[A 13-week oral repeated dose toxicity study 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 dogs followed by a 5-week recovery test].

A 13-week oral repeated dose toxicity study 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 beagle dogs. Male and female dogs were given the drug orally for 13 weeks at doses of 0 (control), 5, 25 and 125 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. No effects related to the treatment were observed on survival. Mydriasis and a decrease in body weight or a suppression of its weight gain were seen in the 25 and 125 mg/kg groups. Vomiting, salivation and a decrease in food consumption were seen in the 125 mg/kg group. Ophthalmologic examination confirmed the mydriasis in the 125 mg/kg group. Electrocardiographic examination and urinalysis showed no abnormalities attributable to the treatment. Hematological examination showed an increase in number of platelets in the 125 mg/kg group. Blood chemical examination revealed increases in GPT and ALP and a decrease in albumin in the 25 and 125 mg/kg groups, and an increase in triglyceride in the 125 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy in the 125 mg/kg group, hyperplasia of smooth-ER and concentric lamellar bodies derived from the smooth-ER, and bile pigments in the bile capillary, hepatocyte and stellate cells of Kupffer in the 25 and 125 mg/kg groups. Megakaryocytes in mesenteric lymph node were observed in the 25 and 125 mg/kg groups. The recovery test showed that the above-mentioned changes were satisfactorily reversible or the degree and frequency of these changes were lowered. No treatment-related effects were seen in the 5 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 5 mg/kg for 13-week oral toxicity in dogs.