Kadota T, Kondoh H, Chikazawa H, Kawano S, Kuroyanagi K, Ohta S, Ishikawa K, Kai S, Kohmura H, Takahashi N
Preclinical Research Laboratories, Bristol-Myers Research Institute, Ltd.
Jpn J Antibiot. 1990 Jul;43(7):1243-59.
In order to investigate the repeated dose oral toxicity of BMY-28100 in juvenile rats, the drug was administered orally to 4-day-old Crj: CD(SD) rats of both sexes at daily doses of 250, 750 and 1,500 mg/kg for 4 weeks. The results obtained are summarized as follows: 1. Soiling around the anus apparently correlated to soft stool or diarrhea was observed at 750 and 1,500 mg/kg and the incidence appeared to be dose-related. Three deaths including 1 death due to cannibalization occurred at 750 and 1,500 mg/kg, but they were considered to have been caused by misadministration. 2. Slightly depressed body weight gains were noted in the 750 and 1,500 mg/kg dose groups during early dosing period. 3. Slightly increased averages of food and water consumption observed predominantly in the 1,500 mg/kg dose group at later dosing period and the recovery period were considered as incidental and unrelated to the treatment. 4. Though average values of some blood chemical parameters were slightly suppressed or elevated compared with those of controls at the completion of the dosing and recovery periods, these differences appeared to be generally within normal ranges and to be irrelevant to the drug treatment. No definitive drug-related changes were detected in hematological examinations and urinalyses. 5. The average absolute and/or relative organ weights of the brain, thymus, lungs and liver from male rats in the 1,500 mg/kg dose group were lower than those of the corresponding organs from controls. However, these findings were not considered to be toxicologically significant because no corroborative changes were detected microscopically. 6. Macroscopic and microscopic examinations demonstrated dilatation of the cecum in a dose-related fashion. This phenomenon has been reported with other antibiotics and appears to be drug-related and reversible caused by an alteration of the gut flora. There were no other microscopic changes that were considered to be related to the administration of the drug. 7. Electron microscopic examination revealed no drug-related changes in the liver and kidneys from rats of the 1,500 mg/kg dose group. Based upon these results, the no-effect dose level of BMY-28100 was estimated to be 250 mg/kg/day for both male and female juvenile rats in the 4-week repeated dose oral toxicity study if the finding of cecum dilatation was not considered.(ABSTRACT TRUNCATED AT 400 WORDS)
为研究BMY - 28100对幼年大鼠的重复剂量口服毒性，对4日龄的Crj:CD(SD)雌雄大鼠每日经口给予剂量分别为250、750和1500 mg/kg的该药物，持续4周。所得结果总结如下：1. 在750和1500 mg/kg剂量组观察到肛门周围明显的粪便污染，这显然与软便或腹泻相关，且发生率似乎与剂量有关。在750和1500 mg/kg剂量组发生了3例死亡，其中1例死于同类相食，但认为是给药失误所致。2. 在给药初期，750和1500 mg/kg剂量组的体重增加略有下降。3. 在给药后期和恢复期，主要在1500 mg/kg剂量组观察到食物和水消耗量的平均值略有增加，这被认为是偶然的，与治疗无关。4. 尽管在给药期和恢复期结束时，一些血液化学参数的平均值与对照组相比略有降低或升高，但这些差异似乎总体在正常范围内，与药物治疗无关。在血液学检查和尿液分析中未检测到明确的药物相关变化。5. 1500 mg/kg剂量组雄性大鼠的大脑、胸腺、肺和肝脏的平均绝对和/或相对器官重量低于对照组相应器官的重量。然而，这些发现不被认为具有毒理学意义，因为在显微镜下未检测到佐证性变化。6. 大体和显微镜检查显示盲肠扩张与剂量相关。这种现象在其他抗生素中也有报道，似乎与药物有关，是由肠道菌群改变引起的，且是可逆的。没有其他被认为与药物给药相关的显微镜下变化。7. 电子显微镜检查显示1500 mg/kg剂量组大鼠的肝脏和肾脏没有药物相关变化。基于这些结果，如果不考虑盲肠扩张这一发现，在为期4周的重复剂量口服毒性研究中，BMY - 28100对雄性和雌性幼年大鼠的无效应剂量水平估计为250 mg/kg/天。（摘要截取自400字）
