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Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t ‐ TUCB in horses with experimentally induced radiocarpal synovitis
Author(s) -
Guedes A. G. P.,
Aristizabal F.,
Sole A.,
Adedeji A.,
Brosnan R.,
Knych H.,
Yang J.,
Hwang S.H.,
Morisseau C.,
Hammock B. D.
Publication year - 2018
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/jvp.12463
Subject(s) - crossover study , nociception , anesthesia , lameness , synovitis , pharmacokinetics , epoxide hydrolase 2 , medicine , allodynia , analgesic , pharmacology , chemistry , synovial fluid , osteoarthritis , hyperalgesia , placebo , arthritis , surgery , biochemistry , pathology , enzyme , receptor , alternative medicine
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.