Comparison of dose regimens for the administration of recombinant pro-urokinase in a canine thrombosis model.
Pro-urokinase represents an important addition to the array of thrombolytic drugs currently available for clinical use because of its high clot specificity but distinctly different mechanism compared with that of t-PA. Recombinant pro-urokinase (r-proUK) is a single-chain precursor of high molecular weight urokinase which has been expressed in a mouse myeloma cell line. The present study was conducted to determine the dosing regimen which would produce optimal clot lysis and restoration of blood flow 2 h after treatment with r-proUK, using a dog model of arterial thrombosis. Efficacy was indicated by lysis of a radio-labelled clot which was formed in the heat-damaged femoral arteries of 39 male beagle dogs. The animals were divided into six heparinized treatment groups, each receiving one of five dosing regimens or the vehicle for r-proUK. The total dose (80,000 U/kg) was divided into an initial loading bolus, followed by either a second bolus or by infusions for various time periods, as shown below: Group Treatment Regimen % Lysis 1 r-proUK Bolus/bolus, 50%/50% at 0 and 15 min 52 +/- 7 2 r-proUK Bolus/bolus, 50%/50% at 0 and 30 min 62 +/- 7 3 r-proUK Bolus/infusion, 20%/80% infused to 30 min 41 +/- 8 4 r-proUK Bolus/infusion, 20%/80% infused to 60 min 66 +/- 5 5 r-proUK Bolus/infusion, 50%/50% infused to 30 min 73 +/- 4 6 Vehicle Bolus/infusion, 50%/50% infused to 30 min 12 +/- 6 It was concluded that optimal clot lysis and restoration of femoral flow was accomplished using a regimen in which 50% of the dose was given as a bolus, followed immediately 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 degradation of fibrinolytic or hemostatic plasma proteins.
Burke
S E
SE
Department of General Pharmacology, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Lubbers
N L
NL
Nelson
R A
RA
Henkin
J
J
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D004285:Dogs; D004334:Drug Administration Schedule; D005263:Femoral Artery; D005340:Fibrinogen / Q000032:analysis; D005341:Fibrinolysin / Q000032:analysis; D005342:Fibrinolysis; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006487:Hemostasis; D006358:Hot Temperature; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D010954:Plasmacytoma; D010958:Plasminogen / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*; D000511:alpha-Macroglobulins / Q000032:analysis
D015415:Biomarkers; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D000511:alpha-Macroglobulins; C024668:plasmin-alpha(2)-macroglobulin complex; D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase