Nakano S, Kuwata M, Hasegawa H, Irimura K, Maruden A, Morita K
Drug Safety Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
J Toxicol Sci. 1989 Oct;14 Suppl 2:13-59. doi: 10.2131/jts.14.supplementii_13.
A subacute toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out using male and female Wistar rats. P-4 was orally administered to rats at dose levels of 2, 10, 50 and 150 mg/kg/day for 13 weeks, followed by 5 weeks recovery period. The results obtained are as follows: 1. In the general conditions, transient salivation was observed immediately after administration and blotted fur at lower abdomen was noted in rats given 50 mg/kg/day or more. There were no deaths related to P-4. 2. Body weight gain was depressed in males given 50 mg/kg/day or more and females given 150 mg/kg/day. No significant changes in food consumption were observed. Water consumption increased in the groups of 50 mg/kg/day or more. 3. Urinalysis revealed an increase of urine volume, decreases of osmotic pressure, protein and urobilinogen, and a slight increase in excretion of electrolyte in rats given 50 mg/kg/day or more. 4. Hematological examinations revealed slight changes such as an increase in erythrocyte count and a shortening of APTT in rats given 150 mg/kg/day. 5. Serum biochemical examinations showed a decrease in triglyceride and increases in gamma-GTP and AlP activities, and urea nitrogen in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Additionally, decreases in total and free cholesterol, and phospholipid for males and an increase of total cholesterol and a decrease of cholinesterase activity for females were detected. 6. At autopsy, atrophy of thymus and spleen was observed in rats given 50 mg/kg/day or more, but without histopathological correlation. Histopathological examinations revealed hypertrophy and fatty degeneration of hepatocytes, which were accompanied with increases of absolute and/or relative liver weight, in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Electron-microscopy showed proliferation of smooth endoplasmic reticulum in the same groups. In the kidney, eosinophilic and intranuclear inclusions in the tubular epithelium were detected, in which cytoplasm there were no toxic injuries, in males given 10 mg/kg/day or more and females given 50 mg/kg/day or more. 7. After 5 weeks recovery period, above-mentioned changes were generally disappeared, suggesting that these were reversible. 8. The non-effective dose levels and the toxic dose levels of P-4 were estimated to be 2 mg/kg/day for males and 10 mg/kg/day for females, and 50 mg/kg/day for males and 150 mg/kg/day for females, respectively.
使用雄性和雌性Wistar大鼠对新型抗尿频药物盐酸丙哌维林（P - 4）进行了亚急性毒性研究。以2、10、50和150mg/kg/天的剂量水平对大鼠口服给药P - 4，持续13周，随后有5周的恢复期。获得的结果如下：1. 在一般状况方面，给药后立即观察到短暂流涎，给予50mg/kg/天及以上剂量的大鼠下腹部被毛有污渍。未出现与P - 4相关的死亡情况。2. 给予50mg/kg/天及以上剂量的雄性大鼠和给予150mg/kg/天的雌性大鼠体重增加受到抑制。未观察到食物消耗量有显著变化。给予50mg/kg/天及以上剂量的组饮水量增加。3. 尿液分析显示，给予50mg/kg/天及以上剂量的大鼠尿量增加、渗透压、蛋白质和尿胆原减少，电解质排泄略有增加。4. 血液学检查显示，给予150mg/kg/天的大鼠有轻微变化，如红细胞计数增加和活化部分凝血活酶时间缩短。5. 血清生化检查显示，给予50mg/kg/天及以上剂量的雄性大鼠和给予150mg/kg/天的雌性大鼠甘油三酯降低，γ-谷氨酰转肽酶和碱性磷酸酶活性以及尿素氮增加。此外，检测到雄性大鼠总胆固醇和游离胆固醇以及磷脂减少，雌性大鼠总胆固醇增加和胆碱酯酶活性降低。6. 尸检时，给予50mg/kg/天及以上剂量的大鼠胸腺和脾脏萎缩，但无组织病理学相关性。组织病理学检查显示，给予50mg/kg/天及以上剂量的雄性大鼠和给予150mg/kg/天的雌性大鼠肝细胞肥大和脂肪变性，伴有肝脏绝对重量和/或相对重量增加。电子显微镜检查显示相同组滑面内质网增生。在肾脏中，给予10mg/kg/天及以上剂量的雄性大鼠和给予50mg/kg/天及以上剂量的雌性大鼠肾小管上皮细胞中有嗜酸性和核内包涵体，其细胞质无毒性损伤。7. 5周恢复期后，上述变化一般消失，表明这些变化是可逆的。8. P - 4的无作用剂量水平估计雄性为2mg/kg/天，雌性为10mg/kg/天；毒性剂量水平估计雄性为50mg/kg/天，雌性为150mg/kg/天。
