丹参素冰片酯的结构表征、质量控制及其药代动力学研究
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摘要
心脑血管疾病(CDV)是“威胁人类健康的第一杀手”,研究和开发高效创新药物是治疗这一疾病的主要手段,也是医药领域研究的热点问题。丹参素冰片酯(简写:DBZ),是由作者所在研究中心应用代谢组学研究技术,在对复方丹参滴丸、丹参饮和冠心丹参片等复方丹参方的深入研究过程中提出,并结合有机合成、现代药理学等技术合成的一个全新化合物,该化合物具有明显的抗大鼠急性心肌缺血、降低血压等作用。本论文以丹参素冰片酯为研究对象,围绕其结构表征、质量控制和体内代谢方法的建立展开研究,对进一步将其开发为1类化学新药具有重要意义。主要研究内容如下:
1、采用MS、IR、NMR等手段对丹参素冰片酯(DBZ)进行了结构表征。结果表明:DBZ分子量为334.2,化学名称为3-(3,4-二羟基苯基)-2-羟基丙酸-1,7,7-三甲基双环[2.2.1]-2-庚醇酯。拟定合成路线,所得产物为旋光异构体,在反相液相色谱图中出峰特征为双峰。
2、围绕样品的性状、理化常数、鉴别、检查及含量测定等初步建立了丹参素冰片酯的质量标准。有机溶剂残留检查结果表明,三批样品均未检测出乙醚、丙酮、四氢呋喃、乙酸乙酯和甲醇,乙醇残留量小于0.5%;有关物质和含量测定的方法学考察表明丹参素冰片酯在5 mg·L~(-1)～1000 mg·L~(-1)范围内线性关系良好,检测限为10 ng,证明所建方法专属性强、灵敏度高,可用于丹参素冰片酯的质量控制研究。稳定性研究表明:丹参素冰片酯在高温、强光照射下不够稳定,应当低温、避光保存。
3、建立了兔含药血浆中丹参素冰片酯的高效液相色谱分析新方法,并采用该方法研究了丹参素冰片酯在正常家兔体内的药代动力学过程。结果显示:丹参素冰片酯在0.08～19.92 mg·L~(-1)范围内具有良好的线性关系,检测限为14.4 ng,回收率、精密度和稳定性等指标均符合美国FDA生物样品分析要求;家兔以30 mg·kg~(-1)的剂量静脉注射丹参素冰片酯后,血浆药-时曲线符合三室开放模型,证明所建方法能用于丹参素冰片酯的非临床药代动力学和生物等效性研究。
Cardiovascular and cerebrovascular diseases(CDV) is the "first killer which threat to human health",the research and development of highly effective new drugs is the main means to remedy the disease,and also the hot topic in the field of medicine research.Bomylβ-(3,4-dihydroxyphenyl)-α-hydroxypropionate(Abbreviation:DBZ) is a new compound which was advanced from in-depth study of Compound Danshen Dripping Pills,Decoction of Radix Salviae Miltiorrrhizae and Fufang Danshen Tablets,and was synthesized with technologies of organic synthesis and modern pharmacology by the research center where the auther works.The compound also presented a strong efficiency for againsting acute myocardial ischemia and lowering blood pressure in rats.In this thesis,DBZ was selected as a target for the investigation on its structrual identification,quality control and establishment of the analyzing method of pharmacokinetic study in vivo.The above investigation could play an important role in developing DBZ as one grade innovative medicine.The main contents of this thesis are showed as following:
1.Mass spectroscopy,infrared spectroscopy and nuclear magnetic resonance spectroscopy method were used for the identification of DBZ.The results showed that the molecular weight of DBZ is 334.2,and its chemical name is 1,7,7-trimethylbicyclo[2.2.1]heptan-2- y1 3-(3,4-dihydroxyphenyl)-2-hydroxy-propanoate. With the proposed synthetic method,the reacting product has the properties of optical isomers and bimodal peak in reverse liquid chroamtogram.
2.A new quality controling method was established for the research on characteristics, physico-chemical constants,identification,examination and determination of DBZ.The results of residual solvents showed that there are no ether,acetone,tetrahydrofuran,ethyl acetate and methanol by investigating three parallel DBZ samples.In addition,the residual quantity of alcohol is lower than 0.5%.Methodology of related substances and determination showed that the linear range of DBZ is 5～1000 mg·L~(-1),and the detection limit is 10.0 ng, demonstrating that the method is specific,sensitive and could be used for quality control of DBZ.The results of stability experment indicated that DBZ is lack of stability under high temperature and strong light,demonstating that it should be stocked without high temperature and strong light.
3.A new high performance liquid chromatography(HPLC) method for analysis of the DBZ in plasma was established.Moreover,the pharmacokinetics of DBZ was studied by the method in healthy rabbit.The results showed that the linear range of DBZ is 0.08~19.92 mg·L~(-1),the detection limit is 14.4 ng.The recovery,relative standard deviations(RSD) of precision and stability were accorded in the requirements of biological sample analysis in Food and drug administration.The time - concentration curve of DBZ with the intravenous dosage of 30 mg·kg~(-1) confirmed to the model of three compartment,indicating that the method could be used to pre-clinical pharmacokinetic and bioequivalence study.
1、采用MS、IR、NMR等手段对丹参素冰片酯(DBZ)进行了结构表征。结果表明:DBZ分子量为334.2,化学名称为3-(3,4-二羟基苯基)-2-羟基丙酸-1,7,7-三甲基双环[2.2.1]-2-庚醇酯。拟定合成路线,所得产物为旋光异构体,在反相液相色谱图中出峰特征为双峰。
2、围绕样品的性状、理化常数、鉴别、检查及含量测定等初步建立了丹参素冰片酯的质量标准。有机溶剂残留检查结果表明,三批样品均未检测出乙醚、丙酮、四氢呋喃、乙酸乙酯和甲醇,乙醇残留量小于0.5%;有关物质和含量测定的方法学考察表明丹参素冰片酯在5 mg·L~(-1)～1000 mg·L~(-1)范围内线性关系良好,检测限为10 ng,证明所建方法专属性强、灵敏度高,可用于丹参素冰片酯的质量控制研究。稳定性研究表明:丹参素冰片酯在高温、强光照射下不够稳定,应当低温、避光保存。
3、建立了兔含药血浆中丹参素冰片酯的高效液相色谱分析新方法,并采用该方法研究了丹参素冰片酯在正常家兔体内的药代动力学过程。结果显示:丹参素冰片酯在0.08～19.92 mg·L~(-1)范围内具有良好的线性关系,检测限为14.4 ng,回收率、精密度和稳定性等指标均符合美国FDA生物样品分析要求;家兔以30 mg·kg~(-1)的剂量静脉注射丹参素冰片酯后,血浆药-时曲线符合三室开放模型,证明所建方法能用于丹参素冰片酯的非临床药代动力学和生物等效性研究。
Cardiovascular and cerebrovascular diseases(CDV) is the "first killer which threat to human health",the research and development of highly effective new drugs is the main means to remedy the disease,and also the hot topic in the field of medicine research.Bomylβ-(3,4-dihydroxyphenyl)-α-hydroxypropionate(Abbreviation:DBZ) is a new compound which was advanced from in-depth study of Compound Danshen Dripping Pills,Decoction of Radix Salviae Miltiorrrhizae and Fufang Danshen Tablets,and was synthesized with technologies of organic synthesis and modern pharmacology by the research center where the auther works.The compound also presented a strong efficiency for againsting acute myocardial ischemia and lowering blood pressure in rats.In this thesis,DBZ was selected as a target for the investigation on its structrual identification,quality control and establishment of the analyzing method of pharmacokinetic study in vivo.The above investigation could play an important role in developing DBZ as one grade innovative medicine.The main contents of this thesis are showed as following:
1.Mass spectroscopy,infrared spectroscopy and nuclear magnetic resonance spectroscopy method were used for the identification of DBZ.The results showed that the molecular weight of DBZ is 334.2,and its chemical name is 1,7,7-trimethylbicyclo[2.2.1]heptan-2- y1 3-(3,4-dihydroxyphenyl)-2-hydroxy-propanoate. With the proposed synthetic method,the reacting product has the properties of optical isomers and bimodal peak in reverse liquid chroamtogram.
2.A new quality controling method was established for the research on characteristics, physico-chemical constants,identification,examination and determination of DBZ.The results of residual solvents showed that there are no ether,acetone,tetrahydrofuran,ethyl acetate and methanol by investigating three parallel DBZ samples.In addition,the residual quantity of alcohol is lower than 0.5%.Methodology of related substances and determination showed that the linear range of DBZ is 5～1000 mg·L~(-1),and the detection limit is 10.0 ng, demonstrating that the method is specific,sensitive and could be used for quality control of DBZ.The results of stability experment indicated that DBZ is lack of stability under high temperature and strong light,demonstating that it should be stocked without high temperature and strong light.
3.A new high performance liquid chromatography(HPLC) method for analysis of the DBZ in plasma was established.Moreover,the pharmacokinetics of DBZ was studied by the method in healthy rabbit.The results showed that the linear range of DBZ is 0.08~19.92 mg·L~(-1),the detection limit is 14.4 ng.The recovery,relative standard deviations(RSD) of precision and stability were accorded in the requirements of biological sample analysis in Food and drug administration.The time - concentration curve of DBZ with the intravenous dosage of 30 mg·kg~(-1) confirmed to the model of three compartment,indicating that the method could be used to pre-clinical pharmacokinetic and bioequivalence study.
引文
[1]胡先明,白丽霞,王丽燕,等.亚健康与心脑血管疾病[J].中西医结合心脑血管病杂志,2007,5(1):65-66
[2]王龙江,韩超慧.预防心脑血管疾病[J].实用糖尿病杂志,2008,4(5):62
[3]刘广泉,包海蓉,姜远英.药食两用菌类降血脂作用研究进展[J].食品科学,2007,28(9):626-629
[4]郭乃超,李威,蔡青林,等.老年人心血管疾病防治[J].临床和实验医学杂志,2006,5(3):237-238
[5]杨学军,郭美玲.老年抑郁症及焦虑症与心脑血管疾病的关系[J].中国实用医药,2008,3(20):152-154
[6]刘永源,贺松其.痰浊与心脑血管疾病相关性的研究进展[J].甘肃中医,2003,16(5):61-64
[7]董佑忠.微生物感染、炎性反应与心脑血管疾病相关性研究现状[J].疑难病杂志,2007,6(12):762-765
[8]郑刚.抗血管壁慢性炎症——动脉粥样硬化防治的新思路[J].中西医结合心脑血管病杂志,2006,4(2):143-146
[9]白雅,卞干兰.心脑血管疾病的预防措施[J].长春中医药大学学报,2008,24(4):448
[10]王同亮.浅谈心脑血管疾病的预防策略与措施[J].中国医药指南,2008,6(1):216-217
[11]张效云,董明纲.心脑血管疾病的预防[J].张家口医学院学报,2003,20(6):51-52
[12]Husseini A.,Abu-Rmeileh N.M.,Mikki N.,et al.Cardiovascular Diseases,Diabetes Mellitus,and Cancer in the Occupied Palestinian Territory[J].The Lancet,2009,373(9668):1041-1049
[13]曾涛,江坤.他汀类调脂药在心脑血管疾病中的应用[J].中国药师,2006,9(8):760-761
[14]Amenta F.,Lanari A.,Mignini E,et al.Nicardipine Use in Cerebrovascular Disease:A Review of Controlled Clinical Studies[J].Journal of the Neurological Sciences,2009,in press
[15]Cleanthis M.,Bhattacharya V.,Smout J.,et al.Combined Aspirin and Cilostazol Treatment is Associated with Reduced Platelet Aggregation and Prevention of Exercise-Induced Platelet Activation[J].European Journal of Vascular and Endovascular Surgery,2009,in press
[16]Priscilla D.H.,Prince ES.M..Cardioprotective Effect of Gallic Acid on Cardiac Troponin-T,Cardiac Marker Enzymes,Lipid Peroxidation Products and Antioxidants in Experimentally Induced Myocardial Infarction in Wistar Rats[J].Chemico-biological interactions,2009,179(2-3):118-124
[17]王兰明.新药研究开发的途径与方法(上)[J].中国药业,2000,9(1):11-13
[18]左风.天然产物中的药物研究[J].国外医学.中医中药分册,2000,22(4):207-210
[19]Yovine A.,Riofrio M.,Blay J.Y.,et al.Phase Ⅱ Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma Patients[J].Journal of clinical oncology,2004,22(5):890-899
[20]王淑民,管华诗.海洋药物的研究进展[J].中国海洋药物,2006,25(6):56-61
[21]Weng J.,Lin Y.,Zhu X..,et al.Effects of PGMS on the Functions of Human Platelets and Endothelial Cells[J].Acta Academiae Medicinae Sinicae,1997,19(6):414-418
[22]王普善.天然产物仍是发现新药的一个重要领域[J].中国新药杂志,2006,15(12):937-940
[23]赵树进,陈念,韩丽萍.药用植物来源的新药研发进展[J].时珍国医国药,2008,19(6):1309-1310
[24]晓宇,刁天喜.新药物再研发途径探讨[J].中国医药技术与市场,2007,7(4):22-24
[25]Kim J.,Ogai A.,Nakatani S.,et al.Impact of Blockade of Histamine H_2 Receptors on Chronic Heart Failure Revealed by Retrospective and Prospective Randomized Studies[J].Journal of the American College of Cardiology,2006,48(7):1378-1384
[26]李玲,罗和生,刘艳.三种H_2受体拮抗剂诱导鼠胃壁细胞H_2受体脱敏的比较[J].世界华人消化杂志,2005,13(17):2145-2147
[27]李兆楼,孙勤枢.新药合成和筛选的高效方法—组合化学[J].济宁医学院学报,2006,29(4):52-55
[28]廖春阳,李伯玉,张梦军,等.组合化学—新药创制的高效方法与技术[J].重庆大学学报,2003,26(4):80-85
[29]吴秀敏,Kauppi O,Siitari H.高通量药物筛选在新药开发中的发展趋势[J].中成药,1999,21(5):271-272
[30]Poughon L.,Dussap C.G.,Gros J.B..Energy Model and Metabolic Flux Analysis for Autotrophic Nitrifiers[J].Biotechnology and Bioengineering,2001,72(4):416-433
[31]Staunton J.,Wilkinson B..Combinatorial Biosynthesis of Polyketides and Nonribosomai Peptides[J].Current Opinion in Chemical Biology,2001,5(2):159-164
[32]Lindell S.D.,Pattenden L.C.,Shannon J..Combinatorial Chemistry in the Agrosciences[J].Bioorganic & Medicinal Chemistry,2009,in press
[33]孟宪军,刘顺航,王平.中药资源的综合利用与可持续发展[J].中国中西医结合杂志,2008,28(5):463-465
[34]杨利民.中药资源生态学及其科学问题[J].吉林农业大学学报,2008,30(4):506-510
[35]徐国龙.关于中药药对应用的思考[J].中国中医基础医学杂志,2001,7(5):49-50
[36]仲芳,王伟铭,陈楠.代谢组学及其在中药体内研究中的应用[J].中国中西医结合肾病杂志,2008,9(10):920-922
[37]杨明星,石学敏.代谢组学技术及其在中医药研究中的展望[J].辽宁中医杂志,2008,35(9):1327-1329
[38]刘昌孝,司端运,万仁忠,等.代谢组学与天然药物和中药研究[J].中国天然药物,2008,6(2):82-88
[39]Khan M.T.H.,Ather A..Metabolomics-Systematic Studies of the Metabolic Profiling[J].Advances in Phytomedicine,2006,2:411-419
[40]Shyur L.F.,Yang N.S..Metabolomics for Phytomedicine Research and Drug Development[J].Current Opinion in Chemical Biology,2008,12(1):66-71
[41]Feng Y.,Wu Z.H.,Zhou X.Z.,et al.Knowledge Discovery in Traditional Chinese Medicine:State of the Art and Perspectives[J].Artificial intelligence in medicine,2006,38(3):219-236
[42]Scaraffia P.Y.,Zhang Q.E,Wysocki V.H.,et al.Analysis of Whole Body Ammonia Metabolism in Aedes Aegypti Uusing[~(15)N]-labeled Compounds and Mass Spectrometry.Insect Biochemistry and Molecular Biology,2006,36(8):614-622
[43]Lewis G.D.,Asnani A.,Gerszten R.E..Application of Metabolomics to Cardiovascular Biomarker and Pathway Discovery[J].Journal of the American College of Cardiology,2008,52(2):117-123
[44]Ralston-Hooper K.,Hopf A.,Oh C..Development of GC×GC/TOF-MS Metabolomics for Use in Ecotoxicological Studies with Invertebrates[J].Aquatic Toxicology,2008,88(1):48-52
[45]许国旺,杨军.代谢组学及其研究进展[J].色谱,2003,21(4):316-320
[46]梁承志.从复方丹参滴丸对心血管疾病的作用看中医治未病的理论[J].中华中医药学刊,2008,26(3):643-644
[47]许振山.复方丹参滴丸的临床应用及其相关药理[J].海峡药学,2008,20(3):98-100
[48]陈为.复方丹参滴丸国内临床应用研究概述[J].海峡药学,2008,20(3):113-115
[49]向柏,潘振华,曹德英.复方丹参滴丸质量控制和药理学研究进展[J].中国药房,2007,18(9):708-710
[50]牛春涛,韩晗,王向峰.活血化淤疗法临床应用法则思考[J].中医杂志,2001,42(3):179-180
[51]黄连玉.谈复方丹参滴丸的组方分析和疗效[J].中外健康文摘,2007,4(10):27-28.
[52]李玉红,徐强,胡利民,等.冰片对大鼠离体心脏冠脉流量的影响[J].现代中西医结合杂志,2008,17(23):3584-3585
[53]李国英,李征.丹参饮在心血管疾病中的应用[J].辽宁中医学院学报,2005,7(2):172-173
[54]张洪泉,柳丽.丹参饮促进胃溃疡愈合作用及其机理研究[J].中国临床药理学与治疗学,2005,10(7):812-817
[55]康广盛,李然,刘立萍.丹参饮对气滞血瘀型大鼠血液流变性的影响[J].中医药信息,2004,21(6):29-30
[56]刘洋,石任兵,刘斌,等.口服丹参饮片煎液大鼠体液化学成分变化研究[J].北京中医药大学学报,2006,29(11):768-771
[57]唐一梅,李仲谨,王世祥,等.檀香对丹参药代动力学的影响研究[J].中国药科大学学报,2007,38(2):149-152
[58]袁梦哲,王超.HPLC法测定冠心丹参片中丹参酮ⅡA的含量[J].河南中医学院学报,2007,22(2):39-40
[59]房海燕,林桂涛,李涛.HPLC法测定冠心丹参片中丹酚酸B的含量[J].山东轻工业学院学 报,2006,20(2):70-72
[60]周文枭,黎格.高效液相色谱法测定冠心丹参片中丹参酮Ⅱ A的含量[J].广西医科大学学报,2004,21(3):402-403
[61]赵蕾,杜文峰,许德义.冠心丹参片对大鼠心肌缺血再灌注损伤的保护作用[J].中国药学杂志,2006,41(19):1468-1471
[62]黄敏琪,甄汉深,李运桂,等.反相高效液相色谱法测定冠心丹参片中丹参酮ⅡA的含量[J].广西医科大学学报,2005,22(3):419-420
[63]Liu R.X.,Wang Q.,Guo H.Z..Simultaneous Determination of 10 Major Flavonoids in Dalbergia odorifera by High Performance Liquid Chromatography[J].Journal of Pharmaceutical and Biomedical Analysis,2005,39(3-4):469-476
[64]王佳红.丹参活性成分药理作用[J].黑龙江医药,2008,21(3):85-86
[65]刘粲,宋阳,李玫.丹参的药理作用研究及临床应用[J].中国误诊学杂志,2006,6(24):4732-4733
[66]付辛芳,刘晓红.丹参的药理作用与临床应用研究进展[J].中国药业,2006,15(1):76-77
[67]黄喜茹,曹冬,詹文红.RP-HPLC法测定复方丹参片中的隐丹参酮、丹参酮Ⅰ和丹参酮ⅡA[J].分析试验室,2006,25(8):116-118
[68]潘桂湘,乔延江,张伯礼,等.HPLC法测定复方丹参方中丹参3种脂溶性成分含量[J].北京中医药大学学报,2003,26(4):61-63
[69]蔡丽萍,习志刚,杨红.丹参酮的药理作用和临床研究进展[J].广东药学院学报,2008,24(3):321-324
[70]张民,张骅,徐鹏,等.丹参酮ⅡA的药理作用研究进展[J].医药导报,2008,27(10):1237-1239
[71]Ai C.B.,Li L.N.,Stereostructure of Salvianolic Acid B and Isolation of Salvianolic Acid C from Salvia Miltiorrhiza[J].Journal of Natural Products,1988,51(1):145-149
[72]贾娜,项海芝,杨松松.丹参水溶性部分丹酚酸的进展述评[J].辽宁中医学院学报,2006,8(3):41-42
[73]王凤美,李磊,沈金灿,等.高效液相色谱-荧光检测法测定丹酚酸B的含量研究[J].中医药学刊,2005,23(5):817-818
[74]潘桂湘,张伯礼,乔延江.HPLC法测定复方丹参中丹参的三种水溶性成分的含量[J].中草药,2002,33(10):901-903
[75]邓喜玲,陈学敏.丹参素的合成和药理作用[J].农垦医学,2002,24(5):362-364
[76]孙锡铭,蔡海江,宋素云,等.丹参素的新药理作用[J].中草药,1991,22(1):20
[77]王文俊,吴咸中,姚智,等.大黄素、丹参素对单核细胞分泌炎性细胞因子的调节[J].中国免疫学杂志,1995,11(6):370
[78]Ding M.,Ye T.X.,Zhao G.R.,et al.Aqueous Extract of Salvia Miltiorrhiza Attenuates Increased Endothelial Permeability Induced by Tumor Necrosis Factor-Alpha[J].International Immunopharmacology,2005,5(11):1641-1651
[79]李跃华,吴翠贞,阒玲莉,等.丹参素增强肝细胞生长及其在药物性肝细胞损伤中的作用[J].南京医科大学学报,1996,16(4):346
[80]张彦文,冯淑华.丹参素及其衍生物的合成[J].天津医科大学学报,2005,11(4):522-524
[81]邓喜玲,陈学敏,江发寿,等.丹参素的合成[J].中国医药工业杂志,2005,36(9):523-524
[82]周志彬.几种冰片的区分[J].中国药业,2006,15(9):57
[83]刘洋,张伯礼,胡利民.冰片的药理实验研究概况[J].天津中医药,2003,20(4):85-87
[84]黄卫东,吕武清.冰片的研究进展[J].中国药业,2008,17(4):64-66
[85]吴寿荣,程刚,冯岩.冰片药理作用的研究进展[J].中草药,2001,32(12):1143-1145
[86]秦伯益.新药评价工作的展望(一)[J].中国新药杂志,1999,8(1):4-7
[87]江力宣,闫海英,阳盛洪,等.药代动力学研究在新药研发中的应用[J].药学实践杂志,2006,24(5):260-263
[88]杨宝峰,苏定冯.药理学[M].北京:人民卫生出版社,2003:21-24
[89]江南,刘翠霞,但汉雄,等.甘草酸二铵对动物血清胆碱酯酶的影响[J].中国医院药学杂志,2003,23(10):595-596
[90]Carceles C.M.,Escudero E.,Femandez-Varon E.,et al.Pharmacokinetics after Intravenous,Intramuscular and Subcutaneous Administration of Moxifloxacin in Sheep[J].Veterinary Journal,2009,180(3):343-347
[91]Yuan C.F.,Huang X.N.,Cheng L.,et al.Evaluation of Antioxidant and Immune Activity of Phellinus Ribis Glucan in Mice[J].Food Chemistry,2009,115(2):581-584
[92]马玉楠.新药(化学药品)质量标准建立的技术要求及常见问题分析[J].中国新药杂志,2000,9(11):801-806
[93]霍秀敏,张玉琥,蒋煜.新药的质量研究和质量标准的建立[J].中国新药杂志,2006,15(20):1708-1710
[94]邓家刚,陈勇,王勤,等.芒果苷原料药的质量标准研究[J].中药材,2007,30(11):1464-1466
[95]邵颖.化学药物质量控制研究与评价原则的思考[J].中国新药杂志,2008,17(8):709-712
[96]Dale J.A.,Dull D.L.,Mosher H.S..α-Methoxy-a-trifluoromethylphenylacetic Acid,a Versatile Reagent for the Determination of Enantiomeric Composition of Alcohols and Amines[J].Journal of Organic Chemistry,1969,34(9):2543-2549
[97]Dale J.A.,Mosher H.S..Nuclear Magnetic Resonance Enantiomer Reagents.Configurational Correlations via Nuclear Magnetic Resonance Chemical Shifts of Diastereomeric Mandelate,O-Methylmandelate,and α-Methoxy-α-tfifluoromethylphenylacetate(MTPA) Esters[J].Journal of the American Chemical Society,1973,95(2):512-519
[98]国家食品药品监督管理局.化学药物杂质研究的技术指导原则[S].2005
[99]Zhu G.D.,Wei J.,Liang W.W.,et al.Determination of Ofloxacin in Human Fallopian Tube,Uterus and Serum by High Performance Liquid Chromatography[J].Acta pharmaceutica Sinica,2002,37(2):134-137
[100]Immanuel C.,Hemanth Kumar A.K..Simple and Rapid High-Performance Liquid Chromatography Method for the Determination of Ofloxacin Concentrations in Plasma and Urine[J].Journal of Chromatography B:Biomedical Sciences and Applications,2001,760(1):91-95
[101]Basci N.E.,Hanioglu-Kargi S.,Soysal H.,et al.Determination of Ofloxacin in Human Aqueous Humour by High-Performance Liquid Chromatography with Fluorescence Detection[J].Journal of pharmaceutical and biomedical analysis,1997,15(5):663-666
[2]王龙江,韩超慧.预防心脑血管疾病[J].实用糖尿病杂志,2008,4(5):62
[3]刘广泉,包海蓉,姜远英.药食两用菌类降血脂作用研究进展[J].食品科学,2007,28(9):626-629
[4]郭乃超,李威,蔡青林,等.老年人心血管疾病防治[J].临床和实验医学杂志,2006,5(3):237-238
[5]杨学军,郭美玲.老年抑郁症及焦虑症与心脑血管疾病的关系[J].中国实用医药,2008,3(20):152-154
[6]刘永源,贺松其.痰浊与心脑血管疾病相关性的研究进展[J].甘肃中医,2003,16(5):61-64
[7]董佑忠.微生物感染、炎性反应与心脑血管疾病相关性研究现状[J].疑难病杂志,2007,6(12):762-765
[8]郑刚.抗血管壁慢性炎症——动脉粥样硬化防治的新思路[J].中西医结合心脑血管病杂志,2006,4(2):143-146
[9]白雅,卞干兰.心脑血管疾病的预防措施[J].长春中医药大学学报,2008,24(4):448
[10]王同亮.浅谈心脑血管疾病的预防策略与措施[J].中国医药指南,2008,6(1):216-217
[11]张效云,董明纲.心脑血管疾病的预防[J].张家口医学院学报,2003,20(6):51-52
[12]Husseini A.,Abu-Rmeileh N.M.,Mikki N.,et al.Cardiovascular Diseases,Diabetes Mellitus,and Cancer in the Occupied Palestinian Territory[J].The Lancet,2009,373(9668):1041-1049
[13]曾涛,江坤.他汀类调脂药在心脑血管疾病中的应用[J].中国药师,2006,9(8):760-761
[14]Amenta F.,Lanari A.,Mignini E,et al.Nicardipine Use in Cerebrovascular Disease:A Review of Controlled Clinical Studies[J].Journal of the Neurological Sciences,2009,in press
[15]Cleanthis M.,Bhattacharya V.,Smout J.,et al.Combined Aspirin and Cilostazol Treatment is Associated with Reduced Platelet Aggregation and Prevention of Exercise-Induced Platelet Activation[J].European Journal of Vascular and Endovascular Surgery,2009,in press
[16]Priscilla D.H.,Prince ES.M..Cardioprotective Effect of Gallic Acid on Cardiac Troponin-T,Cardiac Marker Enzymes,Lipid Peroxidation Products and Antioxidants in Experimentally Induced Myocardial Infarction in Wistar Rats[J].Chemico-biological interactions,2009,179(2-3):118-124
[17]王兰明.新药研究开发的途径与方法(上)[J].中国药业,2000,9(1):11-13
[18]左风.天然产物中的药物研究[J].国外医学.中医中药分册,2000,22(4):207-210
[19]Yovine A.,Riofrio M.,Blay J.Y.,et al.Phase Ⅱ Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma Patients[J].Journal of clinical oncology,2004,22(5):890-899
[20]王淑民,管华诗.海洋药物的研究进展[J].中国海洋药物,2006,25(6):56-61
[21]Weng J.,Lin Y.,Zhu X..,et al.Effects of PGMS on the Functions of Human Platelets and Endothelial Cells[J].Acta Academiae Medicinae Sinicae,1997,19(6):414-418
[22]王普善.天然产物仍是发现新药的一个重要领域[J].中国新药杂志,2006,15(12):937-940
[23]赵树进,陈念,韩丽萍.药用植物来源的新药研发进展[J].时珍国医国药,2008,19(6):1309-1310
[24]晓宇,刁天喜.新药物再研发途径探讨[J].中国医药技术与市场,2007,7(4):22-24
[25]Kim J.,Ogai A.,Nakatani S.,et al.Impact of Blockade of Histamine H_2 Receptors on Chronic Heart Failure Revealed by Retrospective and Prospective Randomized Studies[J].Journal of the American College of Cardiology,2006,48(7):1378-1384
[26]李玲,罗和生,刘艳.三种H_2受体拮抗剂诱导鼠胃壁细胞H_2受体脱敏的比较[J].世界华人消化杂志,2005,13(17):2145-2147
[27]李兆楼,孙勤枢.新药合成和筛选的高效方法—组合化学[J].济宁医学院学报,2006,29(4):52-55
[28]廖春阳,李伯玉,张梦军,等.组合化学—新药创制的高效方法与技术[J].重庆大学学报,2003,26(4):80-85
[29]吴秀敏,Kauppi O,Siitari H.高通量药物筛选在新药开发中的发展趋势[J].中成药,1999,21(5):271-272
[30]Poughon L.,Dussap C.G.,Gros J.B..Energy Model and Metabolic Flux Analysis for Autotrophic Nitrifiers[J].Biotechnology and Bioengineering,2001,72(4):416-433
[31]Staunton J.,Wilkinson B..Combinatorial Biosynthesis of Polyketides and Nonribosomai Peptides[J].Current Opinion in Chemical Biology,2001,5(2):159-164
[32]Lindell S.D.,Pattenden L.C.,Shannon J..Combinatorial Chemistry in the Agrosciences[J].Bioorganic & Medicinal Chemistry,2009,in press
[33]孟宪军,刘顺航,王平.中药资源的综合利用与可持续发展[J].中国中西医结合杂志,2008,28(5):463-465
[34]杨利民.中药资源生态学及其科学问题[J].吉林农业大学学报,2008,30(4):506-510
[35]徐国龙.关于中药药对应用的思考[J].中国中医基础医学杂志,2001,7(5):49-50
[36]仲芳,王伟铭,陈楠.代谢组学及其在中药体内研究中的应用[J].中国中西医结合肾病杂志,2008,9(10):920-922
[37]杨明星,石学敏.代谢组学技术及其在中医药研究中的展望[J].辽宁中医杂志,2008,35(9):1327-1329
[38]刘昌孝,司端运,万仁忠,等.代谢组学与天然药物和中药研究[J].中国天然药物,2008,6(2):82-88
[39]Khan M.T.H.,Ather A..Metabolomics-Systematic Studies of the Metabolic Profiling[J].Advances in Phytomedicine,2006,2:411-419
[40]Shyur L.F.,Yang N.S..Metabolomics for Phytomedicine Research and Drug Development[J].Current Opinion in Chemical Biology,2008,12(1):66-71
[41]Feng Y.,Wu Z.H.,Zhou X.Z.,et al.Knowledge Discovery in Traditional Chinese Medicine:State of the Art and Perspectives[J].Artificial intelligence in medicine,2006,38(3):219-236
[42]Scaraffia P.Y.,Zhang Q.E,Wysocki V.H.,et al.Analysis of Whole Body Ammonia Metabolism in Aedes Aegypti Uusing[~(15)N]-labeled Compounds and Mass Spectrometry.Insect Biochemistry and Molecular Biology,2006,36(8):614-622
[43]Lewis G.D.,Asnani A.,Gerszten R.E..Application of Metabolomics to Cardiovascular Biomarker and Pathway Discovery[J].Journal of the American College of Cardiology,2008,52(2):117-123
[44]Ralston-Hooper K.,Hopf A.,Oh C..Development of GC×GC/TOF-MS Metabolomics for Use in Ecotoxicological Studies with Invertebrates[J].Aquatic Toxicology,2008,88(1):48-52
[45]许国旺,杨军.代谢组学及其研究进展[J].色谱,2003,21(4):316-320
[46]梁承志.从复方丹参滴丸对心血管疾病的作用看中医治未病的理论[J].中华中医药学刊,2008,26(3):643-644
[47]许振山.复方丹参滴丸的临床应用及其相关药理[J].海峡药学,2008,20(3):98-100
[48]陈为.复方丹参滴丸国内临床应用研究概述[J].海峡药学,2008,20(3):113-115
[49]向柏,潘振华,曹德英.复方丹参滴丸质量控制和药理学研究进展[J].中国药房,2007,18(9):708-710
[50]牛春涛,韩晗,王向峰.活血化淤疗法临床应用法则思考[J].中医杂志,2001,42(3):179-180
[51]黄连玉.谈复方丹参滴丸的组方分析和疗效[J].中外健康文摘,2007,4(10):27-28.
[52]李玉红,徐强,胡利民,等.冰片对大鼠离体心脏冠脉流量的影响[J].现代中西医结合杂志,2008,17(23):3584-3585
[53]李国英,李征.丹参饮在心血管疾病中的应用[J].辽宁中医学院学报,2005,7(2):172-173
[54]张洪泉,柳丽.丹参饮促进胃溃疡愈合作用及其机理研究[J].中国临床药理学与治疗学,2005,10(7):812-817
[55]康广盛,李然,刘立萍.丹参饮对气滞血瘀型大鼠血液流变性的影响[J].中医药信息,2004,21(6):29-30
[56]刘洋,石任兵,刘斌,等.口服丹参饮片煎液大鼠体液化学成分变化研究[J].北京中医药大学学报,2006,29(11):768-771
[57]唐一梅,李仲谨,王世祥,等.檀香对丹参药代动力学的影响研究[J].中国药科大学学报,2007,38(2):149-152
[58]袁梦哲,王超.HPLC法测定冠心丹参片中丹参酮ⅡA的含量[J].河南中医学院学报,2007,22(2):39-40
[59]房海燕,林桂涛,李涛.HPLC法测定冠心丹参片中丹酚酸B的含量[J].山东轻工业学院学 报,2006,20(2):70-72
[60]周文枭,黎格.高效液相色谱法测定冠心丹参片中丹参酮Ⅱ A的含量[J].广西医科大学学报,2004,21(3):402-403
[61]赵蕾,杜文峰,许德义.冠心丹参片对大鼠心肌缺血再灌注损伤的保护作用[J].中国药学杂志,2006,41(19):1468-1471
[62]黄敏琪,甄汉深,李运桂,等.反相高效液相色谱法测定冠心丹参片中丹参酮ⅡA的含量[J].广西医科大学学报,2005,22(3):419-420
[63]Liu R.X.,Wang Q.,Guo H.Z..Simultaneous Determination of 10 Major Flavonoids in Dalbergia odorifera by High Performance Liquid Chromatography[J].Journal of Pharmaceutical and Biomedical Analysis,2005,39(3-4):469-476
[64]王佳红.丹参活性成分药理作用[J].黑龙江医药,2008,21(3):85-86
[65]刘粲,宋阳,李玫.丹参的药理作用研究及临床应用[J].中国误诊学杂志,2006,6(24):4732-4733
[66]付辛芳,刘晓红.丹参的药理作用与临床应用研究进展[J].中国药业,2006,15(1):76-77
[67]黄喜茹,曹冬,詹文红.RP-HPLC法测定复方丹参片中的隐丹参酮、丹参酮Ⅰ和丹参酮ⅡA[J].分析试验室,2006,25(8):116-118
[68]潘桂湘,乔延江,张伯礼,等.HPLC法测定复方丹参方中丹参3种脂溶性成分含量[J].北京中医药大学学报,2003,26(4):61-63
[69]蔡丽萍,习志刚,杨红.丹参酮的药理作用和临床研究进展[J].广东药学院学报,2008,24(3):321-324
[70]张民,张骅,徐鹏,等.丹参酮ⅡA的药理作用研究进展[J].医药导报,2008,27(10):1237-1239
[71]Ai C.B.,Li L.N.,Stereostructure of Salvianolic Acid B and Isolation of Salvianolic Acid C from Salvia Miltiorrhiza[J].Journal of Natural Products,1988,51(1):145-149
[72]贾娜,项海芝,杨松松.丹参水溶性部分丹酚酸的进展述评[J].辽宁中医学院学报,2006,8(3):41-42
[73]王凤美,李磊,沈金灿,等.高效液相色谱-荧光检测法测定丹酚酸B的含量研究[J].中医药学刊,2005,23(5):817-818
[74]潘桂湘,张伯礼,乔延江.HPLC法测定复方丹参中丹参的三种水溶性成分的含量[J].中草药,2002,33(10):901-903
[75]邓喜玲,陈学敏.丹参素的合成和药理作用[J].农垦医学,2002,24(5):362-364
[76]孙锡铭,蔡海江,宋素云,等.丹参素的新药理作用[J].中草药,1991,22(1):20
[77]王文俊,吴咸中,姚智,等.大黄素、丹参素对单核细胞分泌炎性细胞因子的调节[J].中国免疫学杂志,1995,11(6):370
[78]Ding M.,Ye T.X.,Zhao G.R.,et al.Aqueous Extract of Salvia Miltiorrhiza Attenuates Increased Endothelial Permeability Induced by Tumor Necrosis Factor-Alpha[J].International Immunopharmacology,2005,5(11):1641-1651
[79]李跃华,吴翠贞,阒玲莉,等.丹参素增强肝细胞生长及其在药物性肝细胞损伤中的作用[J].南京医科大学学报,1996,16(4):346
[80]张彦文,冯淑华.丹参素及其衍生物的合成[J].天津医科大学学报,2005,11(4):522-524
[81]邓喜玲,陈学敏,江发寿,等.丹参素的合成[J].中国医药工业杂志,2005,36(9):523-524
[82]周志彬.几种冰片的区分[J].中国药业,2006,15(9):57
[83]刘洋,张伯礼,胡利民.冰片的药理实验研究概况[J].天津中医药,2003,20(4):85-87
[84]黄卫东,吕武清.冰片的研究进展[J].中国药业,2008,17(4):64-66
[85]吴寿荣,程刚,冯岩.冰片药理作用的研究进展[J].中草药,2001,32(12):1143-1145
[86]秦伯益.新药评价工作的展望(一)[J].中国新药杂志,1999,8(1):4-7
[87]江力宣,闫海英,阳盛洪,等.药代动力学研究在新药研发中的应用[J].药学实践杂志,2006,24(5):260-263
[88]杨宝峰,苏定冯.药理学[M].北京:人民卫生出版社,2003:21-24
[89]江南,刘翠霞,但汉雄,等.甘草酸二铵对动物血清胆碱酯酶的影响[J].中国医院药学杂志,2003,23(10):595-596
[90]Carceles C.M.,Escudero E.,Femandez-Varon E.,et al.Pharmacokinetics after Intravenous,Intramuscular and Subcutaneous Administration of Moxifloxacin in Sheep[J].Veterinary Journal,2009,180(3):343-347
[91]Yuan C.F.,Huang X.N.,Cheng L.,et al.Evaluation of Antioxidant and Immune Activity of Phellinus Ribis Glucan in Mice[J].Food Chemistry,2009,115(2):581-584
[92]马玉楠.新药(化学药品)质量标准建立的技术要求及常见问题分析[J].中国新药杂志,2000,9(11):801-806
[93]霍秀敏,张玉琥,蒋煜.新药的质量研究和质量标准的建立[J].中国新药杂志,2006,15(20):1708-1710
[94]邓家刚,陈勇,王勤,等.芒果苷原料药的质量标准研究[J].中药材,2007,30(11):1464-1466
[95]邵颖.化学药物质量控制研究与评价原则的思考[J].中国新药杂志,2008,17(8):709-712
[96]Dale J.A.,Dull D.L.,Mosher H.S..α-Methoxy-a-trifluoromethylphenylacetic Acid,a Versatile Reagent for the Determination of Enantiomeric Composition of Alcohols and Amines[J].Journal of Organic Chemistry,1969,34(9):2543-2549
[97]Dale J.A.,Mosher H.S..Nuclear Magnetic Resonance Enantiomer Reagents.Configurational Correlations via Nuclear Magnetic Resonance Chemical Shifts of Diastereomeric Mandelate,O-Methylmandelate,and α-Methoxy-α-tfifluoromethylphenylacetate(MTPA) Esters[J].Journal of the American Chemical Society,1973,95(2):512-519
[98]国家食品药品监督管理局.化学药物杂质研究的技术指导原则[S].2005
[99]Zhu G.D.,Wei J.,Liang W.W.,et al.Determination of Ofloxacin in Human Fallopian Tube,Uterus and Serum by High Performance Liquid Chromatography[J].Acta pharmaceutica Sinica,2002,37(2):134-137
[100]Immanuel C.,Hemanth Kumar A.K..Simple and Rapid High-Performance Liquid Chromatography Method for the Determination of Ofloxacin Concentrations in Plasma and Urine[J].Journal of Chromatography B:Biomedical Sciences and Applications,2001,760(1):91-95
[101]Basci N.E.,Hanioglu-Kargi S.,Soysal H.,et al.Determination of Ofloxacin in Human Aqueous Humour by High-Performance Liquid Chromatography with Fluorescence Detection[J].Journal of pharmaceutical and biomedical analysis,1997,15(5):663-666