title: [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].
abstract: 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.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.forename: T
authors.initials: T
authors.lastname: Oka
authors.forename: T
authors.initials: T
authors.lastname: Tawaratani
authors.forename: S
authors.initials: S
authors.lastname: Ishibashi
authors.forename: M
authors.initials: M
authors.lastname: Nakazawa
authors.forename: E
authors.initials: E
authors.lastname: Kitayama
authors.forename: T
authors.initials: T
authors.lastname: Adachi
authors.forename: K
authors.initials: K
authors.lastname: Iwakura
authors.forename: N
authors.initials: N
authors.lastname: Sumi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D008297:Male; D015394:Molecular Structure; D010648:Phenylacetates / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D013997:Time Factors; D014549:Urinary Incontinence / Q000188:drug therapy; D014555:Urination Disorders / Q000188:drug therapy*
chemical_list: D010648:Phenylacetates; C105354:temiverine