COMPARISON OF DOSE REGIMENS FOR THE ADMINISTRATION OF RECOMBINANT PROUROKINASE IN A CANINE THROMBOSIS MODEL

Pro-urokinase represents an important addition to the array of thrombo lytic drugs currently available for clinical use because of its high c lot specificity but distinctly different mechanism compared with that of t-PA. Recombinant pro-urokinase (r-proUK) is a single-chain precurs or of high molecular weight urokinase which has been expressed in a mo use myeloma cell line. The present study was conducted to determine th e dosing regimen which would produce optimal clot lysis and restoratio n of blood flow 2 h after treatment with r-proUK, using a dog model of arterial thrombosis. Efficacy was indicated by lysis of a radiolabell ed clot which was formed in the heat-damaged femoral arteries of 39 ma le beagle dogs. The animals were divided into six heparinized treatmen t groups, each receiving one of five dosing regimens or the vehicle fo r r-proUK. The total dose (80,000 U/kg) was divided into an initial lo ading bolus, followed by either a second bolus or by infusions for var ious time periods, as shown below:[GRAPHICS] It was concluded that opt imal clot lysis and restoration of femoral flow was accomplished using a regimen in which 50% of the dose was given as a bolus, followed imm ediately by the remaining 50% given as a 30 min intravenous infusion ( Group 5). At the dose used in this study, r-proUK did not produce degr adation of fibrinolytic or hemostatic plas ma proteins.