Structures of Active-State Orexin Receptor 2 Rationalize Peptide and Small-Molecule Agonist Recognition and Receptor Activation
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Pipeline of Medications to Treat Substance Use Disorders
Pipeline of Medications to Treat Substance Use Disorders Iván D. Montoya, M.D., M.P.H. Clinical Director and Deputy Director Division of Therapeutics and Medical Consequences NIDA • Cocaine Outline • Methamphetamine • Cannabis Past-Year Prevalence Per 1,000 1,000 People Per NSDUH, 2018 Past-Year Prevalence Per 1,000 1,000 People Per NSDUH, 2018 Number of Overdose Deaths CDC, 2018 Molecular Neurobiology of Stimulant Use Disorders Glutamate Enkephalin or Excitatory Input Dynorphin Inhibitory Neuron k Opioid Dopamine Receptors Enkephalin Receptors Inhibitory Dopamine Neuron GABA Neuron Neuron m Opioid REWARD Receptors GABA-A Receptors GABA Inhibitory Feedback GABA Presynaptic Inhibitory Opioid Neuron Receptors (m, d?) Ventral Tegmental Area Nucleus Accumbens (VTA) (NAc) Adapted from Koop, 2016 • 5HT2c Agonist - Lorcaserin (Belviq XR®) • Orexin 1 antagonists Cocaine • EMB-101 (Oxazepam + Metyrapone) • Buprenorphine + Opioid Antagonist – Clinical Studies • Ketamine • Oxytocin • L-Tetrahydropalmatine (L-THP) 5-HT2C Agonist - Lorcaserin • Clinically available • Selective agonist • Modulate mesolimbic dopamine, decreasing dopamine release • FDA-approved for weight loss • Lorcaserin (Belviq®)10 mg bid • Lorcaserin XR (Belviq XR®) 20 mg qd • Schedule IV • Arena Pharmaceuticals - Eisai Inc. Lorcaserin Pre-clinical Studies - Stimulants • Decrease cocaine self-administration and the reinstatement of responding for cocaine (Grottick et al., 2000; Burmeister et al., 2004; Burbassi and Cervo 2008; Cunningham et al., 2011; Manvich et al., 2012; RüediBettschen -
Therapeutic Medications Against Diabetes: What We Have and What We Expect
Advanced Drug Delivery Reviews 139 (2019) 3–15 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Therapeutic medications against diabetes: What we have and what we expect Cheng Hu a,b, Weiping Jia a,⁎ a Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, People's Republic of China b Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, 6600 Nanfeng Road, Shanghai 200433, People's Republic of China article info abstract Article history: Diabetes has become one of the largest global health and economic burdens, with its increased prevalence and Received 28 June 2018 high complication ratio. Stable and satisfactory blood glucose control are vital to reduce diabetes-related compli- Received in revised form 1 September 2018 cations. Therefore, continuous attempts have been made in antidiabetic drugs, treatment routes, and traditional Accepted 27 November 2018 Chinese medicine to achieve better disease control. New antidiabetic drugs and appropriate combinations of Available online 5 December 2018 these drugs have increased diabetes control significantly. Besides, novel treatment routes including oral antidia- betic peptide delivery, nanocarrier delivery system, implantable drug delivery system are also pivotal for diabetes Keywords: fi Diabetes control, with its greater ef ciency, increased bioavailability, decreased toxicity and reduced dosing frequency. Treatment Among these new routes, nanotechnology, artificial pancreas and islet cell implantation have shown great poten- Drug delivery tial in diabetes therapy. Traditional Chinese medicine also offer new options for diabetes treatment. -
Protocol for Non-Interventional Studies Based on Existing Data
ABCD TITLE PAGE Protocol for non-interventional studies based on existing data TITLE PAGE Note: This template complies with the European Medicines Agency requirements on format, layout and content of a Post Authorisation safety Study (PASS) protocol of 26 Sep 2012. Please do not change structure provided in this template. Document Number: <document number> BI Study Number: <Study Number> BI Investigational Empagliflozin (Jardiance®) Product(s): Empagliflozin + Linagliptin (Glyxambi®) Empagliflozin + Metformin (Synjardy®) Title: Cardiovascular outcomes and mortality in Danish patients with type 2 diabetes who initiate empagliflozin versus liraglutide as second-line therapy: A Danish nationwide comparative effectiveness study Protocol version 1.0 identifier: Date of last version of 15JUL2018 protocol: PASS: No EU PAS register If applicable: Registration number in the EU PAS register; number: indicate “Study not registered” if the study has not been registered in the EU PAS register Active substance: A10BX12 Empagliflozin A10BK03 Empagliflozin A10BD19 Empagliflozin + Linagliptin A10BD20 Empagliflozin + Metformin A10BX07 Liraglutide A10BJ02 Liraglutide A10AE56 Insulin degludec + Liraglutide Medicinal product: Jardiance Glyxambi Synjardy Victoza Xultophy Product reference: Reference number(s) of centrally authorised products and/or, if possible, of nationally authorised products subject to the study 001-MCS-90-124_RD-01 (4.0) Boehringer Ingelheim Page 2 of 55 Protocol for non-interventional studies based on existing data BI Study Number <Study Number> <document number> Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Procedure number: If applicable, Agency or national procedure number(s), e.g. EMA/X/X/XXX Joint PASS: No Research question and To compare, among patients with type 2 diabetes in Denmark, objectives: clinical outcomes among new users (initiators) of empagliflozin versus liraglutide. -
Dual Orexin Receptor Antagonist Induces Changes in Core Body
www.nature.com/scientificreports Corrected: Author Correction OPEN Dual orexin receptor antagonist induces changes in core body temperature in rats after exercise Tristan Martin1, Yves Dauvilliers2, Ouma-Chandrou Koumar1, Valentine Bouet1, Thomas Freret1, Stéphane Besnard1, François Dauphin1 & Nicolas Bessot1* Hypothalamic orexin neurons are involved in various physiological functions, including thermoregulation. The orexinergic system has been considered as a potent mediator of the exercise response. The present study describes how the antagonization of the orexinergic system by a dual orexin receptor antagonist (DORA) modifes the thermoregulatory process during exercise. Core Body Temperature (CBT) and Spontaneous Locomotor Activity (SLA) of 12 male Wistar rats were recorded after either oral administration of DORA (30 mg/kg or 60 mg/kg) or placebo solution, both at rest and in exercise conditions with treadmill running. DORA ingestion decreased SLA for 8 hours (p < 0.001) and CBT for 4 hours (p < 0.01). CBT (°C) response was independent of SLA. The CBT level decreased from the beginning to the end of exercise when orexin receptors were antagonized, with a dose-dependent response (39.09 ± 0.36 and 38.88 ± 0.28 for 30 and 60 mg/kg; p < 0.001) compared to placebo (39.29 ± 0.31; p < 0.001). CBT increased during exercise was also blunted after DORA administration, but without dose efects of DORA. In conclusion, our results favor the role of orexin in the thermoregulation under stress related to exercise conditions. Core Body Temperature (CBT) is modulated by heat production and dissipation mechanisms controlled by the hypothalamus. Tis generates patterns of autonomic, endocrine, motor, and behavioral responses to adapt to environmental challenges1. -
AACE Annual Meeting 2021 Abstracts Editorial Board
June 2021 Volume 27, Number 6S AACE Annual Meeting 2021 Abstracts Editorial board Editor-in-Chief Pauline M. Camacho, MD, FACE Suleiman Mustafa-Kutana, BSC, MB, CHB, MSC Maywood, Illinois, United States Boston, Massachusetts, United States Vin Tangpricha, MD, PhD, FACE Atlanta, Georgia, United States Andrea Coviello, MD, MSE, MMCi Karel Pacak, MD, PhD, DSc Durham, North Carolina, United States Bethesda, Maryland, United States Associate Editors Natalie E. Cusano, MD, MS Amanda Powell, MD Maria Papaleontiou, MD New York, New York, United States Boston, Massachusetts, United States Ann Arbor, Michigan, United States Tobias Else, MD Gregory Randolph, MD Melissa Putman, MD Ann Arbor, Michigan, United States Boston, Massachusetts, United States Boston, Massachusetts, United States Vahab Fatourechi, MD Daniel J. Rubin, MD, MSc Harold Rosen, MD Rochester, Minnesota, United States Philadelphia, Pennsylvania, United States Boston, Massachusetts, United States Ruth Freeman, MD Joshua D. Safer, MD Nicholas Tritos, MD, DS, FACP, FACE New York, New York, United States New York, New York, United States Boston, Massachusetts, United States Rajesh K. Garg, MD Pankaj Shah, MD Boston, Massachusetts, United States Staff Rochester, Minnesota, United States Eliza B. Geer, MD Joseph L. Shaker, MD Paul A. Markowski New York, New York, United States Milwaukee, Wisconsin, United States CEO Roma Gianchandani, MD Lance Sloan, MD, MS Elizabeth Lepkowski Ann Arbor, Michigan, United States Lufkin, Texas, United States Chief Learning Officer Martin M. Grajower, MD, FACP, FACE Takara L. Stanley, MD Lori Clawges The Bronx, New York, United States Boston, Massachusetts, United States Senior Managing Editor Allen S. Ho, MD Devin Steenkamp, MD Corrie Williams Los Angeles, California, United States Boston, Massachusetts, United States Peer Review Manager Michael F. -
PRESCRIBING INFORMATION ------WARNINGS and PRECAUTIONS------These Highlights Do Not Include All the Information Needed to Use JARDIANCE Safely and Effectively
HIGHLIGHTS OF PRESCRIBING INFORMATION -----------------------WARNINGS AND PRECAUTIONS------------------------ These highlights do not include all the information needed to use JARDIANCE safely and effectively. See full prescribing information for Ketoacidosis: Assess patients who present with signs and symptoms of JARDIANCE. metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue JARDIANCE, evaluate and treat promptly. JARDIANCE® (empagliflozin tablets), for oral use Before initiating JARDIANCE, consider risk factors for ketoacidosis. Initial U.S. Approval: 2014 Patients on JARDIANCE may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ---------------------------RECENT MAJOR CHANGES--------------------------- ketoacidosis. (5.1) Volume Depletion: Before initiating JARDIANCE, assess volume status Indications and Usage (1) 8/2021 and renal function in patients with impaired renal function, elderly Dosage and Administration (2.1) 6/2021 patients, or patients on loop diuretics. Monitor for signs and symptoms Dosage and Administration (2.2) 8/2021 during therapy. (5.2, 6.1) Dosage and Administration (2.3) – Removed 8/2021 Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms Contraindications (4) 6/2021 of urinary tract infections and treat promptly, if indicated (5.3) Warnings and Precautions (5.1, 5.2) 6/2021 Hypoglycemia: Consider lowering the dose of insulin secretagogue or Warnings and Precautions (5.3, 5.5) 8/2021 insulin to reduce the risk of hypoglycemia when initiating JARDIANCE Warnings and Precautions (5.9) – Removed 6/2021 (5.4) ----------------------------INDICATIONS AND USAGE--------------------------- Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, JARDIANCE is a sodium-glucose co-transporter 2 (SGLT2) inhibitor life-threatening cases have occurred in both females and males. -
Diverse Functional Autoantibodies in Patients with COVID-19
medRxiv preprint doi: https://doi.org/10.1101/2020.12.10.20247205; this version posted December 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Diverse Functional Autoantibodies in Patients with COVID-19 Eric Y. Wang1,*, Tianyang Mao1,*, Jon Klein1,*, Yile Dai1,*, John D. Huck1, Feimei Liu1, Neil S. Zheng1, Ting Zhou1, Benjamin Israelow1, Patrick Wong1, Carolina Lucas1, Julio Silva1, Ji Eun Oh1, Eric Song1, Emily S. Perotti1, Suzanne Fischer1, Melissa Campbell5, John B. Fournier5, Anne L. Wyllie3, Chantal B. F. Vogels3, Isabel M. Ott3, Chaney C. Kalinich3, Mary E. Petrone3, Anne E. Watkins3, Yale IMPACT Team¶, Charles Dela Cruz4, Shelli F. Farhadian5, Wade L. Schulz6,7, Nathan D. Grubaugh3, Albert I. Ko3,5, Akiko Iwasaki1,3,8,#, Aaron M. Ring1,2,# 1 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA 2 Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA 3 Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA 4 Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale School of Medicine, New Haven, CT, USA 5 Department of Internal Medicine (Infectious Diseases), Yale School of Medicine, New Haven, CT, USA 6 Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA 7 Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA 8 Howard Hughes Medical Institute, Chevy Chase, MD, USA * These authors contributed equally to this work ¶ A list of authors and their affiliations appears at the end of the paper # Correspondence: [email protected] (A.M.R.); [email protected] (A.I.) 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. -
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. -
Molecular Insights Into the Transmembrane Domain of the Thyrotropin Receptor
Molecular Insights into the Transmembrane Domain of the Thyrotropin Receptor Vanessa Chantreau, Bruck Taddese, Mathilde Munier, Louis Gourdin, Daniel Henrion, Patrice Rodien, Marie Chabbert To cite this version: Vanessa Chantreau, Bruck Taddese, Mathilde Munier, Louis Gourdin, Daniel Henrion, et al.. Molecu- lar Insights into the Transmembrane Domain of the Thyrotropin Receptor. PLoS ONE, Public Library of Science, 2015, 10 (11), pp.e0142250. 10.1371/journal.pone.0142250. hal-02318838 HAL Id: hal-02318838 https://hal.archives-ouvertes.fr/hal-02318838 Submitted on 17 Oct 2019 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. RESEARCH ARTICLE Molecular Insights into the Transmembrane Domain of the Thyrotropin Receptor Vanessa Chantreau1, Bruck Taddese1, Mathilde Munier1, Louis Gourdin1,2, Daniel Henrion1, Patrice Rodien1,2, Marie Chabbert1* 1 UMR CNRS 6214 –INSERM 1083, Laboratory of Integrated Neurovascular and Mitochondrial Biology, University of Angers, Angers, France, 2 Reference Centre for the pathologies of hormonal receptivity, Department of Endocrinology, Centre Hospitalier Universitaire of Angers, Angers, France * [email protected] Abstract The thyrotropin receptor (TSHR) is a G protein-coupled receptor (GPCR) that is member of the leucine-rich repeat subfamily (LGR). -
Neuropeptides Controlling Energy Balance: Orexins and Neuromedins
Neuropeptides Controlling Energy Balance: Orexins and Neuromedins Joshua P. Nixon, Catherine M. Kotz, Colleen M. Novak, Charles J. Billington, and Jennifer A. Teske Contents 1 Brain Orexins and Energy Balance ....................................................... 79 1.1 Orexin............................................................................... 79 2 Orexin and Feeding ....................................................................... 80 3 Orexin and Arousal ....................................................................... 83 J.P. Nixon • J.A. Teske Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA C.M. Kotz (*) Veterans Affairs Medical Center, GRECC (11 G), Minneapolis, MN, USA Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA e-mail: [email protected] C.M. Novak Department of Biological Sciences, Kent State University, Kent, OH, USA C.J. Billington Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Veterans Affairs Medical Center, Endocrine Unit (111 G), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA H.-G. Joost (ed.), Appetite Control, Handbook of Experimental Pharmacology 209, 77 DOI 10.1007/978-3-642-24716-3_4, # Springer-Verlag Berlin Heidelberg 2012 78 J.P. Nixon et al. 4 Orexin Actions on Endocrine and Autonomic Systems ................................. 84 5 Orexin, Physical Activity, and Energy Expenditure .................................... -
Identification of Neuropeptide Receptors Expressed By
RESEARCH ARTICLE Identification of Neuropeptide Receptors Expressed by Melanin-Concentrating Hormone Neurons Gregory S. Parks,1,2 Lien Wang,1 Zhiwei Wang,1 and Olivier Civelli1,2,3* 1Department of Pharmacology, University of California Irvine, Irvine, California 92697 2Department of Developmental and Cell Biology, University of California Irvine, Irvine, California 92697 3Department of Pharmaceutical Sciences, University of California Irvine, Irvine, California 92697 ABSTRACT the MCH system or demonstrated high expression lev- Melanin-concentrating hormone (MCH) is a 19-amino- els in the LH and ZI, were tested to determine whether acid cyclic neuropeptide that acts in rodents via the they are expressed by MCH neurons. Overall, 11 neuro- MCH receptor 1 (MCHR1) to regulate a wide variety of peptide receptors were found to exhibit significant physiological functions. MCH is produced by a distinct colocalization with MCH neurons: nociceptin/orphanin population of neurons located in the lateral hypothala- FQ opioid receptor (NOP), MCHR1, both orexin recep- mus (LH) and zona incerta (ZI), but MCHR1 mRNA is tors (ORX), somatostatin receptors 1 and 2 (SSTR1, widely expressed throughout the brain. The physiologi- SSTR2), kisspeptin recepotor (KissR1), neurotensin cal responses and behaviors regulated by the MCH sys- receptor 1 (NTSR1), neuropeptide S receptor (NPSR), tem have been investigated, but less is known about cholecystokinin receptor A (CCKAR), and the j-opioid how MCH neurons are regulated. The effects of most receptor (KOR). Among these receptors, six have never classical neurotransmitters on MCH neurons have been before been linked to the MCH system. Surprisingly, studied, but those of most neuropeptides are poorly several receptors thought to regulate MCH neurons dis- understood. -
Type 2 Diabetes: Latest Drug Approvals and Use of the Newer
9/24/2017 OBJECTIVES Type 2 Diabetes: Latest •Describe the recently approved insulins Drug Approvals and Use •Compare and contrast the GLP-1 receptor agonists and the recent literature supporting of the Newer Agents this drug class •Describe the available SGLT2 inhibitors and Gretchen Ray, PharmD, PhC, BCACP, CDE the efficacy and safety profile of this drug Associate Professor, UNM College of class Pharmacy October 9th, 2017 [email protected] Canagliflozin Alogliptin 2013 Dapagliflozin Empagliflozin Albiglutide UPDATED GUIDELINES DIABETES MEDICATIONS Dulaglutide Afrezza inhaled insulin •Standards of Medical Care in Diabetes 2017. 2014 U-300 Glargine Linagliptin Insulin Degludec Diabetes Care 2017;40(Suppl 1) Basaglar 2011 2015 Insulin Metformin 1922 Sitagliptin AGIs Saxagliptin SUs 2006 1995 2009 1957 1960 1995 2000 2005 2010 2015 Glinides Exenatide Liraglutide TZDs Pramlintide 2010 1997 2005 2012 Exenatide LAR INSULIN GLARGINE 300 UNITS/ML TYPES OF INSULIN (TOUJEO® SOLOSTAR PEN) • Rapid Acting • Higher concentration of Insulin Glargine • Humalog® (lispro) (U-100 and U-200) • Novolog ® (aspart) • Only available in pen form • Apidra ® (glulisine) • Short Acting-Regular Insulin (R) • Lasts slightly longer than 24 hours • Novolin® R • Converting from U-100 Glargine to U-300 • Humulin® R Glargine • Intermediate Acting-NPH (N) • Novolin® N • 1:1 then titrate up • Humulin ® N • Typically a higher dose of Toujeo® is required • Long Acting – Basal Insulin • Converting from U-300 Glargine to U-100 • Levemir® (detemir) • Lantus®/Basaglar ® (U-100 glargine) Glargine • Toujeo® (U-300 glargine) • Use 80% of the dose of Toujeo® • Tresiba®(Degludec U-100 and U-200) Toujeo. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc.