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• W2011699144 abstract "Drugs that inhibit platelet function are widely used to decrease the risk of occlusive arterial events in patients with atherosclerosis. There are three families of anti-aggregating agents with proven clinical efficacy: (i) cyclooxygenase inhibitors, such as aspirin; (ii) ADP receptor antagonists, such as the thienopyridine compounds ticlopidine and clopidogrel; (iii) glycoprotein IIb/IIIa antagonists. All these drugs are used during coronary interventions and in the medical management of acute coronary syndromes, while only aspirin and the thienopyridine compounds are used in long-term prevention of cardiovascular and cerebrovascular events in patients at risk. Both aspirin and the thienopyridines selectively inhibit a single pathway of platelet activation: aspirin affects the arachidonate–thromboxane pathway, while the thienopyridines affect the ADP pathway, by irreversibly blocking the ADP receptor P2Y12. The good antithrombotic efficacy of these drugs, despite their selective mechanism of action, is explained by the fact that both the arachidonate–thromboxane pathway and the ADP pathway contribute to the amplification of platelet activation and are essential for the full aggregation response of platelets under several experimental conditions. Despite the fact that aspirin and thienopyridines have a good risk-to-benefit ratio, they suffer some drawbacks, which justifies the unceasing search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. Although the definition of ‘aspirin resistance’ is still elusive [1Gum P.A. Kottke-Marchant K. Poggio E.D. Gurm H. Welsh P.A. Brooks L. Sapp S.K. Topol E.J. Profile and prevalence of aspirin resistance in patients with cardiovascular disease.Am J Cardiol. 2001; 88: 230-5Abstract Full Text Full Text PDF PubMed Scopus (804) Google Scholar, 2Weber A.A. Przytulski B. Schanz A. Hohlfeld T. Schror K. Towards a definition of aspirin resistance: a typological approach.Platelets. 2002; 13: 37-40Crossref PubMed Scopus (170) Google Scholar], there are indeed reports of patients relatively insensitive to aspirin inhibition of thromboxane production, who seem to be less well protected from vascular events [3Eikelboom J.W. Hirsh J. Weitz J.I. Johnston M. Yi Q. Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events.Circulation. 2002; 105: 1650-5Crossref PubMed Scopus (1033) Google Scholar]: whether this effect is only due to negative interaction with other drugs, such as ibuprofen [4Catella-Lawson F. Reilly M.P. Kapoor S.C. Cucchiara A.J. DeMarco S. Tournier B. Vyas S.N. FitzGerald G.A. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.N Engl J Med. 2001; 345: 1809-17Crossref PubMed Scopus (1297) Google Scholar, 5MacDonald T.M. Wei L. Effect of ibuprofen on cardioprotective effect of aspirin.Lancet. 2003; 361: 573-4Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar], or also to other variables is presently unknown. The problem of drug resistance is certainly more relevant for thienopyridines. Ticlopidine and clopidogrel are prodrugs, which need to be metabolized by the liver in an active metabolite with anti-aggregating activity. Therefore, their pharmacological effect can be detected only several hours after their first administration and, more importantly, the plasma levels of the active metabolite, and, consequently, the degree of inhibition of platelet aggregation may vary widely among subjects. Interference with clopidogrel metabolism by other drugs that are frequently given to patients with atherosclerosis, such as atorvastatin [6Lau W.C. Waskell L.A. Watkins P.B. Neer C.J. Horowitz K. Hopp A.S. Tait A.R. Carville G.M. Guyer K.E. Bates E.R. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug–drug interaction.Circulation. 2003; 107: 32-7Crossref PubMed Scopus (659) Google Scholar, 7Clarke T.A. Waskell L.A. The metabolism of clopidogrel is catalyzed by human cytochrome p450 3A and is inhibited by atorvastatin.Drug Metab Dispos. 2003; 31: 53-9Crossref PubMed Scopus (376) Google Scholar], can increase the number of patients who are resistant to clopidogrel. Safety issues are of less concern for clopidogrel than for ticlopdidine, although thrombotic thrombocytopenic purpura complicating clopidogrel therapy has also been reported [8Bennett C.L. Connors J.M. Carwile J.M. Moake J.L. Bell W.R. Tarantolo S.R. McCarthy L.J. Sarode R. Hatfield A.J. Feldman M.D. Davidson C.J. Tsai H.M. Thrombotic thrombocytopenic purpura associated with clopidogrel.N Engl J Med. 2000; 342: 1773-7Crossref PubMed Scopus (583) Google Scholar]. The combined action of two platelet ADP receptors, P2Y1 (coupled to Gq and PLCβ) and P2Y12 (negatively coupled to adenylyl cyclase through Gi), is necessary for the full platelet aggregation response to ADP [9Cattaneo M. Gachet C. ADP receptors and clinical bleeding disorders.Arterioscler Thromb Vasc Biol. 1999; 19: 2281-5Crossref PubMed Scopus (177) Google Scholar]. The relative role of these receptors in platelet function has been elucidated by studies of patients with congenital P2Y12 deficiency [9Cattaneo M. Gachet C. ADP receptors and clinical bleeding disorders.Arterioscler Thromb Vasc Biol. 1999; 19: 2281-5Crossref PubMed Scopus (177) Google Scholar, 10Cattaneo M. Lecchi A. Randi A.M. McGregor J.L. Mannucci P.M. Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate.Blood. 1992; 80: 2787-96Crossref PubMed Google Scholar], knock-out mice [11Leon C. Hechler B. Freund M. Eckly A. Vial C. Ohlmann P. Dierich A. LeMeur M. Cazenave J.P. Gachet C. Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y (1) receptor-null mice.J Clin Invest. 1999; 104: 1731-7Crossref PubMed Google Scholar, 12Fabre J.E. Nguyen M. Latour A. Keifer J.A. Audoly L.P. Coffman T.M. Koller B.H. Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice.Nat Med. 1999; 5: 1199-202Crossref PubMed Scopus (382) Google Scholar, 13Foster C.J. Prosser D.M. Agans J.M. Zhai Y. Smith M.D. Lachowicz J.E. Zhang F.L. Gustafson E. Monsma Jr, F.J. Wiekowski M.T. Abbondanzo S.J. Cook D.N. Bayne M.L. Lira S.A. Chintala M.S. Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs.J Clin Invest. 2001; 107: 1591-8Crossref PubMed Google Scholar] and selective antagonists [9Cattaneo M. Gachet C. ADP receptors and clinical bleeding disorders.Arterioscler Thromb Vasc Biol. 1999; 19: 2281-5Crossref PubMed Scopus (177) Google Scholar, 14Gachet C. ADP receptors of platelets and their inhibition.Thromb Haemost. 2001; 86: 222-32Crossref PubMed Scopus (372) Google Scholar]. The interaction of ADP with P2Y1 leads to calcium mobilization, platelet shape change and rapidly reversible aggregation, while its interaction with P2Y12 leads to the formation of large and stable platelet aggregates, and amplifies platelet secretion [9Cattaneo M. Gachet C. ADP receptors and clinical bleeding disorders.Arterioscler Thromb Vasc Biol. 1999; 19: 2281-5Crossref PubMed Scopus (177) Google Scholar]. In the last few years, search for selective, direct antagonists of P2Y1 and P2Y12 has been very active. Several ATP-derived antagonists of P2Y12 have been synthesized by Astra-Zeneca, the last of which, AR-C69931MX, proved to have good anti-thrombotic effects in several animal models of thrombosis [15Humphries R.G. Pharmacology of AR-C69931MX and related compounds: from pharmacological tools to clinical trials.Haematologica. 2000; 85: 66-72PubMed Google Scholar]. In addition, a Phase II study of intravenous AR-C69931MX in patients with acute coronary syndromes showed it to be a well-tolerated, effective inhibitor of ADP-induced platelet aggregation, with rapid onset of action and short plasma half-life [16Storey R.F. Oldroyd K.G. Wilcox R.G. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes.Thromb Haemost. 2001; 85: 401-7Crossref PubMed Google Scholar]. A study of a subgroup of these patients showed that a substantially greater P2Y12 blockade can be achieved with AR-C69931MX than with clopidogrel [17Storey R.F. Wilcox R.G. Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease.Platelets. 2002; 13: 407-13Crossref PubMed Scopus (142) Google Scholar]. The question of whether or not inhibition of P2Y1 receptor could result in a safe and effective inhibition of thrombus formation has been addressed more recently. Studies of P2Y1-null mice provided evidence that lack of P2Y1 is compatible with normal life and is associated with defective in vitro and in vivo platelet aggregation, no tendency to spontaneous bleeding and very mild prolongation of the bleeding time [11Leon C. Hechler B. Freund M. Eckly A. Vial C. Ohlmann P. Dierich A. LeMeur M. Cazenave J.P. Gachet C. Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y (1) receptor-null mice.J Clin Invest. 1999; 104: 1731-7Crossref PubMed Google Scholar, 12Fabre J.E. Nguyen M. Latour A. Keifer J.A. Audoly L.P. Coffman T.M. Koller B.H. Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice.Nat Med. 1999; 5: 1199-202Crossref PubMed Scopus (382) Google Scholar]. In this issue of the journal, Lenain et al. [18Lenain N. Freund M. Lèon C. Cazenave J.P. Gachet C. Inhibition of localized thrombosis in P2Y1-deficient mice and rodents treated with MRS2179, a P2Y1 receptor antagonist.J Thromb Haemost. 2003; 1: 1144-9Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar] show that the administration of the P2Y1 antagonist MRS2179 to mice resulted in a significant decrease in localized thrombus formation on mesenteric arterioles exposed to a solution of FeCl3. The degree of inhibition of thrombus formation observed with the P2Y1 antagonist was comparable to that obtained with clopidogrel; interestingly, treatment of P2Y1-null mice with clopidogrel further inhibited thrombus formation, suggesting that the combined inhibition of P2Y1 and P2Y12 can have additive antithrombotic effects. These results, which have been obtained in a model of arterial thrombosis, are compatible with those of previous in vitro studies, which showed that both P2Y1 and P2Y12 play an important role in shear-induced platelet aggregation and platelet thrombus formation under high flow conditions [19Cattaneo M. Lombardi R. Bettega D. Lecchi A. Mannucci P.M. Shear-induced platelet aggregation is potentiated by desmopressin and inhibited by ticlopidine.Arterioscler Thromb. 1993; 13: 393-7Crossref PubMed Google Scholar, 20Cattaneo M. Zighetti M.L. Lombardi R. Mannucci P.M. Role of ADP in platelet aggregation at high shear: studies in a patient with congenital defect of platelet responses to ADP.Br J Haematol. 1994; 88: 826-9Crossref PubMed Google Scholar, 21Cattaneo M. Savage B. Ruggeri Z.M. Effects of pharmacological inhibition of the P2Y1 and P2Y12 receptors on shear-induced platelet aggregation and platelet thrombus formation on a collagen-coated surface under flow conditions.Blood. 2001; 98: 239-40Google Scholar, 22Turner N.A. Moake J.L. McIntire L.V. Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow.Blood. 2001; 98: 3340-5Crossref PubMed Scopus (0) Google Scholar, 23Goto S. Tamura N. Eto K. Ikeda Y. Handa S. Functional significance of adenosine 5′-diphosphate receptor (P2Y(12)) in platelet activation initiated by binding of von Willebrand factor to platelet GP Ibalpha induced by conditions of high shear rate.Circulation. 2002; 105: 2531-6Crossref PubMed Scopus (0) Google Scholar]. The study by Lenain et al., however, shows that the P2Y1 antagonist MRS2179 has antithrombotic effects also under static blood flow conditions, in which thrombin generation plays an essential pathogenic role. Using a Wessler procedure adapted to rats [24Wessler S. Thrombosis in the presence of vascular stasis.Am J Med. 1962; 33: 648Abstract Full Text PDF PubMed Google Scholar], in which venous thrombosis is induced by the intravenous injection of thromboplastin followed by ligature of the vena cava, Lenain et al. showed that thrombi that formed in the vena cava of rats in which MRS2179 had been injected intravenously weighed significantly less than those that developed in placebo-treated animals. Previous studies by the same group showed that MRS2179 led to a significant decrease in the formation of thrombin–antithrombin complexes in mice that had been injected with thromboplastin [25Leon C. Freund M. Ravanat C. Baurand A. Cazenave J.P. Gachet C. Key role of the P2Y(1) receptor in tissue factor-induced thrombin-dependent acute thromboembolism: studies in P2Y(1)-knockout mice and mice treated with a P2Y(1) antagonist.Circulation. 2001; 103: 718-23Crossref PubMed Google Scholar]. This inhibitory effect of MRS2179 on thrombin generation must be due to its antagonism with the P2Y1 receptor on platelets and/or other cells, because the compound did not exhibit anticoagulant effects in a cell-free plasma system. In addition, this effect is shared by antagonists of the P2Y12 receptor [26Herault J.P. Dol F. Gaich C. Bernat A. Herbert J.M. Effect of clopidogrel on thrombin generation in platelet-rich plasma in the rat.Thromb Haemost. 1999; 81: 957-60Crossref PubMed Scopus (62) Google Scholar, 27Storey R.F. Sanderson H.M. White A.E. May J.A. Cameron K.E. Heptinstall S. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity.Br J Haematol. 2000; 110: 925-34Crossref PubMed Scopus (265) Google Scholar, 28Gregorini L. Marco J. Fajadet J. Bernies M. Cassagneau B. Brunel P. Bossi I.M. Mannucci P.M. Ticlopidine and aspirin pretreatment reduces coagulation and platelet activation during coronary dilation procedures.J Am Coll Cardiol. 1997; 29: 13-20Crossref PubMed Scopus (104) Google Scholar], suggesting that ADP is not only important for platelet aggregation and secretion, but also plays a role in the platelet procoagulant activity. In conclusion, agents that directly inhibit the interaction of ADP with its platelet receptors P2Y1 and/or P2Y12 are potentially very efficacious and fast-acting antithrombotic drugs. At the present level of development, these agents are not yet available for oral administration; consequently, further chemical research is necessary to obtain oral antagonists that could be tested in clinical trials of long-term prevention of cardiovascular and cerebrovascular events." @default.
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• W2011699144 title "The platelet P2Y receptors as targets for new antithrombotic drugs" @default.
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