Mousa S A, DeGrado W F, Mu D X, Kapil R P, Lucchesi B R, Reilly T M
Du Pont Merck Pharmaceutical Co, Wilmington, Del. 19880-0400, USA.
Circulation. 1996 Feb 1;93(3):537-43. doi: 10.1161/01.cir.93.3.537.
Currently used antiplatelet drugs, including aspirin and ticlopidine, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP 728 has been characterized as a potent and specific platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist. The goals of the present study were to determine the oral antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models in dogs.
In conscious and anesthetized mongrel dogs, DMP 728 at 0.02 to 1.0 mg/kg PO in gelatin capsules produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and prolonging template bleeding time. DMP 728 effects on bleeding time prolongation could be reversed more rapidly than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 1.0 mg/kg PO. DMP 728 demonstrated dose-dependent oral antiplatelet effects with an absolute oral bioavailability of 8% to 12% in dogs. Additionally, the antithrombotic efficacy of DMP 728 was examined after intravenous and oral administration at different doses in various models of arterial thrombosis. In the coronary artery Folts' model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV and < 0.6 mg/kg PO. Additionally, DMP 728 at 0.1 and 1.0 mg/kg IV or PO demonstrated 60% to 100% prevention of primary thrombosis (P < .01) in an electrolytically induced carotid artery thrombosis model in dogs.
These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an oral antithrombotic agent in coronary and carotid artery thromboembolic disorders.
目前使用的抗血小板药物，包括阿司匹林和噻氯匹定，对许多内源性血小板激活剂中的某些有效，但并非全部有效。由于其疗效有限，仍有大量严重的血栓栓塞并发症发生，这突出表明需要一种更有效的治疗方法。DMP 728已被鉴定为一种强效且特异性的血小板糖蛋白IIb/IIIa复合物（GPIIb/IIIa）拮抗剂。本研究的目的是确定DMP 728在犬类各种动脉血栓形成模型中的口服抗血小板和抗血栓形成疗效。
在清醒和麻醉的杂种犬中，明胶胶囊中口服0.02至1.0 mg/kg的DMP 728在抑制ADP诱导的体外血小板聚集和延长模板出血时间方面产生剂量依赖性抗血小板作用。DMP 728对出血时间延长的作用比其对血小板聚集抑制的作用能更快逆转。口服1.0 mg/kg的DMP 728显示出最大抗血小板作用。DMP 728在犬类中显示出剂量依赖性口服抗血小板作用，绝对口服生物利用度为8%至12%。此外，在各种动脉血栓形成模型中，以不同剂量静脉内和口服给药后检查了DMP 728的抗血栓形成疗效。在犬类冠状动脉Folts模型中，DMP 728在静脉注射0.01 mg/kg和口服<0.6 mg/kg时显示出最大抗血栓形成疗效。此外，在犬类电解诱导的颈动脉血栓形成模型中，静脉注射或口服0.1和1.0 mg/kg的DMP 728可预防60%至100%的原发性血栓形成（P<.01）。
这些数据表明，低分子量GPIIb/IIIa受体拮抗剂DMP 728作为一种口服抗血栓形成药物在冠状动脉和颈动脉血栓栓塞性疾病中可能具有治疗潜力。
