Biemond Bart J, Perzborn Elisabeth, Friederich Philip W, Levi Marcel, Buetehorn Ulf, Büller Harry R
Department of Haematology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Thromb Haemost. 2007 Mar;97(3):471-7.
Current anticoagulant therapies for the prevention and treatment of thromboembolic disorders have many drawbacks: vitamin K antagonists interact with food and drugs and require frequent laboratory monitoring, and heparins require parenteral administration. Oral rivaroxaban (BAY 597939) is a new, highly selective and potent direct factor-Xa (FXa) inhibitor with a predictable pharmacodynamic and pharmacokinetic profile and could therefore be an attractive antithrombotic drug. It was the objective of this study to investigate the antithrombotic efficacy of oral rivaroxaban in two rabbit models of experimental venous thrombosis. In the venous stasis (prevention) model, animals were randomized to receive oral rivaroxaban 0.3, 1.0, 3.0 or 10.0 mg/kg or vehicle control. Thrombosis was induced by jugular vein stasis and injection of thromboplastin into the ear vein. In the venous thrombosis (treatment) model, intravenous (1.0 and 3.0 mg/kg) and oral (3.0 mg/kg) rivaroxaban was compared with intravenous nadroparin (40 U bolus and 20 U/h), fondaparinux (42 microg/kg) and vehicle control. Thrombus growth was assessed by measuring the accretion of radiolabelled fibrinogen into preformed clots in the jugular veins. Bleeding was assessed using an ear bleeding model. In the prevention model, rivaroxaban reduced thrombus formation dose-dependently (calculated ED(50) 1.3 mg/kg). In the treatment model, oral rivaroxaban (3.0 mg/kg) reduced thrombus growth to a similar extent to intravenous rivaroxaban (1.0 mg/kg), nadroparin and fondaparinux. Oral rivaroxaban did not prolong bleeding time. In conclusion, the orally available selective, direct FXa inhibitor rivaroxaban is effective in the prevention and treatment of venous thrombosis in two well-established models of experimental thrombosis.
维生素K拮抗剂会与食物和药物相互作用，且需要频繁进行实验室监测，而肝素需要肠胃外给药。口服利伐沙班（BAY 597939）是一种新型、高选择性且强效的直接Xa因子（FXa）抑制剂，其药效学和药代动力学特征具有可预测性，因此可能是一种有吸引力的抗血栓药物。本研究的目的是在两种实验性静脉血栓形成的兔模型中研究口服利伐沙班的抗血栓疗效。在静脉淤滞（预防）模型中，将动物随机分为接受口服利伐沙班0.3、1.0、3.0或10.0 mg/kg或赋形剂对照。通过颈静脉淤滞并向耳静脉注射凝血活酶诱导血栓形成。在静脉血栓形成（治疗）模型中，将静脉注射（1.0和3.0 mg/kg）和口服（3.0 mg/kg）利伐沙班与静脉注射那屈肝素（40 U推注和20 U/h）、磺达肝癸钠（42 μg/kg）和赋形剂对照进行比较。通过测量放射性标记的纤维蛋白原在颈静脉中预先形成的凝块中的积聚来评估血栓生长。使用耳出血模型评估出血情况。在预防模型中，利伐沙班剂量依赖性地减少血栓形成（计算得出的ED50为1.3 mg/kg）。在治疗模型中，口服利伐沙班（3.0 mg/kg）将血栓生长减少到与静脉注射利伐沙班（1.0 mg/kg）、那屈肝素和磺达肝癸钠相似的程度。口服利伐沙班未延长出血时间。总之，口服可用的选择性直接FXa抑制剂利伐沙班在两种成熟的实验性血栓形成模型中对静脉血栓形成的预防和治疗有效。
