Ohtani A, Murakami J, Hirano-Wakimoto A
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda-shi, Saitama, Japan.
Eur J Pharmacol. 1997 Jul 9;330(2-3):151-6. doi: 10.1016/s0014-2999(97)00174-x.
The aim of this study was to evaluate the antithrombotic potential of T-686 ((3E,4E)-3-benzylidene-4-(3,4,5-trimethoxy-benzylidene)-pyrr olidine-2,5-dione), a novel inhibitor of plasminogen activator inhibitor-1 (PAI-1), in rat thrombosis models. T-686 (0.1-100 mg/kg per day, p.o.) dose dependently decreased the weight of venous thrombi induced by a combination of stasis and hypercoagulability. The antithrombotic effect was enhanced by repeated administration of T-686. Warfarin (0.1 mg/kg per day for 3 days) also prevented thrombus formation. The antithrombotic action by warfarin was accompanied by prolongation of coagulation time, while no effect on coagulation time was observed in T-686-treated rats. T-686 lowered the activity of PAI-1 in plasma. In the arterio-venous shunt model, pretreatment with T-686 (10 mg/kg per day) or ticlopidine (100 mg/kg per day) for 8 days inhibited thrombus formation by 33% and 44%, respectively. T-686 had no effect on collagen-induced platelet aggregation ex vivo, while ticlopidine inhibited platelet aggregation. T-686 did not affect bleeding time at 10-100 times the antithrombotic dose, while warfarin dose dependently prolonged bleeding time at and around the antithrombotic dose. These results suggest that T-686 prevents thrombus formation in rats without impairment of hemostasis.
本研究旨在评估新型纤溶酶原激活物抑制剂-1（PAI-1）抑制剂T-686（(3E,4E)-3-亚苄基-4-(3,4,5-三甲氧基-亚苄基)-吡咯烷-2,5-二酮）在大鼠血栓形成模型中的抗血栓形成潜力。T-686（每天0.1 - 100 mg/kg，口服）剂量依赖性地降低了由血流淤滞和高凝状态联合诱导的静脉血栓重量。重复给予T-686可增强抗血栓形成作用。华法林（每天0.1 mg/kg，共3天）也可预防血栓形成。华法林的抗血栓形成作用伴随着凝血时间延长，而在T-686处理的大鼠中未观察到对凝血时间的影响。T-686降低了血浆中PAI-1的活性。在动静脉分流模型中，用T-686（每天10 mg/kg）或噻氯匹定（每天100 mg/kg）预处理8天，分别抑制血栓形成33%和44%。T-686对体外胶原诱导的血小板聚集无影响，而噻氯匹定抑制血小板聚集。在抗血栓剂量的10 - 100倍时，T-686不影响出血时间，而华法林在抗血栓剂量及附近剂量依赖性地延长出血时间。这些结果表明，T-686可预防大鼠血栓形成，且不损害止血功能。
