated sample size, number of volunteers and reasons for Implementing Pharmacogenetics: 82 19 exclusion, withdrawal and dropping were recorded. Pharmarray® And Pharmacogenetic 83 20 Results: For the included 64 trials, a total of 3575 healthy volunteers Consultation 84 21 signed the informed consent form. During the screening period 1076 A.M. Borobia1,2; R. Lubomirov2; H.Y. Tong1; P. Arias3; 85 22 volunteers (30.1%) were found not to be not suitable for the study. J. Tenorio3; J. Frías1,2; P. Lapunzina3; and A.J. Carcas1,2 86 23 The main reasons were: 508 volunteers withdrawn the informed 1Clinical Pharmacology Department, Hospital La Paz-Carlos 87 24 consent (47.3%), 251 showed analytical abnormalities (23.3%) and III, IdiPAZ, Madrid, Spain; 2Pharmacology and Therapeutics 88 25 80 gave a positive result in urine abuse drug test (7.4%). Therefore Department, School of Medicina, Universidad Autónoma de 89 26 a total of 2500 fulfilled inclusion criteria (69.9%) and 2339 were Madrid, Spain; and 3Institute of Medical and Molecular Genetics 90 27 included (158 volunteers were considered as reserves). During the (INGEMM), La Paz University Hospital, IdiPAZ 91 28 study, 52 volunteers (2.2%) dropped for personal reason and 40 Background: The important growth in pharmacogenetics (PGx) 92 29 were excluded (1.7%). A total of 2252 volunteers were suitable for information has not been paralleled by its application in clinical 93 30 the main analysis. practice, due to some barriers related to the interpretation of PGx 94 31 Conclusions: To select 2252 valid participants in BE trials we needed information and the costs of implementation. Our objective is to 95 32 to obtain the signed informed consent form from 3575 potential describe the strategy adopted in La Paz University Hospital to facili- 96 33 participants and to make the initiation visit in 3282 volunteers. Only tate the implementation of PGx in clinical practice. 97 34 a 6.3% of the healthy volunteers interviewed and fulfilling selection Material and Methods: A Clinical Pharmacogenetic Unit (CPGxU) has 98 35 criteria were finally not included. Post-randomization losses were been set up by the Clinical Pharmacology Service and the Institute of 99 36 also low (3.9 %). Medical and Molecular Genetics. Through this functional unit, we have 100 37 proposed: 1) to design a cost-effective genotyping tool for healthcare 101 38 purposes; and 2) to set up a pharmacogenetic counseling service aimed 102 39 Uam Course on Good Clinical Practice to integrate clinical and genetic information and provide evidence-based 103 40 (Gcps) for Investigators: A 3 Years therapeutic advice to the attending physicians which requested it. 104 41 Experience Results: We have designed and patented an array (PharmArray®, 105 42 106 B. Duque1; A.M. Borobia1,2; R. Lubomirov1; E. Ramirez1,2; Application-MC011608403) using an Open-Array® technology (Life 43 107 P. Guerra1; N. Medrano1; H.Y. Tong2; A.J. Carcas1,2; and J. Frías1,2 Technologies Corporation). It allows genotyping 192 SNPs from 57 44 108 1Pharmacology and Therapeutics Department, School of genes, including drug metabolism enzymes and transporters genes, 45 109 Medicine, Universidad Autónoma de Madrid, Spain; and 2Clinical in about 12 hours. The cost of genotyping 192 SNPs per patient, 46 110 Pharmacology Department, Hospital La Paz-Carlos III, IdiPAZ, including DNA extraction, is 23 € . We have implemented for clinical 47 111 Madrid, Spain use an electronic medical history and pharmacogenetic protocols for 48 112 Background: The Department of Pharmacology and Therapeutics treatment selection and dose adjustments. In addition, we are running 49 113 from the School of Medicine at Universidad Autónoma de Madrid a CPGxU providing advice both by means of an electronic platform 50 114 (UAM) has designed an on-line course to provide investigators with or direct patient consultation. This unit makes a mean of 450 PGx 51 115 basic training in GCPs. It also aims to update investigators in ethical determinations per year, 312 online consultations and a mean of 200 52 116 issues and Spanish legislation concerning the conduct of clinical trials. patients were attended in person. 53 117 Methods: Based in ICH-E6-GCP guideline and Spanish regulation, Conclusions: The implementation of Pharmarray® and a CPGxU 54 118 the course is organized into 9 modules and 3 sections each (a theorical in a tertiary hospital aiming to provide clinically useful information 55 119 part, an exam and a section of questions and answers). The course is feasible and it will avoid adverse drug reactions and improve drug 56 120 is implemented within the tool “e-learning Moodle” of the UAM selection at limited cost. 57 121 (https://formacion.uam.es/). It also includes complementary bibliog- 58 122 raphy and a satisfaction survey that students can voluntarily fill out. 59 123 In order to obtain the certificate students must pass the exams with a 60 Pharmacogenetic Implementation In The 124 score of 100%. The Course is credited with 3.8 credits by the Health 61 Routine Clinical Practice: Design of A 125 Commission for Continuing Education in the Health Professions of 62 Multicenter Pilot Clinical Trial 126 the Community of Madrid/National Health System. 1,2 2 3 1 63 A.M. Borobia ; R. Lubomirov ; F. Abad ; H.Y. Tong ; 127 1,2 1,2 1,2 64 E. Ramírez ; J. Frías ; and A.J. Carcas 128

2015 e1 Clinical Therapeutics

1 1Clinical Pharmacology Department, Hospital La Paz-Carlos OAD during the three examined years (ranging from 19.08 DDDs/ 65 2 III, IdiPAZ, Madrid, Spain; 2Pharmacology and Therapeutics TID in 2010 to 26.56 DDDs/TID in 2012). Sulphonylureas were the 66 3 Department, School of Medicina, Universidad Autónoma de next frequently used class and among them glimepiride was the most 67 4 Madrid, Spain; and 3Clinical Pharmacology Department, Hospital frequently used drug (ranging from 12.03 DDDs/TID in 2010 to 68 5 La Princesa, Madrid, Spain 16.51 DDDs/TID in 2012). The use of thiazolidinediones, DPP-4 69 6 Background: Pre-emptive strategies have been suggested as a desir- inhibitors, meglitinides as well as acarbose remained marginal. 70 7 able and efficient way to implement pharmacogenetics in the routine Conclusion: Diabetologists and clinical pharmacologists should 71 8 clinical practice. In order to obtain the best possible evidence we have explain causes leading to these increase in consumption of OADs 72 9 designed a randomized pragmatic “proof-of-concept” clinical trial and determine side effects of available antidiabetic drugs, either posi- 73 10 to test this strategy. tive or negative, in order to enable their optimum utilization. This 74 11 Design: Five groups of predefined patients expecting to receive the work was supported by the Ministry of Science and Technological 75 12 target treatment will be recruited in this multicentre study. In the Development, Republic of Serbia, project No. 41012. 76 13 initial visit all patients will be genotyped after informed consent has 77 14 been obtained. Those patients receiving the target treatment and 78 15 carring the target mutation(s) will be under stratified randomiza- A Comparison of The Clinical Abuse 79 16 tion to: 1) Pharmacogenetic arm: doctor will contact with the Liability of Mdma and Mephedrone 80 17 Pharmacogenetic Unit (PGx Unit) to obtain a prescription/dosing M. Farré1,2,3; C. Pérez-Mañá1,2; J. Mateus1,2; M. Pujadas1; 81 18 recommendation mainly based in reviews from CPIC and DPWP F. Fonseca4; M. Torrens2,4; R. de la Torre1,4; and E. Papaseit1,5 82 19 (http://www.pharmgkb.org); 2) Control arm: patients will be treated 1Hospital del Mar Medical Research Institute-IMIM, Barcelona, 83 20 as usual without pharmacogenetic information. Spain; 2Universitat Autònoma de Barcelona-UAB, Barcelona, 84 21 Selection Criteria: patients to be enrolled are: 1) Metastatic/advanced Spain; 3Hospital Universitari Germans Trias i Pujol, Badalona, 85 22 colorectal cancer, 2) High risk cardiovascular patients, 3) Patients Spain; 4Addiction Unit, Hospital del Mar, Barcelona, Spain; and 86 23 under bone marrow transplant, 4) Patients with major unipolar 5Universitat Pompeu Fabra-UPF, Barcelona, Spain 87 24 depression and 5) Post-surgery patients. Introduction: Mephedrone is a synthetic cathinone derivative 88 25 Target Drug and Biomarker(s) Pairs for Each Group: 1) fluoro- included in the class of “New-Novel Psychoactive Substances”. 89 26 pyrimidines-DPYD and irinotecan-UGT1A1, 2) high dose statins- Interestingly, synthetic cathinones are marketed as “bath salts” or 90 27 SLCO1B1, 3) voriconazole-CYP2C19, 4) SSRIs-CYP2D6 and 5) “plant food” and have gained notable popularity for them similar 81 28 tramadol/oxicodone-CYP2D6. effects to 4-metylenedioxymethamphetamine (MDMA, ecstasy), 92 29 Outcomes: 1) neutropenia and gastrointestinal toxicity, 2) myopa- amphetamine or cocaine. The aim of the present study was to evalu- 93 30 thy, 3) lack of efficacy (persistent fever), 4) lack of efficacy (need to ate the clinical abuse liability of mephedrone in comparison to 94 31 switch therapies) and 5) lack of efficacy (need of rescue medication) MDMA. 95 32 or toxicity (gastrointestinal toxicity). Materials and Methods: The protocol was approved by the local 96 33 Genotype Assay: We will use an Open Array® technology (Life Research Ethics Committee and registered with ClinicalTrials.gov, 97 34 Technologies Corporation) designed and patented by our group number NCT02232789. Participants signed an informed consent 98 35 (PharmArray®, Application MC011608403). It allows to genotype before inclusion. Twelve healthy male, recreational users of psycho- 99 36 192 SNPs from 57 genes. The cost per patient, including DNA extrac- stimulants participated as outpatients in three experimental sessions. 100 37 tion, is 23 € . They received a single oral dose of mephedrone (200 mg), MDMA 101 38 Conclusions: This “proof of concept” clinical trial will allow to (100 mg) and placebo. Design was double-blind, randomized, cross- 102 39 test in a risky selected population the effectiveness of a preemptive over and controlled with placebo. Study variables included: vital 103 40 pharmacogenetic strategy and it implementation in clinical practice. signs (blood pressure, heart rate, temperature, and pupil diameter), 104 41 subjective effects (visual analogue scales-VAS, ARCI-49 item short 105 42 form, VESSPA questionnaire, and identification class questionnaire). 106 43 The Consumption of Oral Antidiabetics In Blood and urine samples were obtained. 107 44 Serbia Results: Both mephedrone and MDMA produced similar increases 108 45 109 O. Horvat; J. Popržen; Z. Tomić ; V. Mijatović ; N. Stilinović ; and in blood pressure, heart rate and temperature, but MDMA produced 46 A. Sabo more mydriasis. Mephedone and MDMA induced euphoria and 110 47 Department of Pharmacology, Toxicology and Clinical pleasurable effects, slight changes in perceptions but nor hallucina- 111 48 Pharmacology, Faculty of Medicine, University of Novi Sad, tions. Mephedrone effects appeared earlier, were less intense and 112 49 Serbia dissipate faster. Mephedrone was classified as similar to MDMA. 113 50 Introduction: The aim of this study was to give an overall picture Both substances wee well tolerated and no serious side effects were 114 51 of the utilization trends of oral antidiabetics in Serbia between 2010 observed. Mephedrone and MDMA plasma concentrations peaked 115 52 and 2012. at 1.25 and 2 hours, and its elimination half-life were 2.15 and 7.9 116 53 Material and Methods: The study examined consumption of oral hours, respectively. 117 54 antidiabetics during the 3-year period. The data were retrieved from Conclusions: Mephedrone presents an abuse liability similar to 118 55 the annual reports of the Agency for Drugs and Medical Devices of MDMA but its shorter duration of effects could explain a more 119 56 the Republic of Serbia. Consumption was calculated using the ATC/ compulsive pattern of use. 120 57 DDD methodology and results were expressed in DDD/1000 inhabit- Acknowledgements: Supported by grants from Instituto de Salud 121 58 ants/day (DDDs/TID). Carlos III (ISCIII, FIS-FEDER, FIS PI11/0196), ISCIII-Red de 122 59 Results: The total consumption of antidiabetic drugs varied 1.5 Trastornos Adictivos (RTA RD12/0028/0009). Clara Pérez-Mañá and 123 60 fold, ranging from 34.89 DDDs/TID in 2010 to 50.33 DDDs/TID in Esther Papaseit are Rio Hortega fellowship (ISCIII, CM12/00085, 124 61 2012. Biguanides (metformin) were the most frequently used class of CM13/00016). 125 62 126 63 127 64 128

e2 Volume XX Number XX Screening and Recruitment Procedures of Healthy Volunteers In A Phase I Clinical Trial Unit

1 What do you think about generic drugs influence on the stable dose of warfarin are not conclusive while; 65 2 products? Results from a survey there are no studies about its influence on acenocoumarol dosing. 66 3 J.M. Ferrero-Cafiero1; I. Gich1,2,3; R. Morros3,4; C. Vedia3,5; and Material and Methods: This was an observational, prospective study. 67 4 R.M. Antonijoan1,2,3 We recruited 341 patients in La Paz University Hospital between 68 5 1Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau 2008 and 2013 in stable anticoagulant treatment with acenocou- 69 6 (CIM-Sant Pau), Barcelona, Spain; 2Hospital de la Santa Creu i marol for atrial fibrillation, thromboembolic disease and valve 70 7 Sant Pau, Barcelona, Spain; 3Universitat Autònoma de Barcelona, replacement. Data collection included age, gender, race, body weight 71 8 Barcelona, Spain; 4IDIAP Jordi Gol, Barcelona, Spain; and 5SAP and height, INR results and acenocoumarol dose administered in the 72 9 Barcelonès Nord i Maresme, Institut Català de la Salut, Barcelona, last 3 months and concomitant medications. A blood sample was 73 10 Spain prospectively collected for CYP2C9, VKORC1, CYP4F2, APOE and 74 11 Background or Introduction: Generic Drugs Products (GDP) have 2 variant of POR [rs2868177 and rs1057868 (POR*28)]. Multiple 75 12 been subject of discussion for many years, and still now there is some linear regression was performed to determine the influence of POR 76 13 controversy about their quality, effectiveness and safety compared SNPs on the acenocoumarol dosing algorithm previously developed 77 14 to Innovators drugs. This survey tried to find what is the general by our group. 78 15 perception and opinion from physicians and medical students about Results: The real dose of acenocumarol did not differed significantly 79 16 generic drugs products. among carriers of the different polymorphisms of the two POR vari- 80 17 Material and Methods: A questionnaire of 12 items focused mainly ants evaluated (POR*28, P = 0.176) and (POR rs2868177, P = 81 18 in effectiveness, safety, quality and adverse event occurrence was sent 0.534). In the simple regression analysis, none of the POR SNPs was 82 19 to physicians of a third level health care hospital and to medicine identified as being significantly associated with acenocoumarol dose 83 2 20 students. Individual demographic information and clinical practice variation. In the multiple regression analysis, R obtained with the 84 21 data (specialty, years of experience, pharmaceutical sale representa- acenocoumarol dosing algorithm was 48.5%; adding POR*28 or 85 2 22 tive visits, etc.) was asked. POR rs2868177 just increase R in 0.1%. 86 23 Results: One hundred fifty-five subjects answered the survey (n= Conclusions: None of the 2 POR variants evaluated are associated 87 24 157). Physicians from specialties that are less related with clinical with the interindividual variability of acenocoumarol. 88 25 practice (who do not prescribe daily) showed to be more agreed with 89 26 the affirmation that Innovators and GDP products have the same 90 27 quality, effectiveness and adverse event occurrence compare with Manifestations of Unethical Marketing 81 28 physician’s that prescribe daily. Internal medicine specialist tends In Health Care of The Kyrgyz Republic 92 29 to be more agreed with equivalence in term of effectiveness and A.A. Karasheva1; and U.M. Tilekeeva2 93 30 adverse events occurrence than surgical specialist. Years of experi- 1Department of Drug Provision and Medical Equipment Ministry 94 31 ence, number of patients by day and number of pharmaceutical sales of Health, Bishkek, Kyrgyzstan; and 2Kyrgyz State Medical 95 32 representative’s visits by month showed an inversely proportional Academy, Bishkek, Kyrgyzstan 96 33 relationship to be in agreement with equivalence in quality, effective- Unethical marketing of drug is hot topic around the world. It is nec- 97 34 ness and safety. Difference between medicine students and physician essary to study the actual practice, the implementation of technical 98 35 were found in questions related to quality, effectiveness and safety, regulations. 99 36 physicians tend to be more in disagreement with the equivalence in Objective: Identification of unethical marketing of medicines among 100 37 those aspects between GDP and Innovators ones. All commented 29 clinics in Kyrgyzstan. 101 38 results were statistically significant (P values < 0.05). There were seized 412 forms of an unknown sample, self-pads 102 39 Conclusions: We found that physicians have some concerns about with advertising for drug prescribing, pharmacy network, engaged 103 40 equivalence between GDP and Innovators ones regarding the qual- in unethical marketing during the checking of 94 doctors. The lists 104 41 ity, efficacy and safety of generic drugs, this concerns increase with of patients indicated name, phone, address, sheets rewards prizes and 105 42 years’ experience, number of patients visited and number of sales bonuses for prescription drugs. Doctors for prescription drugs were 106 43 representatives visits, the fact of prescribing daily and to be surgical provided with bonuses in monetary terms from 10% to 26% of the 107 44 specialist. Students tend to be more agreed with equivalence between cost of prescribed drug, household and office equipment, cookware 108 45 GDP and Innovators drugs. Nevertheless the response rate is a limita- sets, 5% discount cards, vouchers for petroleum products, mobile 109 46 tion of this study. communications, and trips to luxury resorts. 110 47 During one month 6 pharmaceutical companies have been pre- 111 48 sented one workshop, at one of the institutions for the promotion 112 49 Cytochrome P450 Oxidoreductase of 6 drugs. In violation of the technical regulations medical repre- 113 50 Contribution On An Acenocoumarol sentatives visit doctors during medical reception, distribute hand- 114 51 Dosing Algorithm outs, prescription forms unknown sample, loose-leaf notebooks with 115 52 116 H.Y. Tong1; A.M. Borobia1,2; R. Lubomirov2; R. Hernández1; advertising of medicines, conduct workshops without the consent 53 117 M. Muñoz1; E. Ramírez1,2; J. Frías1,2; and A.J. Carcas1,2 of Department of Drug Provision and Medical Equipment Ministry 54 118 1Clinical Pharmacology Department, Hospital La Paz-Carlos III, of Health. Managers and medical representatives of pharmaceuti- 55 119 IdiPAZ, Madrid, Spain; and 2Pharmacology and Therapeutics cal companies have received official letters on these violations of 56 120 Department, School of Medicina, Universidad Autónoma de the ethical principles of promotion of drugs directed newsletters. To 57 121 Madrid, Spain reduce the harm of unethical marketing of drugs in Kyrgyzstan it is 58 122 Background: The great majority of clinically used drugs are metabo- very important to regulating the monitoring of medical institutions. 59 123 lized by hepatic type II cytocrome P450 enzymes and require the Repeated violations, by law, must revoke licenses for pharmaceutical 60 124 activity of P450 oxidoreductase (POR). The presence of POR poly- activity and registration certificates for drugs. To improve the situa- 61 125 morphism can modify the activity of CYP450. Studies about POR tion we need to restore the system of professional information about 62 drug and of keeping the medical staff. 126 63 127 64 128

2015 e3 Clinical Therapeutics

1 An Internal System for Quality Assure (< 400 or ≥ 400), there was no relationship between Cmin and AUC/ 65 2 With External Audit (Aenor) In A Clinical MIC parameter. Of 50 patients with both measures, 58% achieved 66 3 Pharmacology Service: A Positive AUC/MIC ≥ 400; 2 patients did not exceed 400 μ g.h/mL AUC/MIC 67

4 Experience despite reaching Cmin 15 to 20 μ g/mL, whereas 11 achieved an AUC/ 68 1 1,2 1 5 M. García Sáiz ; E.J. Sanz Álvarez ; M. Cervino Rodriguez ; MIC ≥ 400 μ g.h/mL with Cmin 5 to 10 μ g/mL. 69 6 C. Rodríguez Jiménez1; A. Aldea Perona1; and C. Boada Conclusions: Therapeutic trough levels do not always correlate with 70 7 Fernández del Campo1 AUC/MIC ≥ 400 μ g.h/mL, as they depend on patients’ PK param- 71 8 1University Hospital of Canarias, Tenerife, Spain; and 2University eters and the microorganisms’ MIC. Furthermore, other studies only 72 9 of La Laguna, Tenerife, Spain mention the role of AUC/MIC in lower respiratory-tract infections 73 10 The internal systems for quality assure are being introduced in the and MRSA bacteraemia. Therefore, studies with larger number of 74 11 health care environment, and especially in hospitals. The Clinical patients and different locations are needed to assess the clinical effi- 75 12 Pharmacology Service (CPS) at a University Hospital has implemented cacy of this parameter. 76 13 a quality management system, consistently with ISO 9001:2008 77 14 requirements and subjected to external audits by AENOR. The CPS 78 15 defined 6 processes representing its activity in the hospital, and within Milestones On Orphan Medicinal 79 16 each of those processes defined a number of indicators of the perfor- Products Development: The 100 First 80 17 mance and its quality (process/n indicators): Clinical consultations Drugs for Rare Diseases Approved 81 18 (6), Safety of medicines and pharmacovigilance (7), Therapeutic Drug Throughout Europe 82 19 Monitoring (3), Policy and medicines selection (5), Clinical trials (4) C. Pontes1; J.M. Fontanet1; M. Gomez-Valent1; J. Rios Guillermo1; 83 20 and Clinical research (2). Three of the indicators were satisfaction R. Vives Vilagut1; R. Morros1; J. Martinalbo2; J. Torrent-Farnell1; 84 21 surveys. The implantation period lasted 10 months. In a first phase and F Torres1 85 22 (4 months), the design and documentation of the processes were 1Universitat Autònoma de Barcelona, Barcelona, Spain; and 86 23 developed; 24 procedures, 9 work instructions and 67 forms (or 2European Medicines Agency, London, United Kingdom 87 24 records) were documented and incorporated into the management Background: More than 10 years have lapsed since the issue of 88 25 system. In a second phase (6 months) the system was implemented. the EU orphan drug Regulation (EC No 141/2000), and along this 89 26 The internal and the external audits valued the performance and pathway, substantial experience has been gained on the assessment 90 27 gave the higher standards to the CPS. The certification improved of orphan medicinal product (OMP) marketing applications. In the 81 28 the activity of the CPS by using a structured process, analyzing the framework of an international FP7 collaboration (FP7-HEALTH- 92 29 results, and introducing improvements. Furthermore the activity of 2013-INNOVATION-1, ASTERIX), a review of European Public 93 30 the CPS was clearly visible for the rest of the Hospital and especially Assessment Reports (EPAR) for approved OMP is being conducted 94 31 for the head physician team. The extra bureaucratic work pays off to describe the amount and type of information submitted to the 95 32 for the results obtained. European Medicines Agency (EMA) to support a positive opinion 96 33 for an orphan drug. 97 34 Material and Methods: A review of the EPAR for first 100 OMP 98 35 Application of pharmacodynamic approved in Europe has been performed. Administrative, regulatory 99 36 principles (AUC/MIC) to improve the and clinical data in which the approval was based on have been 100 37 clinical efficacy of individualized extracted from the public information available and have been sys- 101 38 treatment with vancomycin tematized. 102 39 103 C. Rodríguez Jiménez; M.M. García Sáiz; J. Herrera Herrera; and Results: From 2000 to January 2015, 100 OMP including 98 dif- 40 104 P. Masiero Aparicio ferent molecules have been authorised for 125 different therapeutic 41 105 Hospital Universitario de Canarias, La Laguna, Tenerife, Spain indications. Small molecules represented 76% of OMP, biologicals 42 106 Introduction: Vancomycin monitoring is based on determining 23% and there was 1 advanced therapy OMP. According to ATC 43 107 trough levels (C ) before administering next dose; however, the code, oncology accounted for 41.6% of indications, and endocrine 44 min 108 bactericidal effect of in vitro vancomycin and its clinical efficacy has and metabolic diseases for 28%. Most indications had prevalences 45 109 been related to the pharmacodynamic parameter AUC /MIC < 1/10.000 (58.4%), while 8 indications (6.4%) had prevalences 46 0-24 ≥ 110 400 g.h/mL. The aim was to analyse the AUC /MIC availability > 3/10.000. Small and medium-sized enterprises (SME) hold the 47 μ 0-24 111 in patients monitored during 2012 to 2013 and to evaluate if we have marketing authorisation for 13/125 applications; 5 companies were 48 112 reached the therapeutic objective proposed in literature. applicant for 45 (36%) out of all OMP applications. Average (range) 49 113 Materials and Methods: A patient sample (100) with stable values time between orphan designation and approval was 4.1 (0.5–12.9) 50 114 for C and C was obtained. Pharmacokinetic parameters were years. Nineteen OMP were transferred between companies between 51 min max 115 calculated. In cases with presence of MIC for gram-positive micro- the orphan designation and the application, once (15 OMP), twice 52 116 organisms in the antibiogram, AUC/MIC ratio was calculated. The (2 OMP), 4 (1 OMP) or 6 times (1 OMP). 53 117 study was approved by an Ethics Committee. Conclusions: Preliminary description of the first 100 orphan drugs 54 118 Results: Diagnoses in the patient cohort (77 men and 23 women, approved in EU showed that most of drugs approved are chemical 55 119 median age 63) were as follows: pneumonia (36%), heart infections substances, most of OMP are aimed to treat neoplasic diseases and 56 120 (10%), abdominal (15%), musculoskeletal (4%), CNS (5%), MRSA for conditions with prevalence on the low range, and SMEs account 57 121 bacteraemia (2%), coagulase-negative staphylococcal bacteraemia for a very small part of applications. 58 122 (7%), Urinary-tract (4%), and others (13%). Susceptible organisms 59 123 (Coagulase-negative staphylococci, Enterococci, MRSA, MSSA and 60 124 Streptococcus spp.) were isolated in 79 patients, in 44 patients cul- 61 Agomelatine Effectiveness In Sleep 125 tures became negative after 8.5 days (median). In 69 cases, MIC was 62 Disturbances In Autism Spectrum 126 available. Median treatment lasted 10 days; 1000 mg/12h was the 63 Disorder 127 most frequently prescribed dose (71%). According to administered 1 2 3 4 64 P. Ballester ; M.J. Martínez ; A. Javaloyes ; L. Hernández ; and 128 2,5 doses, Cmin achieved (5–10, 10–15, 15–20 and > 20), and AUC/MIC A.M. Peiró

e4 Volume XX Number XX Screening and Recruitment Procedures of Healthy Volunteers In A Phase I Clinical Trial Unit

1 1 The Foundation for the Promotion of Health and Biomedical average. In the period 2011 to 2014, notification went up from< 50 65 2 Research of the Valencian, Community (FISABIO), Alicante, Spain; cases to > 130 per annum, representing easily more than 50% of all 66 3 2University of Murcia, Murcia, Spain; 3Hospital Perpetuo Socorro, notifications in our hospital; 80.7% are severe. 67 4 Alicante, Spain; 4General University Hospital of Alicante, Conclusions: APV programme more than doubled the notifications 68 5 Alicante, Spain; and 5Occupational Observatory, University in our hospital since its implementation, demonstrating the feasibil- 69 6 Miguel Hernández (UMH), Alicante, Spain ity and effectiveness of the active and systematic search for ADR 70 7 Introduction: Sleep disorders (SD) affect up to the 84% of subjects cases. It also encourages interaction with other hospital services and 71 8 with autism spectrum disorders (ASD) increasing cognitive and promotes a habit of notifying among health professionals. These 72 9 behavioural impairments. Even more, SD is a marker of family stress results highlight the importance of joint work between pharma- 73 10 and one of the main reasons for drug treatment. Our aim was to covigilance centres and clinical services, and therefore this activity 74 11 evaluate the effectiveness of the antidepressant agomelatine improv- should be encompassed among the tasks of Clinical Pharmacology 75 12 ing sleep quality by actimetry in ASD. Departments. 76 13 Methods: A randomized, crossover, double-blind, placebo-controlled 77 14 and multicenter clinical trial, was performed in 25 subjects with ASD. 78 15 Participants along two periods of 3 months received (A) agomela- Immunosuppressive Drug Use In Solid 79 16 tine 25 mg/day or (B) placebo. Functional circadian rhythm markers Organ Transplantation: off Label Use 80 17 (wrist temperature, actimetry and position [TAP]) and salivary cor- Characterization 81 18 tisol, were measured during a week at the beginning and at the end M.A. De Cos1; M.C. Almenara2; B. Ruiz3; A. Mediavilla1; 82 19 of each period (random drug sequence: AB or BA). M.B. Sánchez1; and F.J. Adín1 83 20 Results: Participants were 25 adults with low-functioning ASD 1“Marqués de Valdecilla” University Hospital. Santander, Spain; 84 21 (20♂/ 5♀, mean age of 32 ± 2 years). We found significantly differ- 3“Valdecilla” Research Institute IDIVAL, Santander, Spain; and 85 22 ences improving circadian rhythms in agomelatine versus placebo 2“Puerta de Hierro” University Hospital, Madrid, Spain 86 23 (P = 0.018). We observed an absence of difference in cortisol levels Introduction: Immunosuppressive (IS) treatment in solid-organ 87 24 between groups suggesting that hypothalamic–pituitary–adrenal axis transplantation should prevent acute-chronic rejection without 88 25 functioning was unaltered. increasing infections and malignancies through the combination of 89 26 Conclusions: Actigraphy is an objective and useful tool to analyze SD drugs with different action mechanism in three differentiated phases: 90 27 in ASD population, where preliminary, agomelatine seems effective in induction, maintenance and rejection. Off label use is frequent in 81 28 improving sleep patterns compared to placebo. Further analyses will induction and maintenance phases. Utilization studies to characterize 92 29 focus on correlation between actigraphy and genetic and epigenetic these uses are necessaries. 93 30 analyses from sleep genes data. Material and Methods: We conducted a prospective observational 94 31 study in 2 hospitals experienced in transplantation. The principal 95 32 objective was to describe IS use in solid-organ transplantation. 96 33 Detection of unnotified adverse Clinical-Pharmacology Services identified patients and will follow 97 34 drug reactions (adr). Active them up to three years. Clinical, laboratory and pharmacological 98 35 pharmacovigilance (apv) data were collected from clinical history. 99 36 C. Boada Fernández del Campo1; C. Rodriguez Jimenez1; Results: At our data cut-off date 108 patients were included and 100 37 M. García Sánchez Colomer2; E. Fernández Quintana2; followed for 3 months. 101 38 P. Masiero Aparicio1; J. Herrera Herrera1; and M.M. García Saiz1 102 39 1Hospital Universitario de Canarias, La Laguna, Tenerife, Spain; Type of transplant 103 40 and 2Centro Autonómico de Farmacovigilancia e Información 104 41 Terapéutica de Canarias, La Laguna, Tenerife, Spain Heart Liver Lung Kidney 105 42 Introduction: Cases of ADR, which are attended and occur while 106 Patients: n (%) 23 (21.3) 14 (13.0) 41 (38.0) 30 (27.9) 43 hospitalized, are important due to the severity of these reactions. 107 44 Age: median 60 (54–64) 51 (46–57) 62 (57–65) 50 (34–59) 108 Nevertheless, many of these cases are not notified spontaneously. (P25-P75) 45 Different methods have been proposed to obtain this information, Acute rejection: 5 (21.7) 1 (7.1) 17 (41.5) 6 (20.0) 109 n (%) 46 however, their sensitivity and/or specificity is low. Therefore, a pro- 110 47 Fatal 1 (4.3) 0 1 (2.4) 0 111 gramme of Active Pharmacovigilance (APV) was launched in our Cellular 3 (13.0) 1 (7.1) 17 (41.5) 5 (16.7) 48 hospital in 2011. Humoral 2 (8.7) 0 0 1 (3.3) 112 Adverse events: 4 (17.4) 2 (14.3) 11 (26.8) 0 49 Materials and Methods: The Department of Clinical Pharmacology 113 50 n (%) 114 performs a systematic review of patients’ clinical records which serve Required 3 (13.0) 1 (7.1) 2 (4.9) 0 51 to detect suspected ADR cases. This information is completed with treatment 115 Required 2 (8.7) 1 (7.1) 5 (12.2) 0 52 other clinical data (laboratory and imaging tests, primary care his- 116 53 hospitalization 117 tory, etc.) for validation purposes and to proceed to its notification. Infecctions: 4 (17.4) 8 (57.1) 15 (36.6) 2 (6.7) 54 Hospital discharge reports are reviewed weekly, filtering for depart- n (%) 118 Bacterial 3 (13.0) 7 (50) 13 (31.7) 2 (6.7) 55 ments (Internal Medicine and Nephrology) instead of diagnoses. 119 56 Fatal 0 0 1 (2.4) 0 120 Furthermore, progress report of patients attended in the Emergency Induction 4* 0 0 18 57 Department, selected by diagnoses and age, are assessed daily. Thymoglobulin 121 Basiliximab 19* 4* 0 12 58 All reports obtained are digitally available to the evaluating phy- 122 59 Maintenance Tacrolimus + Tacrolimus + *Tacrolimus + Tacrolimus + 123 sicians, to facilitate identification of suspected ADR, and to enable Mycophenolate Mycophenolate *Mycophenolate Mycophenolate 60 124 notification to the National Pharmacovigilance System. + Corticoids + Corticoids + Corticoids + Corticoids 61 Results: Six thousand five hundred five cases have been reviewed 23 14 41 30 125 IS changes 0 TAC-EVE 1 TAC-CsA 6 TAC-SIR 4 62 since implementation of this activity, 587 ADR detected, and 232 126 63 notified. Evaluation of 40 cases per week consumed 3 hours on *Off label 127 64 128

2015 e5 Clinical Therapeutics

1 Conclusions: Following EPARs, off label use accounted for 91.3% According to the culture and sensitivity, 48 patients were positive 65 2 of Heart-T and 28.6% of Liver-T in induction phase and 100% of for enterobacteraerogens, 34 patients from the 48 were sensitive 66 3 Lung transplanted patients. to amikacin and levofloxacin. So, firstly we began with amikacin 67 4 and noticed that only sixteen patients were respond. On the other 68 5 hand addition of levofloxacin to amikacin on the fourth day to treat 69 6 Vincristine-Induced Neuropathic Pain the remaining patients showed complete recovery of the patients as 70 7 In A Cyp3a5 Non-Expresser With Reduced reported by CPIS and CRP. 71 8 Cyp3a4 Activity Results: There is a significant change in both CPIS and CRP in first 72 day versus fourth day in 16 patients that responded to single antibi- 9 M. Bosilkovska; K. Ing Lorenzini; J. Desmeules; Y. Daali; 73 otics amikacin, however, the remaining 18 patients not response to 10 and M. Escher 74 single antibiotic. On the other hand, adding other antibiotic (levo- 11 Geneva University Hospitals, Geneva, Switzerland 75 floxacin) for the remaining eighteen patients showed a significant 12 Background: Vincristine is metabolised by CYP3A5 and CYP3A4 76 changes in both CPIS and CRP in fifth day versus ninth day 13 isoforms with CYP3A5 contributing to 75% of vincristine intrin- 77 Conclusions: It can be concluded that CPIS and CRP play an impor- 14 sic clearance. Vincristine is a substrate of the P-glycoprotein (P-gp) 78 tant role in determination the efficacy of antibiotics that used in 15 transporter. An increase in vincristine neurotoxicity in CYP3A5 non- 79 treatment in nosocomial Pneumonia. 16 expressers has been observed. The severity of neuropathy was found 80 Key words: nosocomial pneumonia, CPIS, CRP, amikacin and 17 to be inversely correlated to vincristine metabolite concentrations. 81 levofloxacin. 18 However, a clear correlation between genetic polymorphisms and 82 19 vincristine toxicity has not been established. 83 20 Case Presentation: We report the case of a 21-year old African male 84 21 patient who received vincristine 2 mg on 3 occasions (on 14.10, 30.10 Retrospective Study of Lacosamide In The 85 22 and 06.11.14) for the treatment of pre-B acute lymphoblastic leuke- Elderly (≥ 60 Years of Age) 86 23 mia. Six weeks after the last vincristine dose the patient complained P.S. Wong1,2; J. Bainbridge1; M. Spitz3; L. Frey3; C. Drees3; 87 24 of bilateral severe burning pain in the toes and allodynia, suggestive C. O’Brien3; L. Strom3; A. Shrestha3; S. Benbadis4; J. Sirven5; 88 25 of neuropathic pain. S. Chung6; E. Maa7; and B. Phillips8 89 26 The patient was genotyped for CYP3A5 using a real-time 1University of Colorado, Aurora, United States; 2Singapore 90 27 PCR method as well as for ABCB1 (coding for P-gp) G2677T/A General Hospital, Singapore; 3University of Colorado Hospital, 81 28 and C3435T SNPs. The results showed that the patient presented Aurora, United States; 4University of South Florida, Tampa, 92 29 a CYP3A5*3/*3 polymorphism indicating that he did not express FL, United States; 5Mayo Clinic, Phoenix, AZ, United States; 93 30 CYP3A5 enzyme. He was a homozygous ‘wild type’ carrier for 6St. Joseph’s Hospital/Barrow Neurological Institute, Phoenix, 94 31 ABCB1 SNPs. AZ; 7Denver Health Medical Center, Denver, United States; and 95 32 Furthermore, CYP activity was evaluated using the Geneva phe- 8Colorado Neurological Institute, Englewood, CO, United States 96 33 notyping cocktail including midazolam as a probe for CYP3A4. The Background: Lacosamide was FDA approved in 2008 for partial 97 34 patient had a decreased CYP3A activity which could not be explained onset seizures. Few studies evaluated its effectiveness in the elderly. 98 35 by the concomitant medication. Similarly he had no CYP3A inhibitor This multi-center study documented the use of lacosamide for 99 36 100 in his medication at the time he received vincristine. patients ≥ 60 years in a naturalistic setting. We evaluated the effi- 37 Conclusion: The lack of CYP3A5 expression together with decreased cacy, safety, tolerability and dosing requirement in this population. 101 38 102 CYP3A4 activity probably led to a decrease in vincristine clearance Methods: Patients with a diagnosis of epilepsy, ≥ 60 years of age and 39 and to an increase in its plasma concentrations. It is a likely explana- started lacosamide between October 2008 and December 2014, were 103 40 tion for the occurrence of neurotoxicity in our patient despite the low identified at the study sites. Patients’ medical history, treatment effi- 104 41 doses of vincristine he received. In patients treated with vincristine, cacy and safety measures were retrospectively reviewed. Primary out- 105 42 CYP phenotyping and genotyping could be crucial in preventing seri- come measure was retention rates at 3, 6, and 12 months. Secondary 106 43 ous side effects. outcome measures were seizure freedom and 50% seizure reduction 107 44 at final maintenance dose, final effective total daily dose, and days 108 45 to achieve effective dose. 109 46 Results: Fifty-two patients were evaluated: 18 were between 60 to 64 110 47 Role of Cpis And Crp In Determination The 111 Efficacy of Chemotherapy In Management years, 16 were between 65 to 69 years, and 18 were 70 years or older. 48 The average time since diagnosis was 24.7 years (SD 23.5). The main 112 49 of Enterobacter Nosocomia Pneumonia 113 K. Maha; A. Josef; and M. Hany seizure type was complex partial seizure (78.8%). Forty-four percent 50 of patients were using lacosamide as monotherapy. Overall 3, 6 and 114 51 Faculty of medicine, Minia University, Minia, Egypt 115 Background: Patients in intensive care unit (ICU) are at risk for death 12-month retention rates were 94.2%, 84.6% and 51.9% respec- 52 tively. Seizure freedom was achieved in 28.8% of patients. Median 116 53 not only from their critical illness but also from secondary processes 117 such as nosocomial infection. Pneumonia is the second most common maintenance total daily dose was 300mg/day (range 100–600mg/ 54 day) in those 60 to 64 years and 65 to 69 years; 200mg/day (range 118 55 nosocomial infection in critically ill patients. 119 Aim of the Work: The present study was conducted to evaluate the 50–400mg/d) in those ≥ 70 years. Average time to maintenance dose 56 was 207 days for those 60 to 64 years, 195 days for those 65 to 69 120 57 role of the clinical pulmonary infection score (CPIS) and C-reactive 121 years and 89 days for those ≥ 70 years. During titration phase, 55.6% 58 protein (CRP) in measurement the efficacy of antibiotic therapy 122 against nosocomial enterobacter pneumonia. of those ≥ 70 years, 62.5% of the 65 to 69 years, and 22.2% of the 59 60 to 64 years experienced neurological side effects. The most com- 123 60 Patients and Methods: After approval of the study by the Research 124 Ethics Committee, 200 patients with manifestation of pneumonia as mon neurological adverse effects were dizziness and balance issues. 61 Conclusions: Lacosamide was effective and well-tolerated in our 125 62 assessed at the onset of ICU administration by calculation the CPIS 126 and daily by CRP detection during the first 8 days of intubation. elderly population. Our findings suggest that this population may 63 require a lower dose and an extended titration schedule. 127 64 128

e6 Volume XX Number XX Screening and Recruitment Procedures of Healthy Volunteers In A Phase I Clinical Trial Unit

1 The Use of Complementary and (CsA) impact the fungal load, a surrogate marker of infection, after 65 2 Alternative Medications Among Dialysis administration of voriconazole. 66 3 Patients Voriconazole (30 mg/kg, i.v.) was administered to six groups of 67 4 R. Koren1,5; H. Zafrir Danieli5; K. Doenyas-Barak4,5; 30 rats randomized according to infectious status and cyclosporine 68 5 T. Ziv-Baran5; M. Berkovitz2,5; and A. Golik1,2,5 dosing regimen. Fungal load was estimated in brain samples (up to 69 6 1Departement of Internal Medicine A, Tel-Aviv Israel; 2Clinical 96 hours) with a quantitative PCR method. Voriconazole plasma and 70 7 Pharmacology Unit, Tel-Aviv Israel; 3Department of Epidemiology cerebrospinal fluid concentrations were quantified using an UPLC/ 71 8 and Preventive Medicine, School of Public Health, Tel-Aviv Israel; MS/MS method and documented up to 48 h after administration. 72 9 4Department of Nephrology, Tel-Aviv Israel; and 5Sackler Faculty Pharmacokinetic parameters were estimated using compartmental 73 10 of Medicine, Tel Aviv University, Tel-Aviv Israel modelling (Monolix®). 74 11 This work was performed in partial fulfillment of the M.D. thesis Plasma and cerebrospinal fluid pharmacokinetics showed a simi- 75 12 requirements of the Sackler Faculty of Medicine, Tel Aviv University. lar profile. In plasma, a mono-compartmental model with zero-order 76 13 Introduction: The use of complementary and alternative medicine input and Michaelis-Menten elimination best fitted the data. In cere- 77 14 (CAM) is on the rise in last decade. Subpopulations of patients with brospinal fluid and plasma, the infectious status and the cyclosporine 78

15 chronic diseases are at risk for adverse events and potential drug–herb dosing regimen had an opposite effect on voriconazole Cmax and 79 16 interactions, among them dialysis patients. This study aimed to evalu- AUC. In the “noninfected” groups, Cmax and AUC were significantly 80 17 ate the prevalence of CAM consumption among dialysis patients and increased in the cyclosporine arm (P < 0.001) while in the “non CsA” 81

18 search for potential interactions. groups Cmax and AUC were significantly lower in the infected arm 82 19 Methods: This is a Cross Sectional study based on questionnaires. (P < 0.01). No significant differences were observed in AUC and Cmax 83 20 The study included patients at the hemodialysis unit at “Assaf when the combination “infection + CsA” was considered. Results 84 21 Harofe” medical center, Zeriffin, Israel. Questionnaires included from quantitative PCR showed a marked reduction of the fungal 85 22 demographic data, information about medical history and the use load in the brain within 48 hours, which was significantly higher in 86 23 of prescription medication (PM) and all relevant history of CAM the infected group receiving CsA. In conclusion, cyclosporine dos- 87 24 use, including the interest of the medical team in the supplements. ing regimen and infection modulate the voriconazole exposition and 88 25 Possible interactions between CAM and PM were evaluated by a consequently the fungal growth. Inhibition of CYP3A4-mediated 89 26 clinical pharmacist and a clinical pharmacologist. metabolism of voriconazole and effect of cyclosporine on the inflam- 90 27 Results: Eighty-four patients participated in the study. Eight patients matory process might explain this observation. 81 28 (9.5%) used CAM, 5 (62.5%) of them women. They tend to be Key words: voriconazole, Scedosporium apiospermum, pharmaco- 92 29 more educated (50% of CAM consumers had academic education vs. dynamics, pharmacokinetics, quantitative PCR. 93 30 18.4% in the nonconsumers group (P = 0.061)). Most of consumers 94 31 had free professions (75%) in comparison with 39.5% of the non- 95 32 consumers, although this was not statistically significant (P = 0.22). Adverse Effect Profile of Anti Epileptic 96 33 No differences were found regarding smoking, alcohol consumption Drugs In Persons With Epilepsy In India: A 97 34 and physical activity habits between consumers and nonconsumers. Cross Sectional Study 98 35 We found a potential drug–herb interaction in 50% of the CAM P. Mohan; P. Gupta; M. Tripathi; and Y.K. Gupta 99 36 consumers. Moderate interactions between aloe vera and diuretics, All India Institute of Medical Sciences, New Delhi, India 100 37 aloe vera (as part of Kalgo) and insulin, niacin (vitamin B3), and Background: Epilepsy has an annual incidence of 27.27 and preva- 101 38 pyridoxine (B6 as part of Nephrovite) with calcium channel block- lence of 572.8 per 1 lakh population in India. Half the persons with 102 39 ers and diuretics. These interactions may result with hypoglycemia, epilepsy (PWEs) on antiepileptic drugs (AEDs) experience trouble- 103 40 hyperglycemia, hypokalemia and lower blood pressure. some adverse effects (AEs) with the potential to affect compliance. 104 41 Conclusions: We found a lower prevalence of CAM consumption in AEs may vary among population and with the type of AED used. The 105 42 dialysis patients than is found in other studies in the general popula- study was planned to map the adverse effect profile of antiepileptic 106 43 tion. Still, unawareness of the harm and potential interactions, lack of drugs in north Indian population. 107 44 data sharing between the patient and caregiver might have disastrous Methods: Adult PWEs attending the neurology OPD of a tertiary 108 45 consequences. Therefore, care givers need to inquire their patients care centre in North India were questioned for AEs after the study 109 46 specifically of the use of CAM, especially in populations with chronic was approved by the Institute Ethics Committee. A 19-item Liverpool 110 47 diseases, let alone patients undergoing dialysis. Adverse Effect Profile (LAEP) dataset was administered to all the 111 48 participants. In addition, demographic profile and treatment history 112 49 were captured in separate case record form. The global LAEP score 113 50 Impact of Cyclosporine Dosing Regimen was calculated and the AEs were classified as frequently problematic 114 51 And Infection on Voriconazole (Likert scale 3&4) and rarely problematic (Likert scale 1&2). 115 52 Pharmacodynamics In An Experimental Results: One hundred PWE (mean age 30.8 ± 8.9 y; 43.2% females). 116 53 Model of Cerebral Scedosporiosis Median no of drugs prescribed was 2 (range 1–5). Average Global 117 54 118 B. Lelièvre1,2; C. Abbara1,2; C. Godon1; P. Legras1,2; P. Vandeputte1; LAEP score was 36.1 ± 7.9. Memory loss (68%), anger (68%), 55 119 M. Briet1,2; J.P. Bouchara1,2; and B. Diquet1,2 nervousness (56%), sleepiness (49%) and difficulty in concentration 56 120 1L’UNAM, Angers, France; and 2CHU, Angers, France (41%) were the most frequently problematic AEs. The least problem- 57 121 Cerebral infections with Scedosporium species are associated with atic AEs were blurred vision (2%), trouble with mouth or gums (3%), 58 122 a severe prognosis in immunocompetent and immunocompromised unsteadiness (10%), problems with skin (10%) and dizziness (11%). 59 123 patients. Voriconazole is the first-line treatment for these infections. Loss of libido was reported by 12% male PWEs as a problematic 60 124 However, few data are available about the PK/PD relation of vori- AE. Global LAEP score correlated poorly with the BMI (Pearson 61 125 conazole in this context. In a rat experimental model of cerebral sce- r = 0.055). It increased with the total number of AEDs (P = 0.053). 62 126 dosporiosis, we aimed to investigate how the infection per se and the Conclusion: Presence of frequently problematic AEs in nearly all the 63 127 pharmacokinetic and pharmacodynamic properties of cyclosporine patients suggests a substantial burden of AED related adverse effects 64 128

2015 e7 Clinical Therapeutics

1 in Indian population. Larger studies are needed to assign causality Sprague-Dawley rats received a 50 μ L left intraplantar injection of 65 2 on individual AEDs and their combinations. commercially available 0.4% articaine (combined with epinephrine). 66 3 Local anesthetic effect was determined as achieve cut-off latency by 67 4 the paw withdrawal latency (PWL) measurements at 20 minutes later 68 5 Informed Consent (Ic) In Clinical Trials articaine injection. Group I (local ondansetron group, n = 7); 50 μ L 69 6 (Ct): An Assessment of Understanding By ondansetron was injected in the same area of articaine. Group II 70 7 Patients and Volunteers And Analysis of (systemic ondansetron group, n = 7); 50 μ L ondansetron was injected 71 8 Ic for Substudies With Biological Samples intraperitoneally. Group III (placebo group, n = 7); 50 μ L saline was 72 injected into the same area of articaine. Observers who performed 9 M.A. Gálvez; I. de Pablo; M. Aguilar; A. Revilla; E. Lorente; 73 to PWL measurements were blind to the drug administrations. The 10 M. del Álamo; and M. Serrano 74 data are reported in terms of duration of block. Statistical compari- 11 Clinical Pharmacology Unit, Ramón y Cajal Hospital, Madrid, 75 sons were made using the Mann-Whitney U test. A P 0.05 were 12 Spain < 76 considered statistically significant. 13 Objective: Documenting how patients included in CT and external 77 Results: Locally injected ondansetron significantly decrease in dura- 14 volunteers understand ICs and the reasons for participating in CT. 78 tion of block when compared to systemic ondansetron and placebo 15 Evaluating the IC of sub-studies collecting biological samples accord- 79 group (92 ± 37 min vs. 176 ± 40 min, and 181 ± 28 min respectively). 16 ing to Spanish legislation. 80 Conclusions: We found that ondansetron significantly reduce the 17 Material and Methods: We gave a survey to patients receiving treat- 81 duration of antinociceptive effect of articaine in thermal pain model 18 ment at the clinical trials unit and to external volunteers. These ICs 82 when applied with the same area of local anesthetics. These data 19 were also evaluated by 3 clinical pharmacologists (CPs). CPs also 83 indicate that ondansetron, a selective 5-HT3-receptor antagonist, 20 evaluated how the ICs corresponding to sub-studies involving bio- 84 might serve as a prototype molecule for development of a novel series 21 logical samples fulfilled the requirements described in the 14/2007 85 of antagonist of local anesthetics. Future studies should be carrying 22 Investigation law. 86 out to clarify the effects on Ondansetron on effect of local anesthetics. 23 Results: Fifty-four patients (from 27 CT) and 27 volunteers filled 87 24 the survey. Median age was 54 and 59 years, respectively. Most of 88 25 participants answered they understood correctly what it means to 89 26 participate in a CT and that their participation was voluntary. In both Stopp/Start Criteria 2014: Comparison 90 27 groups, about 65% took the decision after consulting with relatives of Appoach, Pathology and Therapeutic 81 28 and 20% not understood well the risks. For patients, the most fre- Changes 92 29 quent reason for participating was confidence in the physician and for B. Orol; J. Lagunar; J. Sardá; R. Salas; and E. Vargas 93 30 volunteers was the progress in research. Fifty percent of volunteers Hospital Clínico San Carlos, Madrid, España 94 31 commented that IC was too long. The review by the CP detected that: Introduction: the 2008 STOPP/START criteria for optimization of 95 32 65% of IC were too long, 58% contained numerous technical terms drug prescription in elderly patients have been reviewed in 2014. 96 33 and the risk section was excessively long in 35%. About the 20 IC The aim of the present study is to describe the differences between 97 34 for sub-studies (74% of trials), 85% were considered adapted to our the previous version in terms of general structure, relevance of the 98 35 legislation only in some aspects. different pathologies and pharmacologic groups. 99 36 Conclusions: In general, all sections of the IC document were well Materials and Methods: Both the 2008 and 2014 STOPP/START 100 37 understood but many participants did not understand well the risks. criteria have been revised in terms of the established criteria, number 101 38 Outcomes from patients and volunteers were similar except for the of pathologies included and pharmacological groups. The different 102 39 reason for participation: the most frequent reason for patients was criteria within each disease and pharmacological group have been 103 40 confidence in the physician and for volunteers’ progress in research. defined. 104 41 Regarding trials containing sub-studies with biological samples: Results: Fifty-six percent of the STOPP criteria and 53% of the 105 42 Despite the fact there is an increasing number of CT including these START criteria are new. There has been an increase of 16 and 12 106 43 sub-studies, its ICs do not fulfill entirely the 2007 law requirements. STOPP and START criteria, respectively, throughout the differ- 107 44 ent sections of the 2008 article, to which 6 new sections are added 108 45 in the 2014 version (STOPP: Coagulation System, Renal system, 109 46 Antimuscarinic/anticholinergic drug burden; START: Urogenital 110 47 The Reversal Effect of Ondansetron on 111 Local Anesthesia In The Thermal Pain System, Analgesics and Vaccines). The new criteria include 10 new 48 pathologies and 14 new therapeutic groups. The pathologies that 112 49 Model of Rats 113 1 2 1 3 1 summed more criteria in the 2008 version were pain (10), hyperco- 50 S. Apiliogullari ; Z. Ileri ; O. Onal ; S.B. Taylan ; A.O. Saltali ; 114 3 1 agulability (9) and depression (8), with respect to the 2014 version 51 H. Bariskaner ; and J.B. Celik 115 1 that include hypercoagulability (13), pain (12) and arterial hyperten- 52 Selcuk University, Faculty of Medicine, Konya, Turkey; and 116 2 sion (7). The drugs that accumulate more criteria in the 2008 article 53 Selcuk University, Faculty of Dentistry, Konya, Turkey 117 Background: Up to date there is no agent descripted as local anaes- are NSAIDs (14), antiplatelet agents (10) and anticholinergic (8) and 54 in the 2014 version are blood thinners (11), antiplatelet agents (10), 118 55 thetics antagonist that can reverse the local anaesthesia. Ondansetron 119 a 5-HT3 receptor antagonists interfere with both peripheral and spi- NSAIDs (6), and beta-blockers (6). 56 Conclusions: the new STOPP/START criteria have introduced 120 57 nal serotonin effects on nociception. The aim of this study was to 121 examine the effect of ondansetron on thermal antinociceptive effect quantitative and qualitative changes, covering a greater number of 58 pathologies and pharmaceutical groups in consonance with the new 122 59 of local anesthetic when injected into a rat hind paw. 123 Material and Methods: The experimental protocols were scientific evidence with elderly patients. A periodic revision of the 60 criteria is crucial for prescription optimization. 124 61 approved by the Institutional Animal Care and Use Committee. 125 62 126 63 127 64 128

e8 Volume XX Number XX Screening and Recruitment Procedures of Healthy Volunteers In A Phase I Clinical Trial Unit

1 A Computerized System for Reporting published (Ramirez et al. CPT 2010; 87:74–86). We present the 65 2 and Analysis of Incidents, Errors or results of an improved PPLSH in 2014. 66 3 Adverse Events: Results Of 2014 Methods: Fourteen Automatic Laboratory Signals (ALS) (agranulo- 67 3 4 E. Ramírez1,2; A. Martín2; M. Lorente3; C. Vara2; J. Ojeda2; cytosis (neutrophils < 500 mm ), pancytopenia (white blood cell count 68 e3 5 M. Moro2; R. Gómez2; M.J. Asensio2; M.P. Orduña2; and J. Frías1 < 3.5 × 10 /μ L, hemoglobin < 10 g/dL), and platelet count < 50 × 69 e3 e3 6 1Clinical Pharmacology Department, Hospital La Paz-Carlos III, 10 /μ L), thrombocytopenia (platelet count < 20 × 10 /μ L), anemia 70 7 IdiPAZ, Pharmacology and Therapeutics Department, School (hemoglobin < 6.5 g/dL, coagulopathy (prothrombin activity < 14% 71 8 of Medicine, Universidad Autónoma de Madrid, Madrid, Spain; or cephalin ratio × 3ULN), eosinophilia (eosinophils account and 72 9 2Functional Unit Risk Management, Hospital La Paz-Carlos III, percentage > LSN), liver injury (ALAT × 3ULN), pancreatitis (amyl- 73 10 IdiPAZ, Madrid, Spain; and 3Computing Service, Hospital La Paz- ase × 3ULN or lipase × 3ULN), acute kidney injury (creatine > 4 mg/ 74 11 Carlos III, IdiPAZ, Madrid, Spain dL), rhabdomyolysis (creatine-kinase × 5ULN) , hyponatremia (< 122 75 12 Background: Incidents, errors or adverse events affect 10 to 17% mmol/L), hypokalemia (< 2 mmol/L), hyperkalemia (> 7 mmol/L), 76 13 of hospitalized patients; more than half are related to drugs. The and hypoglucemia (< 30 mg/dL)) were monitored at admission and 77 14 Functional Unit of Risk Management (FURM) has developed a during hospitalization of all wards. Patients who died in the emer- 78 15 Computerized System for Reporting Incidents, errors or adverse gency were also included. 79 16 events (SINOIRES for its acronym in Spanish) which is voluntary, Results: At least 4926 patients experienced at least 1 ALS. The 80 17 anonymous and confidential, allowing the analysis through online review of electronic medical records (EMR) showed that no alterna- 81 18 collaboration with Responsible of Clinical Safety (RCS) of the units tive cause (i.e. no non-SADR explanation) for ALS was identified in 82 19 involved. We described the results of the first year of work. 995 (20%) of the patients. After the individual ALS-patient revalu- 83 20 Methods: SINOIRES has been developed as a project of JAVA pro- ation, a total of 702 SADR (14% of those identified after review- 84 21 gramming Struts frame work as a database using Microsoft SQL ing EMR and 71% of those requiring individual patient evaluation) 85 22 Server with functionalities:(i) reporting form, and subsequent consult were identified: agranulocytosis (29 cases), pancytopenia (21 cases), 86 23 by the notifier by an identification code,(ii) information of method, thrombocytopenia (10 cases), anaemia (71 cases), coagulopathy (44 87 24 characteristics and conditions of the system,(iii) management of inci- cases), eosinophilia (29 cases), liver injury (261 cases), pancreatitis 88 25 dents with 3 profiles: administrator, manager and RCS,(iv) communi- (32 cases), acute kidney injury (71 cases), rhabdomyolysis (28 cases), 89 26 cation between users of the system. Procedure: managers (4 FURM´s hyponatremia (52 cases), hypokalemia (23 cases), hyperkalemia (13 90 27 members) access to the notifications assign state (open, in process, cases), and hypoglucemia (18 cases). In order to identify a single 81 28 implementing improvements, closed), priority (high, medium, low), SADR, we had to review the EMR of 7 patients and personally visit 92 29 and assigned 2 or 3 RCS that analyse the notification. Once the 1.4 patients. 93 30 analysis (not visible to the notifier) has been completed, managers Conclusions: The implementation of PPLSH allowed the detection 94 31 decided the actions (visible to the notifier) and together with RSC and diagnosis of 702 SADR. The election of the ALS and the qual- 95 32 monitoring the recommendations. ity of EMR allowed an improvement in the effort to detection and 96 33 Results: SINOIRES received 203 notifications in 2014: medication/ diagnosis of SADR. 97 34 vaccine (63 notifications), continuity of care (18), infrastructure (17), 98 35 diagnostic test (17), patient monitoring and care (16), patient iden- 99 36 tification (13), therapeutic procedure (10), clinical/diagnosis assess- DOSING OF CIPROFLOXACIN IN 100 37 ment (10), rest of phases (39). Were decided 104 systemic actions, UNCOMPLICATED URINARY TRACT INFECTIONS 101 38 1 1 1 1 1 102 of them one generalizable action to improve “the prescription and Z. Tomić ; A. Tomas ; A. Sabo ; M. Mikov ; S. Vukmirović ; 39 1 1 2 103 administration of intravenous paracetamol”. O. Horvat ; B. Milijašević ; and N. Tomic 40 Conclusions: SINOIRES facilitates the notification and the study of 1Department of Pharmacology, Toxicology and Clinical 104 41 incidents, allowing standardization of the procedure in the hospital, Pharmacology, Faculty of Medicine, University of Novi Sad, Novi 105 42 keeping the main features of confidentiality and feedback from the Sad, Serbia; and 2Clinical Center of Vojvodina, Novi Sad, Serbia 106 43 notifier. The system allows knowing the circumstances that favour Introduction and Background: Uncomplicated urinary tract (UTI) 107 44 the occurrence of human errors and system failures, to improve the infections are the commonest bacterial infections in community. 108 45 defences of the organization. Recently ciprofloxacin has become a popular treatment option. 109 46 However, with increasing resistance to ciprofloxacin, adequacy of 110 47 current dosing regimens became questionable. 111 48 A Pharmacovigilance Program from Methods: Ciprofloxacin sensitivity was tested on 4 urinary bacterial 112 49 Laboratory Signals In Hospitalizaed isolates. Pharmacodynamic parameters (minimum inhibitory con- 113 50 Patients: Results Of 2014 centrations (MIC) and postantibiotic effect) were determined. MIC 114 51 115 E. Ramírez1,2,3; H.Y. Tong1; N. Medrano1; M. Muñoz1; values were incorporated with ciprofloxacin pharmacokinetic pro- 52 116 R. hernández1; A.M. Borobia1,2; A.J. Carcas1,2; and J. Frías1,2 file using pharmacokinetic/pharmacodynamic efficacy index, C / 53 max 117 1Clinical Pharmacology Department, Hospital La Paz-Carlos MIC, which is known to correlate with therapeutic response, in order 54 118 III, IdiPAZ, Madrid, Spain; 2Pharmacology and Therapeutics to compare two dosing regimens of ciprofloxacin: 250mg/12h and 55 119 Department, School of Medicina, Universidad Autónoma de 500mg/24h, usually used in treatment of uncomplicated UTI. 56 120 Madrid, Spain; and 3Functional Unit Risk Management, Hospital Results: Urinary concentrations of ciprofloxacin are twice higher 57 121 La Paz-Carlos III, IdiPAZ, Madrid, Spain) after a single 500 mg dose (15, 16) than after a 250 mg one (236 58 122 Background: Adverse drug reactions (ADR) are considered to be and 518 μ g/mL, respectively) and are still high at the end of dosing 59 123 among the leading cause of morbidity and mortality. Detection, diag- interval (23 and 32 μ g/mL). When PK/PD ratios were calculated, both 60 124 nosis and reporting of serious ADR (SADR) have become impor- dosing regimen produced C /MIC values high above the desired 61 max 125 tant components of activities performed in hospitals. A prospective threshold of 10 for all tested bacteria and for both dosing regimens, 62 126 Pharmacovigilance Program from Laboratory Signals (PVPLS) at concentrations stay above the MIC (T> MIC) through whole dosing 63 127 a Hospital (PPLSH) was developed in 2007, method and results 64 128

2015 e9 Clinical Therapeutics

1 interval. Dosing regimen of 500mg/24h showed supremacy over 250 21 articles were identified by review of the references cited in these 65 2 mg/12h producing higher peak concentrations in urine. publications. Articles were selected based on information related to 66 3 Conclusion: The 500mg/24h dose should produce faster eradication antibiotic therapy and OC’s efficacy relationship. All different classes 67 4 rate and slow the development of resistant strains. With the advan- of antibiotics were analyzed, including 40 different antibiotics, which 68 5 tage of higher compliance once daily 500mg ciprofloxacin seems were crossed with 10 OC data, searching for possible interactions 69 6 better option for treatment of uncomplicated UTI. between antibiotics and OC’s and loss or commitment of efficacy. 70 7 The work is part of Republic project No 41012. Results: Most of the analyzed antibiotics decreased the level or 71 8 effect of OC indirectly by altering intestinal flora, remaining a low 72 9 risk of contraceptive failure. However, the main adverse reactions 73 10 Use of Drugs for Malignancy In Eu Vs Non reported with the use of antibiotics include: nausea, vomiting and 74 11 Eu European Countries diarrhea, which could also have interference on the efficacy of 75 12 1 1 1 1 1 OC’s. Furthermore, some antibiotics can modify the level or effect 76 A Sabo ; Z. Tomić ; Z. Sklenar ; B. Milijašević ; O. Horvat ; and of OC’s by affecting hepatic/ intestinal enzymes metabolism or by 13 M. Šramka2 77 P-glycoprotein (MDR1) efflux transporter. 14 1Medical Faculty Novi Sad, Novi Sad Serbia; and 2University of 78 Conclusions: Some potential severe interactions were identified and 15 Saint Elizabeth, Bratislava, Slovak Republic 79 the mechanisms involved were detected. Pharmacy professionals 16 Background and Introduction: Consumption of drugs for malig- 80 play an essential role regarding the communication of information 17 nancy treatment varies between countries. Developed countries 81 to women consuming OC’s that will start antibiotic therapy. Patients 18 have higher allocations for health protection, more resources for the 82 should be advised to add extra precautions during the therapy and 19 treatment of malignant diseases and better access to expensive drugs. 83 for seven days after finish the antibiotic. 20 Material and Methods: The authors have used the available data on 84 21 consumption of anticancer medicines in Serbia, Slovakia and Norway 85 22 during the year 2012. Data, analyzed using Microsoft Excel, are 86 23 expressed in grams of active ingredient per million in one year as Significant Drug-Drug Interaction 87 24 well as in Euro spent for this drugs. Between Zolpidem and Clarithromycin 88 25 Results: Demographic data indicate that mortality due to malignant Y.J. Lee; J.Y. Byeon; S.H. Kim; Y.H. Kim; H.J. Lee; Y. Lee; 89 26 diseases in Slovakia and Norway was 2100 deaths per million inhab- D.H Kim; H.J. Lim; C.G. Jang; and S.Y. Lee 90 27 itants, while in Serbia mortality was slightly higher, 3050 deaths per School of Pharmacy, Sungkyunkwan University, Suwon, Republic 81 28 million inhabitants. In Slovakia 190 million Euros was allocated for of Korea 92 29 drugs for malignancies, or about 37 million Euros per million. In Introduction: Zolpidem is indicated for the short-term treatment of 93 30 Serbia, only 73 million Euros for anticancer medicines, or about 10 insomnia and belongs to a class of medications called sedative–hyp- 94 31 million Euros per million was allocated, what is much less compared notics. Zolpidem is mainly metabolized by CYP3A4. Clarithromycin, 95 32 to the Slovak republic and Norway. Data on consumption of 10 which is used to treat bacterial infections including pneumonia and 96 33 most expensive oncology drugs show that the least of these drugs bronchitis, is known as a potent CYP3A4 inhibitor. Therefore, the 97 34 are consumed in Serbia regard to the consumption in Slovakia and aim of the study was to investigate the effect of clarithromycin on 98 35 Norway. Among them, the most consumed oncology drug in Serbia the pharmacokinetic parameters of zolpidem. 99 36 is , used in the treatment of metastatic breast cancer. For Material and Methods: Twenty-four healthy Korean subjects were 100 37 this indication is also used cheaper , which has the highest volunteered in the our study. All subject received a single 5 mg oral 101 38 consumption among the most expensive drugs in Slovakia. dose of zolpidem after overnight fasting in the control phase. In 102 39 Conclusion: Countries with lower GDP have less availability of the clarithromycin phase, a single 500 mg oral dose of clarithromy- 103 40 anticancer medicines in amount and in quantity. Despite this fact, cin was administered to every subject twice in a day for 5 consecu- 104 41 between the selected countries there are not drastic differences in tive days. Each subject received a single oral dose of zolpidem and 105 42 mortality. Countries with lower GDP, must use wisely oncology drugs clarithromycin on a study day. Blood samples were collected up to 12 106 43 if they want to allocate their resources for treatment of other diseases hours after drug administration and LC-MS/MS was used to validate 107 44 as well. the plasma concentrations of zolpidem. 108 45 The work is part of Serbian Republic project No 41012. Results: AUC of zolpidem in clarithromycin phase increased by 109 46 0-∞ 110 1.66-fold, compared to control phase (P < 0.001). t1/2 of zolpidem in 47 clarithromycin was significantly prolonged after the administration of 111 48 112 Interactions Between Antibiotics clarithromycin (P < 0.001). Also, the apparent oral clearance (CL/F) 49 zolpidem in clarithromycin phase decreased by 34.8%, compared to 113 50 and oral Contraceptives – A Need For 114 Clarification control phase (P < 0.001). 51 Conclusions: Therefore, clarithromycin had significant impacts on 115 52 C. Matos; J. Lopes; J. Joaquim; and T. Pires 116 Instituto Politécnico de Coimbra, Coimbra Health School – the pharmacokinetics of zolpidem, leading to prolong the plasma 53 exposure of zolpidem. 117 54 ESTESC, Farmácia, Coimbra, Portugal 118 55 Introduction: The discussion about the possible interactions between 119 56 oral antibiotics and oral contraceptives (OCs) is not new. However, 120 57 it remains a subject that generates controversy among the scientific Pharmacokinetics of Zolpidem In 121 58 community. There are several mechanisms proposed that explain Relation To Cyp2c19 Genotype After 122 59 these antibiotic-associated interactions. Although the general risk of Administration of Cyp3a4 Inhibitor 123 60 interaction is low, sporadic cases of oral contraceptive failure during Y.J. Lee; J.Y. Byeon; S.H. Kim; Y.H. Kim; H.J. Lee; Y. Lee; 124 61 antibiotic therapy continue to be reported. The objective of this study D.H. Kim; H.J. Lim; C.G. Jang; and S.Y. Lee 125 62 was to determine the effect of the antibiotic therapy in OC’s efficacy School of Pharmacy, Sungkyunkwan University, Suwon, Republic 126 63 and which mechanisms are involved in that process. of Korea 127 64 Material and Methods: Literature search in PubMed and in Google Introduction: Zolpidem is indicated to treat sleeping problems. 128 Scholar. A total of 52 articles were selected for analysis and other Zolpidem is predominantly metabolized to its inactive metabolite

e10 Volume XX Number XX Screening and Recruitment Procedures of Healthy Volunteers In A Phase I Clinical Trial Unit

1 by CYP3A4, and to a lesser extent CYP2C19 and CYP1A2. As The Influence of Electrolyte Status and 65 2 CYP2C19 is highly polymorphic enzyme, we evaluated the effect Concomitantly Used Medications on 66 3 of CYP2C19 genetic variant on the pharmacokinetic parameters of Corrected Qt Intervals In Methadone 67 4 zolpidem. To clarify the effect of CYP2C19 genetic variant on the Maintenance Treatment Patients – A 68 5 pharmacokinetics of zolpidem, CYP3A4 inhibitor was administered Cross Sectional Study 69 6 to every subject. V. Mijatović ; I. Nosek; G. Knezović ; I. Samojlik; and S. Petković 70 7 Material and Methods: Thirty-seven healthy Korean subjects were Faculty of Medicine, University of Novi Sad, Vojvodina, Serbia 71 8 volunteered and divided into three different groups according Introduction: Methadone is a synthetic agonist of opioid receptors 72 9 to CYP2C19 genotype: CYP2C19EM (CYP2C19*1/*1, n = 15), which is used in methadone maintenance tratment (MMT) of opiate 73 10 CYP2C19IM (CYP2C19*1/*2 or CYP2C19*1/*3, n = 11), and addicts. It belongs to a group of medications which can provoke a 74 11 CYP2C19PM (CYP2C19*2/*2, n = 11). Each subject ingested a prolongation of the QTc (corrected QT) interval in the electrocardio- 75 12 single 5 mg oral dose of zolpidem in control phase. After administra- gram (ECG) and thus increase the risk of the development of poten- 76 13 tion of CYP3A4 inhibitor (500 mg clarithromycin) for five days, all tially fatal arrhythmias - torsades de pointes. The aim of the study 77 14 subjects simultaneously ingested a single oral dose of zolpidem and was to assess the influence of the electrolyte status and concomitantly 78 15 clarithromycin on a study day. Blood samples were collected up to used medications on QTc in MMT patients. 79 16 12 hours after drug ingestion. Plasma concentrations of zolpidem Material and Methods: During January 2015, 40 MMT patients 80 17 were evaluated by liquid chromatography-tandem mass spectrom- were recruited from the outpatient MMT centre. ECG (to calculate 81 18 etry system. QTc interval) and blood sampling (to determine potassium, magne- 82

19 Results: Cmax of zolpidem in control phase was not significantly dif- sium and calcium levels) were performed in all study participants at 83 20 ferent according to CYP2C19 genotype. AUC0-∞ was also not signifi- one time point. Patients were also interviewed about their current 84 21 cant different among three groups (194 ± 74.6 ng·hr/mL, 175 ± 67.7 methadone dose, duration of MMT, recent increase in methadone 85

22 ng·hr/mL, and 186 ± 47.9 ng·hr/mL, respectively). Cmax, AUC0-∞, and dose, and other drugs used in combination with methadone. 86 23 apparent oral clearance of zolpidem in test phase were not signifi- Results: Mean QTc interval was 430.66 ± 29.76 ms. Mean levels 87 24 cantly different in relation to CYP2C19 genotype. of potassium, magnesium and calcium were 4.51 ± 0.41 mmol/L, 88 25 Conclusions: There were no significant differences between control 0.87 ± 0.06 mmol/L and 2.40 ± 0.10 mmol/L, respectively. Mean 89 26 phase and test phase in relation to CYP2C19 genotype. methadone dose was 64.74 ± 18.12 mg, while mean duration of 90 27 MMT was 1086.24 ± 1222.78 days. In the univariate analysis, QTc 81 28 correlated significantly with methadone doses and the duration of 92 29 Cyp2d6 Genetic Polymorphism MMT (r = 0.40, P = 0.01 and r = 0.33, P = 0.04, respectively), while 93 30 Has Significant Effects on The no significant correlation was observed between OTc and electrolyte 94 31 Pharmacokinetics of Propranolol levels (r = 0.06, P = 0.75; r = 0.13, P = 0.46; r = 0.06, P = 0.72, 95 32 Y.J. Lee; J.Y. Byeon; S.H. Kim; and Y.H. Kim respectively). Thirty-three patients used methadone in combination 96 33 School of Pharmacy, Sungkyunkwan University, Suwon, with other drugs. The mean number of concomitants was 1.97 ± 97 34 Republic of Korea 1.21. The most commonly used drug was diazepam, taken by 24 98 35 Introduction: Propranolol is a nonselective beta blocker and is used patients. Neither recent increase in methadone dose, nor concomi- 99 36 to treat hypertension, abnormal heart rhythms, and heart disease. tantly used medications influenced QTc (436.25 ± 29.9 vs 427.56 100 37 Propranolol works by relaxing blood vessels and slowing heart ± 29.82 ms, P = 0.41 and 433.55 ± 23.9 vs 415.07 ± 44.13 ms, P = 101 38 rate. Propranolol is metabolized via 4-hydroxylation by CYP2D6. 0.35, respectively). 102 39 As CYP2D6 is highly polymorphic enzyme, we hypothesized that Conclusion: It is highly advisable for health care professionals to be 103 40 CYP2D6 genetic variant could affect the pharmacokinetics of pro- informed about risk factors for the development of arrhythmias in 104 41 pranolol. Therefore, we investigated the effect of CYP2D6 genetic MMT users, particularly in those receiving higher methadone doses. 105 42 polymorphism on the pharmacokinetics of propranolol. Acknowledgement: The Ministry of Education and Science of the 106 43 Material and Methods: Twenty-six healthy Korean subjects were Republic of Serbia (grant numbered 172050) supported this research 107 44 volunteered and divided into 3 different groups according to work. 108 45 109 CYP2D6 genotype: CYP2D6*wt/*wt (*wt = *1 or *2, n = 10), 46 110 CYP2D6*wt/*10 (n = 8) and CYP2D6*10/*10 (n = 8). A single 40 47 mg oral dose of propranolol was administered to every subject, after Drug Intoxications Treated At The 111 48 overnight fasting. Blood samples were collected up to 24 hours after Emergency Center of Clinical Centre of 112 49 drug intake, and plasma concentrations of propranolol were deter- Vojvodina In 2013 113 50 114 mined by using high-performance liquid chromatography. I. Samojlik; Z. Drvendžija; V. Mijatoviæ; S. Petkoviæ; and 51 115 Results: Although t of propranolol was not significant differ- V. Pajtiæ 52 1/2 116 ent, C and AUC of propranolol in CYP2D6*10/*10 group Faculty of Medicine, University of Novi Sad, Vojvodina, Serbia 53 max 0-∞ 117 was 2.30-fold and 2.42-fold higher, respectively than those of Introduction: Intoxications caused by the large number of xenobi- 54 118 CYP2D6*wt/*wt group. Also, apparent oral clearance (CL/F) of otics have become an increasingly important issue in the emergency 55 119 propranolol in CYP2D6*10/*10 group decreased by 59%, compared medicine. In the etiology of 60 to 80% of intoxications are various 56 120 to CYP2D6*wt/*wt group. drugs. The aim of this survey was to determine the incidence and 57 121 Conclusions: In conclusion, CYP2D*10 allele is associated with the characteristics of drug intoxications in 2013 at the territory of South 58 122 decreased plasma exposure of propranolol. Baèka district. 59 123 60 124 61 125 62 126 63 127 64 128

2015 e11 Clinical Therapeutics

1 Materials and Methods: Data were collected from medical records Acknowledgement: The Ministry of Education and Science of the 65 2 of patients hospitalized under suspicion of drug intoxications at the Republic of Serbia (grant numbered 41012) supported this research 66 3 Emergency Centre of Clinical Centre of Vojvodina during observed work. 67 4 period. 68 5 Results: During 2013, 1078 patients were hospitalized under sus- 69 6 picion of drug intoxication, which was confirmed in 47.22 % of Scren: Spanish Research Netwok; one-Year 70 7 them. The largest number of patients was hospitalized in January Experience 71 8 and December, and most of them were females (62.87%). The aver- E. Vargas1; G. Calv-Rojas2; C. Avendaño3; A. Portoles1; 72 9 age age of patients was 40 years. The most commonly found drugs M. Galvez4; J.M. Arnau5; C. Rosso6; F. Torres3; A. Gómez de la 73 10 were benzodiazepines (89.98%), followed by analgesics (23.18%), Camara7; and M. Pavía1 74 11 antiepileptics (14.15%), antidepressants (11.98%) and antipsychot- 1Hospital Clinico Universitario San Carlos, Madrid, Spain; 75 12 ics (10.61 %). All the patients took drugs orally. Suicidal intention 2Hospital Universitari Clinic, Barcelona, Spain; 3Hospital 76 13 of drug intake was recognized in 72.89 % of patients, while 27.11% Universitario Puerta de Hierro, Madrid, Spain; 4Hospital 77 14 of them took drugs accidentally. A majority of patients (76.23%) Universitario Ramón y Cajal, Madrid, Spain; 5Hospital 78 15 coingested drugs with alcohol, while 23.77 % consumed only drugs. Universitario de Bellvitge, Barcelona, Spain; 6Hospital 79 16 Conclusions: Health and education directives are needed in order to Universitario Virgen del Rocío, Sevilla, Spain; and 7Hospital 80 17 prevent drugs intoxications, as a significant medico-social problem. Universitario 12 de Octubre, Madrid, Spain 81 18 Acknowledgement: This work was supported by grant No III41012 Background or Introduction: The Spanish Clinical Research 82 19 of Ministry of Education and Science of The Republic of Serbia. Network (SCReN) is transversal structure with a decentralized 83 20 organization supported by the Spanish institute of health (Instituto de 84 21 Salud Carlos III), and cofinanced by European Union FEDER funds. 85 22 Role of Benzodiazepines In Cardiac As a professional network provides service for the implementation 86 23 Safety of Low Methadone Doses In of cooperative clinical research projects, (national or international) 87 24 Patients During Methadone Maintenance initiated within the integrated sites, co-operative research groups, 88 25 Treatment academic institutions, health authorities and other fundamental play- 89 26 1 1 1 1 90 S. Petković ; V. Mijatović ; I. Samojlik ; S. Vukmirović ; ers on the scene of biomedical research. SCReN is a network of 29 27 A. Dickov1; and T. Popov2 Clinical Trials Units integrated in healthcare centres across Spain at 81 28 1Faculty of Medicine, University of Novi Sad, Vojvodina, Serbia; both hospital and primary healthcare levels. Clinical Pharmacologists 92 29 and 2Institute of Cardiovascular Diseases Vojvodina, Sremska play a central role in running the network and coordinating activities, 93 30 Kamenica, Serbia in close coordination with other healthcare professionals. 94 31 Introduction: Despite the fact that most of health care profession- Material and Methods: During its first year of life (2014) SCReN 95 32 als are aware of possible respiratory depressant effect of methadone core activity was focused on building a solid network structure 96 33 and benzodiazepines coadministration, recently published data reveal • Definition and acceptance of a strategic model with 97 34 that ventricular arrhythmia and cardiac arrest are currently the most four main areas: Coordination; Regulatory and Monitoring; 98 35 frequent adverse event attributed to methadone and benzodiazepine Pharmacovigilance; Statistics and Data Management. 99 36 comedication. The aim of this study is to assess cardiac safety of low • Harmonizationthrough the approval and implementation of 100 37 methadone doses used concomitantely with benzodiazepines in opiate the quality plan (SOPs). 101 38 addicts in methadone maintenance treatment (MMT). • Nodes interconexion by the definition of the technology archi- 102 39 Material and Methods: A clinical trial in which participated 30 opi- tecture model. 103 40 ate addicts at the start of MMT was performed. ECG (to calculate • Capacitation of the network. 104 41 corrected QT (QTc) interval) and blood sampling (to determine 105 42 methadone and diazepam concentrations​​) were performed in all Results: The resources and efforts invested in the development of the 106 43 study participants at 3 time points (before the introduction of MMT, infrastructure enabled the network to conduct 19 clinical trials, with 107 44 after 1 and 6 mo of MMT). Methadone and diazepam concentra- a total of 219 individual sites collaboration. Additionally, the execu- 108 45 tions in serum were determined by using liquid chromatography-mass tive committee identified 10 high quality trials to be initiated in 2015. 109 46 spectrometry (LC-MS). Conclusions: SCReN was born with the aim to empower the devel- 110 47 Results: The length of QTc interval before the introduction of MMT opment of clinical trials providing a professional network focused 111 48 was 411.87 ± 27.22 ms, after 1 month of MMT 425.20 ± 17.71 ms on no commercial research. SCReN successfully make the first step 112 49 and after 6 months of MMT 423.50 ± 14.72 ms. The mean metha- in achieving our goals with the inclusion of 19 complex clinical tri- 113 50 done concentration at observed time points was 176.77 ± 118.56 als, providing infrastructures to guarantee and preserve the quality 114 51 ng/mL and 342.86 ± 181.54 ng/mL, respectively, while the mean of the studies, the patient safety and data reliability. 2015 will be the 115 52 diazepam concentration was 560.74 ± 436.72 ng/mL and 1045.32 ± consolidation year, when the project related activity would increase. 116 53 932.72 ng/mL, respectively. There was a statistically significant 117 54 increase in the length of QTc interval after 1 and 6 months of MMT 118 55 in comparison to the value before the application of MMT. A statisti- Commercial Movies To Teach Non-Medical 119 56 cally significant correlation between the concentration of methadone And Undesirable Use of Drugs 120 57 and QTc interval length after 1 and 6 months of MMT was observed J. Mateus1,2,3; C. Pérez-Mañá1,2; E. Papaseit1,2; A. Farré2,3; 121 58 and it remained statistically significant if concentration of diazepam L. Galindo2,3; M. Torrens2,3; E. Montané2,4; A. Barriocanal2,4; 122 59 was included. J.E. Baños5; and M. Farré1,2,4 123 60 Conclusions: Further studies could clarify the possible role of ben- 1Hospital del Mar Medical Research Institute-IMIM, Barcelona, 124 61 zodiazepines in the increasing cardiotoxicity of methadone in opiate Spain; 2Universitat Autònoma de Barcelona-UAB, Barcelona, 125 62 addicts in MMT. Spain; 3Institut de Neuropsiquiatria i Adiccions-INAD-IMIM. 126 63 Hospital del Mar, Barcelona, Spain; 4Hospital Universitari 127 64 128

e12 Volume XX Number XX Screening and Recruitment Procedures of Healthy Volunteers In A Phase I Clinical Trial Unit

1 Germans Trias i Pujol, Institut d’Investigació en Ciències de la complied within 30 days. 6) Accreditation of principal investigators 65 2 Salut Germans Trias i Pujol, Badalona, Spain; and 5Universitat (PIs), IECs and the trial sites has been recommended to ensure com- 66 3 Pompeu Fabra-UPF, Barcelona, Spain petence. To ensure adequate trial supervision, number of trials per 67 4 Introduction: The use of commercial films to illustrate a health prob- investigator is being restricted. This regulatory overhaul highlights 68 5 lem is a common experience in university teaching of health sciences. the national commitment to patient safety, ethics and confidential- 69 6 The objective was to illustrate nonmedical or undesirable use of drugs ity. However, there is some apprehension regarding some grey areas. 70 7 using different commercial films in teaching of clinical pharmacology. Once, more clarity emerges, it is envisaged that clinical research in 71 8 Materials and Methods: We selected the following non-medical India will quickly scale up in a much safer, regulated and enabling 72 9 and undesirable uses: chemical submission, induction of addiction, environment. 73 10 poisoning, lethal injection (death penalty), improved sexual perfor- 74 11 mance, neuroenhancement (smart drugs) and drugs and crime. Search 75 12 for movies that had scenes corresponding these uses were collected The Analyze of Consumption of 76 13 using the New York University’s School of Medicine (NYU) litera- Drugs for the Treatment of Chronic 77 14 ture, arts and medicine database, and the Film Affinity and Internet Respiratory Diseases In The Republic of 78 15 Movie Databases (IMDb). In addition we used our own archives and Serbia, Croatia, Norway And Finland 79 16 memories to select the adequate movies. From 2009 To 2012 80 17 Results: We chose the following movies to illustrate such use: Seeking B. Milijasevic; A. Novkovic; Z. Tomic; D. Milijasevic; 81 18 Miguel (2007) for chemical submission, Revenge (1990 for the induc- 82 A. Rašković ; N. Tomic; and N. Stilinovic 19 tion of addiction, Murder my sweet (1944) for poisoning, Dead Man Department of Pharmacology, Toxicology and Clinical 83 20 Walking (1995) for lethal injection, Something’s Gotta Give (2003) Pharmacology, Faculty of Medicine, University of Novi Sad, 84 21 for the use of drugs enhancing sexual performance, Limitless (2011) Republic of Serbia 85 22 for neuroenhancement, and Zulu (2013) for drugs and crime. For Introduction: Chronic respiratory diseases, including asthma and 86 23 each film we redacted a list of learning objectives and a list of ques- chronic obstructive pulmonary disease (COPD), were responsible for 87 24 tions that could be answered by the students the end of the session. 4 million deaths globally in 2012. Drugs for the treatment of chronic 88 25 We have introduced some of films in seminars of clinical pharmacol- respiratory diseases are often used group of drugs. 89 26 ogy and drug addictions. Aim: The aim of this study was to analyze consumption of drugs 90 27 Conclusions: It is concluded that the films are of interest to illustrate for the treatment of chronic respiratory diseases in the Republic of 81 28 how dugs (medicines) could be misused or abused. We think that Serbia, Croatia, Norway, and Finland from 2009 to 2012. 92 29 the films can demonstrate the toxicological interest, usage patterns, Material and Methods: Data about use of drugs were taken from the 93 30 consequences of their use and the ethical connotations that produce Agency for drugs and medical devices of Serbia, Agency for medicinal 94 31 such practices in the domain of medicine and clinical pharmacology. products and medical devices of Croatia, Finnish Medicines Agency 95 32 Acknowledgements: Clara Pérez-Mañá, Esther Papaseit and Liliana Fimea and Norwegian Institute of Public Health. 96 33 Galindo are Rio Hortega fellowship (Instituto de Salud Carlos Results: Drugs which are used in therapy of respiratory diseases 97 34 III-SCIII, CM12/00085, CM13/00016, CM14/00111). are, in Serbia, in the sixth place, in Croatia in the fifth, in Norway 98 35 and Finland they are in the fourth place of total consumption of 99 36 drugs for the period that we observed. In all of the 4 countries the 100 37 Recent Developments In Clinical Trial highest consumption of drugs is the one that is used in therapy of 101 38 Regulations In India chronic obstructive pulmonary disease (R03 group). The most used 102 39 Y.K. Gupta; P. Gupta; and P. Mohan drugs from this group in Serbia and Croatia are Xanthines but in 103 40 Dept of Pharmacology, All India Institute Of Medical Sciences, Norway and Finland those are the drugs of new generations-R03AK 104 41 India (Adrenergics in combination with corticosteroids or other drugs, 105 42 Clinical research was rapidly growing in India because of cost advan- excluding anticholinergics). 106 43 tage, treatment naïve patient, qualified doctors conversant in English Conclusion: The drugs are unequally used in therapy of respiratory 107 44 etc. However isolated unethical incidences resulted in trust deficit diseases in the mentioned countries. In the first place are the drugs 108 45 amongst stake holders. The fluid situation lead to a sharp decline in in therapy of COPD. In Serbia and Croatia the most used drugs of R 109 46 trials during last three years. India accounts for 20% of global disease group are much different in regard to Norway and Finland. 110 47 burden but hosted only 1.5% of global clinical trials in the past 2 Acknowledgement: This research was supported by Provincial 111 48 years. A series of corrective measures, some due to judicial interven- Secretariat for Science and Technological Development, Autonomous 112 49 tion, lead to sweeping changes in drug regulatory scenario. These Province of Vojvodina project No 114-451-2458/2011 and by 113 50 directives include 1) Mandatory registration of clinical trials from Ministry of Science, Republic of Serbia, project no 41012 114 51 February 2013. 2) Compulsory audio–visual recording of informed Key words: COPD, consumption of drugs, pharmacoepidemiol- 115 52 consent process since Jun 2013. 3) Registration of Institutional Ethics ogy 116 53 Committees (IEC) since Februrary 2013. IECs have to monitor and 117 54 report serious adverse events (SAEs) under strict timelines and opine 118 55 on compensation. 4) The drug regulator (DCGI) is required to for- 119 56 Regulatory Guidelines for The 120 ward the reports by investigators, sponsors and ethics committees Development of Topically Applied 57 to the national expert committee within 150 days of SAE occur- 121 58 Products In Atopic Dermatitis and 122 rence. This committee has to analyse and give final recommendations Psoriasis 59 regarding causality and compensation. 5) Financial compensation 123 R. Vives Vilagut; and C. Pontes 60 for trial related injuries or death, calculated as per a comprehensive 124 Universitat Autònoma de Barcelona, Barcelona, Spain 61 formula, is now a mandatory responsibility of sponsor. The formula 125 Background: Obtaining an early proof of activity is one of the 62 ensures that younger participants get more compensation as com- 126 key milestones in drug development. The early development of 63 pared to older participants. The final order of the DCGI has to be 127 64 products for the topical treatment of dermatological inflamma- 128

2015 e13 Clinical Therapeutics

1 tory diseases such as atopic dermatitis (AD) and Psoriasis (P) share expected and reversible. Adverse reaction were usually disappeared 65 2 particularities that make them different from standard development spontaneously or after short-term symptomatic therapy. 66 3 of drugs administered by systemic routes, not only in the early clinical Acknowledgement: This research was supported by Provincial 67 4 development phase but also in the preclinical data required at each Secretariat for Science and Technological Development, Autonomous 68 5 stage of the development. On the other hand, paediatric aspects of Province of Vojvodina project No 114-451-2458/2011 and by 69 6 product development are key in AD. Ministry of Science, Republic of Serbia, project no 41012. 70 7 Material and Methods: In order to conclude recommendation on the Key words: prednisone, dexamethasone, acute lymphoblastic leuke- 71 8 most eficient development approach for early development of topi- mia, adverse effects, children. 72 9 cal treatments for AD and P we reviewed the existing information 73 10 through a search for existing regulatory guidelines from EMA, FDA 74 11 and other national medicines agencies. Anti-histone antibodies in HIV-infected 75 12 Results: We selected 24 regulatory documents including guidelines patients on Nevirapine-containing 76 13 (adopted (N = 8) or draft (N = 4)), questions and answers (Q&A) ANTIRETROVIRAL THERAPY 77 14 documents (N = 4) and concept papers (N = 2) which might con- S.A. Pereira1; A.M.M. Antunes2; C.G. Dias1; A.T. Marinho1; 78 15 tribute with information to guide the development of topical NCE S.G. Harjivan2; M. Fonseca1; S. Maia1; T. Branco3; U. Caixas1,4; 79 16 for the treatment of AD or P. Of these, 6 guidelines and 2 Q&A M.M. Marques2; and E.C. Monteiro1 80 17 document referred specifically to locally applied products, of which 4 1CEDOC, NOVA Medical School, Lisbon, Portugal; 2Centro de 81 18 documents referred to dermatological products. Most guidelines (14) Química Estrutural, Universidade de Lisboa, Lisbon, Portugal; 82 19 covered general preclinical requirements. Only one disease specific 3Hospital Prof. Doutor Fernando da Fonseca, Amadora, Portugal; 83 20 guideline was found focused on psoriasis although specific guidelines and 4Centro Hospitalar de Lisboa Central, Lisbon, Portugal 84 21 for 2 other dermatological pathologies were reviewed. Paediatric Background: The anti-HIV drug Nevirapine (NVP) has been associ- 85 22 aspects of development of topical treatments for AD were not spe- ated with severe liver and skin toxicity. NVP bioactivation in man leads 86 23 cifically addressed. to the formation of electrophilic metabolites that generate covalent 87 24 Conclusions: There is little information available to guide the devel- adducts with proteins (1), a mechanism proposed to be at the genesis 88 25 opment of topical dermatological products for the treatment of AD of NVP toxicity. These results, combined with our reports of NVP- 89 26 and psoriasis. Because recommendations are disperse, and lacking for induced epigenetic alterations in rat(2) and in vitro evidence of histone 90 27 some development aspects, a systematic approach to create specific adduct formation (3), led us to screen anti-histone antibodies(AHA) in 81 28 guidance to development in AD and P may be useful. patients and explore their relationship with NVP metabolites. 92 29 Methods: This study was approved by the Hospitals’ Ethics 93 30 Committees and subjects have signed an informed consent. A com- 94 31 Tolerability of Prednisone and parison was performed between AHA titres in 2 cohorts of patients: 95 32 Dexamethasone In Children With Acute naïve versus treated with NVP for more than 12 weeks. Moreover, 96 33 Lymphoblastic Leukemia we explored the association between the concentrations of NVP 97 34 1 1,2 3 3 98 A. Rašković ; B. Rakić ; J. Kolarović ; N. Konstantinidis ; and metabolites and AHA titres. A prospective exploratory study 35 B. Milijasevic1; M. Mikov1; and A. Sabo1 (weeks 0, 2 and 12) was also conducted to investigate AHA titres in 99 36 1Department of Pharmacology, Toxicology and Clinical patients initiating treatment with NVP (200mg PO qDay for 2 weeks 100 37 Pharmacology, Faculty of Medicine, University of Novi Sad, and 400mg PO qDay thereafter). The concentrations of NVP and 101 38 Republic of Serbia; 2European University-Faculty of Pharmacy, its phase I metabolites were quantified by HPLC (4) and IgG class 102 39 Novi Sad, Republic of Serbia; and 3Institute for Children and autoantibodies to histone H2A-H2B dimers by ELISA. 103 40 104 Youth Health Care, Vojvodina, Novi Sad, Republic of Serbia Results: AHA titres were higher in naïve patients [n = 29, 15 (10-22) 41 105 Introduction: Therapy of acute lymphoblastic leukemia includes the U/mL] than in patients on chronic NVP use [n = 37, 10 (5-15) U/mL, 42 106 use of high doses of glucocorticoides (prednisone and dexametha- P = 0.0084]. Patients with undetectable 2OH-NVP had higher AHA 43 107 sone), which significantly increase the success of therapy because of [n = 14, 15 (12-18) U/mL] than those with detectable concentrations 44 108 its limphocitolitic. [n = 23, 9 (4-14) U/mL, P = 0.007]. AHAs were inversely correlated 45 109 Aim: The aim of the study was to determine tolerability of high doses with the concentration of 2OH-NVP (r = −0.5776, P = 0.0049). 46 110 of prednisone and dexamethasone in children with acute lymphoblas- AHAs (n = 8) in weeks 0, 2 and 12 were respectively 20 (16-21); 47 111 tic leukemia and the structure and the intensity of adverse effects, 4 (3-5) (P = 0.0001) and 17 (14-20) U/mL. 48 occurred following these medicines. Conclusions: Low doses of NVP caused a rapid but short-lasting 112 49 Material and Methods: In a prospective study, histories of the chil- decrease in AHAs. In chronic treatment with therapeutic doses, 113 50 dren suffering acute lymphoblastic leukemia treated in the Institute AHAs were negatively associated with the 2OH-NVP levels in a 114 51 for Child and Youth Health Care of Vojvodina, since December 2010 dose-dependent manner. The significance of these findings is pres- 115 52 until October 2014, were analyzed. This study includes 18 patients, ently unknown and warrants further investigation. 116 53 aged from 2 to 15 years. 117 54 Results: Hyperglycemia appeared in 89% of patients treated with 118 55 119 prednisone and in 61% of patients treated with dexamethasone. To References 56 control the high blood glucose above 10 mmol/L, in 11% of patients 120 57 1. Caixas et al., Toxicology 2012;301:33–92. 121 insulin was used. Hypertension appeared in 28% patients treated 2. Pereira et al, Environ Mol Mutagen, 2010;51:699. 58 with prednisone and dexamethasone. Antihypertensives were needed 122 59 3. Harjivan, et al, 248th ACS National Meeting, USA, TOXI-136, 2014. 123 for regulation in 11% patients. Hypopotassemia and hypocalcaemia 4. Marinho et al., Anal. Methods, 2014;6(5):1575–1580. 60 were significantly more expressed after the use of prednisone in com- 124 61 125 parison to dexamathasone. In 11% of patients, the treatment with Acknowledgments: FCT, Portugal (RECI/QEQMED/0330/2012), 62 126 dexamethasone caused depressive behavior, followed by agitation. (IF/01091/2013/CP1163/CT0001). 63 Conclusion: Adverse effects of dexamethasone and prednisone, 127 64 administered in high doses in children with ALL, were known, 128

e14 Volume XX Number XX Screening and Recruitment Procedures of Healthy Volunteers In A Phase I Clinical Trial Unit

1 Post-Anesthetic Apnea Predictive of tablets and 3 Abilify® ODT) under fasting conditions. Seventy-five 65 2 The Terminal Phase of A Convulsive subjects (48 male and 27 female) received tablets and 90 subjects 66 3 Encephloptahy With A Chromosome (49 male and 41 female) received ODT. Plasma concentrations were 67 4 1q21.1 Micro-Duplication measured by HPLC coupled to mass spectrometry. The pharmacoki- 68 5 A. Coquerel1,2; J. Bourgine1; A. Arion3; J. Alexandre1,2; netic parameters were calculated by a non-compartmental method 69 6 N. Letouzé1,2; M. Sassier1; A.S. Diependaele5; M. Gérard6; using WinNolin program and adjusted for weight. The difference 70 7 M. Jokic4; and S. Fedrizzi1,2 between pharmacokinetics data of tablets versus ODT, and male 71 8 1Service de Pharmacologie, CHU de Caen, France; 2Centre versus females were compared by T test using SPSS. 72 9 Régional de pharmacovigilance, CHU de Caen, France; 3Pédiatrie, Results: Pharmacokinetics data were similar for both formulations: 73 10 CHU de Caen, France; 4Réanimation Pédiatrique, CHU de Caen, 74 11 France; 5Néonatalogie, CHU de Caen, France; and 6Génétique Pharmacokinetic Data 75 AUC C T T 12 médicale, CHU de Caen, France 0-t max max 1/2 76 13 In postoperative periods apnea can be attributed to excessive doses Tablets 10580.41 (2427.73) 320.57(81.46) 3.00 (1-12) 55.50 (25.63) 77 ODT 10551.64 (2417.67) 324.02 (76.97) 3.00 (1-12) 54.21 (30.27) 14 of opioids and/or sedative drugs or pharmacokinetic or pharmacody- Tablets Male 10845.37 (2249.66) 324.11 (84.25) 3.38 (2.42) 52.64 (21.80) 78 15 namic abnormalities, or even dosing errors. Generally the frequency Tablets Female 10109.36 (2695.57) 314.27 (77.41) 3.12 (2.00) 60.60 (31.13) 79 16 ODT Male 10933.79 (1999.43) 338.54 (68.47)* 3.06 (2.23)* 49.44 (30.99) 80 and respiratory rate are returned to normal after a short time with ODT Female 10094.93 (2795.61) 306.67 (83.61) 4.02 (2.33) 59.92 (28.73) 17 help of naloxone administration. Bioavailability tablet vs ODT 81 18 Ratio (90%CI) 100.46 102.42 106.89 93.48 82 Clinical History: Third child in a family without inbreeding nor (93.16-108.34) (95.93-109.36) (89.17-126.30) (84.18-103.81) 19 hereditary disease. Pregnancy and birth were normal. Apgar’s scores: 83 20 10 all the time. Weight, size, and cranial perimeter were normal. For *P < 0.05 84 21 the third month there was a major psychomotor retardation with 85 The results only showed differences in C and T between 22 convulsive encephalopathy. He had amblyopia with major altera- max max 86 males and females for orally disintegrating tablets formulation. 23 tion of visual and auditory evoked potentials. At 5 years old, a MRI 87 Conclusion: Bioavailability of both formulations, standard and 24 displayed diffuse cortico-subcortical atrophy, major lesions of puta- 88 orally disintegrating tablets of Abilify® were similar. There were no 25 men and thalamus. MR spectrometry: increase in lactate in putamen, 89 gender differences in pharmacokinetics for tablets. Only appeared 26 and fluctuations in N-acetyl aspartate decreased in putamen and 90 differences for ODT formulation, C was higher in males than 27 increased in parietal–occipital cortex. De novo genetic abnormality max 81 females and T is higher in females than males and higher than 28 could be characterized: microduplication (1.2–3 Mb) in chromo- max 92 tablets formulation. 29 some 1q21.1. Epilepsy was treated with valproic acid 520 mg/d, 93 30 Gabapentin 1000 / day, Levetiracetam 900 mg/d (usual doses for the 94 31 weight). The child had few surgical interventions for gastrostomy 95 32 and dental extractions. Epidural Methylprednisolone Versus 96 33 Last anesthesia was made by sufentanyl and propofol; 1 hour after Transdermal Fentanyl In Treatment 97 34 lack of spontaneous breathing despite the injection of naloxone. He and Prevention Complication of Acute 98 35 suffered of episodes of hypoventilation with hypercapnia but can Herpetic Lesion 99 1 1 36 be slowly weaned respirators; and returned home at postoperative A. Josef ; and H. Ahmed 100 1 37 D6; the days after appeared anarchic respiration and he was again Faculty of medicine, Minia University, Minia, Egypt 101 38 admitted to pediatric intensive care. The neurological exploration Background: Herpes zoster (HZ) results from reactivation of var- 102 39 confirms the failure of the respiratory drive. His status gradually icella-zoster virus and spreads from a single ganglion to the neural 103 40 worsens and the child died 6 weeks later. Postoperative apnea was tissue of the affected segment and the corresponding cuteneous der- 104 41 considered not related to epileptic equivalents and neither linked to matome. Currently, there are no preventative drug treatments for HZ 105 42 opiate or sedative overdose. or postherpetic neuralgia (PHN), and although some treatments are 106 43 Conclusion: several weeks before the final brainstem failure drug available, pain control is often difficult and unsatisfactory. 107 44 induced apnea revealed the final phase of this encephalopathy whose Patients and Method: This study was performed on 40 outpatients 108 45 etiology remains unknown. suffering from acute herpetic pain below dermatome L1 and skin 109 46 rash. They were classified into 2 groups (group D, group E) accord- 110 47 ing to regimen of treatment as following. Group D received acyclo- 111 48 Comparative Bioavailability of vir with gabapentine with fentanyl trandermal patch 75 µg every 112 49 Aripiprazole Tablets and Orally 3 days for 14 days. Group E received acyclovir with gabapentine 113 50 Disintegrating Tablets In Young Healthy with epidural injection of bupivacaine 6 to 12 mL (0.25%) with 40 114 51 Volunteers mg methylpredinisolone as 3 separate injection for 14 days. In both 115 52 groups, patients followed up by the Wong/Baker faces rating scale 116 M. Román; D. Ochoa; A. Rivas; C. Belmonte; and F. Abad-Santos 53 for pain assessment, and if the pain was continuous after 14 days, the 117 Hospital Universitario de la Princesa, Instituto Teófilo Hernando, 54 treatment was continuous until pain sensation disappeared. 118 Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain 55 Results: In group E, there were no significant changes regarding 119 Introduction: Aripiprazole is a third-generation antipsychotic used 56 analgesic effect when comparing first day pain score with that of 120 in the treatment of schizophrenia and moderate to severe manic epi- 57 fourth day. On other hand, there is a significant change between 1st 121 sodes in bipolar I disorder and for the prevention of a new manic 58 day score and that of the 15th day, 1st, 3rd and 6th months. In group 122 episode in patients who experienced predominantly manic episodes 59 D, there was significant change between first day score and that of 123 and whose manic episodes responded to aripiprazole treatment. The 60 fourth day, 15th day, first, third and sixth months. The incidence of 124 aim of our study was to compare the bioavailability of tablets and 61 PHN is high in group D (40%) as compared with group E (10%). 125 orally disintegrating tablets (ODT), both in men and women. 62 Conclusions: We concluded that regimen used in group D provides 126 Methods: The study population included 167 healthy volunteers 63 an adequate analgesia but carries high risk of developing PHN; on 127 receiving 10 mg aripiprazole in 6 single dose clinical trials (3 Abilify® 64 128

2015 e15 Clinical Therapeutics

1 other hand, regimen used in group E provided inadequate analgesia £800m, of which primary care accounted for approximately £569m. 65 2 but carries low risk of developing PNH. Considerable variation was observed in primary care spend across the 66 3 geographical regions. We examined trends in primary care expendi- 67 4 ture in the 22 regions to determine whether any of the variation 68 5 An Educational Intervention To Improve in prescribing might be associated with differences in deprivation 69 6 Antibiotic Use In The Center Region of measures between regions. 70 7 Portugal Methods: Annual primary care drug usage data (measured as cost 71 per 1000 prescribing units [PUs]) for the 22 regions were obtained 8 F. Roque1,2,3; A. Teixeira-Rodrigue2,4; L. Breitenfeld1; 72 for the period June 2004 to March 2014. Deprivation rank was 9 A. Figueiras5; and M.T. Herdeiro2,6 73 obtained from the Welsh Index of Multiple Deprivation 2014. Trend 10 1Health Sciences Research Centre, University of Beira Interior 74 in expenditure was determined using linear regression analysis and 11 (CICS/UBI; 2Research Unit for Inland Development, Polytechnic 75 the slopes of the regression lines (as well as absolute expenditure for 12 of Guarda (UDI/IPG); 3Institute for Research in Biomedicine – 76 2013–2014) ranked and correlated with deprivation for each region 13 iBiMED & Health Sciences Program, Aveiro, Portugal; 4Faculty 77 using Spearman’s correlation analysis. 14 of Pharmacy, University of Coimbra, Portugal; 5Consortium for 78 Results: The trends in expenditure for the 22 regions ranged from 15 Biomedical Research in Epidemiology & Public Health (CIBER en 79 –£3106 per 1000 PUs per year to £229 per 1000 PUs per year. There 16 Epidemiología y Salud Pública – CIBERESP), Spain; and 6CESPU, 80 was significant positive association between trend in expenditure 17 Instituto de Investigação e Formação Avançada em Ciências e 81 and deprivation (Spearman’s rho 0.50, P 0.018). There was 18 Tecnologias da Saúde, Gandra, Portugal = = 82 also a significant relationship between expenditure for the financial 19 Background: Microbial resistances are one of the most important 83 year 2013–2014 and deprivation index (Spearman’s rho 0.56, P 20 problems of public health, and it has been associated to the misuse = 84 0.007). 21 of antibiotics. Inadequate antibiotic prescription and self-medication = 85 Conclusions: This analysis indicated that although deprivation 22 (with antibiotic leftovers or by acquiring antibiotics directly in the 86 appeared to be related both to absolute primary care expenditure 23 pharmacy without a prescription), are behaviours directly related 87 and the trend in expenditure between geographical regions of Wales, 24 with this misuse, revealing the necessity of interventions directed 88 other factors may also be associated with variation in prescribing 25 to health professionals. The aim of this study is to improve the con- 89 costs and trends. Further work is needed to ascertain the nature of 26 sumption of antibiotics through an educational intervention directed 90 these factors and their relative influence. 27 to community pharmacists and primary care physicians. 81 28 Material and Methods: A cluster randomized trial in the region 92 29 center of Portugal. Of the 8 clusters, 4 clusters received an educa- 93 30 tional intervention and the other four clusters did not received any Off-Label Prescriptions In Palliative Care 94 31 intervention and were included in the control group. Educational Patients At Home Care Unit* 95 32 intervention consisted of group sessions with physicians and group E. Oliete Ramírez1; E. Rubio Gomis2,3; and I. Martínez Mir3 96 33 sessions with pharmacists. In the sessions groups it was presented 1Fundación Instituto Valenciano de Oncología, Valencia, Spain; 97 34 information about the problem of microbial resistances and each 2Universitat de Valencia, Valencia, Spain; and 3Consorcio Hospital 98 35 sessions was focused in the identified attitudes that influence the General Universitario de Valencia, Valencia, Spain 99 36 behaviour of physician during antibiotic prescription or the behav- The use of off-label drugs is considered to be frequent. This study 100 37 iour of pharmacist during the dispensation of antibiotics in pharma- aims to describe and to quantify the off-label use of drugs prescribed 101 38 cies. At the end of each group session, were distributed flyers and to palliative-care patients just before admission in a Home Care Unit 102 39 poster about the importance of the adequate use of antibiotics to be and explore the motives of off-label use. The secondary aim was to 103 40 divulgated to the patients. The data of antibiotics consumption was study if the off-label prescriptions were according to the most used 104 41 compared between the intervention group and the control group. guides in our environment (we tried four of them). 105 42 Results: The intervention was well received for the pharmacists and Methods: A cross-sectional study was carried out. Informed consent 106 43 for the physicians included in the study. Comparing the consumption was obtained from patients admitted to 20 beds at a Home Care 107 44 of antibiotics between the two groups, it was observed a decrease in Unit for a 6 month period. Demographic and anthropometric char- 108 45 the total consumption of antibiotics in the intervention group during acteristics, clinical background, current disease, and prescriptions 109 46 12 months of the follow-up period after the intervention was made. just before admission were registered. Medications were analysed to 110 47 Conclusions: It was possible decrease the consumption of antibiotics determine whether they had been used according to the terms of the 111 48 through an educational intervention directed to community pharma- summary of product characteristics (SmPc). 112 49 cists and primary care physicians. Results: Eighty-seven patients (52 women) were included; mean 113 50 age 67,2; IC95% 64, 4–70,1. They received 678 prescriptions (315 114 51 different pharmaceutical products). Patients received from 2 to 15 115 52 116 (mean = 7.8) medications for treating 553 health problems (113 53 Analysis of Primary Care Medicines 117 Expenditure In Relation To Measures of different diagnoses). Opioid analgesics were the most commonly 54 used drugs according to the pain which was suffered by 86.2% of 118 55 Deprivation In Wales Uk 119 1,2 1 1,2 the patients. One hundred eight prescriptions (15.9%) involving 67 56 P.N. Deslandes ; K.E. Haines ; and P.A. Routledge 120 1 (77.0%) patients were off-label due to their use in disagreement with 57 All Wales Therapeutics and Toxicology Centre, Llandough, 121 United Kingdom; and 2Cardiff University, Cardiff, the indications authorised in the SmPc. Ten medications affecting 7 58 patients were off-label due to the lack of SmPC. The prophylaxis of 122 59 United Kingdom 123 Background: The National Health Service in Wales (UK) provided ulcer by proton pump inhibitors and the palliative care in patients 60 with terminal cancer by corticosteroids were the most frequently used 124 61 healthcare to a population of approximately 3.1 million during the 125 financial year 2013 to 2014. Services were delivered by 7 health off-label drugs. According to the 4 guides included in this study, just 62 24 of the off-label prescriptions were not suggested by the authors. 126 63 boards (subdivided into 22 geographical regions) and 1 hospital 127 64 trust. The combined routine drug expenditure was approximately 128

e16 Volume XX Number XX Screening and Recruitment Procedures of Healthy Volunteers In A Phase I Clinical Trial Unit

1 Conclusion: Off-label use is a common practice in palliative care smaller doses. Frequency of hypoglycaemic episodes was not signifi- 65 2 patients and is clearly shown by the gold-standard guides used in our cantly different between the groups. 66 3 environment. *Supported by the Conselleria de Sanitat. Generalitat 67 4 Valenciana (CP-2/10). 68 5 Estimated Prevalence of 69 6 Contraindicated, Severe and Moderate 70 7 Cyp2c9 Genotype and Clinical Effects of Interactions In Ambulatory Patients With 71 8 Gliclazide Polypharmacy In A Healthcare Provider 72 9 M. Abulula; V. Baranov; N. Vorokhobina; and K. Zagorodnikova In Uruguay 73 10 North-Western State Medical University n.a.I.I.Mechnikov J. García1,2; M. Vaz1; and M. Poggi1 74 11 Introduction: Gliclazide is an oral antidiabetic agent. It belongs to 1Mutualista Hospital Evangélico, Montevideo, Uruguay; and 75 12 sulfonurea derivatives and may be used as a second choice agent. It 2Facultad de Medicina CLAEH, Punta del Este, Uruguay 76 13 is known to be metabolized by cytochromes P450 (CYP) 2C9 and In this paper we present an estimate of the prevalence of contrain- 77 14 2C19. Clinical data showing influence of genetic polymorphisms dicated, severe and moderate interactions in ambulatory patients 78 15 on patient’s individual outcomes are scarce. We evaluated effects of in a healthcare provider in Uruguay. We also present the most 79 16 CYP2C9*2 and CYP2C9*3 polymorphisms on clinical response to problematic drugs in this population, which will be used to make 80 17 gliclazide in Russian diabetic patients. interventions to inform the results to the medical staff. In Uruguay, 81 18 Material and Methods: Seventy-four patients who were diagnosed healthcare providers must dispense medication to outpatients. This 82 19 with type 2 diabetes mellitus, did not have obesity and did not have healthcare provider has 60,000 members and dispenses more than 83 20 contraindications were prescribed gliclazide in the initial dose of 30 61,000 drugs to outpatients per month. Polymedication is defined 84 21 or 60 mg/day based on clinical judgement of endocrinologist. During as the set and daily use of 4 or more drugs. This usually provokes 85 22 clinical observation the dose could be adjusted, or the medication administration errors, low adherence or compliance, increased risk 86 23 could be changed in case of insufficient clinical effect or intolerance. of drug interactions between other consequences. By an informatic 87 24 After initial treatment adjustments, patients were followed up to 6 system we identified 4293 patients (2843 women and1451 men) who 88 25 month. Glycated haemoglobin (HbA1c) and 24-hour monitoring of had taken out four or more drugs during the month of December 89 26 90 glucose levels were registered. Blood samples for genotyping were 2014. 1,863 of them were < 65 years old, which represent 66% of 27 81 collected, and analysed after collection of all clinical data. the population, and 2430 were > 65 years old and represent 34%). 28 Results: Twenty-eight patients (38%) were carrying mutated After identifying the drugs involved we used an informatic system 92 29 CYP2C9 alleles *2 or *3. By the end of the observation all patients to seek incompatibilities, severe or moderate interactions. In 600 93 30 had target HbA1c levels. In the group of mutant alleles carriers 21 drugs involved in polypharmacy, we found 192 contraindications, 94 31 patients (86%) achieved target levels on initial dose of gliclazide, 1979 severe and 2497 moderate interactions. The crossing of these 95 32 96 compared to 14 patients (37%) in the group of noncarriers (P < data with the polymedicated patients profile is under study in order 33 0.001). Mean effective gliclazide dose in mutation carriers was 53 ± to identify which of these interactions actually happen. Once we 97 34 98 13 mg; in non-carriers – 84 ± 26 mg (P < 0.01). Mild hypoglycemic detect the patients involved, we will analyze the status by studying 35 episodes were observed in only 1 patient in the group of mutations the clinical history. If interactions are occurring, an intervention will 99 36 non-carriers and in 4 patients carrying CYP2C9*2 or *3. The dif- take place in the patient’s medical history alerting and explaining the 100 37 ference was not significant. interaction detected to carers physicians. 101 38 Conclusions: Patients carrying CYP2C9*2 or *3 alleles achieved 102 39 clinical effect on gliclazide alone more frequently, and required 103 40 104 41 105 42 106 43 107 44 108 45 109 46 110 47 111 48 112 49 113 50 114 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

2015 e17 Clinical Therapeutics/Volume XX, Number XX, 2015

1 Eeffect Of Sex And Formulation on sub-specialty and since 2004 as a self-standing medical specialty. 65 2 Single-Dose of Pharmacodynamics of After some untoward austerity measures, generation exchanges, 66 3 Aripiprazole unfortunate health policy changes and conceptual ambiguity during 67 4 D. Ochoa; M. Román; T. Cabaleiro; and F. Abad-Santos the previous decade, CP in SR has been put under various pressures, 68 5 Hospital Universitario de la Princesa, Instituto Teófilo Hernando, threatening its existence and service. During the last years, however, 69 6 Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain a new generation of young physicians – clinical pharmacologists has 70 7 Introduction: Aripiprazole is a third-generation antipsychotic agent entered the clinical practice in SR. Simultaneously, the new SSCP 71 8 that possesses a unique mechanism of action. Orthostatic hypoten- leadership, together with other partners, has started a complex pro- 72 9 sion, QT prolongation, bradycardia and syncope are some of adverse cess of reclaiming the place and space for CP within the present 73 10 events associated with aripiprazole. The objective of this study was to SR health care system. Building on the strong foundations inherited 74 11 determinate the effects of aripiprazole on blood pressure and electro- (legal, professional, scientific, conceptual), the “new blood” seems 75 12 cardiogram on single-dose studies in healthy volunteers. full of energy and determination to achieve these ambitious, noble 76 13 Material and Methods: A total of 180 healthy volunteers participat- objectives. 77 14 ing in six crossover bioequivalence clinical trials were included after 78 15 giving informed consent (102 men and 78 women). They received a 79 16 single aripiprazole 10 mg tablet or orodispersable tablet twice. Blood Dispensation Over 4 Drugs to Outpatient 80 17 pressure and heart rate were measured lying down on the days of In A Healthcare Provider In Montevideo, 81 18 admission before taking the medication, 30 minutes, 2, 4, 6 and 8 Uruguay 82 19 hours after the dose. Electrocardiogram was performed before the M. Vaz1; M. Poggi1; and J. García1,2 83 20 administration of the drug, and 4 and 8 hours after. 1Mutualista Hospital Evangélico, Montevideo, Uruguay; and 84 21 Results: Mean blood pressure [systolic blood pressure (SBP)/diastolic 2Facultad de Medicina CLAEH, Punta del Este, Uruguay 85 22 blood pressure (DBP)] at baseline, 30 minutes, 2, 4, 6 and 8 hours In Uruguay healthcare providers must dispense medication to outpa- 86 23 were 116/65, 110/63, 107/59, 109/59, 111/59 and 117/59 mm Hg, tients. This healthcare provider has 60,000 members and dispenses, 87 24 respectively. A decrease between 5 and 9 mm Hg in SBP and 2 and 6 monthly, more than 61,000 drugs to outpatient. 88 25 mm Hg in DBP were showed at all times after administration of drug The prescription of 4 or more drugs usually provoques adminis- 89 26 (P < 0.05) and in all subjects, but no differences were apparent in tration errors, low adherence or compliance, increased risk of drug 90 27 heart rate or between males and females. Moreover, the differences interactions between other consequences. 91 28 between tablet and orodispersable was only showed at 4 hours (P < By an informatic system of outpatient pharmacy we identified 92 29 0.05) post-dose. Mean QTc prolongation was 8 ms at 4 and 8 hours 4,293 patients (2,843 women and 1,451 men) who had taken out 93 30 after dosing (P < 0.05). four or more drugs during the month of December 2014 (1,863 of 94 31 Conclusions: Our data show that a single dose of aripiprazole pro- them were under 65 years old, which represent 66% of the popula- 95 32 duces a small decrease in blood pressure and a small increase in QTc, tion, and 2,430 were over 65 years old and represent 34%). After 96 33 but there was no change in heart rate. There were no differences identifying the drugs involved we used an informatic system to seek 97 34 between females and males. contraindicated, severe or moderate interactions. Variables such as 98 35 age range, gender, number of dispensed drugs and drugs most fre- 99 36 quently associated with multiple dispensations were analyzed. 100 37 Establishing Clinical Pharmacology 19,254 members of the institution used the pharmacy during 101 38 In Slovakia: Past, Present And Future December 2014, of which 4.293 (22%) took out more than four 102 39 Perspectives drugs 22% of the patients who took out more than 4 different drugs 103 40 104 J. Glasa1,2; K. Sobo ová3; H. Glasová1; and J. Holomá 1 were between 45 and 65 years old, 36% were between 65 and 74 41 ň ň 105 1Institute of Pharmacology, Clinical and Experimental years old and 45% over 75 years old. 42 106 Pharmacology; 2Institute of Health Care Ethics, Slovak Among patients with potentially polypharmacy, 47% of them 43 107 Medical University in Bratislava; and 3Department of Clinical took out 4 or 5 different drugs, 47% took out between 6 and 10 44 108 Pharmacology, Faculty Hospital, Nové Zámky, Slovak Republic drugs and the remaining 5.6% took out between 10 and 30 drugs. 45 109 Clinical pharmacology (CP) was successfully developed in Slovakia In all age groups, except that minor to five years old, prevail female 46 110 (SR) since 1970ies as an interdisciplinary medical specialty, endowed gender; the largest difference occurs in the older than 75 years group 47 111 to integrate in its formidable portfolio all scientific expertise, relation- in which 71% were women. 48 112 ships and policy procedures concerning medicinal drugs. Its main Continuous knowledge of this information will enable studies 49 113 aim: improvement of safety and efficacy of practical pharmacother- of drug use, and also make educational interventions in order to 50 114 apy, optimization of medicines utilization processes and medicinal promote the correct use of drugs. 51 115 drugs policies. Albeit developed as a clinical, research based disci- 52 116 pline, the social and ethical aspects of medicinal drugs use, including 53 117 pharmaco-economics and public policy issues, were always at the 54 Influence of Sociodemographic and 118 core of CP expertise and service to the patient. Following similar 55 Professional Characteristics on 119 developments abroad, the first conception of CP as a medical spe- 56 Antibiotic Prescribing: A Cross-Sectional 120 cialty was approved by the SR Ministry of Health in 1979. Hospital 57 Study In The Center Region of Portugal 121 and outpatient CP departments were established at bigger teaching 1,2 1,3,4 2,5 6 58 A. Teixeira-Rodrigues ; F. Roque ; A. Falcão ; A. Figueiras ; 122 hospitals all around the country. The first teaching/research unit of 1,7 59 and M.T. Herdeiro 123 CP was founded at the present Slovak Medical University (SMU) 1 60 Institute for Research in Biomedicine – iBiMED & Health 124 in Bratislava in 1983. A comprehensive of postgraduate education 2 61 Sciences, Aveiro, Portugal; Faculty of Pharmacy, University of 125 and training system in CP was gradually developed. In 1990, the 3 62 Coimbra (FFUC), Portugal; Health Sciences Research Centre, 126 Slovak Society of CP was established (one of the founding societies 4 63 University of Beira Interior (CICS/UBI); Research Unit for Inland 127 of EACPT (1995)). Since 1993, CP has been recognized as a medical 5 64 Development, Polytechnic of Guarda (UDI/IPG); Center for 128

2015 e1 Clinical Therapeutics

1 Neuroscience and Cell Biology. University of Coimbra (CNC/UC), 65 Analyte Patients AUC C t (h) 6 τ max max 2 Portugal; Consortium for Biomedical Research in Epidemiology (n) 66 3 & Public Health (CIBER en Epidemiología y Salud Pública – 67 7 Bosentan 60 1.09 1.10 0.0 4 CIBERESP), Spain; and CESPU, Instituto de Investigação e (1.03; 1.16) (1.03; 1.19) (-3.0; 2.0) 68 5 Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, 69 6 Portugal Conclusions: Bosentan concentrations measured by DBS are good 70 7 Introduction: Antibiotic prescribing is very complex process influ- estimations of bosentan plasma concentrations. DBS can be con- 71 8 enced by medical and non-medical aspects. Accordingly, our aim was sidered as a valid alternative to the plasma method for the analysis 72 9 to evaluate the influence of GPs’ sociodemographic and professional of bosentan PK in children with pulmonary arterial hypertension. 73 10 characteristics on the quality of antibiotic prescribing, in Portugal. Moreover DBS has the advantage of requiring a very low blood vol- 74 11 Material and Methods: An observational cross-sectional study was ume and the samples can be stored at room temperature. 75 12 conducted (November 2011 to February 2012) in the catchment 76 13 area covered by Portugal’s Centre Regional Health Administration 77 14 (1094 General Practitioners (GPs) working at 84 primary care facili- 78 15 ties). A validated, self-administered questionnaire was used to assess Research Ethics Committees In Slovakia: 79 16 sociodemographic and clinical practice information. To evaluate the 25 Years Of Developments And New 80 17 quality of physician antibiotic prescribing, we’ve assessed the twelve Challenges 81 1,2,3 2,3 1,3 18 quality indicators validated by Coenen, S. et al (2007), per physician J. Glasa ; T. Krčméryová ; and H. Glasová 82 1 19 per year (2010, 2011 and 2012). Logistic regression using crude and Institute of Pharmacology, Clinical and Experimental 83 2 20 adjusted analysis was performed. Pharmacology; Institute of Health Care Ethics, Slovak Medical 84 3 21 Results: The response rate was 46.6%. Older GPs revealed to have University in Bratislava; and Institute of Medical Ethics and 85 Bioethics n.f., Bratislava, Slovak Republic 22 better performance of antibiotic prescribing [OR (95% CI) = 2.21; 86 Current system of ethics review in Slovakia (SR) was gradually 23 1.08 – 4.54; P < 0.05]. About GPs who also work at the emergency 87 24 department, statistical significant was found on their relation with established since 1990. It consists of the National Ethics Committee 88 (working at the Ministry of Health), and of the mutually independent 25 poor prescribing [OR (95% CI) = 0.29; 0.16 – 0.54; P < 0.05]. 89 26 Workload also revealed to influence the quality of antibiotic prescrib- local (hospital) and regional (research) ethics committees - (R)ECs. 90 It is based on a specific law (laws No. 576/2004 and No. 362/2011 27 ing: more patients seen per day [OR (95% CI) = 0.97; 0.94 – 1.00; 81 Coll.) and decentralized. A lot is being done for systemic education, 28 P < 0.05] and more patients seen per week in the emergency depart- 92 training and information sharing among SR (R)ECs: national meet- 29 ment [OR (95% CI) = 0.98; 0.97 – 0.99; P < 0.05] were related with 93 30 lower quality on antibiotic prescribing. ings of (R)ECs are held once/twice a year, national centre for (R) 94 31 Conclusions: These findings revealed that sociodemographic and ECs education and consulting operates at the Institute of Medical 95 32 professional characteristics could influence the quality of antibiotic Ethics and Bioethics (IMEB) in Bratislava (partially supported under 96 33 prescribing, which is a very important step to understand this com- EC FP7 EURECNET Project), state accredited education program 97 34 plex process aiming to tackle a global concern: the misprescription in GCP is established for almost 2 decades at the Slovak Medical 98 35 of antibiotics. University in Bratislava, dedicated web page is maintained (www. 99 36 bioetika.sk/www.bioethics.sk), and an international bioethics jour- 100 37 nal is published (IMEB, since 1994: Medical Ethics & Bioethics). 101 There are both positives and negatives of the current SR ER sys- 38 Comparison Between Dried Blood Spot 102 39 tem. Among positives: nation-wide RECs network in health care 103 and Plasma Bosentan Pharmacokinetics and in clinical research facilities; good contact with researchers and 40 In Paediatric Patients With Pulmonary 104 41 (if appropriate) with patients, volunteers and their relatives; posi- 105 Arterial Hypertension tive local reputation and impact; support of local ethics education. 42 M. Gehin; S. Globig; P.N. Sidharta; A. Kusic-Pajic; and 106 43 Among negatives: lower experience/competence of some (R)ECs 107 J. Dingemanse (small facilities); problems in sustaining appropriate membership; 44 Actelion Pharmaceuticals Ltd, Allschwil, Switzerland 108 45 longer review periods; unexpected differences of opinion; possible 109 Background: Plasma has been the historic matrix used for the hidden local agendas. The present developments in biomedical sci- 46 determination of bosentan pharmacokinetic (PK) parameters. The 110 47 ences, bio- and converging technologies, health policies, as well as the 111 FUTURE-3 study (NCT01223352) was a phase III paediatric PK need of effective implementation of the New EU CTs Regulation in 48 trial conducted primarily to compare 2 bosentan dosing regimens in 112 49 SR, pose rather new, complex challenges for RECs competence and 113 children aged from 3 months to 12 years. It offered the opportunity work management. To meet these new demands and responsibility, 50 of sampling and analysis by the dried blood spot (DBS) method and 114 51 RECs would need adequate support and practical action of respective 115 to compare the results to plasma data. regulatory authorities, academic and research community (including 52 Material and Methods: At steady-state, for each of the six time 116 53 expertise in ethics and other humanities), as well as from a better 117 points of the PK profile, approximately 1.2 mL of venous blood was educated general public. 54 collected in an EDTA-coated tube. Prior to centrifugation, blood 118 55 aliquots were taken from each tube and spotted on FTA DMPK-A 119 56 cards (Whatman). To compare whole blood to plasma concentrations 120 57 of bosentan, a blood-to-plasma distribution ratio of 0.6 was applied. Generic Use In Statin Sales In The 121 58 PK parameters obtained with the DBS method were compared to Community of Thessaloniki, Greece 122 59 those obtained with the plasma method by using the geometric mean P. Papaioannidou; and A. Ntaralas 123 60 ratio (DBS/plasma) and its 90% confidence interval for AUC and Aristotle University of Thessaloniki, Thessaloniki, Greece 124 61 τ Introduction: Under the current financial crisis in Greece, an effort 125 Cmax and the tmax median difference and its range. 62 Results: The comparison of bosentan PK parameters is displayed has been made by Health authorities to encourage generic prescrib- 126 63 in the table below: ing, in order to lower medicinal cost. The purpose of this work was to 127 64 use the newly established Electronic Health Records to study trends 128

e2 Volume XX Number XX Influence of Sociodemographic and Profesional Characteristics on Antibiotic Prescribing

1 in statins use, and to calculate the use of generics in statins sales in Implementation of The New Eu Clinical 65 2 a sample from the medicines market of Thessaloniki, the second Trials Regulation In Slovakia: Tasks And 66 3 largest city in Greece. Challenges for The Discipline of Clinical 67 4 Material and Methods: A sample of statins registered sales was Pharmacology 68 1 1,2,3 4 2 5 collected using the new Electronic Health Records, which has been H. Glasová ; J. Glasa ; K. Soboňová ; T. Krčméryová ; and 69 1 6 applied during the last years in Greece. The sample corresponded to J. Holomáň 70 7 a small amount of sales from the market of Thessaloniki during the 1Institute of Pharmacology, Clinical and Experimental 71 8 years 2012 and 2013, including only community and no hospital Pharmacology; 2Institute of Health Care Ethics, Slovak Medical 72 9 sales. All brand names (reference and generics) of statins and their University in Bratislava; 3Institute of Medical Ethics and Bioethics 73 10 relative ratios in the sales were estimated, and the percentage of n.f., Bratislava; and 4Department of Clinical Pharmacology, 74 11 generics in the sale of each medicine was calculated. The amount Faculty Hospital, Nové Zámky, Slovak Republic 75 12 of medicines was estimated in Defined Daily Doses (DDDs) of the Implementation of the new EU Clinical Trials (CTs) Regulation 76 13 reference drug and its generics. (No.536/2014) poses numerous challenges for all parties con- 77 14 Results: Simvastatin and atorvastatin sales corresponded to 81% of cerned, be it national regulators, drug agencies/competent authori- 78 15 total statins sales with almost equal share in the market (41% and ties, sponsors, contract research organizations (CROs), investigators, 79 16 40% respectively). Generic use corresponded to 66% of total sales or research ethics committees (RECs). In Slovakia, the existing CTs 80 17 (56,795 DDDs out of 86,103 DDDs), being 99.7% for simvastatin legislation (law No. 362/2013 Coll.) and existing procedural, pro- 81 18 (35,442 DDDs out of 35,555 DDDs), 54% for atorvastatin (18,274 fessional and scientific background provide a good basis to achieve 82 19 DDDs out of 33,856 DDDs) and 78% for pravastatin (3,066 DDDs smooth and effective transition to the new procedural environment 83 20 out of 3,913 DDDs). provided for by the Regulation. To facilitate the necessary collabora- 84 21 Conclusions: Although the use of generics is generally low in Greece, tion, representative stakeholders’ working groups were established, 85 22 the use of generics in statins sales was very high in the study sample. involving state authorities, professional medical associations, indus- 86 23 try and CROs to deal with concrete problems encountered within 87 24 the implementation processes. Clinical pharmacology (CP), as an 88 25 Utility of Pilot Studies for Prediction of interdisciplinary medical discipline integrating the relevant clinical, 89 26 Bioequivalence Ratio and Intrasubject methodological, ethical and procedural expertise concerning CTs of 90 27 Variability medicinal products and medicinal drugs for human use, seems to be 81 28 I. Moreno-Arza; D. Ochoa; M. Román; T. Cabaleiro; and especially well positioned to be useful in providing necessary exper- 92 29 F. Abad-Santos tise, and even in professionally coordinating these efforts. That’s 93 30 Hospital Universitario de la Princesa, Instituto Teófilo Hernando, why the Slovak Society of CP (SSCP, branch of the Slovak Medical 94 31 Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain Association) has initiated and been involved, together with respective 95 32 Introduction: Sometimes pilot studies are performed to decide if partners, in several ongoing activities at the professional and regu- 96 33 a new generic formulation is adequate for evaluation in a pivotal latory levels, as well as in novel education and teaching initiatives 97 34 bioequivalence trial and to calculate the number of subjects needed aimed at providing and disseminating the necessary know how to the 98 35 in this trial. We aim to analyse if a pilot study can predict the ratio implementation process parties concerned. Among those, national 99 36 between test and reference formulations and the intrasubject vari- CTs and GCP conferences, national meetings of RECs, and an active 100 37 ability, that is the main parameter to calculate the sample size. involvement of physicians – clinical pharmacologists (together with 101 38 Material and Methods: We selected seven replicated crossover other medical specialties, clinical pharmacists, lawyers, and others) 102 39 (4 periods × 4 sequences) trials, with 24 to 36 volunteers each. A in the working groups mentioned above may be the most prominent 103 40 hundred simulations of pilot studies with a 2x2 crossover design examples. Hopefully, active involvement of CP in re-creating effec- 104 41 were carried out including 6 or 12 volunteers, randomly selected from tive and safe environment for conducting of high quality CTs (and, 105 42 these trials keeping a balanced sequence. ANOVA was performed of indirectly, also for other clinical research), brings also new opportuni- 106 43 ties of growth and acknowledgement, needed in the present efforts 107 logarithmically transformed AUC and Cmax, considering sequence, 44 subjects within sequence, period and formulation, to obtain the ratios of re-establishing the discipline within the national clinical research 108 45 and 90% confidence intervals. Intrasubject variability, expressed as and health care systems. 109 46 percent coefficient of variation (CV), was approximated by the square 110 47 root of the error mean square of ANOVA. We calculated the per- 111 48 centage of pilot studies giving a result within ±10% the real value System of Postgraduate Education and 112 49 obtained in the replicated study. Training In Clinical Pharmacology In 113 50 Results: Prediction of ratio of AUC was quite good, especially for Slovakia: Focus on The Patients’ Care and 114 51 12-subjects pilot studies, but prediction of C ratio or CV was poor. Good Therapeutic Practice 115 52 max 116 Percentage of pilot studies obtaining a value ±10% of real value H. Glasová1; J. Glasa1,2; K. Sobo ová3; T. Kr méryová2; and 53 ň č 117 (median and range): J. Holomá 1 54 ň 118 1Institute of Pharmacology, Clinical and Experimental 55 Pilot study AUC ratio C ratio AUC CV C CV 2 119 max max Pharmacology; Institute of Health care Ethics, Slovak 56 120 6 subjects 68 (40–92) 35 (26–55) 18 (8–19) 22 (11–25) Medical University in Bratislava; and 3Department of Clinical 57 121 12 subjects 87 (68–99) 55 (38–75) 27 (20–40) 30 (25–44) Pharmacology, Faculty Hospital, Nové Zámky, Slovak Republic 58 122 System of postgraduate education and training in clinical phar- 59 123 Conclusions: The predictability of pilot studies is greater for AUC macology (CP) has been developed gradually in Slovakia (SR) in 60 124 ratio than for C , possibly due to higher variability of this param- parallel with the continuous efforts aimed at establishing CP as an 61 max 125 eter. The value of pilot studies to decide if a formulation is good independent, but interdisciplinary medical discipline, providing 62 126 enough to proceed with pivotal study is quite low. Pilot studies should necessary expertise and knowledge integration regarding safe and 63 127 include at least 12 subjects. effective medicinal drug use and research, and thus improving the 64 128

2015 e3 Clinical Therapeutics

1 quality of practical pharmacotherapy and patients care. The first Conclusions: An association of statins with insomnia and erectile 65 2 teaching/research unit devoted specifically to CP was founded at the dysfunction was found. These ADR are included in the SmPC. As he 66 3 present Slovak Medical University (SMU) in Bratislava in 1983. It information obtained from this database does not allow to conclude 67 4 led, in the subsequent period, the development and efforts for a full about causality, other pharmacoepidemiological studies should be 68 5 state recognition of a comprehensive system of postgraduate educa- performed. 69 6 tion and training for medical specialists – clinical pharmacologists 70 7 (physicians). It also took an active, albeit relatively minor part in 71 8 the postgraduate education and training of other medical special- Profile of Pediatric Clinical Trials Phase 72 9 ists, and also in the continuous medical education. In this work, it Iii Carried Out In Spain At October 2014 73 10 was greatly helped by the Slovak Society of CP (SSCP, established A. Aldea-Perona1; E. Baute2; M. García-Sáiz1; and E. Sanz1,2 74 11 in 1990). Already since 1993, CP has been recognized in SR as a 1Hospital Universitario of Canarias, Tenerife, Spain; and 75 12 medical sub-specialty and since 2004 as a self-standing medical spe- 2University of La Laguna, Tenerife, Spain 76 13 cialty. In the meantime, the original CP unit has been developed Background and Introduction: Only a limited number of medici- 77 14 into the SMU Institute of Pharmacology, Clinical and Experimental nal products, such as vaccines, had been developed specifically for 78 15 Pharmacology, involved nowadays also in the undergraduate CP edu- children, or have been tested in children, before the clinical trial 79 16 cation of medical students, nurses and other health care professionals, Regulation implementation. With those obligations introduced, the 80 17 and in numerous other research, clinical and consultation activities. companies have to screen every new product for its potential pediatric 81 18 It still serves as a national CP education, training (and examination) use. The aim is to analyze the profile of Phase III clinical trials carried 82 19 centre. At present, the state accredited, comprehensive specialisation out in Spain and available in the EU CT register. 83 20 program in CP lasts at minimum 5 years, while the first 2-3 years of Material and Methods: The available information from the ongoing 84 21 a physician’s education/training are devoted to the so-called internal clinical trials (Phase III) within the European Clinical Trial register at 85 22 medicine (IM) common stem (compulsory for all IM specialties). October 2014 was used to evaluate the therapeutic areas and drugs 86 23 The state accredited certification training programs are available at studied eight years after the new Regulation was implemented. 87 24 PPCEP SMU also in the specific field of clinical trials (CTs) methodol- Results: There were 412 ongoing clinical trials in pediatric popula- 88 25 ogy and Good Clinical Practice, and in pharmaco-economics. tion in Spain at October 2014. It represents the 16% of the CT with 89 26 all age groups. In the pediatric CT, 78% were included the adoles- 90 27 cents (66 of 323 CT were in the Pediatric Investigation Plan (PIP)), 81 28 A case-non case evaluation of the in 56% the children (68 of 229 CT were included in PIP), in 6% the 92 29 psychiatric disorder and statins newborn (11 of 25 were in PIP) and in 4% the preterm newborn and 93 30 association in FEDRA Database infants (6 of 15 CT were in PIP). 94 31 A. Aldea-Perona1; I. Martín2; M. García-Sánchez-Colomer3; The most frequent therapeutic areas studied were congenital dis- 95 32 M. García-Sáiz1; and E Sanz1,2 ease in newborn, and infections and neurological disorders in chil- 96 33 1Hospital Universitario de Canarias, Tenerife, Spain; 2University dren and adolescents. The vaccines were represented in 6% and in 97 34 of La Laguna, Tenerife, Spain; and 3Regional Pharmacovigilance 2% of the clinical trials in children and adolescents, respectively. 98 35 Center, Tenerife, Spain Conclusions: The number of pediatric clinical trials continued to be 99 36 Background and Introduction: The association of neuropsychiatric still low in relation to the total number of clinical trials. The pro- 100 37 reactions and statins have been assessed over the years, by using case moters continued studying vaccines but the number of clinical trials 101 38 series and national registries of spontaneous adverse drug reaction focused on the congenital abnormalities and on drugs for infectious 102 39 reports. However, the available studies have not analyzed the risk in diseases, were predominant. 103 40 different age groups. The objective is to investigate the dispropor- 104 41 tionality in young adults with less probability to suffer comorbidities 105 42 than older adults. 106 43 Adverse Drug Reactions as A Cause of 107 Materials and Methods: Association between psychiatric disorders Hospital Admission Hospital Universitario 44 (SOC) and statins was assessed in FEDRA (analysis of the Spanish 108 45 De La Princesa – Madrid 109 drug safety database up to October 2014) by the case/non-case meth- A. Rivas; S. Valdez; E. González; and F. Abad 46 odology, calculating Reporting Odds Ratio (ROR) as a measure of 110 47 Hospital Universitario de la Pricensa, Madrid, Spain 111 disproportionality. Case was defined as patients less than 45 years Objective: To detect the incidence of adverse drug reactions as cause 48 (young adults) who experienced at least one psychiatric reaction (PT, 112 49 of admission to the Hospital Universitario de la Princesa in Madrid. 113 HLGT, HLT) related to the drugs included in the C10AA ATC group. Materials and Methods: Transversal study, between June to 50 Results: A total of 72 ICSR were notified (81% from 35–45 years 114 51 December of May 2014. An electronic medical records review of 115 aged; 69% male). Atorvastatin and simvastatin were involved in patients admitted through the emergency was performed. We assessed 52 36% and 33% cases, respectively. The most reported psychiatric 116 53 whether the cause of admission was secondary to medication use. 117 reactions were related with sexual dysfunction (26%), the altered Causality was assessed according to the Naranjo algorithm and 54 level of consciousness (24%) and mood disorders (12%). The ROR 118 55 WHO criteria. 119 values, considering the psychiatric disorders in all aged groups, was Results: There were 3917 admissions in that period, with a mean 56 0.93 (95% CI, 0.87–1) and 1.31 (95% CI, 1.04–1.65) in young 120 57 age of 77 years. In a preliminary analysis, we found 222 (being 121 adults. The ROR for the HLGT Sleep disorders and disturbances and the sample size 195 subjects, 45.1% male and 54.9 female) the 58 HLT Erection and ejaculation conditions and disorders, were 1.53 122 59 most representative: NSAID gastrointestinal bleeding/gastrointes- 123 (95% CI, 1.08–2.15) and 11.32 (95% CI, 7.54–16.98), respectively. tinal bleeding on antiplatelet/anticoagulated patient: 37 (16.7%), 60 Insomnia PT and erectile dysfunction PT had ROR significantly over 124 61 Renal Insufficiency: 21 (9.5%), hyponatremia: 21 (9.5%), intrac- 125 than 1. The ROR for nervousness PT was 0.37 (95% CI, 0.14–0.99). ranial haemorrhage on antiplatelet/anticoagulated patient: 31 62 The ROR for Somnolence, anxiety and depression PT were not sig- 126 63 (14%), serotoninergic syndrome: 2 (0.9%), neutropenic fever: 18 127 nificant (P > 0.05). 64 128

e4 Volume XX Number XX Influence of Sociodemographic and Profesional Characteristics on Antibiotic Prescribing

1 (8.1%),diarrhea caused by clostridium difficile: 3 (1.4%) and four of intake, which is 1–7 days after the treatment, the possibility of 65 2 cases of medication error. blood coagulation might also increase, but transiently. Therefore, in 66 3 Conclusions: The incidence of admission by adverse reactions is this study, we investigated whether SSRI affected the Cl− current or 67 4 similar to other studies performed in other countries, around 5.7%, phospholipid scrambling activity of ANO6. 68 5 being the most frequent gastrointestinal bleeding associated with Material and Methods: HEK293T and PANC-1 cells were used. 69 6 antiplatelet drugs or oral anticoagulants. Plasmids expressing hANO6 were transfected to HEK293T cells. 70 7 siRNA of hANO6 was transfected to PANC1 cells for knockdown 71 8 of hANO6. We measured anion channel activities using whole cell 72 9 Molecular Mechanisms That Underlie and inside-out patch clamp techniques with and without treatment 73 10 The [Cl-]I-Sensitive Kinases-Mediated of SSRI. Flow cytometry was performed to evaluate phospholipid 74 11 Regulation of Cftr Anion Selectivity scrambling. 75 Results: In the whole-cell patch mode, SSRIs facilitated Ca2 - 12 I. Jun1; J. Jang2; J. Jung1; Y. Kim1; and M.G. Lee1 + 76 dependent activation of IANO6 in ANO6-transfected cells, as evi- 13 1Department of Pharmacology and Brain Korea 21 PLUS Project 77 denced by a significant decrease in the delay of IANO6 generation. 14 for Medical Sciences, Yonsei University College of Medicine, 78 On the other hand, in the inside-out patch clamp configuration, SSRIs 15 Seoul 120-752, Korea; and 2Department of Hematology, Yonsei 79 showed an inhibitory effect on ANO6 currents, suggesting that SSRIs 16 University College of Medicine, Seoul 120-752, Korea 80 activate ANO6 via an indirect mechanism in intact cells. SSRIs also 17 Introduction: CFTR is cAMP activated anion channel which secretes 81 facilitated Ca2 -dependent PS exposure and -thrombin-induced 18 chloride and bicarbonate in airway, exocrine pancreas, intestine, and + α 82 platelet aggregation. 19 genitourinary systems. Human pancreas secretes pancreatic juice 83 Conclusions: SSRIs at clinically relevant concentrations promote 20 which contains as much as 140 mM bicarbonate (HCO3-) via CFTR. 84 Ca2 - dependent activation of ANO6, which may have potential 21 Recently, we have shown that [Cl-]i-sensitive activation of WNK1- + 85 clinical implications such as the underlying mechanism of SSRI 22 OSR1/SPAK pathway plays a critical role in pancreatic HCO3- 86 induced adverse drug reactions. 23 secretion by increasing the bicarbonate permeability (PHCO3/PCl) 87 24 of CFTR. However, how [Cl-]i-sensitive kinases modulate PHCO3/ 88 25 PCl of CFTR remains elusive. 89 26 Material and Methods: Overexpression and knockdown of each A Review of New Drugs Approved By The 90 27 kinase in HEK293T cells were performed. Using patch clamp, we Spanish Agency of Medicines and Medical 81 28 measured permeability of bicarbonate and halide ions. We did pull- Devices (Aemps): A Quick Method To 92 29 down assay between truncated WNK1 and CFTR at 150mM and Explore Therapeutic Innovation 93 30 0mM Cl- concentrations. A. Pejenaute1; N. Ramos1; J.A. Arnaiz2,3; D. García-Cinca1; and 94 31 Results: WNK1 affects permeability of other anions as well as bicar- G. Calvo2,3 95 32 bonate in patch clamp recordings. Especially, the interval of relative 1Fundació Clínic Recerca Biomèdica, Barcelona, Spain; 2Hospital 96 33 permeabilities (Px/PCl) between each anion was greatly narrowed by Clínic i Provincial, Barcelona, Spain; and 3Universitat de 97 34 WNK1. Consequently, WNK1 increased the dielectric constant of the Barcelona, Barcelona, Spain 98 35 hypothetical selectivity filter of CFTR. And we measured the pore Introduction: It has been questioned whether drug innovation meets 99 36 size of CFTR at each state. WNK1 makes CFTR pore size larger. We societal needs. We undertook a critical review of new approved drugs 100 37 figured out that WNK1 kinase domain binds to CFTR and truncated by the AEMPS from September 2013 to December 2014. 101 38 forms of WNK1 respond to low Cl- concentrations. Methods: A revision of the monthly bulletin published at the AEMPS 102 39 Conclusions: These findings suggest that WNK1 increases the website was performed to gather information on new drugs approved 103 40 bicarbonate permeability of CFTR by modulating the polarizability from September 2013 to December 2014. Key features of new drugs 104 41 of anion selectivity filter and provide insight into the fundamental approved were summarized. The following indicators of innovation 105 42 question of how ion selectivity of anion channels can be regulated were considered: Direct indicators: a) drugs with new mechanism of 106 43 by cytosolic signaling at the molecular level. Furthermore, WNK1 action and b) lack of therapeutic alternatives for the approved indica- 107 44 senses low [Cl-]i, then kinase domain is exposed and binds to tion. Indirect indicators: a) advanced therapy; b) orphan designation; 108 45 CFTR. c) first line vs. second or further line therapies; d) pediatric indication. 109 46 New indications and extension of indications were not considered. 110 47 Results: A total of 82 drugs were approved. Indications fell into the 111 48 following areas: (16, 19%) infectious diseases, (14, 17%) oncology, 112 49 Tmem16f (Ano6) Activation Is Accelerated 113 By Selective Serotonin Reuptake (10, 12%) endocrinology, (6, 7%) neurology and haematology each 50 one, (5, 6%) pneumology, (4, 5%) cardiovascular diseases, (3, 4%) 114 51 Inhibitors 115 1 2 1 1 3 psychiatry, dermatology, digestive system, ophthalmology, gynecol- 52 I. Jun ; J. Jang ; J. Jung ; M.G. Lee ; and J.H. Nam 116 1Department of Pharmacology and Brain Korea 21 PLUS Project ogy and immunology each one, 1% (n = 1) nephrology, metabolism 53 and urology each one. Most were single-active substance drugs (67, 117 54 for Medical Sciences, Yonsei University College of Medicine, Seoul 118 2 82%). Fixe-dosed combinations were mainly antiretrovirals (n = 4) 55 120-752, Korea; Department of Hematology, Yonsei University 119 3 and hypoglycemic agents (n = 3). Only 2 drugs targeted specifically 56 College of Medicine, Seoul 120-752, Korea; and Department of 120 Physiology, Dongguk University College of Medicine pediatric indications and 13 were addressed to both adult and pedi- 57 atric population. Overall, 22 (27%) were orphan drugs. First-line 121 58 Introduction: ANO6 acts as Ca2+-activated Cl− channels and 122 generates outward-rectifying ionic currents in response to intra- agents accounted for 70% of the total (16% in restricted patient 59 populations). 123 60 cellular Ca2+ increase. ANO6 is involved in platelet function by 124 phospholipid scrambling required for blood coagulation. Selective Conclusion: A detailed analysis of newly approved drugs may be 61 used to conduct an at first glance analysis of therapeutic innovation. 125 62 serotonin reuptake inhibitors (SSRIs) are used for the treatment of 126 major depressive disorders. Although chronic treatment of SSRI can The innovative value of new drug development will be presented and 63 discussed according to the indicators proposed. 127 64 increase the risk of upper gastrointestinal bleeding, at the earlier stage 128

2015 e5 Clinical Therapeutics

1 Testing The Intranasal Route For • To describe the implication of ECRIN in European multinational 65 2 Administration of Haloperidol In clinical trials and its added value in fostering the development and 66 3 Emergency Room: Generation of Efficacy enrichment of academic clinical research. 67 4 Data To Support Clinical Practice 68 5 R. Vives Vilagut; R. Duñó; N. Planet; G. Garcia; M. Payés; Materials and Methods: ECRIN is involved in two main courses of 69 6 M. Mariñosa; M.I. Iglesias-Lepine; and C. Pontes action: The ECRIN integrated activity (ECRIN-IA), funded by the FP7 70 7 Hospital de Sabadell. Institut Universitari Parc Taulí- Universitat Infrastructure Programme and supported by nine Work Packages (WP) 71 8 Autònoma de Barcelona and involving 23 European Countries, and the Horizon 2020 Programme, 72 9 Background: Managing schizophrenic patients with agitation in the both in the context of the European Commission (EC). The activity and 73 10 emergency room requires medications with a rapid onset of effect. results of ECRIN will be analyzed on the basis of the expected milestones 74 11 Intravenous administration is impractical, and intramuscular dos- and the reported outcomes achieved within each project. 75 12 ing may be risky for both patients and health care professionals. Results: Seven Framework Programme: 76 13 77 The intranasal route may offer short Tmax with safer administration. 14 Intranasal haloperidol has been reported to achieve similar plasma • 21 academic clinical trials have been funded by the FP7 78 15 concentrations to intravenous dosing, but clinical data on the efficacy Programmes in the context of the ECRIN-PPI, ECRIN-IA and 79 16 and safety of such approach is lacking. Psychiatrists contacted our other FP7 funded Projects. 80 17 Clinical Pharmacology Unit for methodological and logistic support • Of these, 4 clinical trials have concluded and their results have 81 18 to generate clinical information on the affectivity of haloperidol by been published in high-impact scientific journals. 82 19 the intranasal route. We present here the research protocol that was H2020 Programme: 83 20 prepared. 84 21 Methods: An exploratory randomized parallel observer-blinded • Four large academic ECRIN-supported clinical trials, submitted to 85 22 clinical trial was designed to compare the administration of 5mg PHC-13 and 17 H2020 Calls, succeeded to obtain the Grant from 86 23 haloperidol by either intranasal or intramuscular route. The trial will the EC in 2014. In total, 15 countries will be involved in those 87 24 include 40 agitated schizophrenic patients visited in the emergency trials. 88 25 room of Corporació Parc Taulí who are candidates to receive halop- 89 26 eridol and provide previous informed consent (personally or through Conclusions: ECRIN is an infrastructure dedicated to fostering 90 27 representative). Patients will be monitored up to 6 hours for agita- competitiveness of academic multinational clinical research across 81 28 tion, cardiovascular parameters and adverse events. Treatments will Europe, with high ethical and scientific standards. This target is 92 29 be administered by unblinded nurses and agitation will be assessed achieved by the interaction, interoperability and harmonized work 93 30 in blind by an uninvolved psychiatrist. Main efficacy variable is the between European countries and their respective National Clinical 94 31 percentage of patients with score ≤ 9 in the 5 item PANSS-EC scale Research Networks with the coordinated support of ECRIN-ERIC. 95 32 20 minutes after dosing. Sample size is based on subject’s availability 96 33 considering the exploratory nature of the trial. The study will be 97 34 performed according to the Good Clinical Practice. Conversion from Tacrolimus Twice-Daily 98 35 Results: The clinical trial obtained Ethic’s and regulatory approvals to Tacrolimus Once-Daily In Stable Cystic 99 36 during 2014. The first patient was recruited on December 2014. Fibrosis Lung Transplant Recipients: 100 37 Recruitment is ongoing and expected to last 12 months. Comparative Pharmacokinetics 101 38 Conclusions: An exploratory trial has been prepared to help phy- G. Centeno Soto1; B. Ruiz-Antorán1; A. Sancho López1; C. 102 39 sicians to generate initial clinical information on the effectiveness Payares1; F.J. Fernández1; P. Ussetti2; and C. Avendaño-Solá1 103 40 of a simple intervention aimed to improve patient management by 1Department of Clinical Pharmacology, University Hospital Puerta 104 41 healthcare professionals in the emergency room. de Hierro Majadahonda, Madrid, Spain; and 2Department of 105 42 Pneumology, University Hospital Puerta de Hierro Majadahonda, 106 43 Madrid, Spain 107 44 Ecrin (European Clinical Research Objectives: The switch for conversion from tacrolimus (TAC) twice 108 45 Infrastructure Network): The Added daily-once daily recommended 1:1.The aim of this PK study was to 109 46 Value of Interoperability and Pan- evaluate TAC exposure in stable cystic fibrosis (CF) lung transplant 110 47 European Interconnection on Clinical (LT) recipients, converted from TAC twice daily to TAC once daily 111 48 Research in an open-label, prospective, single-centre study. 112 49 113 J.S. Peñataro1; M. Ezzeldin1; N. Sanz1; G. Calvo1,2; X. Carné1,2; Methods: Eligible patients were post-transplant CF patients (18-65 50 114 and C. Kubiak3 years) with stable lung function on stable doses of TAC twice daily 51 115 1Clinical Pharmacology Department, Hospital Clínic, Barcelona; that were candidate to switch to TAC once daily. Twelve consecu- 52 116 2Universidad de Barcelona; and 3ECRIN- European Clinical tive patients were included into the study. Patients had their first PK 53 117 Research Infrastructure Network, Paris, France analysis on day 1, still under the stable TAC twice daily regimen and 54 118 Introduction: ECRIN is a pan-European infrastructure providing were converted to TAC once daily from day 2 onwards. The doses 55 119 coordinated services to multinational academic clinical trials via were adjusted according to clinical judgement to achieve target levels 56 120 its experienced staff. By connecting National Clinical Research and a second 24h PK period profile was obtained once the patient 57 121 Networks from different European countries, ECRIN supports the was on stable dosage on therapeutic range. 58 122 access to patients across Europe and enables academic-driven clinical Results: The mean total (SD) daily dose of TAC twice daily at base- 59 123 trials to overcome cross-border barriers derived from the diversity in line upon enrolment was 0.17 (0.10) mg/kg/day and for TAC once 60 124 health and legislative national systems. daily after adjustments was 0.22 (0.12) mg/kg/day. In order to achieve 61 125 Objectives: target similar in C levels and AUC , eighty-two percent of sub- 62 min 0-24 hr 126 To explain the structure and operative task distribution within jects who were converted to TAC once daily required a mean increase 63 • 127 ECRIN. of 28%, in a range of 9.1–66.7%. 64 128

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1 Conclusions: Our study results indicate that the switch for conver- Impact of A Multicomponent 65 2 sion from TAC twice daily to TAC once daily in patients with CF may Intervention On Registered Nurses To 66 3 need an increase dose in order to reach levels within the therapeutic Increase Reporting Of Adverse Drug 67 4 target. Reactions And Medication Errors 68 5 I. Salcedo de Diego1; P. Serrano Gallardo1,2; B. Ruiz Antorán1,3; 69 6 B. de Andrés Gimeno1,3; M. Revuelta Zamorano1,3; and 70 7 Sentia: A Spanish Systematic Online C. Avendaño Solá1,3 71 8 Monitoring Registry for Children 1Instituto de Investigación Sanitaria Puerta de Hierro, 72 9 And Adolescents Treated With Majadahonda, Spain; 2Universidad Autónoma de Madrid, 73 10 Antipsychotics: Results from A 2-Year, INAECU, Madrid, Spain; and 3Hospital Universitario Puerta de 74 11 Naturalistic Follow-Up Study Hierro Majadahonda, Majadahonda, Spain 75 12 G. Centeno Soto1; B. Ruiz-Antorán1; I. Palanca Maresca2; Background: A total of 37.4% of adverse events in Spanish inpa- 76 13 A. Forti-Buratti2; and C. Avendaño-Solá1 tients are drug related. Spontaneous reporting systems are the most 77 14 1Department of Clinical Pharmacology, University Hospital efficient source of data in pharmacovigilance but underreporting 78 15 Puerta de Hierro Majadahonda, Madrid, Spain; and 2Child and is their main drawback. The objective of the study is to assess the 79 16 Adolescent Psychiatry Unit, University Hospital Puerta de Hierro impact of a multicomponent intervention on hospital Registered 80 17 Majadahonda, Madrid, Spain Nurses (RN) over reporting of ADR and ME. 81 18 SENTIA (SafEty of NeurolepTics in Infancy and Adolescence; Material and Methods: Before-after intervention study. A multi- 82 19 (https://sentia.es), is an online Spanish registry created to track component intervention was designed based on the Patient Safety 83 20 antipsychotic adverse effects in youth.SENTIA is financed by public Institutional Policy and the results of a cross-sectional study carried 84 21 funds. SENTIA is included in the European Network of Centres for out in June 2013 which measured the competence of 339 hospital 85 22 Pharmacoepidemiology and Pharmacovigilance. RN in reporting ADR and ME. The intervention started in fall 2013, 86 23 Objectives: SENTIA has the following aims: 1. Early detection of it is currently ongoing and includes: appointing of patient safety unit 87 24 adverse events. 2. Close monitoring and long term follow-up of leaders, lectures in units, interactive intensive training on reporting 88 25 pediatric patients on antipsychotic treatment. 3. Development of an ME and ADR with electronic supportive training materials handouts 89 26 extensive pharmacovigilance database of antipsychotic treatment in to leaders, set up of a hospital electronic anonymous reporting sys- 90 27 children and adolescents. tem, posters explaining the reporting procedure displayed in every 81 28 Methods: Children and adolescents, regardless of the diagnosis or unit, Institutional mailbox for enquiries and feedback. Descriptive, 92 29 clinical symptoms that motivate the antipsychotics prescription are bivariate analysis comparing two identical periods of time before and 93 30 monitored regularly. The gathered information is structured as fol- after the intervention using non-parametric tests (U-Mann Whitney) 94 31 lows: 1. Sociodemographic data; 2. Medical and psychiatric history; and linear regression analysis to detect trends in reporting were per- 95 32 3. Clinical assessment; 4. Pharmacological history; 5. Therapeutic formed. 96 33 compliance; 6. Health habits; 7. Side effects (AIMS, SAS, SMURF); Results: RN sent 331 drug related reports between April 2013 and 97 2 34 8. Physical examination; 9. Biological parameters. December 2014. R = 0,494 for total reports on the linear regression 98 35 Results: Ninety-six patients have been enrolled, 11.4 ± 2.9 years old, analysis. 99 36 14% are under 8 years old, 75% male. The most frequent clinical Descriptive and bivariate analysis results shown in table below. 100 37 syndromes that motivate prescription are conduct disorder (38.5%) 101 38 and ADHD (26.0%). The most frequently prescribed antipsychotics Before After Intervention U-Mann 102 intervention (n 143) Whitney 39 as were risperidone (48.8%) and aripiprazole (30.2%). During the = 103 40 (n = 33) Apr-Sep14 104 follow-up, 21% of patients changed at least once the antipsychotic. In Apr-Sep13 41 relation to safety assessments, 85.4% of patients had adverse events 105 42 Mean (SD): reports/month 106 related to treatment (AEs). The most frequent AEs were: problems ADR (including harmful ME) 0,667 (1,211) 0,667 (0,816) 0,818 43 related to appetite/weight (59.4%), tiredness and weakness (28.1%), ME (nonharmful) 4,333 (5,853) 22,667 (11,552) 0,009 107 44 sleeping problems (22.9%) and abnormal movements (14.6%). Total reports (including ME with 5,500 (6,862) 23,833 (12,073) 0,009 108 unknown outcome) 45 Thirty-six patients have been exposed to antipsychotics for longer 109 46 than 18 months. Regarding specific adverse events in this group, the 110 Conclusions: The multicomponent intervention seemed effective in 47 most frequent AEs were: headache, problems related to appetite, 111 increasing the number of nonharmful drug related reports but it did 48 hypersalivation and gastrointestinal problem. 112 not change the reporting of ADR. A different approach to improve 49 Conclusions: The creation of an online Pharmacovigilance Registry 113 nurses’ competence in reporting harmful medication events must be 50 (SENTIA) is a useful tool in the longterm systematic assessment of 114 considered. 51 adverse events in the antipsychotic treatment of children and ado- 115 52 lescents that contributes to the increase of knowledge about the still 116 53 too limited knowledge about medium-and long-term safety evidence 117 54 in real-world pediatric population. Results of SENTIA 18-months Use of Alpha-2 Adrenergic Agonists to 118 55 follow-up shows persistence of mild-moderate but potentially risky Improve Surgical Field Visibility In Ear 119 56 AEs that deserves and justify a close clinical monitorization of toler- And Nasal Surgery: A Systematic Review 120 57 ability and safety of APS in children & adolescents. M.A. Quijada-Manuitt1; A. Vallano1; A. Cardesín2; Y. Escamilla2; 121 58 and C. Pontes2 122 59 123 60 124 61 125 62 126 63 127 64 128

2015 e7 Clinical Therapeutics

1 1Hospital Universitario de Bellvitge – IDIBELL – Universitat de Methods: The analysis was conducted from the data included in 65 2 Barcelona, Bellvitge, Spain; and 2Hospital de Sabadell, Institut the prospective, multicentre Spanish registry that includes patients 66 3 Universitari Parc Taulí, Universitat Autònoma de Barcelona. with HCV-genotype-1, and severe fibrosis treated with triple therapy 67 4 Sabadell, Spain (peginterferon alfa-2+ribavirin+boceprevir). The cost-effectiveness 68 5 Background: Controlled hypotension during anaesthesia may analysis includes: costs of antiviral treatment, of concomitant treat- 69 6 improve the quality of the surgical field in Ear-Nose-and-Throat ments and costs related to health-care resources. 70 7 (ENT) interventions. A number of drugs are used to that purpose, Results: One hundred seventy patients were included; 68.2% 71 8 including alpha-2 adrenergic agonists (A2AA). A systematic review of male, age 53 years; 36.5% of patients reported at least one SAE. 72 9 efficacy data on the use of A2AA as part of hypotensive anaesthesia SVRw12 was 46.5%. The cost of triple therapy represented a total 73 10 in ENT has been conducted. of 4,916,652€ , the pharmacological cost (triple therapy + concomi- 74 11 Methods: A MEDLINE and Scopus search (1980-2015) was done to tant treatment) a total of 5,161,168€ . The consumption of health 75 12 identify clinical trials comparing an A2AA as a part of hypotensive resources an additional cost of 240,000€ (1,500€ /patient). The total 76 13 anaesthesia regimen in ENT. Additional references were identified cost per patient cured was 70,262€ . This cost varies greatly based on 77 14 through cross-link references. Abstracts were reviewed by two inves- different baseline characteristics of the patients, with significant dif- 78 15 tigators for eligibility, and full papers were fully reviewed if report- ferences in patients with albumin < 35,120,597€ ; prior null response 79 16 ing randomised trials comparing A2AA in adult patients undergoing 120,727€ and platelets < 90,000,104,464€ . 80 17 ENT surgery. Data was extracted and synthesized for studied popula- Conclusions: The current scenario of hepatitis C treatment is chang- 81 18 tion, surgical procedure, type of anaesthesia, treatments compared, ing. Triple therapy is more costly for patients with severe fibrosis 82 19 bleeding results and overall report quality. Due to heterogeneity in and predictors of poor response. However, keeping in mind that the 83 20 variables, synthesis of data was based on a qualitative description of timeframe for the release of IFN-free-regimens remains uncertain 84 21 trials characteristics, and also of results on the assessments of surgical and considering that the actual access to the new DAA in the real- 85 22 field bleeding, because of the heterogeneity in the type of variables world setting could be delayed, boceprevir could remain as an option 86 23 used for its assessment. for patients with intact liver function and an unmet medical need, 87 24 Results: A total of 79 publications were identified, from which 22 regardless of the degree of liver fibrosis, in locations where a delay 88 25 randomised clinical trials were selected (15 double-blind, 4 single- in the access to the newer therapies is foreseen and hepatic trans- 89 26 blind and 3 open-label) including information on 1278 patients plant would not be readily available. Incorporating clinical criteria 90 27 undergoing either nasal, sinusal or ear surgeries and comparing and definition of subgroups of patients by medical experts influences 81 28 A2AA (clonidine (n = 11) or dexmedetomidine (n = 11)) with significantly the cost-effectiveness and should be taken into account 92 29 placebo (n = 9), remifentanil (n = 3), esmolol (n = 2), midazolam in decisions on public health policies. Current decisions based on 93 30 (n = 2), magnesium sulphate (n = 2), fentanyl (n = 1) or no treatment short-term budgetary impact lead to incorrect decisions. Medium- 94 31 (n = 3). Sixteen trials including 1168 patients measured surgical field term decisions that consider clinical criteria against specific decisions 95 32 bleeding, of which 14 showed better results for A2AA. None of the based on short-term budgetary impact should be favored. 96 33 studies compared directly clonidine and dexmedetomidine. 97 34 Conclusions: Alpha-2 adrenergic agonists have repeatedly shown 98 35 to improve surgical field bleeding during ENT surgery; there are no Randomized Clinical Trial, Placebo 99 36 comparative data between different A2AA. Compared To Evaluate The Efficacy And 100 37 Safety of Minocycline In Angelman 101 38 Syndrome (A-Manece Study) 102 39 Cost-Effectiveness Analysis of Triple B. Ruiz-Antorán1; A. Sancho López1; R. Cazorla2; G. Iglesias2; 103 40 Therapy With Peginterferon, Ribavirin, J. Lara2; L. López Pájaro3; E. Marín3; and C. Avendaño-Solá1 104 41 And Boceprevir For The Treatment of 1Department of Clinical Pharmacology, University 105 42 Chronic Hepatitis C Virus Genotype 1 Hospital Puerta de Hierro Majadahonda, Madrid, Spain; 106 43 With Severe Fibrosis Under “Real-Life” 2Department of Neuropediatrics, University Hospital Puerta 107 44 Conditions de Hierro Majadahonda, Madrid, Spain; and 3Department 108 45 B. Ruiz-Antorán1; J.M. Pascasio2; J. de la Revilla3; J. Crespo4; of Neurophysiology, University Hospital Puerta de Hierro 109 46 I. Salcedo de Diego1; C. Payares1; X. Forns5; J.L. Calleja3; Majadahonda, Madrid, Spain 110 47 C. Avendaño-Solá;1 and Spanish Group for the study of the use of Angelman syndrome (AS) is a rare disease with serious developmental 111 48 Direct-Acting Drugs Hepatitis C with Severe Fibrosis disorder. Until now, no cure for AS exists. Recently published studies 112 49 1Department of Clinical Pharmacology, University Hospital show an improvement of motor function, cognition and increased syn- 113 50 Puerta de Hierro Majadahonda, Madrid, Spain; 2Unit for aptic function in animal models with minocycline administration. A non- 114 51 Clinical Management of Digestive Diseases, H. Virgen del Rocio, controlled treatment initiative in children with AS has been reported. 115 52 IBIS and CIBEREHD, Sevilla, Spain; 3Department of Gastroe Methods: Randomized, crossover, double-blind, placebo-controlled, 116 53 nterology and Hepatology, University Hospital Puerta de Hierro independent clinical trial to explore the efficacy and safety of myno- 117 54 Majadahonda, IDIPHIM and CIBEREHD, Madrid, Spain; cicline in AS. The primary objective was to compare the efficacy (in 118 55 4Department of Gastroenterology and Hepatology, Hospital terms of increase in age of development) of 8-week treatment with 119 56 Universitario Marques de Valdecilla, IDIVAL, Santander, Spain; mynocicline or placebo. The efficacy assessment was performed with 120 57 and 5Liver Unit, Hospital Clinic, IDIPABS and CIBEREHD, validated scales (Scale Marrill-Palmer-R) and EEG parameters. Safety 121 58 Barcelona, Spain analysis was conducted through direct collection of adverse events, 122 59 Objectives: Studies based on the data of clinical trials have proved physical examination and laboratory tests. 123 60 that the triple therapy for hepatitis C is cost-effective. This study Results: Thirty-two subjects enrolled, median age of 12 (6–29) years, 124 61 we assessed the cost-effectiveness of triple therapy in treatment of 50% male. No differences in basal characteristics were observed. A 125 62 Chronic Hepatitis C with Severe Fibrosis under “real-life” conditions. summary of key results is shown in Table 1. 126 63 127 64 128

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1 pressure), ECG and clinical laboratory parameters were not affected 65 Age of development Improvement* Magnitude of Mean (range) of 2 by study treatments. Lung function parameters did not decrease 66 (N = 32) (N)(%) improvement change (months) 3 (months) relevantly (> 5%) for mean FEV1 after any treatment. Fifteen subjects 67 4 TOTAL INDEX experienced treatment-emergent AEs: 2 subjects after treatment 125 68 5 Mynocicline (N = 21) 14 (66.7%) 3.4 1.9 (−4 – 11) mg ASA, 3 after 250 mg, 5 after 500 mg and 5 after 750 mg ASA. 69 6 Placebo (N = 11) 7 (63.7%) 3.7 2.0 (−1 – 9) Drug related treatment-emergent AEs were throat irritation in 14 70 Cognitive 7 Mynocicline (N = 21) 13 (61.9) 2.8 1.5 (−2 – 6) subjects (36% of subjects) and productive cough in 3 subjects (7% 71 8 Placebo (N = 11) 8 (72.7%) 5.4 3.5 (−2 – 13) of subjects). 72 9 Gross Motor PK analysis for ASA showed dose proportionality regarding AUC. 73 10 Mynocicline (N = 21) 14 (66.7%) 2.9 1.2 (−8 – 5) Conclusion: LASAG administered as a single oral inhalation up to 74 Placebo (N = 11) 5 (45.5%) 4.6 0 (−16 – 15) 11 Fine Motor 750 mg to 38 healthy male subjects was safe and well tolerated and 75 12 Mynocicline (N = 21) 11 (52.4%) 4.5 2.0 (−3 – 13) showed dose proportional total (systemic) exposure for ASA. Based 76 13 Placebo (N = 11) 8 (72.7%) 4.4. 2.6 (−3 – 10) on these results the antiviral effects through a host cell-mediated 77 14 Total Index language mechanism may be evaluated in a PoC study. 78 Mynocicline (N = 21) 0 15 Placebo (N = 11) 0 79 16 Processing speed 80 17 Mynocicline (N = 21) 0 The Use of Complementary And 81 18 Placebo (N = 11) 0 82 Adaptive behaviour/daily Alternative Medicine In Hospitalized 19 life skills Patients With Type 2 Diabetes Mellitus In 83 20 Mynocicline (N = 21) 10 (47.6%) 3.2 0.9 (−4 – 11) Israel 84 Placebo (N = 11) 5 (45.5%) 4.2 1.0 (−5 – 13) 21 R. Koren1,4; A. Lerner4; S. Koren2; R. Zaidenstein2; T. Ziv-Baran3; 85 22 *At least 1 month increase and A. Golik1,4 86 23 1Department of Internal Medicine A, Tel Aviv, Israel; 2Diabetes 87 24 No significant changes in the EEG were observed. Minocycline unit, Assaf Harofeh Medical Center, Zerifin, Israel, Affiliated to 88 25 was well tolerated. Sackler School of Medicine, Tel Aviv University; 3Department of 89 26 Conclusion: The clinical and neuropsychological measures suggest Epidemiology and Preventive Medicine, School of Public Health, 90 27 minocycline is not superior to placebo in children with AS. There was Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 81 28 no significant improvement in the mean raw scores of the subdomains and 4Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 92 29 of Marrill-Palmer-R Scale attributable to minocycline. Improvement Israel 93 30 observed in both groups could be related to the multidisciplinary *This work was performed in partial fulfillment of the M.D. 94 31 intervention during the course of the study. thesis requirements of the Sackler Faculty of Medicine, Tel Aviv 95 32 University. 96 33 **Ayelet Lerner and Ronit Koren contributed equally to this work. 97 34 First-In-Man Dose Escalation Study Introduction: The use of complementary and alternative medicine 98 35 of Aspirin® Inhaled For The Clinical (CAM) is on the rise in recent years in the general population, as well 99 36 Development of A New Antiviral as among patients with chronic diseases such as diabetes mellitus. 100 37 Treatment of Resistant Influenza The aim of this study was to add information regarding the use of 101 38 102 1 1 1 CAM in patients with type 2 diabetes mellitus (DM2) in Israel and 39 J. Nagelschmitz ; Ch. Scheerans ; J. Kraetzschmar ; 103 1 2 1 explore possible interactions between CAM and prescription medi- 40 G. von Degenfeld ; B. Müllinger ; and G. Wensing 104 1 cation (PM). 41 Bayer Pharma AG, Pharma Research Center, Clinical Science, 105 2 Methods: This is a Cross Sectional study based on questionnaires. 42 42096 Wuppertal, Germany; and Vectura GmbH, Robert-Koch- 106 Allee 29, 82131 Gauting, Germany The study included type 2 diabetic patients who were hospitalized in 43 an internal medicine department at “Assaf Harofe” medical center, 107 44 Introduction: D, L-lysine acetylsalicylate (ASA) glycine (LASAG, 108 Aspirin i.v.®) has antiviral activity including resistant viral strains: Zeriffin, Israel between 12.2013 and 12.2014. Possible interactions 45 between CAM and PM were evaluated by a clinical pharmacist and 109 46 inhalation of nebulized LASAG leads to dose-dependent lung virus 110 titer reduction in mice, decreases disease severity and weight loss. a clinical pharmacologist. 47 Results: A total of 23.4% of 111 diabetic patients used CAM. 111 48 Mortality is reduced dose-dependently. Proof-of-concept (PoC) 112 is planned by measuring viral load and clinical symptoms after There was no significant difference between the consumers and non- 49 consumers in terms of age, education, income, smoking or alcohol 113 50 Influenza infection in patients. 114 Material and Methods: First-in-man dose escalation for evaluation habits. Only 11 of the 26 CAM consumers informed their physician 51 regarding the use. We found possible drug-herb interactions in 19 115 52 of safety and pharmacokinetics (PK) of treatment was conducted as 116 placebo-controlled dose escalation in healthy male subjects: Safety of the 26 CAM consumers. A major interaction was found between 53 omega-3 and anti-aggregates and was encountered in seven (26.9%) 117 54 was evaluated by questioning for AEs, controlling vital parameters, 118 ECG, lung function and laboratory. PK was measured in plasma and of the CAM consumers. Other minor and major interactions were 55 found with Vitamin E, Ginkgo-biloba, Q10, Green tea, Fenugreek 119 56 thromboxane B2 was analysed in serum. Thirty-eight subjects were 120 treated with nebulized LASAG, in 5 subjects with 62.5 mg, 5 with seeds, pyridoxine and dandelion. 57 Conclusions: Since CAM consumption is on the rise, it is desirable to 121 58 125 mg, 6 each with 250 mg, 500 mg or 750 mg ASA. Ten subjects 122 received inactive control. improve our knowledge concerning their potential effects and adverse 59 effects, especially in conjunction with PM. Given the complexity of 123 60 Results: Inhalative doses up to 750 mg ASA were safe and well tol- 124 61 erated without serious adverse events. Vital signs (heart rate, blood 125 62 126 63 127 64 128

2015 e9 Clinical Therapeutics

1 pharmaceutics in patients with chronic diseases, among them patients Cyp450 Geno-Phenotype Analysis: 65 2 with DM, use of supplementary medicine cannot be ignored. Application of Ceiba Cocktail To Mexican 66 3 Populations 67 4 F. de Andrés1; B.P. Lazalde-Ramos3; M. Sosa-Macías3; and 68 5 Sampling Strategies To Estimate Cyps A. Llerena1,2 69 6 Phenotype: Implications For Ceiba 1CICAB, Clinical Research Centre, Extremadura University 70 7 Cocktail Approach Hospital, Badajoz, Spain; 2Faculty of Medicine, University of 71 3 8 F. de Andrés1; S. Terán3; M. Bovera4; H. Fariñas1; E. Terán3; and Extremadura, Badajoz, Spain; and Centro Interdisciplinario de 72 9 A. Llerena1,2 Investigación para el Desarrollo Integral Regional del IPN Unidad 73 10 1CICAB, Clinical Research Centre, Extremadura University Durango, Durango, México 74 11 Hospital, Badajoz, Spain; 2Faculty of Medicine, University of Introduction: For the CYP450 enzymes, there is significant variabil- 75 12 Extremadura, Badajoz, Spain; 3Colegio de Ciencias de la Salud, ity of actual activity within a genotype group, i.e. genotype does not 76 1 13 Universidad San Francisco de Quito, Quito, Ecuador; and always correlate with the functional phenotype. Therefore, the most 77 14 4Servicio de Laboratorio, Hospital de los Valles, Quito, Ecuador relevant genetic variants should be analyzed, together with the simul- 78 15 Introduction: According to EMA recommendations, development taneous analysis of the CYP450 isoforms hydroxylation capacities. 79 16 of phenotyping procedures for drug interactions studies and clinical Considering this lack of accuracy and the void of pharmacogenetic 80 2 17 research are highly recommended,1 due to the discordances found information in ethnically specific regions, this study aimed to explore 81 18 between genotypes determined of the main CYP enzymes and their the relationship between the main CYP450 (i.e. CYP1A2, CYP2C9, 82 19 actual enzymatic activity.2 Recently, CEIBA cocktail approach to CYP2C19, and CYP2D6) polymorphisms and the metabolic ratios 83 20 measure metabolic activity of the main CYPs in just one experi- (MRs) in a group of Mexican subjects. 84 21 ment has been designed.3 However, its optimal design remains to be Material and Methods: Six hundred fifty-four healthy native indi- 85 22 elucidated, which is the main objective of this research, in order to viduals from Mexico were genotyped and additionally phenotyped 86 3 23 appropriately select the sample to be analyzed and an optimal single by the CEIBA cocktail. Plasma concentrations of the drugs and 87 24 time point for the analysis, to avoid diminish costs and discomfort metabolites were quantified and MRs calculated to determine the 88 25 to the volunteers without compromising the reliability of the results. actual CYPs metabolic capacity. The geno-phenotype relationship 89 26 Material and Methods: Thirteen healthy subjects were given low was evaluated by correlation analysis between ‘activity score (AS)’ 90 27 oral doses of 100mg caffeine, 25mg losartan, 20mg omeprazole and and logMR. 81 28 30mg dextromethorphan, and blood and urine samples were taken Results: No adverse effects were reported. The prevalence of PM gen- 92 29 at different time points (predose, 0.5, 1, 2, 3, 4, 6, 8, and 12h) to otypes is ≤ 2%, whereas for CYP2C19 and CYP2D6, an ultrarrapid 93 30 assay the concentration3 and pharmacokinetic parameters (AUC). metabolizer prevalence of 3.7% and 12.8%, respectively, was found. 94 31 The MRs for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 MRs correlated with AS for CYP2C9, CYP2C19 and CYP2D6, and 95 32 were calculated at each time point and their correlation with AUC MRs varied across subjects with different AS. Those individuals with 96 33 ratios calculated. All subjects were genotyped. 2 or more active genes showed lower MRs than those with one or no 97 34 Results: The cocktail was well tolerated and single time point MRs active genes. The frequency histograms and probit analysis showed 98 35 at 4h or 6h (only for CYP2C9) after dosing showed high correlations no clear bimodality. Not all the phenotypically PMs carried zero 99 36 with corresponding AUC ratios and can, therefore, be proposed as active genes, whereas those individuals whose metabolism is faster 100 37 simple phenotyping metrics. On the other hand, metabolic ratios in exhibit at least two active genes. 101 38 urine samples were not comparable to plasma ratios. Conclusion: This is the first study of simultaneous determination 102 39 Conclusion: This cocktail was proven to reliably reflect the selected of genotypes, phenotypes and its correlation analysis for different 103 40 CYPs activities for the evaluation of CYPs hydroxylation capacity. CYPs on a Mexican population. The influence of the genetics on the 104 41 The proposed simplified sampling scheme could facilitate clinical enzyme hydroxylation capacity is confirmed, though further research 105 42 application of CYPs phenotyping with one blood sample collection, on genotype-phenotype relationship is required due to the overlap 106 43 in a single analysis. among different genotypes and that other factors can potentially 107 44 Supported by AEXCID of GOBEX (11IA002) to Sociedad influence the activity of these enzymes. 108 45 Iberoamericana de Farmacogenética, Instituto de Salud Carlos III- Supported by AEXCID-GOBEX (11IA002) to SIFF, and ISCIII- 109 46 Sara Borrell program (CD13/00348), and Collaboration grant from Sara Borrell program (CD13/00348). Coordinated by the RIBEF 110 47 USFQ (ET); coordinated by the RIBEF network. network. 111 48 Disclosure of Interest: None Declared. Disclosure of Interest: None Declared 112 49 113 50 114 51 References 115 References 116 52 1. Llerena A, Dorado P, Ramírez R, et al.CYP2D6 genotype and 1. European Medicines Agency. Guideline on the investigation of drug 117 53 debrisoquine hydroxylation phenotype in Cubans and Nicaraguans. interactions. EMA/CHMP/EWP/125211/2010. 2012;1–60. 118 54 Pharmacogenomics J. 2012;12:176–183. 2. Llerena A, Dorado P, Ramírez R, et al. CYP2D6 genotype and 119 55 2. McGraw J, Waller D. Cytochrome P450 variations in different ethnic debrisoquine hydroxylation phenotype in Cubans and Nicaraguans. 120 56 populations. Expert Opin Drug Metab Toxicol. 2012;8:371–382. Pharmacogenomics J. 2012;12:176–183. 121 57 3. De Andrés F, Sosa-Macías M, Llerena A. A rapid and simple LC–MS/ 3. De Andrés F, Sosa-Macías M, Llerena A. A rapid and simple LC–MS/ 122 58 MS method for the simultaneous evaluation of CYP1A2, CYP2C9, MS method for the simultaneous evaluation of CYP1A2, CYP2C9, 123 59 CYP2C19, CYP2D6 and CYP3A4 hydroxylation capacity. Bioanalysis. CYP2C19, CYP2D6 and CYP3A4 hydroxylation capacity. Bioanalysis. 124 60 2014;6:683–696. 61 2014;6:683–696. 125 62 126 63 127 64 128

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1 Student Views on The Student-Run causality assessment, (scientific) pharmacological explanation, feed- 65 2 Pharmacovigilance Program back letter to the reporter, and summary for the pharmacovigilance- 66 3 T. Schutte1,2; J. Tichelaar1,2; M.O. Reumerman1; R. van Eekeren3,4; databases of the European Medicines Agency and WHO. 67 4 S. Groenland1; L. Rolfes3,4; M.C. Richir1,2; E. van Puijenbroek3,4; Results: From May 2014-January 2015, 100 different ADR-reports 68 5 and M.A. van Agtmael1,2 selected by Lareb staff were handled by 43 students. Before participat- 69 6 1VU University Medical Center, Amsterdam, the Netherlands; ing in the pilot < 25% knew how to report ADRs. After participation 70 7 2RECIPE (Research & Expertise Center In Pharmacotherapy > 70% knew how to report, and were even able to name impor- 71 8 Education), Amsterdam, the Netherlands; 3The Netherlands tant details for ADR-reporting. Intention towards ADR-reporting 72 9 Pharmacovigilance Centre Lareb (Lareb); and 4University of was assessed using a 7-point Likert scale (1: extremely unlikely-7: 73 10 Groningen, Groningen, The Netherlands extremely likely). Students indicated they intend to report serious 74 11 Background: Pharmacovigilance centers play a vital role in the (6.44 SD 0.73) and unknown (6.44 SD 0.63) future encountered 75 12 monitoring of drug safety after approval for marketing, and depend ADRs. On a 5 point Likert scale students disagreed (2.50 SD 1.15) 76 13 mainly on the quantity and quality of reported adverse drug reac- their current curriculum covered pharmacovigilance well, found par- 77 14 tions (ADRs). To ensure future ADR-reporting and increase phar- ticipation educational (4.56 SD 0.63) and more interesting than fic- 78 15 macovigilance awareness among medical students, we developed and tive casuistry (4.56 SD 0.73). Furthermore besides students reported 79 16 aim to evaluate student outcomes of participation in our Student-run they learned how to asses ADRs, they stated to have learned skills/ 80 17 Pharmacovigilance program. knowledge regarding critical appraisal of information, understanding 81 18 Method: A pilot study was performed in which student attitudes, of pharmacological mechanisms and scientific writing. 82 19 knowledge and skills on ADR-reporting were evaluated using an Conclusion: The Student-run pharmacovigilance program is a valu- 83 20 e-questionnaire before and after participation in the student-run able and novel educational experience. It creates awareness in future 84 21 pharmacovigilance program. Teams of (1st-4th year) medical stu- doctors with the potential to increase ADR-reporting, lets students 85 22 dents assessed real ADR-reports from healthcare-professionals/ practice in searching and writing scientifically and teaches the basics 86 23 patients reported to Lareb. These student-assessments included a of pharmacovigilance in real life. 87 24 88 25 89 26 90 27 81 28 92 29 93 30 94 31 95 32 96 33 97 34 98 35 99 36 100 37 101 38 102 39 103 40 104 41 105 42 106 43 107 44 108 45 109 46 110 47 111 48 112 49 113 50 114 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

2015 e11 Clinical Therapeutics/Volume XX, Number XX, 2015

1 Therapeutic innovation: does industry Results: There are different measures to decrease the burden of many 65 2 research meet the needs of society? diseases other than drugs. The term disease mongering has been used 66 3 Defending no since 1992 to refer to clinical conditions that are not “real” medical 67 4 X. Carné needs. Neglected diseases and poverty-related diseases are also terms that 68 5 Hospital Clinic, Barcelona, Spain; and Institut d’Investigacions have been used by WHO and other international bodies to define “real 69 6 Biomèdiques August Pi i Sunyer (IDIBAPS), University of needs” from non-affluent societies. Rare diseases and elusive clinical 70 7 Barcelona, Spain conditions are also situations where big Pharma are reluctant to invest. 71 8 Educational Objectives: The Holy Grail of a big Pharma CEO is to Conclusions: 72 9 “address unmet medical needs” of the society. However this general ▪ Pure market sources cannot meet the needs of society as a whole 73 10 objective should be specified: Which medical needs we refer to? and ▪ Bias towards profit or self-interest is universal 74 11 of which societies? ▪ Not only R&D but also availability of drugs is also a major issue 75 12 Purpose: The purpose of the debate is to make clear this general goal ▪ Adequate and appropriate incentives are needed to ensure R&D 76 13 is being fulfilled, looking for the real medical needs that are not been for new medicines 77 14 currently addressed. ▪ Problem-oriented research should balance the drug-oriented 78 15 Methods: Literature review searching for terms like “medical needs”, approach currently dominating the scene 79 16 “disease mongering”, “neglected diseases” or “poverty-related dis- ▪ There is a strong need of academic, non-for-profit, problem ori- 80 17 eases”. ented research networks. 81 18 82 19 83 20 84 21 85 22 86 23 87 24 88 25 89 26 90 27 91 28 92 29 93 30 94 31 95 32 96 33 97 34 98 35 99 36 100 37 101 38 102 39 103 40 104 41 105 42 106 43 107 44 108 45 109 46 110 47 111 48 112 49 113 50 114 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

2015 e1 Clinical Therapeutics/Volume XX, Number XX, 2015

1 Clinical dili networks and consortia: Conclusions: A web-based database of clinical pharmacological 65 2 what lessons have we learnt? analyses in Norway has ensured access to a continuously updated 66 3 R.J. Andrade national overview of the field and has led to increasing standardiza- 67 4 Head, Department of Medicine and Gastroenterology Service, tion and cooperation between the laboratories. 68 5 Instituto de Investigación Biomédica de Málaga (IBIMA), 69 6 Hospital Universitario Virgen de la Victoria, Universidad de 70 7 Málaga, Málaga, Spain; and Centro de Investigación Biomédica Literature 71 8 en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 1.Westin AA et al. Tidsskr Nor Legeforen. 2012;132:2382.7. 72 9 Madrid, Spain doi:10.4045/tidsskr.12.0383. 73 10 Drug-induced liver injury (DILI) is a rare but potentially severe 2. Westin AA et al. Bioingeniøren. 2014;2:17–22, http://www.nito.no/ 74 11 adverse event concerning mostly patients but also pharmaceuti- dm/public/385427.PDF [Article in Norwegian] 75 12 cal industry, clinicians, and regulatory authorities. The necessity 76 13 of concerted efforts to obtain reliable information on DILI causal 77 14 agents, phenotypes, and risk factors has stimulated groups in USA The Sfinx/Pharao Computerized Decision 78 15 and Europe to develop large DILI prospective registries. The Spanish Support System (Cdss) On Drug-Drug 79 16 DILI Registry (www.spanishdili.uma.es) and the Drug-Induced Liver Interactions And Pharmacodynamics 80 17 Injury Network (http://dilin.duke.edu) are collaborative multicenter 81 Y. Böttiger 18 networks with large databases and biosample collections of pro- 82 Linköping University, Linköping, Sweden 19 spectively recorded DILI cases in Spain and the US, respectively, and 83 Educational Objectives: At the conclusion of this presentation, the 20 subsequently important resources for hepatotoxicity studies. The 84 participants should be able to recognize the special demands that has 21 Spanish DILI Registry has recently initiated a new branch into South 85 to be met for the collection, classification, and structure of drug infor- 22 America, the Spanish-Latin American DILI Network (SLATINDILI; 86 mation in connection with computerized decision support systems, 23 www.slatindili.uma.es), and into Europe, leading the EuroProDILI 87 as well as organizational aspects of implementation, education, and 24 Registry fostered by the European Association for the Study of the 88 follow-up of such systems. 25 Liver. In this presentation I will discuss on how DILI registries have 89 Summary: The presentation will include a background description 26 expanded our knowledge on this fascinating yet challenging and 90 of the development of the SFINX database on drug–drug interactions 27 complex disease. 91 28 and the PHARAO database on pharmacodynamics. The latter data- 92 29 base contains information on pharmacodynamic properties of active 93 drug substances, such as anticholinergic, serotonergic, and sedative 30 WWW.Farmakologiportalen.No – A 94 31 properties, as a basis for a summarized pharmacological risk profile 95 Common National Database For for a patients complete drug list. Data from epidemiological studies 32 Pharmacological Laboratory Services 96 33 in connection to the use of the SFINX database will be presented, as 97 T. Bjånes1; and A. Westin2 34 well as results from pilot testing of the PHARAO system in geriatric 98 1Haukeland University hospital, Bergen, Norway; and 2St Olavs 35 and primary health care settings. The experience from the working 99 University hospital, Trondheim, Norway 36 group behind these systems will be discussed in the broader context of 100 Introduction: Over the last 2 decades there has been an increasing 37 computerized decision support systems for rational drug treatment. 101 demand for pharmacological laboratory services in Norway, both for 38 102 therapeutic drug monitoring and drugs-of-abuse testing. By 2012, 39 103 more than 50 Norwegian laboratories offered analyses of 150 40 > Literature Reference 104 different therapeutic drugs (1) and 200 drugs-of-abuse (2). Since 41 > 1. SFINX-a drug-drug interaction database designed for clinical 105 the repertoires vary between laboratories and over time, national 42 decision support systems. 106 overviews quickly become outdated and unreliable. Further, different 43 2. Böttiger Y, Laine K, Andersson ML et al. Eur J Clin Pharmacol. 107 reference ranges and interpretation algorithms between laboratories 44 2009;65:627–633. 108 entail unnecessary sources of confusion. We developed a nationwide 45 3. Impact of the drug-drug interaction database SFINX on prevalence 109 web-based database for all pharmacological analyses in Norway to 46 of potentially serious drug-drug interactions in primary health care. 110 ensure a continuously updated overview of the field and to stimulate 47 Andersson ML, Böttiger Y, Lindh JD et al. Eur J Clin Pharmacol. 111 cooperation and standardization between laboratories. 48 2013;69:565–571. 112 Materials and methods: A used-friendly database was developed in 49 113 cooperation with a professional web design company, with funding 50 114 from the Norwegian Medical Association (approximately 500,000 51 115 NOK). The core of the database was a substance registry on which How risks are perceived. Recent research 52 116 all published information converged. A group of editors (clinical findings 53 1 2 1 117 pharmacologists) were responsible for the facts presented about each D. Way ; F. Bouder ; and R. Löfstedt 54 1 2 118 substance, such as substance class, trade names, pharmacokinetic King’s College London; and Maastricht University 55 119 properties, etc. The laboratories published and edited their own rep- Educational Objectives: This research presents the opportunity to 56 120 ertoires and linked them to the substance registry. better understand the drivers affecting medical risk perception as 57 121 Results: The database is published online and made publicly avail- well as concrete lessons and implication for policy. 58 122 able (www.farmako logiportalen.no). It provides detailed informa- Purpose: Pharmaceutical regulatory agencies across the Atlantic have 59 123 tion on substances and a continuously updated national repertoire been increasingly committed to releasing risk information, mainly via 60 124 on each substance. Furthermore, each laboratory has their own sub- online portals or open access to regulatory data, yet few studies have 61 125 page where all analyses performed are listed and to which common critically examined the effectiveness of the regulators' policies on 62 126 national details on substances are linked. the achievement of public policy objectives (eg, behavioural change, 63 building trust, and empowering patients to make better decisions). 127 64 128

2015 e1 Clinical Therapeutics

1 Methods: The authors conducted a large European survey (N = understand the complexity of the EU regulatory network and will 65 2 2015) comparing the views of medical doctors (N = 1010) and get a flavour of the discussions behind EU opinions on medicinal 66 3 patients (N = 1005) from Spain, Germany, France, and the UK. products. 67 4 Results: The study adds empirical evidence on the effects of Purpose: The aim of the training session is to provide important 68 5 European pharmaceutical policies on the end-users of “disclosed” background information to participants interested in drug regulation 69 6 information (ie, doctors and patients). The study found that the types to understand the complexity of the EU regulatory network and how 70 7 of transparency policies adopted by European regulators are likely to the system deals with divergent opinions. 71 8 be ineffective in achieving its policy objectives: building doctor and Methods: The training course will start with a 15-minute pres- 72 9 patient trust and providing a better understanding of agency decision- entation of the general aspects on the marketing authorisation of 73 10 making (eg, why a medicine was approved). The large majority of medicines, with particular attention to the community procedures 74 11 respondents were found to have poor knowledge of how the regu- and how opinions are reached within the EU network. This will be 75 12 lators assess the safety of medicines and would be unconfident in followed by two 35-min sessions where 2 recent examples, an anti- 76 13 interpreting what safety-related information means (eg, as contained coagulant and an oncologic drug, will be presented in an informal 77 14 in documents being made publically available). Doctors and patients way with the aim to stimulate questions and discussion within the 78 15 were also found to differ significantly over key transparency issues, audience. All participants, speakers and attendees, are expected to 79 16 including when safety information should be made publically avail- interact in these discussions. 80 17 able in the first place. Results: Despite common technical requirements within the EU 81 18 Conclusions: There is an urgent need to better connect medical Network, differences in the interpretation of data supporting mar- 82 19 transparency and communication policies to perception studies. The keting authorisation applications may lead to divergent opinions on 83 20 presenter concludes by discussing recommendations on improving the benefit/risk balance of a given medicinal product. Attempts to 84 21 transparency discussions that centre on achieving positive outcomes reach opinions by consensus are done throughout every procedure, 85 22 for patients and healthcare professionals. and this is usually reached. However, in a portion of cases this is not 86 23 possible, and a public declaration of the motivations behind a diver- 87 24 gent opinion will be signed by the representatives of the concerned 88 25 SGLT2 inhibitors member states. 89 26 M. Brito Conclusions: The evaluation of marketing authorisation applica- 90 27 Hospital Puerta de Hierro Majadahonda, Madrid, Spain tions within the EU Regulatory Network is complex. Divergent 81 28 Diabetes treatment is evolving fast in the last years. New algorithms views enrich the discussions behind every single opinion on medici- 92 29 are published frequently to cover all the new drug developments. We nal products, and a final decision is either reached by consensus or 93 30 will review published data from the proof of concept to the pharma- absolute majority. For transparency reasons, both discussions and 94 31 cological development of different molecules. EMA approved SGLT2 where applicable divergent opinions are publicly available. 95 32 inhibitors currently on the market are dapagliflozin, empagliflozin, The authors of this paper declare not to have any conflict of 96 33 and canagliflozin. Although the efficacy is considered modest, the interest that may affect the conduct of this training session. They 97 34 strengths of the class are low risk of hypoglycaemia, promotion of have public Declarations of Interests that can be consulted at EMA 98 35 weight loss, good tolerance, durability, and mechanism of action website. 99 36 non-insulin dependent, so they can be used regardless of diabetes 100 37 duration. There are some limitations to their use: renal failure and 101 38 concomitant use of diuretics. This new class of antihyperglycemic Rational Pharmacotherapy In Children – 102 39 drugs can be used through most of the natural history of the disease Issues Concerning off-Label Drug Use 103 40 from early stages to long standing. There is a great chance that they I. Choonara 104 41 become part of the treatment of most diabetic patients in a near University of Nottingham, Derbyshire Childrens Hospital, Derby, 105 42 future. UK 106 43 Review: Many medicines used in children are used in an off-label 107 44 manner. This means they are used either at a greater dose than that 108 45 recommended in the product licence, for an alternative indication, or 109 46 Training Course on Medicines Regulation: 110 How the Eu Regulatory Network Deals in an age group for which the medicine was not originally authorised. 47 The main issue with regards to the use of medicines is not whether 111 48 With Divergent Views 112 1 1 2 3 they are off-label but whether there is an evidence basis to justify 49 J. Camarero ; A. Gomez Outes ; F. Torres ; M. Weise ; and 113 4 their use in that particular condition. This means, specifically, has the 50 A. Sancho 114 1 medicine been used in a rational manner or not. Rational prescribing 51 Agencia Española de Medicamentos y Productos Sanitarios 115 (AEMPS), Madrid, España; 2Biostatistics and Data Management has been recognised as an important issue in low-income and lower 52 middle-income countries. It has not been considered a major issue 116 53 Core Facility, IDIBAPS - Hospital Clinic Barcelona; Biostatistics 117 Unit, Faculty of Medicine, Universitat Autònoma de Barcelona in high-income countries. This is unfortunate as many medicines are 54 used inappropriately. There is significant variation in the utilisation 118 55 (UAB), Barcelona, España. SAWP and BSWP member at EMA; 119 3Bundesinstitut für Arzneimittel und Medizinprodukte (BFARM), of antibiotics. Broad-spectrum antibiotics in particular are often used 56 inappropriately. Polypharmacy is often used when this is inappropri- 120 57 Bonn, Germany. Alternate Member CHMP, Member of the 121 BMWP, CVWP; and 4Research Institute Hospital Puerta de Hierro ate. Other examples of inappropriate drug use include the overutilisa- 58 tion of medicines for infants with gastro-oesophageal reflux. 122 59 Majadahonda, Madrid, España, Alternate Member CHMP, RIWP 123 60 Member 124 61 Objectives: Despite the existence of common technical and scientific 125 62 requirements, divergent opinions among MS may exist throughout Literature Reference 126 63 European marketing authorisation procedures. Participants will 1. Choonara I. Rational prescribing is important in all settings. Arch 127 64 Dis Child. 2013;98:720. 128

e2 Volume XX Number XX Clinical dili networks and consortia: what lessons have we learnt?

1 2. Puntis JW. Gastro-oesophageal reflux in young babies: who should supports the management of multinational trials. ECRIN is open to 65 2 be treated? Arch Dis Child 2015; 0: 1-5. doi:10.1136/archdischild- the whole clinical research community, covering any disease area. 66 3 2014-306232. Support to the management of multinational trials is provided after 67 4 scientific evaluation of the full protocol. Most ECRIN-supported 68 5 trials are funded by the FP7 and H2020; however, other funding 69 6 Initiative on Medication Reviews and mechanisms are being explored. 70 7 Dialogues Typical ECRIN users are multinational investigator consortia 71 8 M.B. Christensen; K.M. Harboe; J.P.K. Kampmann; A. Kobberø; conducting independent trials. In our experience, structuring inves- 72 9 G. Jürgens; J. Sonne; L. Reuther; and H.R. Christensen tigation capacity through the development of pan-European investi- 73 10 Copenhagen University Hospital Bispebjerg and Frederiksberg, gation networks has a tremendous impact on the development and 74 11 Copenhagen, Denmark the conduct of the project. For this reason, ECRIN also promotes the 75 12 We have successfully implemented a multifaceted initiative to enhance structuring of pan-European, disease-oriented investigation networks 76 13 rational pharmacotherapy, pharmacological focus, and clinical phar- that become strategic partners, providing the scientific content and 77 14 macological decision making across health care systems in our region. investigation capacity, whereas ECRIN supports the trial manage- 78 15 The initiative promotes clinical pharmacology as a clinical discipline ment. This is for instance achieved in the current FP7 ECRIN-IA 79 16 and consists of 4 key elements: project for the rare disease, medical device, and nutrition investiga- 80 17 1. Primary practice and hospitals in the region are offered system- tor communities, and similar partnerships are being developed with 81 18 atic reviews of a patient’s list of medicines forwarded by e-mail, fax, other disease areas. 82 19 or phone. Medication reviews are aimed at optimising the combined 83 20 list of medicines focusing on efficacy, interactions, adverse effects, 84 21 collective drug burden, and cost-effectiveness of the medication. The Impact of biosimilar medicinal products 85 22 medication review is performed by junior doctors and approved by in the EU pharmaceutical market 86 23 a specialist in clinical pharmacology and returned to the inquirer A. Grozdanova; K. Ancevska Netkovska; Z. Sterjev; Z. 87 24 within 2 days. Naumovska; A. Kapedanovska Nestorovska; and L.j Suturkova 88 25 2. Acute medical ward medication review. Clinical pharmacists Faculty of Pharmacy, University Ss. Cyril and Methodius, Skopje, 89 26 employed at the acute medicine department of the local hospital Macedonia 90 27 are supported with 1) patient-specific acute clinical pharmacologi- Biosimilar medicinal products marketed for almost a decade are still 81 28 cal input when necessary and 2) evaluation and education based relatively small segment of the EU pharmaceutical market, but with 92 29 on appraisal and grading of the clinical pharmacist’s suggestions in strong annual growth. The presence of biosimilars has enhanced com- 93 30 relation to the individual patient charts. Clinical scientific projects petition and offered a less costly alternative to existing biologicals. 94 31 concerning medication reviews as an alliance between clinical phar- There is a strong interest by healthcare stakeholders in measuring 95 32 macists and clinical pharmacologist are in development. the biosimilar utilization and impact on the market entry. Regulatory 96 33 3. Psychiatric medication dialogues. Medication reviews of com- issues, manufacturing, safety, pricing, and physician and patient 97 34 plex psychiatric patient’s medication. The cases, chosen beforehand acceptance have a part in developing the biosimilar market much 98 35 and submitted by psychiatrists, are reviewed by a clinical pharmacol- different from the generic market. The lack of automatic substitu- 99 36 ogist. Problematic areas of the medication are subsequently discussed tion and interchangeability made the entry of biosimilars even more 100 37 bilaterally at conference meeting held at the psychiatric department. difficult. 101 38 4. Primary practice medication dialogues. Medication reviews of The purpose of this research was to evaluate the information 102 39 primary practice patient’s medication. The cases, chosen beforehand related to impact of biosimilars and their potential to penetrate the 103 40 and submitted by general practitioners, are reviewed by a pharmacist EU market. The assessment of the biosimilar market uptake is done 104 41 followed by a specialist in clinical pharmacology. Suggestions for using data from several sources, measuring volume consumption and 105 42 change and optimisation are subsequently presented to the general pricing information in EU countries where they are marketed. 106 43 practitioner at a dialogue based meeting held in the general practi- Different types of biosimilars have different market penetration 107 44 tioners private practice. potential, with very limited data for biosimilar monoclonal antibodies 108 45 and biosimilar insulins. Noticeable differences in the use of biosimi- 109 46 lars across EU countries are reflection of national treatment practices 110 47 and guidelines, which are influenced by funding decisions and payer 111 48 Clinical Research Networks as A Support 112 to Independent Clinical Trials actions. The theoretical prediction that biosimilar competition will lead 49 to major price erosion in practice has not been so significant. Despite 113 50 J. Demotes-Mainard 114 ECRIN, Paris, France those difficulties, it is expected that the biosimilar market will develop, 51 mainly driven by potential profits with patent expiration in the next 115 52 Independent multinational trials are key instruments to optimise 116 healthcare strategies and to promote evidence-based medical prac- years. Even though the most important conditions for market uptake 53 of biosimilars are driven by commercial factors, still, real clinical evi- 117 54 tice in Europe and globally. However conducting multinational trials 118 raises major obstacles for academic institutions, both on the trial dence, clear regulatory framework, and postmarketing data on the use 55 of biosimilars will influence their market access. 119 56 management side and on the clinical investigation side. 120 57 Due to the fragmentation of health and legislative systems, infra- 121 58 structure, tools, procedures, and funding, a majority of non-com- 122 59 mercial sponsors and clinical trial units (CTUs) lack the capacity to Personalised Pharmacotherapy In 123 60 initiate and manage trials in foreign countries. ECRIN (European Routine Clinical Pharmacological 124 61 Clinical Research Infrastructure Network, www.ecrin.org) was Practice 125 62 designed to overcome these barriers, as a distributed, non-profit M. Grundmann 126 63 infrastructure supporting multinational clinical trials in Europe. Department of Clinical Pharmacology, Faculty of Medicine, 127 64 By connecting and coordinating national CTU networks, ECRIN University of Ostrava, Czech Republic 128

2015 e3 Clinical Therapeutics

1 Personalised pharmacotherapy as a part of personalised medicine is Future evaluations will reveal if training in clinical pharmacology 65 2 looking for the right drug, right patient, right dose, and right dosage can improve the quality of patient care. 66 3 interval. Selection of the right drug given to the right patient can be 67 4 solved a priori using pharmacogenetics (eg, warfarin, azathioprine, 68 5 etc). A posteriori therapeutic drug monitoring (TDM) can be used Research Ethics Committees: Adaptation 69 6 for the selection of the right dose and dosage interval. TDM refers to to The New European Regulation of 70 7 the individualization of drug dosage by maintaining plasma or blood Clinical Trials – A Viewpoint From 71 8 drug concentrations within a targeted therapeutic range or window Germany 72 9 for optimal patient benefit. Traditionally, TDM involves measur- J. Hasford 73 10 ing drug concentrations in various biological fluids and interpreting Association of Research Ethics Committees in Germany, Germany 74 11 these concentrations in terms of relevant clinical parameters. For By the end of 2016 the EU regulation 536/2014 will come into full 75 12 > 100 drugs (aminoglycosides, vancomycin, antimycotics, digoxin, force. By then the EU portal and its related databases, which are 76 13 amiodarone, theophylline, antiepileptic drugs, immunosuppressive essential for the submission of the trial applications and the com- 77 14 drugs, psychopharmaceuticals, cytostatics, etc) with better relation- munication between the sponsors and the member states, shall be 78 15 ship between plasma or blood concentration-response than dose- operational. According to Art, 4 of the regulation, the ethical review 79 16 response, the measurement of plasma or blood concentrations has of the clinical trial has to be performed by an ethics committee (EC), 80 17 become a valuable surrogate index of drug exposure in the body. but it is left up to the individual member states to decide whether 81 18 Next step, advanced TDM includes the estimation of metabolites and the EC reviews Part II (informed consent material and quality of the 82 19 probe drugs (phenotyping), free drug concentrations, and genotyp- study centers and its staff) only or Part I (trial protocol and risk/ 83 20 ing. The estimation of the phenotype shows actual metabolic status, benefit assessment), too. 84 21 and genotyping seems to be very useful for the explanation of some The ECs need an unrestricted access to the EU portal. The German 85 22 differences. Cohort studies and case reports from the routine clinical ECs have asked the government to decide that the ECs are respon- 86 23 practice will be demonstrated. sibly involved in the following aspects of the process: the review of 87 24 the ethical and scientific aspects of Part I and II and of substantial 88 25 modifications, review of the classification as low-intervention trial, 89 26 Courses in clinical pharmacology for notification relating to an end, early termination or temporary halt of 90 27 nurses and young doctors – narrowing a clinical trial, the receipt and review of safety reports, and initiation 81 28 the gap of ignorance? of corrective measures. The responsible EC and drug authority shall 92 29 K.M. Harboe1; E. Jimenez-Solem1; A. Bondesen2; C.B. evaluate Part I independently. The EC participate in the consolidation 93 30 Rasmussen2; L.Ø. Reuther1; M.V. Hansen1; and H.R. Christensen1 of the final assessment report, too. The competent EC finally has to 94 31 1Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; provide a vote regarding the authorisation of the trial. 95 32 and 2Center for Human Ressources, Gentofte Hospital, The text of the implementation law is not yet available, but there 96 33 Copenhagen, Denmark is considerable agreement to proceed as outlined here. The ECs in 97 34 Background: Young doctors and nurses in Denmark lack sufficient Germany are convinced that clinical research is urgently needed, that 98 35 training in clinical pharmacology and knowledge of medicines in gen- Europe should be an attractive location for clinical trials, and that it 99 36 eral due to a lower pregraduate priority. The Department of Clinical is possible to safeguard the autonomy, the safety, and the well-being 100 37 Pharmacology has therefore developed courses in clinical pharmacol- of research participants and to foster research-friendly conditions 101 38 ogy for both nurses and doctors. at the same time. 102 39 Material and Methods: The courses are planned in cooperation with 103 40 the HR department and supported financially by the Capital Region 104 41 105 of Copenhagen. The nurse’s course is a 5 × 2-day course, targeting A computerized physician order entry- 42 experienced nurses and qualifying them as “medication responsible 106 43 based system to prevent hbv reactivation 107 nurses” at their departments. The doctor’s course is a 1-day “crash- in patients treated with biologic agents. 44 course” for residents and junior doctors. The doctor’s course is acces- 108 45 The prescrib project 109 sible to all residents in the region. The courses are mainly taught 1,2 3 46 C. Hernandez-Lopez ; and J. Crespo 110 by junior doctors in specialist training for clinical pharmacology as 1 47 Tauli Parc Hospital, Autonomous University of Barcelona, 111 part of their own education with feedback by experienced educators. 2 48 Sabadell, Barcelona, Spain; Medical Department, Gilead Sciences, 112 Results: The courses have been held 2 to 4 times yearly since 2011. Madrid, Spain; and 3Marques de Valdecilla Hospital, Santander, 49 Altogether, 270 nurses have completed the nurse’s course, and in a 113 50 Spain 114 2-year period 438 junior doctors have attended the crash-course. The Educational Objectives: Demonstrate that a multifunctional team 51 nurse’s course is a combination of theoretical and applied pharmacol- 115 52 can design an effective strategy to minimize risk of hepatitis B virus 116 ogy, with focus on project management and clinical implementation. reactivation (HBVr) of patients receiving immunosuppressive thera- 53 All nurses are offered a 1-day refresh course twice a year. The doc- 117 54 pies. 118 tor’s course is divided into half a day with lectures on PK/PD, ADR, Purpose: The aim of the PRESCRIB project was to create a simple 55 drug interactions, risk patients, and toxicology and half day with 119 56 and useful tool in an academic hospital to facilitate the HBV screen- 120 case-based teaching. The participants work in groups with actual ing of all patients who were to be treated with biological drugs (BDs) 57 medication lists and patient case stories. Both courses are highly 121 58 by medical specialists. 122 rated, have continuously been evaluated, and the curricula adjusted Methods: In 2011 a preliminary phase was done to characterize 59 to improve quality. 123 60 routine practices in HBV screening of major specialties prescribing 124 Conclusions: The Department of Clinical Pharmacology has devel- BDs by means of a physician survey and the analysis of patients’ 61 oped successful and popular courses in clinical pharmacology for both 125 62 records. After this, the project was structured into three phases. The 126 nurses and doctors. Doctors in specialist training for clinical phar- first phase included educational activities in HBVr and the creation 63 macology are furthermore trained in education and communication. 127 64 of the new CPOE (computerized physician order entry) application. 128

e4 Volume XX Number XX Clinical dili networks and consortia: what lessons have we learnt?

1 The CPOE system allowed for the introduction of an alert of the ADEs, and is a learning platform for young physicians manning the 65 2 risk for HBVr with a BD at the time the drug is prescribed. Together, ADEM. 66 3 the prescriber was prompted to enter the patient’s serological status. 67 4 Alternatively, the program itself generates a test order for the patient’s 68 5 HBV serological profile. After that, there was the implementation E Learning on Pharmacotherapy 69 6 phase (May–Nov 2012) in which participation was voluntary. In C. Kramers 70 7 the subsequent universalization phase (Nov 2012–May 2013), the 71 8 participants were recruited with targeted screening conducted by the Problems due to pharmacotherapy occur frequently in hospitalized 72 9 Hepatology Unit. patients. Many of these derive from prescribing errors that lead to 73 10 Results: A total of 1076 patients undergoing BD treatment were potential preventable morbidity, mortality, and costs. The majority 74 11 included in this project (May 2012–2013), resulting in the identifica- are caused by pain medication (NSAIDs and opiates), (combination 75 12 tion of 4 HBsAg-positive and 69 anti-HBc-positive/HBsAg-negative of) anticoagulants, antidiabetics, and cardiovascular drugs. Also 76 13 patients. Over 90% of patients who were prescribed a BD have drugs which are renally excreted confer a risk. 77 14 undergone serological screening to detect HBV infection. The use of The care for these patients is provided by relatively inexperienced 78 15 CPOE has increased the screening rate from less than 50% to 94% physicians. These junior doctors do not consider themselves well 79 16 for HBsAg and from less than 30% to 85% for anti-HBc. enough trained to prescribe. Last, they are supervised by surgeons 80 17 Conclusions: This study demonstrates the feasibility of implement- who have no specific expertise for this complex pharmacotherapy. 81 18 ing a CPOE system in a tertiary hospital increasing HBV screening A strategy to reduce prescribing errors aims at educating the pre- 82 19 among medical specialties prescribing BDs. It would be interesting scriber. This has been shown to reduce prescribing errors. 83 20 to determine whether this experience can be extrapolated to other Currently, an e-learning program aimed to educate starting physi- 84 21 centers with CPOE systems and whether this is cost-effective for cians in the hospital is being developed both in Dutch and English. 85 22 hospitals. Subjects that will be covered by the program are pain management, 86 23 anticoagulant therapy, fluid and electrolyte management, and glucose 87 24 management. Currently, the program on pain management is availa- 88 25 Literature Reference ble. The program starts and ends with a test. Ultimately, the program 89 26 1. Sampedro B, Hernandez-Lopez C, Ferrandiz J.R., et al. Computerized could be used to test whether a starting physician is able to prescribe 90 27 Physician Order Entry-Based System to Prevent HBV Reactivation in safely in a hospital setting and deserves a “license to prescribe.” 81 28 Patients Treated With Biologic Agents: The PRESCRIB Project. 92 29 Hepatology. 2014;60:106–113. 93 30 94 31 The Dutch/Flemish Prescribing Assessment 95 32 Project 96 increasing the number of Adverse drug 1 2 3 33 C. Kramers ; A. Maassen van den Brink ; M.H. Hessel ; 97 events by the use of an Adverse Drug 4 5 6 3 34 B. Janssen ; W. Knol ; W.M. Mulder ; R. Rissmann ; and 98 Event Manager (ADEM) 7 35 J. Tichelaar 99 E. Jimenez-Solem; S. Vinther; K.M. Harboe; P. Klarskov; and 1 36 Radboud University Medical Center, Nijmegen, the Netherlands; 100 H.R. Christensen 2 37 Erasmus University Medical Center Rotterdam, the Netherlands; 101 Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark 3 38 Leiden University Medical Center, Leiden, the Netherlands; 102 Introduction: Spontaneous reporting of suspected adverse drug 4 39 Maastricht University Medical Center, Maastricht, the 103 events (ADEs) from health care professional (HCPs) is a cornerstone 5 40 Netherlands; University Medical Center Utrecht, Utrecht, 104 in pharmacovigilance and an important factor in adverse drug reac- 6 41 the Netherlands; Academic Medical Center, Amsterdam, 105 tion (ADR) signal detection. However, underreporting is a major 7 42 the Netherlands; and VU Medical Center, Amsterdam, the 106 challenge, due to lack of awareness of ADEs and the limited time 43 Netherlands on behalf of the Dutch/Flemish pharmacotherapy end 107 available for HCPs. 44 test initiative 108 Materials and methods: We report the effects of introducing an 45 Educational Objectives: To develop a pharmacotherapy end test 109 adverse drug event manager (ADEM), a service offered by the 46 aimed to improve safe prescribing in the Netherlands and Flanders. 110 Capital Region of Denmark and handled at a Department of Clinical 47 At the conclusion of this presentation, participants know about the 111 Pharmacology. Via email or telephone, the HCP spends 2 minutes 48 philosophy behind and practical implications of this test. 112 reporting the ADE to the ADEM, a junior medical doctor, who 49 Purpose: The project aims to develop a Dutch/Flemish pharmaco- 113 then spends approximately 30 minutes completing the report to the 50 therapy end test. 114 Danish Health and Medicines Authority authorities. 51 Methods: Most preventable serious adverse events are due to a rela- 115 Results: After a successful pilot project at one hospital, the service 52 tive small list of drugs (eg, pain killers, anticoagulants, cardiovas- 116 was expanded to all hospitals in the Capital Region of Denmark 53 cular drugs, antidiabetics1). Based on these drug-related problems 117 (1.6 million inhabitants). The number of reported ADEs from the 54 and on basic pharmacological principles (pharmacokinetics, good 118 ADEM increased by 44% from 2013 to 2014 and contributed to 55 prescribing, prescribing laws), a list of end terms has been formu- 119 a 50% increase in reports overall from the whole Capital Region. 56 lated, which each prescriber has to know before starting to prescribe 120 Approximately 85% of all suspected ADEs from hospitals in the 57 independently. A test has been developed covering these end terms. 121 Capital Region of Denmark are now reported through the ADEM. 58 Education material to prepare for this pharmacotherapy end test has 122 Conclusion: The ADEM has relieved HCPs of the administrative 59 been developed. Ultimately, each medical student in the Netherlands 123 burden of reporting adverse drug events, and it has increased the 60 and Flanders has to pass this test before graduating. 124 number of adverse drug events reported to the Danish Health and 61 Results: End terms covering 11 different subjects have been devel- 125 Medicines Authority. The ADEM has contributed to a substantial 62 oped. Educational material (youtube channel, pharmacotherapy 126 increase in the number of reported ADEs from the Capital Region. 63 reader, cases in www.pscribe.nl) has been made available. A total 127 The ADEM delivers high-quality reports, increases awareness of 64 of 215 multiple choice questions covering the end terms have been 128

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1 developed. Based on these, the pharmacotherapy end test has been The IUPHAR Clinical Division is contributing at the 12th Conference 65 2 taken since September 2014 in Nijmegen, the Netherlands. About of the European Association for Clinical Pharmacology and 66 3 30% of students fail per test; however, ultimately all students pass. Therapeutics (EACPT) to be held in Madrid, 27 to 30 June 2015, 67 4 The other universities in the Netherlands and Flanders are preparing sponsoring a symposium along with the EACPT titled “Clinical 68 5 to start the test. Networks and Consortia in Drug-Induced Liver Injury (DILI): an 69 6 Conclusions: A Dutch/Flemish pharmacotherapy end test has been opportunity for advancing Safety Science. 70 7 developed based on end terms covering the most frequent preventable Over the past decade several concerted efforts have facilitate an 71 8 serious adverse events and basic pharmacotherapy principles. The test unprecedented grow in clinical and translational research in DILI, 72 9 has been taken in Nijmegen, the Netherlands since September 2014. which have certainly contributed to highlight the relevance of this 73 10 The other universities in the Netherlands and Flanders are prepar- safety concern among all stakeholders. 74 11 ing to start testing. Whether this test will lead to safe prescribing is In this session we will update some of the most important steps 75 12 subject of an oncoming study. set forward and the challenges that still remain. We will discuss the 76 13 prospective networking initiatives that allow collecting well-vetted 77 14 DILI cases which have provided new insights in clinical phenotypes 78 15 Reference and severity. The systematic collection of biological samples has 79 16 1. Leendertse et al. Arch Intern Med. 2008 Sep 22;168. enabled to perform pharmacogenetic and mechanistic approaches, 80 17 providing the rationale for future studies. The discovery, qualifica- 81 18 tion, and validation of new mechanistic and liver specific biomarkers 82 19 Pharmacovigilance And Risk Management: have become an unmet need that can now be dealt through the joined 83 20 How to Detect, Evaluate and Minimize The collaborative efforts of the respective hepatotoxicity working groups 84 21 Risks: A European Point of View of the European IMI SAFE-T Consortium and the Predictive Safety 85 22 Testing Consortium (PSTC) in the US. 86 H. Le Louet 23 Finally, the role of health regulatory agencies to address the major 87 Head of Pharmacovigilance Federation at Paris University 24 risk of DILI for new compounds to reduce drug attrition, improve 88 Hospitals (APHP), Pharmacovigilance Risk Assessment 25 safety assessment through risk minimization plans, support con- 89 Committee Member (PRAC/EMA) 26 ditional approval of new chemical entities with toxicity potential 90 In the seventies, use of thalidomide led to one of the most prominent 27 and to move towards truly safety personalized medicine will be also 81 disasters in the history of drug development. This catastrophe initi- 28 addressed. 92 ated a change of paradigm in the world with regard to drug safety. 29 93 Quickly after, a global system called pharmacovigilance was imple- 30 94 mented in different parts of the world. Pharmacovigilance concerns 31 95 the science and activities relating to the detection, assessment, under- Promoting Utility of Pk/Tdm Principles 32 96 standing, and prevention of adverse effects or any other drug-related Among Practitioners Facilitates Dialog 33 97 problem (WHO 2002). Towards Rationalization of Drug use 34 98 The pharmacovigilance system is mainly based on spontaneous R. Maciulaitis 35 99 reporting signal detection and methods for causality assessment. But Institute of Physiology and Pharmacology, Lithuanian University 36 100 the only use of spontaneous reporting may lead to extreme regula- of Health Sciences 37 101 tory decisions with product withdrawal (today the DILI are one of Clinical pharmacology has been an educational subject of during 38 102 the main cause of drug withdrawals), delay, or refusal of marketing. undergraduate studies for > 20 years as a short course (2 ECTC 39 103 There is no efficient or risky drug for the whole population. credits) during sixth year of medical studies. This education showed 40 104 Therefore, the concept of global drug risk management with imple- certain limitation in employment and interpretation of various thera- 41 105 mentation of risk management plan appeared in the early 2000 and peutic drug monitoring options. We did analyze the practice of thera- 42 106 is mandatory for all new drugs in Europe since July 2012. The goal peutic drug monitoring (TDM) in our hospital and observed clear 43 107 is to define an early (preapproval) and proactive approach in order areas for possible improvements. As a consequence, we did initiate 44 108 to ensure that the benefit always outweigh the risks during all the a soft interactive intervention by illustrating and summarizing prob- 45 109 lifecycle of the drug and to better target the drug in subpopulation lems observed in TDM and discussing possible ways of improvements 46 110 with a high benefit risk balance. of patient care with colleagues from intensive care unit. This friendly 47 111 Several approaches mainly from European Medicines Agency interaction was accepted quite positively by colleagues also showing 48 112 (EMA) and US Food and Drug Administration (FDA) have been certain positive trends in TDM improvements. The interaction event 49 113 developed in the frame of ICH recommendations. This presentation was a timely option also to update colleagues with innovations utiliz- 50 114 will focus on EMA plan. ing new PK/TDM knowledge and principles for rational drug use. We 51 will share with the audience our findings and specific arguments used 115 52 by us to encourage colleagues to seek for consultancies and studies 116 53 in clinical pharmacology area. 117 54 Clinical Networks And Consortia In 118 55 Drug-Induced Liver Injury (Dili): An 119 56 Opportunity For Advancing Safety 120 57 Science Junior Doctor-Led “Near-Peer” Education 121 58 M. Isabel Lucena1,2 S. Maxwell 122 59 1Head, Department of Clinical Pharmacology, Instituto Clinical Pharmacology Unit, University of Edinburgh, United 123 60 de Investigación Biomédica de Málaga (IBIMA), Hospital Kingdom 124 61 Universitario Virgen de la Victoria, Universidad de Málaga, Near-peer teaching (NPT) provides a means of delivering training in 125 62 Málaga, Spain; and 2Centro de Investigación Biomédica en Red de practical skills to medical students by tapping into the large resource 126 63 Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, of junior doctors as an important and effective pool of teachers. Not 127 64 Spain only does this approach provide much needed teaching for students 128

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1 but it also provided a vital introduction to teaching skills for the in 2008 and revised in 2014. They are emerging as reference criteria 65 2 doctors of the future. This approach is particularly relevant to the throughout Europe. 66 3 delivery of prescribing education, which has proved to be a major 67 4 challenge for many undergraduate programmes. This brief presenta- 68 5 tion will review the development of a NPT programme in prescribing Heterogeneity, the problem with the 69 6 education based in the hospitals of South-East Scotland over the last 8 averages and the new regulatory 70 7 years based on one hour tutorials delivered by junior doctors to small challenge: “whom to treat” 71 8 groups of students. It will address (i) the motivations for developing C. Pontes 72 9 the programme, (ii) the prerequisites for establishing such a pro- Unitat de Farmacologia Clínica, Hospital de Sabadell, Institut 73 10 gramme, (iii) the barriers to implementation, (iv) the potential ben- Universitari Parc Taulí - Universitat Autònoma de Barcelona, 74 11 efits for the tutors and students, (v) the limitations of this approach, Spain 75 12 and (iv) the importance of addressing the need for sustainability. Any regulatory assessment has the ultimate aim to safeguard public 76 13 health, by ensuring that, for a given medicinal product, the potential 77 14 risks are outweighed by its therapeutic efficacy in the intended condi- 78 15 References tions of use. Evidence is required to reliably predict how the observed 79 16 1. Qureshi ZU, Gibson KR, Ross M, Maxwell S. Perceived tutor benefits effects in a limited sample will translate into a wide population if the 80 17 of teaching near peers: insights from two near peer teaching product is commercialized, and such prediction requires to be pre- 81 18 programmes in South East Scotland. Med Teach. 2013;35:261–262. cise, since any failure may potentially have a huge impact on public 82 19 2. Gibson KR, Qureshi Z, Ross MT, Maxwell S. Junior doctor-led ‘near- health. Testing for homogeneity of the effects across different types 83 20 peer’ prescribing education for medical students. Br J Clin of subjects is then a necessary step, but may also serve as a useful tool 84 21 Pharmacol. 2014;77:122–129. to find markers of risk or therapeutic response that may help to bet- 85 22 ter define the medical use of the compounds. However, risks derived 86 23 from multiplicity of assessments may lead to misleading conclusions, 87 24 Joint efforts for the development and and thus clear rules for a priori confirmatory testing of certain sources 88 25 qualification of biomarkers in dili. of heterogeneity are required, as well as clear understanding on what 89 26 Where do we stand now? constitutes exploratory analysis of data aimed to hypothesis genera- 90 27 81 M. Merz tion. Besides, the huge implications of the development of precision 28 92 Discovery and Investigative Safety, Novartis Institutes for medicine have to be considered, since a full new paradigm in which 29 93 BioMedical Research, Werk Klybeck, Bassell, Project Coordinator indications become narrower while achieving higher response rates 30 94 IMI SAFE-T may challenge the current methodology of regulatory assessments. 31 95 Timely detection and in-depth assessment of drug-induced liver The enrichment of patient populations based on predictive biomark- 32 96 injury (DILI), in particular of idiosyncratic forms, is still one of the ers may allow an early obtaining of evidence on benefits, but also 33 97 big safety challenges for clinical drug development. What is needed represents a challenge to the current methods of assessing the risk of 34 98 urgently is a set of biomarkers of hepatic function more sensitive new drugs. The consideration of new timings and sources of safety 35 99 than bilirubin and of hepatocellular injury more specific than ALT information on medicinal products is required, but also the assess- 36 100 and AST. As idiosyncratic DILI by nature is a rare, but serious event, ment of their potential implications from many perspectives, includ- 37 101 large prospective studies across different patient populations and ing the economic impact to healthcare systems and those derived 38 102 healthy volunteers are required for clinical qualification of new mark- from a greater involvement of patients in decision making. 39 103 ers. The IMI SAFE-T (Safer And Faster Evidence-based Translation) 40 104 consortium has undertaken this effort in close collaboration with 41 105 Critical Path Institute’s Predictive Safety Testing Consortium (PSTC). 42 Role of physicians in drug selection 106 The talk will present an overview on SAFE-T’s objectives and quali- 43 policies. A neglected responsibility? 107 fication program, discuss results of the program for a set of new 44 D. Pouchain 108 DILI biomarkers, share lessons learned from collaborating in a large 45 Medical University of Tours, Tours, France 109 public-private partnership, and provide an outlook on planned future 46 Educational Objectives: At the end of this presentation, the partici- 110 activities. 47 pants should be able to understand how the French Transparency 111 48 Committee (TC) works to recommend the reimbursement (R) of new 112 49 drugs in France. 113 50 Update In Strategies for Approppriate Purpose: To describe what Medical Value (SMR) and Added Medical 114 51 Prescription In older Patients Value (ASMR) are and imply on a physician point of view. 115 52 B.M. Errasquín Methods: Descriptive analysis of the criteria for the 4 levels of SMR 116 53 for reimbursement, and for the 5 levels of ASMR for price negotiation 117 54 Inappropriate drugs prescription may have severe impact on health in a second step. Some real examples will illustrate the presentation. 118 55 outcomes, especially in the elderly population. Older patients have Results: Based on severity of the disease, type of the drug (preven- 119 56 an increased risk of adverse drugs reactions, morbidity and mortal- tive, curative or symptomatic), unmet needs, available alternatives, 120 57 ity, adverse drug reaction-related hospital admissions, and increased efficacy/tolerance balance (on relevant clinical outcomes), place in the 121 58 health care systems costs. This higher vulnerability is due to age- therapeutic strategy, and public health value, SMR can be important 122 59 related physiological changes, pharmacokinetics and pharmaco- (R = 65% or 100%), moderate (R = 30%), weak (R = 15%), or 123 60 dynamics, the presence of comorbidities, geriatric syndromes, and insufficient (R= 0%). 124 61 polypharmacy and health care by several specialists in different set- Based on head to head comparison with an active and reimbursed 125 62 tings. The use of explicit criteria to identify and prevent inappropriate comparator in the same indication (and at the same line of treatment), 126 63 use of drugs can be done within a comprehensive geriatric assessment. ASMR can be 1 (revolution = high price) to 5 (no added medical 127 64 Among these criteria are the STOPP-START criteria, first published value = low price). ASMR 1 (major improvement) to 5 (none) is 128

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1 mainly based on magnitude of effect (NNT and/or NNH on rel- However, the changes are complex and poorly understood, and long- 65 2 evant clinical outcomes) observed in direct comparative head to head lasting mucosal adaptation of intestinal functions may occur. 66 3 trial(s). Medico-economic data are never taken into account in the Therefore, potential transcriptional and posttranscriptional adap- 67 4 procedure followed by the Transparency Committee. Improvement tation mechanisms in the small intestine of patients with morbid 68 5 on clinical benefit and safety outcomes is the key driver of the final obesity one year after RYGB surgery will be discussed, primarily 69 6 decision for reimbursement. with reference to intestinal drug metabolizing enzymes and drug 70 7 Conclusions: Advices launched by the TC are “scientific”, but 20 of transporters. Data are provided as obtained by genome-wide mRNA, 71 8 the 25 members of the TC are first physicians with an everyday prac- microRNA, and targeted proteom analysis in the jejunum and by a 72 9 tice, and second highly skilled in methodology and clinical practice. pharmacokinetic study using probe drugs before and after bypass 73 10 Physicians are involved in drug selection policies in France. surgery. The results are compared with data obtained from healthy 74 11 subjects (organ donors). There is evidence that multiple adaptation 75 12 processes may compensate initial changes in drug absorption after 76 13 The drug information centre in bypass surgery. 77 14 2015 – still a valid concept? 78 15 L.A. Reppe1,2; J. Schjøtt3; and O. Spigset2,4 79 16 1Nord-Trøndelag University College, Steinkjer, Norway; Systematic Introduction of New 80 17 2Norwegian University of Science and Technology, Trondheim, Therapies Within The Stockholm County 81 18 Norway; 3University of Bergen, Bergen, Norway; and 4St. Olav and The Karolinska University Hospital 82 19 University Hospital, Trondheim, Norway R.E. Malmström; and C.-O. Stiller 83 20 Educational Objectives: Participants should be able to identify fac- Drug Safety and Evaluation Sector, Clinical Pharmacology, 84 21 tors that may increase and/or decrease the quality of DICs’ written Karolinska University Hospital, SE-171 76 Stockholm, Sweden 85 22 responses. Ten years ago, a model for structured introduction of new medicines 86 23 Purpose: To assess the quality of written responses to drug-related in Stockholm County was suggested as these were concluded to 87 24 queries, in order to identify factors increasing and/or decreasing their drive drug expenditures in years to come. The model is led by the 88 25 quality. Stockholm Drug and Therapeutics Committee and has since been 89 26 Methods: During an 8-week period in 2013, 6 drug-related study stepwise implemented including a) horizon scanning and early drug 90 27 queries were posed simultaneously by e-mail to 7 Scandinavian DICs. evaluations, b) forecasting of drug expenditures, and c) projects to 81 28 The DICs were informed about the study, but staff members were secure a structured introduction and follow-up of new medicines. 92 29 blinded in terms of which queries were study queries, as the study Part of the model is currently a national collaboration, whereby a 93 30 queries were sent from local general practitioners in their own names. couple of counties contribute and all has access to the findings and 94 31 Six general practitioners (external experts) and seven clinical pharma- deliverables. Meanwhile, at the Karolinska University Hospital, 95 32 cologists (internal experts) assessed the responses individually using strategic funds can, when available, be claimed for new drugs or 96 33 a registry form allowing qualitative assessment. indications through the Hospital Medicines Council that provides 97 34 Results: Responses were generally concordant in terms of profes- a recommendation to the Priority Council of the Hospital Board. 98 35 sional content, but varied in terms of quality of references, advice Pivotal questions that need to be addressed in connection with these 99 36 and conclusions. In total, internal and external experts gave 334 requests include type of indication, estimated number of patients, 100 37 comments. With 3 to 4 exceptions, the 42 responses were assessed evidence for efficacy (symptoms, quality of life, survival, biomarker, 101 38 as satisfactorily to good. Both expert groups were concerned with etc) and responder rate, cost per treated patient, and priority of the 102 39 whether specific conclusions and/or advices were given, especially drug in national and international guidelines, by the pharmaceutical 103 40 in patient-specific queries. Use of secondary and tertiary sources as benefits agency, and by the Regional Drug and Therapeutics com- 104 41 references, as opposed to primary sources, was criticised by some mittee. Based on the above information, the Hospital Medicines 105 42 experts. Council review and propose horizontal prioritization of any stra- 106 43 Conclusions: To our knowledge, this is the first study using qualita- tegic resources available to Priority Council to decide how these are 107 44 tive data to identify factors increasing and/or decreasing the quality of keyed out on operations. Further, the prerequisites for structured 108 45 DICs’ responses. The presentation of specific advices and conclusions introduction of new medicines include a description of the treat- 109 46 seem to be especially important when responding to drug-related ment decision process and follow-up procedures and a treatment 110 47 queries. The study has prompted discussions about quality of the decision protocol including clinical criteria to fulfill for treatment. 111 48 written responses in the participating DICs, and the results may also Inclusion and exclusion criteria are selected according to pivotal 112 49 attain a more general interest. documentation for the approved indication, steps to avoid indica- 113 50 tion drift and uncontrolled introduction with unclear benefits/safety 114 51 at an early stage. A protocol for each patient is completed, signed, 115 52 and sent to the Hospital Medicines Council for the go-ahead, and 116 53 Impact of Bariatric Surgery on Drug 117 Transport And Metabolism subsequent registration and monitoring of a continued rigorous 54 implementation process. 118 55 W. Siegmund 119 56 Department of Clinical Pharmacology, University Medicine 120 57 Greifswald, Germany 121 58 Bariatric surgery often provides for patients with morbid obesity the Student-Led Education 122 59 only alternative to achieve sustaining weight loss and substantial M.A. van Agtmael 123 60 improvement or remission of obesity related comorbidity. The surgi- VU university medical center – Internal Medicine, Amsterdam, 124 61 cal intervention as the Roux-en-Y gastric bypass technique leads to Netherlands 125 62 substantial anatomical and physiological changes associated with Educational Objectives: After this presentation participants should 126 63 micronutrient deficiency and changes in pharmacokinetics of drugs. be able to recognize the value of a new concept of education. 127 64 128

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1 Purpose: Pharmacotherapeutic skills are best learned in the context Renal Function In Older People - Validity 65 2 of clinical practice; learning by doing. By giving medical students of the Gfr-Estimating Equations And 66 3 responsibility and independence they will gain intrinsic motivation Implication for Clinical Practice 67 4 and this is associated with deep learning. E. Vidal-Petiot 68 5 Methods: Evidence to support the concept of student-led education is Department of Physiology – Hopital Bichat, Paris, France 69 6 discussed in part 1 of the presentation. It is illustrated by the project Glomerular filtration rate (GFR) is the best marker of renal func- 70 7 “student-run clinic,” presented by a student in part 2. tion. Its evaluation is mandatory for diagnosis and classification of 71 8 Results: Students reported improved skills and indicated that they chronic kidney disease (CKD), as well as for drug dosage adaptation. 72 9 had acquired knowledge they were unlikely to have gained elsewhere The prevalence of CKD is very high in the elderly, due to physi- 73 10 in the curriculum. The quality of specific aspects of care delivered by ological aging of the kidney, to lifelong pathological insults, and to 74 11 students was comparable with that of regular care. comorbidities. However, the GFR estimating equations, such as the 75 12 Conclusions: Students should take the lead in their own education, Cockcroft-Gault, MDRD, and CKD-EPI equations, have not been 76 13 coached by the senior teacher. Medical students should be trained as developed specifically in elderly patients. The presentation will review 77 14 professionals with responsibility for patient care. the performances of the GFR estimating equations in studies which 78 15 included elderly patients, and discuss which methodology should be 79 16 preferred in this population. 80 17 Literature Reference 81 18 1. Learning in student-run clinics: a systematic review. T. Schutte ea. 82 19 Medical Education 2015:49:249–263 Variability In Drug Response and Clinical 83 20 Reality: the Example of Psychiatric 84 21 Diseases 85 22 86 Alert fatigue – an overdose of drug E. Vieta 23 87 information? Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 24 88 I.H. van der Sijs Barcelona, Catalonia, Spain 25 89 Erasmus University Medical Center, Rotterdam, the Netherlands Educational Objectives: At the conclusion of this presentation, the 26 90 Educational Objectives: At the end of this presentation, the partici- participants should be able to demonstrate a deep understanding of 27 81 pants should be able to explain what alert fatigue is, and what its the major causes of heterogeneity and variability of drug response in 28 92 causes and consequences are. Furthermore, they understand how clinical practice, and in particular in the area of psychiatry. 29 93 both alert fatigue and potential measures to avoid it can be inves- Purpose: To identify and summarize the main factors involved in 30 94 tigated. drug response variability in patients with mental disorders, and its 31 95 Purpose: Define alert fatigue, its causes, consequences and investi- implications. 32 96 gational challenges. Methods: A systematic review of the topic was carried out using 33 97 Methods: Literature review, disguised observation, retrospective “variability”, “drug response” and mental disorders” as PubMed 34 98 analysis of alert overrides, think-aloud study, chart review. key words. 35 99 Results: Alert Fatigue is the mental state that is the result from alerts Results: The systematic review yielded 741 PubMed publications. 36 100 consuming too much time and energy, which can cause relevant After careful screening, 18 were considered truly relevant for the 37 101 alerts to be unjustifiably overridden among clinical irrelevant ones. study purpose. The current evidence, based on the 18 selected pub- 38 102 Unjustified overriding is a medication error that may result in adverse lications, indicates that Psychiatry is an area with blurred borders 39 103 drug events, although this causal relationship has not been confirmed between conditions and high variability of treatment response. 40 104 in studies yet. Alert fatigue is often caused by low specificity of alerts, Conclusions: Drugs do not have the same effects in all patients. 41 105 but other error-producing conditions in the electronic prescribing Part of that variability may be genetically mediated and part may 42 106 system, insufficient training, and cultural aspects may also play a be environment-dependent. Psychiatry is an area of medicine where 43 107 role. The optimal specificity and sensitivity are unknown, as are other variability of drug response is particularly high. The results of clinical 44 108 aspects affecting alert fatigue. To investigate alert fatigue, override trials cannot be directly extrapolated to individuals. Even drugs with 45 109 reasons are an important source of information, but often difficult very similar mechanism of action may work differently in the same 46 110 to obtain. Clinical pharmacologists may play a role in determining patient and the same drug may work differently in the same patient 47 111 cut-off points for alert generation. across different illness episodes. Drugs for psychiatric conditions 48 112 Conclusions: Alert fatigue is a ubiquitous problem and much is still cannot be judged exclusively based on their efficacy and tolerability. 49 113 unknown. To gain optimal benefit of electronic prescribing with Stratification is needed in psychiatry to identify specific subpopula- 50 114 clinical decision support, more research should be performed on tions that may be more or less responsive to given drugs. 51 115 this topic. 52 116 53 117 54 Literature Reference 118 55 Literature Reference 1. Vieta E, Pappadopulos E, Mandel FS, Lombardo I. Impact of 119 56 1. Van der Sijs IH. Drug Safety Alerting in Computerized Physician geographical and cultural factors on clinical trials in acute mania: 120 57 Order Entry. Unraveling and Counteracting Alert Fatigue (PhD lessons from a ziprasidone and haloperidol placebo-controlled 121 58 Thesis http://repub.eur.nl/pub/16936). study. Int J Neuropsychopharmacol. 2011 Sep;14(8):1017–1027. 122 59 2. Coleman J et al. On the alert: future priorities for alerts in clinical 2. Vieta E. Personalized medicine applied to mental health: Precision 123 60 decision support for computerized physician order entry identified psychiatry. Rev Psiquiatr Salud Mental, 2015, in press. 124 61 from a European workshop. BMC. BMC Med Inform Decis Mak. 125 62 2013;13:111. 126 63 127 64 128

2015 e9 Clinical Therapeutics

1 Uk Translational Medicine and The dili-sim initiative. Integrated systems 65 2 Therapeutics (Tmat) Phd Training pharmacology modeling to explain and 66 3 D.J. Webb predict drug hepatotoxicity 67 4 Clinical Pharmacology Unit, University of Edinburgh, Edinburgh, P. Watkins 68 5 UK The Hammer Institute, USA 69 6 Within the last 10 years, 2 major UK funding bodies (Medical Drugs-induced liver injury (DILI) can occur through a variety of 70 7 Research Council [MRC] and Wellcome Trust) have supported clini- adverse outcome pathways. Understanding and predicting the effects 71 8 cal PhD programmes designed to build capacity in clinical pharma- of multiple toxicity pathways as a function of time and exposure 72 9 cology and therapeutics, focusing on the translational difficulties in are difficult without systematic organization. Quantitative systems 73 10 getting laboratory findings, which might be exploited therapeutically, modeling can combine multiple drug effects to address this challenge. 74 11 into the clinic (a major translational “block”). This model builds The DILIsim Initiative is a public-private partnership involving sci- 75 12 on a concept argued by Garret Fitzgerald (UPenn) that there is a entists from 14 major pharmaceutical companies and the FDA; it is 76 13 need for physicians with skills including, but going beyond, those of now entering its fourth year. In addition to financial support, com- 77 14 the traditional clinical pharmacologist. These individuals will drive panies provide often unpublished data and perform in kind research 78 15 translational research, working in a pivotal role between the lab and to fill gaps in knowledge. The software produced by the initiative, 79 16 the clinic [1]. They will need an understanding of the potential of DILIsym®, is a highly specified, mechanistic, hepatic model that 80 17 omics, quantitative analysis, imaging and bioinformatics as well as utilizes extensive kinetic information among interrelated biological 81 18 skills in pharmacology, PK/PD, statistics, trial design and first-in- processes to explore the hepatotoxic underpinnings via simulations. 82 19 human studies. Such new training schemes gain from collaboration Mechanisms currently included in the model are oxidative stress, 83 20 with industry, and create clinical pharmacologists well able to move mitochondrial dysfunction, bile acid transporter inhibition, and lipo- 84 21 from identifying a clinical problem and undertaking an enabling pro- toxicity. The Dilisym® software was originally developed to explain 85 22 gramme of laboratory science, to building a drug development pro- and predict interspecies differences in dose dependent hepatotoxicity 86 23 gramme. The Wellcome Trust funded four UK centres, in Cambridge, to help inform first in man dosing. However, the modeling effort has 87 24 London, Newcastle and Scotland (led from Edinburgh), while MRC expanded to improve interpretation of traditional and mechanistic 88 25 funded two, in Liverpool and Scotland (led from Glasgow). A link serum biomarkers including miR122, CK18 and its caspase-cleaved 89 26 with pathology in the Glasgow scheme has particular attraction for fragment, and HMGB1. It is now possible to utilize DILIsym® to 90 27 identifying drug targets. Around 50 clinicians, many with consider- predict the range of percent hepatocyte loss through necrosis or 81 28 able academic potential, have been attracted into these schemes, to apoptosis from measurements of these biomarkers in serial serum 92 29 enhance capacity in translational medicine and therapeutics, and con- samples archived from clinical trials. By varying parameters within 93 30 tribute to drug development by working with (or indeed within) the Dilisym®, it is possible to create simulated patient populations that 94 31 pharmaceutical industry, ultimately to promote health and wealth. mimic selected clinic populations in terms of susceptibility to DILI. 95 32 This approach successfully recently predicted the latency and inci- 96 33 dence of serum ALT elevations that were observed in the clinical trials 97 34 Literature Reference of troglitazone (ClinPharmacolTher. 96(5):589–598, 2014). Systems 98 99 35 1. Fitzgerald GA. Opinion: Anticipating change in drug development: modeling tools such as DILIsym® will increasingly be used to support 100 36 the emerging era of translational medicine and therapeutics. Nat decision making throughout the life cycle of new drug candidates. 101 37 Rev Drug Discov. 2005;4:815–818. 38 102 39 103 40 104 41 105 42 106 43 107 44 108 45 109 46 110 47 111 48 112 49 113 50 114 51 115 52 116 53 117 54 118 55 119 56 120 57 121 58 122 59 123 60 124 61 125 62 126 63 127 64 128

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