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

Abstract

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.

Keywords

• cytokine
• endotoxemia
• equine
• sepsis
• SIRS