Morishita K, Iwamoto M
New Product Research Laboratories 2, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Thromb Res. 1998 Dec 15;92(6):261-6. doi: 10.1016/s0049-3848(98)00140-6.
Argatroban, a synthetic thrombin inhibitor, and ticlopidine, an anti-platelet agent, are major antithrombotic agents. We investigated the antithrombotic effects of a combination of argatroban and ticlopidine in the rat venous thrombosis model. Argatroban or ticlopidine inhibited thrombus formation in a dose-dependent manner; 50% inhibition (ED50) is obtained with 1.0 mg/kg/h (infusion) argatroban or 30 mg/kg (p.o.) ticlopidine. The combination of argatroban and ticlopidine inhibited thrombus formation in a dose-dependent manner; ED50 is obtained with 0.25 mg/kg/h argatroban plus 10 mg/kg ticlopidine and 0.5 mg/kg/h argatroban plus 3 mg/kg ticlopidine, whereas 0.5 mg/kg/h argatroban alone or 10 mg/kg ticlopidine alone had negligible effect (<20% inhibition). Isobole analysis showed that the antithrombotic effects of the combination of argatroban and ticlopidine involved synergism with potentiation. In contrast, the combination of argatroban and ticlopidine did not prolong the bleeding time synergistically. These data showed that the combination therapy of argatroban and ticlopidine should be clinically beneficial, but the different administration route may restrict the clinical usage.
阿加曲班是一种合成凝血酶抑制剂，噻氯匹定是一种抗血小板药物，二者均为主要的抗血栓形成药物。我们在大鼠静脉血栓形成模型中研究了阿加曲班与噻氯匹定联合使用的抗血栓形成作用。阿加曲班或噻氯匹定均以剂量依赖性方式抑制血栓形成；阿加曲班以1.0mg/kg/h（静脉输注）、噻氯匹定以30mg/kg（口服）给药时可产生50%的抑制作用（半数有效剂量）。阿加曲班与噻氯匹定联合使用同样以剂量依赖性方式抑制血栓形成；阿加曲班0.25mg/kg/h加噻氯匹定10mg/kg以及阿加曲班0.5mg/kg/h加噻氯匹定3mg/kg时可产生半数有效剂量，而单独使用阿加曲班0.5mg/kg/h或噻氯匹定10mg/kg时作用可忽略不计（抑制率<20%）。等效线分析表明，阿加曲班与噻氯匹定联合使用的抗血栓形成作用存在协同增效。相比之下，阿加曲班与噻氯匹定联合使用并不会协同延长出血时间。这些数据表明，阿加曲班与噻氯匹定联合治疗在临床上可能有益，但不同的给药途径可能会限制其临床应用。
