Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Two weeks dose range-finding and four weeks repeated dose oral toxicity study of a novel reversible monoamine oxidase B inhibitor KDS2010 in cynomolgus monkeys

  • Kyung‑Tai Kim (Jeonbuk Branch Institute, Korea Institute of Toxicology) ;
  • Doo‑Wan Cho (Jeonbuk Branch Institute, Korea Institute of Toxicology) ;
  • Jae‑woo Cho (Department of Advanced Toxicology Research, Korea Institute of Toxicology (KIT)) ;
  • Wan‑Jung Im (Department of Advanced Toxicology Research, Korea Institute of Toxicology (KIT)) ;
  • Da‑Hee Kim (Jeonbuk Branch Institute, Korea Institute of Toxicology) ;
  • Jong‑Hyun Park (Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST)) ;
  • Ki Duk Park (Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST)) ;
  • Young‑Su Yang (Jeonbuk Branch Institute, Korea Institute of Toxicology) ;
  • Su‑Cheol Han (Jeonbuk Branch Institute, Korea Institute of Toxicology)
  • Received : 2022.08.13
  • Accepted : 2023.04.04
  • Published : 2023.10.15
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Abstract

A novel reversible monoamine oxidase B inhibitor, KDS2010, has been developed as a therapeutic candidate for neurodegenerative diseases. This study investigated its potential toxicity in non-human primates before human clinical trials. Daily KDS2010 doses (25, 50, or 100 mg/kg) were orally administered to cynomolgus monkeys (1 animal/sex/group, 4 males and 4 females) for 2 weeks to determine the dose range. One male was moribund, and one female was found dead in the 100 mg/kg/day group. One male was also found dead in the 50 mg/kg/day group. The death was considered an adverse effect in both sexes since distal tubules/collecting duct dilation and hypertrophy in the epithelium of the papillary duct were observed in their kidneys. Based on dose range finding results, KDS2010 (10, 20, or 40 mg/kg/day) was administered orally for 4 weeks, and animals were given 2 weeks for recovery. No significant changes were observed during daily clinical observations and macro-and microscopic examinations, including body weight, food consumption, hematology, clinical chemistry, and organ weight. And, the kidney was seen as the primary target organ of KDS2010 in the 2 weeks study, but no adverse effect was observed in the 4 weeks study. Therefore, 40 mg/kg/day is considered the no-observed-adverse-effect level in both sexes of cynomolgus monkeys.

Keywords

Acknowledgement

The authors thank the National Research Council of Science & Technology (NST) for its financial support of this study.

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