The inhibitory effect of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, compared with enoxaparin and r-hirudin on ex vivo thrombin generation in human plasma

被引:15
作者
Boström, SL
Hansson, GFH
Sarich, TC
Wolzt, M
机构
[1] AstraZeneca R&D, Mol Pharmacol, S-43183 Molndal, Sweden
[2] AstraZeneca LP, Wilmington, DE USA
[3] Univ Vienna, Allgemeines Krankenhaus Wien, Vienna, Austria
关键词
ximetagatran; metagatran; direct thrombin inhibitor; enoxaparin; hirudin; thrombin generation;
D O I
10.1016/j.thromres.2004.02.009
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Introduction: The effect of the oral direct thrombin inhibitor (DTI) ximelagatran (Exanta(TM), AstraZeneca) on the endogenous thrombin potential (ETP) of activated plasma was investigated ex vivo using a thrombin generation assay and compared with recombinant (r)-hirudin and enoxaparin. Materials and methods: 120 healthy mate volunteers were randomized to one of six treatment groups (n = 20 in each): oral ximetagatran (15, 30, or 60 mg), intravenous r-hirudin (0.4 mg/kg bolus, 0.15 mg/kg/h infusion for 2 h, followed by 0.075 mg/kg/h infusion for 2 h), subcutaneous enoxaparin (100 IU/kg), or control (tap water administered orally). Venous blood was collected predose and at 2, 4, and 10 h postdosing. Thrombin generation was triggered by the addition of tissue factor to ptatetet-poor plasma, and the ETP and time to peak thrombin generation were measured. Results and conclusions: A significant and dose-dependent reduction in ETP was observed 2 and 4 h after the administration of ximetagatran 30 mg (70.3% of predose, 95% confidence intervals 63.0-78.5, P< 0.0001 at 2 h) and 60 mg (49.8%, 43.2-57.4, P< 0.0001 at 2 h), r-hirudin (19.5%, 10.1 -37.6, P< 0.0001 at 2 h), and enoxaparin (34.2%, 21.4-54.7, P<0.0001 at 2 h). Ximelagatran (30 mg, 3.79 min, 3.52-4.08 at 2 h), r-hirudin (6.23 min, 4.93-7.86 at 2 h), and enoxaparin (4.68 min, 3.30-6.64 at 2 h) also delayed the tag phase before the thrombin generation burst compared to placebo (2.92 min, 2.71 -3.25 at 2 h). The oral DTI ximelagatran, in its active form melagatran, is a potent thrombin inhibitor that efficiently decreases ETP and delays the generation of thrombin in plasma in this ex vivo model. (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码:85 / 91
页数:7
相关论文
共 28 条
[1]  
Albers GW, 2003, LANCET, V362, P1691
[2]  
Béguin S, 1999, HAEMOSTASIS, V29, P170
[3]   Inhibition of thrombin-induced feedback activation of factor V:: a potential pathway for inhibition of thrombin generation by melagatran [J].
Boström, SL ;
Dagnelid, E ;
Hansson, GFH ;
Ulvinge, JC .
BLOOD COAGULATION & FIBRINOLYSIS, 2004, 15 (01) :25-30
[4]   Effects of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and dalteparin on the endogenous thrombin potential in venous blood from healthy male subjects [J].
Boström, SL ;
Hansson, GFH ;
Kjaer, M ;
Sarich, TC .
BLOOD COAGULATION & FIBRINOLYSIS, 2003, 14 (05) :457-462
[5]   USE OF SITE-DIRECTED MUTAGENESIS TO INVESTIGATE THE BASIS FOR THE SPECIFICITY OF HIRUDIN [J].
BRAUN, PJ ;
DENNIS, S ;
HOFSTEENGE, J ;
STONE, SR .
BIOCHEMISTRY, 1988, 27 (17) :6517-6522
[6]   EFFECTS OF RECOMBINANT HIRUDIN (R-HIRUDIN, HBW-023) ON COAGULATION AND PLATELET ACTIVATION IN-VIVO - COMPARISON WITH UNFRACTIONATED HEPARIN AND A LOW-MOLECULAR-WEIGHT HEPARIN PREPARATION (FRAGMIN) [J].
EICHINGER, S ;
WOLZT, M ;
SCHNEIDER, B ;
NIESZPAURLOS, M ;
HEINRICHS, H ;
LECHNER, K ;
EICHLER, HG ;
KYRLE, PA .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1995, 15 (07) :886-892
[7]   The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement:: the EXPRESS study [J].
Eriksson, BI ;
Agnelli, G ;
Cohen, AT ;
Dahl, OE ;
Lassen, MR ;
Mouret, P ;
Rosencher, N ;
Kälebo, P ;
Panfilov, S ;
Eskilson, C ;
Andersson, M .
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2003, 1 (12) :2490-2496
[8]   A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis:: THRIVE I [J].
Eriksson, H ;
Wählander, K ;
Gustafsson, D ;
Welin, LT ;
Frison, L ;
Schulman, S .
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2003, 1 (01) :41-47
[9]   Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement [J].
Francis, CW ;
Berkowitz, SD ;
Comp, PC ;
Lieberman, JR ;
Ginsberg, JS ;
Paiement, G ;
Peters, GR ;
Roth, AW ;
McElhattan, J ;
Colwell, CW .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (18) :1703-1712
[10]   Recombinant hirudin in clinical practice - Focus on lepirudin [J].
Greinacher, A ;
Lubenow, N .
CIRCULATION, 2001, 103 (10) :1479-1484