Prediction of the therapeutic index of marketed anti-coagulants and anti-platelet agents by guinea pig models of thrombosis and hemostasis.
BACKGROUND
Animal models of thrombosis and hemostasis are critical for target validation in pharmaceutical research. Guinea pig haemostatic mechanisms, such as the platelet thrombin receptor repertoire, resemble those of humans. Measuring the performance characteristics of marketed antithrombotic drugs in guinea pig models is a key to predicting therapeutic indices of new agents. The goal of the current study was to benchmark representative marketed drugs in thrombosis and hemostasis models in guinea pigs.


METHODS
Effects of the cyclooxygenase inhibitor, aspirin, the P2Y(12) antagonist, clopidogrel, the glycoprotein IIb/IIIa inhibitor, tirofiban, and the direct thrombin inhibitors, argatroban and hirudin, were evaluated in this study. Antithrombotic agents were tested in FeCl(3)-induced carotid artery thrombosis and arterio-venous shunt thrombosis models. Haemostatic effects of drugs were evaluated in cuticle and renal bleeding models. Ex vivo measurements of platelet function and coagulation inhibition were performed to benchmark preclinical doses of each agent to those used clinically.


RESULTS
The overall rank-order of potency in thrombosis models based on per cent of vessels occluded, average carotid blood flow, and thrombus weight was aspirin=argatroban=tirofiban<hirudin=clopidogrel. In bleeding models, the rank order was: aspirin<clopidogrel=argatroban=tirofiban<hirudin.


CONCLUSIONS
This characterization of representative drugs from two important classes of anti-coagulant and anti-platelet agents in efficacy and bleeding models in guinea pigs provides a reference point for evaluation of new antithrombotic agents.
Bird
J Eileen
JE
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. eileen.bird@bms.com
Giancarli
Mary R
MR
Allegretto
Nick
N
Barbera
Frank
F
Wong
Pancras
P
Schumacher
William A
WA
Ogletree
Martin L
ML
Seiffert
Dietmar
D
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects; D001241:Aspirin / Q000627:therapeutic use; D001760:Bleeding Time; D002712:Chlorides; D005290:Ferric Compounds / Q000494:pharmacology; D006168:Guinea Pigs; D006487:Hemostasis / Q000187:drug effects*; D008297:Male; D010875:Pipecolic Acids / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D013449:Sulfonamides; D013927:Thrombosis / Q000188:drug therapy*; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000627:therapeutic use
D000925:Anticoagulants; D002712:Chlorides; D005290:Ferric Compounds; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D014443:Tyrosine; D001120:Arginine; D000077466:Tirofiban; C031942:argatroban; D001241:Aspirin; C024555:ferric chloride