Abstract | OBJECTIVE: 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 i.v. (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 119.1 microM and 0.31 microM, 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 (77 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 non-steroidal 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 non-steroidal anti-inflammatory drugs.
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Authors | Margaret E McCann, Donald R Andersen, Donghui Zhang, Christine Brideau, W Cameron Black, Peter D Hanson, Gerard J Hickey |
Journal | American journal of veterinary research
(Am J Vet Res)
Vol. 65
Issue 4
Pg. 503-12
(Apr 2004)
ISSN: 0002-9645 [Print] United States |
PMID | 15077695
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Carbazoles
- Cyclooxygenase Inhibitors
- Sulfonamides
- Sulfones
- carprofen
- 4-Butyrolactone
- deracoxib
- firocoxib
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Topics |
- 4-Butyrolactone
(analogs & derivatives, pharmacokinetics, therapeutic use)
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(pharmacokinetics, therapeutic use)
- Carbazoles
- Cyclooxygenase Inhibitors
(pharmacokinetics, therapeutic use)
- Dog Diseases
(drug therapy)
- Dogs
- Dose-Response Relationship, Drug
- Sulfonamides
- Sulfones
(pharmacokinetics, therapeutic use)
- Synovitis
(drug therapy, veterinary)
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