title: Metabolite-inactive etomidate analogues alleviating suppression on adrenal function in Beagle dogs.
abstract: Owing to rapid generation in body, the metabolites of etomidate softdrug are able to accumulate in either the brain or periphery and subsequently affect the recovery from anaesthesia or cause corticosteroid suppression. This study was designed to investigate the ability of two etomidate analogues (ET-26, ET-42) with inactive metabolites to provide anaesthesia with lesser corticosteroid suppression. The 50% effective dose (ED50) of ET-26, ET-42, Etomidate, MOC-ET (an etomidate softdrug) and CPMM (an improved etomidate softdrug) required to induce anaesthesia intravenously in Beagle dogs were 1.44mg/kg, 0.72mg/kg, 0.43mg/kg 23.12mg/kg and 0.59mg/kg, respectively. After adrenocorticotropic hormone (ACTH) stimulation, the serum concentrations of cortisol and corticosterone in the ET-26, ET-42 and CPMM groups were similar to those of controls, and significantly higher than those of the etomidate and MOC-etomidate groups (P<0.05). Furthermore, no significant differences in serum concentrations of cortisol and corticosterone after ACTH-stimulation between ET-26, ET-42, CPMM, and blank control groups were observed. In this study, anaesthetic potencies of ET-26 (ED50=1.44mg/kg) and ET-42 (ED50=0.72mg/kg) were determined. Both analogues can significantly reduce the corticosteroid suppression in vivo. Metabolite-inactive etomidate derivatives with slow metabolism might provide a novel strategy to improve Etomidate associated corticosteroid suppression.
authors.affiliation: Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Linghui
authors.initials: L
authors.lastname: Yang
authors.affiliation: Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: zhang_ws@scu.edu.cn.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects*; D000324:Adrenocorticotropic Hormone; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004285:Dogs; D005045:Etomidate / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D005260:Female; D006854:Hydrocortisone / Q000097:blood; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D008297:Male
chemical_list: C000621869:ET-26 compound; D006993:Hypnotics and Sedatives; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D006854:Hydrocortisone; D005045:Etomidate
keywords: Etomidate analogues; Inactive metabolite; Intravenous anaesthetic drug; Reduced corticosteroid suppression; Slow metabolism