| Autor: |
Gao, Mei, Chen, Kai, Gu, Wei, Liu, Xiaoyu, Liu, Tianbin, Ying, Yong, Cao, Chong, Zhang, Yanhua, Zhang, Daizhou, Yang, Guiwen |
| Předmět: |
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| Zdroj: |
Journal of Applied Toxicology; Apr2023, Vol. 43 Issue 4, p577-588, 12p |
| Abstrakt: |
GW117 is new melatonergic antidepressant being developed to show better antidepressant action than agomelatine. The purpose of this study was to evaluate the toxicity and to determine potential target organs after oral (gavage) administration of the test article GW117 for 28 days and to assess the reversibility after a 4‐week recovery phase in beagle dogs. Toxicokinetics was also evaluated. Four groups were designed in this study, including the vehicle control group and the GW117 50, 150 and 500 mg/kg/day groups, with 5 dogs/sex/group. Body weight, hematology, clinical chemistry, gross necropsy, organ weight, histopathology, and other indicators were examined. Results showed that animals dosed at ≥150 mg/kg/day showed gastrointestinal reactions (watery feces and dark green/red brown feces), with a dose–response relationship in the incidence and severity grade. Female dogs at 500 mg/kg/day had an increase in organ weight and ratios of the liver at the end of the dosing phase. Histopathology examination showed that some animals at 500 mg/kg/day, especially female animals, had minimal centrilobular hepatocyte hypertrophy in the liver, which reversed after 28‐day recovery. With the exception of the above, no GW117‐related abnormality was noted. Meanwhile, there were no sexual differences in drug exposure and accumulation after the first and last dosing. The no observed adverse effect dose level (NOAEL) was 150 mg/kg/day, under which mean Cmax and AUC0 → t were 583.5 and 2767.0 ng/ml*h for females and 663.2 and 4046.3 ng/ml*h for males on Day 28. Animals dosed at ≥150 mg/kg/day led to gastrointestinal reactions. Female dogs at 500 mg/kg/day had an increase in organ weight and ratios of liver and minimal centrilobular hepatocyte hypertrophy in liver. There were no sexual differences in drug exposure and accumulation after the first and last dosing. The no observed adverse effect dose (NOAEL) was 150 mg/kg/day. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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