Furukawa S, Nishida I, Kikumori M, Taniguchi Y, Nishimori T, Ishibashi S, Iwakura K, Sumi N
Environmental Biological Life Science Research Center Inc., Shiga, Japan.
J Toxicol Sci. 1995 Dec;20 Suppl 2:191-213. doi: 10.2131/jts.20.supplementii_191.
A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Sprague-Dawley rats. Male and female rats were given the drug intravenously for 26 weeks at doses of 0 (control), 0.0004, 0.02, 1 and 50 mg/kg. After discontinuation of the treatment, a 9-week recovery test was also conducted in the 0, 1 and 50 mg/kg groups. No deaths related to the treatment were observed. Tremor and polyuria were seen in the 50 mg/kg group. There were decrease in body weight gain, and increase in water consumption in the 1 and 50 mg/kg groups. In those dose groups of males, decrease in food consumption was observed. Ophthalmoscopic examination failed to show any abnormalities attributable to the treatment. Blood chemical examination disclosed decrease in total cholesterol in the 50 mg/kg group. There were also decreases in phospholipid in the 50 mg/kg group of females, and in triglyceride in the 1 and 50 mg/kg groups of males. Urinalysis and hematologic examination failed to show any abnormalities attributable to the treatment. In pathological examination, serous cell hypertrophy and increase in organ weight of the submandibular gland were observed in the 1 and 50 mg/kg groups, and increase in organ weight of thyroid was revealed in the 0.02 mg/kg group and over. The changes mentioned above were satisfactorily reversible except for the decrease in food consumption in the 50 mg/kg group of males. Increased thyroid weight in the 0.02 mg/kg group was considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.02 mg/kg for 26-week repeated dose toxicity in rats.
对一种用于治疗意识障碍的新药水合蒙特瑞林（NS-3）进行了重复剂量毒性研究，实验对象为Sprague-Dawley大鼠。雄性和雌性大鼠静脉注射该药物，持续26周，剂量分别为0（对照）、0.0004、0.02、1和50mg/kg。治疗停止后，还对0、1和50mg/kg组进行了为期9周的恢复试验。未观察到与治疗相关的死亡情况。50mg/kg组出现震颤和多尿症状。1和50mg/kg组体重增加减少，饮水量增加。在这些剂量组的雄性大鼠中，观察到食物摄入量减少。眼科检查未发现任何可归因于治疗的异常情况。血液化学检查显示50mg/kg组总胆固醇降低。50mg/kg组雌性大鼠的磷脂以及1和50mg/kg组雄性大鼠的甘油三酯也有所降低。尿液分析和血液学检查未发现任何可归因于治疗的异常情况。病理检查发现，1和50mg/kg组下颌下腺浆液细胞肥大且器官重量增加，0.02mg/kg及以上剂量组甲状腺器官重量增加。除50mg/kg组雄性大鼠食物摄入量减少外，上述变化均可满意地逆转。0.02mg/kg组甲状腺重量增加被认为无毒理学意义。这些结果表明，水合蒙特瑞林对大鼠进行26周重复剂量毒性试验的无观察到有害作用水平为0.02mg/kg。
