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In vitro effects and in vivo efficacy of a novel cyclooxygenase-2 inhibitor in dogs with experimentally induced synovitis

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  • 1 Department of Animal Health Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.
  • | 2 Present address is Department of Pharmacology, Merck Research Laboratories, 126 E Lincoln Ave, R80Y-245, Rahway, NJ 07065.
  • | 3 Department of Animal Health Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.
  • | 4 Department of Biometrics Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.
  • | 5 Department of Biochemistry & Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, QC, Canada, H9R4P8.
  • | 6 Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Kirkland, QC, Canada, H9R4P8.
  • | 7 Merial, 3239 Satellite Blvd, Duluth, GA, 30096.
  • | 8 Department of Animal Health Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065.

Abstract

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 2004;65:503–512)

Abstract

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 2004;65:503–512)