DOCSLIB.ORG

Methods and Compositions for Treating Nephrogenic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Methods and Compositions for Treating Nephrogenic (19) TZZ Z_T (11) EP 2 750 676 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/7076 (2006.01) A61K 31/64 (2006.01) 10.01.2018 Bulletin 2018/02 A61K 31/519 (2006.01) A61K 31/517 (2006.01) A61K 31/4365 (2006.01) A61K 33/00 (2006.01) (2006.01) (2006.01) (21) Application number: 12828322.3 A61P 13/12 A61K 45/06 (22) Date of filing: 29.08.2012 (86) International application number: PCT/US2012/052819 (87) International publication number: WO 2013/033178 (07.03.2013 Gazette 2013/10) (54) METHODS AND COMPOSITIONS FOR TREATING NEPHROGENIC DIABETES INSIPIDUS VERFAHREN UND ZUSAMMENSETZUNGEN ZUR BEHANDLUNG VON NEPHROGENEM DIABETES INSIPIDUS PROCÉDÉS ET COMPOSITIONS POUR TRAITER LE DIABÈTE INSIPIDE NÉPHROGÉNIQUE (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB WO-A2-2005/076007 WO-A2-2010/075861 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO US-A1- 2009 297 497 PL PT RO RS SE SI SK SM TR • ALAN D MICHELSON: "New P2Y12 antagonists", (30) Priority: 30.08.2011 US 201161529227 P CURRENT OPINION IN HEMATOLOGY, vol. 16, no. 5, 1 September 2009 (2009-09-01), pages (43) Date of publication of application: 371-377, XP055165128, ISSN: 1065-6251, DOI: 09.07.2014 Bulletin 2014/28 10.1097/MOH.0b013e32832ea2f2 • CHOUDHURY DEVASMITA ET AL: (73) Proprietor: University of Utah Research "Drug-associated renal dysfunction and injury", Foundation NATURE CLINICAL PRACTICE NEPHROLOGY, Salt Lake City, UT 84108 (US) NATURE PUBLISHING GROUP, LONDON, GB, vol. 2, no. 2, 1 February 2006 (2006-02-01), pages (72) Inventors: 80-91, XP007907333, ISSN: 1745-8323, DOI: • KISHORE, Bellamkonda, K. 10.1038/NCPNEPH0076 Sandy, UT 84094 (US) • TIAN ET AL.: ’Downregulation of renal • CARLSON, Noel, G. vasopressin V2 receptor and aquaporin-2 Salt Lake City, UT 84124 (US) expression parallels age-associated defects in • ZHANG, Yue urine concentration.’ AM J PHYSIOL RENAL Salt Lake City, UT 84115 (US) PHYSIOL. vol. 287, 2004, pages F797 - F805, XP055144677 (74) Representative: Michalski Hüttermann & Partner Patentanwälte mbB Speditionstraße 21 40221 Düsseldorf (DE) 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. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 750 676 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 750 676 B1 Description BACKGROUND 5 [0001] Acquired nephrogenic diabetes insipidus (acquired NDI) is a common debilitating and morbid condition in the clinic due to a variety of causes. The salient feature of all forms of acquired NDI is resistance of the kidney to the action of the anti-diuretic hormone (ADH or arginine vasopressin, AVP), and so it is often associated with increased blood ADH levels. Acquired NDI is characterized by polydipsia (increased water intake), polyuria (increased urine output) and impaired concentrating ability of the kidney (decreased urine osmolality), associated with marked decrease in ADH- 10 regulated AQP2 water channel in the kidney medulla. This is due to the resistance of the kidney to the action of the anti- diuretic hormone (ADH or AVP). Vasopressin (AVP or ADH), acting through its V2 receptor in the collecting duct principal cells of the kidney, and the associated cAMP signaling pathway and aquaporin (AQP) water channels, plays a central role in water homeostasis (for reviews see Schrier, R.W. (2007) Curr Opin Investig Drugs. 8:304-11; Boone M. and Deen, P.M. (2008) Pflugers Arch. 456:1005-24). However, a variety of autocrine and paracrine agents, acting through 15 their respective membrane receptors in the collecting duct have been shown to modulate the action of AVP. [0002] Acquired NDI is a common condition in the clinic with significant degree of morbidity, or even mortality if not treated properly. Apart from social inconvenience, NDI is a debilitating condition, with an elevated risk of dehydration, hypernatremia, altered consciousness, and hemodynamic instability from hypovolemia, especially in elderly patients. The most common causes of acquired NDI are lithium-induced or hypokalemic or hypercalcemic nephropathy or post- 20 obstructive uropathy. [0003] International patent application WO 2010/075861 relates to compounds for treatment that protects the endothe- lium, prevent pathologic thrombus formation in the microcirculation and preserve platelet number and function. It discloses compounds for the treatment of or prophylaxis of organ failure due to renal diseases such as inter alia acute/chronic kidney failure or nephrogenic diabetes insipidus. Michelson, AD, Current Opinion in Hematology (2009) 16, 5, 371-377, 25 reviews the status in 2009 of clopidogrel and new P2Y12 antagonists. Choudhury, D, and Ahmed, Z, Nature Clinical Practice Nephrology, (2006) 2, 2, 80-91, review the clinical features and basic processes underlying renal injury related to the use of common drugs. [0004] Currently used therapies for acquired NDI, such as administration of cyclooxygenase (COX) inhibitors or thi- azides or amiloride, are associated with varying degrees of success as well as adverse effects, especially in critically ill 30 and elderly patients. Hence, there is a need to introduce newer therapies with fewer side effects and better tolerability in all patients. [0005] Despite advances in the treatment of renal disease and disorders, there is still a scarcity of compounds that are effective in the treatment of acquired NDI. These needs and other needs are satisfied by the present invention. 35 SUMMARY [0006] In accordance with the purpose(s) of the invention the invention, in one aspect, relates to an ADP-(P2Y 12)-like receptor modulator for use in the treatment of lithium-induced nephrogenic diabetes insipidus in a subject having a neurological disorder, comprising the step of administering to a mammal a ADP-(P2Y 12)-like receptor modulator, thereby 40 treating nephrogenic diabetes insipidus. The exogenously administered ADP-(P2Y 12)-like receptor modulator for use is a compound or agent that decreases the activity of an ADP-(P2Y12)-like receptor compared to the activity of an ADP-(P2Y12)-like receptor in the absence of the exogenously administered modulator of the ADP-(P2Y 12)-like receptor. Disclosed is also the treatment of nephrogenic diabetes insipidus (NDI).Also disclosed are methods of co-treatment of nephrogenic diabetes insipidus and a neurological or psychiatric disorder comprising the step of co-administering to the 45 mammal an effective amount of a ADP-(P2Y12)-like receptor modulator and an effective amount of a lithium salt, thereby treating, respectively, the nephrogenic diabetes insipidus and the neurological or psychiatric disorder. [0007] Also disclosed are methods of treating nephrogenic diabetes insipidus comprising the step of administering an effective amount of a ADP-(P2Y12)-like receptor modulator to a mammal that is administered a lithium salt, thereby treating the nephrogenic diabetes insipidus. 50 [0008] Also disclosed are methods for the treatment of nephrogenic diabetes insipidus in a mammal comprising the step of administering to the mammal an effective amount of a compound selected from clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor, and elinogrel. [0009] Also disclosed are methods for co-treatment of nephrogenic diabetes insipidus and a neurological or psychiatric disorder comprising the step of co-administering to the mammal an effective amount of a lithium salt and an effective 55 amount of a compound selected from clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor, and elinogrel, thereby treating, respectively, the neurological or psychiatric disorder and the nephrogenic diabetes insipidus. [0010] Also disclosed are methods for treating nephrogenic diabetes insipidus comprising the step of administering an effective amount of a compound selected from clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor, and elinogrel 2 EP 2 750 676 B1 to a mammal that is administered a lithium salt, thereby treating the nephrogenic diabetes insipidus. [0011] Also disclosed are pharmaceutical compositions comprising an effective amount of a lithium salt in combination with an effective amount of a second agent that is a ADP-(P2Y12)-like receptor modulator. [0012] In a further aspect, the invention relates to a pharmaceutical composition comprising an effective amount of a 5 lithium salt in combination with an effective amount of a second agent comprising the ADP-(P2Y 12)-likereceptor modulator according to the above aspect, and a pharmaceutically acceptable carrier. [0013] Disclosed are also pharmaceutical compositions comprising an effective amount of a lithium salt in combination with an effective amount of a second agent selected from clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor, and elinogrel. In a still further aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective 10 amount of a disclosed compound and a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. [0014] Also disclosed are uses of a disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Disclosed is also a pharmaceutical compositions comprising
Load more

Recommended publications
  • A Comparative Study of Molecular Structure, Pka, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs
    International Journal of Molecular Sciences Article A Comparative Study of Molecular Structure, pKa, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs Milan Remko 1,*, Anna Remková 2 and Ria Broer 3 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, SK-832 32 Bratislava, Slovakia 2 Department of Internal Medicine, Faculty of Medicine, Slovak Medical University, Limbová 12, SK–833 03 Bratislava, Slovakia; [email protected] 3 Department of Theoretical Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands; [email protected] * Correspondence: [email protected]; Tel.: +421-2-5011-7291 Academic Editor: Michael Henein Received: 18 February 2016; Accepted: 11 March 2016; Published: 19 March 2016 Abstract: Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel) and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5–3.5 logP values). The polar surface area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3–255 Å2.
    [Show full text]
  • Clinical Update
    Atualização Clínica Antiagregantes Plaquetários na Prevenção Primária e Secundária de Eventos Aterotrombóticos Platelet Antiaggregants in Primary and Secondary Prevention of Atherothrombotic Events Marcos Vinícius Ferreira Silva1, Luci Maria SantAna Dusse1, Lauro Mello Vieira, Maria das Graças Carvalho1 Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais1, Belo Horizonte, MG – Brasil Resumo prevenção primária e secundária de tais eventos. Os fatores A aterotrombose e suas complicações correspondem, de risco associados ao desenvolvimento desses eventos hoje, à principal causa de mortalidade no mundo todo, estão intimamente associados à exacerbação da ativação e sua incidência encontra-se em franca expansão. plaquetária que, por sua vez, favorece a formação de As plaquetas desempenham um papel essencial na agregados plaquetários e geração de trombina, resultando patogênese dos eventos aterotrombóticos, justificando a em trombos ricos em plaquetas (trombos brancos). Dessa utilização dos antiagregantes plaquetários na prevenção forma, o uso de antiagregantes plaquetários tem sido dos mesmos. Desse modo, é essencial que se conheça o benéfico na prevenção primária e secundária de eventos perfil de eficácia e segurança desses fármacos em prevenção mediados por trombos. primária e secundária de eventos aterotrombóticos. Dentro As características dos principais antiagregantes plaquetários desse contexto, a presente revisão foi realizada com o utilizados na prática clínica e em fase de estudos estão objetivo de descrever e sintetizar os resultados dos principais descritos na Tabela 13-9, e as proteínas de membrana com as ensaios, envolvendo a utilização de antiagregantes nos dois quais eles interagem e as vias metabólicas nas quais atuam níveis de prevenção, e avaliando a eficácia e os principais são ilustrados Figura 110.
    [Show full text]
  • Use of Antiplatelet Therapies During Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction
    REVIEW Use of antiplatelet therapies during primary percutaneous coronary intervention for acute myocardial infarction Inhibition of platelet function is necessary to achieve successful and long-lasting primary percutaneous coronary intervention (PCI) for acute myocardial infarction. For many years, antiplatelet therapy in the setting of primary PCI consisted of two drugs that inhibit platelet activation (aspirin and clopidogrel) and an intravenous blocker of platelet aggregation (abciximab). The development of new, more potent oral antiplatelet drugs (prasugrel and ticagrelor) as well as new data on clopidogrel dosing regimens limited the use of abciximab after pretreatment with aspirin and clopidogrel. Thus, intracoronary administration of abciximab and the use of small molecule glycoprotein IIb/IIIa blockers (tirofiban or eptifibatide) challenge the contemporary schemes of antiplatelet treatment in primary PCI. We review recently published data with particular attention on patients and drug characteristics and propose an update of existing recommendations. 1 KEYWORDS: acute myocardial infarction n antiplatelet therapy n aspirin n cilostazol Łukasz A Małek n clopidogrel n glycoprotein IIb/IIIa blockers n prasugrel n primary percutaneous & Adam Witkowski†1 coronary intervention n ticagrelor 1Department of Interventional Cardiology & Angiology, Institute of Cardiology, Alpejska 42, Rupture of the vulnerable atherosclerotic many years, antiplatelet therapy in the setting 04‑628 Warsaw, Poland plaque in the coronary artery wall leading of primary PCI included two oral antiplate- †Author for correspondence: Tel.: +48 22 343 4127 to activation and aggregation of platelets to let drugs, which irreversibly block platelet Fax: +48 22 613 3819 form an artery occluding thrombus is the most activation (aspirin and clopidogrel) together [email protected] frequent cause of acute myocardial infarc- with an inhibition of platelet aggregation by tion (AMI) [1–3].
    [Show full text]
  • P2X and P2Y Receptors
    Tocris Scientific Review Series Tocri-lu-2945 P2X and P2Y Receptors Kenneth A. Jacobson Subtypes and Structures of P2 Receptor Molecular Recognition Section, Laboratory of Bioorganic Families Chemistry, National Institute of Diabetes and Digestive and The P2 receptors for extracellular nucleotides are widely Kidney Diseases, National Institutes of Health, Bethesda, distributed in the body and participate in regulation of nearly Maryland 20892, USA. E-mail: [email protected] every physiological process.1,2 Of particular interest are nucleotide Kenneth Jacobson serves as Chief of the Laboratory of Bioorganic receptors in the immune, inflammatory, cardiovascular, muscular, Chemistry and the Molecular Recognition Section at the National and central and peripheral nervous systems. The ubiquitous Institute of Diabetes and Digestive and Kidney Diseases, National signaling properties of extracellular nucleotides acting at two Institutes of Health in Bethesda, Maryland, USA. Dr. Jacobson is distinct families of P2 receptors – fast P2X ion channels and P2Y a medicinal chemist with interests in the structure and receptors (G-protein-coupled receptors) – are now well pharmacology of G-protein-coupled receptors, in particular recognized. These extracellular nucleotides are produced in receptors for adenosine and for purine and pyrimidine response to tissue stress and cell damage and in the processes nucleotides. of neurotransmitter release and channel formation. Their concentrations can vary dramatically depending on circumstances. Thus, the state of activation of these receptors can be highly dependent on the stress conditions or disease states affecting a given organ. The P2 receptors respond to various extracellular mono- and dinucleotides (Table 1). The P2X receptors are more structurally restrictive than P2Y receptors in agonist selectivity.
    [Show full text]
  • Platelet-Inhibiting Drugs: a Hematologist’S Perspective
    Platelet-Inhibiting Drugs: A Hematologist’s Perspective A. Koneti Rao, M.D., Sol Sherry Professor of Medicine Chief, Hematology Section Co-Director, Sol Sherry Thrombosis Research Center Temple University School of Medicine 2012 Chile Akkerman JW, Bouma BN, Sixma JJ. Atlas of Hemostasis, 1979. STRATEGIES FOR ANTITHROMBOTIC THERAPY VASCULAR INJURY RISK FACTOR REDUCTION PLATELET ADHERANCE PLATELET AGGREGATION INHIBITORS COAGULATION ACTIVATION THROMBIN GENERATION ANTICOAGULANTS FIBRIN FORMATION PLASMIN GENERATION THROMBOLYTICS FIBRINOLYSIS AKR/2003 Platelet Responses to Activation Membrane Shape Change Aggregation Dense AGONIST Receptor Granule Secretion Thromboxane Alpha Granule Production TxA2 Acid Hydrolase ADP / Serotonin Rao/2010 GPIIb/IIIa GPIIb/IIIa Fibrinogen GPIIb/IIIa GPVI GPIa/IIa a5b1 GPIb/V/IX GPIV Damaged vWF Fibronectin Endothelium Collagen AKR/2004 Platelet-Inhibiting Drugs Platelet Inhibiting Drugs Aspirin Sulfinpyrazone Dipyridamole P2Y12 Antagonists • Thienopyridines - Ticlopidine, Clopidogrel, Prasugrel (Effient) • Non-Thienopyridine - Ticagrelor (Brilinta) GPIIb/IIIa Inhibitors Abciximab (c7E3 Fab, ReoPro) Eptifibatide (Integrilin) Tirofiban (Aggrastat) Cilostazol (Pletal) AKR-2012 Cyclooxygenase Arachidonic Acid Ser OH 529 COOH OCOCH 3 PGG2, PGH2 Aspirin Cyclooxygenase Thromboxane A2 Ser OCOCH 3 AKR/09 529 GPIIb-IIIa cAMP Fibrinogen ADP (P2Y12) Gi AC Aggregation Ticlopidine P ATP Pleckstrin Clopidogrel GP IIb/IIIa Prasugrel PKC Antagonists TxA2 ADP Gq Secretion (P2Y1) DG TS Gq PGG2/PGH2 Thrombin PLC PIP2 CO Aspirin
    [Show full text]
  • Drug-Like Antagonists of P2Y Receptors - from Lead Identification to Drug Development
    Drug-like antagonists of P2Y receptors - from lead identification to drug development Sean Conroy, Nicholas Kindon, Barrie Kellam, Michael J. Stocks* Centre for Biomolecular Sciences, University Park Nottingham, Nottingham, NG7 2RD, UK. Abstract P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions including platelet aggregation, smooth muscle cell proliferation and immune regulation. The P2Y receptors belong to the GPCR superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups based on their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date there have only been a limited number of small molecule P2Y receptor antagonists that have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation. Introduction Although nucleotides, such as adenosine-5’-triphosphate (ATP) and uridine triphosphate (UTP) are important intracellular molecules, they are also released into extracellular fluids by various mechanisms. The receptors for these extracellular nucleotides have been progressively characterized and classified as purinergic receptors.1 The subdivision of these purinergic receptors into P1 (adenosine) and P2 (ATP, ADP) was originally proposed by Burnstock in
    [Show full text]
  • Platelet Activation in Vascular Disease from Animal Studies to Clinical Consequences
    Platelet Activation in Vascular Disease from Animal Studies to Clinical Consequences Erik Tournoij Platelet Activation in Vascular Disease: from Animal Studies to Clinical Consequences © E. Tournoij, 2010. All rights reserved Thesis, Utrecht University, the Netherlands ISBN: 978-94-61080-26-4 Printed by: Gildeprint Drukkerijen B.V., Enschede Lay-out: E. Tournoij Cover design: W.A. van der Wal, R.A.M. Lathouwers and E.Tournoij Cover: Processed photograph of the Beijing National Aquatics Centre ‘the Water Cube’. Platelet Activation in Vascular Disease: from Animal Studies to Clinical Consequences Plaatjesactivatie in vaatziekte: van studies in proefdieren naar klinische consequenties (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. J.C. Stoof, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 6 april 2010 des middags te 2.30 uur door Erik Tournoij geboren op 30 juli 1981 te Eindhoven Promotoren: Prof. dr. F.L. Moll Prof. dr. J.W.N. Akkerman Prof. dr. S. Schulte-Merker Financial support for the reproduction of this thesis was generously provided by: Chirurgisch fonds UMC Utrecht, B. Braun Medical B.V. Contents: Chapter 1 General introduction and outline of the thesis 7 PART A: The zebrafish as a model to study platelet function Chapter 2 Mlck1a is expressed in zebrafish thrombocytes and an 19 essential component for thrombus formation PART B: Prevention of atherothrombosis by platelet
    [Show full text]
  • Advances in Interventional Cardiology New Directions In
    Advances in Interventional Cardiology New Directions in Antiplatelet Therapy Jose´ Luis Ferreiro, MD; Dominick J. Angiolillo, MD, PhD therosclerosis is a chronic inflammatory process that is A2 (TXA2) from arachidonic acid through selective acetylation Aknown to be the underlying cause of coronary artery of a serine residue at position 529 (Ser529). TXA2 causes disease (CAD).1 In addition to being the first step of primary changes in platelet shape and enhances recruitment and aggre- hemostasis, platelets play a pivotal role in the thrombotic gation of platelets through its binding to thromboxane and process that follows rupture, fissure, or erosion of an athero- prostaglandin endoperoxide (TP) receptors. Therefore, aspirin sclerotic plaque.2 Because atherothrombotic events are essen- decreases platelet activation and aggregation processes mediated tially platelet-driven processes, this underscores the impor- by TP receptor pathways.7 tance of antiplatelet agents, which represent the cornerstone Although the optimal dose of aspirin has been the subject of treatment, particularly in the settings of patients with acute of debate, the efficacy of low-dose aspirin is supported by the coronary syndromes (ACS) and undergoing percutaneous results of numerous studies.8–10 In these investigations, a coronary intervention (PCI). dose-dependent risk for bleeding, particularly upper gastro- Currently, there are 3 different classes of antiplatelet drugs that are approved for clinical use and recommended per intestinal bleeding, with no increase in
    [Show full text]
  • Antiplatelet Therapy in Diabetes: Efficacy and Limitations of Current
    Bench to Clinic Symposia EDITORIAL REVIEW Antiplatelet Therapy in Diabetes: Efficacy and Limitations of Current Treatment Strategies and Future Directions DOMINICK J. ANGIOLILLO, MD, PHD of low-dose aspirin (75–162 mg/day) as a primary prevention strategy in patients with type 1 or type 2 diabetes at increased Ͼ ardiovascular disease is the leading patients undergoing percutaneous coro- cardiovascular risk, including those 40 cause of morbidity and mortality in nary interventions (PCI) (4). However, years of age or who have additional risk C patients with diabetes (1). The con- these agents are available only for paren- factors (family history of cardiovascular comitant presence of multiple classical teral use and have a short duration of ac- disease, hypertension, smoking, dyslipi- cardiovascular risk factors in diabetic tion, which impedes their use for long- demia, or albuminuria) (8). However, subjects contributes to enhanced athero- term protection. The need for alternative aspirin therapy should not be recom- thrombotic risk (2). However, other risk antiplatelet treatment strategies led to the mended for patients aged Ͻ21 years be- factors may be important such as abnor- evaluation of effects obtained from a com- cause this may increase the risk of Reye’s mal platelet function (3). Platelets, in fact, bination of oral antiplatelet agents inhib- syndrome. The role of aspirin in diabetic play a key role in atherogenesis, and its iting other platelet-activating pathways. patients aged Ͻ30 years remains unclear thrombotic complications and measures, Ticlopidine is a first-generation thienopy- because it has not been investigated. which lead to blockade of one or multiple ridine, which irreversibly blocks the Several clinical trials have evaluated the efficacy of aspirin in diabetic patients pathways modulating platelet activation platelet ADP P2Y12 receptor (6).
    [Show full text]
  • Adenosine-Mediated Effects of Ticagrelor Evidence and Potential Clinical Relevance
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 63, No. 23, 2014 Ó 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2014.03.031 Adenosine-Mediated Effects of Ticagrelor Evidence and Potential Clinical Relevance Marco Cattaneo, MD,* Rainer Schulz, MD, PHD,y Sven Nylander, PHDz Milan, Italy; Giessen, Germany; and Mölndal, Sweden This review constitutes a critical evaluation of recent publications that have described an additional mode of action of the P2Y12 receptor antagonist ticagrelor. The effect is mediated by inhibition of the adenosine transporter ENT1 (type 1 equilibrative nucleoside transporter), which provides protection for adenosine from intracellular metabolism, thus increasing its concentration and biological activity, particularly at sites of ischemia and tissue injury where it is formed. Understanding the mode of action of ticagrelor is of particular interest given that its clinical profile, both in terms of efficacy and adverse events, differs from that of thienopyridine P2Y12 antagonists. (J Am Coll Cardiol 2014;63:2503–9) ª 2014 by the American College of Cardiology Foundation Ticagrelor is a direct-acting, reversibly binding P2Y12 Outcomes) study, ticagrelor was superior to clopidogrel in antagonist that provides rapid onset of antiplatelet effects preventing cardiovascular death, myocardial infarction, or after oral administration. P2Y12, 1 of the 2 purinergic stroke (9.8% vs. 11.7%, a 16% reduction) in patients with receptors for adenosine diphosphate (ADP) expressed by acute coronary syndrome (ACS); two-thirds of these pa- platelets, is essential for normal ADP-induced platelet tients had undergone percutaneous coronary intervention fi aggregation.
    [Show full text]
  • Variabilidad Farmacodinámica En La Respuesta a Clopidogrel: Mecanismos Implicados Y Uso De Inhibidores Más Potentes Del Recept
    Variabilidad Farm acodinámica en la Respuesta a Clopidogrel: Mecanismos Implicados y Uso de Inhibidores Más Potentes del Receptor Plaquetario P2Y 12 en Pacientes con Enfermedad Coronaria Jorge Carlos Espinós Pérez ADVERTIMENT . La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX ( www.tdx.cat ) i a través del Dipòsit Digital de la UB ( diposit.ub.edu ) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB . No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de prese ntació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA . La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La dif usión de esta tesis por medio del servicio TDR ( www.tdx.cat ) y a través del Repositorio Digital de la UB ( diposit.ub.edu ) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB .
    [Show full text]
  • Clopidogrel, Prasugrel and Ticagrelor in Adults with Acute Coronary Syndrome: a Review of the Clinical Effectiveness
    TITLE: Clopidogrel, Prasugrel and Ticagrelor in Adults with Acute Coronary Syndrome: A Review of the Clinical Effectiveness DATE: 15 August 2011 CONTEXT AND POLICY ISSUES: Acute coronary syndrome (ACS) is a collective term used to describe the acute onset of myocardial ischemia resulting from the occlusion of coronary arteries and includes the following designations: ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA).1 When patients present with sign and symptoms of ACS, they receive an immediate oral administration of dual antiplatelet therapy consisting of acetylsalicylic acid (aspirin; ASA) and a thienopyridine.2 Thienopyridines are a class of P2Y12 platelet ADP receptor antagonists and the one that is most commonly administered to ACS patients is clopidogrel.3 ACS (STEMI, or NSTEMI/UA) is classified based on the characteristics of electrocardiograms (ECG) and the level of cardiac enzymes circulating in the blood.4 STEMI patients receive immediate care, which may include percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or management by drug alone.5,6 NSTEMI patients receive similar treatment options, but the administration of these treatments are less time-critical than in STEMI patients.6,7 Currently, dual therapy with clopidogrel and ASA is the standard treatment for ACS patients in Canada.6 Clopidogrel has many limitations including a slow onset of action, incomplete platelet inhibition, poor antiplatelet response to some patients, and an irreversible antiplatelet effect.8 A new thienopyridine, prasugrel, has been observed to provide a faster response and better clinical efficacy than clopidogrel, at the expense of an increased risk of major bleeding.9 Like clopidogrel, prasugrel irreversibly inhibits platelet aggregation by binding to the P2Y12 platelet ADP receptor for the entire 8-9 day life span.
    [Show full text]