title: [A 26-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 rats followed by a 9-week recovery test].
abstract: A 26-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 Sprague-Dawley rats. Male and female rats were given the drug orally for 26 weeks at doses of 0 (control), 5, 50 and 500 mg/kg. After discontinuation of the treatment, a 9-week recovery test was also conducted. Two cases of death occurred in the 500 mg/kg group. Mydriasis, salivation and lacrimation were seen in the 50 and 500 mg/kg groups. Alopecia, a suppression of body weight gain and an increase in water consumption were seen in the 500 mg/kg group. Food consumption measurement showed no abnormalities attributable to the treatment. Ophthalmologic examination confirmed mydriasis in the 50 and 500 mg/kg groups. Urinalysis showed an increase in urine volume in the 50 and 500 mg/kg groups, and an increase in urinary protein and decreases in Na+, K+ and Cl- excretions in the 500 mg/kg group. Hematological examination showed decreases in hemoglobin, hematocrit, MCV, MCH, MCHC and lymphocytes in the 500 mg/kg group. Blood chemical examination showed increases in total cholesterol, phospholipid and total protein and decreases in glucose, triglyceride, free T3 and T4 in the 500 mg/kg group. Measurements of liver drug-metabolizing enzymes showed an increase in T4UDP-GT activity in the 50 and 500 mg/kg groups, and an increase in cytochrome P-450 in the 500 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy caused by hyperplasia of smooth-ER in the 50 and 500 mg/kg groups, and a decrease in number of glycogen granules in the 500 mg/kg group. Stimulated thyroid follicles were seen in the 50 and 500 mg/kg groups. Increases in incidence and severity of chronic progressive nephropathy were also observed in the 500 mg/kg group. In this dose group, adrenocortical hypertrophy was also observed. The recovery test showed that the above-mentioned changes were satisfactorily reversible. 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 5 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 5 mg/kg for 26-week oral toxicity in rats.
authors.affiliation: Shin Nippon Biomedical Laboratories, Ltd., Kagoshima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Okasaki
authors.forename: S
authors.initials: S
authors.lastname: Baba
authors.forename: H
authors.initials: H
authors.lastname: Ikeda
authors.forename: Y
authors.initials: Y
authors.lastname: Chihaya
authors.forename: S
authors.initials: S
authors.lastname: Satake
authors.forename: R
authors.initials: R
authors.lastname: Nagata
authors.forename: S
authors.initials: S
authors.lastname: Ishibashi
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; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D008297:Male; D010648:Phenylacetates / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014549:Urinary Incontinence / Q000188:drug therapy; D014555:Urination Disorders / Q000188:drug therapy*
chemical_list: D010648:Phenylacetates; C105354:temiverine