Predicting the pharmacology of thrombin inhibitors.
Thrombotic disorders can lead to uncontrolled thrombin generation and clot formation within the circulatory system leading to vascular thrombosis. Direct inhibitors of thrombin have been developed and tested in clinical trials for the treatment of a variety of these thrombotic disorders. The bleeding complications observed during these trials have raised questions about their clinical use. The development of a computer-based model of coagulation using the kinetic rates of individual reactions and concentrations of the constituents involved in each reaction within blood has made it possible to study coagulation pathologies in silico. We present an extension of our initial model of coagulation to include several specific thrombin inhibitors. Using this model we have studied the effect of a variety of inhibitors on thrombin generation and compared these results with the clinically observed data. The data suggest that numerical models will be useful in predicting the effectiveness of inhibitors of coagulation.
Adams
T E
TE
Department of Biochemistry, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA. tadams@zoo.uvm.edu
Everse
S J
SJ
Mann
K G
KG
D000925:Anticoagulants / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D001384:Azetidines; D001596:Benzylamines; D001777:Blood Coagulation / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006629:Hirudins / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008955:Models, Cardiovascular; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D006629:Hirudins; D009842:Oligopeptides; D010446:Peptide Fragments; D010875:Pipecolic Acids; D011994:Recombinant Proteins; D013449:Sulfonamides; C109573:melagatran; D001120:Arginine; D013917:Thrombin; C031942:argatroban; D005998:Glycine; C074619:bivalirudin; C064289:efegatran