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• W2000251419 abstract "The P2Y12 receptor for adenosine diphosphate (ADP) plays a central role in the physiological process of hemostasis and thrombosis. It has proven to be a key target in the prevention of complications associated with atherosclerotic vascular disease especially in the context of percutaneous coronary intervention. Thienopyridines specifically target this receptor and have become the cornerstone of treatment in this setting, showing significant reduction in adverse events in trials that initially compared ticlopidine and aspirin with either aspirin alone or with warfarin and aspirin. The CAPRIE (clopidogrel versus aspirin in patients at risk of ischaemic events) trial was the first large randomized trial that have established the benefit of clopidogrel over aspirin in atherothrombotic patients, by reducing the rate of recurrent myocardial infarction [1]. Clopidogrel showed a better tolerance profile than ticlopidine, and the benefit of a loading dose and long term treatment was then confirmed [2]. A survival effect of clopidogrel against placebo was then shown in a large randomized non-PCI study performed in ST-elevation myocardial infarction (STEMI) patients exposed to aspirin [3] but no single study has shown a reduction in mortality with clopidogrel when used in the setting of Percutaneous Coronary Intervention (PCI) or in STEMI patients treated by PCI.Due to the sub-optimal pharmacodynamic and pharmacokinetic profile of clopidogrel, new P2Y12 inhibitors have been developed that are more potent and have a faster onset of action than clopidogrel, characteristics that make them particularly attractive for PCI. Four new P2Y12 inhibitors have now been tested in several clinical studies that recruited STEMI, Non-ST-Elevation-Acute Coronary Syndrome (NSTE-ACS) and Stable Coronary Artery Disease patients, predominantly treated with PCI. Each of these antagonists have differ properties, targeting the P2Y12 receptor in different ways: prasugrel is an oral prodrug leading to irreversible blockade of the P2Y12 receptor; ticagrelor is a direct acting and reversible inhibitor of the P2Y12 receptor with potentially more pleiotropic effects; cangrelor is an intravenous direct and reversible inhibitor of the P2Y12 receptor providing the highest level of inhibition; and elinogrel is an intravenous and oral P2Y12 antagonist with a direct and reversible action. With the advent of these new therapies comes potential for individualized therapy based on platelet function analysis and genetic testing, of which the feasibility and efficaciousness has yet to be confirmed [4, 5] (Table 1). Table 1Different agents with mode of actionPlatelet activation and the P2Y receptorsPlatelet activation and aggregation is an intrinsic component in hemostasis and arterial thrombus formation. ADP plays a crucial role as a key mediator in this process [6]. Atherosclerotic plaque rupture and endothelial activation causes localized adhesion of platelets leading to platelet activation in response to various platelet agonists including thrombin, thromboxane A2 (TXA2 and collagen) [7]. ADP is secreted in high concentrations from platelet dense granules and acts to amplify the platelet activation induced by these agents. Its proaggregatory effects are via its interaction with the two G protein-coupled receptors, P2Y1 and P2Y12. These belong to a family of P2Y receptors whose ligands are purine and pyrimidine nucleotides. They are divided into to two distinct subgroups based on structural difference: Gq-coupled subtypes and Gi-coupled subtypes [8, 9].The P2Y1 receptor couples to Gαq which, in response to ADP, mediates phospholipase activation and calcium mobilization from internal stores leading to platelet shape change and weak and transient aggregation. Concomitant ADP activation of the P2Y12 receptor through its G protein, Gi2 is essential for complete aggregation [10].The P2Y12 receptor, previously named P2TAC, P2CYC and P2YADP, was the last receptor to be identified and cloned but a great deal of knowledge was accumulated previous to this from the observed pharmacocological effects of ticlopidine and clopidogrel [11]. Its presence is limited to platelets, endothelial cells, glial cells and smooth muscle cells thus making it an attractive target for antiplatelet drugs. Structurally, it contains 342 aminoacid residues, including four extracellular Cys residues and exists mainly as homo-oligomers within lipid rafts [12]. The P2Y12 receptor is coupled to Gαi2 protein and appears to influence platelet activation and aggregation through several intracellular pathways downstream of the receptor. Activation of Gαi2 leads to inhibition of cyclic adenosine monophosphate (cAMP), which has a facilitating effect on platelet activation by inhibition of the cAMP-dependant protein kinase mediated phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) [13, 14]. VASP is an actin regulatory protein and a negative modulator of the αIIbβ3 integrin activation. Thus, levels of VASP phosphorylation/dephosphorylation reflect P2Y12 inhibition/activation state, which constitutes a sensitive marker to identify the effects of P2Y12 antagonists [15, 16]. The other pathways by which P2Y12 amplifies platelet response include stimulation of phophatidyl inositol-3 kinase (PI-3 K) activity [17, 18] leading to sustained aggregation; and activation of small GTPase Rap1b through a PI-3 K dependant mechanism [19, 20]. Finally, P2Y12 also has an effect on the activation of the glycoprotein (GP) GIIb/IIIa receptor which in turn binds fibrinogen and links platelets [21].The important role of P2Y12 in thrombosis has been further demonstrated in studies of patients with congenital selective defects of the receptor and of ADP-induced platelet aggregation having a history of mild to moderate excessive bleeding [22]. This is also shown in studies of P2Y12 knockout mice. This underlines its relevance as a key target of efficient antithrombotic therapy." @default.
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• W2000251419 date "2011-06-28" @default.
• W2000251419 modified "2023-09-30" @default.
• W2000251419 title "The P2Y12 receptor as a target of antithrombotic drugs" @default.
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• W2000251419 doi "https://doi.org/10.1007/s11302-011-9241-z" @default.
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