一种对大鼠具有较少肾上腺皮质功能抑制，稳定血液动力学和改善行为恢复的依托咪酯类似物
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An Etomidate Analogue With Less Adrenocortical Suppression, Stable Hemodynamics, and Improved Behavioral Recovery in Rats
背景与目的
ET-26盐酸盐（ET-26HCl）是一种新型的依托咪酯类似物，作用是缓解依托咪酯引起的肾上腺皮质激素抑制，同时保持依托咪酯快速镇静催眠和血液动力学稳定的特征。本研究比较了ET-26HCl、依托咪酯和镇静催眠药物异丙酚对大鼠的麻醉效果、血流动力学稳定性和恢复情况。
方 法
采用高效液相色谱分析3只大鼠的血浆和肝脏匀浆样品，体外测定ET-26HCl的代谢半衰期。通过上下方法测定ET-26HCl、依托咪酯和异丙酚的催眠中值有效剂量（HD50）。给大鼠使用静脉注射（IV）等剂量的异丙酚、依托咪酯和ET-26HCl，评估麻醉效果和平均动脉压。通过酶联免疫吸附测定分析血清皮质酮浓度。在使用等剂量的异丙酚、依托咪酯、ET-26HCl和生理盐水后对大鼠进行开放式Feld和Morris水迷宫试验，评估大鼠从镇静催眠作用中恢复的能力。
结 果
大鼠血浆和培养肝脏匀浆中的ET-26HCl代谢半衰期分别为81±6分钟和的126±12分钟（平均值±标准偏差）。在体实验表明，ET-26HCl在大鼠中引起正常反应丧失的效价比依托咪酯低3倍。静脉注射异丙酚导致平均动脉压相对于基线（-27.9 mm Hg）比ET-26HCl（-10.7 mm Hg）和依托咪酯（-19.4 mm Hg）在等剂量下降低更明显。给药后ET-26HCl组血清皮质酮水平明显高于依托咪酯组，相当于用促肾上腺皮质激素（ACTH1-24）刺激后15（P <0.001），30（P <0.001）和60（P = .002）分钟的效能。静脉注射ET-26HCl麻醉引起的空间分布与丙泊酚相比更快，但自发性活动的恢复较慢。
结 论
ET-26HCl具有类似于依托咪酯的麻醉效力和血液动力学稳定的特性，但与依托咪酯相比，其引起的肾上腺皮质激素合成抑制比依托咪酯较轻，麻醉时空间分布比异丙酚更快，这与依托咪酯类似。
原始文献摘要
B Wang ， J Yang ， J Chen ， Y Kang ，An Etomidate Analogue With Less Adrenocortical Suppression, Stable Hemodynamics, and Improved Behavioral Recovery in Rats.Anesth Analg 2017;125:442–50.
Background: ET-26 hydrochloride (ET-26HCl) is a novel etomidate analogue designed to alleviate the adrenocortical suppression caused by etomidate while retaining the rapid sedative-hypnotic onset and stable hemodynamic features of etomidate. This study compared the anesthetic effect, hemodynamic stability, and recovery profiles of ET-26HCl, etomidate, and the sedative-hypnotic drug propofol in rats.
Methods: The metabolic half-life of ET-26HCl was determined in vitro using high performance liquid chromatography analysis of samples of rat plasma and liver homogenates taken from 3 animals. Hypnotic median effective doses (HD50) of ET-26HCl, etomidate, and propofol were determined by up-and-down methods. Anesthesia effect and mean arterial pressure were estimated using equivalent intravenous (IV) doses of propofol, etomidate, and ET-26HCl in the rats. Serum concentrations of corticosterone were analyzed by enzyme-linked immunosorbent assay. The ability of rats to recover from the sedative-hypnotic effects of the drugs was evaluated using open field and Morris water maze tests at equipotent doses of propofol, etomidate, ET-26HCl, and normal saline.
Results: The metabolic half-life of ET-26HCl was 81 ± 6 minutes in rat plasma and 126 ± 12 minutes in incubation liver homogenate (mean ± standard deviation), respectively. In vivo experiments showed that the potency of ET-26HCl to cause a loss of righting reflex in rats was 3 times lower than that of etomidate in the rats. IV propofol caused a greater decrease in mean arterial pressure relative to the baseline (-27.9 mm Hg) than did ET-26HCl (-10.7 mm Hg) and etomidate (-19.4 mm Hg) at equipotent doses. Serum corticosterone levels after drug administration were significantly higher in the ET-26HCl group than in the etomidate group at equivalent doses when measured 15 (P < .001), 30 (P < .001), and 60 (P = .002) minutes after stimulation with adrenocorticotropic hormone (ACTH1-24). Recovery of spatial orientation from anesthesia induced by an IV bolus injection was faster with ET-26HCl than with propofol, but recovery of spontaneous activity was slower.
Conclusions: ET-26HCl has anesthetic potency and hemodynamic stability similar to etomidate, but it caused less adrenocortical hormone synthesis suppression than etomidate and faster spatial orientation recovery from anesthesia than propofol, which was similar to etomidate.
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