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[Mutagenicity studies of montirelin hydrate (NS-3)]
K Iwakura1, H Tamura, Y Yamashita
1Research Laboratories, Nippon Shinyaku Col Ltd., Kyoto, Japan.
Abstract:
Montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was examined for mutagenicity in the reverse mutation test, the chromosome aberration test in vitro, and the micronucleus test in mice. The reverse mutation test was performed at dose range of 156.25-5,000 micrograms/plate using Salmonella typhimurium strains, TA1535, TA100, TA1537, and TA98, and Escherichia coli WP2uvrA. The drug did not increase revertant colonies significantly in any of the test strains with or without metabolic activation system (S-9mix). The chromosome aberration test was carried out at dose range of 300-4,800 micrograms/ml using cultured Chinese hamster lung cells (CHL/IU). No significant increases of the frequencies of cells with chromosomal aberrations were observed with or without metabolic activations. The micronucleus test was conducted in the bone marrow cells of Slc:ddY male mice. Mice were given the drug by a single intraperitoneal administration at doses of 0, 250, 500, 1,000, and 2,000 mg/kg. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes at any dose levels. These results show that montirelin hydrate has no mutagenic activity in vitro or in vivo.
Insights
Montirelin hydrate, a novel treatment for disturbed consciousness, demonstrated no mutagenic effects in bacterial reverse mutation, chromosome aberration, and mouse micronucleus tests. These findings indicate the drug is safe regarding genetic toxicity.
Area of Science:
- Pharmacology
- Toxicology
- Genetics
Context:
- Montirelin hydrate (NS-3) is a new pharmaceutical agent developed for treating disorders of consciousness.
- Assessing the mutagenicity of new drugs is a critical step in their safety evaluation.
- Previous research on montirelin hydrate's efficacy is complemented by this genotoxicity study.
Purpose:
- To evaluate the potential mutagenic activity of montirelin hydrate.
- To determine if montirelin hydrate causes genetic mutations or chromosomal damage.
- To assess genotoxicity across multiple in vitro and in vivo models.
Summary:
- Montirelin hydrate was tested using the Ames test (Salmonella typhimurium, Escherichia coli), an in vitro chromosome aberration test (Chinese hamster lung cells), and an in vivo micronucleus test (mouse bone marrow).
- No significant increases in revertant colonies were observed in the Ames test with or without metabolic activation (S-9 mix).
- Neither the in vitro chromosome aberration test nor the in vivo micronucleus test showed significant increases in chromosomal aberrations or micronucleated cells, respectively, at tested doses.
Impact:
- Montirelin hydrate exhibits no mutagenic potential in standard genotoxicity assays.
- The study provides crucial safety data supporting the further development of montirelin hydrate for clinical use.
- These findings contribute to the understanding of montirelin hydrate's toxicological profile.