Storey R F, Oldroyd K G, Wilcox R G
Division of Cardiovascular Medicine, University Hospital, Nottingham, UK.
Thromb Haemost. 2001 Mar;85(3):401-7.
Platelet aggregation is the central process in the pathophysiology of acute coronary syndromes. ADP contributes to thrombosis by activating platelets, and AR-C69931MX is a specific antagonist of this process acting at the P2T receptor. At 5 hospitals, 39 patients with unstable angina or non-Q wave myocardial infarction, who were receiving aspirin and heparin, were administered intravenous AR-C69931MX with stepped dose increments over 3 h to a plateau of either 2 microg/kg/min for 21 h (Part 1; n = 12) or up to 69 h (Part 2; n = 13) or 4 microg/kg/min for up to 69 h (Part 3: n = 14). Safety parameters, platelet aggregation (PA) induced by ADP 3 micromol/L (impedance aggregometry), bleeding time (BT) and plasma concentrations of AR-C69931XX were assessed. AR-C69931MX was well tolerated. 33 patients completed the study. There were no deaths at 30 days and no serious adverse events attributed to AR-C69931MX. Trivial bleeding (56%) was common. At 24 h, mean inhibition of PA was 96.0 +/- 8.6, 94.9 +/- 14.4 and 98.7 +/- 2.1% and BT was 9.5 +/- 8.4, 14.0 +/- 9.7 and 16.0 +/- 11.1 min for Parts 1, 2 and 3 respectively. At 1 h post-infusion, mean inhibition of PA was 36.2 +/- 39.2, 20.7 +/- 25.9 and 40.7 +/- 36.7% respectively. 90% patients had a plasma half-life for AR-C69931XX of <9 min. In conclusion, AR-C69931MX is a potent, short-acting platelet ADP receptor antagonist suitable for further studies as an antithrombotic agent.
血小板聚集是急性冠脉综合征病理生理学的核心过程。ADP通过激活血小板促进血栓形成，而AR-C69931MX是作用于P2T受体的该过程的特异性拮抗剂。在5家医院，39例接受阿司匹林和肝素治疗的不稳定型心绞痛或非Q波心肌梗死患者，静脉给予AR-C69931MX，剂量在3小时内逐步增加至平台期，分别为2μg/kg/min持续21小时（第1部分；n = 12）或长达69小时（第2部分；n = 13）或4μg/kg/min长达69小时（第3部分：n = 14）。评估了安全性参数、3μmol/L ADP诱导的血小板聚集（PA）（阻抗聚集法）、出血时间（BT）和AR-C69931XX的血浆浓度。AR-C69931MX耐受性良好。33例患者完成了研究。30天内无死亡病例，也无归因于AR-C69931MX的严重不良事件。轻微出血（56%）很常见。在24小时时，第1、2和3部分的PA平均抑制率分别为96.0±8.6%、94.9±14.4%和98.7±2.1%，BT分别为9.5±8.4分钟（第1部分）、14.0±9.7分钟（第2部分）和16.0±11.1分钟（第3部分）。输注后1小时，PA平均抑制率分别为36.2±39.2%、20.7±25.9%和40.7±36.7%。90%的患者AR-C69931XX的血浆半衰期<9分钟。总之，AR-C69931MX是一种强效、短效的血小板ADP受体拮抗剂，适合作为抗血栓药物进行进一步研究。
