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Home / Equine Research Bank / J Vet Pharmacol Ther / Pharmacokinetics and antinociceptive effects of the soluble ...
Journal of veterinary pharmacology and therapeutics2017; 41(2); 230-238; doi: 10.1111/jvp.12463

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

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  kg . 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.
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Publication Date: 2017-10-25 PubMed ID: 29067696PubMed Central: PMC5920688DOI: 10.1111/jvp.12463Google Scholar: Lookup
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  • Journal Article
  • Randomized Controlled Trial

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research paper presents findings of a study which investigated the pain-relieving and inflammation-reducing effects of the soluble epoxide hydrolase (sEH) inhibitor t-TUCB in horses experimentally inflicted with joint inflammation. The therapeutic compound was found to be significant at a certain dosage level, with limited anti-inflammatory capabilities.

Research Overview

The research aimed to:

  • Understand the pharmacokinetics, antinociceptive (pain-killing), and anti-inflammatory effects of the sEH inhibitor t-TUCB in horses.
  • Explore the efficacy of the treatment on horses with Lipopolysaccharide (LPS)-induced radiocarpal synovitis, which is an induced form of joint inflammation.

Methodology

The process used in the research included:

  • Administering LPS to create joint inflammation in seven adult healthy mares.
  • Injecting t-TUCB intravenously at varying doses, with a control group receiving no t-TUCB.
  • Using a randomized crossover design, meaning each horse, after a minimum three weeks of washout period, received each treatment; this prevents the potential bias that could have arisen from a horse’s specific reaction to a specific drug dose.
  • Assessing pain levels, lameness, and hypersensitivity to touch (tactile allodynia) up to 48 hours post treatment.
  • Measuring t-TUCB concentrations in the plasma and synovial fluid (the fluid that lubricates joints) pre and post treatment.
  • Collecting blood and synovial fluid for clinical laboratory evaluations within the same 48-hour window.

Results

From the research, the team found:

  • The 1mg/kg dosage of t-TUCB significantly reduced pain, lameness, and tactile allodynia compared to the control group and the groups with lower dosages. This indicates that specific dosage was necessary for therapeutic effects.
  • Plasma terminal half-lives varied according to dosage, which can tell us how quickly the body processes and eliminates t-TUCB.
  • The 1 mg/kg t-TUCB was found in the synovial fluid at high concentrations, further affirming the necessity of this dosage.
  • On the downside, the compound did not present any significant anti-inflammatory effects, indicating it worked more towards alleviating pain rather than reducing the inflammation itself in this setup.

Conclusion

In conclusion, the study has shown that sEH inhibition with t-TUCB can serve as a significant analgesic for horses with inflammatory joint pain. The relief was predominantly directed at the symptoms of pain rather than the inflammation itself, suggesting the compound’s primary role in pain mitigation.

Cite This Article

APA
Guedes AGP, Aristizabal F, Sole A, Adedeji A, Brosnan R, Knych H, Yang J, Hwang SH, Morisseau C, Hammock BD. (2017). Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t-TUCB in horses with experimentally induced radiocarpal synovitis. J Vet Pharmacol Ther, 41(2), 230-238. https://doi.org/10.1111/jvp.12463

Publication

Journal of veterinary pharmacology and therapeutics
ISSN: 1365-2885
NlmUniqueID: 7910920
Country: England
Language: English
Volume: 41
Issue: 2
Pages: 230-238

Researcher Affiliations

Guedes, A G P
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.
Aristizabal, F
  • Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
Sole, A
  • Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
Adedeji, A
  • Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
Brosnan, R
  • Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
Knych, H
  • K. L. Maddy Equine Analytical Chemistry Laboratory, School of Veterinary Medicine, University of California, Davis, CA, USA.
Yang, J
  • Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA.
Hwang, S-H
  • Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA.
Morisseau, C
  • Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA.
Hammock, B D
  • Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA.

MeSH Terms

  • Analgesics / pharmacokinetics
  • Analgesics / pharmacology
  • Animals
  • Benzoates / pharmacokinetics
  • Benzoates / pharmacology
  • Carpus, Animal
  • Cross-Over Studies
  • Epoxide Hydrolases / antagonists & inhibitors
  • Female
  • Horse Diseases / drug therapy
  • Horses
  • Joint Diseases / drug therapy
  • Joint Diseases / veterinary
  • Lameness, Animal / drug therapy
  • Lameness, Animal / etiology
  • Phenylurea Compounds / pharmacokinetics
  • Phenylurea Compounds / pharmacology
  • Synovitis / drug therapy
  • Synovitis / veterinary

Grant Funding

  • P42 ES004699 / NIEHS NIH HHS
  • R01 ES002710 / NIEHS NIH HHS
  • R37 ES002710 / NIEHS NIH HHS

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