Smalling R W
University of Texas Medical School, Houston, USA.
Am J Health Syst Pharm. 1997 Nov 15;54 Suppl 1:S17-22. doi: 10.1093/ajhp/54.suppl_1.S17.
The molecular pharmacology of plasminogen activators and its implications for thrombolytic therapy are discussed. The benefits of coronary thrombolysis were first demonstrated with intracoronary and i.v. streptokinase. Tissue plasminogen activator (t-PA) or recombinant t-PA (alteplase) proved to be superior to streptokinase with respect to speed of reperfusion and reperfusion efficacy. Since alteplase neither lessened the risk of bleeding found with streptokinase nor generated Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow rates above about 50%, the quest for faster-acting, safer, and more effective thrombolytic agents has continued. The ideal agent would be highly efficient at converting plasminogen to plasmin, have an intermediate half-life, have a low affinity for fibrin, and be of reasonable cost. Genetic engineering of the wild-type t-PA molecule resulted in reteplase, which has a longer half-life than alteplase and may be superior in terms of lytic activity, myocardial salvage, and survival. Also under investigation are TNK-t-PA and n-PA, which have longer half-lives and, in animal models, seem to produce more rapid and complete thrombolysis, at less risk of intracranial bleeding, than alteplase. The risk of intracranial bleeding remains a problem with all thrombolytics; the risk versus the benefit will have to be assessed in large randomized trials. An understanding of the functions of various regions of the t-PA molecule has led to genetic engineering of new and promising plasminogen activators.
本文讨论了纤溶酶原激活剂的分子药理学及其对溶栓治疗的意义。冠状动脉溶栓的益处首先通过冠状动脉内和静脉注射链激酶得到证实。组织纤溶酶原激活剂（t-PA）或重组t-PA（阿替普酶）在再灌注速度和再灌注疗效方面被证明优于链激酶。由于阿替普酶既没有降低链激酶所具有的出血风险，也没有使心肌梗死溶栓（TIMI）3级血流率超过约50%，因此对作用更快、更安全和更有效的溶栓剂的探索仍在继续。理想的药物应能高效地将纤溶酶原转化为纤溶酶，具有中等半衰期，对纤维蛋白亲和力低，且成本合理。野生型t-PA分子的基因工程产生了瑞替普酶，其半衰期比阿替普酶长，在溶栓活性、心肌挽救和生存率方面可能更具优势。正在研究的还有替奈普酶和n-PA，它们的半衰期更长，在动物模型中，与阿替普酶相比，似乎能产生更快、更完全的溶栓效果，且颅内出血风险更低。颅内出血风险仍然是所有溶栓剂面临的问题；风险与益处必须在大型随机试验中进行评估。对t-PA分子各个区域功能的了解已导致新型且有前景的纤溶酶原激活剂的基因工程。
