Smalling R W
Division of Cardiology, University of Texas Medical School at Houston 77030, USA.
Am J Cardiol. 1996 Dec 19;78(12A):2-7. doi: 10.1016/s0002-9149(96)00736-9.
The initial work on thrombolytic therapy for acute myocardial infarction (AMI) focused on intracoronary administration of streptokinase. Continuing research has given rise to the development of both second- and third-generation agents and consequent refinements in thrombolytic regimens. Intravenous recombinant tissue plasminogen activator (t-PA, or alteplase) proved superior to both intracoronary and intravenous streptokinase with regard to reperfusion efficacy and impact on survival. An accelerated dosage regimen was later devised to allow the administration of t-PA over a shorter period of time. Unfortunately, t-PA failed to lessen the risk of bleeding complications that had plagued the use of streptokinase. The wild-type t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less bleeding risk. Among these third-generation agents is reteplase (r-PA); compared with alteplase, reteplase has a prolonged half-life and seems to offer more rapid thrombolysis. Promising results have been obtained in large, randomized trials of reteplase. Another new agent is the TNK mutant of t-PA, which also has a prolonged half-life and seems to produce more rapid and complete thrombolysis, as well as less risk of intracranial bleeding than with alteplase in animal models. Although large, randomized trials have not yet been conducted, encouraging results have emerged from preliminary dose-ranging trials with TNK. A third new agent, n-PA, has an even longer half-life and has shown improved lytic activity in animal models. A dose-ranging trial of n-PA is currently under way. Despite the fact that each of the third-generation drugs has shown considerable potential with regard to improving the efficacy of thrombolytic therapy, the risk of intracranial bleeding remains problematic and will need to be assessed in large, randomized trials.
急性心肌梗死（AMI）溶栓治疗的初期工作集中在冠状动脉内注射链激酶。持续的研究推动了第二代和第三代药物的开发以及溶栓方案的相应改进。静脉注射重组组织型纤溶酶原激活剂（t-PA，即阿替普酶）在再灌注疗效和对生存率的影响方面被证明优于冠状动脉内注射和静脉注射链激酶。后来设计了加速给药方案，以便在更短的时间内给予t-PA。不幸的是，t-PA未能降低困扰链激酶使用的出血并发症风险。此后，野生型t-PA分子已被改造，试图在降低出血风险的同时实现更好的溶解特性。这些第三代药物中有瑞替普酶（r-PA）；与阿替普酶相比，瑞替普酶半衰期延长，似乎能实现更快的溶栓效果。在瑞替普酶的大型随机试验中已取得了有前景的结果。另一种新药是t-PA的TNK突变体，其半衰期也延长，在动物模型中似乎能产生更快、更完全的溶栓效果，且颅内出血风险低于阿替普酶。虽然尚未进行大型随机试验，但TNK的初步剂量范围试验已出现令人鼓舞的结果。第三种新药n-PA半衰期更长，在动物模型中显示出改善的溶解活性。目前正在进行n-PA剂量范围试验。尽管每种第三代药物在提高溶栓治疗疗效方面都显示出相当大的潜力，但颅内出血风险仍然存在问题，需要在大型随机试验中进行评估。
