Profile of recombinant pro-urokinase given by intraarterial versus intravenous routes of administration in a canine thrombosis model

Catheter-directed thrombolysis has gained increasing acceptance for the tre atment of patients who present with vascular occlusion; however, intravenou s injection may be preferable in selected patients. Recombinant prourokinas e (r-proUK) is a recently-developed fibrin-selective thrombolytic agent wit h specificity for clot-bound plasminogen. To compare the effects of r-proUK on clot lysis and restoration of blood flow when injected by either intraa rterial or intravenous routes of administration, we utilized a dog model of arterial thrombosis in which a radiolabelled clot is formed in the femoral artery. The r-proUK was given by intravenous infusion to one group of 18 a nimals in doses ranging from 10,000 IU/kg to 100,000 IU/kg; a second group of 27 dogs was treated with r-proUK administered by the intra-arterial rout e in a dose range from 300 IU to 10,000 IU. Clot lysis was measured by moni toring the loss of counts from the radiolabelled clot over time; blood flow was also monitored throughout the experimental period. Animals which recei ved intravenous treatment showed dose-related clot lysis ranging from 14% t o 70% at 2 h, while those which received intra-arterial infusions showed ly sis ranging from 22% to 79% over the same period. For similar degrees of cl ot lysis attained at the highest dose levels of 100,000 IU/kg and 10,000 IU , blood flow was restored to 77% and 35% of control levels in dogs which re ceived intravenous and intraarterial treatment, respectively. The hemostati c protein fibrinogen was not reduced in any of the treatment groups. The re sults indicate that 100 rimes more intravenous than intra-arterial r-proUK is required to produce similar clot lysis in this canine model, and that th e agent can be administered at this level without induction of a systemic l ytic state.