Harling R J, Gopinath C, Matthiesen T, Ishibashi S, Iwakura K, Sumi N
Huntingdon Research Centre Ltd., Cambridgeshire, England.
J Toxicol Sci. 1995 Dec;20 Suppl 2:215-36. doi: 10.2131/jts.20.supplementii_215.
A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in beagle dogs. The dogs were given the drug intravenously for 4 weeks at doses of 0 (control), 0.0002, 0.002, 0.02, 0.2, 2 and 20 mg/kg in males and 0, 0.2, 2 and 20 mg/kg in females. After discontinuation of the treatment, a 4-week recovery test was also conducted in the 0 and 20 mg/kg groups. No deaths related to the treatment were observed. There were no changes in body weight gain, and food and water consumptions. Nasal discharge was seen in all dose groups. Salivation, emesis and hypoactivity were observed in the 0.2 mg/kg group and over. Licking chops were seen in the 2 and 20 mg/kg groups. Trembling and agitated/restless behavior were seen in the 20 mg/kg group. Electrocardiographic examination revealed elevated heart rate in the 0.2 mg/kg group and over. Ophthalmoscopic and hematologic examinations, and urinalysis failed to show any abnormalities attributable to the treatment. Blood chemical examination disclosed increases in T3 level in the 2 and 20 mg/kg groups of males and in T4 level in the 0.2 mg/kg group and over of males. There were no pathological findings attributable to the treatment. The changes mentioned above were satisfactorily reversible. The nasal discharge seen in the 0.02 mg/kg group and below was considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.02 mg/kg for 4-week repeated dose toxicity in dogs.
对用于治疗意识障碍的新药水合孟替瑞林（NS - 3）进行了比格犬重复给药毒性研究。雄性犬以0（对照）、0.0002、0.002、0.02、0.2、2和20mg/kg的剂量静脉注射给药4周，雌性犬以0、0.2、2和20mg/kg的剂量给药。停药后，还对0和20mg/kg组进行了为期4周的恢复试验。未观察到与治疗相关的死亡。体重增加、食物和水消耗均无变化。所有剂量组均出现鼻分泌物。在0.2mg/kg及以上剂量组观察到流涎、呕吐和活动减少。在2和20mg/kg组观察到咂嘴。在20mg/kg组观察到颤抖和激动/不安行为。心电图检查显示0.2mg/kg及以上剂量组心率升高。眼科和血液学检查以及尿液分析未显示任何与治疗相关的异常。血液化学检查显示，雄性2和20mg/kg组T3水平升高，雄性0.2mg/kg及以上剂量组T4水平升高。未发现与治疗相关的病理结果。上述变化可令人满意地逆转。0.02mg/kg及以下剂量组出现的鼻分泌物被认为无毒理学意义。这些结果表明，水合孟替瑞林对犬进行4周重复给药毒性的无观察到有害作用水平为0.02mg/kg。
