Preclinical safety evaluation of ET-26 hydrochloride, a novel intravenous anesthetic agent, in beagle dogs.
J Appl Toxicol
; 40(5): 679-690, 2020 05.
Article
en En
| MEDLINE
| ID: mdl-31867768
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pruebas de Toxicidad
/
Anestésicos Intravenosos
/
Etomidato
Tipo de estudio:
Etiology_studies
/
Guideline
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
J Appl Toxicol
Año:
2020
Tipo del documento:
Article
País de afiliación:
China