Kaku S, Kawasaki T, Hisamichi N, Sakai Y, Taniuchi Y, Inagaki O, Yano S, Suzuki K, Terazaki C, Masuho Y, Satoh N, Takenaka T, Yanagi K, Ohshima N
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Thromb Haemost. 1996 Apr;75(4):679-84.
The antiplatelet and antithrombotic effects of the Fab fragment of the humanized antiplatelet glycoprotein (GP) IIb/IIIa monoclonal antibody C4G1 (YM337) were investigated in monkeys. First, the relationship between the inhibition of platelet aggregation and the prolongation of bleeding time was studied in rhesus monkeys. YM337 dose-dependently inhibited ex vivo platelet aggregation, with complete inhibition at doses higher than 0.25 mg/kg intravenous injection or 1.5 micrograms/kg/min infusion. At 0.25 mg/kg bolus injection followed by 1.5 micrograms/kg/min infusion, YM337 immediately and continuously inhibited platelet aggregation during the 6-h infusion period with platelet aggregation rapidly returning to over 50% of baseline within 1 h after the cessation of infusion. Template-bleeding time was significantly prolonged during the period of complete inhibition of platelet aggregation. Second, the antithrombotic effects of YM337 were investigated in a photochemically-induced thrombosis model in squirrel monkeys. YM337 at a dose of 1 mg/kg intravenous injection followed by 6 micrograms/kg/min infusion for 60 min prevented occlusive thrombus formation in all 4 monkeys. In contrast, time to occlusive thrombus formation did not change on intravenous bolus injection of aspirin 17 mg/kg (11.3 +/- 5.2 min) or sodium ozagrel (9.4 +/- 3.0 min) compared with saline (13.3 +/- 4.0 min). YM337 but not aspirin or sodium ozagrel significantly inhibited ex vivo ADP-induced platelet aggregation, while all drugs completely inhibited arachidonic acid-induced platelet aggregation. However, while aspirin and sodium ozagrel inhibited the thromboxane B2 generation accompanying arachidonic acid-induced platelet aggregation, YM337 had no effect on this variable. Platelet counts and bleeding time showed no significant change in any group in this squirrel monkey model. These results indicate that YM337, with a short half-life, may be a useful therapeutic agent in patients with thrombotic disorders.
在猴子身上研究了人源化抗血小板糖蛋白（GP）IIb/IIIa单克隆抗体C4G1（YM337）Fab片段的抗血小板和抗血栓形成作用。首先，在恒河猴中研究了血小板聚集抑制与出血时间延长之间的关系。YM337剂量依赖性地抑制体外血小板聚集，静脉注射剂量高于0.25mg/kg或输注剂量为1.5μg/kg/min时可完全抑制。静脉推注0.25mg/kg后接着以1.5μg/kg/min输注，YM337在6小时输注期间立即并持续抑制血小板聚集，输注停止后1小时内血小板聚集迅速恢复至基线的50%以上。在血小板聚集完全抑制期间，模板出血时间显著延长。其次，在松鼠猴的光化学诱导血栓形成模型中研究了YM337的抗血栓形成作用。静脉注射1mg/kg YM337后接着以6μg/kg/min输注60分钟，可防止所有4只猴子形成闭塞性血栓。相比之下，静脉推注17mg/kg阿司匹林（11.3±5.2分钟）或奥扎格雷钠（9.4±3.0分钟）与注射生理盐水（13.3±4.0分钟）相比，闭塞性血栓形成时间没有变化。YM337可显著抑制体外ADP诱导的血小板聚集，但阿司匹林和奥扎格雷钠则不能，而所有药物均可完全抑制花生四烯酸诱导的血小板聚集。然而，阿司匹林和奥扎格雷钠可抑制花生四烯酸诱导的血小板聚集时伴随的血栓素B2生成，而YM337对该变量无影响。在该松鼠猴模型中，任何组的血小板计数和出血时间均无显著变化。这些结果表明，半衰期较短的YM337可能是血栓性疾病患者的一种有用治疗药物。
