Synergistic combinations of recombinant human tissue-type plasmingen activator and human single-chain urokinase-type plasminogen activator. Effect on thrombolysis and reocclusion in a canine coronary artery thrombosis model with high-grade stenosis

A. A. Ziskind, H. K. Gold, T. Yasuda, M. Kanke, J. L. Guerrero, J. T. Fallon, T. Saito, D. Collen

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Abstract

The synergistic effects of recombinant human tissue-type plasminogen activator (rt-PA) and single-chain urokinase-type plasminogen activator (scu-PA) on coronary arterial thrombolysis were investigated in open-chest dogs with thrombosis of the left anterior descending coronary artery and a superimposed high-grade stenosis. A 90% stenosis was generated by external constriction, reducing blood flow to 40 ± 10% of baseline. Localized thrombosis was produced by endothelial cell injury and instillation of thrombin and fresh blood. Intravenous infusion for 60 minutes of either 30 μg/kg/min rt-PA alone or 10 μg/kg/min scu-PA alone consistently produced coronary artery recanalization (six of eight dogs and five of five dogs, respectively) but was almost always associated with reocclusion during or shortly after the end of the infusion (four of six dogs and five of five dogs, respectively). Infusion of either 15 μg/kg/min rt-PA or 5 μg/kg/min scu-PA for 60 minutes did not cause coronary artery recanalization (none of four dogs in each group). Combined infusion of 7.5 μg/kg/min rt-PA and 2.5 μg/kg/min scu-PA for 60 minutes (one fourth of the minimum thrombolytic dose of each agent) induced coronary artery recanalization (six of six dogs) but was also associated with early reocclusion (six of six dogs). Combined infusion of 3.75 μg/kg/min rt-PA and 1.25 μg/kg/min scu-PA for 60 minutes did not consistently cause recanalization (one of four dogs). Combined infusion of 15 μg/kg/min rt-PA and 5 μg/kg/min scu-PA for 60 minutes caused recanalization in all of six dogs but was associated with reocclusion in all six. Pathologic examination revealed that reocclusion was caused by platelet-rich thrombotic material. Bolus injection of 0.6 mg/kg of a monoclonal antibody (7E3) directed against the platelet GPIIb/IIIa receptor 10 minutes before the start of a combined infusion of 7.5 μg/kg/min rt-PA and 2.5 μg/kg/min scu-PA for 60 minutes abolished reocclusion. It is concluded that rt-PA and scu-PA used in equipotent fractional combinations act synergistically on coronary arterial thrombolysis in this dog model. As observed previously in a rabbit venous thrombosis model, synergism only occurs in a relatively narrow concentration range representing twofold to fourfold pharmacologic synergism. Furthermore, in the presence of high-grade stenosis, recanalization with the synergistic combination is consistently associated with reocclusion that can be prevented with the use of a potent monoclonal antiplatelet GPIIb/IIIA antibody. The combination therapy thus may allow a reduction of the total thrombolytic dose but does not eliminate th eproblem of reocclusion.

Original languageEnglish
Pages (from-to)393-399
Number of pages7
JournalCirculation
Volume79
Issue number2
DOIs
StatePublished - 1989
Externally publishedYes

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