Preclinical safety evaluation of ET‐26 hydrochloride, a novel intravenous anesthetic agent, in beagle dogs

摘要

Abstract ET‐26 hydrochloride (ET‐26HCl) is a novel etomidate analogue, approved for clinical trials, which has an effective sedative‐hypnotic effect, a stable myocardial performance, and milder adrenocortical suppression than etomidate in rats and beagle dogs. Additionally, ET‐26HCl showed similar hemodynamic stability as etomidate in the rat uncontrolled hemorrhagic shock model. Furthermore, ET‐26HCl, in the rat lipopolysaccharide‐induced sepsis model, was found to have a higher survival rate, a lower inflammatory reaction, and less organ injury. In the present study, we measured the potential adverse effects of ET‐26HCl in beagle dogs in accordance with the Guidance on single‐ and repeated‐dose toxicity published by the China Food and Drug Administration. In toxicity studies, single and repeated (14 days) intravenous doses of up to 16 mg/kg were well tolerated, with only pharmacologically related clinical signs seen in both studies. Thus, the no‐observed‐adverse‐effect level (NOAEL) of ET‐26HCl was found at 16 mg/kg/day. Toxicokinetic examination demonstrated that ET‐26HCl showed a dose‐dependent increase to exposure, no gender difference, and no evidence of accumulation. These results provide useful information for guiding a phase I clinical trial of ET‐26HCl in healthy volunteers.