Comparison of the recombinant Escherichia coli-produced protease domain of tissue-type plasminogen activator with alteplase, reteplase and streptokinase in a canine model of coronary artery thrombolysis.
Recent in vitro studies have shown that although recombinant Escherichia coli-produced protease domain of tissue-type plasminogen activator (t-PA) has no appreciable fibrin binding and less plasminforming activity compared to the wild-type, it is nevertheless an effective fibrinolytic agent in a dynamic in vitro plasma clot lysis system. The purpose of the present study was to evaluate the pharmacological profile of the protease in a canine model of coronary artery thrombosis. The effects of a single i.v. bolus injection of 1 mg/kg protease were compared with those of alteplase, reteplase and streptokinase at clinically relevant doses and dosing regimens in eight dogs per group. The protease rapidly restored coronary blood flow at 12 +/- 1 min in all treated dogs with a significantly higher maximal coronary blood flow than in the reference groups, but was associated with short cycles of reocclusion in 4/8 animals. Overall, the coronary blood flow quality of the protease was not significantly different from that of the reference thrombolytics. Although fibrinogen was nearly completely degraded during protease treatment, the bleeding time was not significantly more prolonged than in reference groups. In conclusion, the protease domain is a rapidly acting, effective, bolus-injectable thrombolytic agent associated with a systemic lytic state and does not appear to cause significantly more bleeding than the reference thrombolytic agents.
Martin
U
U
Department of Pharmacology, Boehringer Mannheim GmbH, Penzberg, Germany. ulrich_martin@bmg.boehringer-mannheim.com
Kohnert
U
U
Stern
A
A
Popp
F
F
Fischer
S
S
D000818:Animals; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004285:Dogs; D010450:Endopeptidases / Q000008:administration & dosage / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D007275:Injections, Intravenous; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics; D010960:Plasminogen Activators / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D013300:Streptokinase / Q000008:administration & dosage*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000235:genetics
D010446:Peptide Fragments; D011994:Recombinant Proteins; C087896:reteplase; D010450:Endopeptidases; D013300:Streptokinase; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator