Smalling R W
Division of Cardiology, University of Texas Medical School at Houston 77030, USA.
Eur Heart J. 1997 Dec;18 Suppl F:F11-6. doi: 10.1093/eurheartj/18.suppl_f.11.
Thrombolytic therapy has been recognized as a significant improvement in the management of acute myocardial infarction. Thrombolytic agents however have been limited by short half-lives that necessitate complex administration protocols and by the potential for bleeding complications. The native t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding. Reteplase is a third-generation recombinant mutant of tissue-type plasminogen activator (t-PA) that is expressed in Escherichia coli cells and consists of the kringle 2 and the protease domains of t-PA. Compared with t-PA, reteplase has a lower fibrin binding, which may translate to improved clot penetration. As well as a longer half-life and a more rapid initiation of thrombolysis. Preclinical pharmacology studies have indicated that reteplase has potent in vivo thrombolytic activity and leads to rapid reperfusion; these findings have been confirmed by promising results obtained in large-scale clinical trials. Other new agents developed by modifying the native t-PA molecule include the n-PA and the TNK mutants of t-PA. These novel, genetically modified thrombolytic agents all lyse clots better than the native t-PA; however, they differ with respect to their half-lives and fibrin-binding activity. Although all the third-generation thrombolytic agents have shown considerable potential in improving the efficacy of thrombolytic therapy, their risk of intracranial bleeding remains problematic and is still somewhat uncertain.
溶栓疗法已被公认为是急性心肌梗死治疗方面的一项重大进展。然而，溶栓药物存在局限性，其半衰期短，需要复杂的给药方案，且有出血并发症的风险。此后，天然组织型纤溶酶原激活剂（t-PA）分子已被改造，旨在实现更好的溶栓特性，同时降低出血风险。瑞替普酶是组织型纤溶酶原激活剂（t-PA）的第三代重组突变体，在大肠杆菌细胞中表达，由t-PA的kringle 2和蛋白酶结构域组成。与t-PA相比，瑞替普酶与纤维蛋白的结合力较低，这可能意味着其对血栓的穿透性更好。此外，它还具有更长的半衰期和更快启动溶栓作用。临床前药理学研究表明，瑞替普酶具有强大的体内溶栓活性并能实现快速再灌注；大规模临床试验取得的良好结果证实了这些发现。通过改造天然t-PA分子开发的其他新药包括n-PA和t-PA的TNK突变体。这些新型的、经过基因改造的溶栓药物在溶解血栓方面均优于天然t-PA；然而，它们在半衰期和纤维蛋白结合活性方面存在差异。尽管所有第三代溶栓药物在提高溶栓治疗疗效方面都显示出了相当大的潜力，但它们的颅内出血风险仍然存在问题，且仍有些不确定。
