Kim J-C, Shin D-H, Ahn T-H, Kang S-S, Song S-W, Han J, Kim C-Y, Ha C-S, Chung M-K
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, South Korea.
Food Chem Toxicol. 2003 May;41(5):637-45. doi: 10.1016/s0278-6915(02)00325-3.
The purpose of this study is to investigate the potential subchronic toxicity of DW-116 by a 26-week repeated oral dose in Sprague-Dawley rats. The test article, DW-116, was administered daily by gavage to male and female rats at dose levels of 0, 5, 25 and 125 mg/kg/day. At the end of the treatment period, 12 rats/sex/group were sacrificed, while six extra rats/sex in the vehicle control and highest dose groups were sacrificed after a 4-week recovery. During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. There was no treatment-related mortality. An increase in the incidence of post-dosing salivation was observed in both sexes of the highest dose group. At the scheduled autopsy, an increase in the liver weight was observed in males of the highest dose group in a dose-dependent manner. Hematological investigations revealed a dose-dependent increase in the total white blood cell (WBC) and lymphocyte counts in males treated with the 125 mg/kg dose. Total bilirubin and alanine aminotransferase (ALT) values were also increased in males at the same dose. These effects were completely reversible during the recovery period. There were no adverse effects on body weight, food and water consumption, ophthalmoscopy, urinalysis, necropsy findings and histopathology in any treatment group. Based on these results, it was concluded that the 26-week repeated oral dose of DW-116 caused increases in the liver weight, WBC counts, total bilirubin and ALT values in males at a dose level of 125 mg/kg/day. The target organ was determined to be the liver and WBC in males, but not in females. The no-observed-adverse-effect level (NOAEL) was considered to be 25 mg/kg/day for males and 125 mg/kg/day for females.
本研究的目的是通过对Sprague-Dawley大鼠进行26周重复口服给药，研究DW-116的潜在亚慢性毒性。受试物DW-116以0、5、25和125mg/kg/天的剂量水平每日经口灌胃给予雄性和雌性大鼠。在治疗期结束时，每组处死12只/性别大鼠，而溶剂对照组和最高剂量组中额外的6只/性别大鼠在4周恢复期后处死。在试验期间，检查了临床体征、死亡率、体重、食物和水消耗量、检眼镜检查、尿液分析、血液学、血清生物化学、大体检查结果、器官重量和组织病理学。未观察到与治疗相关的死亡。在最高剂量组的两性中均观察到给药后流涎发生率增加。在预定的尸检中，最高剂量组雄性大鼠的肝脏重量呈剂量依赖性增加。血液学研究显示，接受125mg/kg剂量治疗的雄性大鼠的总白细胞（WBC）和淋巴细胞计数呈剂量依赖性增加。相同剂量下雄性大鼠的总胆红素和丙氨酸转氨酶（ALT）值也升高。这些影响在恢复期完全可逆。任何治疗组的体重、食物和水消耗量、检眼镜检查、尿液分析、尸检结果和组织病理学均未出现不良反应。基于这些结果，得出结论：26周重复口服DW-116导致雄性大鼠在125mg/kg/天的剂量水平下肝脏重量、WBC计数、总胆红素和ALT值增加。确定雄性大鼠的靶器官为肝脏和WBC，而雌性大鼠不是。雄性大鼠的未观察到不良反应水平（NOAEL）被认为是25mg/kg/天，雌性大鼠为125mg/kg/天。
