Effect of the p38 MAPK inhibitor doramapimod on the systemic inflammatory response to intravenous lipopolysaccharide in horses.
Authors: Bauquier Jennifer, Tudor Elizabeth, Bailey Simon
Journal: Journal of veterinary internal medicine
Summary
# Editorial Summary Researchers from the University of Melbourne investigated doramapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor with documented anti-inflammatory properties in equine blood cultures, to establish its safety profile and efficacy in reducing systemic inflammation during experimentally induced endotoxaemia. The team conducted a two-phase study: first confirming tolerability of intravenous doramapimod administration in six Standardbred horses, then employing a blinded, randomised, placebo-controlled crossover design in which animals received either doramapimod or placebo prior to low-dose lipopolysaccharide (LPS) infusion, with clinical variables and inflammatory markers (TNF-α, IL-1β, leucocyte counts) monitored for six hours post-LPS challenge. Horses treated with doramapimod demonstrated significantly attenuated systemic responses compared to placebo controls: lower heart rates (P = 0.03), reduced rectal temperatures (P = 0.03), lower pro-inflammatory cytokine concentrations (P = 0.03), and paradoxically elevated white blood cell counts (P = 0.03), whilst the safety study revealed no adverse effects or pathological changes. The findings suggest doramapimod effectively modulates the innate immune response by suppressing leukocyte activation and cytokine release—mechanisms highly relevant to systemic inflammatory response syndrome in clinical practice. Although these controlled results are encouraging, progression to clinical trials in naturally occurring disease will be essential before practitioners can evaluate doramapimod's utility for conditions such as endotoxaemia, sepsis, and post-operative inflammation in equine patients.
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Practical Takeaways
- •Doramapimod shows promise as a potential anti-inflammatory therapy for systemic inflammatory response in horses, though clinical efficacy in natural disease requires further investigation
- •The drug appears safe for IV administration and may help modulate excessive inflammatory responses by reducing pro-inflammatory cytokine production
- •This is preliminary evidence; clinical trials in naturally occurring disease are needed before recommending doramapimod as standard treatment for equine systemic inflammation
Key Findings
- •Doramapimod was well tolerated with no adverse effects or clinicopathological changes in safety study
- •Doramapimod-treated horses showed significantly lower heart rates (P=0.03) and rectal temperatures (P=0.03) after LPS infusion compared to placebo
- •TNF-α and IL-1β concentrations were significantly lower in doramapimod-treated horses (P=0.03) following LPS challenge
- •White blood cell count was significantly higher in doramapimod-treated horses (P=0.03), suggesting decreased leukocyte activation