Cattaneo Marco
Professor of Internal Medicine and Director of the Unita Ematologia e Trombosi, Ospedale San Paolo--Universita Milano, Milano, Italy.
Timely Top Med Cardiovasc Dis. 2006 Sep 1;10:E22.
The interaction of adenosine-5'-diphosphate (ADP) with its platelet receptors (P2Y1 and P2Y12) plays a very important role in thrombogenesis. The thienopyridine ticlopidine was the first specific antagonist of the platelet P2Y12 ADP receptor to be tested in randomized clinical trials for the prevention of arterial thrombotic events. Although ticlopidine reduces the incidence of vascular events in patients at risk, it also unfortunately has some significant drawbacks: a relatively high incidence of toxic effects, which may be fatal in some cases; delayed onset of action; and a high interindividual variability in response. A second thienopyridine, clopidogrel, has superseded ticlopidine, because it is also an efficacious antithrombotic drug and is less toxic than ticlopidine. However, clopidogrel is not completely free from faults: severe toxic effects, albeit occurring much less frequently than with ticlopidine, may still complicate its administration to patients; the onset of pharmacologic action can be accelerated by the use of large loading doses, but may still not be optimal; the high interpatient variability in response remains an important issue. These concerns justify the continued search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound, prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y12 antagonists, cangrelor and AZD6140, feature very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new the P2Y12 antagonists, inhibitors of the other platelet receptor for ADP, the antagonists P2Y1, are under development and may prove to be effective antithrombotic agents.
腺苷 - 5'-二磷酸（ADP）与其血小板受体（P2Y1和P2Y12）的相互作用在血栓形成过程中起着非常重要的作用。噻吩吡啶类药物噻氯匹定是首个在预防动脉血栓形成事件的随机临床试验中进行测试的血小板P2Y12 ADP受体特异性拮抗剂。尽管噻氯匹定可降低高危患者血管事件的发生率，但不幸的是它也存在一些显著缺点：毒性作用发生率相对较高，在某些情况下可能是致命的；起效延迟；个体反应差异较大。第二种噻吩吡啶类药物氯吡格雷已取代了噻氯匹定，因为它也是一种有效的抗血栓药物，且毒性比噻氯匹定小。然而，氯吡格雷并非完全没有缺点：严重的毒性作用虽然比噻氯匹定发生的频率低得多，但仍可能使患者用药复杂化；使用大剂量负荷给药可加速药理作用的起效，但可能仍不理想；患者间反应的高变异性仍然是一个重要问题。这些问题使得人们有理由继续寻找能够通过更高的疗效和/或安全性进一步改善动脉粥样硬化患者临床结局的药物。一种新型噻吩吡啶化合物普拉格雷目前正在进行临床评估，它的特点是与氯吡格雷相比具有更高的效力和更快的起效速度。两种直接且可逆的P2Y12拮抗剂坎格雷洛和AZD6140具有非常快速的血小板抑制起效和逆转作用，这使它们成为噻吩吡啶类药物有吸引力的替代品，特别是在需要快速抑制血小板聚集或快速逆转其作用时。除了新型P2Y12拮抗剂外，针对ADP的另一种血小板受体P2Y1的抑制剂也在研发中，可能被证明是有效的抗血栓药物。
