Bacher P, Walenga J M, Iqbal O, Bajusz S, Breddin K, Fareed J
Hemostasis Research Laboratories, Loyola University Medical Center, Maywood, IL 60153.
Thromb Res. 1993 Aug 15;71(4):251-63. doi: 10.1016/0049-3848(93)90195-t.
The pharmacologic activities of two thrombin inhibitors (D-MePhe-Pro-Arg-H, recombinant-hirudin) were compared in two animal models. The antithrombotic effect was investigated in vivo in rabbits using a modified Wessler stasis thrombosis model. During these experiments, blood was drawn for ex vivo testing to determine the coagulation profile and to determine plasma concentrations using pre-constructed calibration curves. A dose-dependent antithrombotic effect was observed for both agents. On an equigravimetric basis (100 micrograms/kg i.v.), r-hirudin showed a stronger antithrombotic effect than the tripeptide, which correlated well with the ex vivo anticoagulant effect. No adverse reactions were observed during this study. In a rabbit ear bleeding model, a dose and time dependent hemorrhagic effect was observed for both agents. Only slight bleeding effects were observed at 1.0 mg/kg dosages. These studies show that the tripeptide D-MePhe-Pro-Arg-H and r-hirudin are specific thrombin inhibitors with potent antithrombotic effects and a high therapeutic (antithrombotic/hemorrhagic) index. Furthermore, the results of these two animal models and ex vivo analyses can be used to determine the therapeutic index of thrombin inhibitors.
在两种动物模型中比较了两种凝血酶抑制剂（D - 甲基苯丙氨酸 - 脯氨酸 - 精氨酸 - H，重组水蛭素）的药理活性。使用改良的韦氏淤滞血栓形成模型在兔体内研究抗血栓形成作用。在这些实验过程中，抽取血液进行体外测试，以确定凝血谱并使用预先构建的校准曲线确定血浆浓度。两种药物均观察到剂量依赖性抗血栓形成作用。在等重量基础上（静脉注射100微克/千克），重组水蛭素显示出比三肽更强的抗血栓形成作用，这与体外抗凝作用密切相关。在本研究中未观察到不良反应。在兔耳出血模型中，两种药物均观察到剂量和时间依赖性出血效应。在1.0毫克/千克剂量下仅观察到轻微出血效应。这些研究表明，三肽D - 甲基苯丙氨酸 - 脯氨酸 - 精氨酸 - H和重组水蛭素是具有强大抗血栓形成作用和高治疗（抗血栓形成/出血）指数的特异性凝血酶抑制剂。此外，这两种动物模型和体外分析的结果可用于确定凝血酶抑制剂的治疗指数。
