Yoshida M, Oka T, Tawaratani T, Ishibashi S, Nakazawa M, Kitayama E, Adachi T, Iwakura K, Sumi N
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
J Toxicol Sci. 1997 Apr;22 Suppl 1:125-46. doi: 10.2131/jts.22.supplementi_125.
A 13-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 beagle dogs. Male and female dogs were given the drug orally for 13 weeks at doses of 0 (control), 5, 25 and 125 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. No effects related to the treatment were observed on survival. Mydriasis and a decrease in body weight or a suppression of its weight gain were seen in the 25 and 125 mg/kg groups. Vomiting, salivation and a decrease in food consumption were seen in the 125 mg/kg group. Ophthalmologic examination confirmed the mydriasis in the 125 mg/kg group. Electrocardiographic examination and urinalysis showed no abnormalities attributable to the treatment. Hematological examination showed an increase in number of platelets in the 125 mg/kg group. Blood chemical examination revealed increases in GPT and ALP and a decrease in albumin in the 25 and 125 mg/kg groups, and an increase in triglyceride in the 125 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy in the 125 mg/kg group, hyperplasia of smooth-ER and concentric lamellar bodies derived from the smooth-ER, and bile pigments in the bile capillary, hepatocyte and stellate cells of Kupffer in the 25 and 125 mg/kg groups. Megakaryocytes in mesenteric lymph node were observed in the 25 and 125 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. 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 13-week oral toxicity in dogs.
对一种用于治疗尿频和尿失禁的新药（±）-4-二乙氨基-1,1-二甲基丁-2-炔-1-基 2-环己基-2-羟基-2-苯基乙酸酯盐酸盐一水合物（NS-21）进行了为期 13 周的比格犬口服重复剂量毒性研究。雄性和雌性犬分别按 0（对照）、5、25 和 125 mg/kg 的剂量口服给药 13 周。停药后，还进行了为期 5 周的恢复试验。未观察到与治疗相关的对存活的影响。在 25 和 125 mg/kg 组中出现瞳孔散大以及体重减轻或体重增加受抑制的情况。在 125 mg/kg 组中出现呕吐、流涎和食物摄入量减少的情况。眼科检查证实 125 mg/kg 组存在瞳孔散大。心电图检查和尿液分析未显示出与治疗相关的异常。血液学检查显示 125 mg/kg 组血小板数量增加。血液生化检查显示 25 和 125 mg/kg 组谷丙转氨酶（GPT）和碱性磷酸酶（ALP）升高以及白蛋白降低，125 mg/kg 组甘油三酯升高。病理检查发现 125 mg/kg 组肝细胞肥大，25 和 125 mg/kg 组滑面内质网增生以及源自滑面内质网的同心板层小体，并且在 25 和 125 mg/kg 组的胆小管、肝细胞和库普弗星状细胞中发现胆色素。在 25 和 125 mg/kg 组中观察到肠系膜淋巴结中的巨核细胞。恢复试验表明上述变化可令人满意地逆转，或者这些变化的程度和频率降低。5 mg/kg 组未观察到与治疗相关的影响。这些结果表明，NS-21 在犬口服 13 周毒性试验中的无观察到有害作用水平（NOAEL）为 5 mg/kg。
