MOLECULAR-BIOLOGY OF PLASMINOGEN ACTIVATORS - WHAT ARE THE CLINICAL IMPLICATIONS OF DRUG DESIGN

The initial work on thrombolytic therapy for acute myocardial infarcti on (AMI) focused on intracoronary administration of streptokinase. Con tinuing research has given rise to the development of both second- and third-generation agents and consequent refinements in thrombolytic re gimens, Intravenous recombinant tissue plasminogen activator (t-PA, or alteplase) proved superior to both intracoronary and intravenous stre ptokinase with regard to reperfusion efficacy and impact on survival, An accelerated dosage regimen was later devised to allow the administr ation of t-PA over a shorter period of time. Unfortunately, t-PA faile d to lessen the risk of bleeding complications that had plagued the us e of streptokinase. The wild-type t-PA molecule has since been modifie d in an attempt to achieve improved lytic characteristics with less bl eeding 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 obtaine d in large, randomized trials of reteplase. Another new agent is the T NK mutant of t-PA, which also has a prolonged half-life and seems to p roduce more rapid and complete thrombolysis, as well as less risk of i ntracranial bleeding than with alteplase in animal models. Although la rge, randomized trials have not yet been conducted, encouraging result s 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 l ytic activity in animal models. A dose-ranging trial of n-PA is curren tly under way, Despite the fact that each of the third-generation drug s has shown considerable potential with regard to improving the effica cy of thrombolytic therapy, the risk of intracranial bleeding remains problematic and will need to be assessed in large, randomized trials. (C) 1996 by Excerpta Medica, Inc.