title: In vitro effects and in vivo efficacy of a novel cyclooxygenase-2 inhibitor in dogs with experimentally induced synovitis.
abstract: OBJECTIVE
  To determine cyclooxygenase-2 (COX-2) selectivity, pharmacokinetic properties, and in vivo efficacy of ML-1,785,713 in dogs.
  
  
  METHODS
  21 healthy male and female mixed-breed dogs and 24 healthy male Beagles.
  
  
  METHODS
  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
  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.
authors.affiliation: Departments of Animal Health Research, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065, USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCann
authors.forename: Donald R
authors.initials: DR
authors.lastname: Andersen
authors.forename: Donghui
authors.initials: D
authors.lastname: Zhang
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Peter D
authors.initials: PD
authors.lastname: Hanson
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Hickey
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002227:Carbazoles; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D013449:Sulfonamides; D013450:Sulfones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013585:Synovitis / Q000188:drug therapy / Q000662:veterinary*; D000096926:Benzenesulfonamides
chemical_list: D015107:4-Butyrolactone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D016861:Cyclooxygenase Inhibitors; D013449:Sulfonamides; D013450:Sulfones; C007005:carprofen; C471996:deracoxib; D000096926:Benzenesulfonamides; C487384:firocoxib