Antithrombotic effects and bleeding time prolongation with synthetic platelet GPIIb/IIIa inhibitors in animal models of platelet-mediated thrombosis.

Abstract

Cyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-alpha-aspartyl- cyclic (1-->5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-propyl-L-arginyl-glycyl-L-alpha- aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1-->9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor. The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 micrograms/kg, ex vivo ADP-induced platelet aggregation with ID50 of 10 micrograms/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 +/- 9 to 1,100 +/- 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 micrograms/kg, ex vivo platelet aggregation with an ID50 of 50 micrograms/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 micrograms/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induced ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 +/- 0.4 to 12 +/- 2 min.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: D Collen, H R Lu, J M Stassen, I Vreys, T Yasuda, S Bunting, H K Gold
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 71 Issue 1 Pg. 95-102 (Jan 1994) ISSN: 0340-6245 [Print] Germany
• PMID: 8165652 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibrinolytic Agents
• Oligopeptides
• Peptides, Cyclic
• Platelet Membrane Glycoproteins
• Sulfoxides
• G 4120
• arginyl-glycyl-aspartic acid
• TP 9201

Topics

• Amino Acid Sequence
• Animals
• Bleeding Time
• Blood Platelets (physiology)
• Blood Vessel Prosthesis
• Carotid Arteries
• Cricetinae
• Dogs
• Female
• Femoral Artery (surgery)
• Fibrinolytic Agents (pharmacology)
• Graft Occlusion, Vascular
• Humans
• Male
• Molecular Sequence Data
• Myocardial Ischemia (drug therapy)
• Oligopeptides (pharmacology)
• Partial Thromboplastin Time
• Peptides, Cyclic (pharmacology)
• Platelet Membrane Glycoproteins (antagonists & inhibitors)
• Regional Blood Flow
• Species Specificity
• Sulfoxides (pharmacology)
• Thrombosis (etiology, prevention & control)