芩黄清肺散的急性毒性和长期毒性研究
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摘要
为探索芩黄清肺散(Qinhuang qingfei powder,QQP)的安全性,对其进行急性毒性试验和长期毒性试验。急性毒性试验中,小鼠灌服QQP水煎液(6.00mg/g体重)1周,测定其半数致死量(LD50);长期毒性试验中,将96只SD大鼠随机分为高、中、低剂量组(QQP 32.00、16.00、8.00mg/g体重,相当于临床拟用剂量的96、48和24倍)和对照组。每组24只,雌雄各半。QQP制成药化饲料,喂养30d。每周记录大鼠的饮水量、耗料量、体重及精神活动等,在喂养第30天和恢复期(第45天)分别对大鼠进行血液学、血液生化、病理学方面的检查。结果表明,急性毒性试验小鼠LD50>6.00mg/g体重,实际无毒;长期毒性试验中,各剂量组大鼠饮水量、耗料量、体重、血液学指标、血液生化指标和脏器系数与对照组相比均无显著差异(P>0.05)。大鼠主要器官大体解剖和心脏、肝脏、脾脏、肺脏、肾脏、睾丸/卵巢等脏器组织病理学检查未见任何病变。综合以上结果,芩黄清肺散临床用药具有安全性。
The acute toxicity and long-term toxicity tests were carried out in order to explore the safety of Qinhuang qingfei powder(QQP).In the acute toxicity test,mice were given QQP decoction(6.00 mg/(g·BW))for one week,and the LD50 was measured.In long-term toxicity test,96 SD rats were randomly divided into high,middle and low dose groups(giving QQP decoction32.00,16.00 and 8.00 mg/(g·BW),respectively,which was equivalent to 96,48 and 24 times clinical dose)and control group,each group of 24,half male and half female.QQP was processed and added to rats' feed for 30 d.The rats were weighed every week and the rats' water intake,feed intake,body weight and mental activity were recorded.On the 30 th day and the 45 th day of feeding,blood samples were taken for measuring the indexes of hematology,blood biochemistry and pathology.The results showed that LD50 of mice was more than 6.00 mg/(g·BW)in acute toxicity test.It was non-toxic actually.In the long-term toxicity test,the differences were not significant in body weight,water intake,feed intake,hematological index or blood biochemical index between dose groups and control group(P>0.05).Most of the major organs of rats were dissected without any lesions and no lesion was observed within histopathological samples(inclu-ding heart,liver,spleen,lung,kidney and testis/ovary).The test showed that QQP was a safe drug in clinical practice.
The acute toxicity and long-term toxicity tests were carried out in order to explore the safety of Qinhuang qingfei powder(QQP).In the acute toxicity test,mice were given QQP decoction(6.00 mg/(g·BW))for one week,and the LD50 was measured.In long-term toxicity test,96 SD rats were randomly divided into high,middle and low dose groups(giving QQP decoction32.00,16.00 and 8.00 mg/(g·BW),respectively,which was equivalent to 96,48 and 24 times clinical dose)and control group,each group of 24,half male and half female.QQP was processed and added to rats' feed for 30 d.The rats were weighed every week and the rats' water intake,feed intake,body weight and mental activity were recorded.On the 30 th day and the 45 th day of feeding,blood samples were taken for measuring the indexes of hematology,blood biochemistry and pathology.The results showed that LD50 of mice was more than 6.00 mg/(g·BW)in acute toxicity test.It was non-toxic actually.In the long-term toxicity test,the differences were not significant in body weight,water intake,feed intake,hematological index or blood biochemical index between dose groups and control group(P>0.05).Most of the major organs of rats were dissected without any lesions and no lesion was observed within histopathological samples(inclu-ding heart,liver,spleen,lung,kidney and testis/ovary).The test showed that QQP was a safe drug in clinical practice.
引文
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[7]GARRIDO V,BARROS C,MELCHIADES V A,et al.Subchronic toxicity and anti-HSV-1activity in experimental animal of dolabelladienetriol from the seaweed,Dictyota pfaffii[J].Regulatory Toxicology&Pharmacology,2017,86:193-198.
[8]GOPI S,JACOB J,MATHUR K Y.Acute andsubchronic oral toxicity studies of hydrogenated curcuminoid formulation‘CuroWhite’in rats[J].Toxicology Reports,2016,3:817-825.
[9]CHRISTAPHER P V,PARASURAMAN S,ASMAWI M Z,et al.Acute andsubchronic toxicity studies of methanol extract of Polygonum minus,leaves in Sprague Dawley rats[J].Regulatory Toxicology&Pharmacology,2017,86:33-41.
[10]李胜坤,王胜义,崔东安,等.乌锦颗粒剂的急性毒性与亚慢性毒性试验研究[J].中国畜牧兽医,2015,42(5):1203-1210.LI S K,WANG S Y,CUI D A,et al.Study on acute and sub-chronic toxicity of Wu Jin granules[J].China Animal Husbandry&Veterinary Medicine,2015,42(5):1203-1210.(in Chinese)
[11]ZHU Q,QIAN Y,YANG Y,et al.Effects of carbonyl iron powder on iron deficiency anemia and itssubchronic toxicity[J].Journal of Food&Drug Analysis,2016,24(4):746-753.
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[13]WANG C,CHENG K,ZHOU L,et al.Evaluation of long-term toxicity of oral zinc oxide nanoparticles and zinc sulfate in mice[J].Biological Trace Element Research,2017,178(2):276-282.
[14]张淑香,王萌影,刘学伟,等.复方灵芝降糖胶囊大鼠给药长期毒性研究[J].中国实验方剂学杂志,2015,21(17):146-151.ZHANG S X,WANG M Y,LIU X W,et al.Toxicity of long-term intragastic administration with compound Lingzhi jiangtang capsule in rats[J].Chinese Journal of Experimental Formulas of Chinese Medicine,2015,21(17):146-151.(in Chinese)
[15]吴建华,黄宏业,杨善忠,等.胆翘注射液急性和亚慢性毒性试验[J].动物医学进展,2017,38(4):88-92.WU J H,HUANG H Y,YANG S Z,et al.Study on acute and subchronic toxicity of Danqiao injection[J].Progress in Veterinary Medicine,2017,38(4):88-92.(in Chinese)
[16]苏玉严,朱海明,杜文超,等.金克痤胶囊浸膏粉对大鼠的长期毒性试验[J].中国医院药学杂志,2014,34(16):1350-1355.SU Y Y,ZHU H M,DU W C,et al.The long-term toxicity of Jinkecuo capsules’powdered extract in rats[J].Chinese Journal of Hospital Pharmacy,2014,34(16):1350-1355.(in Chinese)
[17]邱赛红,汤淮波,李飞艳,等.常用苦寒药的急性毒性实验研究[J].中南药学,2004,2(1):37-38.QIU S H,TANG W B,LI F Y,et al.Experimental study of the acute toxicity of common-used bitter and cold medicines[J].Central South Pharmacy,2004,2(1):37-38.(in Chinese)
[18]高建波,刘云.大黄颗粒对大鼠的长期毒性试验研究[J].中国当代医药,2013,20(22):4-6.GAO J B,LIU Y.The study on the long-term toxicity of rhubarb granule torats[J].Contemporary Chinese Medicine,2013,20(22):4-6.(in Chinese)
[19]朱广双,胡元亮,刘家国,等.黄芩解毒散灌胃对小鼠的急性和亚慢性毒性试验[J].中国实验方剂学杂志,2008,14(10):80-81.ZHU G S,HU Y L,LIU J G,et al.Acute and chronic toxicity test of Scutellariae radix jiedu scattered lavage in mice[J].Chinese Journal of Experimental Traditional Medical Formulae,2008,14(10):80-81.(in Chinese)
[20]陈凯,姚景春,商庆节,等.大鼠静脉注射用银黄(冻干)1个月长期毒性[J].中国药理学与毒理学杂志,2013,27(3):533.CHEN K,YAO J C,SHANG Q J,et al.One month long-term toxicity of intravenous injection of rats with silver yellow(lyophilization)[J].Chinese Journal of Pharmacology and Toxicology,2013,27(3):533.(in Chinese)
[21]于子浇.参黄胶囊基本制备工艺及毒理学研究[D].泸州:泸州医学院,2013.YU Z J.The basic preparation process and toxicologyreseach of Yellow capsule[D].Luzhou:Luzhou Medical University,2013.(in Chinese)
[22]陈秀娟,刘香梅,庞增雄,等.枇杷叶水提物的急性毒性和遗传毒性[J].癌变·畸变·突变,2016,28(5):403-406.CHEN X J,LIU X M,PANG Z X,et al.Acute and genetic toxicity of aqueous extract of Eriobotryajaponicaleaves[J].Canceration,Aberration and Mutation,2016,28(5):403-406.(in Chinese)
[23]程艳芹,王英姿,李明春.甘草5种方法提取液主要药效学及急性毒性比较[J].中国医院药学杂志,2013,33(6):435-439.CHENG Y Q,WANG Y Z,LI M C.Comparision on the main pharmacodynamic activities of Licorice extracts picked up by 5methods and their acute toxicity[J].China Journal of Hospital Pharmacy,2013,33(6):435-439.(in Chinese)
[24]李长雷,舒细记,陈晓青,等.不同周龄和性别的SPF级SD大鼠血液生理生化指标的测定与比较分析[J].江汉大学学报(自然科学版),2016,44(1):58-63.LI C L,SHU X J,CHEN X Q,et al.Determination and comparison of blood physiological and biochemical indicators in SPF SD rats of different ages and genders[J].Journal of Jianghan University(Social Science),2016,44(1):58-63.(in Chinese)
[2]汤承,岳华,俞宁,等.复方中药制剂治疗鸡传染性喉气管炎的研究[J].西南民族大学学报(自然科学版),2006,32(6):1213-1214.TANG C,YUE H,YU N,et al.The study of treating infectious laryngotracheitis by compound chinese herbal[J].Journal of Southwest University for Nationalities(Natural Science Edition),2006,32(6):1213-1214.(in Chinese)
[3]李景峰,冯光毅.中药“喉宁散”对鸡传染性喉气管炎的防治[J].中兽医学杂志,2011,1:6-7.LI J F,FENG G Y.The prevention and control of infectious laryngotracheitis with traditional Chinese medicine“hou ning san”[J].Chinese Journal of Traditional Veterinary Science,2011,1:6-7.(in Chinese)
[4]何永明,张浩吉,杨鸿,等.“黄芩、大黄”合剂对人工诱发传染性喉气管炎患鸡血液SOD、MDA水平的影响[J].中国家禽,2003,25(17):12-14.HE Y M,ZHANG H J,YANG H,et al.Influence on SOD,MDA in blood of ILT chickens by the herbal remedies of“Huangqin&Dahuang”[J].China Poultry,2003,25(17):12-14.(in Chinese)
[5]姜玲玲,陈鸿宇,史开志,等.一种新兽用止泻中药复方制剂对大鼠的急性及亚慢性毒性试验[J].中国畜牧兽医,2016,43(11):3073-3079.JIANG L L,CHEN H Y,SH K Z,et al.Acute and sub-chronic toxicity test on rats of a new kind of antidiarrheal Chinese herbal medicine compound preparation for livestock[J].China Animal Husbandry&Veterinary Medicine,2016,43(11):3073-3079.(in Chinese)
[6]JIA R L,XU S,GUO Y F,et al.Acute and subchronic toxicity as well as evaluation of safety pharmacology of modified Pulsatilla granules[J].Journal of Integrative Agriculture,2017,16(3):671-678.
[7]GARRIDO V,BARROS C,MELCHIADES V A,et al.Subchronic toxicity and anti-HSV-1activity in experimental animal of dolabelladienetriol from the seaweed,Dictyota pfaffii[J].Regulatory Toxicology&Pharmacology,2017,86:193-198.
[8]GOPI S,JACOB J,MATHUR K Y.Acute andsubchronic oral toxicity studies of hydrogenated curcuminoid formulation‘CuroWhite’in rats[J].Toxicology Reports,2016,3:817-825.
[9]CHRISTAPHER P V,PARASURAMAN S,ASMAWI M Z,et al.Acute andsubchronic toxicity studies of methanol extract of Polygonum minus,leaves in Sprague Dawley rats[J].Regulatory Toxicology&Pharmacology,2017,86:33-41.
[10]李胜坤,王胜义,崔东安,等.乌锦颗粒剂的急性毒性与亚慢性毒性试验研究[J].中国畜牧兽医,2015,42(5):1203-1210.LI S K,WANG S Y,CUI D A,et al.Study on acute and sub-chronic toxicity of Wu Jin granules[J].China Animal Husbandry&Veterinary Medicine,2015,42(5):1203-1210.(in Chinese)
[11]ZHU Q,QIAN Y,YANG Y,et al.Effects of carbonyl iron powder on iron deficiency anemia and itssubchronic toxicity[J].Journal of Food&Drug Analysis,2016,24(4):746-753.
[12]彭健波,陶卿,李锦辉,等.蟾酥微丸的急性与亚慢性毒性研究[J].中国畜牧兽医,2017,44(5):1508-1517.PENG J B,TAO Q,LI J H,et al.Acute and subchronic toxicity study of Chansu pellets[J].China Animal Husbandry&Veterinary Medicine,2017,44(5):1508-1517.(in Chinese)
[13]WANG C,CHENG K,ZHOU L,et al.Evaluation of long-term toxicity of oral zinc oxide nanoparticles and zinc sulfate in mice[J].Biological Trace Element Research,2017,178(2):276-282.
[14]张淑香,王萌影,刘学伟,等.复方灵芝降糖胶囊大鼠给药长期毒性研究[J].中国实验方剂学杂志,2015,21(17):146-151.ZHANG S X,WANG M Y,LIU X W,et al.Toxicity of long-term intragastic administration with compound Lingzhi jiangtang capsule in rats[J].Chinese Journal of Experimental Formulas of Chinese Medicine,2015,21(17):146-151.(in Chinese)
[15]吴建华,黄宏业,杨善忠,等.胆翘注射液急性和亚慢性毒性试验[J].动物医学进展,2017,38(4):88-92.WU J H,HUANG H Y,YANG S Z,et al.Study on acute and subchronic toxicity of Danqiao injection[J].Progress in Veterinary Medicine,2017,38(4):88-92.(in Chinese)
[16]苏玉严,朱海明,杜文超,等.金克痤胶囊浸膏粉对大鼠的长期毒性试验[J].中国医院药学杂志,2014,34(16):1350-1355.SU Y Y,ZHU H M,DU W C,et al.The long-term toxicity of Jinkecuo capsules’powdered extract in rats[J].Chinese Journal of Hospital Pharmacy,2014,34(16):1350-1355.(in Chinese)
[17]邱赛红,汤淮波,李飞艳,等.常用苦寒药的急性毒性实验研究[J].中南药学,2004,2(1):37-38.QIU S H,TANG W B,LI F Y,et al.Experimental study of the acute toxicity of common-used bitter and cold medicines[J].Central South Pharmacy,2004,2(1):37-38.(in Chinese)
[18]高建波,刘云.大黄颗粒对大鼠的长期毒性试验研究[J].中国当代医药,2013,20(22):4-6.GAO J B,LIU Y.The study on the long-term toxicity of rhubarb granule torats[J].Contemporary Chinese Medicine,2013,20(22):4-6.(in Chinese)
[19]朱广双,胡元亮,刘家国,等.黄芩解毒散灌胃对小鼠的急性和亚慢性毒性试验[J].中国实验方剂学杂志,2008,14(10):80-81.ZHU G S,HU Y L,LIU J G,et al.Acute and chronic toxicity test of Scutellariae radix jiedu scattered lavage in mice[J].Chinese Journal of Experimental Traditional Medical Formulae,2008,14(10):80-81.(in Chinese)
[20]陈凯,姚景春,商庆节,等.大鼠静脉注射用银黄(冻干)1个月长期毒性[J].中国药理学与毒理学杂志,2013,27(3):533.CHEN K,YAO J C,SHANG Q J,et al.One month long-term toxicity of intravenous injection of rats with silver yellow(lyophilization)[J].Chinese Journal of Pharmacology and Toxicology,2013,27(3):533.(in Chinese)
[21]于子浇.参黄胶囊基本制备工艺及毒理学研究[D].泸州:泸州医学院,2013.YU Z J.The basic preparation process and toxicologyreseach of Yellow capsule[D].Luzhou:Luzhou Medical University,2013.(in Chinese)
[22]陈秀娟,刘香梅,庞增雄,等.枇杷叶水提物的急性毒性和遗传毒性[J].癌变·畸变·突变,2016,28(5):403-406.CHEN X J,LIU X M,PANG Z X,et al.Acute and genetic toxicity of aqueous extract of Eriobotryajaponicaleaves[J].Canceration,Aberration and Mutation,2016,28(5):403-406.(in Chinese)
[23]程艳芹,王英姿,李明春.甘草5种方法提取液主要药效学及急性毒性比较[J].中国医院药学杂志,2013,33(6):435-439.CHENG Y Q,WANG Y Z,LI M C.Comparision on the main pharmacodynamic activities of Licorice extracts picked up by 5methods and their acute toxicity[J].China Journal of Hospital Pharmacy,2013,33(6):435-439.(in Chinese)
[24]李长雷,舒细记,陈晓青,等.不同周龄和性别的SPF级SD大鼠血液生理生化指标的测定与比较分析[J].江汉大学学报(自然科学版),2016,44(1):58-63.LI C L,SHU X J,CHEN X Q,et al.Determination and comparison of blood physiological and biochemical indicators in SPF SD rats of different ages and genders[J].Journal of Jianghan University(Social Science),2016,44(1):58-63.(in Chinese)