Chi L, Mertz T E, Rogers K L, Janiczek N, Peng Y W, Saganek L, Bousley R F, Juneau P L, Uprichard A C, Gallagher K P
Cardiovascular Therapeutics Section, Parke-Davis Pharmaceutical Research Division, Warner Lambert Company, Ann Arbor, Michigan 48105, USA.
J Thromb Thrombolysis. 2001 Feb;11(1):19-31. doi: 10.1023/a:1008900109285.
LB-30057 (CI-1028) is a novel, orally bioavailable, direct thrombin inhibitor with a Ki of 0.38 nM against human thrombin. The effects of LB-30057 on thrombus formation and hemostasis were evaluated in a veno-venous shunt model of thrombosis in rabbits, and compared with inogatran, another direct inhibitor of thrombin. Each compound was studied at 5 or 6 different doses with 5 or 6 rabbits in each group. After administration as a bolus i.v. injection followed by continuous infusion, both LB-30057 and inogatran dose-dependently inhibited thrombus formation, which was measured as an increase in time to occlusion (TTO) and a decrease in thrombus weight. Both compounds also improved vena caval blood flow and reduced the overall incidence of thrombotic occlusion. LB-30057 significantly prolonged TTO from 23 +/- 4 min (before dose) to 110 +/- 10 min at the highest dose (0.7 mg/kg + 47 microg/kg/min) (p < 0.001), and reduced thrombus weight from 57 +/- 2 mg to 15 +/- 5 mg (p < 0.001). Occlusive thrombus formed in only one of six rabbits that received the highest dose of LB-30057 (vs. 13/13 in the control group, p < 0.01). At the dose that produced the maximum antithrombotic effect (0.7 mg/kg + 47 microg/kg/min), LB-30057 increased aPTT and bleeding time approximately 2-and 2.5-fold above baseline, respectively. On a gravimetric basis, LB-30057 and inogatran displayed comparable in vivo antithrombotic efficacy. When compared to equally effective anti thrombotic doses of inogatran, LB-30057 caused less prolongation in aPTT, had no effect on PT, and tended to have less of effect on bleeding time. These results indicate that LB-30057 is an effective antithrombotic compound and it appears to have a better benefit/risk profile than inogatran in this experimental model.
LB - 30057（CI - 1028）是一种新型的、口服生物可利用的直接凝血酶抑制剂，对人凝血酶的Ki值为0.38 nM。在兔静脉 - 静脉分流血栓形成模型中评估了LB - 30057对血栓形成和止血的影响，并与另一种直接凝血酶抑制剂依诺加群进行了比较。每组用5或6只兔子，对每种化合物在5或6个不同剂量下进行研究。静脉推注给药后持续输注，LB - 30057和依诺加群均剂量依赖性地抑制血栓形成，通过闭塞时间（TTO）延长和血栓重量减轻来衡量。两种化合物还改善了腔静脉血流并降低了血栓闭塞的总体发生率。LB - 30057在最高剂量（0.7 mg/kg + 47 μg/kg/min）时，显著将TTO从23±4分钟（给药前）延长至110±10分钟（p < 0.001），并将血栓重量从57±2 mg降至15±5 mg（p < 0.001）。接受最高剂量LB - 30057的6只兔子中仅1只形成了闭塞性血栓（对照组为13/13，p < 0.01）。在产生最大抗血栓作用的剂量（0.7 mg/kg + 47 μg/kg/min）下，LB - 30057使活化部分凝血活酶时间（aPTT）和出血时间分别比基线增加约2倍和2.5倍。以重量法计算，LB - 30057和依诺加群在体内显示出相当的抗血栓疗效。与依诺加群同等有效的抗血栓剂量相比，LB - 30057引起的aPTT延长较少，对凝血酶原时间（PT）无影响，并且对出血时间的影响似乎较小。这些结果表明，LB - 30057是一种有效的抗血栓化合物，在该实验模型中，其效益/风险比似乎优于依诺加群。
