[Intraperitoneal single-dose toxicity studies of active metabolite, optical isomers, hydrolysis products and bi-product 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, in mice].
NS-21, (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, is a new drug for the treatment of urinary frequency and incontinence. To evaluate acute toxicities of its related compounds including the optical isomers of NS-21 ((S)NS-21 and (R)NS-21), the active metabolite of NS-21 ((R/S)RCC-36), the optical isomers of (R/S)RCC-36 ((S)RCC-36 and (R)RCC-36), the hydrolysis products of NS-21 (RCC-32 and RCC-38) and the bi-product of NS-21 (RCC-66), single-dose intraperitoneal toxicity studies were conducted in ddY mice. The LD50 values of these compounds in male and female mice were as follows: 199 and 184 mg/kg for (S)NS-21, 261 and 240 mg/kg for (R)NS-21, 74 and 100-150 mg/kg for (R/S)RCC-36, 93 mg/kg for (S)RCC-36 in both sexes, 83 and 104 mg/kg for (R)RCC-36, higher than 510 mg/kg for RCC-32 in both sexes, 340-510 mg/kg for RCC-38 in both sexes, and 1000-2000 mg/kg for RCC-66 in both sexes, respectively. The clinical signs included decreased spontaneous locomotor activity, prone or lateral position, ataxic gait, clonic convulsion, hypopnea, hypothermia, pale skin, mydriasis, abdominal distention and unkempt fur for (S)NS-21, (R)NS-21, (R/S)RCC-36, (S)RCC-36 and (R)RCC-36, decreased spontaneous locomotor activity, prone position, ataxic gait, clonic convulsion, tail elevation and hypopnea for RCC-32 and RCC-38, and decreased spontaneous locomotor activity and unkempt fur for RCC-66. Body weight was decreased or its gain was suppressed for every compound examined. Pathological examination of the dead mice showed atrophy of the thymus and spleen, intestinal distention with the retention of dark red contents, white spots or white materials in the abdominal fatty tissue for (S)NS-21, (R)NS-21, (R/S)RCC-36, (S)RCC-36, (R)RCC-36 and RCC-66, but no treatment related change for RCC-32 and RCC-38. Adhesion between the abdominal organs was observed in survivors treated with (S)NS-21, (R)NS-21, (S)RCC-36, (R)RCC-36, RCC-32 and RCC-66.
Nishimura
N
N
Gotemba Laboratory, Bozo Research Center Inc., Shizuoka, Japan.
Kobayashi
J
J
Moro
M
M
Katsumata
T
T
Nishiguchi
Y
Y
Iwakura
K
K
Sumi
N
N
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006868:Hydrolysis; D007274:Injections, Intraperitoneal; D007536:Isomerism; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010648:Phenylacetates / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D014549:Urinary Incontinence / Q000188:drug therapy; D014555:Urination Disorders / Q000188:drug therapy*
D010648:Phenylacetates; C105354:temiverine