Comparison of dose regimens for the administration of recombinant pro-urokinase in a canine thrombosis model.

Abstract

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.

• Authors: S E Burke, N L Lubbers, R A Nelson, J Henkin
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 77 Issue 5 Pg. 1025-30 (May 1997) ISSN: 0340-6245 [Print] Germany
• PMID: 9184422 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Biomarkers
• Fibrinolytic Agents
• Recombinant Proteins
• alpha-Macroglobulins
• plasmin-alpha(2)-macroglobulin complex
• Fibrinogen
• Plasminogen
• Tissue Plasminogen Activator
• Fibrinolysin
• Urokinase-Type Plasminogen Activator
• saruplase

Topics

• Animals
• Biomarkers (blood)
• Cell Line
• Dogs
• Drug Administration Schedule
• Femoral Artery
• Fibrinogen (analysis)
• Fibrinolysin (analysis)
• Fibrinolysis
• Fibrinolytic Agents (administration & dosage, therapeutic use)
• Hemostasis
• Hot Temperature
• Infusions, Intravenous
• Injections, Intravenous
• Male
• Mice
• Plasmacytoma
• Plasminogen (analysis)
• Recombinant Proteins (administration & dosage, therapeutic use)
• Thrombosis (drug therapy)
• Tissue Plasminogen Activator (therapeutic use)
• Urokinase-Type Plasminogen Activator (administration & dosage, therapeutic use)
• alpha-Macroglobulins (analysis)