Giardino Edward C, Haertlein Barbara J, de Garavilla Lawrence, Costanzo Michael J, Damiano Bruce P, Andrade-Gordon Patricia, Maryanoff Bruce E
Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Roads, Spring House, PA 19477, USA.
Blood Coagul Fibrinolysis. 2010 Mar;21(2):128-34. doi: 10.1097/MBC.0b013e3283358100.
Whereas heparin functions as an antithrombotic agent by promoting antithrombin III-based inhibition of thrombin and factor Xa, there is less appreciation for the combination behavior with small-molecule, direct inhibitors of these proteases. We conducted a study in a high-shear arterial environment to explore the potential for a cooperative antithrombotic effect with a thrombin inhibitor (argatroban), a factor Xa inhibitor (YM-60828), and a dual thrombin/factor Xa inhibitor (RWJ-445167). We employed a platelet-dependent vascular injury model in which rats were subjected to an acute electrical injury to the carotid artery. Antithrombotic efficacy was measured for thrombin inhibitor argatroban and factor Xa inhibitor YM-60828 administered alone or in combination. The results indicate that there is a cooperative antithrombotic effect in vivo when both thrombin and factor Xa are inhibited simultaneously. The dual thrombin/factor Xa inhibitor RWJ-445167 was found to have potent antithrombotic activity in this high-shear environment. A comparison of results for RWJ-445167 and argatroban showed additional efficacy with RWJ-445167, suggestive of drug synergy.
肝素通过促进基于抗凝血酶III的凝血酶和因子Xa抑制作用而发挥抗血栓形成剂的功能，而对于其与这些蛋白酶的小分子直接抑制剂的联合作用了解较少。我们在高剪切动脉环境中进行了一项研究，以探索与凝血酶抑制剂（阿加曲班）、因子Xa抑制剂（YM-60828）和双重凝血酶/因子Xa抑制剂（RWJ-445167）产生协同抗血栓形成作用的可能性。我们采用了一种血小板依赖性血管损伤模型，对大鼠的颈动脉进行急性电损伤。测量了单独或联合给药的凝血酶抑制剂阿加曲班和因子Xa抑制剂YM-60828的抗血栓形成功效。结果表明，当凝血酶和因子Xa同时受到抑制时，体内存在协同抗血栓形成作用。发现双重凝血酶/因子Xa抑制剂RWJ-445167在这种高剪切环境中具有强大的抗血栓形成活性。RWJ-445167和阿加曲班的结果比较显示，RWJ-445167具有额外的功效，提示药物协同作用。
