细辛中马兜铃酸的炮制脱毒研究
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摘要
细辛为马兜铃科植物北细辛、汉城细辛、或华细辛的根及根茎。始载于《神农本草经》,列为上品。具有祛风散寒、温肺化饮,通窍止痛的功效。
细辛被国家医药管理局推荐为重点发展的63种紧缺中药材之一,同时又被列为国家两个重点中药材之一,是国际国内需求量较大的常用中药。据部颁成方制剂标准和《中国药典》等得不完全统计,处方中含有细辛的中成药有176个。细辛作为马兜铃科植物含有马兜铃酸,马兜铃酸有致癌及肾损害作用。“马兜铃酸肾病”曾在国际上引起了轩然大波,2000年5月31日,FDA发布了“FDA对卫生行业的有关含有马兜铃酸植物药物和食品的通告”,并附有相关药物的目录。其中,在可能混杂有马兜铃酸的植物药物(B类)中,包括细辛这位药。2000年6月9曰,FDA在“至今未收到类似不利事件报告”的情况下,命令停止进口、制造和销售已知含有和“怀疑含有马兜铃酸的原料和成品”。至此,含有马兜铃酸的中药材陆续遭到了不同程度的禁用,对我国中药产业产生了极不良影响。
为解决细辛及众多含马兜铃酸药材的毒性问题,以去毒存效为目的,根据马兜铃酸的化学性质,采取碱制的炮制手段,将细辛中的马兜铃酸选择性的去除,而对其有效成分得以保留或少流失,在去除毒性成分的前提下,又保证不影响药材的药效。
利用HPLC、GC手段对药典规定的三个品种、五个不同产地的细辛做了质量评价的研究,筛选出了有效成分含量高、马兜铃酸含量低的品种。对细辛的不同产地、不同入药部位的有效成分和马兜铃酸的含量做了差异比较分析。结果表明,华细辛的马兜铃酸含量最高,汉城细辛的有效成分含量最高。以华细辛为供试品,以马兜铃酸A含量为指标,从七种炮制方法中筛选出碱制为最佳炮制方法。并通过正交试验确定了碱制的最佳工艺。
用HPLC、GC法对经碱制最佳工艺炮制后的细辛的毒性成分和有效成分含量做了考察。结果表明,经炮制后细辛中毒性成分马兜铃酸A含量下降了85%左右。马兜铃总酸含量下降了74%。细辛脂素含量无明显变化。细辛经炮制后马兜铃酸只痕量存在。说明碱制方法可以有效的去除细辛中的马兜铃酸而使有效成分可以大部份被保留。达到了去毒存效的炮制目的。
为了从总体上探究生品与炮制品的化学成分的变化,对炮制前后细辛大中小极性浸出物的含量作了比较。实验结果表明,炮制品较生品四种浸出物百分比含量均有下降。水及乙醇浸出物含量下降最多,环己烷浸出物次之,乙酸乙酯浸出物最少。但浸出物含量的下降与有效成分含量的降低及药效的下降是否相关有待进一步考察。
为了考察细辛炮制后的化学成分的具体变化,本文应用了当今国际上普遍承认的指纹图谱技术,对炮制前后的细辛的整体成分做了完整的比较和分析。经碱制后细辛的甲醇提取物部分变化明显。其中马兜铃酸A峰值减少。有两个峰消失。乙酸乙酯提取物部分有两组峰消失,共有峰峰面积均有减小。环己烷提取物部分无非共有峰,共有峰峰面积减小。
Herba Asari is root and rhizoma from Aristolochia plant Asarum heterotropoides Fr.Schmidt var.mandshuricum(Maxim.)Kitag,Asarum sieboldii Miq.v&r.seoulense,and Asarun sieboldii Miq,were earliest listed in the "Shen NongBenCaoJing ",as Shangpin.With qufengsanha- n,wenfeihuaxin,tongqiaozhitong effect.
As one of 63 kinds of Chinese herbal medicine in shortage,Asarum was recommended by the State Pharmaceutical Administration Bureau for focus developing.At the same time was also listed as two key medicines to our country,is now commonly used Traditional Chinese Medicine for great demand.According to Bubanchengfang preparation standards and the Chinese Pharmacopoeia's incomplete summary,there were 176 prescriptions include Herba Asari.Herba Asari as Aristolochiac plant,contains aristolochic acid,that has renal toxicity and carcinogenesis. Aristolochic Acid Renal Toxicity has caused great turbulence all over the world.By May 31rd 2000,the FDA issued a 'FDA notice on health-related plants containing aristolochic acid in drugs and food',which followed with a related-prescription catalog.Among the medicinal plants those may mixed with aristolochic acid mentioned(B),Herba Asari was listed.By June 9th 2000,FDA pressed an order to prohibit importing,manufacturing,and selling any 'aristolochic acid suspected materials and products',although they did not receive any reports of similar adverse events until then.By now,TCM within aristolochic acid were forbidden to different extent,caused great side-effect to domestic TCM industry.
For removing the toxicity in Asarum and other aristolochic acid- containing medicines,in order to remove toxicity and maintain pharmacodynamic activity,according to the chemical nature of aristolochic acid,we adopted base-processing to remove aristolochic acid in Herba Asari selectively,and retain its active ingredients.
By means of HPLC and GC,we studied queality standard of 3 spieces and 5 different habits, selected a high content of active ingredient,and low aristolochic acid spieces.Analysed effective components and aristolochic acid in Asarum from different habits,and different parts of the herb.The results showed that,the highest content of aristolochic acid was Asarun sieboldii Miq.the highest content of active ingredients was Asarum sieboldii Miq.var.seoulense.
Asarun sieboldii Miq used as experiment material,and aristolochic acid as index,selected NaHCO_3 processing method from seven processes as the best,defined the optimal process by orthogonal experiment.
GC and HPLC were used to measure toxicity components and active ingredients in Herba Asari after processing.The result indicated that after being processed aristolochic acid A in Herba Asari had been 85%off.Total aristolochic acid decreased 74%.Asarmin contents has no obvious change.It is verified that NaHCO_3 processing could reduce aristolochic acid A effectively and remain active ingredients mostly.Processing purpose is achieved.
In order to study the change of chemical composition in crude and processed Asarun sieboldii Miq,we compared contents of extracts in crude and processed Asarun sieboldii Miq from different polar solvent.The result indicated that contents of all four extracts had decreased.The extracts from aqeous and ethanal decreased most,cycloh exane less,and acetic ether least.The relationship between decrease of extracts' contents and pharmacodynamic action need to be investigated in future.
To investigate the specific chemical change in crude and processed Herba Asari,the experiment uses the finger prints technology to compare and analsyse total components of Herba Asari.After being processed,methanol extracts had changed obviously.Aristolochic acid A's chromatographic peak value decreased,and two chromatographic peaks vanished.Acetic ether extracts had two chromatographic peaks vanished.Chromatographic peak value owed by both had diminished.cyclohexane extracts chromatographic peak value decreased and composition of chromatographic peak had no change.
细辛被国家医药管理局推荐为重点发展的63种紧缺中药材之一,同时又被列为国家两个重点中药材之一,是国际国内需求量较大的常用中药。据部颁成方制剂标准和《中国药典》等得不完全统计,处方中含有细辛的中成药有176个。细辛作为马兜铃科植物含有马兜铃酸,马兜铃酸有致癌及肾损害作用。“马兜铃酸肾病”曾在国际上引起了轩然大波,2000年5月31日,FDA发布了“FDA对卫生行业的有关含有马兜铃酸植物药物和食品的通告”,并附有相关药物的目录。其中,在可能混杂有马兜铃酸的植物药物(B类)中,包括细辛这位药。2000年6月9曰,FDA在“至今未收到类似不利事件报告”的情况下,命令停止进口、制造和销售已知含有和“怀疑含有马兜铃酸的原料和成品”。至此,含有马兜铃酸的中药材陆续遭到了不同程度的禁用,对我国中药产业产生了极不良影响。
为解决细辛及众多含马兜铃酸药材的毒性问题,以去毒存效为目的,根据马兜铃酸的化学性质,采取碱制的炮制手段,将细辛中的马兜铃酸选择性的去除,而对其有效成分得以保留或少流失,在去除毒性成分的前提下,又保证不影响药材的药效。
利用HPLC、GC手段对药典规定的三个品种、五个不同产地的细辛做了质量评价的研究,筛选出了有效成分含量高、马兜铃酸含量低的品种。对细辛的不同产地、不同入药部位的有效成分和马兜铃酸的含量做了差异比较分析。结果表明,华细辛的马兜铃酸含量最高,汉城细辛的有效成分含量最高。以华细辛为供试品,以马兜铃酸A含量为指标,从七种炮制方法中筛选出碱制为最佳炮制方法。并通过正交试验确定了碱制的最佳工艺。
用HPLC、GC法对经碱制最佳工艺炮制后的细辛的毒性成分和有效成分含量做了考察。结果表明,经炮制后细辛中毒性成分马兜铃酸A含量下降了85%左右。马兜铃总酸含量下降了74%。细辛脂素含量无明显变化。细辛经炮制后马兜铃酸只痕量存在。说明碱制方法可以有效的去除细辛中的马兜铃酸而使有效成分可以大部份被保留。达到了去毒存效的炮制目的。
为了从总体上探究生品与炮制品的化学成分的变化,对炮制前后细辛大中小极性浸出物的含量作了比较。实验结果表明,炮制品较生品四种浸出物百分比含量均有下降。水及乙醇浸出物含量下降最多,环己烷浸出物次之,乙酸乙酯浸出物最少。但浸出物含量的下降与有效成分含量的降低及药效的下降是否相关有待进一步考察。
为了考察细辛炮制后的化学成分的具体变化,本文应用了当今国际上普遍承认的指纹图谱技术,对炮制前后的细辛的整体成分做了完整的比较和分析。经碱制后细辛的甲醇提取物部分变化明显。其中马兜铃酸A峰值减少。有两个峰消失。乙酸乙酯提取物部分有两组峰消失,共有峰峰面积均有减小。环己烷提取物部分无非共有峰,共有峰峰面积减小。
Herba Asari is root and rhizoma from Aristolochia plant Asarum heterotropoides Fr.Schmidt var.mandshuricum(Maxim.)Kitag,Asarum sieboldii Miq.v&r.seoulense,and Asarun sieboldii Miq,were earliest listed in the "Shen NongBenCaoJing ",as Shangpin.With qufengsanha- n,wenfeihuaxin,tongqiaozhitong effect.
As one of 63 kinds of Chinese herbal medicine in shortage,Asarum was recommended by the State Pharmaceutical Administration Bureau for focus developing.At the same time was also listed as two key medicines to our country,is now commonly used Traditional Chinese Medicine for great demand.According to Bubanchengfang preparation standards and the Chinese Pharmacopoeia's incomplete summary,there were 176 prescriptions include Herba Asari.Herba Asari as Aristolochiac plant,contains aristolochic acid,that has renal toxicity and carcinogenesis. Aristolochic Acid Renal Toxicity has caused great turbulence all over the world.By May 31rd 2000,the FDA issued a 'FDA notice on health-related plants containing aristolochic acid in drugs and food',which followed with a related-prescription catalog.Among the medicinal plants those may mixed with aristolochic acid mentioned(B),Herba Asari was listed.By June 9th 2000,FDA pressed an order to prohibit importing,manufacturing,and selling any 'aristolochic acid suspected materials and products',although they did not receive any reports of similar adverse events until then.By now,TCM within aristolochic acid were forbidden to different extent,caused great side-effect to domestic TCM industry.
For removing the toxicity in Asarum and other aristolochic acid- containing medicines,in order to remove toxicity and maintain pharmacodynamic activity,according to the chemical nature of aristolochic acid,we adopted base-processing to remove aristolochic acid in Herba Asari selectively,and retain its active ingredients.
By means of HPLC and GC,we studied queality standard of 3 spieces and 5 different habits, selected a high content of active ingredient,and low aristolochic acid spieces.Analysed effective components and aristolochic acid in Asarum from different habits,and different parts of the herb.The results showed that,the highest content of aristolochic acid was Asarun sieboldii Miq.the highest content of active ingredients was Asarum sieboldii Miq.var.seoulense.
Asarun sieboldii Miq used as experiment material,and aristolochic acid as index,selected NaHCO_3 processing method from seven processes as the best,defined the optimal process by orthogonal experiment.
GC and HPLC were used to measure toxicity components and active ingredients in Herba Asari after processing.The result indicated that after being processed aristolochic acid A in Herba Asari had been 85%off.Total aristolochic acid decreased 74%.Asarmin contents has no obvious change.It is verified that NaHCO_3 processing could reduce aristolochic acid A effectively and remain active ingredients mostly.Processing purpose is achieved.
In order to study the change of chemical composition in crude and processed Asarun sieboldii Miq,we compared contents of extracts in crude and processed Asarun sieboldii Miq from different polar solvent.The result indicated that contents of all four extracts had decreased.The extracts from aqeous and ethanal decreased most,cycloh exane less,and acetic ether least.The relationship between decrease of extracts' contents and pharmacodynamic action need to be investigated in future.
To investigate the specific chemical change in crude and processed Herba Asari,the experiment uses the finger prints technology to compare and analsyse total components of Herba Asari.After being processed,methanol extracts had changed obviously.Aristolochic acid A's chromatographic peak value decreased,and two chromatographic peaks vanished.Acetic ether extracts had two chromatographic peaks vanished.Chromatographic peak value owed by both had diminished.cyclohexane extracts chromatographic peak value decreased and composition of chromatographic peak had no change.
引文
[1]中华人民共和国药典委员会.中华人民共和国药典[M].化学工业出版社,2005,159.
[2]郭增军.刘辉.HPLC法测定不同品种商品细辛中细辛脂素和芝麻脂素的含量[J].中药材,2001,24(4):273-274.
[3]宋立群.王丽哲.马艳春等.细辛对大功告功能及组织形态学的影响[J].中医药学刊,2004,22(11):146-148.
[4]王智民。含有马兜铃酸的中成药情况分析[J].中国中药杂志,2002,27(10):800.
[5]孙建宁.徐秋苹.王风仁等.三种细辛属植物挥发油对中枢神经系统的作用[J].中国药学杂志,1991,26(8):470.
[6]陈超.郑卫红.熊素兵等.细辛与verapamil镇痛协同作用的实验研究[J].中国药理学通报,2003,19(3):337.
[7]樊景坡.苍耳子、细辛、枸杞子、白术对小鼠组织自由基代谢的影响[J].中医药信息,1994,(2):48.
[8]栗坤.郑福禄.白晶等.细辛、杜仲及其合剂对D-半乳糖所致衰老小鼠NO、NOS和MDA的影响[J].中国老年学杂志,2001,21(3):131.
[9]栗坤.郑福禄.龚淑珍等.细辛、杜仲及其合剂对D-半乳糖所致衰老小鼠NO、NOS和MDA的影响[J].黑龙江医药科学,2001,24(4):1.
[10]栗坤.曲凤玉.魏晓东等.细辛、杜仲及其合剂对D-半乳糖所致衰老小鼠心、肝组织中谷胱甘肽过氧化物酶活性的影响[J].黑龙江医药科学,1999,22(4):6.
[11]何秀芬.施子棣.蒋时红等.细辛对体外培养乳鼠心肌细胞的影响[J].河南中医药学刊,1994,9(5):26.
[12]徐军.胡月娟.纪绿屏.细辛油的血管平滑肌作用及致突变作用研究[J].中成药,1992,14(12):32.
[13]王宗先.田洪海.王责文等.细辛煎剂对动物心血管的作用[J].滨州医学院学报,1990,13(1):82.
[14]钱立群.钱大玮.谢伟等.细辛挥发油对实验性炎症大鼠血清、肝脏中锌、铜含量的影响[J].中草药.1996,27(5):290.
[15]周祯祥.李军.陈泽斌等.细辛散剂半数致死量的测定[J].湖北中医杂志,2003,25(10):52.
[16]姜廷良.关于某些中草药的动物致癌性[J].中草药,1980,11(9):425.
[17]赵辉.张健夫等.马兜铃酸的结构分析和性质研究[J].周口师范学院学报,2003,20(3):34.
[18]朱大元.蒋福祥.徐任生等.朱砂莲化学成分研究Ⅱ[J].中草药,1981,12(12):1.
[19]王宁生.马兜铃酸的毒性作用[J].中药新药与临床药理,2001,12(6):394.
[20]丁林生.马兜铃属植物的化学成分[J].中草药,1983,(9):40-48.
[21]樊均明.唐嵘等.含马兜铃酸中草药及马兜铃酸肾病的循证医学观点[J].中药新药与临床药理,2001,12(6):396-399.
[22]王浴生.中药药理与应用(第2版)[M].北京:人民卫生出版社,1998,231.
[23]王本祥.现代中药药理学[M].天津:天津科学技术出版社,1996,102.
[24]高玉桥.钟希文.梅全喜.马兜铃酸毒性作用的研究进展[J].中国药业,2004,13(11):72.
[25]林求成.林永廉.马兜铃肾病研究进展[J].福建中医学院学报,2002,12(8):59-62.
[26]吴松寒.木通所致急性肾功能衰竭2例报告[J].江苏中医,1964,(10):14.
[27]梁晓春.从马兜铃肾病谈合理使用中草药[J].中华全科医师杂志,2003,2(4):204.
[28]黎克湖.马兜铃属植物药理学研究[J].武警医学院学报,2000,9(3):230-232.
[29]叶定江主编.中药炮制学[M].上海科学技术出版社,2000:16-17.
[30]瞿京红.厚朴皮与叶及不同炮制法酚性成分的比较[J].中国医院药学杂志,2000,20(12):766.
[31]金传山.晓国.周本春等.草果炮制的初步研究[J].中成药,1998,20(2):15-16.
[32]荆伟.黄国理.柴胡的不同炮制方法对其有效成分影响的研究[J].中药材,1995,18(1):21-24.
[33]李群.卢炜.王文兰等.千金子炮制品中秦皮乙素含量的测定[J].中成药,2000,22(2):137-139.
[34]蒋纪洋.棣敏友.刘晓等.小蓟炭炮制工艺研究[J].中国中药杂志,1997,22(4):218-219.
[35]查文清.王孝涛.原思逋.炮制对直序商陆毒性成分的影响[J].北京中医药大学学报,2000,23(5):50-51.
[36]陈康.叶桥.炮制对青皮中黄酮类成分的影响[J].中药材,1996,19(4):185-186.
[37]姜翠敏.王洪隶.棣建东等.薄层扫描法测定牛膝及其炮制品中齐敦果酸含量[J].上海铁道大学学报(医学版),1998,19(11):9-10.
[38]赵亚男.周健.臧景岳.不同炮制品的毫白芍质量研究[J].基层中药杂志,2000,14(4):22-23.
[39]越斌.李晓是.方翔等.吴萸连及其炮制辅料吴茱萸的薄层层析鉴别[J].中成药,1996,18(9):21-22.
[40]刘乃强.周桂生.张新琴.用正交试验法对硅胶柱准离子交换色谱溶剂系绕的研究[J].中国药学杂志,1997,32(1):31-34.
[41]周桂生.荆乃强.孙佰功等.硅胶柱准离子交换色谱测定马钱子中士的宁含量[J].中国药学杂志,1997,32(9):553-555.
[42]刘惠茹.唐家福.凌辉伦等.姜厚朴炮制工艺及辅料的研究[J].基层中药杂志,2000,14(3):28-29.
[43]丁安伟.郭戎.林爱琴等.炮制对栀子中栀于苷含量的影响[J].中药材,1995,18(11):562-564.
[44]董玉珍.李爱群.黄志海等.盐蒸法炮制补骨脂的合理性[J].广州中医药大学学报,1999,16(3):227-229.
[45]顾志平.连文琰.刘慧灵等.中药马钱子商品中士的宁和马钱子碱的含量测定[J].中国药学杂志, 1996,31(12):747-749.
[46]刘幸平.郭戎.叶定江等.炮制对藤黄中新藤黄酸含量的影响[J].中成药,1996,18(3):17-18.
[47]丁安伟.韩戎.徐菊如等.丹皮炭中丹皮酚含量的高效液相色谱测定[J].中国中药杂志,1996,21(1):23-24.
[48]郝武常.朱志峰.束宇红.炮制对杜仲中松脂醇二葡萄糖菅含量的影响[J].中国中药杂志,1996,21(7):410-411.
[49]房德敏.中药指纹图谱技术的研究与应用[J].中草药,2005,36(4):236-237.
[50]王天松.毛细管电泳与中草药指纹图谱[J].中成药,2000,22(6):397.
[51]徐胜艳.浅谈中药指纹图谱技术的发展现状[J].黑龙江医药,2006,19(6):475.
[52]李琳.王智民.高慧敏.含马兜铃酸类中药材中马兜铃总酸的含量[J].中国实验方剂学杂志,2006,12(2):11.
[53]KazunoriHzshimoto.MasamiHiguchi.Bunsho Makino.Etal.Quantitative analysis of aristolochic acids toxic comoounds,contained in some medicinal plants.J Ethnopharm,1999,64:185.
[54]尚明英.李军.胡波等.中药关木通中马兜铃酸的含量测定[J].中草药,2000,31(12):899.
[55]姜旭.王智民.由丽双等.RP-HPLC测定不同产地青木香和细辛中马兜铃酸A的含量[J].中国药学杂志,2004,29(5):408.
[56]谢昭明.李顺祥.廖汉城.HPLC法测定细辛药材中马兜铃酸A的含量[J].中南药学,2003,1(3):36.
[57]赵霓.来剑锋.毕开顺等.反相离子色谱法测定青木香中马兜铃酸A的含量[J].沈阳药科大学学报,2001,18(2):125.
[58]常朝霞.聂贵华.陈汇强等.薄层扫描法测定青木香中马兜铃酸的含量[J].中成药,2000,22(3):229.
[59]尚明英.李军.胡波等.中药关木通中中马兜铃酸的含量测定[J].中草药,2000,31(12):899.
[60]高钧.李伟.魏峰.高效液相色谱法测定华细辛中马兜铃酸A含量[J].中国药学杂志,2005,40(20):1579-1580.
[61]蔡少青.王禾.陈世忠.北细辛非挥发性化学成分的研究[J].北京医科大学学报,1996,28(3):228.
[62]吴艳容.贾凌云.高福坤等.不同产地和采收期辽细辛挥发油的含量测定[J].沈阳药科大学学报,2006,23(5):285.
[63]张峰.付少平.徐青等.细辛GC指纹图谱的初步研究[J].中国中药杂志,2004,29(5):411.
[64]王智民.由丽双.姜旭等.利用炮制技术去除关木通毒性成分的方法学研究[J].中国中药杂志,2005,30(16):1243-1246.
[2]郭增军.刘辉.HPLC法测定不同品种商品细辛中细辛脂素和芝麻脂素的含量[J].中药材,2001,24(4):273-274.
[3]宋立群.王丽哲.马艳春等.细辛对大功告功能及组织形态学的影响[J].中医药学刊,2004,22(11):146-148.
[4]王智民。含有马兜铃酸的中成药情况分析[J].中国中药杂志,2002,27(10):800.
[5]孙建宁.徐秋苹.王风仁等.三种细辛属植物挥发油对中枢神经系统的作用[J].中国药学杂志,1991,26(8):470.
[6]陈超.郑卫红.熊素兵等.细辛与verapamil镇痛协同作用的实验研究[J].中国药理学通报,2003,19(3):337.
[7]樊景坡.苍耳子、细辛、枸杞子、白术对小鼠组织自由基代谢的影响[J].中医药信息,1994,(2):48.
[8]栗坤.郑福禄.白晶等.细辛、杜仲及其合剂对D-半乳糖所致衰老小鼠NO、NOS和MDA的影响[J].中国老年学杂志,2001,21(3):131.
[9]栗坤.郑福禄.龚淑珍等.细辛、杜仲及其合剂对D-半乳糖所致衰老小鼠NO、NOS和MDA的影响[J].黑龙江医药科学,2001,24(4):1.
[10]栗坤.曲凤玉.魏晓东等.细辛、杜仲及其合剂对D-半乳糖所致衰老小鼠心、肝组织中谷胱甘肽过氧化物酶活性的影响[J].黑龙江医药科学,1999,22(4):6.
[11]何秀芬.施子棣.蒋时红等.细辛对体外培养乳鼠心肌细胞的影响[J].河南中医药学刊,1994,9(5):26.
[12]徐军.胡月娟.纪绿屏.细辛油的血管平滑肌作用及致突变作用研究[J].中成药,1992,14(12):32.
[13]王宗先.田洪海.王责文等.细辛煎剂对动物心血管的作用[J].滨州医学院学报,1990,13(1):82.
[14]钱立群.钱大玮.谢伟等.细辛挥发油对实验性炎症大鼠血清、肝脏中锌、铜含量的影响[J].中草药.1996,27(5):290.
[15]周祯祥.李军.陈泽斌等.细辛散剂半数致死量的测定[J].湖北中医杂志,2003,25(10):52.
[16]姜廷良.关于某些中草药的动物致癌性[J].中草药,1980,11(9):425.
[17]赵辉.张健夫等.马兜铃酸的结构分析和性质研究[J].周口师范学院学报,2003,20(3):34.
[18]朱大元.蒋福祥.徐任生等.朱砂莲化学成分研究Ⅱ[J].中草药,1981,12(12):1.
[19]王宁生.马兜铃酸的毒性作用[J].中药新药与临床药理,2001,12(6):394.
[20]丁林生.马兜铃属植物的化学成分[J].中草药,1983,(9):40-48.
[21]樊均明.唐嵘等.含马兜铃酸中草药及马兜铃酸肾病的循证医学观点[J].中药新药与临床药理,2001,12(6):396-399.
[22]王浴生.中药药理与应用(第2版)[M].北京:人民卫生出版社,1998,231.
[23]王本祥.现代中药药理学[M].天津:天津科学技术出版社,1996,102.
[24]高玉桥.钟希文.梅全喜.马兜铃酸毒性作用的研究进展[J].中国药业,2004,13(11):72.
[25]林求成.林永廉.马兜铃肾病研究进展[J].福建中医学院学报,2002,12(8):59-62.
[26]吴松寒.木通所致急性肾功能衰竭2例报告[J].江苏中医,1964,(10):14.
[27]梁晓春.从马兜铃肾病谈合理使用中草药[J].中华全科医师杂志,2003,2(4):204.
[28]黎克湖.马兜铃属植物药理学研究[J].武警医学院学报,2000,9(3):230-232.
[29]叶定江主编.中药炮制学[M].上海科学技术出版社,2000:16-17.
[30]瞿京红.厚朴皮与叶及不同炮制法酚性成分的比较[J].中国医院药学杂志,2000,20(12):766.
[31]金传山.晓国.周本春等.草果炮制的初步研究[J].中成药,1998,20(2):15-16.
[32]荆伟.黄国理.柴胡的不同炮制方法对其有效成分影响的研究[J].中药材,1995,18(1):21-24.
[33]李群.卢炜.王文兰等.千金子炮制品中秦皮乙素含量的测定[J].中成药,2000,22(2):137-139.
[34]蒋纪洋.棣敏友.刘晓等.小蓟炭炮制工艺研究[J].中国中药杂志,1997,22(4):218-219.
[35]查文清.王孝涛.原思逋.炮制对直序商陆毒性成分的影响[J].北京中医药大学学报,2000,23(5):50-51.
[36]陈康.叶桥.炮制对青皮中黄酮类成分的影响[J].中药材,1996,19(4):185-186.
[37]姜翠敏.王洪隶.棣建东等.薄层扫描法测定牛膝及其炮制品中齐敦果酸含量[J].上海铁道大学学报(医学版),1998,19(11):9-10.
[38]赵亚男.周健.臧景岳.不同炮制品的毫白芍质量研究[J].基层中药杂志,2000,14(4):22-23.
[39]越斌.李晓是.方翔等.吴萸连及其炮制辅料吴茱萸的薄层层析鉴别[J].中成药,1996,18(9):21-22.
[40]刘乃强.周桂生.张新琴.用正交试验法对硅胶柱准离子交换色谱溶剂系绕的研究[J].中国药学杂志,1997,32(1):31-34.
[41]周桂生.荆乃强.孙佰功等.硅胶柱准离子交换色谱测定马钱子中士的宁含量[J].中国药学杂志,1997,32(9):553-555.
[42]刘惠茹.唐家福.凌辉伦等.姜厚朴炮制工艺及辅料的研究[J].基层中药杂志,2000,14(3):28-29.
[43]丁安伟.郭戎.林爱琴等.炮制对栀子中栀于苷含量的影响[J].中药材,1995,18(11):562-564.
[44]董玉珍.李爱群.黄志海等.盐蒸法炮制补骨脂的合理性[J].广州中医药大学学报,1999,16(3):227-229.
[45]顾志平.连文琰.刘慧灵等.中药马钱子商品中士的宁和马钱子碱的含量测定[J].中国药学杂志, 1996,31(12):747-749.
[46]刘幸平.郭戎.叶定江等.炮制对藤黄中新藤黄酸含量的影响[J].中成药,1996,18(3):17-18.
[47]丁安伟.韩戎.徐菊如等.丹皮炭中丹皮酚含量的高效液相色谱测定[J].中国中药杂志,1996,21(1):23-24.
[48]郝武常.朱志峰.束宇红.炮制对杜仲中松脂醇二葡萄糖菅含量的影响[J].中国中药杂志,1996,21(7):410-411.
[49]房德敏.中药指纹图谱技术的研究与应用[J].中草药,2005,36(4):236-237.
[50]王天松.毛细管电泳与中草药指纹图谱[J].中成药,2000,22(6):397.
[51]徐胜艳.浅谈中药指纹图谱技术的发展现状[J].黑龙江医药,2006,19(6):475.
[52]李琳.王智民.高慧敏.含马兜铃酸类中药材中马兜铃总酸的含量[J].中国实验方剂学杂志,2006,12(2):11.
[53]KazunoriHzshimoto.MasamiHiguchi.Bunsho Makino.Etal.Quantitative analysis of aristolochic acids toxic comoounds,contained in some medicinal plants.J Ethnopharm,1999,64:185.
[54]尚明英.李军.胡波等.中药关木通中马兜铃酸的含量测定[J].中草药,2000,31(12):899.
[55]姜旭.王智民.由丽双等.RP-HPLC测定不同产地青木香和细辛中马兜铃酸A的含量[J].中国药学杂志,2004,29(5):408.
[56]谢昭明.李顺祥.廖汉城.HPLC法测定细辛药材中马兜铃酸A的含量[J].中南药学,2003,1(3):36.
[57]赵霓.来剑锋.毕开顺等.反相离子色谱法测定青木香中马兜铃酸A的含量[J].沈阳药科大学学报,2001,18(2):125.
[58]常朝霞.聂贵华.陈汇强等.薄层扫描法测定青木香中马兜铃酸的含量[J].中成药,2000,22(3):229.
[59]尚明英.李军.胡波等.中药关木通中中马兜铃酸的含量测定[J].中草药,2000,31(12):899.
[60]高钧.李伟.魏峰.高效液相色谱法测定华细辛中马兜铃酸A含量[J].中国药学杂志,2005,40(20):1579-1580.
[61]蔡少青.王禾.陈世忠.北细辛非挥发性化学成分的研究[J].北京医科大学学报,1996,28(3):228.
[62]吴艳容.贾凌云.高福坤等.不同产地和采收期辽细辛挥发油的含量测定[J].沈阳药科大学学报,2006,23(5):285.
[63]张峰.付少平.徐青等.细辛GC指纹图谱的初步研究[J].中国中药杂志,2004,29(5):411.
[64]王智民.由丽双.姜旭等.利用炮制技术去除关木通毒性成分的方法学研究[J].中国中药杂志,2005,30(16):1243-1246.