Fibrinolytic mechanism, biochemistry, and preclinical pharmacology of recombinant prourokinase.
The purpose of this review is to provide a biochemical characterization of recombinant prourokinase (r-ProUK [ABT-187]), including a description of its clot-specific fibrinolytic mechanism. In addition, the preclinical data will be briefly reviewed, demonstrating the efficacy of r-ProUK as a potent therapeutic plasminogen activator. r-ProUK was purified to homogeneity from the culture medium of SP2/0 mouse hybridoma cells. The fibrinolytic potency of r-ProUK was characterized by both in vitro clot lysis experiments in human plasma and a canine femoral artery thrombosis model. In the in vitro clot lysis system, with use of clots prepared from fresh frozen human plasma, r-ProUK exhibits a lag phase to the onset of lysis and a concentration-dependent threshold effect due to the presence of the inhibitors alpha 2-antiplasmin and plasminogen activator inhibitor ( PAI-1). Effective clot lysis can be achieved without degradation of the fibrinogen in the surrounding plasma. Over a dose range of 50,000-220,000 IU, the canine femoral artery thrombosis model shows a dose-dependent relationship for r-ProUK and effective clot lysis. The lytic activity of r-ProUK is significantly enhanced in this model by the concomitant administration of heparin as an adjunctive agent for thrombolytic treatment. Fibrinogen, plasminogen, and alpha 2-antiplasmin levels in the systemic circulation were unaltered during the 30-minute infusion period and a 4-hour observation period, in which 85% lysis was achieved with r-ProUK (100,000 IU) and heparin. Moreover, restoration of blood flow in the previously fully occluded femoral artery was achieved within minutes of the start of the r-ProUK infusion. The experimental findings presented here are consistent with the clot-specific fibrinolytic mechanism of r-ProUK. Effective clot lysis can be achieved without alteration of the systemic coagulation and fibrinolytic parameters.[1]References
- Fibrinolytic mechanism, biochemistry, and preclinical pharmacology of recombinant prourokinase. Credo, R.B., Burke, S.E. Journal of vascular and interventional radiology : JVIR. (1995) [Pubmed]
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