世界中医药

作者	单位
郝二伟1，2，王勤1，谭珍瑗3，王峥屹4，邓家刚1，2	1 广西中医药大学广西中药药效研究重点实验室，南宁，530200； 2 广西农作物废弃物功能成分研究协同创新中心，南宁，530200； 3 广西医科大学，南宁，530021； 4 四川天然药物研究所，成都，610041

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中文摘要:

目的：通过Beagle犬长期灌胃给药，考察芒果苷的长期毒性，为临床安全用药的剂量设计提供参考。方法：芒果苷以0.2,1.0,0 g/kg剂量灌服给予Beagle犬，对照组给予0.5%CMC-Na。给药1次/d，连续1个月。测体重、体温1次/周，并根据体重调整给药量。于给药前、给药结束和恢复结束时进行眼科检查、心电图分析、尿液分析，并采血进行血液、血液生化学、血液电解质、血凝等检测，给药结束时各组取4只犬麻醉后取骨髓涂片检查，然后放血处死，进行系统尸解和组织病理学检查。给药结束后各组剩余2只犬停药，常规喂2周，进行可逆性和延迟毒性观察。结果：在给药期间，给药犬粪便颜色加深，但粪便形状、排便次数、排便量均正常；其余外观体征、行为活动、腺体分泌、摄食情况等无明显异常。芒果苷连续给予Beagle 1犬1个月：犬体重增长正常，各给药组在各时点对对照组比较，差异均无统计学意义（P>0.05）；犬心率G波、PR间期、QRS间期、QT间期、ST段偏移量均正常，各给药组在各时点与对照组比较，心率差异无统计学意义（P>0.05）；血液学各指标均正常；血液生化学各指标均正常。无论给药前，还是给药后，各犬左右两眼曲光介质透明度、视网膜、血管、视乳头均基本正常，未见有供试品引起的明显改变。芒果苷连续给予Beagle犬1个月，与对照组比较，给药犬骨髓增生活跃，粒系细胞与红系有核细胞比例正常，粒系及红系各阶段细胞比例未见异常，淋巴系和巨核细胞系亦无特殊，属正常骨髓象；各给药组在各时点与对照组比较，骨髓各类细胞均无明显异常。芒果苷连续给予Beagle犬1个月及停药恢复2周，与对照组比较，给药犬脏器重量及系数基本正常，各给药组在各时点与对照组比较，高剂量组在给药结束时睾丸和附睾重量和系数均明显高于对照组，差异有统计学意义（P<0.05）。结论：芒果苷连续给药1个月和停药恢复2周，各给药组均有一些散在病变发生，但病变特征没有共性，也未见有剂量-毒性关系，且部分改变也见于对照组，未发现在供试品剂量范围，因供试品导致的Beagle犬的特征病变和毒性靶器官，给药剂量与药时曲线下面积呈正相关，长期经口给予芒果苷于Beagle犬体内显露无蓄积倾向。Beagle犬安全剂量上限范围为4 g/kg，为人临床拟推荐剂量的127倍。因此，按临床拟推荐剂量用药应是比较安全的。

English Summary:

To study long-term toxicity of mangiferin and to provide reference for the safety dose of clinical drugs.Methods:Mangiferin was given to Beagle dogs at a dose of 0.2 g/kg,1 g/kg and 4 g/ kg.The control group was given 0.5% CMC-Na once a day,lasting 1 month.To measure body weight once a week,body temperature 1 times,and adjust the dosage according to body weight.The blood,blood biochemistry,blood electrolytes,blood clotting and other tests were performed at the end of administration.Also,the blood samples were collected at the end of the administration.After given anesthesia,take bone marrow smear,and then bleeding dogs to death for autopsy and histopathological examination.At the end of the administration,the remaining 2 dogs in each group were routinely fed for 2 weeks to observe reversibility and delayed toxicity.Results:During the period,the color of the dogs was deepened,but their stool shape,defecation frequency and defecation volume were normal.Other signs including behavioral activities,glandular secretion and feeding did not change obviously.Results:Showed that there was no significant difference between the control group and the experiment group at each time point.The dog heart rate G wave,PR interval,QRS interval,QT interval,ST segment offset were normal.At each time point,compared with the control group,heart rate were of no significant difference,hematology indicators were normal and blood biochemical indicators were normal in the treatment groups.Before and after treatment,eyes light media transparency,retina,blood vessels,optic papilla are basically normal in all groups,and no significant changes was caused by the test sample.Mangiferins were given to Beagle dogs for 1 month,and compared with the control group,the bone marrow hyperplasia was active,the proportion of granulocytes and erythroid nucleated cells,the proportion of granulocytes and erythrocytes,megakaryocyte cell line are all normal.Compared with the control group,bone marrow cells were with no significant abnormalities in all treatment group.Mangiferins were given Beagle dogs for 1 month and recovered for 2 weeks.Compared with the control group,the weight and coefficient of the organs in the treatment group were normal at each time point.The weight and coefficient of testes and epididymis were significantly higher than those of the control group at the end of the experiment (P<0.05).Conclusion:Mangiferin was administered continuously for 1 week and stopped for 2 weeks.There were some scattered lesions in the treatment group,but the lesion was not common and no dose-toxicity relationship was observed.In the control group,it was found that the dose and the target organ of Beagle dogs caused by the test product were positively correlated with the area under the curve,and the long-term oral administration of mangiferin showed a tendency to accumulate in Beagle dogs.The Beagle dogs have a maximum dose limit of 4 g / kg,which is 127 times higher than the clinical recommended dose.Therefore,clinical recommended dose should be safe.

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