糖网明目颗粒对大鼠长期毒性研究

Repeated dose toxicity of Tangwang Mingmu granules in Sprague-Dawley rats

目的观察大鼠连续灌胃给予糖网明目颗粒26周的毒性反应、程度及可逆性。方法连续灌胃给予SD大鼠糖网明目颗粒26周(以8.4、4.2和2.1 g/kg的高、中、低3个剂量给药3周,后调整为14.0、8.4和4.2 g/kg的高、中、低剂量给药23周),另设溶剂对照组(蒸馏水),每组40只;每天观察大鼠一般状态、体征、饮食情况及尿、粪便,每周称体质量1次并计算摄食量;给药中期(13周)、给药结束(26周)及恢复期(4周)后进行血液学、血液生化学、血凝指标及病理组织学检查。结果与同期对照组相比,给药期间高、中、低剂量组雄性动物体质量出现小幅降低,高、中剂量组摄食量出现降低(P<0.05);高剂量MCHC、ALT、TBIL和Na+出现降低(P<0.05),TP、ALB和D-BIL增高(P<0.05);中剂量雄性动物胸腺质量与脏器系数降低(P<0.05),高剂量雄性动物肝脏、肾脏脏器系数等升高(P<0.05);病理镜检发现,各组动物肝脏、肾脏等脏器存在不同程度的慢性炎性细胞浸润灶,雄性动物前列腺间质炎性细胞浸润。以上的个别指标虽有统计学差异,但未见明显的剂量-毒性关系,且均在正常范围内波动;其他各项指标差异均无统计学意义,未见与药物作用有关的病理变化。结论在本实验条件下,糖网明目颗粒对SD大鼠的无毒性反应剂量(NOAEL)为14.0 g/kg体质量(相当于临床成人拟用剂量的50倍)。

Objective To observe toxic symptoms and signs, toxic damage extents and reversibility in rats after oral administration of Tangwang Mingmu granules. Methods Four dose groups with 40 rats in each group were designed in this study, including control group fed with distilled water and three groups at different dosages of the test drug. Tangwang Mingmu granules were orally administered to SD rats at the dosage of 8.4, 4.2 and 2.1 g/kg for 3 weeks and 14.0, 8.4 and 4.2 g/kg for 23 weeks, for 26 consecutive weeks. The general state of the rats was observed every day, while body mass and food consumption were calculated once a week. Halfway through and at the end of the administration （ 13 and 26 weeks） and after four weeks of recovery, parameters of body mass, hematology, hematological biochemistry, organ/body mass ratio and histopathology were measured. Results Compared with the control group at the same time-point, body mass of male rats in the other three groups was slightly reduced. Food consumption in high and medium dose groups was reduced （P 〈 0.05） , MCHC, ALT, TBIL and Na ＋ in high dose group were decreased （P 〈 0.05 ）, TP, ALB and D-BIL were increased （P 〈0.05 ） , the mean body mass and relative organ weight of thymus in medium dose male rats were decreased （ P 〈 0.05 ） , relative organ weight of the liver and kidney in high dose male rats was increased （ P 〈 0.05 ）, and focal chronic inflammation to different extent was observed in the liver, kidney and prostate gland. No dose-effect relationship was found in these perturbations that were all within the normal range of animals. No significant drug-related pathological changes were found. Conclusion The NOAEL of Tangwang Mingmu granules is considered to be 14.0 g/kg body mass/ day （equal to 50 times the proposed clinical adult dosage） for the 26-week repeated dose oral toxicity study in male and female rats.