[Pro-urokinase for infarct therapy].
The development of new thrombolytic agents is concentrating on substances which are more effective and more fibrin specific than streptokinase. Prourokinase is a single chain urokinase-type plasminogen activator (scu-PA). The recombinant unglycosylated prourokinase (saruplase) is synthesized in transformed E coli bacteria. The dominant half life is 9 minutes. With the standard dosage regimen about 28% of saruplase is converted into two chain urokinase-type plasminogen activator (tcu-PA), which is rapidly inactivated by plasma inhibitors whereas saruplase is not. Saruplase is fibrin-specific since it predominantly activates plasminogen bound to fibrin. Even without measurable conversion to tcu-PA, saruplase appears able to activate fibrin. The fibrin specific action is dose dependent and correlates inversely with the rate of saruplase 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 effective thrombolytic regimen. In the PASS-study 1,698 patients were treated with saruplase. The results of the PASS-study (Table 1) confirmed the efficacy and safety of the 20/60 mg dosage. This standard dosage has been compared with streptokinase, urokinase and alteplase in randomized multicenter-studies. The systemic fibrinolytic activity is less in comparison to streptokinase but higher than the systemic fibrinolytic activity of alteplase. In the PRIM1-study the early patency (60: minutes) was significantly higher with saruplase in comparison to streptokinase (Figure 1). Patency after 90 minutes and 24 to 36 hours did not differ significantly between both substances. Bleeding complications were less frequent with saruplase. Urokinase was compared with saruplase in the SUTA-MI-study. The patency rates (TIMI-flow 2 and 3) at 24 to 72 hours were similar in both groups (saruplase 75.4%, urokinase 74.2%). Hospital mortality was higher in the urokinase group (8.1% vs 4.4%), but this difference was not significant. The efficacy and safety 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 earlier patency with saruplase at 45 min (Figure 2). Complication rates and hospital mortality were similar in both groups. The importance of heparin comedication was investigated in the LIMITS-study.(ABSTRACT TRUNCATED AT 400 WORDS)
II. Medizinische Klinik und Poliklinik, Johannes-Gutenberg-Universität Mainz.
M
M
Spiecker
J
J
Meyer
D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D017052:Hospital Mortality; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects
D000925:Anticoagulants; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase
Prourokinase für die Infarkttherapie.