Coronary thrombolysis with facilitated absorption of intramuscularly injected tissue-type plasminogen activator

Conventional activators of the fibrinolytic system used for coronary thrombolysis entail unavoidable delay, risk of bleeding, or both in contrast to tissue-type plasminogen activator (t-PA). Because the potential benefit of coronary thrombolysis is inversely related to the duration of antecedent ischemia, this study was performed to develop an approach for facilitated absorption of intramuscularly injected t-PA potentially adaptable for prompt, self-medication. In rabbits, absorption was markedly potentiated by hydroxylamine hydrochloride and electrical stimulation at the injection site. Intramuscular administration of t-PA in doses of 1 mg/kg of body weight, comparable to amounts given intravenously to patients (0.5-0.75 mg/kg), elicited peak blood levels of 431 +/- 52 (SEM) ng/ml 5 min after injection, well within the therapeutic range. In dogs, absorption facilitated by hydroxylamine promptly elicited angiographically documented coronary thrombolysis as well. The approach developed should ultimately permit prompt coronary thrombolysis and enhanced salvage of jeopardized ischemic myocardium in patients with life-threatening coronary thrombi.