Comparative study of a mutant tissue-type plasminogen activator, YM866, with a tissue-type plasminogen activator in a canine model of femoral arterial thrombosis.
Because tissue-type plasminogen activator (tPA), used to treat myocardial infarction, has several disadvantages thought to be connected with its low half-life, mutants of tPA have been prepared with longer half-lives. We have compared the thrombolytic effect of such a mutant, YM866, with that of tPA in copper-coil-induced femoral arterial thrombosis in dogs. One hour after thrombus formation, YM866 was administered by intravenous bolus injection, while tPA was given by the same method or by 60-min infusion under adequate heparinization. Both agents exhibited dose-dependent thrombolysis without systemic fibrinogenolysis. The recanalization rate and recanalization time of YM866 by bolus at 0.2 mg kg-1 were, however, equivalent to those of tPA by infusion at 0.4 mg kg-1 (total dose), whereas the recanalization rate of tPA by bolus was low (0.4 mg kg-1). No significant difference in reocclusion rate, reocclusion time, or patency status after successful thrombolysis was seen. These results suggest that YM866 administered at a lower dose by intravenous bolus injection exerted a thrombolytic effect equivalent to that of tPA by infusion, and that heparin could not prevent reocclusion after successful thrombolysis even under adequate anticoagulation.
Kawasaki
T
T
Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Kaku
S
S
Sakai
Y
Y
Takenaka
T
T
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D004285:Dogs; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D011994:Recombinant Proteins / Q000627:therapeutic use; D012039:Regional Blood Flow / Q000187:drug effects; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; C085027:pamiteplase