Coronary thrombolytic properties of a novel recombinant plasminogen activator (BM 06.022) in a canine model.
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)
Martin
U
U
Department of Pharmacology, Boehringer Mannheim GmbH, Germany.
Fischer
S
S
Kohnert
U
U
Rudolph
R
R
Sponer
G
G
Stern
A
A
Strein
K
K
D000758:Anesthesia; D000818:Animals; D001760:Bleeding Time; D003326:Coronary Circulation / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents; D006487:Hemostasis / Q000187:drug effects; D008297:Male; D010958:Plasminogen / Q000378:metabolism; D010960:Plasminogen Activators / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012044:Regression Analysis; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D000979:alpha-2-Antiplasmin / Q000378:metabolism
D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D000979:alpha-2-Antiplasmin; D005340:Fibrinogen; D010958:Plasminogen; C087896:reteplase; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator