Martin U, Fischer S, Kohnert U, Opitz U, Rudolph R, Sponer G, Stern A, Strein K
Department of Pharmacology, Mannheim, FRG.
Thromb Haemost. 1991 May 6;65(5):560-4.
The recombinant plasminogen activator BM 06.022 consists of the kringle 2 and the protease domains of human t-PA and is unglycosylated because of the expression in Escherichia coli. The thrombolytic and pharmacokinetic properties as well as the hemostasis effects of BM 06.022 were investigated in the rabbit model of jugular vein thrombosis. The thrombi were 125I-fibrin labeled. Intravenous bolus injection of 50, 100, 200, and 400 kU/kg BM 06.022 or 400, 800, and 1600 kU/kg alteplase over 15 s to six rabbits/dose produced a dose-dependent increase of thrombolysis determined 2 h post injection. The dose-response curve of BM 06.022 was located left compared with that of alteplase. The effective dose of 50% thrombolysis (ED50) obtained by half-logarithmic regression analysis was 163 kU/kg (= 0.28 mg/kg) for BM 06.022 and 871 kU/kg (= 1.09 mg/kg) for alteplase. At equipotent doses (50% thrombolysis), the residual concentration of fibrinogen was 74.2% and 76.5%, that of plasminogen 66.7% and 69.4%, and that of alpha 2-antiplasmin 47.3% and 46% for BM 06.022 and alteplase, respectively. Pharmacokinetic analysis for plasma activity at a dose of 400 kU/kg revealed a half-life of 18.9 +/- 1.5 min for BM 06.022, whereas alteplase was distributed with a half-life of 2.1 +/- 0.1 min, accounting for 86.7 +/- 1.9% of the total AUC, followed by a beta-phase with a half-life of 13.8 +/- 0.9 min. Plasma clearance of BM 06.022 was 4.7 +/- 0.7 ml min-1 kg-1 compared with 20 +/- 1.2 ml min-1 kg-1 for alteplase.(ABSTRACT TRUNCATED AT 250 WORDS)
重组纤溶酶原激活剂BM 06.022由人组织型纤溶酶原激活剂（t-PA）的kringle 2结构域和蛋白酶结构域组成，由于在大肠杆菌中表达，其未进行糖基化修饰。在兔颈静脉血栓形成模型中研究了BM 06.022的溶栓、药代动力学特性以及止血作用。血栓用125I-纤维蛋白标记。以50、100、200和400 kU/kg的剂量或400、800和1600 kU/kg的阿替普酶在15秒内静脉推注给药，每个剂量组6只兔，注射后2小时测定溶栓效果呈剂量依赖性增加。BM 06.022的剂量-反应曲线位于阿替普酶的左侧。通过半对数回归分析得到的50%溶栓有效剂量（ED50），BM 06.022为163 kU/kg（=0.28 mg/kg），阿替普酶为871 kU/kg（=1.09 mg/kg）。在等效剂量（50%溶栓）下，BM 06.022和阿替普酶的纤维蛋白原残留浓度分别为74.2%和76.5%，纤溶酶原残留浓度分别为66.7%和69.4%，α2-抗纤溶酶残留浓度分别为47.3%和46%。对400 kU/kg剂量的血浆活性进行药代动力学分析显示，BM 06.022的半衰期为18.9±1.5分钟，而阿替普酶分布半衰期为2.1±0.1分钟，占总药时曲线下面积（AUC）的86.7±1.9%，随后是β相，半衰期为13.8±0.9分钟。BM 06.022的血浆清除率为4.7±0.7 ml·min-1·kg-1，而阿替普酶为20±1.2 ml·min-1·kg-1。（摘要截取自250字）
