Safety Pharmacology Study of ET-26 Hydrochloride, a Potential Drug for Intravenous General Anesthesia, in Rats and Beagle Dogs.

Abstract

Background: ET-26 hydrochloride (ET-26HCl), a class 1 new drug, was developed to reserve the advantages of etomidate with a mild adrenocortical inhibition. Purpose: this study was to evaluate the potential adverse effects on the cardiovascular system of beagle dogs and the respiratory and central nervous systems of rats. Methods: three established methods, the whole-body plethysmography for respiratory function, the prototype telemetry transmitter for cardiovascular function, and the standardized functional observational battery for central nervous system function, were accomplished with Good Laboratory Practice standards. Results: no significant difference in the tidal volume, but the respiratory rate and minute ventilation were reduced. The degree of inhibition was the most serious in the first 15 min after dosing and function fully recovered after 1 h. For male rats, the respiratory rate of male rats was reduced significantly at 15 min after injection with ET-26HCl (4 mg/kg, 28.6%, p ≤ 0.01; 8 mg/kg, 24.5%, p ≤ 0.01; 16 mg/kg, 44.5%, p ≤ 0.001), and the minute ventilation at 15 min was decreased by 20.1% (4 mg/kg, p = 0.034), 22.2% (8 mg/kg, p = 0.019), and 44.6% (16 mg/kg, p ≤ 0.001) as compared to control group. As with male rats, the respiratory rate of the female rats was reduced significantly at 15 min (4 mg/kg, 23.3%, p ≤ 0.01; 8 mg/kg, 29.2%, p ≤ 0.001; 16 mg/kg, 44.1%, p ≤ 0.001), and the minute ventilation was decreased by 25.2% (4 mg/kg, p ≤ 0.001), 23.0% (8 mg/kg, p ≤ 0.01), and 47.6% (16 mg/kg, p ≤ 0.001). Then, all the variations in cardiovascular functions were within the expected range for normal biological variation, we concluded that ET-26HCl, even at 10-fold ED50, still does not exert toxicological effects on the cardiovascular system. For male beagle dogs, the systolic blood pressure after 24 h following administration of vehicle control or 8, 12, or 16 mg/kg ET-26HCl was 137.80 ± 5.55, 131.76 ± 10.03, 139.88 ± 8.35, and 141.28 ± 8.75 mmHg, respectively. The diastolic blood pressure was 71.16 ± 4.84, 66.52 ± 8.50, 73.64 ± 8.51, and 74.24 ± 8.68 mmHg, respectively. For female beagle dogs, the systolic blood pressure after 24 h following administration of vehicle control or 8, 12, or 16 mg/kg ET-26HCl was 128.28 ± 5.22, 124.76 ± 7.29, 134.88 ± 5.56, and 135.36 ± 8.72 mmHg, respectively. The diastolic blood pressure was 67.00 ± 4.10, 62.12 ± 7.87, 69.44 ± 6.40, and 70.20 ± 8.42 mmHg, respectively. In central nervous system function experiment, all the changes observed in the functional observational battery tests, including motor activity, behavior, coordination, and sensory and motor reflex responses, and reduced body temperature, were resulted in general anesthesia effect of ET-26HCl. Conclusion: ET-26HCl exerts mild, reversible effects on respiratory, cardiovascular, and central nervous system function as verified by standard in vivo animal models.