The Use of Physiology-Based PK and PD Modeling in the Discovery of the Dual
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Filorexant | Medchemexpress
Inhibitors Product Data Sheet Filorexant • Agonists Cat. No.: HY-15653 CAS No.: 1088991-73-4 Molecular Formula: C₂₄H₂₅FN₄O₂ • Molecular Weight: 420.48 Screening Libraries Target: Orexin Receptor (OX Receptor) Pathway: GPCR/G Protein; Neuronal Signaling Storage: Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month SOLVENT & SOLUBILITY In Vitro DMSO : 100 mg/mL (237.82 mM; Need ultrasonic) Mass Solvent 1 mg 5 mg 10 mg Concentration Preparing 1 mM 2.3782 mL 11.8912 mL 23.7823 mL Stock Solutions 5 mM 0.4756 mL 2.3782 mL 4.7565 mL 10 mM 0.2378 mL 1.1891 mL 2.3782 mL Please refer to the solubility information to select the appropriate solvent. In Vivo 1. Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline Solubility: ≥ 2.5 mg/mL (5.95 mM); Clear solution 2. Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline) Solubility: ≥ 2.5 mg/mL (5.95 mM); Clear solution 3. Add each solvent one by one: 10% DMSO >> 90% corn oil Solubility: ≥ 2.5 mg/mL (5.95 mM); Clear solution BIOLOGICAL ACTIVITY Description Filorexant (MK-6096) is an orally bioavailable potent and selective reversible antagonist of OX1 and OX2 receptor(<3 nM in binding). IC₅₀ & Target Ki: < 3 nM(Orexin receptor)[1]. In Vitro In radioligand binding and functional cell based assays Filorexant (MK-6096) demonstrated potent binding and antagonism of both human OX(1)R and OX(2)R (<3 nM in binding, 11 nM in FLIPR), with no significant off-target activities against a panel Page 1 of 2 www.MedChemExpress.com of >170 receptors and enzymes. -
204569Orig1s000
CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 204569Orig1s000 MEDICAL REVIEW(S) Cross Discipline Team Leader Review 3. CMC/Device Dr. Khairuzzaman found the drug product portion of the NDA to be acceptable, and without need for phase 4 commitments. Dr. Sapru’s review stated that with the exception of a pending issue concerning the control of potential genotoxic impurity (b) (4) the NDA was approvable in terms of drug substance. Dr. Suarez found that the NDA was acceptable from a biopharmaceutics perspective. The Office of Compliance issuance of an acceptable recommendation for drug substance manufacturing and testing facilities was pending at the time of this review. 4. Nonclinical Pharmacology/Toxicology Dr. Richard Siarey completed the primary nonclinical review, and Dr. Lois Freed completed a supervisory memo. Dr. Siarey’s overall conclusion was that from a nonclinical perspective, approval of the suvorexant NDA was recommended. However, he found evidence that catapelxy was observed in dogs exposed to MK-4305 (suvorexant) near Tmax, although he concluded that additional information could have been gained by studying the drug in an experimental model that has been used for diagnosing cataplexy in dogs. Dr. Siarey suggested that since cataplexy occurred in dogs near Tmax, a time at which if used for insomnia patients would ordinarily be in bed, safety concern for humans was reduced. Dr. Siarey also found that the neurobehavioral assessment in the pre- and post-natal developmental study was not complete, as the passive avoidance tests was performed too early in development, while learning/acquisition tests and retention/memory tests were not conducted. -
Preventive Report Appendix
Title Authors Published Journal Volume Issue Pages DOI Final Status Exclusion Reason Nasal sumatriptan is effective in treatment of migraine attacks in children: A Ahonen K.; Hamalainen ML.; Rantala H.; 2004 Neurology 62 6 883-7 10.1212/01.wnl.0000115105.05966.a7 Deemed irrelevant in initial screening Seasonal variation in migraine. Alstadhaug KB.; Salvesen R.; Bekkelund SI. Cephalalgia : an 2005 international journal 25 10 811-6 10.1111/j.1468-2982.2005.01018.x Deemed irrelevant in initial screening Flunarizine, a calcium channel blocker: a new prophylactic drug in migraine. Amery WK. 1983 Headache 23 2 70-4 10.1111/j.1526-4610.1983.hed2302070 Deemed irrelevant in initial screening Monoamine oxidase inhibitors in the control of migraine. Anthony M.; Lance JW. Proceedings of the 1970 Australian 7 45-7 Deemed irrelevant in initial screening Prostaglandins and prostaglandin receptor antagonism in migraine. Antonova M. 2013 Danish medical 60 5 B4635 Deemed irrelevant in initial screening Divalproex extended-release in adolescent migraine prophylaxis: results of a Apostol G.; Cady RK.; Laforet GA.; Robieson randomized, double-blind, placebo-controlled study. WZ.; Olson E.; Abi-Saab WM.; Saltarelli M. 2008 Headache 48 7 1012-25 10.1111/j.1526-4610.2008.01081.x Deemed irrelevant in initial screening Divalproex sodium extended-release for the prophylaxis of migraine headache in Apostol G.; Lewis DW.; Laforet GA.; adolescents: results of a stand-alone, long-term open-label safety study. Robieson WZ.; Fugate JM.; Abi-Saab WM.; 2009 Headache 49 1 45-53 10.1111/j.1526-4610.2008.01279.x Deemed irrelevant in initial screening Safety and tolerability of divalproex sodium extended-release in the prophylaxis of Apostol G.; Pakalnis A.; Laforet GA.; migraine headaches: results of an open-label extension trial in adolescents. -
Anti-Infectives Industry Over the Next 5 Years and Beyond
Bridging the innovation gap... New Drug Futures: Products that could change the pharma market to 2013 and beyond Over 70 pipeline prospects This new major and insightful 450 page in 8 major therapy areas analysis evaluates, compares and contrasts the are analysed in this report prospects for the development compounds that could revolutionise the pharmaceutical Anti-infectives industry over the next 5 years and beyond. Cardiovascular CNS The report provides: Gastrointestinal Detailed background and market context for Metabolic each therapy area covered: Musculoskeletal Addressable patient population Oncology Current treatments Sales drivers Respiratory Sales breakers Future treatments Market dynamics – winners and losers Key drug launches by 2013 Unique sales forecasts by major product to 2013 Over 70 key products assessed Unique evaluation scores for key areas such as novelty of mechanism, clinical data and competition Critical and detailed appraisal of each product‟s research and development Extensive pipeline listings, putting the profiled products into their competitive context The search – and need – for new products has never been greater and what’s in the development pipeline has never generated more interest. That is why this analysis is so important! GLOBAL PHARMA MARKET IN CONTEXT THE Are there too many prophets of doom ready to write-off the research-based pharma industry in the future? Too few novel There is plenty on which to base such anxiety. The research-based industry products and an must achieve a fair price in the face of greater cost control, while the aggressive generic burden of regulation is setting the bar high for successful product sector are taking introduction. -
Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products. -
The Dual Orexin Receptor Antagonist TCS1102 Does Not Affect Reinstatement of Nicotine- Seeking
RESEARCH ARTICLE The dual orexin receptor antagonist TCS1102 does not affect reinstatement of nicotine- seeking Shaun Yon-Seng Khoo, Gavan P. McNally, Kelly J. Clemens* School of Psychology, University of New South Wales, Sydney, Australia * [email protected] a1111111111 a1111111111 a1111111111 Abstract a1111111111 a1111111111 The orexin/hypocretin system is important for appetitive motivation towards multiple drugs of abuse, including nicotine. Both OX1 and OX2 receptors individually have been shown to influence nicotine self-administration and reinstatement. Due to the increasing clinical use of dual orexin receptor antagonists in the treatment of disorders such as insomnia, we OPEN ACCESS examined whether a dual orexin receptor antagonist may also be effective in reducing nico- Citation: Khoo SY-S, McNally GP, Clemens KJ tine seeking. We tested the effect of intracerebroventricular (i.c.v.) administration of the (2017) The dual orexin receptor antagonist potent and selective dual orexin receptor antagonist TCS1102 on orexin-A-induced food TCS1102 does not affect reinstatement of nicotine- self-administration, nicotine self-administration and reinstatement of nicotine-seeking in seeking. PLoS ONE 12(3): e0173967. https://doi. org/10.1371/journal.pone.0173967 rats. Our results show that 30 μg of TCS1102 i.c.v. abolishes orexin-A-induced increases in food self-administration but does not reduce nicotine self-administration. Neither i.c.v. 10 μg Editor: Judith Homberg, Radboud University Medical Centre, NETHERLANDS nor 30 μg of TCS1102 reduced compound reinstatement after short-term (15 days) self- administration nicotine, but 30 μg transiently reduced cue/nicotine compound reinstatement Received: November 24, 2016 after chronic self-administration (29 days). -
Annual HFHS Publications List 2017 This Bibliography Aims to Recognize
Annual HFHS Publications List 2017 This bibliography aims to recognize the scholarly activity and provide ease of access to journal articles, meeting abstracts, book chapters, books and other works published by Henry Ford Health System personnel. Searches were conducted in PubMed, Embase, Web of Science, and Google Scholar during 2017, and then imported into EndNote for formatting. The searches captured over 1,500 unique publications from Henry Ford Health System authors for 2017. Click the “Full Text” link to view the articles to which Sladen Library provides access. If the full-text of the article is not available, you may request it through ILLiad by clicking on the “Article Request Form,” or by calling us at 313-916-2550. If you would like to be added to the monthly email distribution list to automatically receive a PDF of this bibliography in your inbox, or you have any questions or comments, please contact Angela Cabrera at [email protected]. Administration Omar J, Heidemann DL, Blum-Alexandar B, Uju-Eke C, Alam Z, Willens DE, and Wisdom K. Fresh prescription: Improving nutrition education and access to fresh produce in Detroit J Gen Intern Med 2017; 32(2):S752. PMID: Not assigned. Abstract Administration Smith KL, Fedel P, and Heitman J. Incapacitated surrogates: A new and increasing dilemma in hospital care J Clin Ethics 2017; 28(4):279-289. PMID: 29257763. Article Request Form Allergy Brown KR, Krouse RZ, Calatroni A, Visness CM, Sivaprasad U, Kercsmar CM, Matsui EC, West JB, Makhija MM, Gill MA, Kim H, Kattan M, Pillai D, Gern JE, Busse WW, Togias A, Liu AH, and Khurana Hershey GK. -
2017 Research Annual Report Table of Contents Summaries of 2017
2017 RESEARCH ANNUAL REPORT TABLE OF CONTENTS SUMMARIES OF 2017 NATIONAL INSTITUTES OF HEALTH AND OTHER FEDERAL GRANTS AWARDED TO HFHS PART I – INTERNAL MEDICINE DEPARTMENT_________________________________ ALLERGY AND IMMUNOLOGY ................................................................................................. 1 CARDIOLOGY/CARDIOVASCULAR RESEARCH…………………………………………….1 ENDOCRINOLOGY AND METABOLISM .................................................................................. 2 GASTROENTEROLOGY ............................................................................................................. .3 HEMATOLOGY/ONCOLOGY…………………………………………………………………...4 HYPERTENSION AND VASCULAR RESEARCH……………………………………………...5 INFECTIOUS DISEASE…………………………………………………………………………..9 PULMONARY……………………………………………………………………………………10 SLEEP MEDICINE ....................................................................................................................... 11 GENERAL INTERNAL MEDICINE…………………………………………………………….13 PART II – ALL OTHER CLINICAL DEPARTMENTS_______________________________ DERMATOLOGY ........................................................................................................................ 14 NEUROLOGY .............................................................................................................................. 15 NEUROSURGERY……………………………………………………………………………….23 ORTHOPAEDICS/BONE & JOINT……………………………………………………………..24 PATHOLOGY .............................................................................................................................. -
Perspective Rxpipeline a Pharmacy
A PHARMACY ON PERSPECTIVE THE RXPIPELINE Understanding changes in the medication market and their impact on cost and care. EnvisionPharmacies continuously monitors the drug pipeline. As treatment options change, we evaluate and share our perspective on the clinical benefits, cost-effectiveness and overall impact to payers, physicians and patients. Our Perspective on the Rx Pipeline report provides insights on what you should expect from your pharmacy partners to get patients the treatment they need. Included in this Edition } Clinical Pipeline } FDA Drug Approvals } New Indications } Upcoming and Recent Generic Launches } FDA Safety Update } Drug Shortages and Discontinuations 1 | A PHARMACY PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Clinical Pipeline PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market crizanlizumab SEG101 Manufacturer: Novartis Indication/Use: Sickle cell disease Dosage Form: Infusion Pipeline Stage: PDUFA 1/2020 Sickle cell disease is a debilitating genetic blood disorder that affects approximately 100,000 Americans.[1] Patients with sickle cell disease can suffer from vaso-occlusive crises (VOCs) that are incredibly painful and can cause irreversible tissue infarction and vasculopathy. VOCs are also associated with increased morbidity and mortality. [2] Hydroxyurea and pharmacy-grade L-glutamine are the only two FDA-approved pharmacotherapies currently available for the prevention of VOCs.[3] Crizanlizumab is a monoclonal antibody that works through selectin -
Study Protocol
Confidential Page 1 Protocol No. Everolimus Investigator-initiated Protocol Template RAD001 (Everolimus) Clinical evaluation of everolimus (a rapamycin analog) in restoring salivary gland function to patients treated with radiotherapy for head and neck cancer CRAD001XUS274T Authors: Panayiotis Savvides, MD PhD MPH (Principal Investigator) Kirsten Limesand, PhD (co-Investigator) Denise Roe, DrPH (co-Investigator) Sun Yi, MD (co-Investigator) Julie Bauman, MD (co-Investigator) Daruka Mahadevan, MD PhD (co-Investigator) Version number: 1.2 Release date 06/22/2018 Referenced Investigator Brochure 15, release date 27-April-2016 Edition IRB NUMBER: PHXB-17-0072-70-15 IRB APPROVAL DATE: 07/03/2018 Confidential Page 2 Protocol No. Table of contents Table of contents..................................................................................................................2 List of figures.......................................................................................................................3 List of tables.........................................................................................................................3 List of abbreviations ............................................................................................................4 Glossary of terms.................................................................................................................6 Schema.................................................................................................................................8 1 -
Clinical Pharmacology of Daridorexant, a Novel Dual Orexin Receptor Antagonist
Clinical pharmacology of daridorexant, a novel dual orexin receptor antagonist Inauguraldissertation zur Erlangung der Würde eines Dr. sc. med. Vorgelegt der Medizinischen Fakultät der Universität Basel Von Clemens Mühlan aus 4055 Basel, Schweiz Basel, 2021 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Genehmigt von der Medizinischen Fakultät auf Antrag von Prof. Dr. Stephan Krähenbühl Prof. Dr. Matthias Liechti Dr. Alexander Jetter Dr. Jasper Dingemanse Basel, 24. Februar 2021 Dekan Prof. Dr. Primo Leo Schär 2 of 118 TABLE OF CONTENTS LIST OF ABBREVIATIONS AND ACRONYMS ............................................................4 ACKNOWLEDGEMENTS .................................................................................................8 SUMMARY .........................................................................................................................9 1 BACKGROUND AND INTRODUCTION ................................................................15 1.1 Insomnia .......................................................................................................15 1.2 The orexin system as a therapeutic target .....................................................18 1.3 Review of orexin receptor antagonists .........................................................20 1.4 Selective vs dual orexin receptor antagonism ..............................................23 1.5 Orexin receptor antagonists available in clinical practice ............................24 1.6 Orexin receptor -
G Protein-Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.