PROUROKINASE TREATMENT OF MYOCARDIAL-INFA RCTION

The development of new thrombolytic agents is concentrating on substan ces which are more effective and more fibrin specific than streptokina se. Prourokinase is a single chain urokinase-type plasminogen activato r (scu-PA). The recombinant unglycosylated prourokinase (saruplase) is synthesized in transformed E. coli bacteria. The dominant half life i s 9 minutes. With the standard dosage regimen about 28% of saruplase i s converted into two chain urokinase-type plasminogen activator (tcu-P A), which is rapidly inactivated by plasma inhibitors whereas saruplas e is not. Saruplase is fibrin-specific since it predominantly activate s plasminogen bound to fibrin. Even without measurable conversion to t cu-PA, saruplase appears able to activate fibrin. The fibrin specific action is dose dependent and correlates inversely with the rate of sar uplase converted to tcu-PA. Dose finding studies have shown that a 20 mg bolus followed by 60 mg given intravenously over 60 minutes is an e ffective thrombolytic regimen. In the PASS-study 1,698 patients were t reated with saruplase. The results of the PASS-study (Table 1) confirm ed the efficacy and safety of the 20/60 mg dosage. This standard dosag e has been compared with streptokinase, urokinase and alteplase in ran domized multicenter-studies. The systemic fibrinolytic activity is les s in comparison to streptokinase but higher than the systemic fibrinol ytic activity of alteplase. In the PRIMI-study the early patency (60 m inutes) was significantly higher with saruplase in comparison to strep tokinase (Figure 1). Patency after 90 minutes and 24 to 36 hours did n ot differ significantly between both substances. Bleeding complication s were less frequent with saruplase. Urokinase was compared with sarup lase in the SUTA-MI-study. The patency rates (TIMI-flow 2 and 3) at 24 to 72 hours were similiar in both groups (saruplase 75.4%, urokinase 74.2%). Hospital mortality was higher in the urokinase group (8.1% vs 4.3%), but this difference was not significant. The efficacy and safet y of saruplase (80 mg, 1 hour) was compared with alteplase (100 mg, 3 hours) in the SESAM-study. There was a non significant trend towards e arlier patency with saruplase at 45 min (Figure 2). Complication rates and hospital mortality were similiar in both groups. The importance o f heparin comedication was investigated in the LIMITS-study. With a he parin bolus before starting XO mg saruplase the patency at 6 to 12 hou rs was significantly higher than without heparin bolus (78.6% vs 56.5% ). Heparin had no effect on the bleeding rates. Comedication with the prostacyclin-analogon taprostene was compared with placebo in the STAR T-study. Prostacyclin analogs inhibit platelet aggretation and neutrop hil leucocytes. However, taprostene failed to improve the patency rate s achievable with saruplase alone (Table 2). Safety and efficacy data of saruplase in myocardial infarction are available for a total number of 2,570 patients. Hemorrhagic stroke occured in 0.6%, overall hospit al mortality was 5.3% (Table 4). Early patency rate at 90 minutes in 4 34 patients was 75%. Thus, saruplase can be regarded as a safe thrombo lytic agent with an efficacy comparable to alteplase. Comedication wit h heparin improves the efficacy of saruplase. The combination therapy with glycosylated and unglycosylated prourokinase and alteplase has be en investigated with conflicting results (Table 3). A number of prouro kinase-antibody-conjugates and chimeric molecules has been investigate d in vitro and in vivo. Some of them improve the lyric potency of prou rokinase significantly. The clinical importance of these molecule Vari ations is still unknown.