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

AbstractOBJECTIVE:
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 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.
AuthorsMargaret E McCann, Donald R Andersen, Donghui Zhang, Christine Brideau, W Cameron Black, Peter D Hanson, Gerard J Hickey
JournalAmerican journal of veterinary research (Am J Vet Res) Vol. 65 Issue 4 Pg. 503-12 (Apr 2004) ISSN: 0002-9645 [Print] United States
PMID15077695 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Carbazoles
  • Cyclooxygenase Inhibitors
  • Sulfonamides
  • Sulfones
  • carprofen
  • 4-Butyrolactone
  • deracoxib
  • firocoxib
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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