[Mutagenicity studies of (+/-)-4-diethylamino-1,1,-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence].
The mutagenicity of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was investigated by the reverse mutation test in bacteria, the chromosome aberration test in vitro, and the micronucleus test in mice. The reverse mutation test was performed at a dose from 31.3 to 4000 micrograms/plate, at which dose cell killing was observed, using Salmonella typhimurium TA100, TA1535, TA98, and TA1537, and Escherichia coli WP2uvrA. NS-21 did not increase revertant colonies significantly in any of the test strains with or without metabolic activation system (S9 mix). The chromosome aberration test was carried out at a dose from 3.75 to 140 micrograms/ml, at which dose more than 50% cell proliferation was inhibited, using cultured Chinese hamster lung cells (CHL/IU). No significant increases of the frequencies of cells with chromosome aberrations were observed with or without S9 mix. The micronucleus test was conducted in the bone marrow cells of Slc : ddY male mice. Mice were given NS-21 by a single oral administration at doses of 0, 43.8, 87.5, 175, and 350 mg/kg, the geometric mean dose between the maximum tolerated dose and the minimum lethal dose. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes at any dose levels. These results show that NS-21 has no mutagenic activity in vitro or in vivo.
Otsuka
M
M
Hita Research Laboratories Chemical Biotesting Center, Chemical Inspection & testing Institute, Hita Oita, Japan.
Kajiwara
Y
Y
Ajimi
S
S
Shimazaki
H
H
Kikuno
T
T
Ogura
S
S
Inai
T
T
Kakimoto
K
K
Tamura
H
H
Watanabe
M
M
Sumi
N
N
D000818:Animals; D002478:Cells, Cultured; D002875:Chromosomes / Q000187:drug effects; D006224:Cricetinae; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D010648:Phenylacetates / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000254:growth & development; D014549:Urinary Incontinence / Q000188:drug therapy; D014555:Urination Disorders / Q000188:drug therapy*
D009153:Mutagens; D010648:Phenylacetates; C105354:temiverine