title: [One-year chronic oral toxicity study of propiverine hydrochloride in dogs followed by one-month recovery].
abstract: The chronic oral toxicity of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was studied in beagle dogs. Groups of 6 males and 6 females were treated with P-4 at doses of 0, 0.3, 1, 3, 9 mg/kg/day for one year and thereafter 2 animals of both sexes in each group were placed on withdrawal for one month. During administration and recovery period, no death occurred in any dosed animals. As a toxic sign, only the frequency of vomiting was increased in animals of 1, 3 and 9 mg/kg/day groups. Body weight, food and water consumption were not affected by the P-4 administration. In serum chemical examinations, gamma-GTP activity was increased in both sexes of 9 mg/kg/day group at 6 month of administration. Further decrease in total and free cholesterol, triglyceride and phospholipid, increase in GPT activity were detected in some animals of 9 mg/kg/day group at 12 month of administration. In addition decreasing tendency in levels of albumin was noted in males of 9 mg/kg/day group at 9 and 12 month of administration. And also, a gradual increase in total protein level and a gradual decrease in alkaline phosphatase activity were seen in control group, but in females or males of 9 mg/kg/day group, those changes were mild. Urine pH rised slightly in females of 3 mg/kg/day group and in both sexes of 9 mg/kg/day group. No specific findings attributable to P-4 treatment were detected in ECG, heart rate, funduscopy, hematology, fecal occult blood test and necropsy. The absolute and/or relative liver weight in males of 3 and 9 mg/kg/day groups were significantly increased. Light-microscopically, the hypertrophy of hepatocytes characterized by homogenization and enlargement of cytoplasmic space, and concentric inclusions in hepatocytic cytoplasm were detected in both sexes of 3 and 9 mg/kg/day groups. Corresponding to these microscopical findings, the following changes were observed electron-microscopically, the proliferation of smooth surfaced endoplasmic reticulum in hepatocytes in both sexes of 1, 3 and 9 mg/kg/day groups, lamellar bodies in hepatocytes in females of 3 mg/kg/day group, and in both sexes of 9 mg/kg/day group, and annulate lamellae in hepatocytes were detected in one female of 9 mg/kg/day group. After the recovery period, the above mentioned abnormalities were markedly attenuated or disappeared except the changes in hepatocytes. From these results, it seemed that 9 mg/kg/day of P-4 might be safety dose.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Hamamatsu Seigiken Research Co., Ltd., Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kohda
authors.forename: H
authors.initials: H
authors.lastname: Nishikawa
authors.forename: M
authors.initials: M
authors.lastname: Sumino
authors.forename: M
authors.initials: M
authors.lastname: Sano
authors.forename: J
authors.initials: J
authors.lastname: Kuroda
authors.forename: K
authors.initials: K
authors.lastname: Miura
authors.forename: M
authors.initials: M
authors.lastname: Tsuchitani
authors.forename: I
authors.initials: I
authors.lastname: Narama
authors.forename: H
authors.initials: H
authors.lastname: Yada
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001561:Benzilates / Q000633:toxicity*; D004285:Dogs; D005260:Female; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010276:Parasympatholytics / Q000633:toxicity*; D013997:Time Factors; D014555:Urination Disorders / Q000188:drug therapy
chemical_list: D001561:Benzilates; D010276:Parasympatholytics; C015586:propiverine