Coronary thrombolytic properties of a novel recombinant plasminogen activator (BM 06.022) in a canine model.

Abstract

We studied the thrombolytic dose-response relationship of a recombinant plasminogen activator (rPA) (BM 06.022) compared with alteplase in a canine model of coronary artery thrombosis. BM 06.022 consists of the kringle 2 and protease domains of human tissue PA (tPA) and lacks oligosaccharide side chains because of its expression in Escherichia coli. Thrombus formation in anesthetized, open-chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery in the presence of a critical stenosis. Intravenous bolus injection of BM 06.022 (50, 100, 140, and 200 kU/kg) or of alteplase (200, 800, 1,130, and 1,600 kU/kg) 30 min after coronary occlusion to six heparinized dogs per group achieved a dose-dependent increase in reperfusion rate and decrease in residual thrombus wet weight. Vehicle-treated dogs did not reperfuse. Semilogarithmic regression analysis showed that the effective dose that produced 50% reperfusion of BM 06.022 (83 kU/kg) was 11.6-fold lower than that of alteplase (951 kU/kg). Comparison with infusion experiments showed that intravenous bolus injection of 140 kU/kg of BM 06.022 was equieffective to a 90-min infusion of 800 kU/kg (= 1 mg/kg) of alteplase as a standard treatment regarding reperfusion rate (66%) and time to reperfusion (15 +/- 6 vs. 18 +/- 8 min). Pharmacokinetic analysis for functionally active BM 06.022 or alteplase in plasma revealed a total plasma clearance of 4.1-6.6 ml/min/kg for BM 06.022 and of 12.6-42.3 ml/min/kg for alteplase.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: U Martin, S Fischer, U Kohnert, R Rudolph, G Sponer, A Stern, K Strein
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 18 Issue 1 Pg. 111-9 (Jul 1991) ISSN: 0160-2446 [Print] United States
• PMID: 1719279 (Publication Type: Journal Article)

Chemical References

• Fibrinolytic Agents
• Recombinant Proteins
• alpha-2-Antiplasmin
• Fibrinogen
• Plasminogen
• reteplase
• Plasminogen Activators
• Tissue Plasminogen Activator

Topics

• Anesthesia
• Animals
• Bleeding Time
• Coronary Circulation (drug effects)
• Dogs
• Dose-Response Relationship, Drug
• Escherichia coli (genetics, metabolism)
• Female
• Fibrinogen (metabolism)
• Fibrinolytic Agents
• Hemostasis (drug effects)
• Male
• Plasminogen (metabolism)
• Plasminogen Activators (genetics, pharmacokinetics, pharmacology)
• Recombinant Proteins (pharmacology)
• Regression Analysis
• Tissue Plasminogen Activator (pharmacology)
• alpha-2-Antiplasmin (metabolism)