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Opioid-Induced Hyperalgesia in Humans Molecular Mechanisms and Clinical Considerations
SPECIAL TOPIC SERIES Opioid-induced Hyperalgesia in Humans Molecular Mechanisms and Clinical Considerations Larry F. Chu, MD, MS (BCHM), MS (Epidemiology),* Martin S. Angst, MD,* and David Clark, MD, PhD*w treatment of acute and cancer-related pain. However, Abstract: Opioid-induced hyperalgesia (OIH) is most broadly recent evidence suggests that opioid medications may also defined as a state of nociceptive sensitization caused by exposure be useful for the treatment of chronic noncancer pain, at to opioids. The state is characterized by a paradoxical response least in the short term.3–14 whereby a patient receiving opioids for the treatment of pain Perhaps because of this new evidence, opioid may actually become more sensitive to certain painful stimuli. medications have been increasingly prescribed by primary The type of pain experienced may or may not be different from care physicians and other patient care providers for the original underlying painful condition. Although the precise chronic painful conditions.15,16 Indeed, opioids are molecular mechanism is not yet understood, it is generally among the most common medications prescribed by thought to result from neuroplastic changes in the peripheral physicians in the United States17 and accounted for 235 and central nervous systems that lead to sensitization of million prescriptions in the year 2004.18 pronociceptive pathways. OIH seems to be a distinct, definable, One of the principal factors that differentiate the use and characteristic phenomenon that may explain loss of opioid of opioids for the treatment of pain concerns the duration efficacy in some cases. Clinicians should suspect expression of of intended use. -
WO 2017/145013 Al 31 August 2017 (31.08.2017) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/145013 Al 31 August 2017 (31.08.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 498/04 (2006.01) A61K 31/5365 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 519/00 (2006.01) A61P 25/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/IB20 17/050844 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, (22) International Filing Date: KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, 15 February 2017 (15.02.2017) MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (25) Filing Language: English RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (26) Publication Language: English TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/298,657 23 February 2016 (23.02.2016) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, New York, New York 10017 (US). -
Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking
Neuropsychopharmacology (2013) 38, 2657–2665 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking 1 1 1 1 ,1 Xiaohu Xie , Amy A Arguello , Audrey M Wells , Andrew M Reittinger and Rita A Fuchs* 1 Department of Psychology, University of North Carolina, Chapel Hill, NC, USA Glutamatergic neurotransmission in the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaine- seeking behavior in an animal model of drug relapse. Furthermore, in vitro studies suggest that the Src family of tyrosine kinases critically regulates glutamatergic cellular functions within the DH. Thus, Src-family kinases in the DH may similarly control contextual cocaine- seeking behavior. To test this hypothesis, rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after AP5 (N-methyl-D-aspartate glutamate (NMDA) receptor (NMDAR) antagonist; 0.25 or 2.5 mg/0.5 ml/hemisphere), PP2 (Src-family kinase inhibitor; 6.25 or 62.5 ng/0.5 ml/hemisphere), Ro25-6981 (NR2B subunit- containing NMDAR antagonist; 0.2 or 2 mg/0.5 ml/hemisphere), or vehicle administration into the DH. Administration of AP5, PP2, or Ro25-6981 into the DH dose-dependently impaired drug context-induced reinstatement of cocaine-seeking behavior relative to vehicle, without altering instrumental behavior in the extinction context or food-reinforced instrumental responding and general motor activity in control experiments. -
Metabolism and Pharmacokinetics in the Development of New Therapeutics for Cocaine and Opioid Abuse
University of Mississippi eGrove Electronic Theses and Dissertations Graduate School 2012 Metabolism And Pharmacokinetics In The Development Of New Therapeutics For Cocaine And Opioid Abuse Pradeep Kumar Vuppala University of Mississippi Follow this and additional works at: https://egrove.olemiss.edu/etd Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Vuppala, Pradeep Kumar, "Metabolism And Pharmacokinetics In The Development Of New Therapeutics For Cocaine And Opioid Abuse" (2012). Electronic Theses and Dissertations. 731. https://egrove.olemiss.edu/etd/731 This Dissertation is brought to you for free and open access by the Graduate School at eGrove. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of eGrove. For more information, please contact [email protected]. METABOLISM AND PHARMACOKINETICS IN THE DEVELOPMENT OF NEW THERAPEUTICS FOR COCAINE AND OPIOID ABUSE A Dissertation presented in partial fulfillment of requirements for the degree of Doctor of Philosophy in Pharmaceutical Sciences in the Department of Pharmaceutics The University of Mississippi by PRADEEP KUMAR VUPPALA April 2012 Copyright © 2012 by Pradeep Kumar Vuppala All rights reserved ABSTRACT Cocaine and opioid abuse are a major public health concern and the cause of significant morbidity and mortality worldwide. The development of effective medication for cocaine and opioid abuse is necessary to reduce the impact of this issue upon the individual and society. The pharmacologic treatment for drug abuse has been based on one of the following strategies: agonist substitution, antagonist treatment, or symptomatic treatment. This dissertation is focused on the role of metabolism and pharmacokinetics in the development of new pharmacotherapies, CM304 (sigma-1 receptor antagonist), mitragynine and 7-hydroxymitragynine (µ-opioid receptor agonists), for the treatment of drug abuse. -
A Role for Histone Modification in the Mechanism of Action of Antidepressant and Stimulant Drugs: a Dissertation
University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2007-12-28 A Role for Histone Modification in the Mechanism of Action of Antidepressant and Stimulant Drugs: a Dissertation Frederick Albert Schroeder University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Amino Acids, Peptides, and Proteins Commons, Cells Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Mental Disorders Commons, Nervous System Commons, and the Therapeutics Commons Repository Citation Schroeder FA. (2007). A Role for Histone Modification in the Mechanism of Action of Antidepressant and Stimulant Drugs: a Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/7bk0-a687. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/370 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. A Dissertation Presented by Frederick Albert Schroeder Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences Worcester, Massachusetts, USA in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 28, 2007 Program in Neuroscience A Role for Histone Modification in the Mechanism of Action of Antidepressant and Stimulant Drugs A Dissertation Presented By Frederick Albert Schroeder Approved as to style and content by: _____________________________________ Alonzo Ross, Ph.D., Chair of Committee _____________________________________ Pradeep Bhide, Ph.D., Member of Committee _____________________________________ Craig L. -
Tinnitus Hopes Put to Sleep by Latest Auris Failure
March 14, 2018 Tinnitus hopes put to sleep by latest Auris failure Madeleine Armstrong Ketamine is best known as a horse tranquiliser or a recreational drug, but it has also been proposed as a treatment for various disorders from depression to Alzheimer’s. Hopes of developing the drug in tinnitus have been dashed by the failure of Auris’s Keyzilen in a second phase III trial. As well as leaving Auris’s future looking bleak – Keyzilen is the second of its phase III candidates to flunk in four months – the setback could also be bad news for the sparse tinnitus pipeline. According to EvaluatePharma there is only one other candidate in active clinical development, Otonomy’s OTO-313, and this uses the same mechanism of action as Keyzilen (see table below). Tinnitus pipeline Generic Project Company Pharma class Trial(s) Notes name Phase III Auris Esketamine TACTT2 Keyzilen NMDA antagonist Failed Aug 2016 Medical hydrochloride (NCT01803646) TACTT3 Failed Mar 2018 (NCT02040194) Phase I OTO- Phase I/II trial to OTO-311 abandoned in Otonomy NMDA antagonist Gacyclidine 313 start H1 2019 favour of this formulation Preclinical Auris AM-102 Undisclosed - - Medical KCNQ2 Knopp Kv7 potassium - - Program Biosciences channel modulator Source: EvaluatePharma. Both projects are psychoactive drugs targeting the NMDA receptor. Tinnitus is commonly caused by loud noise and resulting damage to the sensory hair cells in the cochlea. Initial trauma to the inner ear has been shown to trigger excess production of glutamate, which leads to the hyperactivation of NMDA receptors and, in turn, cell death. Blocking the NMDA receptor could therefore have a protective effect – but it is unclear how this mechanism would work once the damage to hair cells had been done. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
The Evaluation of Drug Regulation - Economic Approaches Into the Valuation and Evaluation of the Drug Regulatory Framework
The Evaluation of Drug Regulation - Economic approaches into the valuation and evaluation of the drug regulatory framework Jacoline Bouvy The evaluation of drug regulation – Economic approaches into the valuation and evaluation of the drug regulatory framework Bouvy, JC. ISBN 000000 Author Jacoline Bouvy Cover photo Bigstock.com Printed by Drukkerij Mostert en Van Onderen! The evaluation of drug regulation – Economic approaches into the valuation and evaluation of the drug regulatory framework Evaluatie van geneesmiddelenregulering – Economische toepassingen in de waardering en evaluatie van het regulatoire geneesmiddelensysteem (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op woensdag 23 januari 2013 des middags te 12.45 uur door Jacoline Catharina Bouvy geboren op 27 maart 1985 te Rotterdam Promotor: Prof. dr. H. Schellekens Co-promotor: Dr. M.A. Koopmanschap The studies presented in this thesis were performed in the context of the Escher project (T6- 202), a project of the Dutch Top Institute Pharma. ‘It is our choices, Harry, that show what we truly are, far more than our abilities.’ Albus Dumbledore (In J.K. Rowling’s Harry Potter and the Chamber of Secrets) Glossary ADR Adverse drug reaction CBG-MEB Dutch Medicines Evaluation Board CKD Chronic Kidney Disease DCE Discrete Choice Experiment DHPC Direct Healthcare -
Differential Effects of Extended Exercise and Memantine Treatment on Adult Neurogenesis in Male and Female Rats
bioRxiv preprint doi: https://doi.org/10.1101/332890; this version posted May 29, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. DIFFERENTIAL EFFECTS OF EXTENDED EXERCISE AND MEMANTINE TREATMENT ON ADULT NEUROGENESIS IN MALE AND FEMALE RATS Shaina P Cahill, John Darby Cole, Ru Qi Yu, Jack Clemans-Gibbon, Jason S Snyder* Department of Psychology Djavad Mowafaghian Centre for Brain Health University of British Columbia Vancouver, BC, Canada *Corresponding author email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/332890; this version posted May 29, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. ABSTRACT The creation of new neurons in adulthood has potential for treating a number of disorders that are characterized by neurodegeneration or impaired plasticity. Animal models of reduced neurogenesis, and studies of the volume and structural integrity of the hippocampus in humans, suggest a possible therapeutic role for adult neurogenesis in age-related cognitive decline, depression, and schizophrenia. Research over the past 20 years has identified a number of approaches for enhancing adult neurogenesis, such as exercise, NMDA receptor antagonists, antidepressant drugs and environmental enrichment. However, despite the chronic nature of many disorders that impact the human hippocampus, most animal studies have only examined the efficacy of neurogenic treatments over relatively short timescales (~1 month or less). -
(12) United States Patent (10) Patent No.: US 8,603,526 B2 Tygesen Et Al
USOO8603526B2 (12) United States Patent (10) Patent No.: US 8,603,526 B2 Tygesen et al. (45) Date of Patent: Dec. 10, 2013 (54) PHARMACEUTICAL COMPOSITIONS 2008. O152595 A1 6/2008 Emigh et al. RESISTANT TO ABUSE 2008. O166407 A1 7/2008 Shalaby et al. 2008/0299.199 A1 12/2008 Bar-Shalom et al. 2008/0311205 A1 12/2008 Habib et al. (75) Inventors: Peter Holm Tygesen, Smoerum (DK); 2009/0022790 A1 1/2009 Flath et al. Jan Martin Oevergaard, Frederikssund 2010/0203129 A1 8/2010 Andersen et al. (DK); Karsten Lindhardt, Haslev (DK); 2010/0204259 A1 8/2010 Tygesen et al. Louise Inoka Lyhne-versen, Gentofte 2010/0239667 A1 9/2010 Hemmingsen et al. (DK); Martin Rex Olsen, Holbaek 2010, O291205 A1 11/2010 Downie et al. (DK); Anne-Mette Haahr, Birkeroed 2011 O159100 A1 6/2011 Andersen et al. (DK); Jacob Aas Hoellund-Jensen, FOREIGN PATENT DOCUMENTS Frederikssund (DK); Pemille Kristine Hoeyrup Hemmingsen, Bagsvaerd DE 20 2006 014131 1, 2007 (DK) EP O435,726 8, 1991 EP O493513 7, 1992 EP O406315 11, 1992 (73) Assignee: Egalet Ltd., London (GB) EP 1213014 6, 2002 WO WO 89,09066 10, 1989 (*) Notice: Subject to any disclaimer, the term of this WO WO91,040 15 4f1991 patent is extended or adjusted under 35 WO WO95/22962 8, 1995 U.S.C. 154(b) by 489 days. WO WO99,51208 10, 1999 WO WOOOf 41704 T 2000 WO WO 03/024426 3, 2003 (21) Appl. No.: 12/701,429 WO WOO3,O24429 3, 2003 WO WOO3,O24430 3, 2003 (22) Filed: Feb. -
Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed Hipscs To
Hindawi Publishing Corporation Stem Cells International Volume 2013, Article ID 784629, 25 pages http://dx.doi.org/10.1155/2013/784629 Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny Leonhard Linta,1 Marianne Stockmann,1 Qiong Lin,2 André Lechel,3 Christian Proepper,1 Tobias M. Boeckers,1 Alexander Kleger,3 and Stefan Liebau1 1 InstituteforAnatomyCellBiology,UlmUniversity,Albert-EinsteinAllee11,89081Ulm,Germany 2 Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany 3 Department of Internal Medicine I, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany Correspondence should be addressed to Alexander Kleger; [email protected] and Stefan Liebau; [email protected] Received 31 January 2013; Accepted 6 March 2013 Academic Editor: Michael Levin Copyright © 2013 Leonhard Linta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated. -
American College of Epidemiology Annual Meeting Abstracts, September 7-10, 2019, Pasadena, California
Annals of Epidemiology 36 (2019) 66e78 Contents lists available at ScienceDirect Annals of Epidemiology journal homepage: www.annalsofepidemiology.org American College of Epidemiology Annual Meeting Abstracts, September 7-10, 2019, Pasadena, California Oral Presentations Exploring uniformity of gestational diabetes Methods: We estimated the percentage of overdose deaths reported in the screening and diagnosis using real-world National Vital Statistics System with missing toxicology results from 2010- ’ electronic health record data 2016, overall and by decedents demographic and geographic characteristics. We used a multi-level model to evaluate prevalence of missingness by decedent characteristics, accounting for geographic clustering. & J.M. Lawrence, X. Li. Department of Research Evaluation, Kaiser Results: One-fifth of 351,345 drug overdose deaths from 2010-2016 did not Permanente Southern California, Pasadena, CA indicate a specific drug, declining from 24.4% in 2010 to 14.6% in 2016. In a multi-level model controlling for all predictors, deaths were less likely to Purpose: Gestational diabetes (GDM) surveillance frequently relies on In- have missing information if they occurred in metro counties compared to ternational Classification of Disease (ICD) codes to identify cases. GDM di- rural counties (aOR: 0.31, 95%CI: 0.24, 0.41) and in counties with medical agnoses can be based on several criteria including Carpenter & Coustan examiners versus coroners (aOR: 0.57, 95%CI: 0.47, 0.69). Male decedents (C&C) and International Association of Diabetes in Pregnancy Group were less likely to have missing information than females (aOR: 0.73, 95% (IADPSG). Our objectives were to describe GDM testing patterns within one CI: 0.69, 0.77), and non-Hispanic whites were more likely to have missing large health system and evaluate how well diagnostic coding corresponds information than non-Hispanic blacks (aOR: 1.31, 95%CI: 1.2, 1.4).