[A 12-month 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 2-month recovery test].
A 12-month 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 12 months at doses of 0 (control), 3, 17.5 and 100 mg/kg. After discontinuation of the treatment, a 2-month recovery test was also conducted. No effects related to the treatment were observed on survival and water consumption. Mydriasis, vomiting and a decrease in body weight or a suppression of its weight gain were seen in the 17.5 and 100 mg/kg groups. Salivation and a decrease in food consumption were seen in the 100 mg/kg group. Ophthalmologic examination confirmed the mydriasis in the 17.5 and 100 mg/kg groups. Electrocardiographic and hematological examinations and urinalysis showed no abnormalities attributable to the treatment. Blood chemical examination revealed increases in GPT and ALP in the 17.5 and 100 mg/kg groups, increases in GOT and triglyceride and a decrease in total protein in the 100 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy and concentric lamellar bodies derived from the smooth-ER in the 100 mg/kg group, and hyperplasia of smooth-ER, an increase in number of lysosomes and bile pigments in the bile capillary, hepatocyte and stellate cells of Kupffer in the 17.5 and 100 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. The serum concentrations of NS-21 and its active metabolite. RCC-36, in the treated groups were increased in a dose-dependent manner. No treatment-related effects were seen in the 3 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 3 mg/kg for 12-month oral toxicity in dogs.
Yoshida
M
M
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Kawaminami
A
A
Tawaratani
T
T
Ishibashi
S
S
Nakazawa
M
M
Kitayama
E
E
Oka
T
T
Adachi
T
T
Iwakura
K
K
Sumi
N
N
D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D008099:Liver / Q000187:drug effects / Q000473:pathology; 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*
D010648:Phenylacetates; C105354:temiverine