Thrombolytic Effect of Human Tissue-type Plasminogen Activator (t-PA, MMR 701) on a Canine Coronary Thrombosis Model

The effect of recombinant human single-chain tissue-type plasminogen activator (MMR701) on the patency rate of infarct-related coronary arteries was investigated in anesthetized dogs with coronary thrombi induced by inserting a copper coil into the left anterior descending coronary artery (LAD).The efficacy of MMR701 in six regimens was evaluated by continuous intravenous infusion over 60 minutes alone (Regimen A-C), and then in combination with various initial intravenous bolus injections (Regimen D-F). In the former experiments, patency was respectively observed in 60%, 100%, and 100% of 5 dogs infused for 60 minutes with 150IU/kg/min (Regimen A), 500IU/kg/min (Regimen B), and 1500IU/kg/min (Regimen C) of MMR701. Both the time needed for achieving patency and the weight of undissolved thrombi in the vessels decreased dose-dependently. In the latter experiments, four dosage regimens (Regimen A and Regimen D-F) with different bolus/infusion ratios were compared using equal amounts (9000IU/kg) of MMR701, in order to evaluate the optimal therapeutic regimen of MMR701. Among regimens with an initial bolus injection of 0% (Regimen A), 10% (Regimen D), 50% (Regimen E), or 90% (Regimen F) of the total amount used and subsequent continuous infusion of the remaining amount over 60 minutes, the regimen with an initial 10% bolus (Regimen D) was the most effective, achieving the highest rate of patency (100%), shortest time needed for achieving patency, and highest thrombolytic activity. Plasma levels of fibrinolytic and hemostatic parameters, such as α2-plasmin inhibitor, plasminogen, and fibrinogen, were not decreased significantly in all regimens.It is concluded that MMR701 produces a thrombolytic effect with no remarkable disorders of the fibrinolytic and hemostatic systems in the canine myocardial infarction model. It is also suggested that the regimen with a 10% bolus injection may have a great advantage in the treatment of acute myocardial infarction.