RPR120844, a novel, specific inhibitor of coagulation factor Xa inhibits venous thrombosis in the rabbit

作     者：Bostwick, JS Bentley, R Morgan, S Brown, K Chu, V Ewing, WR Spada, AP Pauls, H Perrone, MH Dunwiddie, CT Leadley, RJ 

作者机构：Rhone Poulenc Rorer Res & Dev Cardiovasc Drug Discovery Collegeville PA 19426 USA 

出 版 物：《THROMBOSIS AND HAEMOSTASIS》 (Thromb. Haemost.)

年 卷 期：1999年第81卷第1期

页      面：157-160页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

主　　题：剂量效应关系 药物 因子Ⅹa/拮抗剂和抑制剂 纤维蛋白溶解药/化学 纤维蛋白溶解药/药理学 部分促凝血酶原时间 磺胺类/化学 磺胺类/药理学 噻吩类/化学 噻吩类/药理学 静脉血栓形成/血液 静脉血栓形成/药物疗法 动物 兔 

摘      要：The in vivo antithrombotic activity of RPR120844, a novel synthetic coagulation factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TMI measured at the end of a 50 min infusion, was significantly reduced (p 0.05 vs saline-treated animals) by RPR120844 at 30 and 100 mu g/kg/min. At doses of 10, 30 and 100 mu g/kg/min: APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8 +/- 0.3, 1.5 +/- 0.9 and 2.4 +/- 0.6 mu M, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment Values 30 min after termination of treatment. The results suggest that RPR120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.