In vitro effects of cyclooxygenase inhibitors in whole blood of horses, dogs, and cats.
OBJECTIVE
To determine potency and selectivity of nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase- (COX-) specific inhibitors in whole blood from horses, dogs, and cats.


METHODS
Blood samples from 30 healthy horses, 48 healthy dogs, and 9 healthy cats.


METHODS
Activities of COX-1 and COX-2 were determined by measuring coagulation-induced thromboxane and lipopolysaccharide-induced prostaglandin E2 concentrations, respectively, in whole blood with and without the addition of various concentrations of phenylbutazone, flunixin meglumine, ketoprofen, diclofenac, indomethacin, meloxicam, carprofen, 5-bromo-2[4-fluorophenyl]-3-14-methylsulfonylphenyl]-thiophene (DuP 697), 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furan one (DFU), 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (MF-tricyclic), and celecoxib. Potency of each test compound was determined by calculating the concentration that resulted in inhibition of 50% of COX activity (IC50). Selectivity was determined by calculating the ratio of IC50 for COX-1 to IC50 for COX-2 (COX-1/COX-2 ratio).


RESULTS
The novel compound DFU was the most selective COX-2 inhibitor in equine, canine, and feline blood; COX-1/COX-2 ratios were 775, 74, and 69, respectively. Carprofen was the weakest inhibitor of COX-2, compared with the other COX-2 selective inhibitors, and did not inhibit COX-2 activity in equine blood. In contrast, NSAID such as phenylbutazone and flunixin meglumine were more potent inhibitors of COX-1 than COX-2 in canine and equine blood.


CONCLUSIONS
The novel COX-2 inhibitor DFU was more potent and selective in canine, equine, and feline blood, compared with phenylbutazone, flunixin meglumine, and carprofen. Compounds that specifically inhibit COX-2 may result in a lower incidence of adverse effects, compared with NSAID, when administered at therapeutic dosages to horses, dogs, and cats.
Brideau
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Department of Biochemistry, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.
Van Staden
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Chan
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D002415:Cats / Q000097:blood*; D003002:Clonixin / Q000031:analogs & derivatives / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000097:blood; D004285:Dogs / Q000097:blood*; D005260:Female; D005663:Furans / Q000494:pharmacology; D006736:Horses / Q000097:blood*; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000097:blood; D008297:Male; D010653:Phenylbutazone / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007527:Isoenzymes; D013929:Thromboxane B2; C014558:flunixin meglumine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C007005:carprofen; D010653:Phenylbutazone; D015232:Dinoprostone; D003002:Clonixin