DEVELOPMENT OF NEW FIBRINOLYTIC AGENTS

Early treatment with thrombolytic drugs has been shown to reduce morta lity in patients with acute myocardial infarction. Thrombolytic therap y with early, complete and sustained patency of the infarct related ar tery is associated with a low inhospital mortality of 3 to 4% (Figure 1). Even with the most effective thrombolytic regimens this aim at pre sent is achieved in only about 50% of the patients. The optimal thromb olytic drug should be effective (rapid, complete and sustained recanal ization of the infarct related artery), safe (low incidence of severe bleedings), easy to administer (e.g. bolus application) and cost effec tive. Attempts to improve thrombolytic treatment include the search fo r better fibrinolytic agents and more effective adjunctive therapies. In the field of adjunctive therapy new more specific thrombininhibitor s appear promising and are currently under investigation. In dose-find ing studies recombinant hirudin reduced reocclusions and reinfarctions after t-PA thrombolysis. There are several approaches for the improve ment of plasminogen activation (Table 1). While new improved dose regi mens (e.g. ''front-loaded'' t-PA) and combination therapies are not su bject of this article, it will deal with the recombinant production of naturally occuring plasminogen activators and the development of ''de signer drugs'', which were created in the laboratory by altering the n atural occurring molecules t-PA and scu-PA. t-PA contains four domains with different functional properties (Figure 3). Of a variety of muta nts and variants of t-PA with altered fibrin-affinity, half-life or fi brin 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 t o 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 wi th regard to early patency (Table 3). Chimeric plasminogen activators (Figure 4) consisting of parts of the t-PA and the single-chain urokin ase-type plasminogen activator (scu-PA) did not significantly improve at the same time fibrin specificity and thrombolytic potency of the na tural occuring molecules. Complexes of plasminogen activators and mono clonal antibodies against platelets or fibrin improve the specificity and thrombolytic activity of the plasminogen activators (Figure 5). Ho wever, these molecules are potentially antigenic, costly and not in cl inical use vet. Recombinant production of naturally occuring plasminog en activators seems at least as promising as the production of the abo ve mentioned socalled designer drugs. Plasminogen activators of the sa livary of the vampire bat Desmodus rotundus (DSPA) have a long half-li fe and a high fibrin specificity preserved in vivo (Figure 6). In anim al models DSPA, given as bolus injection, seems superior to t-PA with regard to recanalisation and reocclusion rates (Table 4). Clinical use might be limited by the potential antigenicity of these drugs. Staphy lokinase is more fibrin specific than streptokinase (Figure 7), but in duces as well as streptokinase the production of antibodies and seems to be as antigenic as streptokinase. First clinical applications in sm all numbers of patients showed good recanalisation rates. For the clin ical development of new thrombolytic agents phase II and III studies a re needed. In the phase II (dose finding), to avoid treatment with ine ffective dosages in too many patients, dose-escalation studies with a sequential design (GRECO) seem preferable to the standard parallel des ign trials. To test the efficacy and safety of new drugs against appro ved standard regimens large mortality trials with several thousands of patients are still neccessary (phase III). The ''optimal'' thrombolys is will finally be achieved not by a fibrinolytic drug with a high ear ly recanalisation rate alone but by combining fibrinolytic therapy wit h effective conjunctive therapy with thrombin- and/or platelet-functio n inhibitors.