[Development of new thrombolytic substances]

Early treatment with thrombolytic drugs has been shown to reduce mortality in patients with acute myocardial infarction. Thrombolytic therapy with early, complete and sustained patency of the infarct related artery is associated with a low inhospital mortality of 3 to 4% (Figure 1). Even with the most effective thrombolytic regimens this aim at present is achieved in only about 50% of the patients. The optimal thrombolytic drug should be effective (rapid, complete and sustained recanalization of the infarct related artery), safe (low incidence of severe bleedings), easy to administer (e.g. bolus application) and cost effective. Attempts to improve thrombolytic treatment include the search for better fibrinolytic agents and more effective adjunctive therapies. In the field of adjunctive therapy new more specific thrombininhibitors appear promising and are currently under investigation. In dose-finding studies recombinant hirudin reduced reocclusions and reinfarctions after t-PA thrombolysis. There are several approaches for the improvement of plasminogen activation (Table 1). While new improved dose regimens (e.g. "front-loaded" t-PA) and combination therapies are not subject of this article, it will deal with the recombinant production of naturally occurring plasminogen activators and the development of "designer drugs", which were created in the laboratory by altering the natural occurring molecules t-PA and scu-PA. t-PA contains four domains with different functional properties (Figure 3). Of a variety of mutants and variants of t-PA with altered fibrin-affinity half-life or fibrin specificity one recombinant plasminogen activator (r-PA) is under clinical investigation. r-PA, a deletion mutant of t-PA consisting of the kringle-2 and protease domains, in a dose escalation study (GRECO) showed high early patency rates (Table 2), while there was a trend to a higher incidence of very early reocclusions. In a randomised trial (RAPID), comparing three different r-PA regimens with standard t-PA (100 mg/3 h) a double bolus of 10 MU+ 10 MU r-PA was most effective with regard to early patency (Table 3). Chimeric plasminogen activators (Figure 4) consisting of parts of t-PA and the single-chain urokinase-type plasminogen activator (scu-PA) did not significantly improve at the same time fibrin specificity and thrombolytic potency of the natural occurring molecules. Complexes of plasminogen activators and monoclonal antibodies against platelets or fibrin improve the specificity and thrombolytic activity of the plasminogen activators (Figure 5). However, these molecules are potentially antigenic, costly and not in clinical use yet. Recombinant production of naturally occurring plasminogen activators seems at least as promising as the production of the above mentioned socalled designer drugs.(ABSTRACT TRUNCATED AT 400 WORDS)