DOCSLIB.ORG

Patent Application Publication ( 10 ) Pub . No . : US 2018 / 0325884 A1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Patent Application Publication ( 10 ) Pub . No . : US 2018 / 0325884 A1 US 20180325884A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 /0325884 A1 ZARNITSYN et al. ( 43 ) Pub . Date: Nov . 15 , 2018 ( 54 ) METHODS AND DEVICES FOR THE A61K 47 /38 ( 2006 .01 ) TREATMENT OF OCULAR DISEASES IN A61K 9 / 00 (2006 .01 ) HUMAN SUBJECTS A61K 9 / 10 ( 2006 .01 ) A61K 9 / 16 ( 2006 .01 ) (71 ) Applicant: CLEARSIDE BIOMEDICAL , INC. , A61K 31 /573 (2006 . 01) Alpharetta , GA (US ) A61M 37 / 00 ( 2006 .01 ) ( 72 ) Inventors : Vladimir ZARNITSYN , Atlanta , GA A61K 47 / 26 ( 2006 .01 ) (US ) ; Samirkumar PATEL , Atlanta , A61K 47 / 12 ( 2006 .01 ) GA (US ) ; Daniel WHITE , Suwanee, A61K 45 /06 ( 2006 . 01 ) GA (US ) ; Glenn NORONHA , Atlanta , A61K 39/ 00 ( 2006 . 01 ) GA (US ) ; Brian BURKE , Cary , NC ( 52) U . S . CI. (US ) CPC . A61K 31/ 4439 ( 2013 . 01 ) ; A61M 2037 /0061 (2013 . 01 ) ; A61K 47/ 38 ( 2013 .01 ) ; A61K (21 ) Appl . No. : 16 / 041, 067 9 /0048 ( 2013 .01 ) ; A61K 9 / 10 (2013 . 01 ) ; A61K 9 / 16 ( 2013 .01 ) ; A61K 31 /573 ( 2013 .01 ) ; ( 22 ) Filed : Jul. 20 , 2018 A61M 37/ 0015 ( 2013 . 01 ) ; A61K 9 /0019 ( 2013 .01 ) ; A61K 47/ 26 ( 2013 .01 ) ; A61K 47/ 12 Related U . S . Application Data ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; A61K (63 ) Continuation of application No . 15 /454 ,636 , filed on 2039 / 54 (2013 .01 ) ; A61K 2300 /00 ( 2013 .01 ) ; Mar. 9 , 2017 , which is a continuation of application A6IK 2039 / 505 ( 2013 .01 ) ; A61M 2037 /0023 No . 14 /441 , 151, filed on May 6 , 2015 , now aban (2013 . 01 ) ; CO7K 16 / 22 ( 2013 . 01 ) doned , filed as application No . PCT /US2013 / 069156 on Nov. 8 , 2013 . (60 ) Provisional application No . 61 /898 ,926 , filed on Nov. (57 ) ABSTRACT 1 , 2013 , provisional application No . 61 / 873 ,660 , filed on Sep . 4 , 2013 , provisional application No . 61 /819 , 388 , filed on May 3 , 2013 , provisional application Methods and devices are provided for targeted non -surgical No . 61/ 785 ,229 , filed on Mar. 14 , 2013 , provisional administration of a drug formulation to the suprachoroidal application No . 61 /773 , 124 , filed on Mar . 5 , 2013 , space (SCS ) of the eye of a human subject for the treatment provisional application No . 61 /745 ,237 , filed on Dec . of a posterior ocular disorder or a choroidal malady . In one 21 , 2012 , provisional application No. 61 /734 , 872 , embodiment, the method comprises inserting a hollow filed on Dec. 7 , 2012 , provisional application No . microneedle into the eye at an insertion site and infusing a 61 / 724 , 144 , filed on Nov . 8 , 2012 . drug formulation through the inserted microneedle and into the suprachoroidal space of the eye, wherein the infused Publication Classification drug formulation flows within the suprachoroidal space (51 ) Int . Ci. away from the insertion site during the infusion . In one A61K 31 /4439 ( 2006 . 01 ) embodiment, the fluid drug formulation comprises drug CO7K 16 /22 ( 2006 .01 ) nanoparticles or microparticles . vedimoni 4 mg TA TAConcentrationinPlasma(ng/mL) per servisserseitepunderie o ninguna cosa estar en e ngele changes Study Day Patent Application Publication Nov . 15 , 2018 Sheet 1 of 40 US 2018 /0325884 A1 . 1B.FIG **** * $ . Ninh www TV #eatrjvar *** * ** ietim **** * * ** * * * 141010FIC www. N iis*** ** ** or h *** * ** r * : * **** * * * * * * * * *** ** * * * * * * ** * * * * Site *** * * * * ** berkes ** went ** Huvirinimo FIG.1A Patent Application Publication Nov . 15 , 2018 Sheet 2 of 40 US 2018 /0325884 A1 wwwwwwww FIG.1D emis sis . 7 . turistes FIG.10 Patent Application Publication Nov . 15 , 2018 Sheet 3 of 40 US 2018 /0325884 A1 FIG.3 FIG.2 ?????????????????????????????????????????????????????????????????????????????????????????????????? Patent Application Publication Nov . 15 , 2018 Sheet 4 of 40 US 2018 /0325884 A1 FIG.5 FIG.4 va Patent Application Publication Nov . 15 , 2018 Sheet 5 of 40 US 2018 / 0325884 A1 ???? :** FIG.6B :: ** * * * : .. :: : :: *** * ** * * * * * * EMTV *** FIG.6A Patent Application Publication Nov . 15 , 2018 Sheet 6 of 40 US 2018 /0325884 A1 Suction tohold intes . FIG.7B Insert Microneedle ** ** * SEN Sclera Choroid Retina Cannulato induce intraocular pressure FIG.7A Patent Application Publication Nov . 15 , 2018 Sheet 7 of 40 US 2018 /0325884 A1 w wwww ws w FIG.8B SuprachoidalSpace Choroid Retina FIG.8A *** * Sclera Choroid Vitreous Patent Application Publication Nov . 15 , 2018 Sheet 8 of 40 US 2018 /0325884 A1 .4 FIG.9C FIG.9D FIG.9A FIG.9B Patent Application Publication Nov . 15 , 2018 Sheet 9 of 40 US 2018 /0325884 A1 *. FIG.10B FIG.10A w Patent Application Publication Nov . 15 , 2018 Sheet 10 of 40 US 2018 /0325884 A1 350 . InfusionPressure(kPa) FIG.11B 100nmParticles 150200250300 IM moeten700um wayto800um A900um -1000um ) %( InjectionsSO Successful 350 InfusionPressure(kPa) FIG.11A 20nmParticles 150200250300 many700um wyth800um 900um 1000um ) %( Injections Successful Patent Application Publication Nov . 15 , 2018 Sheet 11 of 40 US 2018 /0325884 A1 350 InfusionPressure(kPa) FIG.11D 1000nmParticles 150200250300 700um way800um metu900um nogiu1000um * ) %( 8 Injections Successful * 350 InfusionPressure(kPa) 11C.FIG 500nmParticles 150200250300 morethan700um modernen800um vanons900um inon1000um ) % ( Injections. Successful ??00 Patent Application Publication Nov. 15, 2018 Sheet 12 of 40 US 2018 / 0325884 A1 FIG.12B FIG.12A wo Patent Application Publication Nov . 15 , 2018 Sheet 13 of 40 US 2018 /0325884 A1 southeast800um 1000uminwat wetmomentin700um 300 continue.ww FIG.13B t 250 InfusionPressure(kPa) 36mmHgIOP ist!: : : : ** *!* 4 ! ! T art + 14 200 . 150 ) %( Injections Successful unooormeer *** * * ** 300 **** * * * * * * * * ** * * FIG.13A *** * * * ** * * * * * * * * * * * * * erritin 250 18mmHgIOP **** * * ** : InfusionPressure(kPa) 11** *rd * 150200 22 ) %( Injections*0000 Successfulcom Patent Application Publication Nov . 15 , 2018 Sheet 14 of 40 US 2018 /0325884 A1 30 25 20 3 Time(hr) Sinis 15 FIG,15 SCSFluoresceinInjection 0510 *Mid-Vitreous 10000 )OMml / ng( ConcentrationA 160 5min 140 120 Lens 100 80 FIG.14 S: Vitreous 60 Position 40 iRetina 20 0 1400 1300 book Hook Intensity FluorescentDooOo Patent Application Publication Nov . 15 , 2018 Sheet 15 of 40 US 2018 /0325884 A1 30 25 101520 FIG.17 SCS500nmInjection 28 )days(TimeSCS . Mid-Vitreous 5 - 10000 0 Intensity13 : Fluorescence 40 * 35 * * 30 days)Time(SCS SCS20nmInjection 510152025 Mid-Vitreous 0 10000 Intensity Fluorescence Patent Application Publication Nov . 15 , 2018 Sheet 16 of 40 US 2018 /0325884 A1 Repositioningof insertedmicroneedle No Yes FIG.18 microneedleintothe scleraoftheeye Applyingapressuretoinduce Continuedinfusionof selectedvolumeoffluid fromtheeye Insertingahollow infusionofadrugformulation throughthehollowmicroneedle Evaluating whetherthere hasbeensuccessfuldelivery intosuprachoroidalspace andawayfromisertion siteofhollow microneedle drugformulationbefore removingpressure Retractingofmicroneedle Patent Application Publication Nov . 15 , 2018 Sheet 17 of 40 US 2018 /0325884 A1 *120days NeryOptic (lefttorightforeachgroup) Lens NervOptic aut Lens Suprachoroidalinjection segAnt : segAnt P FIG.19B Intravitrealinjection STE Retina p101040 Choroid2 Sclera TAPO pg. TA 120 90 t1/2=39.8days days3.13=/21 FIG.19A intravitreal 60 Time,days 30 0 0.5 Patent Application Publication Nov . 15 , 2018 Sheet 18 of 40 US 2018 /0325884 A1 IVT SCS 120 120 - SOOOOAAAAAA!. 6090 Lens:Choroid 306090 Lens:Retina Time,days FIG.190 Time,days NATYTOSEDI . 1AAAA. 30 . vy AAAA 0 concentration TA concentration TA Patent Application Publication Nov . 15 , 2018 Sheet 19 of 40 US 2018 /0325884 A1 . Vehicle *3.2mgTA. -5.2mgTA 89 28 FIG.20A 17 . StudyDay * *** ** 0 -1 iiiiiiiiiii 266 ) mmHg( IOP Patent Application Publication Nov . 15 , 2018 Sheet 20 of 40 US 2018 /0325884 A1 . ? ?????+ tte FIG.20B ???? Patent Application Publication Nov . 15 , 2018 Sheet 21 of 40 US 2018 /0325884 A1 highdose(5.2mgTA) lowdose(3.2mgTA) SystemicExposure,n=10rabbits FIG.200 SingleDoseGLPToxicologyinRabbits highlow dosedose highlow dose Day1142860 lowdose highdose lowdose highdose Patent Application Publication Nov . 15 , 2018 Sheet 22 of 40 US 2018 /0325884 A1 30 .. : :. ! Sclera/choroid .. ! .! :.. 25 . Roo . :8 . 20 og .. Lens . Retina iiiiii. .. como . Time(days) . 15 . wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww RabbitOcularTissueLevelsAfterSCSInjectionofTA . FIG.200 co w .. opers . 10 . ICB. Vitreous 40000000. 5 wiiiiiiii 100 10000 1000 0.001 tissue & / TA ug Concentration Patent Application Publication Nov . 15 , 2018 Sheet 23 of 40 US 2018 /0325884 A1 30 25 HighDoseTA LowDoseTA 20 ww oooooooooooooo 15 Time(days) FIG.20F Triamcinolone(TA)intheRetina W highdose MAMERTEMAMAN 10 1lowdosessoramento 5 0 ] ug( TA of Mass # halflife# days12 30 # 9days 25 WO TADoseHigh* hetLowDoseTA NhighdoseSongs 20 Triamcinolone(TA)intheSclera-Choroid 15 Time(days) FIG.20E lowdose 10 5 MAAAAAAAAAAAAAAAAAAAAAAAAAA 0 ) ug( TA of MassAU Patent Application Publication Nov . 15 , 2018 Sheet 24 of 40 US 2018 /0325884 A1 ) days are s ' #( images fundus Rabbit **** * * * FIG.21B . Vehicle SCS SCS *VehicleScs(left) middle)SCS(TAmg4* *4mgTAIVT(right) eyesgroup FIG.21A RabbitUveitisModel:DetailedScores ? 1 maammanaman iamman mimni Daysaftertoxin: Scores Daysaftertreatment Shadduck - McDonald Cumulative Patent Application Publication Nov . 15 , 2018 Sheet 25 of 40 US 2018 /0325884 A1 viviu VehicleSCS *4mgTASCSIVTTA mg4 TreatmentTime(days) w FIG.21D . [6Hww ) ) IOP ( Pressure Intraocular TAIVT)C(SCSControl)B(A FIG.210 33 4. Inflammatory Cumulative Patent Application
Load more

Recommended publications
  • BAFF-Neutralizing Interaction of Belimumab Related to Its Therapeutic Efficacy for Treating Systemic Lupus Erythematosus
    ARTICLE DOI: 10.1038/s41467-018-03620-2 OPEN BAFF-neutralizing interaction of belimumab related to its therapeutic efficacy for treating systemic lupus erythematosus Woori Shin1, Hyun Tae Lee1, Heejin Lim1, Sang Hyung Lee1, Ji Young Son1, Jee Un Lee1, Ki-Young Yoo1, Seong Eon Ryu2, Jaejun Rhie1, Ju Yeon Lee1 & Yong-Seok Heo1 1234567890():,; BAFF, a member of the TNF superfamily, has been recognized as a good target for auto- immune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved by the FDA for use in treating systemic lupus erythematosus. However, the molecular basis of BAFF neutralization by belimumab remains unclear. Here our crystal structure of the BAFF–belimumab Fab complex shows the precise epitope and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the therapeutic activity of belimumab involves not only antagonizing the BAFF–receptor interaction, but also disrupting the for- mation of the more active BAFF 60-mer to favor the induction of the less active BAFF trimer through interaction with the flap region of BAFF. In addition, the belimumab HCDR3 loop mimics the DxL(V/L) motif of BAFF receptors, thereby binding to BAFF in a similar manner as endogenous BAFF receptors. Our data thus provides insights for the design of new drugs targeting BAFF for the treatment of autoimmune diseases. 1 Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea. 2 Department of Bio Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea. These authors contributed equally: Woori Shin, Hyun Tae Lee, Heejin Lim, Sang Hyung Lee.
    [Show full text]
  • Table S1: Sensitivity, Specificity, PPV, NPV, and F1 Score of NLP Vs. ICD for Identification of Symptoms for (A) Biome Developm
    Table S1: Sensitivity, specificity, PPV, NPV, and F1 score of NLP vs. ICD for identification of symptoms for (A) BioMe development cohort; (B) BioMe validation cohort; (C) MIMIC-III; (D) 1 year of notes from patients in BioMe calculated using manual chart review. A) Fatigue Nausea and/or vomiting Anxiety Depression NLP (95% ICD (95% CI) P NLP (95% CI) ICD (95% CI) P NLP (95% CI) ICD (95% CI) P NLP (95% CI) ICD (95% CI) P CI) 0.99 (0.93- 0.59 (0.43- <0.00 0.25 (0.12- <0.00 <0.00 0.54 (0.33- Sensitivity 0.99 (0.9 – 1) 0.98 (0.88 -1) 0.3 (0.15-0.5) 0.85 (0.65-96) 0.02 1) 0.73) 1 0.42) 1 1 0.73) 0.57 (0.29- 0.9 (0.68- Specificity 0.89 (0.4-1) 0.75 (0.19-1) 0.68 0.97 (0.77-1) 0.03 0.98 (0.83-1) 0.22 0.81 (0.53-0.9) 0.96 (0.79-1) 0.06 0.82) 0.99) 0.99 (0.92- 0.86 (0.71- 0.94 (0.79- 0.79 (0.59- PPV 0.96 (0.82-1) 0.3 0.95 (0.66-1) 0.02 0.95 (0.66-1) 0.16 0.93 (0.68-1) 0.12 1) 0.95) 0.99) 0.92) 0.13 (0.03- <0.00 0.49 (0.33- <0.00 0.66 (0.48- NPV 0.89 (0.4-1) 0.007 0.94 (0.63-1) 0.34 (0.2-0.51) 0.97 (0.81-1) 0.86 (0.6-0.95) 0.04 0.35) 1 0.65) 1 0.81) <0.00 <0.00 <0.00 F1 Score 0.99 0.83 0.88 0.57 0.95 0.63 0.82 0.79 0.002 1 1 1 Itching Cramp Pain NLP (95% ICD (95% CI) P NLP (95% CI) ICD (95% CI) P NLP (95% CI) ICD (95% CI) P CI) 0.98 (0.86- 0.24 (0.09- <0.00 0.09 (0.01- <0.00 0.52 (0.37- <0.00 Sensitivity 0.98 (0.85-1) 0.99 (0.93-1) 1) 0.45) 1 0.29) 1 0.66) 1 0.89 (0.72- 0.5 (0.37- Specificity 0.96 (0.8-1) 0.98 (0.86-1) 0.68 0.98 (0.88-1) 0.18 0.5 (0-1) 1 0.98) 0.66) 0.88 (0.69- PPV 0.96 (0.8-1) 0.8 (0.54-1) 0.32 0.8 (0.16-1) 0.22 0.99 (0.93-1) 0.98 (0.87-1) NA* 0.97) 0.98 (0.85- 0.57 (0.41- <0.00 0.58 (0.43- <0.00 NPV 0.98 (0.86-1) 0.5 (0-1) 0.02 (0-0.08) NA* 1) 0.72) 1 0.72) 1 <0.00 <0.00 <0.00 F1 Score 0.97 0.56 0.91 0.28 0.99 0.68 1 1 1 *Denotes 95% confidence intervals and P values that could not be calculated due to insufficient cells in 2x2 tables.
    [Show full text]
  • Clinical Policy: Baricitinib (Olumiant) Reference Number: ERX.SPA.291 Effective Date: 07.24.18 Last Review Date: 11.18 Revision Log
    Clinical Policy: Baricitinib (Olumiant) Reference Number: ERX.SPA.291 Effective Date: 07.24.18 Last Review Date: 11.18 Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Baricitinib (Olumiant®) is Janus kinase (JAK) inhibitor. FDA Approved Indication(s) Olumiant is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. Limitation(s) of use: Use of Olumiant in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Envolve Pharmacy Solutions™ that Olumiant is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Rheumatoid Arthritis (must meet all): 1. Diagnosis of RA; 2. Prescribed by or in consultation with a rheumatologist; 3. Age ≥ 18 years; 4. Member meets one of the following (a or b): a. Failure of a ≥ 3 consecutive month trial of methotrexate (MTX) at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced; b. If intolerance or contraindication to MTX (see Appendix D), failure of a ≥ 3 consecutive month trial of at least ONE conventional DMARD (e.g., sulfasalazine, leflunomide, hydroxychloroquine) at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced; 5.
    [Show full text]
  • Quality Report 2020/21 Royal Devon and Exeter NHS Foundation Trust
    Quality Report 2020/21 Royal Devon and Exeter NHS Foundation Trust HOME . COMMUNITY- .1 HOSPITAL - WE WORK TOGETHER Quality Report 2020/21 CONTENTS Page Chief Executive’s Introduction ......................................................................................................................1 Progress on our 2020/21 Priorities: Governor Priorities ..............................................................................3 Progress on our 2020/21 Priorities: Trust Priorities .....................................................................................6 Improvements to Quality and Safety 2020/21 .............................................................................................7 Our Priorities for 2021/22: Governor Priorities ..........................................................................................15 Our Priorities for 2021/22: Trust Priorities .................................................................................................16 Duty of Candour ..........................................................................................................................................18 Learning from Deaths ..................................................................................................................................18 Seven Day Services ......................................................................................................................................21 NHS Staff Survey Results for indicators KR19 and KF27 ...........................................................................21
    [Show full text]
  • Classification of Medicinal Drugs and Driving: Co-Ordination and Synthesis Report
    Project No. TREN-05-FP6TR-S07.61320-518404-DRUID DRUID Driving under the Influence of Drugs, Alcohol and Medicines Integrated Project 1.6. Sustainable Development, Global Change and Ecosystem 1.6.2: Sustainable Surface Transport 6th Framework Programme Deliverable 4.4.1 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Due date of deliverable: 21.07.2011 Actual submission date: 21.07.2011 Revision date: 21.07.2011 Start date of project: 15.10.2006 Duration: 48 months Organisation name of lead contractor for this deliverable: UVA Revision 0.0 Project co-funded by the European Commission within the Sixth Framework Programme (2002-2006) Dissemination Level PU Public PP Restricted to other programme participants (including the Commission x Services) RE Restricted to a group specified by the consortium (including the Commission Services) CO Confidential, only for members of the consortium (including the Commission Services) DRUID 6th Framework Programme Deliverable D.4.4.1 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Page 1 of 243 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Authors Trinidad Gómez-Talegón, Inmaculada Fierro, M. Carmen Del Río, F. Javier Álvarez (UVa, University of Valladolid, Spain) Partners - Silvia Ravera, Susana Monteiro, Han de Gier (RUGPha, University of Groningen, the Netherlands) - Gertrude Van der Linden, Sara-Ann Legrand, Kristof Pil, Alain Verstraete (UGent, Ghent University, Belgium) - Michel Mallaret, Charles Mercier-Guyon, Isabelle Mercier-Guyon (UGren, University of Grenoble, Centre Regional de Pharmacovigilance, France) - Katerina Touliou (CERT-HIT, Centre for Research and Technology Hellas, Greece) - Michael Hei βing (BASt, Bundesanstalt für Straßenwesen, Germany).
    [Show full text]
  • R&D Briefing 76
    The Impact of Recent Regulatory Developments on the Mexican Therapeutic Landscape Access to innovative medicines is key to El acceso a medicamentos innovadores es clave para improving overall population health, reducing mejorar la salud de toda la población, para reducir los hospitalisation time and decreasing morbidity and tiempos de hospitalización, la morbilidad y la mortalidad mortality. An efficient regulatory process can be de un país. Un proceso regulatorio eficiente tiene un reflected in measurable positive health impacts; impacto positivo medible en la salud, y por el contrario, conversely, activities that slow or impede acciones que retrasan o impiden la eficiencia regulatoria y regulatory efficiency and predictability can be su predictibilidad pueden ser perjudiciales. La parálisis detrimental. Recent developments in the Mexican reciente del Sistema regulatorio mexicano respecto a la regulatory system for the assessments of evaluación de nuevos medicamentos innovadores innovative new products have had a negative conlleva un impacto negativo en la salud de la población impact on Mexican public health. mexicana. This Briefing addresses the impact of suspending Este informe analiza el impacto de la suspensión de las the activities of the New Molecules Committee actividades del Comité de Moléculas Nuevas (NMC, por (NMC) on the Mexican therapeutic landscape. sus siglas en inglés) sobre el horizonte terapéutico de First, we compared the way that “new medicines” México. En primer lugar, comparamos la definición de are defined within the context of the Mexican nuevos medicamentos según el contexto regulatorio regulatory system, with definitions used by mexicano con las definiciones adoptadas por otras comparable regulators and health organisations. agencias reguladoras u organizaciones de salud del We have also investigated the extent to which mundo.
    [Show full text]
  • Study Protocol
    PROTOCOL SYNOPSIS A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Study Evaluating the Efficacy and Safety of Two Doses of Anifrolumab in Adult Subjects with Active Systemic Lupus Erythematosus International Coordinating Investigator Study site(s) and number of subjects planned Approximately 450 subjects are planned at approximately 173 sites. Study period Phase of development Estimated date of first subject enrolled Q2 2015 3 Estimated date of last subject completed Q2 2018 Study design This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab (150 mg or 300 mg) versus placebo in subjects with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment. The study will be performed in adult subjects aged 18 to 70 years of age. Approximately 450 subjects receiving SOC treatment will be randomised in a 1:2:2 ratio to receive a fixed intravenous dose of 150 mg anifrolumab, 300 mg anifrolumab, or placebo every 4 weeks (Q4W) for a total of 13 doses (Week 0 to Week 48), with the primary endpoint evaluated at the Week 52 visit. Investigational product will be administered as an intravenous (IV) infusion via an infusion pump over a minimum of 30 minutes, Q4W. Subjects must be taking either 1 or any combination of the following: oral corticosteroids (OCS), antimalarial, and/or immunosuppressants. Randomisation will be stratified using the following factors: SLE Disease Activity Index 2000 (SLEDAI-2K) score at screening (<10 points versus ≥10 points); Week 0 (Day 1) OCS dose 2(125) Revised Clinical Study Protocol Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00005 Edition Number 5 Date 18 May 2016 (<10 mg/day versus ≥10 mg/day prednisone or equivalent); and results of a type 1 interferon (IFN) test (high versus low).
    [Show full text]
  • Health Reports for Mutual Recognition of Medical Prescriptions: State of Play
    The information and views set out in this report are those of the author(s) and do not necessarily reflect the official opinion of the European Union. Neither the European Union institutions and bodies nor any person acting on their behalf may be held responsible for the use which may be made of the information contained therein. Executive Agency for Health and Consumers Health Reports for Mutual Recognition of Medical Prescriptions: State of Play 24 January 2012 Final Report Health Reports for Mutual Recognition of Medical Prescriptions: State of Play Acknowledgements Matrix Insight Ltd would like to thank everyone who has contributed to this research. We are especially grateful to the following institutions for their support throughout the study: the Pharmaceutical Group of the European Union (PGEU) including their national member associations in Denmark, France, Germany, Greece, the Netherlands, Poland and the United Kingdom; the European Medical Association (EMANET); the Observatoire Social Européen (OSE); and The Netherlands Institute for Health Service Research (NIVEL). For questions about the report, please contact Dr Gabriele Birnberg ([email protected] ). Matrix Insight | 24 January 2012 2 Health Reports for Mutual Recognition of Medical Prescriptions: State of Play Executive Summary This study has been carried out in the context of Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the application of patients’ rights in cross- border healthcare (CBHC). The CBHC Directive stipulates that the European Commission shall adopt measures to facilitate the recognition of prescriptions issued in another Member State (Article 11). At the time of submission of this report, the European Commission was preparing an impact assessment with regards to these measures, designed to help implement Article 11.
    [Show full text]
  • Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: a Review of Oncology and Medicinal Chemistry Literature
    pharmaceuticals Review Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature Alessandra Pannunzio and Mauro Coluccia * Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, Via E. Orabona 4, I-70125 Bari, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-080-544-2788 Received: 4 September 2018; Accepted: 9 October 2018; Published: 11 October 2018 Abstract: Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE2) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway and to the effects of prostaglandins already known for their ability of affecting the tumor phenotype. A knowledge-based choice of the most appropriate tumor cell models, and a major effort in investigating the COX-1 issue in the more general context of arachidonic acid metabolic network by using the systems biology approaches, should be strongly encouraged.
    [Show full text]
  • A New Venue of TNF Targeting
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 2 April 2018 doi:10.20944/preprints201804.0015.v1 Peer-reviewed version available at Int. J. Mol. Sci. 2018, 19, 1442; doi:10.3390/ijms19051442 1 Review 2 A new venue of TNF targeting 3 Sophie Steeland1, Claude Libert2 and Roosmarijn E. Vandenbroucke3,* 4 1 Barriers in Inflammation, VIB Center for Inflammation Research, Ghent; Department of Biomedical Molecular 5 Science, Ghent University, Ghent Belgium; [email protected] 6 2 Mouse Genetics in Inflammation, VIB Center for Inflammation Research, Ghent; Department of Biomedical 7 Molecular Science, Ghent University, Ghent Belgium; [email protected] 8 3 Barriers in Inflammation, VIB Center for Inflammation Research, Ghent; Department of Biomedical Molecular 9 Science, Ghent University, Ghent Belgium; [email protected] 10 * Correspondence: [email protected]; Tel.: +32 9 331 35 87 11 Received: date; Accepted: date; Published: date 12 13 Abstract: The first FDA-approved drugs were small, chemically-manufactured and highly active 14 molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology 15 allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind 16 a specific protein and are becoming increasingly important in the therapeutic landscape. A very 17 prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases 18 that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the 19 treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, 20 some of them directly associated with the inherent nature of this drug class such as immunogenicity, 21 whereas others are linked with their mechanism of action.
    [Show full text]
  • Diabetes Reduces Mesenchymal Stem Cells in Fracture Healing Through a Tnfα-Mediated Mechanism
    Diabetologia DOI 10.1007/s00125-014-3470-y ARTICLE Diabetes reduces mesenchymal stem cells in fracture healing through a TNFα-mediated mechanism Kang I. Ko & Leila S. Coimbra & Chen Tian & Jazia Alblowi & Rayyan A. Kayal & Thomas A. Einhorn & LouisC.Gerstenfeld& Robert J. Pignolo & Dana T. Graves Received: 31 July 2014 /Accepted: 19 November 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract (Sca-1) antibodies in areas of new endochondral bone forma- Aims/hypothesis Diabetes interferes with bone formation and tion in the calluses. MSC apoptosis was measured by TUNEL impairs fracture healing, an important complication in humans assay and proliferation was measured by Ki67 antibody. In and animal models. The aim of this study was to examine the vitro apoptosis and proliferation were examined in C3H10T1/ impact of diabetes on mesenchymal stem cells (MSCs) during 2 and human-bone-marrow-derived MSCs following transfec- fracture repair. tion with FOXO1 small interfering (si)RNA. Methods Fracture of the long bones was induced in a Results Diabetes significantly increased TNFα levels and streptozotocin-induced type 1 diabetic mouse model with or reduced MSC numbers in new bone area. MSC numbers were without insulin or a specific TNFα inhibitor, pegsunercept. restored to normal levels with insulin or pegsunercept treat- MSCs were detected with cluster designation-271 (also ment. Inhibition of TNFα significantly reduced MSC loss by known as p75 neurotrophin receptor) or stem cell antigen-1 increasing MSC proliferation and decreasing MSC apoptosis in diabetic animals, but had no effect on MSCs in normoglycaemic animals. In vitro experiments established Kang I. Ko and Leila S.
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]