Reproductive and developmental toxicity 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 (2). Teratogenicity study in rats by oral administration

Abstract

A study of teratogenicity and developmental toxicity 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 conducted in Crl:CD rats. Female rats were given NS-21 orally at dose levels of 0 (control), 2, 25 and 300 mg/kg from day 7 to day 17 of pregnancy. Twenty-two female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the remaining pregnant rats (twenty-three per dose level) were allowed to deliver naturally for postnatal examination of their offspring. At the 300 mg/kg dosage level, rales, partially closed eyes and reduced activity were observed in pregnant rats. Decreases in body weight gain, food consumption and water consumption were observed in the dams at the 300 mg/kg dosage level. Fetal body weights were decreased at the 300 mg/kg dosage level. The drug never altered the numbers of corpora lutea and implantations, fetal mortality, the number of live fetuses, sex ratio, placental weight, and external, visceral and skeletal development of fetuses. NS-21 did not affect the delivery of dams, the number of live newborns, birth index, body weight or survival index. Nor did NS-21 have any adverse effect on the postnatal development of the offspring, including physical and functional development, emotionality, motor activity, learning ability and reproductive performance. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 25 mg/kg for general toxicity in mother animals. 300 mg/kg for reproductive function in mother animal and 25 mg/kg for developmental toxicity.