Document Detail

Comparison of thrombin active site and exosite inhibitors and heparin in experimental models of arterial and venous thrombosis and bleeding.
MedLine Citation:
PMID:  8263785     Owner:  NLM     Status:  MEDLINE    
Different pharmacological approaches to thrombin inhibition were compared for their effects on thrombosis and bleeding time in anesthetized rats. Thrombosis was induced in the carotid artery by transmural vessel injury and in the vena cava by partial blood flow stasis combined with mild endothelial disruption. Small mesenteric arteries were punctured with a hypodermic needle to measure the bleeding time. Dose-response relationships were determined with a thrombin active site inhibitor, N-methyl (GYKI 14,766); a thrombin exosite inhibitor, succinyl-Phe-Glu-Pro-Ile-Pro-Glu-Glu-Tyr-cyclohexylalanine-Gln (BMS 180,742); and heparin. BMS 180,742 interferes with fibrinogen binding to the thrombin exosite but, unlike GYKI 14,766, it does not block thrombin's catalytic site. The effects on thrombosis and bleeding time were correlated with ex vivo clotting times using the activated partial thromboplastin time for heparin and the thrombin time for GYKI 14,766 and BMS 180,742. Venous thrombosis was inhibited more than 90% by all three inhibitors at doses that either produced threshold increases or had no effect on bleeding and clotting times. Arterial thrombosis was inhibited 82% by GYKI 14,766 and 63% by heparin but it was not inhibited by BMS 180,742. These antithrombotic activities were accompanied by a maximal activated partial thromboplastin time increase and doubling of the bleeding time with heparin and a maximal thrombin time prolongation and 35% increase in bleeding time with GYKI 14,766. These results suggest that thrombin inhibitors, which act at the active site or exosite or through antithrombin III, are equally efficacious against venous thrombosis but active site inhibitors are the most effective against arterial thrombosis.
W A Schumacher; T E Steinbacher; C L Heran; S M Seiler; I M Michel; M L Ogletree
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  267     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1993 Dec 
Date Detail:
Created Date:  1994-01-27     Completed Date:  1994-01-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1237-42     Citation Subset:  IM    
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
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MeSH Terms
Amino Acid Sequence
Anticoagulants / therapeutic use*
Binding Sites
Bleeding Time
Carotid Artery Thrombosis / prevention & control*
Disease Models, Animal
Dose-Response Relationship, Drug
Heparin / therapeutic use*
Mesenteric Arteries / drug effects,  physiology
Molecular Sequence Data
Oligopeptides / therapeutic use*
Peptides / therapeutic use*
Platelet Aggregation Inhibitors / therapeutic use*
Rats, Sprague-Dawley
Thrombin / antagonists & inhibitors*
Thrombophlebitis / prevention & control*
Reg. No./Substance:
0/Anticoagulants; 0/Oligopeptides; 0/Peptides; 0/Platelet Aggregation Inhibitors; 105806-65-3/efegatran; 138828-04-3/BMS 180742; 9005-49-6/Heparin; EC

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