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

Abstract

Background: 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. Animals: 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 and Clinical Importance: 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.