ABSTRACT
The most important characteristics to be improved for an ideal thrombolytic drug are simple and
rapid administration, fibrin specificity, and an improved safety profile compared with tissue
plasminogen activator (t-PA). We have developed a novel modified t-PA, monteplase (Cleactor)
that was constructed by replacing a single amino acid, cysteine 84 with serine, in the epidermal
growth factor domain. Monteplase has a decreased clearance and slightly less fibrin specificity
than t-PA, allowing bolus intravenous administration and providing potent efficacy for throm-
bolysis without causing bleeding complications in in vitro and in vivo models. In canine
coronary thrombolysis models, early complete reperfusion with a bolus intravenous injection of
monteplase protected left ventricular function, 4 h or 1 week after treatment. Dose-finding,
efficacy, and safety studies revealed that, due to its prolonged half-life, a single-bolus
intravenous injection of monteplase resulted in a higher rate of early recanalization of infarct-
related arteries than that of native t-PA in patients with acute myocardial infarction. There was no
evidence for a higher incidence in bleeding complications in monteplase-treated patients than
with native t-PA-treated patients. Thus, on the basis of preclinical and clinical investigations,
monteplase is a safe and efficacious novel thrombolytic agent.
