DOCSLIB.ORG

Adenosine-Mediated Effects of Ticagrelor Evidence and Potential Clinical Relevance

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. P2Y12 signaling ampli es platelet responses (PCI) (3). Prasugrel was also superior to clopidogrel in to agonists that cause ADP release from delta granules, preventing the same composite endpoint in patients with stabilizes platelet aggregates, and opposes the anti- ACS who underwent PCI in the TRITON (Therapeutic platelet effects of natural platelet inhibitors such as pro- Outcomes by Optimizing Platelet Inhibition With Pra- stacyclin that induce production of the inhibitory cyclic sugrel) trial (4). Although the 2 trials had quite different adenosine monophosphate (cAMP) by activating adenylyl designs, they showed that more rapid, higher, and more cyclase (1). consistent P2Y12 inhibition than afforded by clopidogrel The essential role of P2Y12 in hemostasis and thrombosis was associated with better clinical outcome. PLATO and is demonstrated by observations that patients with inherited TRITON did display some differences. In PLATO, tica- fi P2Y12 defects have a bleeding diathesis and that the grelor slightly but signi cantly reduced the incidence of administration of antagonists reduces the incidence of major cardiovascular (4.0% vs. 5.1%) and total (4.5% vs. 5.9%) adverse cardiovascular events in patients at risk (1). The mortality compared with clopidogrel, whereas no significant most widely used P2Y12 antagonist is the thienopyridine reduction in cardiovascular (2.1% vs. 2.4%) or total (3.0% prodrug clopidogrel, which, through hepatic conversion to vs. 3.2%) mortality was observed with prasugrel versus its active metabolite, irreversibly inhibits P2Y12. Compared clopidogrel in TRITON (3,4). In addition, a greater inci- with clopidogrel, ticagrelor provides higher and much less dence of dyspnea and ventricular pauses was observed with variable P2Y12 inhibition. This is also true for the third- ticagrelor (3). Although the accuracy of the PLATO generation thienopyridine prasugrel (1), albeit ticagrelor mortality data has been questioned by some authors (5), has been shown to provide slightly greater platelet inhibi- their allegations have been rebutted by the PLATO in- tion (2). In the PLATO (Platelet Inhibition and Patient vestigators (6). Thus, although alternative interpretations exist (7), the PLATO data on mortality suggest that ticagrelor may have unique and clinically relevant effects, From the *Unità di Medicina 3, Ospedale San Paolo, Dipartimento di Scienze as also demonstrated by the observed increased incidence of della Salute, Università degli Studi di Milano, Milan, Italy; yInstitute of Physiology, Justus-Liebig University Giessen, Giessen, Germany; and zAstraZeneca Research and dyspnea and ventricular pauses (3). These effects of tica- Development, Mölndal, Sweden. Dr. Cattaneo has received research grants from grelor may be accounted for by its reversible binding to AstraZeneca, Eli Lilly, Daiichi Sankyo, and Evolva; and has received honoraria P2Y12, its systemic presence at pharmacologically active for lectures or for service on advisory boards from AstraZeneca, Eli Lilly, Daiichi Sankyo, Evolva, Sanofi-Aventis, and Merck Sharp & Dohme. Dr. Schulz has received concentrations over 24 h of the day (8),and/orbyaddi- research grants from Zealand Pharma and honoraria for lectures and membership tional P2Y12-independent effects (9). on advisory boards from AstraZeneca, Recordati, Sanofi-Aventis, and Servier. Here, we will review the experimental and clinical evi- Dr. Nylander is an employee of AstraZeneca. Manuscript received February 4, 2014; revised manuscript received March 21, 2014, dence that ticagrelor increases the half-life and plasma accepted March 24, 2014. concentration of adenosine, and critically evaluate whether 2504 Cattaneo et al. JACC Vol. 63, No. 23, 2014 Ticagrelor and Adenosine Mode of Action June 17, 2014:2503–9 Abbreviations this additional effect of tica- relevance. Importantly, it has been demonstrated that tica- and Acronyms grelor may explain the drug’s grelor does not display relevant direct activity on adenosine clinical profile. receptors (11,18) and is not metabolized to adenosine (19). ACS = acute coronary syndrome(s) ADP = adenosine Ticagrelor Inhibits Cellular Biological Effects of Adenosine diphosphate Uptake of Adenosine Adenosine exerts its biological effects by interacting with 4 cAMP = cyclic adenosine – monophosphate Adenosine is a purine nucleoside G-protein coupled receptors: A1R and A3R are coupled to CNT = concentrative produced primarily through the Gi, the inhibitory G protein, which inhibits adenylyl cyclase nucleoside transporter metabolism of ADP or adenosine and thus decreases intracellular cAMP, whereas A2AR and ENT1 = equilibrative triphosphate by the nucleotidases A2BR are coupled to the stimulatory G protein, Gs, which nucleoside transporter CD39 and CD73; its plasma levels stimulates adenylyl cyclase, increasing intracellular cAMP. PCI = percutaneous coronary increase after cellular stresses such Of the 2 A2R subtypes, A2A is the high- and A2B the low- intervention as injury, ischemia/reperfusion, or affinity receptor (12,20). fl in ammation (10). Adenosine is Effects of adenosine on blood vessels. A2AR is the main rapidly taken up by cells through adenosine receptor responsible for coronary vasodilation, sodium-independent equilibrative nucleoside transporters (ENT which is mediated by both nitric oxide-dependent and 1/2) and sodium-dependent concentrative nucleoside -independent pathways (21).A2BR also mediates coronary transporters (CNT 2/3) (11). Intracellular adenosine is vasodilation, whereas both A1R and A3R negatively metabolized to inosine by adenosine deaminase or modulate coronary vasodilation induced by A2AR and/or – transformed into adenine nucleotides by adenosine kinase A2BR activation (22 24). Adenosine also induces endothe- (10,12). Because of its rapid cellular uptake and metabolism, lial progenitor cell migration via A2A and A3 (25). extracellular adenosine has a half-life of a few seconds (13), Effects of adenosine on platelets. Adenosine is a potent which can be prolonged by inhibition of its transport into inhibitor of platelet aggregation in platelet-rich plasma but cells (Fig. 1). not in whole blood as a consequence of its rapid uptake by Several studies provide evidence that ticagrelor inhibits erythrocytes. This discrepancy is abolished by the addition of cellular uptake of adenosine (11,14,15). Ticagrelor inhibited dipyridamole to whole blood samples (26). Adenosine in- adenosine uptake by washed human erythrocytes and by hu- hibits platelet activation mainly via A2AR but also via A2BR man, dog, and rat cell lines. Considering that the experiments (27). The gene that encodes for A2B is up-regulated after were performed under sodium-free conditions and with cell injury and systemic inflammation in vivo; as a consequence, lines that express ENT1 but not ENT2, it was assumed that the contribution of A2B to adenosine-mediated platelet in- ticagrelor inhibits sodium-independent ENT1 (14).The hibition appears to increase under stress conditions (28). identity of the target transporter was recently confirmed with Effects of adenosine on inflammatory responses. Ade- cells transfected with human transporters (ENT1, ENT2, nosine modulates the inflammatory responses to a variety of CNT2, and CNT3). In these experiments, ticagrelor signif- stressful conditions. Low concentrations of adenosine, icantly inhibited adenosine uptake only in cells that expressed which activate A1R and A3R, promote neutrophil chemo- ENT1 (11). Compared with dipyridamole, an established taxis and phagocytosis, whereas high concentrations of fi ENT1 inhibitor (16), ticagrelor displayed a lower af nity adenosine,
Load more

Recommended publications
  • Additions and Deletions to the Drug Product List
    Prescription and Over-the-Counter Drug Product List 40TH EDITION Cumulative Supplement Number 09 : September 2020 ADDITIONS/DELETIONS FOR PRESCRIPTION DRUG PRODUCT LIST ACETAMINOPHEN; BUTALBITAL; CAFFEINE TABLET;ORAL BUTALBITAL, ACETAMINOPHEN AND CAFFEINE >A> AA STRIDES PHARMA 325MG;50MG;40MG A 203647 001 Sep 21, 2020 Sep NEWA ACETAMINOPHEN; CODEINE PHOSPHATE SOLUTION;ORAL ACETAMINOPHEN AND CODEINE PHOSPHATE >D> AA WOCKHARDT BIO AG 120MG/5ML;12MG/5ML A 087006 001 Jul 22, 1981 Sep DISC >A> @ 120MG/5ML;12MG/5ML A 087006 001 Jul 22, 1981 Sep DISC TABLET;ORAL ACETAMINOPHEN AND CODEINE PHOSPHATE >A> AA NOSTRUM LABS INC 300MG;15MG A 088627 001 Mar 06, 1985 Sep CAHN >A> AA 300MG;30MG A 088628 001 Mar 06, 1985 Sep CAHN >A> AA ! 300MG;60MG A 088629 001 Mar 06, 1985 Sep CAHN >D> AA TEVA 300MG;15MG A 088627 001 Mar 06, 1985 Sep CAHN >D> AA 300MG;30MG A 088628 001 Mar 06, 1985 Sep CAHN >D> AA ! 300MG;60MG A 088629 001 Mar 06, 1985 Sep CAHN ACETAMINOPHEN; HYDROCODONE BITARTRATE TABLET;ORAL HYDROCODONE BITARTRATE AND ACETAMINOPHEN >A> @ CEROVENE INC 325MG;5MG A 211690 001 Feb 07, 2020 Sep CAHN >A> @ 325MG;7.5MG A 211690 002 Feb 07, 2020 Sep CAHN >A> @ 325MG;10MG A 211690 003 Feb 07, 2020 Sep CAHN >D> AA VINTAGE PHARMS 300MG;5MG A 090415 001 Jan 24, 2011 Sep DISC >A> @ 300MG;5MG A 090415 001 Jan 24, 2011 Sep DISC >D> AA 300MG;7.5MG A 090415 002 Jan 24, 2011 Sep DISC >A> @ 300MG;7.5MG A 090415 002 Jan 24, 2011 Sep DISC >D> AA 300MG;10MG A 090415 003 Jan 24, 2011 Sep DISC >A> @ 300MG;10MG A 090415 003 Jan 24, 2011 Sep DISC >D> @ XIROMED 325MG;5MG A 211690
    [Show full text]
  • Lysophosphatidic Acid and Its Receptors: Pharmacology and Therapeutic Potential in Atherosclerosis and Vascular Disease
    JPT-107404; No of Pages 13 Pharmacology & Therapeutics xxx (2019) xxx Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis and vascular disease Ying Zhou a, Peter J. Little a,b, Hang T. Ta a,c, Suowen Xu d, Danielle Kamato a,b,⁎ a School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia b Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China c Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, St Lucia, QLD 4072, Australia d Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA article info abstract Available online xxxx Lysophosphatidic acid (LPA) is a collective name for a set of bioactive lipid species. Via six widely distributed G protein-coupled receptors (GPCRs), LPA elicits a plethora of biological responses, contributing to inflammation, Keywords: thrombosis and atherosclerosis. There have recently been considerable advances in GPCR signaling especially Lysophosphatidic acid recognition of the extended role for GPCR transactivation of tyrosine and serine/threonine kinase growth factor G-protein coupled receptors receptors. This review covers LPA signaling pathways in the light of new information. The use of transgenic and Atherosclerosis gene knockout animals, gene manipulated cells, pharmacological LPA receptor agonists and antagonists have Gproteins fi β-arrestins provided many insights into the biological signi cance of LPA and individual LPA receptors in the progression Transactivation of atherosclerosis and vascular diseases.
    [Show full text]
  • SYNTHESIS and BIOLOGICAL Actnnry of CONFORMATIONALLY CONSTRAINED WLEOSIDES and NUCLEOTIDES
    SYNTHESIS AND BIOLOGICAL ACTnnrY OF CONFORMATIONALLY CONSTRAINED WLEOSIDES AND NUCLEOTIDES A thesis submitted in conformity with the requirements for the degree of Masters of Science Graduate Department of Chemistry University of Toronto National Library Bibliothèque nationaie B*m ofCanada du Canada Acquisitions and Acquisitions et Bibliographie Setvices services bibliographiques 395 Wellington Street 395. rue Wellington ûttawaON K1AW OctawaON KlAW canada canada The author has granted a non- L'auteur a accorde une licence non exclusive Licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, distn'buer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/fïlm, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Spthesis and Biologicai Activity of Conformationaliy Constrained NucIeosides and Nuc1eotides Degree of Master of Science, 1998 by Girolamo Tusa Graduate Department of Chemistry, University of Toronto This thesis outhes the synthesis of a variety of confonnationally constrained nucleosides and nucleotide analogues. The conformationally 'locked" analogues closely resemble specific conformers of natural nucleosides and nucieotides and were used to probe the conformationai specificity of particular physiological processes in PC 12 ce&; nucleoside transport (NT) activity and Pt-purinoceptor response.
    [Show full text]
  • Extracellular Adenosine Triphosphate and Adenosine in Cancer
    Oncogene (2010) 29, 5346–5358 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW Extracellular adenosine triphosphate and adenosine in cancer J Stagg and MJ Smyth Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia Adenosine triphosphate (ATP) is actively released in the mulated the hypothesis of purinergic neurotransmission extracellular environment in response to tissue damage (Burnstock, 1972). Burnstock’s hypothesis that ATP and cellular stress. Through the activation of P2X and could be released by cells to perform intercellular P2Y receptors, extracellular ATP enhances tissue repair, signaling was initially met with skepticism, as it seemed promotes the recruitment of immune phagocytes and unlikely that a molecule that acts as an intracellular dendritic cells, and acts as a co-activator of NLR family, source of energy would also function as an extracellular pyrin domain-containing 3 (NLRP3) inflammasomes. messenger. Nevertheless, Burnstock pursued his work The conversion of extracellular ATP to adenosine, in and, together with Che Su and John Bevan, reported contrast, essentially through the enzymatic activity of the that ATP was also released from sympathetic nerves ecto-nucleotidases CD39 and CD73, acts as a negative- during stimulation (Su et al., 1971). Three decades later, feedback mechanism to prevent excessive immune responses. following the cloning and characterization of ATP and Here we review the effects of extracellular ATP and adenosine adenosine cell surface receptors, purinergic signaling is a on tumorigenesis. First, we summarize the functions of well-established concept and constitutes an expanding extracellular ATP and adenosine in the context of tumor field of research in health and disease, including cancer immunity.
    [Show full text]
  • THE ROLE of CILOSTAZOL in ISCHEMIC STROKE
    Since 1960 MedicineMedicine KoratKorat โรงพยาบาลมหาราชนครราชสีมา THE ROLE of CILOSTAZOL in ISCHEMIC STROKE PAWUT MEKAWICHAI MD DEPARTMENT of MEDICINE MAHARAT NAKHON RATCHASIMA HOSPITAL This presentation is supported by Thai Osuka CONTENT 1 Mechanism of cilostazol 2 Acute Ischemic Stroke (within 48h) 3 Secondary Prevention and Recurrence 4 Bleeding Complication CONTENT 1 Mechanism of cilostazol 2 Acute Ischemic Stroke (within 48h) 3 Secondary Prevention and Recurrence 4 Bleeding Complication Phosphodiesterase Inhibitor Increase cAMP → reduce platelet function Decrease cAMP → increase platelet function PDE enzyme change cAMP to 5-AMP Inhibit PDE enzyme → incrase cAMP → reduce platelet function Phosphodiesterase inhibitor Cilostazol Dipyridamole Classification of PDE Isozyme 9 family of PDE enzyme (PDE1-9) PDE-3 Site: platelet, heart, vascular SM, adipose tissue Inhibitor: Cilostazol PDE-5 Site: platelet, heart, vascular SM, corpus carvernosum Inhibitor: Dipyridamole, Sidenafil Distribution of PDE Isozyme Cell Platelet Heart Vascular Adipose SMC tissue Dominant III III III III Subordinate II V I II IV IV I II Inhibit PDE-3 antiplatelet action vasodilatation → headache ? inhibit vascular SMC proliferation tachycardia and palpitation increase HDL and decrease TG Which antiplatelet drug that can use in acute ischemic stroke? 1. ASA 81 mg 2. ASA 300 mg 3. Clopidogrel 4. Dipyridamole+ASA 5. Cilostazol CONTENT 1 Mechanism of cilostazol 2 Acute Ischemic Stroke (within 48h) 3 Secondary Prevention and Recurrence 4 Bleeding Complication ASPIRIN International Stroke Trial (IST) 1 ASA 300 mg-reduce mortality and recurrence in 2 wk) Chinese Acute Stroke Trial (CAST) 2 ASA 160 mg-reduce mortality and recurrence) reduce mortality rate 9/1,000 OR 0.92 (0.87-0.98) good functional outcome 7/1,000 OR 1.02 (1.01-1.04) increase severe bleeding (within 2-4 wk) 4/1,000 OR 1.69 (1.35-2.11) no evidence for difference dose of ASA 1.Lancet 1997; 349: 1569-81.
    [Show full text]
  • Chronotropic, Dromotropic and Inotropic Effects of Dilazep in the Intact Dog Heart and Isolated Atrial Preparation Shigetoshi CH
    Chronotropic, Dromotropic and Inotropic Effects of Dilazep in the Intact Dog Heart and Isolated Atrial Preparation Shigetoshi CHIBA, M.D., Miyoharu KOBAYASHI, M.D., Masahiro SHIMOTORI,M.D., Yasuyuki FURUKAWA, M.D., and Kimiaki SAEGUSA, M.D. SUMMARY When dilazep was administered intravenously to the anesthe- tized donor dog, mean systemic blood pressure was dose depend- ently decreased. At a dose of 0.1mg/Kg i.v., the mean blood pressure was not changed but a slight decrease in heart rate was usually observed in the donor dog. At the same time, a slight but significant decrease in atrial rate and developed tension of the iso- lated atrium was induced. Within a dose range of 0.3 to 1mg/Kg i.v., dilazep caused a dose related decrease in mean blood pressure, bradycardia in the donor dog, and negative chronotropic, dromo- tropic and inotropic effects in the isolated atrium. At larger doses of 3 and 10mg/Kg i.v., dilazep caused marked hypotension, fre- quently with severe sinus bradycardia or sinus arrest, especially in isolated atria. When dilazep was infused intraarterially at a rate of 0.2-1 ƒÊ g/min into the cannulated sinus node artery of the isolated atrium, negative chrono- and inotropic effects were dose dependently in- duced. With respect to dromotropism, SA conduction time (SACT) was prolonged at infusion rates of 0.2 and 0.4ƒÊg/min. But at 1ƒÊg, dilazep caused an increase or decrease of SACT, indicating a shift of the SA nodal pacemaker. It is concluded that dilazep has direct negative chrono-, dromo- and inotropic properties on the heart at doses which produced no significant hypotension.
    [Show full text]
  • P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases
    International Journal of Molecular Sciences Review P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases Derek Strassheim 1, Alexander Verin 2, Robert Batori 2 , Hala Nijmeh 3, Nana Burns 1, Anita Kovacs-Kasa 2, Nagavedi S. Umapathy 4, Janavi Kotamarthi 5, Yash S. Gokhale 5, Vijaya Karoor 1, Kurt R. Stenmark 1,3 and Evgenia Gerasimovskaya 1,3,* 1 The Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA; [email protected] (D.S.); [email protected] (N.B.); [email protected] (V.K.); [email protected] (K.R.S.) 2 Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; [email protected] (A.V.); [email protected] (R.B.); [email protected] (A.K.-K.) 3 The Department of Pediatrics, Division of Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045, USA; [email protected] 4 Center for Blood Disorders, Augusta University, Augusta, GA 30912, USA; [email protected] 5 The Department of BioMedical Engineering, University of Wisconsin, Madison, WI 53706, USA; [email protected] (J.K.); [email protected] (Y.S.G.) * Correspondence: [email protected]; Tel.: +1-303-724-5614 Received: 25 August 2020; Accepted: 15 September 2020; Published: 18 September 2020 Abstract: Purinergic G-protein-coupled receptors are ancient and the most abundant group of G-protein-coupled receptors (GPCRs). The wide distribution of purinergic receptors in the cardiovascular system, together with the expression of multiple receptor subtypes in endothelial cells (ECs) and other vascular cells demonstrates the physiological importance of the purinergic signaling system in the regulation of the cardiovascular system.
    [Show full text]
  • 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]
  • NIH Public Access Author Manuscript Neuron Glia Biol
    NIH Public Access Author Manuscript Neuron Glia Biol. Author manuscript; available in PMC 2006 May 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Neuron Glia Biol. 2006 May ; 2(2): 125±138. Purinergic receptors activating rapid intracellular Ca2+ increases in microglia Alan R. Light1, Ying Wu2, Ronald W. Hughen1, and Peter B. Guthrie3 1 Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA 2 Oral Biology Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27510, USA 3 Scientific Review Administrator, Center for Scientific Review, National Institutes of Health, 6701 Rockledge Drive, Room 4142 Msc 7850, Bethesda, MD 20892-7850, USA Abstract We provide both molecular and pharmacological evidence that the metabotropic, purinergic, P2Y6, P2Y12 and P2Y13 receptors and the ionotropic P2X4 receptor contribute strongly to the rapid calcium response caused by ATP and its analogues in mouse microglia. Real-time PCR demonstrates that the most prevalent P2 receptor in microglia is P2Y6 followed, in order, by P2X4, P2Y12, and P2X7 = P2Y13. Only very small quantities of mRNA for P2Y1, P2Y2, P2Y4, P2Y14, P2X3 and P2X5 were found. Dose-response curves of the rapid calcium response gave a potency order of: 2MeSADP>ADP=UDP=IDP=UTP>ATP>BzATP, whereas A2P4 had little effect. Pertussis toxin partially blocked responses to 2MeSADP, ADP and UDP. The P2X4 antagonist suramin, but not PPADS, significantly blocked responses to ATP. These data indicate that P2Y6, P2Y12, P2Y13 and P2X receptors mediate much of the rapid calcium responses and shape changes in microglia to low concentrations of ATP, presumably at least partly because ATP is rapidly hydrolyzed to ADP.
    [Show full text]
  • Use of Uridine in Combination with Choline for the Treatment Of
    (19) TZZ ¥ _T (11) EP 2 329 829 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/7072 (2006.01) A61K 31/14 (2006.01) 16.04.2014 Bulletin 2014/16 A61K 31/685 (2006.01) A61P 25/28 (2006.01) (21) Application number: 10075661.8 (22) Date of filing: 30.07.1999 (54) Use of uridine in combination with choline for the treatment of neurological disorders Verwendung von Uridin in Kombination mit Cholin zur Behandlung neurologischer Erkrankungen Utilisation de l’uridine en combinaison avec la choline pour le traitement des maladies neurologiques (84) Designated Contracting States: • CACABELOSR ET AL: "THERAPEUTIC EFFECTS AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU OF CDP-CHOLINE IN ALZHEIMER’S DISEASE MC NL PT SE COGNITION, BRAIN MAPPING, CEREBROVASCULAR HEMODYNAMICS, AND (30) Priority: 31.07.1998 US 95002 P IMMUNE FACTORS", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, NEW YORK (43) Date of publication of application: ACADEMY OF SCIENCES, NEW YORK, NY, US, 1 08.06.2011 Bulletin 2011/23 January 1996 (1996-01-01), pages 399-403, XP008065562, ISSN: 0077-8923 (62) Document number(s) of the earlier application(s) in • SPIERS P A ET AL: "CITICOLINE IMPROVES accordance with Art. 76 EPC: VERBAL MEMORY IN AGING", ARCHIVES OF 09173495.4 / 2 145 627 NEUROLOGY, AMERICAN MEDICAL 07116909.8 / 1 870 103 ASSOCIATION, CHICAGO, IL, US, vol. 53, no. 5, 99937631.2 / 1 140 104 1 May 1996 (1996-05-01), pages 441-448, XP008028412, ISSN: 0003-9942 (73) Proprietor: Massachusetts Institute of Technology • WEISS G B: "Metabolism and actions of CDP- Cambridge, Massachusetts 02142-1601 (US) choline as an endogenous compound and administered exogenously as citicoline.", LIFE (72) Inventors: SCIENCES 1995 LNKD- PUBMED:7869846, vol.
    [Show full text]
  • Health and Social Outcomes Associated with High-Risk Alcohol Use
    Manitoba Centre for Health Policy Health and Social Outcomes Associated with High-Risk Alcohol Use Summer 2018 Nathan C Nickel, MPH, PhD Jeff Valdivia, MNRM, CAPM Deepa Singal, PhD James Bolton, MD Christine Leong, PharmD Susan Burchill, BMus Leonard MacWilliam, MSc, MNRM Geoffrey Konrad, MD Randy Walld, BSc, BComm (Hons) Okechukwu Ekuma, MSc Greg Finlayson, PhD Leanne Rajotte, BComm (Hons) Heather Prior, MSc Josh Nepon, MD Michael Paille, BHSc This report is produced and published by the Manitoba Centre for Health Policy (MCHP). It is also available in PDF format on our website at: http://mchp-appserv.cpe.umanitoba.ca/deliverablesList.html Information concerning this report or any other report produced by MCHP can be obtained by contacting: Manitoba Centre for Health Policy Rady Faculty of Health Sciences Max Rady College of Medicine, University of Manitoba 4th Floor, Room 408 727 McDermot Avenue Winnipeg, Manitoba, Canada R3E 3P5 Email: [email protected] Phone: (204) 789-3819 Fax: (204) 789-3910 How to cite this report: Nathan C Nickel, James Bolton, Leonard MacWilliam, Okechukwu Ekuma, Heather Prior, Jeff Valdivia, Christine Leong, Geoffrey Konrad, Greg Finlayson, Josh Nepon, Deepa Singal, Susan Burchill, Randy Walld, Leanne Rajotte, Michael Paille. Health and Social Outcomes Associated with High-Risk Alcohol Use. Winnipeg, MB. Manitoba Centre for Health Policy, Summer 2018. Legal Deposit: Manitoba Legislative Library National Library of Canada ISBN 978-1-896489-90-2 ©Manitoba Health This report may be reproduced, in whole or in part, provided the source is cited. 1st printing (Summer 2018) This report was prepared at the request of Manitoba Health, Seniors and Active Living (MHSAL), a department within the Government of Manitoba, as part of the contract between the University of Manitoba and MHSAL.
    [Show full text]
  • Long-Term Oral Administration of Dipyridamole Improves Both
    913 Hypertens Res Vol.30 (2007) No.10 p.913-919 Original Article Long-Term Oral Administration of Dipyridamole Improves Both Cardiac and Physical Status in Patients with Mild to Moderate Chronic Heart Failure: A Prospective Open-Randomized Study Shoji SANADA1),2), Hiroshi ASANUMA3), Yukihiro KORETSUNE4), Kouki WATANABE5), Shinsuke NANTO6), Nobuhisa AWATA7), Noritake HOKI2), Masatake FUKUNAMI2), Masafumi KITAKAZE3), and Masatsugu HORI1) Adenosine is known as an endogenous cardioprotectant. We previously reported that plasma adenosine lev- els increase in patients with chronic heart failure (CHF), and that a treatment that further elevates plasma adenosine levels may improve the pathophysiology of CHF. Therefore, we performed a prospective, open- randomized clinical trial to determine whether or not exposure to dipyridamole for 1 year improves CHF pathophysiology compared with conventional treatments. The study enrolled 28 patients (mean±SEM: 66±4 years of age) attending specialized CHF outpatient clinics with New York Heart Association (NYHA) class II or III, no major complications, and stable CHF status during the most recent 6 months under fixed medica- tions. They were randomized into three groups with or without dipyridamole (Control: n=9; 75 mg/day: n=9; 300 mg/day: n=10) in addition to their original medications and were followed up for 1 year. The other drugs were not altered. Among the enrolled patients, 100%, 4%, 100%, and 79% received angiotensin-converting enzyme inhibitors, aldosterone analogue, loop diuretics, and β-adrenoceptor blocker, respectively. Fifteen patients suffered from dilated cardiomyopathy, and 7/3/3 patients suffered from ischemic/valvular/hyperten- sive heart diseases, respectively. Mean blood pressure was comparable among the groups.
    [Show full text]