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.
Sample Population—Blood samples from 30 healthy
horses, 48 healthy dogs, and 9 healthy cats.
Procedure—Activities of COX-1 and COX-2 were
determined by measuring coagulation-induced thromboxane
B2 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,
methylsulfonylphenyl]-thiophene (DuP 697), 5,5-
phenyl-2(5H)-furan one (DFU), 3-(3,4-difluorophenyl)-
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 77.5, 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 and Clinical Relevance—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. (Am J Vet Res
Objective—To determine cyclooxygenase-2 (COX-2)
selectivity, pharmacokinetic properties, and in vivo
efficacy of ML-1,785,713 in dogs.
Animals—21 healthy male and female mixed-breed
dogs and 24 healthy male Beagles.
Procedure—Selectivity of ML-1,785,713 for inhibiting
COX-2 was determined by comparing the potency for
inhibiting cyclooxygenase-1 (COX-1) with that of COX-2 in canine blood. Pharmacokinetic properties were
determined after IV (2 mg/kg) and oral (8 mg/kg)
administration in female mixed-breed dogs. In vivo
efficacy was evaluated in male mixed-breed dogs
with urate crystal-induced synovitis. Prophylactic efficacy
was evaluated by administering ML-1,785,713
two hours before induction of synovitis whereas therapeutic
efficacy was determined by administering
ML-1,785,713 one hour after induction of synovitis.
Results—Blood concentrations that resulted in 50%
inhibition of COX-1 and COX-2 activity in vitro were
119.1µM and 0.31µM, respectively, and selectivity
ratio for inhibiting COX-2 relative to COX-1 was 384.
ML-1,785,713 had high oral bioavailability (101%), low
systemic clearance (7.7 mL/min/kg), and an elimination
half-life of 5.9 hours. ML-1,785,713 was efficacious
when administered prophylactically and therapeutically
to dogs with urate crystal-induced synovitis.
Conclusions and Clinical Relevance—ML-1,785,713
is a novel, potent COX-2 inhibitor that is the most
selective COX-2 inhibitor described for use in dogs to
date. ML-1,785,713 has oral bioavailability and low
systemic clearance that is comparable to other nonsteroidal
anti-inflammatory drugs. It is effective after
prophylactic and therapeutic administration in attenuating
lameness in dogs with urate crystal-induced
synovitis. Drugs that specifically inhibit COX-2 and not
COX-1 at therapeutic doses may have an improved
tolerability profile, compared with nonselective nonsteroidal
anti-inflammatory drugs. (Am J Vet Res
Objective—To determine cyclooxygenase (COX)-2
selectivity, pharmacokinetic properties, and in vivo
efficacy of firocoxib (ML-1,785,713) in cats.
Animals—5 healthy male and 14 healthy female
domestic shorthair cats.
Procedure—Selectivity of firocoxib for inhibiting COX-2 was determined by comparing the potency for
inhibiting COX-1 with that of COX-2 in feline blood.
Pharmacokinetic properties were determined after IV
(2 mg/kg) and oral (3 mg/kg) administration in male
cats. In vivo efficacy was evaluated in female cats with
lipopolysaccharide (LPS)-induced pyrexia with administration
of firocoxib 1 or 14 hours before LPS challenge.
Results—Blood concentrations resulting in 50% inhibition
of COX-1 and COX-2 activity in vitro were 7.5 ±
2µM and 0.13 ± 0.03µM, respectively, and selectivity
for inhibiting COX-2 relative to COX-1 was 58.
Firocoxib had moderate to high oral bioavailability
(54% to 70%), low plasma clearance (4.7 to
5.8 mL/min/kg), and an elimination half-life of 8.7 to
12.2 hours. Firocoxib at doses from 0.75 to 3 mg/kg
was efficacious in attenuating fever when administered
to cats 1 or 14 hours before LPS challenge.
Conclusions and Clinical Relevance—Firocoxib is a
potent COX-2 inhibitor and is the only selective COX-2
inhibitor described for use in cats to date. It is effective
in attenuating febrile responses in cats when administered
14 hours before LPS challenge, suggesting it
would be suitable for once-a-day dosing. Because
selective COX-2 inhibitors have an improved therapeutic
index relative to nonselective nonsteroidal antiinflammatory
drugs in humans, firocoxib has the
potential to be a safe, effective anti-inflammatory
agent for cats. (Am J Vet Res 2005;66:1278–1284)