Janssen P A, Niemegeers C J, Marsboom R P
Arch Int Pharmacodyn Ther. 1975 Mar;214(1):92 -132.
Etomidate, R-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate was found to be a potent, short-acting and safe hypnotic; when given intravenously in single doses to mice, rats, guinea-pigs, rabbits and dogs. In rats of different body weight (50, 100, 200 and 300 g) two injection rates were used (2 sec and 2 min). By rapid iv injection in rats of 200 g etomidate (ED50 equal to 0.57 mg/kg) is about 6 times more potent than methohexital (ED50 equal to 3.51 mg/kg) and 25 times more potent than propanidid and thiopental (ED50's equal to 13.4 mg/kg). The safety margin (LD50/ED50) in these rats is 26.0 for etomidate, 9.5 for methohexital, 6.7 for propanidid and 4.6 for thiopental. Potency and toxicity of etomidate slightly increase with increasing injection rates without affecting the safety margin. The duration of hypnosis with etomidate is dose-dependent and the safety margin will therefore be widened when sleep of short duration is aimed at. Recovery after etomidate is very rapid. With lower body weights, higher doses in mg/kg are required for inducing hypnosis of comparable duration. No systematic differences were found after etomidate injection in incidence and duration of hypnosis nor in mortality between animals of different sex. ECG, blood pressure, haematological and biochemical analysis, urinalysis and histopathology did not reveal any drug-related adverse effect after daily injection of etomidate for 3 weeks in rats (highest dose 5.0 mg/kg) and 2 weeks in dogs (highest dose 1.50 mg/kg). No tolerance was observed after repeated administration. Etomidate is devoid of any teratogenic effect in rats (highest dose: 5.0 mg/kg daily from day 6 through day 15 of pregnancy), and in New Zealand white rabbits (highest dose: 4.5 mg/kg daily from day 6 through day 18 of pregnancy). The hypnotic effects of etomidate at very low dose levels in different laboratory animals are compared with the effects obtained in human subjects, in which successful induction of anaesthesia was obtained without producing any release of histamine and with only minimal effects on cardiovascular and respiratory functions.
依托咪酯，R-(+)-乙基-1-(1-苯乙基)-1H-咪唑-5-羧酸酯被发现是一种强效、短效且安全的催眠药；当以单剂量静脉注射给小鼠、大鼠、豚鼠、兔子和狗时。在不同体重（50、100、200和300克）的大鼠中使用了两种注射速率（2秒和2分钟）。通过对200克大鼠快速静脉注射依托咪酯（半数有效量等于0.57毫克/千克），其效力约为美索比妥（半数有效量等于3.51毫克/千克）的6倍，比普罗帕脒和硫喷妥钠（半数有效量等于13.4毫克/千克）强25倍。在这些大鼠中，依托咪酯的安全系数（半数致死量/半数有效量）为26.0，美索比妥为9.5，普罗帕脒为6.7，硫喷妥钠为4.6。依托咪酯的效力和毒性随注射速率增加而略有增加，但不影响安全系数。依托咪酯催眠持续时间呈剂量依赖性，因此当旨在实现短时间睡眠时，安全系数会增大。依托咪酯注射后的恢复非常迅速。体重较低时，诱导可比持续时间的催眠需要更高毫克/千克剂量。在不同性别的动物中，注射依托咪酯后，催眠的发生率和持续时间以及死亡率均未发现系统性差异。在大鼠中每日注射依托咪酯3周（最高剂量5.0毫克/千克）和在狗中注射2周（最高剂量1.50毫克/千克）后，心电图、血压、血液学和生化分析、尿液分析及组织病理学均未显示任何与药物相关的不良反应。重复给药后未观察到耐受性。依托咪酯在大鼠（最高剂量：妊娠第6天至第15天每日5.0毫克/千克）和新西兰白兔（最高剂量：妊娠第6天至第18天每日4.5毫克/千克）中无任何致畸作用。将依托咪酯在非常低剂量水平下对不同实验动物的催眠作用与在人类受试者中获得的作用进行了比较，在人类受试者中成功诱导了麻醉，且未产生任何组胺释放，对心血管和呼吸功能的影响也极小。
