Hursting M J, Alford K L, Becker J C, Brooks R L, Joffrion J L, Knappenberger G D, Kogan P W, Kogan T P, McKinney A A, Schwarz R P
Texas Biotechnology Corporation, Houston 77030, USA.
Semin Thromb Hemost. 1997;23(6):503-16. doi: 10.1055/s-2007-996128.
Because of the unsatisfactory options available for safe and effective antithrombotic therapy, recent, intense research and development efforts have focused on direct, or site-directed, thrombin inhibitors. Argatroban is a small-molecule, reversible, direct thrombin inhibitor selective for the catalytic site of the thrombin molecule. Argatroban's molecular properties (small molecule; fast, selective, and reversible inhibition of the thrombin catalytic site; and similar in vitro potency for inhibiting both clot-bound and soluble thrombin) offer the potential for significant antithrombotic efficacy with minimal systemic anticoagulant effects. Its clinical pharmacologic properties offer the potential for minimal risk of bleeding, very rapid achievement of therapeutic antithrombotic efficacy, predictable dose response, and rapid restoration of the hemostatic systems to baseline on termination of intravenous infusion. The intravenous agent Novastan (brand of argatroban) is currently approved for clinical use in Japan for the treatment of peripheral arterial occlusive disease. Novastan is in advanced clinical development in North and South America for several indications, including (1) anticoagulant/antithrombotic therapy in heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia, and thrombosis syndrome (HITTS); and (2) adjunctive therapy to thrombolytic agents in acute myocardial infarction. Results from these trials are projected to be available by early 1997.
由于目前可供选择的安全有效的抗血栓治疗方法并不理想，近期大量的研究和开发工作都集中在直接（或位点特异性）凝血酶抑制剂上。阿加曲班是一种小分子、可逆的直接凝血酶抑制剂，对凝血酶分子的催化位点具有选择性。阿加曲班的分子特性（小分子；对凝血酶催化位点的快速、选择性和可逆抑制；对结合于凝块的凝血酶和可溶性凝血酶具有相似的体外抑制效力）使其具有显著的抗血栓疗效，同时全身抗凝作用最小。其临床药理学特性使其具有出血风险最小、能非常迅速地达到治疗性抗血栓疗效、剂量反应可预测以及在静脉输注终止后止血系统能迅速恢复到基线水平的潜力。静脉制剂诺瓦斯坦（阿加曲班的商品名）目前在日本已被批准用于治疗外周动脉闭塞性疾病。诺瓦斯坦在北美洲和南美洲正处于针对多种适应症的临床后期开发阶段，包括：（1）用于肝素诱导血小板减少症（HIT）和肝素诱导血小板减少症及血栓形成综合征（HITTS）的抗凝/抗血栓治疗；（2）在急性心肌梗死中作为溶栓药物的辅助治疗。这些试验的结果预计在1997年初可得。
