DOCSLIB.ORG

Genetic Determinants of Acenocoumarol And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic Determinants of Acenocoumarol And Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements Janne Cadamuro, Benjamin Dieplinger, Thomas Felder, Igor Kedenko, Thomas Mueller, Meinhard Haltmayer, Wolfgang Patsch, Hannes Oberkofler To cite this version: Janne Cadamuro, Benjamin Dieplinger, Thomas Felder, Igor Kedenko, Thomas Mueller, et al.. Ge- netic determinants of acenocoumarol and phenprocoumon maintenance dose requirements. European Journal of Clinical Pharmacology, Springer Verlag, 2009, 66 (3), pp.253-260. 10.1007/s00228-009- 0768-7. hal-00547972 HAL Id: hal-00547972 https://hal.archives-ouvertes.fr/hal-00547972 Submitted on 18 Dec 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Eur J Clin Pharmacol (2010) 66:253–260 DOI 10.1007/s00228-009-0768-7 PHARMACOGENETICS Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements Janne Cadamuro & Benjamin Dieplinger & Thomas Felder & Igor Kedenko & Thomas Mueller & Meinhard Haltmayer & Wolfgang Patsch & Hannes Oberkofler Received: 5 August 2009 /Accepted: 19 November 2009 /Published online: 18 December 2009 # Springer-Verlag 2009 Abstract gous CYP2C9*1*1 subjects (P=0.0004 and P=0.0017, Objective The variability in warfarin dose requirement is respectively). A multiple regression model including age, attributable to genetic and environmental factors. Acenocou- sex, last INR, VKORC1,andCYP2C9 genotypes explained marol (AC) and phenprocoumon (PC) are coumarin derivates ~50% of the variability in AC/PC dose requirements. CALU widely prescribed in European countries for the prevention genotype combinations showed minor effects on PC dose and treatment of thromboembolic events. The aim of our study requirements. No associations with AC or PC dose require- was to investigate the contribution of genes involved in the ments were observed for sequence substitutions in the GGCX vitamin K cycle to AC and PC maintenance doses. or APOE genes. Methods Common single nucleotide polymorphisms Conclusion These results reveal that interindividual variability (SNPs) in the genes encoding cytochrome P450 family in weekly AC and PC maintenance dose requirement is mainly member 2C9 (CYP2C9), vitamin K epoxide reductase dependent on the VKORC1 1173C>T and the CYP2C9*3 complex subunit 1 (VKORC1), γ-glutamyl carboxylase alleles. VKORC1 and CYP2C9 genotyping might provide (GGCX), calumenin (CALU) and apolipoprotein E (APOE) helpful information to prevent serious bleeding events in were studied in 206 patients receiving AC or PC. subjects receiving AC or PC. Results Compared to patients with the VKORC1 C1173C genotype, maintenance doses for AC or PC were reduced to Keywords Pharmacogenetics . Single nucleotide 74.6 or 70.2% in heterozygous C1173T subjects and to 48.6 or polymorphisms . Phenprocoumon . Acenocoumarol 48.1% in homozygous T1173T subjects (P<0.0001). Further- more maintenance doses for AC and PC were significantly Abbreviations lower in heterozygous CYP2C9*1*3, CYP2C9*2*3,andin AC Acenocoumarol CYP2C9*3*3 homozygote individuals compared to homozy- PC Phenprocoumon SNP Single nucleotide polymorphism Electronic supplementary material The online version of this article CYP2C9 Cytochrome P450 family member 2C9 (doi:10.1007/s00228-009-0768-7) contains supplementary material, VKORC1 Vitamin K epoxide reductase complex subunit 1 which is available to authorized users. GGCX γ-Glutamyl carboxylase J. Cadamuro : T. Felder : I. Kedenko : W. Patsch : ApoE Apolipoprotein E H. Oberkofler (*) RFLP Restriction fragment length polymorphism Department of Laboratory Medicine, ANOVA Analysis of variance Paracelsus Medical University and Universitätsklinikum Salzburg, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria e-mail: [email protected] Introduction B. Dieplinger : T. Mueller : M. Haltmayer Department of Laboratory Medicine, Konventhospital Barmherzige Brueder Linz, The coumarin-based vitamin K antagonists acenocoumarol Linz, Austria (AC) and phenprocoumon (PC) are oral anticoagulant drugs 254 Eur J Clin Pharmacol (2010) 66:253–260 widely prescribed in continental European and Latin- scribed previously [22]. Based on numerous studies on American countries for the prophylaxis and treatment of warfarin, it is well accepted that the relationship between thromboembolic events [1]. Oral anticoagulant manage- the prescribed dose and the individual response in oral ment is challenging and requires frequent monitoring due to anticoagulant therapy is determined to a considerable extent the marked inter- and intraindividual variability in dose by genetic factors [23]. However our present knowledge on requirements and the risk of serious bleeding. Although the the implications of candidate genes and their allelic variants variation in the initial and maintenance dose is known to in the dose requirement of other frequently used coumarin- depend on body weight, age, dietary vitamin K intake, and derived drugs including AC or PC is less well established. absorption, as well as on environmental factors such as In the present study we aimed to evaluate the impact of comedication and hypermetabolic states, there is growing polymorphic sequence substitutions in genes encoding for evidence for a strong hereditary component [2]. CYP2C9, VKORC1, GGCX, CALU, and APOE on antico- The highly polymorphic cytochrome P450 family member agulant therapy with AC and PC. 2C9 (CYP2C9) is the main liver enzyme responsible for the rate limiting metabolism of AC and, at least in part, of PC [3]. Single nucleotide polymorphisms (SNPs) in the CYP2C9 Materials and methods gene, including the CYP2C9*2 and CYP2C9*3 variants, have been shown to decrease enzymatic activity [4], have Study population been associated with lower warfarin dose requirements [5, 6], and have been demonstrated to increase the risk for Unrelated subjects of Austrian-German descent between 17 serious bleeding complications [7, 8]. Coumarin-derived and 87 years of age (n=206) who were prescribed oral drugs exert their anticoagulant effect by interfering with the anticoagulants were consecutively recruited from April recycling of reduced vitamin K [9], required as a cofactor for 2006 to December 2007. Information on patient’s age, γ-glutamyl carboxylase (GGCX)[10] to activate the precur- sex, indication for anticoagulation therapy, date of initiation sor forms of several clotting factors. Recently, a component of AC/PC therapy, target INR range, initial AC/PC dose, of the vitamin K-dependent γ-carboxylation system, the and concomitant medications as well as history of major vitamin K epoxide reductase complex subunit 1 (VKORC1), and minor bleeding episodes was collected using a has been identified as a molecular target of coumarin-based standardized questionnaire or was obtained from medical anticoagulants [11]. Rare mutations in VKORC1 are associ- records. Major indications for oral anticoagulation treat- ated with hereditary forms of warfarin resistance [12]. In ment included thromoboembolic disease, atrial fibrillation, addition several SNPs, including 1173C>T (rs9934438), and joint replacement (Table 1). Study participants had 1639G>A (rs9923231), and 3730G>A (rs7294), have been been under oral anticoagulation at the time of blood identified that significantly contribute to the observed collection for more than 4 weeks and their individual target variability in coumarin-based anticoagulant dose require- INR had been stabilized. The therapeutic target INR range ments [13, 14] and have been shown to increase the risk for was determined by each patient’s physician and differed severe bleeding complications [15]. according to the indication for anticoagulation treatment. Although these common genetic variants in the Interacting concomitant medications were grouped into VKORC1 and CYP2C9 genes, together with environmental drugs that might potentiate or attenuate the anticoagulant factors, account for up to 50–60% of the variance in effect of AC and PC [24, 25]. Only patients with warfarin dose requirement [2], other genes involved in the unchanged maintenance doses and stable INR measure- action and biotransformation of coumarin-based anticoagu- ments within the therapeutic range (mean target INR ± 0.4) lants may also contribute to the variable phenotype. at four consecutive clinic visits were included in our study. Associations of allelic variants with warfarin sensitivity All study subjects provided informed consent, and study have been described for GGCX [16] as well as for the protocols were approved by the local ethics committee. chaperone calumenin [17], which binds to and inhibits GGCX [18]. It is also well known that a high dietary intake DNA extraction and genotyping of vitamin K antagonizes the anticoagulant effects of coumarins [19]. Bound to chylomicrons and chylomicron Genomic DNA was isolated from peripheral white blood remnants, lipid soluble vitamin K is cleared form the cells as described previously [26]. Real-time PCR followed plasma through ApoE receptor-mediated endocytosis [20]. by melting curve analysis was performed on the Light- ApoE
Load more

Recommended publications
  • Low Molecular Weight Heparin Versus Acenocoumarol in the Secondary Prophylaxis of Deep Vein Thrombosis
    Thromb Haemost 1999; 81: 26–31 © 1999 Schattauer Verlag, Stuttgart Low Molecular Weight Heparin versus Acenocoumarol in the Secondary Prophylaxis of Deep Vein Thrombosis S. Lopaciuk, H. Bielska-Falda1, W. Noszczyk1, M. Bielawiec 2, W. Witkiewicz 3, S. Filipecki 4, J. Michalak 5, L. Ciesielski 6, Z. Mackiewicz 7, E. Czestochowska 8, K. Zawilska 9, A. Cencora 10, among others* From the Institute of Hematology and Blood Transfusion, Warsaw, 1st 1Department of Surgery, Medical School, Warsaw, 2Department of Hematology, Medical School, Bialystok, 3Department of Vascular Surgery, District General Hospital, Wroclaw, 4Department of Internal Medicine, Institute of Tuberculosis and Lung Diseases, Warsaw, 5Department of Vascular Surgery, Medical School, Lublin, 1st 6Department of Surgery, Medical School, Lodz, 7Department of Vascular Surgery, Medical School, Bydgoszcz, 3rd 8Department of Internal Medicine, Medical School, Gdansk, 9Department of Hematology, Medical School, Poznan, and 10Department of Vascular Surgery, District General Hospital, Krakow, Poland Summary oral anticoagulant for at least 3 months (secondary prophylaxis). Al- though long-term anticoagulation with coumarin drugs, the most popu- The aim of this study was to determine the efficacy and safety of lar of which are warfarin and acenocoumarol, has been repeatedly dem- subcutaneous weight-adjusted dose low molecular weight heparin onstrated effective in the prevention of recurrent venous thromboembo- (LMWH) compared with oral anticoagulant (OA) in the prevention of lism, it suffers from a number of limitations. This treatment requires recurrent venous thromboembolism. In a prospective multicenter trial, strict laboratory control and consequent adjustments of the drug dosage 202 patients with symptomatic proximal deep vein thrombosis (DVT) and carries a substantial risk of bleeding complications (1).
    [Show full text]
  • Occurrence, Elimination, and Risk of Anticoagulant Rodenticides in Wastewater and Sludge
    Occurrence, elimination, and risk of anticoagulant rodenticides in wastewater and sludge Silvia Lacorte, Cristian Gómez- Canela Department of Environmental Chemistry, IDAEA-CSIC, Jordi Girona 18-26, 08034 Barcelona Rats and super-rats Neverending story 1967 Coumachlor 1 tn rodenticides /city per campaign “It will be the LAST ONE” Rodenticides Biocides: use regulated according to EU. Used mainly as bait formulations. First generation: multiple feedings, less persistent in tissues, commensal and outdoor use. Second generation: single feeding (more toxic), more persistent in tissue, commensal use only. Toxic: vitamin K antagonists that cause mortality by blocking an animal’s ability to produce several key blood clotting factors. High oral, dermal and inhalation toxicity. Origin and fate of rodenticides Study site: Catalonia (7.5 M inhabitants) 1693 km of sewage corridor 13 fluvial tanks (70.000 m3) 130,000,000 € / 8 YEARS 32,000 km2 378,742 kg/y AI 2,077,000 € Objectives 1. To develop an analytical method to determine most widely used rodenticides in wastewater and sludge. 2. To monitor the presence of rodenticides within 9 WWTP receiving urban and agricultural waters. 3. To evaluate the risk of rodenticides using Daphnia magna as aquatic toxicological model. 4. To study the accumulation of rodenticides in sludge. Compounds studied Coumachlor* Pindone C19H15ClO4 C14H14O3 Dicoumarol Warfarin C19H12O6 C19H16O4 Coumatetralyl Ferulenol FGARs C19H16O3 C24H30O3 Acenocoumarol Chlorophacinone • Solubility C19H15NO6 C23H15ClO3 0.001-128 mg/L • pKa 3.4-6.6 Flocoumafen Bromadiolone C H F O C H BrO 33 25 3 40 30 23 4 • Log P 1.92-8.5 Brodifacoum Fluindione C H BrO 31 23 3 C15H9FO2 SGARs Difenacoum Fenindione C31H24O3 C15H10O2 1.
    [Show full text]
  • STUDY PROTOCOL Study Information Title Apixaban Drug
    Apixaban B0661076NON-INTERVENTIONAL STUDY PROTOCOL Final, 15-Feb-2016 NON-INTERVENTIONAL (NI) STUDY PROTOCOL Study information Title Apixaban drug utilization study in Stroke prevention in atrial fibrillation (SPAF) Protocol number B0661076 AEMPS Code PFI-API-2016-01 Protocol version identifier 4.0 Date of last version of protocol 15-Feb-2016 Active substance Apixaban B01AF02 Medicinal product Eliquis® Research question and objectives Evaluate the apixaban utilization according to the approved SPAF indication and recommendations by EMA. The study objectives are: Objective 1: To characterise patients using apixaban according to demographics, comorbidity, risk of thromboembolic events (CHADS2 and CHA2DS2-Vasc scores), risk of bleeding events (HAS-BLED score), comedications and compare it with the profile of patients treated with VKA, dabigatran and rivaroxaban. Objective 2: Describe the level of appropriate usage according to the posology recommended in the apixaban SmPC. Objective 3: Describe the potential interactions with other drugs prescribed concomitantly according with the SmPC recommendations. Objective 4: Estimate the level of apixaban adherence by the medication possession ratio (MPR) and discontinuation rates and compare it with VKA, dabigatran and CT24-GSOP-RF03 NI Study Protocol Template; Version 3.0, Effective Date 10-Oct-2014 Pfizer Confidential Page 1 of 28 Apixaban B0661076NON-INTERVENTIONAL STUDY PROTOCOL Final, 15-Feb-2016 rivaroxaban cohort. Objective 5: To analyze INR (International Normalized Ratio) values during the last 12 months and to obtain TTR (Time in Therapeutic Range) values in patients previously treated with VKA and, during the whole study period for those in the cohort treated with VKA Author Ángeles Quijada Manuitt, IDIAP Jordi Gol Rosa Morros Pedrós, IDIAP Jordi Gol Jordi Cortés, IDIAP Jordi Gol José Chaves Puertas, Pfizer SLU Sponsor Pfizer S.L.U Avda.
    [Show full text]
  • Review of Anticoagulant Drugs in Paediatric Thromboembolic Disease
    18th Expert Committee on the Selection and Use of Essential Medicines (21 to 25 March 2011) Section 12: Cardiovascular medicines 12.5 Antithrombotic medicines Review of Anticoagulant Drugs in Paediatric Thromboembolic Disease September 2010 Prepared by: Fiona Newall Anticoagulation Nurse Manager/ Senior Research Fellow Royal Children’s Hospital/ The University of Melbourne Melbourne, Australia 1 Contents Intent of Review Review of indications for antithrombotic therapy in children Venous thromboembolism Arterial thrombeombolism Anticoagulant Drugs Unfractionated heparin Mechanism of action and pharmacology Dosing and administration Monitoring Adverse events Formulary Summary recommendations Vitamin K antagonists Mechanism of action and pharmacology Dosing and administration Monitoring Adverse events Formulary Summary recommendations Low Molecular Weight Heparins Mechanism of action and pharmacology Dosing and administration Monitoring Adverse events Formulary Summary recommendations ??Novel anticoagulants Summary 2 1. Intent of Review To review the indications for anticoagulant therapies in children. To review the epidemiology of thromboembolic events in children. To review the literature and collate the evidence regarding dosing, administration and monitoring of anticoagulant therapies in childhood. To review the safety of anticoagulant therapies and supervision required To give recommendations for the inclusion of anticoagulants on the WHO Essential Medicines List 2. Review of indications for antithrombotic therapy in children Anticoagulant therapies are given for the prevention or treatment of venous and/or arterial thrombosis. The process of ‘development haemostasis’, whereby the proteins involved in coagulation change quantitatively and qualitatively with age across childhood, essentially protects children against thrombosis(1-5). For this reason, insults such as immobilization are unlikely to trigger the development of thrombotic diseases in children.
    [Show full text]
  • Pharmacokinetics of Anticoagulant Rodenticides in Target and Non-Target Organisms Katherine Horak U.S
    University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln USDA National Wildlife Research Center - Staff U.S. Department of Agriculture: Animal and Plant Publications Health Inspection Service 2018 Pharmacokinetics of Anticoagulant Rodenticides in Target and Non-target Organisms Katherine Horak U.S. Department of Agriculture, [email protected] Penny M. Fisher Landcare Research Brian M. Hopkins Landcare Research Follow this and additional works at: https://digitalcommons.unl.edu/icwdm_usdanwrc Part of the Life Sciences Commons Horak, Katherine; Fisher, Penny M.; and Hopkins, Brian M., "Pharmacokinetics of Anticoagulant Rodenticides in Target and Non- target Organisms" (2018). USDA National Wildlife Research Center - Staff Publications. 2091. https://digitalcommons.unl.edu/icwdm_usdanwrc/2091 This Article is brought to you for free and open access by the U.S. Department of Agriculture: Animal and Plant Health Inspection Service at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in USDA National Wildlife Research Center - Staff ubP lications by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Chapter 4 Pharmacokinetics of Anticoagulant Rodenticides in Target and Non-target Organisms Katherine E. Horak, Penny M. Fisher, and Brian Hopkins 1 Introduction The concentration of a compound at the site of action is a determinant of its toxicity. This principle is affected by a variety of factors including the chemical properties of the compound (pKa, lipophilicity, molecular size), receptor binding affinity, route of exposure, and physiological properties of the organism. Many compounds have to undergo chemical changes, biotransformation, into more toxic or less toxic forms. Because of all of these variables, predicting toxic effects and performing risk assess- ments of compounds based solely on dose are less accurate than those that include data on absorption, distribution, metabolism (biotransformation), and excretion of the compound.
    [Show full text]
  • Heavy Rainfall Provokes Anticoagulant Rodenticides' Release from Baited
    Journal Pre-proof Heavy rainfall provokes anticoagulant rodenticides’ release from baited sewer systems and outdoor surfaces into receiving streams Julia Regnery1,*, Robert S. Schulz1, Pia Parrhysius1, Julia Bachtin1, Marvin Brinke1, Sabine Schäfer1, Georg Reifferscheid1, Anton Friesen2 1 Department of Biochemistry, Ecotoxicology, Federal Institute of Hydrology, 56068 Koblenz, Germany 2 Section IV 1.2 Biocides, German Environment Agency, 06813 Dessau-Rosslau, Germany *Corresponding author. Email: [email protected] (J. Regnery); phone: +49 261 1306 5987 Journal Pre-proof A manuscript prepared for possible publication in: Science of the Total Environment May 2020 1 Journal Pre-proof Abstract Prevalent findings of anticoagulant rodenticide (AR) residues in liver tissue of freshwater fish recently emphasized the existence of aquatic exposure pathways. Thus, a comprehensive wastewater treatment plant and surface water monitoring campaign was conducted at two urban catchments in Germany in 2018 and 2019 to investigate potential emission sources of ARs into the aquatic environment. Over several months, the occurrence and fate of all eight ARs authorized in the European Union as well as two pharmaceutical anticoagulants was monitored in a variety of aqueous, solid, and biological environmental matrices during and after widespread sewer baiting with AR-containing bait. As a result, sewer baiting in combined sewer systems, besides outdoor rodent control at the surface, was identified as a substantial contributor of these biocidal active ingredients in the aquatic environment. In conjunction with heavy or prolonged precipitation during bait application in combined sewer systems, a direct link between sewer baiting and AR residues in wastewater treatment plant influent, effluent, and the liver of freshwater fish was established.
    [Show full text]
  • Acenocoumarol
    PATIENT & CAREGIVER EDUCATION Acenocoumarol This information from Lexicomp® explains what you need to know about this medication, including what it’s used for, how to take it, its side effects, and when to call your healthcare provider. Brand Names: Canada Sintrom What is this drug used for? It is used to thin the blood so that clots will not form. It is used to treat blood clots. What do I need to tell my doctor BEFORE I take this drug? If you have an allergy to acenocoumarol or any other part of this drug. If you are allergic to this drug; any part of this drug; or any other drugs, foods, or substances. Tell your doctor about the allergy and what signs you had. If you have any of these health problems: Blood vessel problems like aneurysm or dissecting aorta; bleeding problems; bleeding in the brain; active ulcer; bleeding of the stomach, bowel, urinary tract, genitals, or respiratory tract; blood problems; Acenocoumarol 1/9 heart problems like pericarditis or heart valve infection; kidney disease; liver disease; low platelet count; recent surgery, including surgery of the eye or brain; very high blood pressure; low vitamin C levels; arthritis; or mental problems. If you have any of these health problems: A certain health problem called pre-eclampsia, seizures during pregnancy (eclampsia), induction of labor, or threatened spontaneous abortion. If you abuse alcohol or have a drinking problem. If you know that you will not take the drug or have your blood work (PT/INR) checked as you have been told. If you are pregnant or may be pregnant.
    [Show full text]
  • 1 SUPPLEMENTAL MATERIAL the Effectiveness of Interventions for The
    SUPPLEMENTAL MATERIAL The effectiveness of interventions for the implementation of thromboprophylaxis in hospitalized patients at risk for venous thromboembolism: an updated abridged Cochrane systematic review and meta-analysis of Randomized Controlled Trials (RCT). Susan R Kahn1,2,3, Gisèle Diendéré2, David R Morrison2, Alexandre Piché4, Kristian B Filion2,5, Adi J Klil-Drori1,2, James D Douketis6, Jessica Emed7, André Roussin8, Vicky Tagalakis2,3, Martin Morris9, William Geerts10 1Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada 2Centre for Clinical Epidemiology and Community Studies, Jewish General Hospital, McGill University, Montreal, Canada 3Division of Internal Medicine and Department of Medicine, McGill University, Montreal, Canada 4Department of Mathematics and Statistics, McGill University, Montreal, Canada 5Departments of Medicine and of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada 6Department of Medicine, McMaster University and St. Josephs Hospital, Hamilton, Canada 7Department of Nursing, Jewish General Hospital, Montreal, Canada 8Department of Medicine, University of Montreal and Thrombosis Canada, Montreal, Canada 9Schulich Library of Physical Sciences, Life Sciences and Engineering, McGill University, Montreal, Canada 10Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada Corresponding author: Dr Susan R Kahn MD MSc FRCPC GCBA Canada Research Chair Professor of Medicine, McGill University Director, McGill Thrombosis Fellowship Director, JGH Centre of Excellence in Thrombosis and Anticoagulation Care Division of Internal Medicine & Center for Clinical Epidemiology Jewish General Hospital 3755 Cote Ste. Catherine Room B-304.16 Montreal QC CANADA H3T 1E2 Tel. + 1 514 340 8222 X 24667 or 514 340 7587 Fax. 514 340 7564 E-mail: [email protected] 1 Search Criteria 1.
    [Show full text]
  • Fully Automated LC-MS/MS Analysis of Anticoagulants Using a Stable Isotope Labelled Internal Standards
    PO-CON1851E Fully Automated LC-MS/MS Analysis of Anticoagulants Using a Stable Isotope Labelled Internal Standards ASMS 2019 Toshikazu Minohata1, 2, Yuki Uno1, Sigrid Baumgarten3, Stéphane Moreau3, Fanny Dayot2, Jean-François Hoefer2 1. Shimadzu Corporation, Kyoto, Japan 2. ALSACHIM SAS, Illkirch, France 3. Shimadzu Europa GmbH, Duisburg, Germany Fully Automated LC-MS/MS Analysis of Anticoagulants Using a Stable Isotope Labelled Internal Standards Overview • This work describes a fully automated method to quantify 9 anticoagulant drugs in plasma. • The method has been designed to meet the needs of monitoring anticoagulant drugs in routine clinical pathology. Introduction Novel oral anticoagulants (NOACs) are, as an alternative Such analysis is mainly done by liquid chromatography therapy to vitamin K antagonists, used frequently to treat coupled to tandem mass spectrometry (LC-MS/MS). To and prevent thromboembolism. Their precise quantitation streamline the workow, we developed a complete is necessary to identify the presence/absence of an solution including stable isotope labeled standards for anticoagulant effect or to determine the concentration of better precision and accuracy, and investigated the use of a drug that may be helpful for patient management. fully automated sample preparation system coupled online Furthermore, anticoagulants screening is required for with LC-MS/MS. interventional emergency, emergency bleeding and programmed surgery for the elderly. CLAM-2000 DOSINACO™ method Sample preparation method Mobile Pump A Phase
    [Show full text]
  • Meta-Regression of Randomized Control Trials with Antithrombotics
    www.nature.com/scientificreports OPEN Meta‑regression of randomized control trials with antithrombotics: weak correlation between net clinical beneft and all cause‑mortality Roubi Kilo1,5,12*, Silvy Laporte2,3, Rama Arab5, Sabine Mainbourg4,5, Steeve Provencher6, Guillaume Grenet7, Laurent Bertoletti8,9, Laurent Villeneuve10,11, Michel Cucherat5 & Jean‑Christophe Lega4,5 & META‑EMBOL Group This study aimed to explore the validity of the use of the net clinical beneft (NCB), i.e. the sum of major bleeding and thrombotic events, as a potential surrogate for all‑cause mortality in clinical trials assessing antithrombotics. Published randomized controlled trials testing anticoagulants in the prevention or treatment of venous thromboembolism (VTE) and non‑valvular atrial fbrillation (NVAF) were systematically reviewed. The validity of NCB as a surrogate endpoint was estimated by calculating the strength of correlation of determination (R2) and its 95% confdence interval (CI) between the relative risks of NCB and all‑cause mortality. Amongst the 125 trials retrieved, 2 2 the highest R trial values were estimated for NVAF (R trial = 0.41, 95% CI [0.03; 0.48]), and acute VTE 2 (R trial = 0.30, 95% CI [0.04; 0.84]). Conversely, the NCB did not correlate with all‑cause mortality in 2 2 prevention studies with medical (R trial = 0.12, 95% CI [0.00; 0.36]), surgical (R trial = 0.05, 95% CI [0.00; 2 0.23]), and cancer patients (R trial = 0.006, 95% CI [0.00; 1.00]). A weak correlation between NCB and all cause‑mortality was found in NVAF and acute VTE, whereas no correlation was observed in clinical situations where the mortality rate was low.
    [Show full text]
  • Nadroparin Calcium a Review of Its Pharmacology and Clinical Use in the Prevention and Treatment of Thromboembolic Disorders
    Drugs & Aging 1997 Apr; 10 (4): 299-322 AD IS DRUG EVALUATION 1170-22'1X/97/0004-{)299/$12.DO/O © Adis International Umited. All rights reserved, Nadroparin Calcium A Review of its Pharmacology and Clinical Use in the Prevention and Treatment of Thromboembolic Disorders Rick Davis and Diana Faulds Adis International Limited, Auckland, New Zealand Various sections of the manuscript reviewed by: S. Beguin, Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands; D. Bergqvist, Department of Surgery, Uppsala University, Uppsala, Sweden; L. Borris, Department of Orthopaedics, University Hospital of Aarhus, Aarhus, Denmark; P. Denoncourt, Frenchman Bay Orthopedics, Ellsworth, Maine, USA; J. Fareed, Department of Pathology and Pharmacology; Loyola University Medical Center, Chicago, Illinois, USA; B. Forette, Saint Perine Hospital, Paris, France; E. Gurfinkel, Institute of Cardiology and Cardiovascular Surgery, Buenos Aires, Argentina; J. Harenberg, Department of Medicine, University of Heidelberg, Heidelberg, Germany; D.C. Heaton, Haematology Department, Christchurch Hospital, Christchurch, New Zealand; R.J. Kandrotas, Department of Pharmaceutical Services, Miami Children's Hospital, Miami, Florida, USA; R. Kay, Department of Medicine, Prince of Wales Hospital, Hong Kong; M. Koopman, Department of Haemostasis and Thrombosis, University of Amsterdam, Amsterdam, The Netherlands; T. Matsuo, Hyogo Prefectural Awaji Hospital, Sumoto, Japan; c. Thery, Department of Cardiology, University of Lille, Lille, France. Contents Summary ......................... 300 1. Overview of Pharmacodynamic Properties ..... 304 1.1 Mechanism of Action of Unfractionated Heparin 304 1.2 Antithrombotic Profile of Nadroparin . 304 2. Overview of Pharmacokinetic Properties . 306 2.1 Absorption, Distribution and Elimination 306 2.2 Effect of Renal Impairment . 307 3. Clinical Efficacy ............... 308 3.1 Prophylaxis of Thromboembolic Events 308 3.1.1 General Surgery .....
    [Show full text]
  • Some Aspects of the Pharmacology of Oral Anticoagulants
    Some aspects of the pharmacology of oral anticoagulants The pharmacology of oral anticoagulants ls discussed with particular rejerence to data of value in the management of therapy. The importance of individual variability in response and drug interaction is stressed. Other effects of these agents which may have clinical utility are noted. William W. Coon, M.D., and Park W. Willis 111, M.D., Ann Arbor, Mich. The Departments of Surgery (Section of General Surgery) and Medicine, University of Michigan Medical School In the twenty-five years sinee the isola­ dividual struetural features but by a com­ tion of the hemorrhagie faetor in spoiled bination of several: molecular shape, in­ sweet clever," the gradually inereasing creased aetivity with 6 membered hetero­ utilization of oral antieoagulants for the eyclic rings with a substituent in position prevention and therapy of thromboembolie 8 and with a methoxyl rather than a free disease has made them one of the most hydroxl group. Also important is the dernon­ widely used groups of pharmacologic stration that levorotatory warfarin is seven agents. This review is restrieted to as­ times more aetive than its enantiomer.F" peets of the pharmaeology of these agents As Hunter and Shepherd'" have pointed whieh may be important to their proper out, the failure to obtain a precise cor­ clinieal utilization. relation between strueture and antieoagu­ lant aetivity is "not surprising in view of Relation of structure to function the influence of small struetural changes The oral antieoagulants have been di­ on sueh variables as solubility, rate of ab­ vided into four main groups on the basis sorption, ease of distribution, degree of of ehemieal strueture (Fig.
    [Show full text]