DOCSLIB.ORG

Investigation Into the Effects of Specific Muscarinic Acetylcholine Receptor

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Investigation Into the Effects of Specific Muscarinic Acetylcholine Receptor Investigation into the effects of specific muscarinic acetylcholine receptor antagonists on the myocardium in pre- clinical conditions of ischaemia reperfusion injury and oxidative stress model Khan, J. Submitted version deposited in CURVE March 2016 Original citation: Khan, J. (2015) Investigation into the effects of specific muscarinic acetylcholine receptor antagonists on the myocardium in pre-clinical conditions of ischaemia reperfusion injury and oxidative stress model. Unpublished PhD Thesis. Coventry: Coventry University Copyright © and Moral Rights are retained by the author. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders. Some materials have been removed from this thesis due to third party copyright. Pages where material has been removed are clearly marked in the electronic version. The unabridged version of the thesis can be viewed at the Lanchester Library, Coventry University. CURVE is the Institutional Repository for Coventry University http://curve.coventry.ac.uk/open Investigation into the effects of specific muscarinic acetylcholine receptor antagonists on the myocardium in pre-clinical conditions of ischaemia reperfusion injury and oxidative stress model By Jawad Ahmed Khan November 2015 A thesis submitted in partial fulfilment of the University’s requirements for the Degree of Doctor of Philosophy 1 Acknowledgements I would like to express my deepest appreciation to my supervisors; Prof. Helen Maddock and Dr. Afthab Hussain for giving me the opportunity to undertake this project and also for their continuous support throughout my PhD. I would also like to thank Coventry University and Brookes Pharmaceuticals for funding my PhD. In addition, I would also like to thank the lab technician, Mark Bodycote for his support and patience throughout the period of my PhD. Furthermore, I would like to express my gratitude to my friends and lab colleagues Aaron Nagra, Maryam Babba and Mayel Gharanea for their support and friendship. Most importantly, I am indebted to my parents, my wife and her parents for their continuous encouragement, love and support at all times throughout my PhD. I am very privileged to have such a loving and caring family around me as without their assistance, completing my PhD would not have been possible. 2 Abstract Muscarinic acetylcholine receptors (mAChRs) are G-protein coupled receptors that mediate various actions of Acetylcholine (ACh) in the central nervous system and peripheral nervous system. In mammals, five distinct mAChR subtypes (M1-M5) have been recognised with the M2 subtype being predominantly present in the heart. The mAChR antagonists are routinely used for the treatment of various pathophysiological conditions including respiratory conditions. However, it has been postulated that mAChR antagonists may increase morbidity and mortality in chronic obstructive pulmonary disorder (COPD) and asthma patients with underlying cardiovascular disease, raising concerns regarding the cardiovascular safety of these agents. The current study was therefore undertaken to investigate the effects of individual mAChR antagonists in the setting of myocardial ischaemia reperfusion injury and oxidative stress models. We also investigated whether the inhibition of the mitochondrial permeability transition pore (MPTP) with cyclosporine-A (CsA) in the presence and absence of individual mAChR antagonists provided protection against ischaemia reperfusion injury. Furthermore, we also aimed to investigate the intracellular signalling pathway associated with mAChRs antagonists mediated myocardial injury under the stress conditions. Langendorff results showed that the non-selective M1-M3 mAChR antagonist, ipratropium bromide, the M2 mAChR antagonist, AF-DX 116 and the M3 mAChR antagonist, DAU 5884 significantly increased the infarct size to risk ratio of the heart in conditions of ischaemia and reperfusion. Detrimental effects of AF-DX 116 and DAU 5884 were abrogated by co-treatment of these drugs with mAChR agonist, acetylcholine (ACh) and/or CsA. Cell viability data of isolated cardiac myocytes revealed that AF-DX 116 and DAU 5884 caused a concentration 3 dependent decrease in the viability of cardiac myocytes as well as causing a reduction in the time taken to depolarisation and hypercontracture under oxidative stress. AF-DX 116 and DAU 5884 significantly increased the levels of p-SAPK/JNK and decreased the levels of p-Akt and p-ERK. In addition, ACh and CsA showed to activate p-Akt and p-ERK. To conclude, the data suggest that AF-DX 116 and DAU 5884 caused cardiotoxicity at cellular, tissue and protein level in conditions of ischaemia reperfusion injury and oxidative stress. Furthermore, inhibition of the mitochondrial transition pore with CsA protected against the AF- DX 116 and DAU 5884 induced injury via activation of the pro-survival proteins, p-Akt and p- ERK. 4 Contents Page Acknowledgement………………………………………………………………………………2 Abstract……………………………………………………………………….............................3 Table of contents………………………………………………………………………………...5 List of figures……………………………………………………………………………………12 List of tables…………………………………………………………………………………......19 Abbreviations……………………………………………………………………………………22 Chapter One: General Introduction…………………………………………………………..26 1.1 Chronic Obstructive Pulmonary Disease………………………………………………..26 1.1.2 COPD treatment………………………………………………………............................28 1.1.3 Side effects associated with ipratropium and tiotropium………………………………...31 1.2 Coronary heart disease…………………………………………………………………...31 1.2.1 Oxygen derived free radicals…………………………………………………………….33 1.2.2 Calcium overload………………………………………………………………………...34 1.2.3 Apoptosis………………………………………………………………………………...37 1.2.4 Necrosis…………………………………………………………………………………..42 1.2.5 Autophagy…………………………………......................................................................43 1.3 Myocardial injury signalling pathway…………………………………………………...44 1.3.1 Mitogen activated protein kinase………………………………………………………...44 1.3.2 Phosphatidylinositol-3-Kinase.…………………………………………………………..46 1.3.3 G protein coupled receptors……………………………………………………………...48 1.4 Muscarinic receptors……………………………………………………………………..49 1.4.1 M1 receptors……………………………………………………………………………...50 1.4.2 M2 receptors……………………………………………………………………………...51 1.4.3 M3 receptors……………………………………………………………………………...51 1.4.4 Adenylyl cyclase…………………………………………………………………………52 1.4.5 Phospholipase C………………………………………………………………………….54 1.5 Acetylcholine…………………………………………………………………………….55 5 1.5.1 Clinical relevance of mAChRs…………………………………………………………..57 1.5.2 Alzheimer’s disease and cognitive impairments…………………………………………57 1.5.3 Overactive bladder…………………………………………………………………….....58 1.5.4 Irritable bowel syndrome…………………………………………………………….......60 1.6 Mitochondrial permeability transition pore……………………………………………...56 1.7 Biomarkers of myocardial injury………………………………………………………...62 1.7.1 Clinical cardiac biomarkers……………………………………………………………...63 1.7.2 Micro RNA……………………………………………………………………………....64 1.7.3 miRNAs as biomarkers…………………………………………………………………..65 Hypotheses……………………………………………………………………………………….67 Chapter Two: Methods…………………………………………………………………………68 2.1.1 Animals………………………………………………………………………………….68 2.1.2 Materials………………………………………………………………………………...68 2.2 Isolated perfused heart preparation………………………………………………………69 2.3.1 Isolation of cardiac myocyte…………………………………………………………......72 2.3.2 MTT assay……………………………………………………………………………….73 2.4 MPTP oxidative stress model protocol……………………………………………….....74 2.5 Western blot…………………………………………………………………..................75 2.5.1 Tissue preparation…………………………………………………………………….....75 2.5.2 Gel electrophoresis………………………………………………………………………76 2.5.3 Transfer………………………………………………………………………………….76 2.5.4 Antibody incubation…………………………………………………………………......77 2.5.5 Detection of proteins…………………………………………………………………….77 2.6 miRNA analysis…………………………………………………………………………77 2.7.1 Statistical analysis………………………………………………………………………..78 2.7.2 miRNA data calculation and analysis……………………………………………………79 6 Chapter Three: Investigation into the effects of Ipratropium bromide and Telenzepine dihydrochloride on heart undergoing ischaemia reperfusion injury and cardiac myocytes undergoing oxidative stress…………….................................................................................80 3.1 Introduction……………………………………………………………………………80 3.2 Methods……………………………………………………………………………......81 3.2.1 Isolated perfused heart preparation……………………………………………….........81 3.2.2 Langendorff protocol…………………………………………………………………..81 3.2.3 MTT analysis of cell viability…………………………………………………….........82 3.2.4 Statistical analysis……………………………………………………………………....82 3.3 Results………………………………………………………………………………….83 3.3.1 The effects of ipratropium bromide on the infarct size from the Langendorff experiments under normoxic conditions……………………………………………………………..83 3.3.2 The effects of ipratropium bromide on the infarct size from the Langendorff experiments undergoing ischaemia reperfusion injury……………………………………………....83 3.3.3 The effects of ipratropium bromide on the viability of isolated cardiac myoctes under normoxic conditions……………………………………………………………………85 3.3.4 The effects of ipratropium bromide on the viability of isolated cardiac myoctes under hypoxia and re-oxygenation……………………………………………………………86
Load more

Recommended publications
  • Alzheimer's Disease Clinical Trials
    Clinical Trial Perspective 5 Clinical Trial Perspective Alzheimer’s disease clinical trials: past failures and future opportunities Clin. Invest. (Lond.) Over a decade has elapsed since the US FDA has approved a medication for Alzheimer’s Roy Yaari*,1,2 & Ann Hake1,2 disease (AD) despite clinical trials of numerous agents over a wide array of mechanisms 1Eli Lilly & Company, Lilly Corporate including neurotransmitter modulation and disease modifying therapy targeting Center, Indianapolis, IN 46285, USA 2Indiana University School of Medicine, amyloid and tau. The failures of clinical trials in AD may be due to inadequate Department of Neurology, Indianapolis, understanding of mechanisms of action and/or poor target engagement; however, IN 46202, USA other factors could include inadequate study design, stage of AD along the continuum *Author for correspondence: studied, inclusion of participants without Alzheimer’s pathology into clinical trials Tel.: +1 317 651 6163 and limited power of endpoint measures. Future studies will need to carefully assess [email protected] these possible shortcomings in design of upcoming trials, especially as the field moves toward studies of disease modifying agents (as opposed to symptomatic treatment) of AD and to patients that are very early in the disease spectrum. Keywords: Alzheimer’s disease • Alzheimer’s disease biomarkers • amyloid • clinical trials • preclinical Alzheimer’s disease • tau US FDA approved medications continue to provide significant, but modest More than three decades ago, the choliner- symptomatic benefit[5–7] . gic hypothesis proposed that degeneration The compound memantine introduced a of cholinergic neurons in the basal fore- second mechanism for symptomatic treat- brain and the associated loss of cholinergic ment of AD into clinical practice.
    [Show full text]
  • Co-Administration of Pimavanserin with Other Agents Coadministration Von Pimavanserin Mit Anderen Mitteln Co-Administration De Pimavansérine Avec D’Autres Agents
    (19) TZZ ZZ_Z_T (11) EP 2 200 610 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4468 (2006.01) A61P 25/00 (2006.01) 10.01.2018 Bulletin 2018/02 (86) International application number: (21) Application number: 08831500.7 PCT/US2008/077139 (22) Date of filing: 19.09.2008 (87) International publication number: WO 2009/039460 (26.03.2009 Gazette 2009/13) (54) CO-ADMINISTRATION OF PIMAVANSERIN WITH OTHER AGENTS COADMINISTRATION VON PIMAVANSERIN MIT ANDEREN MITTELN CO-ADMINISTRATION DE PIMAVANSÉRINE AVEC D’AUTRES AGENTS (84) Designated Contracting States: • MCFARLAND, Krista AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Walnut Creek, CA 94597 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR (74) Representative: Savic, Bojan et al Designated Extension States: Jones Day AL BA MK RS Rechtsanwälte Attorneys-at-Law Patentanwälte Prinzregentenstraße 11 (30) Priority: 21.09.2007 US 974426 P 80538 München (DE) 07.11.2007 US 986250 P 06.05.2008 US 50976 (56) References cited: EP-A1- 1 576 985 WO-A-2004/064738 (43) Date of publication of application: WO-A-2005/112927 US-A1- 2005 261 340 30.06.2010 Bulletin 2010/26 Remarks: (73) Proprietor: Acadia Pharmaceuticals Inc. Thefile contains technical information submitted after San Diego, CA 92139 (US) the application was filed and not included in this specification (72) Inventors: • HACKSELL, Uli Tampa, FL 33639 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations.
    [Show full text]
  • Proc. Intl. Soc. Mag. Reson. Med. 22 (2014) 0160
    Assessment of cholinergic synaptic transmission modulation in the mouse brain using resting-state functional Magnetic Resonance Imaging (rsfMRI) Disha Shah1, Rafael Delgado y Palacios1, Pieter-Jan Guns1, Elisabeth Jonckers1, Marleen Verhoye1, and Annemie Van der Linden1 1University of Antwerp, Bio-Imaging Lab, Wilrijk, Antwerp, Belgium Introduction: Resting state functional magnetic resonance imaging (rsfMRI) is an upcoming technique used to evaluate functional connectivity (FC) in the brain. This technique has been applied in neurodegenerative disorders (ND) such as Alzheimer’s disease (AD). Synaptic dysfunction is thougth to be a key event in AD and occurs at a relatively early stage [1], leading to alterations in neuronal transmission. We hypothesize that these synaptic transmission deficits could be reflected as altered FC in the brain. In the current study we investigate whether synaptic transmission defects, induced by the muscarinic acetylcholine receptor (mAChR) antagonist scopolamine, can be detected as altered FC using rsfMRI in mice. Furthermore, we investigate whether scopolamine induced FC deficits can be reversed with milameline (an AChR agonist). Material and methods: All MR imaging procedures were performed on a 9.4T Biospec MRI system (Bruker BioSpec, Germany). RsfMRI measurements were acquired using a single shot gradient echo EPI sequence (TE 15ms, TR 2s, FOV 20mm, matrix 128x64, 16 axial slices). C57BL/6 mice (N=15/group) were subcutaneously injected with saline (10ml/kg), methylscopolamine (3mg/kg) or scopolamine (0.5;1;3mg/kg), after which they were subjected to rsfMRI. For an additional group of mice (N=8), rsfMRI scans of the same animal were acquired first at baseline, then after the administration of scopolamine (1mg/kg) and finally after the additonal injection of milameline (1mg/kg).
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,673,964 B2 Lautt (45) Date of Patent: Mar
    USOO8673964B2 (12) United States Patent (10) Patent No.: US 8,673,964 B2 Lautt (45) Date of Patent: Mar. 18, 2014 (54) USE OF DRUG COMBINATIONS FOR OTHER PUBLICATIONS TREATING INSULIN RESISTANCE Yki-Jarvinen (Cobination Therapies with Insulin in Type 2 diabetes, Deabetes care, vol. 24, No. 4, pp. 758-767).* (75) Inventor: Wilfred Wayne Lautt, Winnipeg (CA) Holz (Glucagol-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus, Curr Med (73) Assignee: DiaMedica Inc. (CA) Chem, Nov. 2003, 10(22): pp. 2471-2483).* Nodari (Efficacy and tolerability of the long-term administration of (*) Notice: Subject to any disclaimer, the term of this carvedilol in patients with chronic heart failure with and without patent is extended or adjusted under 35 concomitant diabetes mellitus, The European Journal of Heart Fail ure, 2003, vol. 4, pp. 803-809).* U.S.C. 154(b) by 971 days. Beyer et al. "Assessment of Insulin Needs in Insulin-Dependent Diabetics and Healthy Volunteers under Fasting Conditions' Horm (21) Appl. No.: 11/597,032 Metab Res Suppl 1990; vol. 24 p.71-77. Brownlee “Biochemistry and molecular cell biology of diabetic com (22) PCT Filed: May 20, 2005 plications' Nature vol. 414, Dec. 2001 p. 813-820. Hsu et al. “Five Cysteine-Containing Compounds Delay Diabetic Deterioration in Balb/cA Mice' J. Nutr, 2004 134:3245-3249. (86). PCT No.: PCT/CA2005/000775 Lautt “Hepatic Parasympathetic Neuropathy as cause of Maturity S371 (c)(1), Onset Diabetes?” Gen. Pharmac. vol. 11 p. 343-345. Xie et al. “Induction of insulin resistance by cholinergic blockade (2), (4) Date: May 7, 2008 with atropine in the cat' J.
    [Show full text]
  • Alzheimer Syllabus
    Update on Alzheimer’s Disease June, 2006 Stephen S. Flitman, MD, Medical Director 21 st Century Neurology 3100 North Third Ave Suite 100, Phoenix, Arizona (602) 265-6500 www.neurozone.org Alzheimer’s Disease (AD), first described by Dr. Alois Alzheimer in 1907, is a disorder that 10 million Americans are thought to have, but less than 40% are diagnosed or receiving treatment now. It is very common, affecting people ages 40-90 with 2-4% prevalence at ages 65- 75 and increasing in subsequent decades. After heart disease, cancer, and stroke it is the fourth leading cause of death in the US. AD is a disorder of the gray matter of the cerebral cortex. It is characterized clinically by gradually progressive dementia and pathologically by extraneuronal plaques and intraneuronal neurofibrillary tangles by light microscopy. AD progresses anatomically via the connections made by affected neurons. It starts in the entorhinal cortex and then spreads to the hippocampus, basal nuclei, and then to the neocortex. It spares primary motor and sensory cortices, preferentially attacking association areas in the frontal, parietal, and temporal lobes. Affected regions have neurochemical deficits of acetylcholine, glutamate, and serotonin. The degree of dementia correlates with the decline in these neurotransmitters in biopsy or autopsy tissue. While short-term memory deficits predominate early in the progressive dementias, the term dementia is reserved for a clinical syndrome of memory disorder plus at least one other cognitive realm: language, motor or procedural memory (praxis), spatial function, and executive function (decision-making, planning, overall control of behavior). As an etiology for dementia, AD accounts for about two-thirds of cases, with metabolic causes and Lewy body disease making up the lion’s share of the remaining third.
    [Show full text]
  • United States Patent (10) Patent No.: US 8,003,632 B2 Tracey Et Al
    US008.003632B2 (12) United States Patent (10) Patent No.: US 8,003,632 B2 Tracey et al. (45) Date of Patent: Aug. 23, 2011 (54) CHOLINESTERASE INHIBITORS FOR Sg: A t 3. Ryaninomiya et et alal. TREATING INFLAMMATION 5,536,728 A 7/1996 Ninomiya et al. 5,554,780 A 9, 1996 Wolf (75) Inventors: Kevin J. Tracey, Old Greenwich, CT 5,693,668 A 12, 1997 Sain et al. (US); Valentin A. Pavlov, Ridgewood, 5,760,267 A 6/1998 Gandolfi et al. NY (US) 5,861.411 A 1/1999 Ninomiya et al. 5,929,084 A 7, 1999 Zhu et al. 5,981,549 A 11, 1999 V (73) Assignee: The Feinstein Institute for Medical 6, 194403 B1 2, 2001 E. al. Research, Manhasset, NY (US) 6,433,173 B1 8, 2002 Omori 6,610,713 B2 * 8/2003 Tracey .......................... 514,343 (*) Notice: Subject to any disclaimer, the term of this 6,838,471 B2 ck 1/2005 Tracey ded or adiusted under 35 2003. O139391 A1 7/2003 Parys et al. .............. 514,214.03 patent 1s extende 2004/0214.863 A1 10, 2004 Pratt U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 11/893,116 EP O 633 251 A1 1/1995 JP 571 14512 7, 1982 (22) Filed: Aug. 14, 2007 WO WO98/OO119 A 1, 1998 9 WO WO99,08672 2, 1999 O O WO WOO1,89526 A 11, 2001 (65) Prior Publication Data WO WO 2004/034963 A 4, 2004 US 2008/OO70901 A1 Mar. 20, 2008 OTHER PUBLICATIONS Rees et al., Cardiovascular Research (1993)27:453-458.* Related U.S.
    [Show full text]
  • And 19-Month-Old Tg2576 Mice Using Multimodal in Vivo Imaging: Limitations As a Translatable Model of Alzheimer’S Disease Feng Luoa, Nathan R
    Neurobiology of Aging 33 (2012) 933–944 www.elsevier.com/locate/neuaging Characterization of 7- and 19-month-old Tg2576 mice using multimodal in vivo imaging: limitations as a translatable model of Alzheimer’s disease Feng Luoa, Nathan R. Rustaya, Ulrich Ebertb, Vincent P. Hradila, Todd B. Colea, Daniel A. Llanoc, Sarah R. Muddd, Yumin Zhanga, Gerard B. Foxa, Mark Daya,* a Experimental Imaging/Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA b CNS Discovery Research, Abbott Laboratories, Ludwigshafen, Germany c Neuroscience Development, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA d School of Pharmacy, University of Wisconsin, Madison, WI , USA Received 12 January 2010; received in revised form 7 July 2010; accepted 9 August 2010 Abstract With 90% of neuroscience clinical trials failing to see efficacy, there is a clear need for the development of disease biomarkers that can improve the ability to predict human Alzheimer’s disease (AD) trial outcomes from animal studies. Several lines of evidence, including genetic susceptibility and disease studies, suggest the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) as a potential biomarker with congruency between humans and animal models. For example, early in AD, patients present with decreased glucose metabolism in the entorhinal cortex and several regions of the brain associated with disease pathology and cognitive decline. While several of the commonly used AD mouse models fail to show all the hallmarks of the disease or the limbic to cortical trajectory, there has not been a systematic evaluation of imaging-derived biomarkers across animal models of AD, contrary to what has been achieved in recent years in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Miller, 2009).
    [Show full text]
  • Drug Development in Alzheimer's Disease: the Contribution of PET and SPECT
    fphar-07-00088 March 29, 2016 Time: 15:21 # 1 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 31 March 2016 doi: 10.3389/fphar.2016.00088 Drug Development in Alzheimer’s Disease: The Contribution of PET and SPECT Lieven D. Declercq1, Rik Vandenberghe2, Koen Van Laere3, Alfons Verbruggen1 and Guy Bormans1* 1 Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium, 2 Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium, 3 Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium Clinical trials aiming to develop disease-altering drugs for Alzheimer’s disease (AD), a neurodegenerative disorder with devastating consequences, are failing at an alarming rate. Poorly defined inclusion-and outcome criteria, due to a limited amount of objective biomarkers, is one of the major concerns. Non-invasive molecular imaging techniques, positron emission tomography and single photon emission (computed) tomography (PET and SPE(C)T), allow visualization and quantification of a wide variety of (patho)physiological processes and allow early (differential) diagnosis in many disorders. Edited by: Albert D. Windhorst, PET and SPECT have the ability to provide biomarkers that permit spatial assessment VU University Medical Center, of pathophysiological molecular changes and therefore objectively evaluate and follow Netherlands up therapeutic response, especially in the brain. A number of specific PET/SPECT Reviewed by: biomarkers used in support of emerging clinical therapies in AD are discussed in this Bashir M. Rezk, Southern University at New Orleans, review.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Clinical Trials and Late-Stage Drug Development in Alzheimer's Disease: an Appraisal from 1984 to 2014
    WellBeing International WBI Studies Repository 3-2014 Clinical trials and late-stage drug development in Alzheimer’s disease: An appraisal from 1984 to 2014 L. S. Schneider University of Southern California F. Mangialasche Karolinska Institutet and Stockholm University S. Andreasen Karolinska University Hospital H. Feldman University of British Columbia E. Giacobini University of Geneva See next page for additional authors Follow this and additional works at: https://www.wellbeingintlstudiesrepository.org/humctri Part of the Bioethics and Medical Ethics Commons, Clinical Trials Commons, and the Laboratory and Basic Science Research Commons Recommended Citation Schneider, L. S., Mangialasche, F., Andreasen, N., Feldman, H., Giacobini, E., Jones, R., ... & Kivipelto, M. (2014). Clinical trials and late‐stage drug development for A lzheimer's disease: an appraisal from 1984 to 2014. Journal of internal medicine, 275(3), 251-283. This material is brought to you for free and open access by WellBeing International. It has been accepted for inclusion by an authorized administrator of the WBI Studies Repository. For more information, please contact [email protected]. Authors L. S. Schneider, F. Mangialasche, S. Andreasen, H. Feldman, E. Giacobini, R. Jones, V. Mantua, P. Mecocci, L. Pani, B. Winblad, and M. Kivipelto This conference proceeding is available at WBI Studies Repository: https://www.wellbeingintlstudiesrepository.org/ humctri/3 Key Symposium Click here for more articles from the symposium doi: 10.1111/joim.12191 Watch Guest Editor Professor Mila Kivipelto talk about the 9th Key Symposium: Updating Alzheimer’s Disease Diagnosis here. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014 L.
    [Show full text]
  • The Treatment of Alzheimers Disease by Using Donopezil Loaded Transdermal Patch
    Available online www.jocpr.com Journal of Chemical and Pharmaceutical Research, 2015, 7(3):806-813 ISSN : 0975-7384 Review Article CODEN(USA) : JCPRC5 The treatment of alzheimers disease by using donopezil loaded transdermal patch G. Ravi* and N. Vishal Gupta Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore, Karnataka, India _____________________________________________________________________________________________ ABSTRACT Alzheimer’s disease (AD) is the most common type of dementia, more than 100 years ago the alzheimer’s disease was first identified, but research into its risk factors, causes, symptoms, and treatment has gained momentum only in the last 30 years. The cholinesterase inhibitors (ChEIs) were the first anti-Alzheimer drugs approved by the Food and Drug Administration (FDA), by inhibiting acetylcholinesterase these are capable of improving cholinergic neurotransmission. Rivastigmine, galantamine, and donepezil these are the most common ChEIs used to treat cognitive symptoms in mild to moderate AD. In particular, to treat AD patients worldwide the lattermost drug has been widely because it is significantly less hepatotoxic and superior tolerated than its predecessor, tetra hydro amino acridine. It also demonstrates high selectivity towards acetylcholinesterase inhibition and has a long duration of action. For the donepezil these are the formulations available like sustained release (23 mg), immediate release (5 or 10 mg), and orally disintegrating (5 or 10 mg) tablets, all of which are proposed for oral-route administration. Since the oral donepezil therapy is associated with adverse events in the gastrointestinal system and in fluctuations of plasma, an alternative route of administration, such as the transdermal one, has been recently attempted.
    [Show full text]
  • Characterization of a CNS Penetrant, Selective M1 Muscarinic Receptor Agonist, 77-LH-28-1
    British Journal of Pharmacology (2008) 154, 1104–1115 & 2008 Nature Publishing Group All rights reserved 0007– 1188/08 $30.00 www.brjpharmacol.org RESEARCH PAPER Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1 CJ Langmead1, NE Austin1, CL Branch1, JT Brown2, KA Buchanan3, CH Davies1, IT Forbes1, VAH Fry1, JJ Hagan1, HJ Herdon1, GA Jones1, R Jeggo4, JNC Kew1, A Mazzali5, R Melarange1, N Patel1, J Pardoe1, AD Randall2, C Roberts1, A Roopun6, KR Starr1, A Teriakidis2, MD Wood1, M Whittington6,ZWu7 and J Watson1 1Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK; 2Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK; 3MRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol School of Medical Sciences, University Walk, Bristol, UK; 4NeuroSolutions Ltd., Coventry, UK; 5Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Verona, Italy; 6School of Neurology, Neurobiology and Psychiatry, Newcastle University, Newcastle upon Tyne, UK and 7Molecular Discovery Research, GlaxoSmithKline, Upper Providence, Collegeville, PA, USA Background and purpose: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer’s disease and schizophrenia. However, the discovery of subtype- selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n- butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M1 mAChR subtype.
    [Show full text]