DOCSLIB.ORG

In Vivo Pharmacological Profiling in Xenopus Embryos Defines a Subset of A1 Adenosine Receptor-Selective Antagonists with Potent

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
In Vivo Pharmacological Profiling in Xenopus Embryos Defines a Subset of A1 Adenosine Receptor-Selective Antagonists with Potent Aus dem Biomedizinischen Zentrum Institut für Chirurgische Forschung (Walter-Brendel-Zentrum für experimentelle Medizin) der Ludwig-Maximilians-Universität München Kommissarischer Vorstand: Prof. Dr. med. dent. Reinhard Hickel In vivo pharmacological profiling in Xenopus embryos defines a subset of A1 adenosine receptor-selective antagonists with potent anti-angiogenic activities Dissertation zum Erwerb des Doktorgrades der Naturwissenschaften an der Medizinischen Fakultät der Ludwig-Maximilians-Universität München vorgelegt von Mazhar Gull aus Pakistan 2016 Mit Genehmigung der Medizinischen Fakultät der Universität München Erstgutachter: Prof. Dr. phil. André W. Brändli Zweitgutachter: Prof. Dr. Ralph A.W. Rupp Dekan: Prof. Dr. med. dent. Reinhard Hickel Tag der mündlichen Prüfung: 07.07.2017 “You never change things by fighting the existing reality. To change something, build a new model that makes the existing model obsolete.” R. Buckminster Fuller Table of Contents: Table of figures ........................................................................................ IX Table of tables ......................................................................................... XI Abstract ................................................................................................ XIII Zusammenfassung ................................................................................. XIV Introduction .............................................................................................. 1 A chemical genetic screen in Xenopus embryos defines adenosine receptor antagonists as modulators of the vasculature ............................................. 2 G-protein coupled receptors constitute key mediators of cellular response ..... 7 Structural diversity of the GPCR superfamily .............................................. 8 Guanosine nucleotide-binding proteins ..................................................... 12 GPCR activation and signaling ................................................................. 14 Adenosine ............................................................................................ 16 The adenosine receptor family of GPCRs .................................................. 18 AR signaling and biological functions ....................................................... 19 Crystal structures of adenosine receptors ................................................. 23 Expression of adenosine receptors .......................................................... 29 Genetic analysis of adenosine receptor functions ....................................... 31 Roles for adenosine receptors in angiogenesis and lymphangiogenesis......... 33 Adenosine receptors as therapeutic targets .............................................. 37 Hypothesis and Aims ............................................................................. 40 V Materials and methods .............................................................................. 41 Obtaining Xenopus embryos ................................................................... 42 Pharmacological treatments of Xenopus embryos ...................................... 43 Whole mount in situ hybridizations .......................................................... 45 Marker genes for antisense probe synthesis ............................................. 49 Microinjection of morpholino oligonucleotides ........................................... 49 Mammalian cell culture .......................................................................... 49 Chemical treatments and immunostaining of cell cultures .......................... 50 FACS analysis of A1 AR antagonist treated cells ......................................... 50 Proliferation and sprouting assays ........................................................... 51 Results ................................................................................................... 53 Reanalysis of an in vivo chemical library screen defines AR-subtype specific antagonists for testing in Xenopus embryos ............................................. 54 Widespread expression of ARs in Xenopus embryos ................................... 59 Antagonists with selectivity for A1 ARs are effective at inducing edema in Xenopus embryos ................................................................................. 61 Combination treatments with antagonists targeting A2A, A2B or A3 ARs were ineffective at inducing edema formation ................................................... 65 AR antagonists affecting blood and lymph vessel morphogenesis ................ 68 DEPX and 7CN treatments disrupt lymph vessel morphogenesis .................. 70 7CN and DEPX specific antagonists did not affect hematopoiesis, erythrocyte dispersal and muscle differentiation ......................................................... 73 VI Effects of DEPX and 7CN on endothelial cell proliferation and sprouting in vitro .......................................................................................................... 75 Structure-activity relationship studies ...................................................... 78 The in vivo activity of DEPX is influenced by side chain length .................... 78 Endothelial cell proliferation is not affected by DEPX derivatives.................. 84 The in vivo activity of 7CN requires the presence of a phenyl ring ............... 85 7MN inhibits endothelial cell proliferation and sprouting ............................. 89 7MN and 7CN cause mitotic arrest in vitro ................................................ 91 7MN and 7CN disrupt the microtubular cytoskeleton .................................. 93 Discussion ............................................................................................... 96 In vivo identification of vascular disruptive agents .................................... 97 Xenopus embryos as a powerful model to identify the vascular disruptive agents in vivo ....................................................................................... 98 AR agonists fail to induce edema in Xenopus embryos ............................. 100 Pharmacological inhibition of A2A, A2B or A3 AR signaling does not affect vascular development .......................................................................... 101 A1 AR antagonists induce edema in vivo ................................................. 102 Only a subset of A1 AR antagonists affect blood and lymph vessel development in vivo ............................................................................................... 104 Structure-activity relationship studies reveal critical molecular determinants for bioactivity in vivo ........................................................................... 105 Physicochemical properties and in vivo bioactivities of AR antagonists ....... 108 Endothelial cells are direct targets of 7CN and 7MN ................................. 109 VII DEPX and DPPX exert their anti-angiogenic activities via an indirect mechanism ........................................................................................ 109 7CN and 7MN inhibit endothelial cell proliferation and sprouting by destabilization of the microtubular cytoskeleton ...................................... 111 Tissue and cell-type selectivities of the active compounds ........................ 112 Conclusions ........................................................................................... 115 Outlook................................................................................................. 116 Bibliography .......................................................................................... 119 Acknowledgements ................................................................................ 132 Deklaration ........................................................................................... 134 Appendix .............................................................................................. 135 Abbreviation ....................................................................................... 135 Curriculum Vitae ................................................................................. 138 VIII Table of figures Figure 1. Schematic illustration of the relationship between the blood circulation and the lymphatic system. .......................................................................... 2 Figure 2. Two-step whole-organism based chemical library screening strategy to identify modulators of vascular development in Xenopus embryos. ................... 5 Figure 3. Human GPCR superfamily sequence homology tree. ........................ 10 Figure 4. GPCR subfamilies and their ligands. .............................................. 11 Figure 5. Classification, expression, and function of G protein α subunit family members. ............................................................................................... 13 Figure 6. Diversity of GPCRs activation and signaling. ................................... 15 Figure 7. Structures and extracellular degradation of ATP to adenosine. .......... 17 Figure 8. Overview of the intracellular signaling pathways activated by ARs. ... 22 Figure 9. Agonist bound crystal structure of A2A AR. ..................................... 26 Figure 10. Comparison of the ligand binding sites of A2A adenosine receptors bound to various ligands. .......................................................................... 28 Figure 11. General structural
Load more

Recommended publications
  • Annexes to the EMA Annual Report 2009
    Annual report 2009 Annexes The main body of this annual report is available on the website of the European Medicines Agency (EMA) at: http://www.ema.europa.eu/htms/general/direct/ar.htm 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2010. Reproduction is authorised provided the source is acknowledged. Contents Annex 1 Members of the Management Board..................................................... 3 Annex 2 Members of the Committee for Medicinal Products for Human Use .......... 5 Annex 3 Members of the Committee for Medicinal Products for Veterinary Use ....... 8 Annex 4 Members of the Committee on Orphan Medicinal Products .................... 10 Annex 5 Members of the Committee on Herbal Medicinal Products ..................... 12 Annex 6 Members of the Paediatric Committee................................................ 14 Annex 7 National competent authority partners ............................................... 16 Annex 8 Budget summaries 2008–2009 ......................................................... 27 Annex 9 European Medicines Agency Establishment Plan .................................. 28 Annex 10 CHMP opinions in 2009 on medicinal products for human use .............. 29 Annex 11 CVMP opinions in 2009 on medicinal products for veterinary use.......... 53 Annex 12 COMP opinions in 2009 on designation of orphan medicinal products
    [Show full text]
  • Myocardial Metabolism in Heart Failure: Purinergic Signalling and Other
    Accepted Manuscript Myocardial metbolism in heart failure: Purinergic signalling and other metabolic concepts Andreas L. Birkenfeld, Jens Jordan, Markus Dworak, Tobias Merkel, Geoffrey Burnstock PII: S0163-7258(18)30153-0 DOI: doi:10.1016/j.pharmthera.2018.08.015 Reference: JPT 7270 To appear in: Pharmacology and Therapeutics Please cite this article as: Andreas L. Birkenfeld, Jens Jordan, Markus Dworak, Tobias Merkel, Geoffrey Burnstock , Myocardial metbolism in heart failure: Purinergic signalling and other metabolic concepts. Jpt (2018), doi:10.1016/j.pharmthera.2018.08.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Myocardial metbolism in heart failure: Purinergic signalling and other metabolic concepts Andreas L. Birkenfeld MD1,2,3,4, Jens Jordan MD5, Markus Dworak PhD6, Tobias Merkel PhD6 and Geoffrey Burnstock PhD7,8. Affiliations 1Medical Clinic III, Universitätsklinikum "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany 2Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, Dresden, German Center for Diabetes Research
    [Show full text]
  • Adenosine A1 Receptor Antagonists in Clinical Research and Development Berthold Hocher1,2
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector mini review http://www.kidney-international.org & 2010 International Society of Nephrology Adenosine A1 receptor antagonists in clinical research and development Berthold Hocher1,2 1Institute of Nutritional Science, University of Potsdam, Potsdam, Germany and 2Center for Cardiovascular Research/Department of Pharmacology and Toxicology, Charite´, Campus Mitte, Berlin, Germany Selective adenosine A1 receptor antagonists targeting renal Various lines of evidence implicate impaired renal function as microcirculation are novel pharmacologic agents that are a risk factor in patients with congestive heart failure (CHF). currently under development for the treatment of acute Conventional diuretics may aggravate renal dysfunction and heart failure as well as for chronic heart failure. Despite can result in neurohumoral activation and activation of the several studies showing improvement of renal function TGF mechanism in the kidney.1 Impaired kidney function and/or increased diuresis with adenosine A1 antagonists, might not just be a risk factor, but is also currently observed particularly in chronic heart failure, these findings were as having a role—and thus potentially as target—in disease not confirmed in a large phase III trial in acute heart failure progression of heart failure patients.1 Evolving new ther- patients. However, lessons can be learned from these and apeutic strategies that enhance renal function include other studies, and there might still be a potential role for administration of B-type natriuretic peptide, adenosine the clinical use of adenosine A1 antagonists. and vasopressin antagonists, and ultrafiltration methods. We review the role of adenosine A1 receptors in the Prospective studies are needed to evaluate whether these new regulation of renal function, and emerging data regarding renal-enhancing strategies will improve patient outcome in the safety and efficacy of A1 adenosine receptor antagonists CHF.
    [Show full text]
  • Illinois College Jacksonville, Illinois
    TRANSACTIONS OF THE ILLINOIS STATE ACADEMY OF SCIENCE Supplement to Volume 106 105th Annual Meeting April 5-6, 2013 Illinois College Jacksonville, Illinois Illinois State Academy of Science Founded 1907 Affiliated with the Illinois State Museum, Springfield, Illinois TABLE OF CONTENTS Schedule of Events 3 Presentation Schedules At-a-Glance 4 ORAL AND POSTER PRESENTATION SESSIONS Oral Presentation Sessions: Title and Author Listings Session 1: Physics, Mathematics, & Astronomy 5 Session 2: Botany 5 Session 3: Cell, Molecular, & Developmental Biology 7 Session 4: Chemistry & Computer Science 8 Session 5: Environmental Science/Zoology 9 Session 6: Health Sciences, Microbiology, and STEM Education 10 Session 7: Zoology 11 Poster Presentation Sessions: Title and Author Listings Agriculture 13 Botany 13 Cell, Molecular, & Developmental Biology 15 Chemistry 16 Computer Science 17 Earth Science 18 Environmental Science 18 Health Sciences 19 Microbiology 19 Physics, Mathematics, & Astronomy 20 Zoology 21 1 ORAL AND POSTER PRESENTATION ABSTRACTS Oral Presentation Abstracts Session 1: Physics, Mathematics, & Astronomy 24 Session 2: Botany 25 Session 3: Cell, Molecular, & Developmental Biology 30 Session 4: Chemistry & Computer Science 35 Session 5: Environmental Science/Zoology 38 Session 6: Health Sciences, Microbiology, and STEM 42 Session 7: Zoology 45 Poster Presentation Abstracts Agriculture 50 Botany 50 Cell, Molecular, & Developmental Biology 59 Chemistry 66 Computer Science 70 Earth Science 71 Environmental Science 72 Health Sciences 74 Microbiology
    [Show full text]
  • Heart Failure Guidelines
    ; ; ; † § ** ; ; † † * ; ; † † ; ; ¶ † ; * † * ; . 2013;128:e240–e327. † ; DOI: 10.1161/CIR.0b013e31829e8776 †‡ Circulation * †† * ; Tamara Horwich, MD, FACC Tamara ; ‖ ; Barbara Riegel, DNSc, RN, FAHA ; Barbara Riegel, ; Patrick E. McBride, MD, MPH, FACC ; Patrick † ; Wayne C. Levy, MD, FACC C. Levy, Wayne ; # † † ; Emily J. Tsai, MD, FACC ; Emily J. ; Biykem Bozkurt, MD, PhD, FACC, FAHA Bozkurt, MD, PhD, FACC, ; Biykem ; Gregg C. Fonarow, MD, FACC, FAHA MD, FACC, C. Fonarow, ; Gregg † † † * * * e240 ; Lynne W. Stevenson, MD, FACC Stevenson, W. ; Lynne ; Judith E. Mitchell, MD, FACC, FAHA ; Judith E. Mitchell, MD, FACC, † † ; Maryl R. Johnson, MD, FACC, FAHA ; Maryl R. Johnson, MD, FACC, * † * ; Donald E. Casey, Jr, MD, MPH, MBA, FACP, FAHA FACP, MD, MPH, MBA, Jr, ; Donald E. Casey, † * WRITING COMMITTEE MEMBERS Bruce L. Wilkoff, MD, FACC, FHRS MD, FACC, Wilkoff, Bruce L. Journal of the American College of Cardiology. American College of the Journal Management of Heart Failure Clyde W. Yancy, MD, MSc, FACC, FAHA, Chair FAHA, MD, MSc, FACC, Yancy, W. Clyde ACCF/AHA Practice Guideline ACCF/AHA International Society for Heart and Lung Transplantation International Society for Heart and Lung 2013 ACCF/AHA Guideline for the Guideline for ACCF/AHA 2013 W.H. Wilson Tang, MD, FACC Tang, Wilson W.H. Flora Sam, MD, FACC, FAHA Flora Sam, MD, FACC, Heart Association Task Force on Practice Guidelines Force Task Association Heart Edward K. Kasper, MD, FACC, FAHA MD, FACC, K. Kasper, Edward James L. Januzzi, MD, FACC John J.V. McMurray, MD, FACC McMurray, John J.V. Stephen A. Geraci, MD, FACC, FAHA, FCCP FAHA, A. Geraci, MD, FACC, Stephen . 2013;128:e240-e327.) is available at http://circ.ahajournals.org is available Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation Association of Cardiovascular American by the Endorsed Pamela N.
    [Show full text]
  • WO 2011/089216 Al
    (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 t 28 July 2011 (28.07.2011) WO 2011/089216 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 47/48 (2006.01) C07K 1/13 (2006.01) kind of national protection available): AE, AG, AL, AM, C07K 1/1 07 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) Number: International Application DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP201 1/050821 HN, HR, HU, ID, J , IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 2 1 January 201 1 (21 .01 .201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 1015 1465. 1 22 January 2010 (22.01 .2010) EP kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (71) Applicant (for all designated States except US): AS- ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, CENDIS PHARMA AS [DK/DK]; Tuborg Boulevard TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 12, DK-2900 Hellerup (DK).
    [Show full text]
  • MK-7418 Prot. No. 301-302 PROTECT 2. Synopsis
    MK-7418 Prot. No. 301-302 PROTECT 2. Synopsis MERCK RESEARCH CLINICAL STUDY REPORT LABORATORIES SYNOPSIS MK-7418 rolofylline, IV Congestive Heart Failure PROTOCOL TITLE/NO.: A Multicenter, Randomized, Double-Blind, Placebo- #301-302 Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms and Renal Function in Subjects with Acute Heart Failure Syndrome and Renal Impairment who are Hospitalized for Volume Overload and Require Intravenous Diuretic Therapy. PROTECTION OF HUMAN SUBJECTS: This study was conducted in conformance with applicable country or local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research. For study audit information see [16.1.8]. INVESTIGATOR(S)/STUDY CENTER(S): Multicenter 239 sites Worldwide, 18 countries [16.1.3.1; 16.1.4.1] PUBLICATION(S): PRIMARY THERAPY PERIOD: 02May2007 to 23JAN2009. CLINICAL III Day 60 Follow-Up completed 23MAR2009; Day 180 Follow-up PHASE: completed 30JUL2009. DURATION OF TREATMENT: All patients were treated with active drug or exact match placebo given as a 4-hour intravenous infusion for up to 3 days or until discharge, whichever occurred first. OBJECTIVE(S): The objectives of this study were to evaluate the effect of rolofylline in addition to intravenous (IV) loop diuretic therapy on heart failure signs and symptoms, persistent renal dysfunction, morbidity and mortality, and safety in subjects hospitalized with acute heart failure syndrome (AHFS), volume overload, and renal impairment, and to estimate and compare within-trial medical resource utilization and direct medical costs between patients treated with rolofylline and placebo.
    [Show full text]
  • Diagnosis and Management of Acute Heart Failure
    860 Consensus Report Diagnosis and management of acute heart failure Dilek Ural, Yüksel Çavuşoğlu1, Mehmet Eren2, Kurtuluş Karaüzüm, Ahmet Temizhan3, Mehmet Birhan Yılmaz4, Mehdi Zoghi5, Kumudha Ramassubu6, Biykem Bozkurt6 Department of Cardiology, Medical Faculty of Kocaeli University; Kocaeli-Turkey; 1Department of Cardiology, Medical Faculty of Eskişehir Osmangazi University; Eskişehir-Turkey; 2Department of Cardiology, Siyami Ersek Hospital; İstanbul-Turkey; 3Department of Cardiology, Turkey Yüksek İhtisas Hospital; Ankara-Turkey; 4Department of Cardiology, Medical Faculty of Cumhuriyet University; Sivas-Turkey; 5Department of Cardiology, Medical Faculty of Ege University; İzmir-Turkey 6Department of Cardiology, Baylor College of Medicine and University of Texas Medical School; Texas-USA ABSTRACT Acute heart failure (AHF) is a life threatening clinical syndrome with a progressively increasing incidence in general population. Turkey is a country with a high cardiovascular mortality and recent national statistics show that the population structure has turned to an 'aged' population. As a consequence, AHF has become one of the main reasons of admission to cardiology clinics. This consensus report summarizes clinical and prognostic classification of AHF, its worldwide and national epidemiology, diagnostic work-up, principles of approach in emergency department, intensive care unit and ward, treatment in different clinical scenarios and approach in special conditions and how to plan hospital discharge. (Anatol J Cardiol 2015: 15; 860-89) Keywords: acute heart failure, diagnosis, management 1. Introduction of Academic Emergency Medicine (5) do also take attention of cardiologists. However, Turkish AHF patients show some epide- Acute heart failure (AHF) is defined as a life threatening clini- miological differences than European or American AHF patients cal syndrome with rapidly developing or worsening typical heart and some pharmacological (e.g.
    [Show full text]
  • Adenosine Receptor P1 Receptor
    Adenosine Receptor P1 receptor Adenosine receptors (ARs) comprise a group of G protein-coupled receptors (GPCR) which mediate the physiological actions of adenosine. To date, four AR subtypes have been cloned and identified in different tissues. These receptors have distinct localization, signal transduction pathways and different means of regulation upon exposure to agonists. A key property of some of Adenosine receptors is their ability to serve as sensors of cellular oxidative stress, which is transmitted by transcription factors, such as NF-κB, to regulate the expression of ARs. The importance of Adenosine receptors in the regulation of normal and pathological processes such as sleep, the development of cancers and in protection against hearing loss will be examined. www.MedChemExpress.com 1 Adenosine Receptor Inhibitors, Agonists, Antagonists, Activators & Modulators (Rac)-Mirabegron D5 5'-N-Ethylcarboxamidoadenosine ((Rac)-YM178 D5) Cat. No.: HY-14773S (NECA) Cat. No.: HY-103173 (Rac)-Mirabegron D5 ((Rac)-YM178 D5) is a 5'-N-Ethylcarboxamidoadenosine (NECA) is a deuterium labeled (Rac)-Mirabegron. nonselective adenosine receptor agonist. (Rac)-Mirabegron is the racemate of Mirabegron. Mirabegron is a selective β3-adrenoceptor agonist. Purity: >98% Purity: 99.86% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 5 mg, 10 mg 8-Cyclopentyl-1,3-dimethylxanthine A2A receptor antagonist 1 Cat. No.: HY-W011955 (CPI-444 analog) Cat. No.: HY-102024 8-Cyclopentyl-1,3-dimethylxanthine (Compound 2a) A2A receptor antagonist 1 (CPI-444 analog) is an is a selective adenosine A1 receptor antagonist antagonist of both adenosine A2A receptor and with Kis of 10.9 nM and 1440 nM for A1 receptor A1 receptor with Ki values of 4 and 264 nM, and A2 receptor, respectively.
    [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]
  • Xanthine Derivatives in the Heart: Blessed Or Cursed?
    Current Medicinal Chemistry, 2011, 18, 3695-3706 3695 Xanthine Derivatives in the Heart: Blessed or Cursed? A. J. Szentmiklósi*,#,1, Á. Cseppent#,1, R. Gesztelyi2, J. Zsuga3, Á. Körtvély4 , G. Harmati4 and P.P. Nánási4 1Department of Pharmacology and Pharmacotherapy, University of Debrecen, Medical and Health Science Center, Debrecen, H-4012, Hungary 2Department of Pharmacodynamics, University of Debrecen, Medical and Health Science Center, Debrecen, H-4012, Hungary 3Department of Neurology, University of Debrecen, Medical and Health Science Center, Debrecen, H-4032, Hungary 4Department of Physiology, University of Debrecen, Medical and Health Science Center, Debrecen, H-4012, Hungary Abstract: Methylxanthines, such as theophylline, have been used to treat cardiorespiratory disorders, whereas caffeine is the most widely consumed psychoactive agent in various soft drinks. Because of the worldwide use of these drugs and the recently synthesized xanthine derivatives, an intensive research on the cardiac actions of these substances is under progress. This review focuses on the molecular mechanisms involved in the actions of xanthine derivatives with special reference to their adenosine receptor antagonistic properties. The main basic and human studies on the action of xanthines on impulse initiation and conduction, as well as the electrophysiological and mechanical activity of the working myocardium will be overviewed. The potential beneficial and harmful actions of the methylxanthines will be discussed in light of the recent experimental and clinical findings. The pharmacological features and clinical observations with adenosine receptor subtype-specific xanthine antagonists are also the subject of this paper. Based on the adenosine receptor-antagonistic activity of these compounds, it can be raised that xanthine derivatives might inhibit the cardioprotective action of endogenous adenosine on various subtypes (A1, A2A, A2B and A3) of adenosine receptors.
    [Show full text]
  • Modulation of the Arrhythmia Substrate in Cardiovascular Disease
    Modulation of the Arrhythmia Substrate in Cardiovascular Disease DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Victor Paul Long III Graduate Program in Pharmaceutical Sciences The Ohio State University 2016 Dissertation Committee: Dr. Cynthia A. Carnes, Advisor Dr. Sandor Györke Dr. Kari Hoyt Dr. Peter J Mohler Copyright by Victor Paul Long III 2016 Abstract Heart failure remains a leading cause of morbidity and mortality in the United States. Many of the deaths attributed to heart failure are sudden, presumably due to lethal arrhythmia. It is a combination of structural and electrical remodeling within the failing heart that promotes the abnormalities of normal rhythm that lead to arrhythmia. This remodeling can occur in the ventricle, resulting in tachyarrhythmia or the sinus node, where it can cause either brady- or tachyarrhythmias. Potassium currents mediate the repolarization phase of ventricular action potential, as well as the diastolic phase of the sinoatrial node action potential. One of the purposes of the research described in this dissertation is to understand, from the standpoint of cellular electrophysiology, how alterations of potassium currents play a role in heart-failure induced arrhythmia. The second purpose is to determine if management of serum potassium levels by pharmacists is an effective strategy in patients to minimize proarrhythmia risk in patients taking antiarrhythmic medications. We found that heart failure duration is very important in the progressive reduction of the repolarization reserve of K+ currents in the ventricle. Our results differ from other models, as we were able to identify IKr reduction in chronic heart failure compared to short-term duration heart failure.
    [Show full text]