[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].

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.

[Antigenicity 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].

An antigenicity 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 Hartley guinea pigs and BALB/cAnN mice. The following results were obtained. No active systemic anaphylaxis reactions were found in guinea pigs immunized by subcutaneous injection of NS-21 alone or in combination with Freund's complete adjuvant (FCA). No 24-hr heterologous passive cutaneous anaphylaxis reactions were elicited in rats by sera from mice immunized by intraperitoneal injection of NS-21 alone or in combination with 3% aluminum hydroxide gel. No passive hemagglutination reactions were elicited by sera from mice immunized by subcutaneous injection of NS-21 in combination with FCA. These results show that NS-21 has no antigenicity under the present experimental conditions.

[Single dose toxicity study of lactitol (NS-4) in dogs].

Male beagle dogs were orally given lactitol, a hepatic encephalopathy drug, in a single dose of 7.5, 15.0 or 30.0 g/kg. Vomiting was seen within 30 minutes after dosing in all treated groups. Diarrhea was observed 3 or 5 hours after dosing in the 15.0 and 30.0 g/kg dose groups. There were no drug related effects on survival, food and water consumption, body weight gain or tissues and organs.

[13-week oral toxicity study of lactitol (NS-4) in dogs followed by 4-week recovery test].

UNLABELLED: 13-week repeated dose toxicity studies were conducted on lactitol, a hepatic encephalopathy drug. In the experiment I, male and female dogs were orally treated with lactitol at doses of 0, 1.0, 2.5 and 6.25 g/kg/day for 13 weeks, followed by 4 weeks recovery period. In the experiment II, male and female dogs were orally treated with lactitol at doses of 0, 0.25, 0.50 and 1.0 g/kg/day for 13 weeks in order to require the no-toxic dose. RESULTS: 1. Soft stool and diarrhea were observed at the 0.50 g/kg group and above, and vomiting was observed at the 1.0 g/kg group and above. Increased water consumption was observed at the 6.25 g/kg group. No deaths occurred at all groups. 2. In urinalysis, increased urine volume was observed at the 6.25 g/kg group. 3. Blood chemistry showed decreased BUN at the 6.25 g/kg group. 4. There were no drug-related changes in body weight, food consumption, ophthalmological examination, electrocardiography, hematology and pathology. 5. At the end of the recovery period, all these changes observed at the end of the administration period were disappeared. Based on these results, it was considered that the no-toxic dose of lactitol is 0.25 g/kg/day.

[Antigenicity study on lactitol (NS-4)].

Lactitol hydrate (lactitol) was tested for its antigenicity in guinea pigs and mice. The following results were obtained. 1. No active systemic anaphylaxis reactions were found in guinea pigs sensitized subcutaneously with lactitol alone or in combination with Freund's complete adjuvant (FCA). 2. No 24 hr heterologous passive cutaneous anaphylaxis reactions were elicited in rats by sera from mice sensitized intraperitoneally with lactitol alone or in combination with 3% aluminum hydroxide gel. 3. No passive hemagglutination reactions were elicited by sera from mice sensitized subcutaneously with lactitol in combination with FCA. From these results, it is concluded that lactitol has no antigenicity under the present experimental conditions.

[The effect of inhalation of sevoflurane for an hour on the liver of beagles].

The effect of sevoflurane in comparison with that of enflurane and halothane, each at 1.8 MAC, on the liver was examined after inhalation exposure to beagles under controlled respiration for 1 hr. No abnormalities were observed in general conditions in the animals exposed to any of these anesthetics. Recovery time to spontaneous respiration after the end of anesthesia was similar for each group, but the awakening was quickest in sevoflurane exposed group. Blood pressure dropped immediately after the initiation of exposure in each group, but it recovered quickly to preexposure levels after the end of the exposure. Minor and reversible elevations in the values of GOT, GPT, LDH and bilirubin were noted without the organic change of the liver in beagles after the inhalation exposure to 1.8 MAC of each anesthetic. Since similar changes were observed in beagles exposed to enflurane or halothane, we conclude that no change in the liver specifically associated with sevoflurane was found under these experimental conditions.