灯盏花素对正常和眼底病变模型大鼠影响的比较研究

目的：通过比较灯盏花素对正常和眼底病变大鼠的影响，探索以模型动物评价中药安全性的可行性及注意事项。方法：将160只SD大鼠随机分为空白对照组、模型组、灯盏花素(正常动物)2.0 g/kg组(简称正常-高组)、灯盏花素(模型动物)0.8 g/kg(简称模型-低组)、灯盏花素(模型动物)2.0 g/kg组(简称模型-高组)，每组32只，雌雄各半。各组的给药容积均为15 mL/kg,1次/d，连续给予灭菌动物饮用水和浓度为0.05、0.13 g/mL的灯盏花素混悬液9 d后，模型组和模型-低、高组以0.06 g/kg剂量腹腔注射碘酸钠(NaIO3)溶液1次造模，空白对照组、正常-高组同法注射氯化钠注射液。造模次日各组继续给药，实际给药天数分别为11、15、29、36 d，停药后继续观察至造模后第41、62天。试验期间每天观察动物一般体征、每周称量体质量，于造模后第3、7、21、28、41、62天随机抽取大鼠腹主动脉采血进行血清生化学指标检测，主要脏器称重和组织病理学检查。结果：灯盏花素对大鼠体质量和正常大鼠一般体征均没有影响，但可减少因注射NaIO3引起稀便的大鼠数量；正常-高组大鼠血清生化学指标无毒理学意义的轻微波动，但模型-低组和模型-高组大鼠造模初期血清化学指标升高。连续给药11 d可使模型-高组雌鼠肾上腺重量和正常-高组雄鼠胸腺重量增大，给药15 d可使正常雌鼠肾上腺重量减轻，上述指标组间比较均具有显著性差异(P<0.05)。灯盏花素两个剂量对正常大鼠脏器组织形态均没有影响，但可明显减轻模型大鼠的视网膜病变。结论：灯盏花素模型大鼠重复给药的无毒性反应剂量(NOAEL)低于正常动物，以模型动物开展临床前安全性评价存在降低受试物安全剂量范围的可能性，在模型动物的选择方面应排除造模药物的影响，包括考虑造模药物和评价药物之间的相互作用和模型背景数据的建立等。

Comparative Study of Breviscapine on Normal Fundus and Fundus Lesion in Rats

Objective:To explore the feasibility and precautions of using model animals to evaluate the safety of Chinese medicinal,by comparing the effects of breviscapine on normal fundus and fundus lesion in rats.Methods:160 SD rats were randomly divided into the blank control group,the model group,the breviscapine(normal animal) 2.0 g/kg group(abbreviated as normal-high group),the breviscapine(model animal) 0.8 g/kg(abbreviated as model-low group),and the breviscapine(model animal) 2.0 g/kg(abbreviated as model-high group),with 32 rats in each group.Each group was given the sterilized animal drinking water and breviscapine suspension(0.05 g/ml or 0.13 g/ml) with a dose of 15 ml/kg and a frequency of one time per 24h.9 days after administration,the model group,the model-low group and the model-high group were intraperitoneally injected with NaIO3 once at a dose of 0.06 g/kg,the blank control group and the normalhigh group were injected with NaCl at the same dose.The next day after modeling,each group continued to give the corresponding solvent and breviscapine suspension,the actual days of administration were 11 d,15 d,29 d and 36 d,respectively.After drug withdrawal,the observation continued until the 41 st and 62 nd days after model establishment.During the study period,the general signs were observed every day,the body weight was measured every week.On the 3 rd,7 th,21 st,28 th,41 st and 62 nd days after modeling,rats were randomly selected and their blood were collected from abdominal aorta to detect serum biochemical indicators,organ weighing and histopathology were carried out.Results:Breviscapine had no effect on body weight and general signs of the normal rats,however it can reduce the number of rats with loose stool caused by NaIO3.There was slight fluctuations in biochemical indexes but without toxic significance in the normalhigh group,but the biochemical indexes were increased in the model-low group and the model-high group at the early stage of modeling.After 11 days of continuous administration,the adrenal gland weight of the female rats in the model-high group and thymus weight of the male rats in the normal-high group were increased;after 15 days of administration,the adrenal gland weight of the normal female rats was reduced;there were statistical differences in the above indexes among the groups(P<0.05).Breviscapine had no effect on all organs of the normal rats,but it had preventive and therapeutic effect on retinopathy of the modeling rats.Conclusion:The no observed adverse effect level(NOAEL) of repeated administration was lower in the rats of the model-breviscapine groups than that in the normal rats.It was possible to reduce the safe dose range of drugs by conducting preclinical safety evaluation research on model animals.When selecting model animals,the influence of modeling drugs should be excluded,including considering the interaction between modeling drugs and evaluation drugs,as well as considering establishment of model background data.