Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t-TUCB in horses with experimentally induced radiocarpal synovitis

A. G.P. Guedes, F. Aristizabal, A. Sole, A. Adedeji, Robert J Brosnan, Heather K Knych, J. Yang, S. H. Hwang, C. Morisseau, B. D. Hammock

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Abstract

This study determined the pharmacokinetics, antinociceptive, and anti-inflammatory effects of the soluble epoxide hydrolase (sEH) inhibitor t-TUCB (trans-4-(4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy)-benzoic acid) in horses with lipopolysaccharide (LPS)-induced radiocarpal synovitis. A total of seven adult healthy mares (n = 4-6/treatment) were administered 3 μg LPS into one radiocarpal joint and t-TUCB intravenously (i.v.) at 0 (control), 0.03, 0.1, 0.3, and 1 mg/kg in a blinded, randomized, crossover design with at least 3 weeks washout between. Two investigators independently assigned pain scores (at rest, walk and trot) and lameness scores before and up to 48 hr after t-TUCB/LPS. Responses to touching the joint skin to assess tactile allodynia, plasma, and synovial fluid (SF) t-TUCB concentrations were determined before and up to 48 hr after t-TUCB/LPS. Blood and SF were collected for clinical laboratory evaluations before and up to 48 hr after t-TUCB/LPS. Areas under the curves of pain and lameness scores were calculated and compared between control and treatments. Data were analyzed using repeated measures ANOVA with Dunnett or Bonferroni post-test. p < .05 was considered significant. Data are mean ± SEM. Compared to control, pain, lameness, and tactile allodynia were significantly lower with 1 mg/kg t-TUCB, but not the other doses. For 0.1, 0.3, and 1 mg/kg t-TUCB treatments, plasma terminal half-lives were 13 ± 3, 13 ± 0.5, and 24 ± 5 hr, and clearances were 68 ± 15, 48 ± 5, and 14 ± 1 ml hr-1 kg-1. The 1 mg/kg t-TUCB reached the SF at high concentrations. There were no important anti-inflammatory effects. In conclusion, sEH inhibition with t-TUCB may provide analgesia in horses with inflammatory joint pain. 2017 John Wiley & Sons Ltd.

Original languageEnglish (US)
JournalJournal of Veterinary Pharmacology and Therapeutics
DOIs
StateAccepted/In press - 2017

Fingerprint

epoxide hydrolase
synovitis
Epoxide Hydrolases
Synovitis
analgesic effect
benzoic acid
pharmacokinetics
Horses
Pharmacokinetics
horses
lipopolysaccharides
Lipopolysaccharides
synovial fluid
pain
Synovial Fluid
lameness
Hyperalgesia
anti-inflammatory activity
Pain
Anti-Inflammatory Agents

Keywords

  • Arthritis
  • Fatty acid
  • Lameness
  • Musculoskeletal
  • Pain

ASJC Scopus subject areas

  • Pharmacology
  • veterinary(all)

Cite this

Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t-TUCB in horses with experimentally induced radiocarpal synovitis. / Guedes, A. G.P.; Aristizabal, F.; Sole, A.; Adedeji, A.; Brosnan, Robert J; Knych, Heather K; Yang, J.; Hwang, S. H.; Morisseau, C.; Hammock, B. D.

In: Journal of Veterinary Pharmacology and Therapeutics, 2017.

Research output: Contribution to journalArticle

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AU - Guedes, A. G.P.

AU - Aristizabal, F.

AU - Sole, A.

AU - Adedeji, A.

AU - Brosnan, Robert J

AU - Knych, Heather K

AU - Yang, J.

AU - Hwang, S. H.

AU - Morisseau, C.

AU - Hammock, B. D.

PY - 2017

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KW - Fatty acid

KW - Lameness

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