[Research and development of novel modified tissue-type plasminogen activator (t-PA), pamiteplase]

Tissue-type plasminogen activator (t-PA) is a potent thrombolytic agent that, owing to its strict fibrin specificity, is superior to urokinase and streptekinase. However, due to its extremely short half life (approximately 5 min), it is necessary to administer this drug by high-dosage infusion, increasing the possibility of systemic bleeding. We therefore considered it clinically desirable to create a thrombolytic agent with a prolonged plasma half life that can be administered by bolus injection. To this end, we created several genetically modified t-PA analogues and screened them for thrombolytic activity and in vivo pharmacokinetics. Of these, Pamiteplase (YM866) showed an improved plasma clearance profile without a reduction in fibrinolytic potency and fibrin specificity. In clinical studies on acute myocardial infarction (AMI), patients were injected with bolus Pamiteplase intravenously at dosages of 0.05, 0.1, or 0.2 mg/kg-body weight. Angiographical examination of coronary artery showed that high incidence (70-76%) of reperfusion evaluated as TIMI grade II or III was achieved by the injection of 0.1 or 0.2 mg/kg of Pamiteplase. No anti-Pamiteplase antibodies have thus far been detected in the blood of patients. From these results, we conclude that it is of great clinical significance that Pamiteplase can be administered by single bolus injection to AMI patients.