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Journal of veterinary internal medicine2020; 34(5); 2109-2116; doi: 10.1111/jvim.15847

Effect of the p38 MAPK inhibitor doramapimod on the systemic inflammatory response to intravenous lipopolysaccharide in horses.

Abstract: Doramapimod, a p38 MAPK inhibitor, is a potent anti-inflammatory drug that decreases inflammatory cytokine production in equine whole blood in vitro. It may have benefits for treating systemic inflammation in horses. Objective: To determine whether doramapimod is well tolerated when administered IV to horses, and whether it has anti-inflammatory effects in horses in a low-dose endotoxemia model. Methods: Six Standardbred horses. Methods: Tolerability study, followed by a blinded, randomized, placebo-controlled cross-over study. Horses were given doramapimod, and clinical and clinicopathological variables were monitored for 24 hours. Horses then were treated with doramapimod or placebo, followed by a low dose infusion of lipopolysaccharide (LPS). Clinical variables (heart rate, rectal temperature, noninvasive blood pressure), leukocyte count and tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) concentrations were measured at multiple time points until 6 hours post-LPS infusion. Results: No adverse effects or clinicopathological changes were seen in the safety study. When treated with doramapimod as compared to placebo, horses had significantly lower heart rates (P = .03), rectal temperatures (P = .03), and cytokine concentrations (P = .03 for TNF-α and IL-1β), and a significantly higher white blood cell count (P = .03) after LPS infusion. Conclusions: Doramapimod has clinically relevant anti-inflammatory effects in horses, likely mediated by a decrease in leukocyte activation and decrease in the release of pro-inflammatory cytokines. To evaluate its potential as a novel treatment for systemic inflammatory response syndrome in horses, clinical trials will be necessary to determine its efficacy in naturally occurring disease.
© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.
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Publication Date: 2020-07-23 PubMed ID: 32700419PubMed Central: PMC7517855DOI: 10.1111/jvim.15847Google Scholar: Lookup
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  • Journal Article
  • Randomized Controlled Trial
  • Veterinary

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.

The study investigates the effects of the drug doramapimod on the body’s inflammatory response in horses when given lipopolysaccharides (LPS). The researchers found that the drug, which inhibits a protein known to cause inflammation, has no adverse effects, lowers heart rate and temperature, reduces levels of pro-inflammatory factors and increases white blood cell count in horses, suggesting it could be beneficial for treating systemic inflammation in horses.

Research Objectives and Methods

  • The primary objective of the research was to determine the effects and tolerability of the drug, doramapimod, when given intravenously to horses. Another key aim was to inspect its anti-inflammatory influences in horses.
  • The experimental design was a two-part study, first focusing on the tolerability of the drug, followed by a blinded, randomized, placebo-controlled cross-over study.
  • For the experiments, six Standardbred horses were initially given doramapimod and monitored for 24 hours. Post this, they were either treated with doramapimod or a placebo before receiving a low dose of LPS. Basic vital signs, white blood cell count and certain protein levels were measured up to six hours after the LPS was administered.

Results of the Study

  • The study found no detected adverse effects or clinicopathological changes correlated with doramapimod in horses.
  • When horses were treated with doramapimod, compared to a placebo, it was found that they displayed lower heart rates, rectal temperatures, and pro-inflammatory cytokine concentrations. Doramapimod also led to an increased white blood cell count post LPS administration.

Conclusion and Future Implications

  • The research concludes that doramapimod has clinically relevant anti-inflammatory effects on horses, which are likely attributed to a decrease in the activation of white blood cells and the reduced release of pro-inflammatory proteins.
  • The significance of these findings underscores the potential of doramapimod as a novel treatment for systemic inflammatory response syndrome (a severe body-wide inflammatory state) in horses. However, clinical trials would be needed to assess its efficacy in treating naturally occurring diseases.

Cite This Article

APA
Bauquier J, Tudor E, Bailey S. (2020). Effect of the p38 MAPK inhibitor doramapimod on the systemic inflammatory response to intravenous lipopolysaccharide in horses. J Vet Intern Med, 34(5), 2109-2116. https://doi.org/10.1111/jvim.15847

Publication

Journal of veterinary internal medicine
ISSN: 1939-1676
NlmUniqueID: 8708660
Country: United States
Language: English
Volume: 34
Issue: 5
Pages: 2109-2116

Researcher Affiliations

Bauquier, Jennifer
  • Department of Veterinary Clinical Sciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Werribee, Victoria, Australia.
Tudor, Elizabeth
  • Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Australia.
Bailey, Simon
  • Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Australia.

MeSH Terms

  • Animals
  • Cross-Over Studies
  • Horse Diseases / drug therapy
  • Horses
  • Lipopolysaccharides
  • Naphthalenes
  • Pyrazoles
  • Systemic Inflammatory Response Syndrome / drug therapy
  • Systemic Inflammatory Response Syndrome / veterinary
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases

Conflict of Interest Statement

This compound is the subject of a patent application filed by the University of Melbourne (Patent number PCT/AU2018/050120, filed 15 Feb 2018).

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