贯叶连翘提取物对Beagle犬长期毒性研究

Studies on Chronic Toxicity of Hypericum Perforatum Extract on Beagle Dogs

目的 观察贯叶连翘提取物经口给药9个月对Beagle犬长期毒性反应.方法 选用Beagle犬28条,随机分为4组,每组6～8条,雌雄各半.以0.3、0.55、1.0 g/kg剂量的贯叶连翘提取物（胶囊）经口给药,每日1次,每周6次,连续38周,停药恢复期8周.在整个实验期间,每日观察受试动物的一般活动状况,每周称体质量1次,并于给药前、给药10、20、30、38周、停药8周时,作心电图（Ⅱ导联ECG）检查,前肢抽血作血液学和血清生化学检测,收集尿液作尿常规检验,给药20、38周、停药8周时,处死部分动物取主要脏器和组织称重,并作组织形态学检查.结果 在给药10、20、30、38周和停药恢复期8周时,各剂量组和对照组动物一般活动状况、心电图检查、血液学和尿常规检测均未见有明显的异常改变.但在给药20、30周时高剂量组动物ALP、给药38周时中、高剂量组TBIL升高（P＜0.05或P＜0.01）,届时,高剂量组动物肝脏系数上升（P＜0.05）.病理检查亦显示,给药20周时,高剂量组雌、雄各有1条动物肝细胞轻度颗粒变性,雌性有1条肾曲管轻度颗粒样变性;给药38周时,仅高剂量组动物少量肝细胞或肾近曲小管有轻度颗粒样变性.其余各剂量组动物各时点的血液学和血清生化学指标、脏器系数、组织形态学变化与相应对照组比均无显著性差异（P＞0.05）.结论 贯叶连翘提取物连续给药20、38周时,0.55、1.0 g/kg组Beagle犬肝、肾组织形态和功能呈现轻度的毒性反应,但停药后可随时间而逐步恢复正常,其毒性反应程度与给药剂量和服用持续时间呈正相关.贯叶连翘提取物经口给Beagle犬的安全剂量为0.3 g/kg,相当临床治疗抑郁症拟用剂量的40倍.

Objective To investigate the chronic toxicity of Hypericum perforatum extract through oral administration for 9 months on Beagle dogs. Methods Twenty-eight Beagle dogs were randomly divided into blank control group and low, middle and high dose groups,which were treated respectively with Hypericum perforatum extract （0.3, 0.55, 1.0 g/kg） by oral administration, once a day, 6 times weekly for 38 weeks. During the whole experimental period, the Beagle dogs were treated with Hypericum perforatum extract through deglutiatur administration once a day for successive 38 weeks, meanwhile the activities of the dogs were observed once a day, the body weight were weighed weekly. Electrocardiographic examination, blood counts determination, serum biochemical measurement, urinalysis test and histomorphologic observation were conducted on the 10th, 20th, 30th, 38th week with successive administration and on the 46th week without administration for 8 weeks. Some animal in each group were sacrificed, whose organs and tissues were harvested, of which the main ones were weighted and examined histopathologically on the 20th, the 38th week with administration and the 46th week without administration for 8 weeks. Results During the whole experimental period, the animal activities, electrocardiographic examination, blood counts determination and urinalysis test showed no obvious abnormalities. But ALP increased in blood of the Beagle dogs in the 1.0 g/kg groups on the 20th and the 30th week with administration, TBIL increased in the 0.55 g/kg and 1.0 g/kg groups on the 38th week （P 〈0.05 or P〈0.01）. Meanwhile, liver coefficient increased in the 1.0 g/kg groups （P〈0.05） on the 20 th, 38th week after administration. Pathological examination showed that slightly granular degeneration ap- peared in the liver cells of 2 animals （1 ~ ,1 $ ） and in the renal tubules of 1 animal （ ♀ ） in the 1.0 g/kg groups on the 20th and 38th weeks, regardless of sex. There was no significant difference between the rest of the treatment groups and the corresponding control group in hematological and serum biochemi- cal indexes, the organ coefficient, the morphological changes （P〉0.05）. Conclusion Some mild toxic effects on the liver and kidney function or organization were found on the 20th and 38th week when the Beagle dogs were treated with Hypericum perforatum extract （0.55, 1.0 g/kg） through successive oral administration once a day for 38 weeks, but could disappear gradually over time after withdrawn. The degree of toxicity was positively correlated with the dose of administration and the medication cycle. The safe dosage of Hypericum perforatum extract by intragastric administration is 0.3 g/kg, equivalent to 40 times of clinical depression treatment dose.