原儿茶酸冰片酯的设计、合成及代谢研究
|
摘要
中药作为中医临床治疗疾病的主要手段,通过几千年的实践积累了丰富的有关中药配伍应用的经验和理论。以中药为源泉的创新药物开发必须在中医药理论指导下进行才会有更广阔的发展空间。因此,本文以“君-使”药对理论为着眼点,以治疗血瘀证的君药丹参、广枣等药材中广泛存在的原儿茶酸和使药冰片为原料,设计合成了全新化合物原儿茶酸冰片酯。运用代谢组学等手段对其药物动力学、体内组织分布及代谢产物的变化进行深入研究。发现原儿茶酸冰片酯可以针对血瘀证的病因,增强机体的统血、行血的能力,从而产生活血化瘀的作用。本文所提出的创新药物开发思路可以开发出具有临床意义的创新药物,并可为以中药及天然产物为基础的创新药物开发提供有益的借鉴与模式。全文共分五章,主要研究内容如下：
1.以原儿茶酸和冰片为原料,设计并通过多种方法合成了原儿茶酸冰片酯。
2.采用平衡透析结合高效液相色谱法测定原儿茶酸冰片酯与大鼠血浆蛋白结合率。发现在实验浓度范围内,原儿茶酸冰片酯与大鼠血浆蛋白的结合率较高。
3.建立了大鼠血浆及组织中原儿茶酸冰片酯的高效液相色谱-飞行时间质谱测定方法,并运用该方法对原儿茶酸冰片酯在正常及模型大鼠体内的药代动力学过程及组织分布特征进行研究。发现原儿茶酸冰片酯在正常及模型大鼠体内的药代动力学过程符合三室开放模型,作用持久；原儿茶酸冰片酯在正常及模型大鼠体内组织分布特征分别为c脾>c心>c肺>c脑>c肾>c肝和c脾>c心>c肝>c肺>c脑>c肾,该方法可用于原儿茶酸冰片酯的非临床和临床动力学研究。在研究原儿茶酸冰片酯体内代谢过程时发现了其甲基化产物,并鉴定其结构为香草酸冰片酯。
4.以香草酸和冰片为原料,运用直接酯化法合成了香草酸冰片酯。
5.建立了大鼠血浆及组织中香草酸冰片酯的高效液相色谱-飞行时间质谱测定方法,并运用该方法对香草酸冰片酯在正常及模型大鼠体内的药代动力学过程及组织分布特征进行研究。发现香草酸冰片酯在正常及模型大鼠体内的药代动力学过程符合一室开放模型,半衰期长；在正常及模型大鼠体内组织分布特征分别为c肺>c心>c肾>c脾>c肝>c脑和c心>c肾>c脾>c肺>c肝>c脑,该方法可用于香草酸冰片酯的非临床和临床动力学研究。
Traditional Chinese medicine, a Chinese clinical treatment of disease mainly means, through the thousands of years of practice has accumulated rich experience of Chinese crude drug compatibility on application and theory. Chinese medicines as a source of innovative drug development, must be under the guidance of the theory of Chinese medicine, it would have the broader space for development. Therefore, based on the jun-shi compatible herbs theory, the author synthesized a new compounds, bornyl protocatechuate, and used metabolism and other means depth to investigative its pharmacokinetics, in vivo tissue distribution and metabolite changes. The author found bornyl protocatechuate could against the origin of blood stasis, consequently enhance the ability of the body to controlling blood circulation, resulting in promoting blood circulation and eliminating stasis. This paper proposed the new drug development idea can be developed a new drug clinical significance, and can in traditional Chinese medicine and natural products for the innovation of the foundation offer beneficial reference for the drug development and mode. This dissertation consist of five chapters, the main contents are as follows:
1. The author design and synthesized bornyl protocatechuate, protocatechuic acid and borneol as raw materials.
2. The author use the balanced dialysis combined with HPLC method for the determination of bornyl protocatechuate with rats plasma protein binding rate. Found in the experimental concentration range, the bornyl protocatechuater and rats plasma protein binding rate is higher.
3. A novel high performance liquid chromatography/time-of-flight mass spectrometry method to determinate the bornyl protocatechuate in rat (or stasis rat) plasma and tissue was established, and applied it in its pharmacokinetic study and tissue distribution after intravenous injection bornyl protocatechuate. The statistical results indicated that the plasma concentration-time course of bornyl protocatechuate in rat (or stasis rat) confirmed to a3-compartment open model, and lasting effect, and the its tissue distribution was of c spleen>c heart＞c lung＞c brain＞c kidney>c liver (or c spleen＞c heart＞c liver＞c lung＞c brain＞c kidney), demonstrating that the method can be applied in studying the clinical and non-clinical pharmacokinetic of bornyl protocatechuate. The author found a methylated product of bornyl protocatechuate in vivo metabolic process, and identified the structure is bornyl vanillate.
4. The author synthesized bornyl vanillate by direct esterification, vanillic acid and borneol as raw materials.
5. A novel high performance liquid chromatography/time-of-flight mass spectrometry method to determinate the bornyl vanillate in rat (or stasis rat) plasma and tissue was established, and applied it in its pharmacokinetic study and tissue distribution after intravenous injection bomyl protocatechuate. The statistical results indicated that the plasma concentration-time course of bornyl vanillate in rat (or stasis rat) confirmed to a1-compartment open model with long half-life and the its tissue distribution was of c lung>c heart＞c kidney＞c spleen＞c liver＞c brain(or c heart＞c kidney＞c spleen＞c lung＞c liver＞c brain), demonstrating that the method can be applied in studying the clinical and non-clinical pharmacokinetic of bornyl vanillate.
1.以原儿茶酸和冰片为原料,设计并通过多种方法合成了原儿茶酸冰片酯。
2.采用平衡透析结合高效液相色谱法测定原儿茶酸冰片酯与大鼠血浆蛋白结合率。发现在实验浓度范围内,原儿茶酸冰片酯与大鼠血浆蛋白的结合率较高。
3.建立了大鼠血浆及组织中原儿茶酸冰片酯的高效液相色谱-飞行时间质谱测定方法,并运用该方法对原儿茶酸冰片酯在正常及模型大鼠体内的药代动力学过程及组织分布特征进行研究。发现原儿茶酸冰片酯在正常及模型大鼠体内的药代动力学过程符合三室开放模型,作用持久；原儿茶酸冰片酯在正常及模型大鼠体内组织分布特征分别为c脾>c心>c肺>c脑>c肾>c肝和c脾>c心>c肝>c肺>c脑>c肾,该方法可用于原儿茶酸冰片酯的非临床和临床动力学研究。在研究原儿茶酸冰片酯体内代谢过程时发现了其甲基化产物,并鉴定其结构为香草酸冰片酯。
4.以香草酸和冰片为原料,运用直接酯化法合成了香草酸冰片酯。
5.建立了大鼠血浆及组织中香草酸冰片酯的高效液相色谱-飞行时间质谱测定方法,并运用该方法对香草酸冰片酯在正常及模型大鼠体内的药代动力学过程及组织分布特征进行研究。发现香草酸冰片酯在正常及模型大鼠体内的药代动力学过程符合一室开放模型,半衰期长；在正常及模型大鼠体内组织分布特征分别为c肺>c心>c肾>c脾>c肝>c脑和c心>c肾>c脾>c肺>c肝>c脑,该方法可用于香草酸冰片酯的非临床和临床动力学研究。
Traditional Chinese medicine, a Chinese clinical treatment of disease mainly means, through the thousands of years of practice has accumulated rich experience of Chinese crude drug compatibility on application and theory. Chinese medicines as a source of innovative drug development, must be under the guidance of the theory of Chinese medicine, it would have the broader space for development. Therefore, based on the jun-shi compatible herbs theory, the author synthesized a new compounds, bornyl protocatechuate, and used metabolism and other means depth to investigative its pharmacokinetics, in vivo tissue distribution and metabolite changes. The author found bornyl protocatechuate could against the origin of blood stasis, consequently enhance the ability of the body to controlling blood circulation, resulting in promoting blood circulation and eliminating stasis. This paper proposed the new drug development idea can be developed a new drug clinical significance, and can in traditional Chinese medicine and natural products for the innovation of the foundation offer beneficial reference for the drug development and mode. This dissertation consist of five chapters, the main contents are as follows:
1. The author design and synthesized bornyl protocatechuate, protocatechuic acid and borneol as raw materials.
2. The author use the balanced dialysis combined with HPLC method for the determination of bornyl protocatechuate with rats plasma protein binding rate. Found in the experimental concentration range, the bornyl protocatechuater and rats plasma protein binding rate is higher.
3. A novel high performance liquid chromatography/time-of-flight mass spectrometry method to determinate the bornyl protocatechuate in rat (or stasis rat) plasma and tissue was established, and applied it in its pharmacokinetic study and tissue distribution after intravenous injection bornyl protocatechuate. The statistical results indicated that the plasma concentration-time course of bornyl protocatechuate in rat (or stasis rat) confirmed to a3-compartment open model, and lasting effect, and the its tissue distribution was of c spleen>c heart＞c lung＞c brain＞c kidney>c liver (or c spleen＞c heart＞c liver＞c lung＞c brain＞c kidney), demonstrating that the method can be applied in studying the clinical and non-clinical pharmacokinetic of bornyl protocatechuate. The author found a methylated product of bornyl protocatechuate in vivo metabolic process, and identified the structure is bornyl vanillate.
4. The author synthesized bornyl vanillate by direct esterification, vanillic acid and borneol as raw materials.
5. A novel high performance liquid chromatography/time-of-flight mass spectrometry method to determinate the bornyl vanillate in rat (or stasis rat) plasma and tissue was established, and applied it in its pharmacokinetic study and tissue distribution after intravenous injection bomyl protocatechuate. The statistical results indicated that the plasma concentration-time course of bornyl vanillate in rat (or stasis rat) confirmed to a1-compartment open model with long half-life and the its tissue distribution was of c lung>c heart＞c kidney＞c spleen＞c liver＞c brain(or c heart＞c kidney＞c spleen＞c lung＞c liver＞c brain), demonstrating that the method can be applied in studying the clinical and non-clinical pharmacokinetic of bornyl vanillate.
引文
[I]Bhuwan B.M., Vinod K.T.. Natural products:an evolving role in future drug discovery[J]. European Journal of Medicinal Chemistry,2011,46(10):4769-4807.
[2]Alan L.H.. Medicines from nature:are natural products still relevant to drug discovery[J]? Trends in pharmacological sciences,1999,20(5):196-198.
[3]于德泉.展望从天然产物创新药物研究[J].中国医学科学院学报,2002,24(4)：335-338.
[4]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.
[5]杜冠华,胡娟娟,夏丽娟,等.药物筛选的发展与现状[J].药学学报,1998,33(11)：876-879.
[6]Chan K.C., Muschik G.M., Issaq H.J., et al. High-speed screening of polymerase chain reaction products by capillary electrophoresis[J]. Analytical Biochemistry,1996,243(1): 133-139.
[7]Dias J.M., Go N.F., Hart C.P., et al. Genetic recombination as a reporter for screening steroid receptor agonists and antagonists[J]. Analytical Biochemistry,1998,258(1): 96-102.
[8]Game S.M., Rajapurohit P.K., Clifford M., et al. Scintillation proximity assay for E-, P-, and L-selectin utilizing polyacrylamide-based neoglycoconjugates as ligands[J]. Analytical Biochemistry,1998,258(1):127-135.
[9]Shuber A.P., Michalowsky L.A., Nass G.S., et al. High throughput parallel analysis of hundreds of patient samples for more than 100 mutations in multiple disease genes[J]. Human Molecular Genetics,1997,6(3):337-347.
[10]Jayawickreme C.K., Kost T.A.. Gene expression systems in the development of high-throughput screens[J]. Current Opinion in Biotechnology,1997,8(5):629-634.
[11]Von S.O.D., Thies W.G., Hofmann M.. A high throughput screening for rarely transcribed differentially expressed genes[J]. Nucleic Acids Research,1997,25(13): 2598-2602.
[12]Hegde S., Schmidt M.. To Market, To Market-2007[J]. Annual Reports in Medicinal Chemistry,2008,43:455-497.
[13]Hegde S., Schmidt M.. To Market, To Market-2008[J]. Annual Reports in Medicinal Chemistry,2009,44:577-632.
[14]Hegde S., Schmidt M.. To Market, To Market-2009[J]. Annual Reports in Medicinal Chemistry,2010,45:466-537.
[15]Graul A.I., Sorbera L., Pina P., et al. The year's new drugs and biologies-2009[J]. Drug News Perspect,2010,23(1):7-36.
[16]于国安.我国新药研发问题与出路[J].创新科技,2008,(1)：20-21.
[17]周群,陈伟,王方敏,等.中国新药研发现状及药品审评模式探讨[J].中国药事,2004,18(3)：172-174.
[18]赵芳,徐立,许立.中药复方作用物质基础研究思路与方法[J].中国中西医结合杂志,2007,27(1)：80-82.
[19]王阶,张林国,孟淑环.中药复方配伍规律研究的思考[J].中国中药杂志,2001,26(12)：799-801.
[20]裘索.中药西药新药研究的异同点及开发的独特性[J].中医药学刊,2005,23(2)：01.
[21]宋军,陈可冀.中药新药开发若干重要问题的思考[J].中国处方药,2005,8(41)：17-21.
[22]吴文博.中药与新药开发的思考[J].中医药研究,2000,16(2)：52-53.
[23]Wani M.C., Taylor H.L., Wall M.E., et al. Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia [J]. Journal of the American Chemical Society,1971,93(9):2325-2327.
[24]Holton R.A., Somoza C., Kim H.B., et al. First total synthesis of taxol.1. functionalization of the B ring [J]. Journal of the American Chemical Society,1994, 116(4):1597-1598.
[25]Nicolaou K.C., Yang Z., Liu J.J., et al. Total synthesis of taxol.[J]. Nature,1994,367: 630-634.
[26]王淑月,王洪亮.前药原理与新药设计[J].河北工业科技,2003,20(1)：54-57.
[27]王介庆,吉民.兽用原料药的化学结构修饰[J].兽药与饲料添加剂,2001,6(1)：11-12.
[28]Denmeade S.R., Jakobsen C.M., Janssen S., et al. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer[J]. Journal of the National Cancer Institute,2003,95(13):990-1000.
[29]Dubowchik G.G., Mosure K., Knipe J.O., et al. Cathepsin B-sensitive dipeptide prodrugs. 2. models of anticancer drugs paclitaxel (taxol), mitomycin C and doxorubicin[J]. Bioorg Med Chem,1998,8(23):3347-3352.
[30]Bradley M.O., Swindell C.S., Anthony F.H., et al. Tumor targeting by conjugation of DHA to paclitaxel[J]. Journal of Controlled Release,2001,74(1-3):233-236.
[31]Walko C.M., Lindley C.. Capecitabine:a Review[J]. Clinical Therapeutics,2005,27(1): 23-44.
[32]Ouchi T., Tada M., Matsumoto M., et al. Design of macromolecular prodrug of sfluorouracil using N-acetylpolygalactosamine as a targeting carrier to hepatoma[J]. Reactive Functional Polymers,1998,37(1-3):235-244.
[33]Jensen B.D., Schmitt T.C., Slezak S.E.. Labeling of mammalian cells for in vivo tracking by a fluorescence method[J]. Progress in Clinical and Biological Research,1990, 355:199-207.
[34]Baker M.A., Gray B.D., Ohlsson-Wilhelm BM, et al. Zyn-Linked colchicines: Controlled-release lipophilic prodrugs with enhanced antitumor efficacy[J]. Journal of Controlled Release,1996,40(1):89-100.
[35]郭鲁宏.单宁酶的制备及酶法制取没食子酸及其丙酯研究[D].沈阳：中国科学院沈阳应用生态研究所,2000年.
[36]喻晓蔚.有机介质体系单宁酶生物合成酸酯键的研究[D].杭州：浙江大学,2006年.
[37]晏仁义,陈若芸.天然产物中先导化合物的发现与优化[J].中国天然药物,2005,3(6)：332-335.
[38]仉文升,李安良.药物化学[M].北京：高等教育出版社,1999,114-118.
[39]Zhang X., Li Y., Chen X., et al. Synthesis and characterization of the paclitaxel/MPEG-PLA block copolymer conjugate[J]. Biomaterials,2005,26 (14): 2121-2128.
[40]Greenwald R.B.. PEG drugs:an overview[J]. Journal of Controlled Release,2001, 74(1-3):159-171.
[41]Lundberg B.B., Risovic V., Ramaswamy M., et al. A lipophilic paclitaxel derivative incorporated in a lipid emulsion for parenteral administration [J]. Journal of Controlled Release,2003,86(1):93-100.
[42]Bundgaard H., Nielsen N.M.. Prodrugs as drug delivery systems.74. Facile hydrolysis of N-(acyloxymethyl) amide derivatives and implications for the design of prodrugs of NH-acidic compounds and of carboxylic acids [J]. Acta Pharmaceutica Suecica,1987, 24(5):233-246.
[43]Jolimatre P., Andr B.C., Malet M.M., et al. A new method for the synthesis of 5-fluorouracil prodrugs[J]. Synlett,1999,11(1):1829-1831.
[44]Jolimaitre P., Malet M.M, Martino R.. Fluorouracil prodrugs for the treatment of proliferative vitreoretinopathy:formulation in silicone oil and in vitro release of fluorouracil[J]. International Journal of Pharmaceutics,2003,259 (1-2):181-192.
[45]Deutsch H.M., Glinski J.A., Hermandez M., et al. Synthesis of congeners and prodrugs. 3. Water-soluble prodrugs of taxol with potent antitumor activity[J]. Journal of Medicinal Chemistry,1989,32 (4):788-792.
[46]Zhao Z.Y., David G., Kingston I.. Modified taxols 6 preparation of water-soluble prodrugs of taxol[J]. Journal of Natural Products,1991,54 (6):1607-1611.
[47]Mathew A.E., Mejillano M.R., Nath J.P., et al. Synthesis and evaluation of some water-soluble prodrugs and derivatives of paclitaxel with antitumor activity [J]. Journal of Medicinal Chemistry,1992,35 (1):145-151.
[48]Moosavi M.A.A., Hakimelahi S., Chamani J., et al. Design, synthesis, and anticancer activity of phosphonic acid diphosphate derivative of adenine-containing butenolide and its water-soluble derivatives of paclitaxel with high antitumor activity [J]. Bioorganic & Medicinal Chemistry,2003,11(20):4303-4313.
[49]Vrudhula V.M., Macmaster J.F., Li Z.G., et al. Reductively activated disulfide prodrugs of paclitaxel [J]. Bioorganic & Medicinal Chemistry Letters,2002,12(24):3591-3594.
[50]Greenwald R.B., Gibert C.W., Pendri A., et al. Drug delivery systems:water soluble taxol 2'-poly (ethylene glycol) ester prodrugs-design and in vivo effectiveness [J]. Journal of Medicinal Chemistry,1996,39(2):424-431.
[51]Schmidt F., Monneret C.. Prodrug. Prodrug Mono Therapy:synthesis and biological evaluation of an etoposide glucuronide-prodrug[J]. Bioorganic & Medicinal Chemistry, 2003,11(10):2277-2283.
[52]陈福伟.噻托溴铵联合沙丁胺醇治疗慢性阻塞性肺病30例[J].中国医药科学,2012,2(1)：111.
[53]平天洲.川芎嗪联合奥扎格雷钠治疗急性脑梗死的临床观察[J].西南军医,2012,14(1)：74-75.
[54]陈缓,周枚.自由基医学[M].北京：人民军医出版社,1991：465-466.
[55]张大平,陆伟根.新药开发中药物的盐型选择[J].中国医药工业杂志,2011,42(8)：631-635.
[56]Berge S.M., Bighley L.D., Monkhouse D.C.. Pharmaceutical salts[J]. Journal of Pharmaceutical Sciences,1977,66(1):1-19.
[57]Banerjee R., Bhatt P.M., Ravindra N.V., et al. Saccharin salts of active pharmaceutical ingredients, their crystal structure, and increased water solubilities[J]. Crystal Growth & Design,2005,5(6):2299-2309.
[58]Bastin R.J., Bowker M.J., Slater B.J.. Salt selection and optimisation procedures for pharmaceutical new chemical entities [J]. Organic Progress Research & Development, 2000,4(5):427-435.
[59]Lam K.W., Xu J., Ng K.M., et al. Pharmaceutical salt formation guided by phase diagram[J]. Industrial & Engineering Chemistry Research,2010,49(24):12503-12512.
[60]Li S., Doyle P., Metz S., et al. Effect of chloride ion on dissolution of different salt forms of haloperidol, a model basic drug[J]. Journal of Pharmaceutical Sciences,2005, 94(10):2224-2231
[61]曹观坤.成酯反应[J].药学进展,1986,3：41-47.
[62]陈道仁,王夏炎,胡绍渝.小檗碱9-为脱甲基及成酯的一种简便方法[J].现代应用药学,1988,5(3)：25-26.
[63]计榆,陶淑娟,徐莉英.(E)-3-苯基丙烯酸衍生物的合成及抗炎活性考察[J].沈阳药科大学学报,2007,24(2)：82-85.
[64]国家药典委员会.中华人民共和国药典(一部)[M].北京：中国医药科技出版社,2010,70.
[65]郭宝林,冯毓秀,赵杨景.丹参种质资源研究进展[J].中国中药杂志,2002,27(7)：492-495.
[66]郑国樨,柿浑宽.丹参化学成分的研究概况[J].中国药学杂志,1989,24(1)：6.
[67]Honda G., Koezuke Y., Tabata M., et al. Isolation of an antiderm atophytic substance from the root of Salvia miltiorrhiza. Chemical and Pharmaceutical Bulletin,1988,36(1): 408-411.
[68]Hiroshi K., Teruo H., Toshiko Y. Structures of isotanshinones. Tetrahedron Letters,1969, (5):301-304.
[69]钱名堃,杨保津,顾文华,等.丹参有效成分的研究[J].化学学报,1978,36(3)：199-206.
[70]徐任生.丹参——生物学及其应用[M].北京：科学出版社,1990：81.
[71]杨东,罗厚蔚.丹参二萜醌的结构修饰[J].中国药科大学学报,1998,29(4)：255-258.
[72]Tetsugo H., Hiroshi K., Hong Y.H., et al. Structure of miltirone, a new diterpenoid quinone[J]. Journal of the Chemical Society [Section] D:Chemical Communications, 1970, (5):299.
[73]Nasipuri D., Mitra A.K.. Synthetic studies in the diterpene series. VIII. Synthesis of miltirone, a diterpenoid quinone[J]. Journal of the Chemical Society, Perkin Transactions 1:Organic and Bio-Organic Chemistry,1973, (3):285-287.
[74]Fumika A., Takenori K., Guozhi Z.. Cryptoacetalide and epicryptoacetalide, novel spirolactone diterpenoids from Salvia miltiorrhiza[J]. Chemistry Letters,1990, (10): 1885-1888.
[75]Haro G., Hiroshi K.. Miltipolone, a new diterpenoid tropolone possessing cytotoxic activities from Salvia miltiorrhiza Bunge[J]. Chemistry Letters,1990, (9):1599-1602.
[76]Hiroshi K. Tetsugo H, Handa T, et al. Structure of salviol, a new phenolic diterpene[J]. Journal of the Chemical Society [Section] D:Chemical Communications,1971, (11): 541-542.
[77]杨保津,钱名堃,泰国伟,等.丹参有效成分的研究[J].药学学报,1981,16(11)：837-841.
[78]Haro G., Takenori K., Ishitsuka M.O., et al. Salviolone, a cytotoxic bisnorditerpene with a benzotropolone chromophore from a Chinese drug Dan-Shen (Salvia miltiorrhiza)[J). Tetrahedron Letters,1988,29(36):4603-4606.
[79]Masahito M., Yoshinobu I., Hiroshi K.. Synthesis of salviolone, a cytotoxic benzotropolonoid bisnorditerpene from Salvia miltiorrhiza[J].Chemistry Letters,1989, (6):1021-1022.
[80]Haro G, Mori M., Ishitsuka M.O., et al. Structures of diterpenoid tropolones, salviolone and miltipolone, from the root of Salvia miltiorrhiza Bunge[J]. Bulletin of the Chemical Society of Japan,1991,64(11):3422-3426.
[81]陈政雄,顾文华,黄慧珠,等.丹参中水溶性酚酸成分的研究[J].中国药学杂志,1981,16(9)：536-537.
[82]余世春,琚小龙,段广勋.丹参的化学成分和药理活性研究概况[J].安徽卫生职业技术学院学报,2002,1(2)：43-47.
[83]赵淑娟,章国瑛,刘涤,等.丹参水溶性酚酸类化合物药理及生物合成途径研究进展[J].中草药,2004,35(3)：341-344.
[84]周长新,罗厚蔚,丹羽正武.丹参水溶性化学成分的研究[J].中国药科大学学报, 1999,30(6)：411-416.
[85]Li L.N., Tan R., Chen W.M.. Salvianolic acid A, a new depside from Salvia miltiorrhiza[J]. Planta Medica,1984,50:227-231.
[86]Ai C.B., Li L.N.. Stereo structure of salvianolic acid B and isolation of salvianolic acid C from Salvia miltiorrhiza[J]. Journal of Natural Products,1988,51(1):145-149.
[87]Ai C.B., Li L.N.. Salvianolic acid D and E:Two new depsides from Salvia miltiorrhiza[J]. Planta Medica,1992,58:197-202.
[88]Guo Y.X., Han J., Zhang D.Y., et al. An ammonium sulfate/ethanol aqueous two-phase system combined with ultrasonication for the separation and purification of lithospermic acid B from Salvia miltiorrhiza Bunge[J]. Ultrasonics Sonochemistry,2012,19(4): 719-724.
[89]关昕.注射用丹参化学对照品的制备、提取工艺及所用药材丹参质量标准研究[D].沈阳：沈阳药科大学,2005年.
[90]钱名堃,杨保津,顾文华,等.丹参有效成分的研究[J].化学学报,1978,36(3)：199-206.
[91]郭济贤.丹参的研究与临床应用[M].北京：中国医药科技出版社,1992,39.
[92]Yang Y, Yang S., Chen M.Z., et al. Compound Astragalus and Salvia miltiorrhiza extract exerts anti-fibrosis by mediating TGF-(3/S mad signaling in myofibroblasts[J]. Journal of Ethnopharmacology,2008,118(2):264-270.
[93]Francis F.Y.L., John H.K.Y., Yiu W.K., et al. Salvianolic acid B, an aqueous component of danshen (Salvia miltiorrhiza), relaxes rat coronary artery by inhibition of calcium channels[J]. European Journal of Pharmacology,2006,553(1-3):240-245.
[94]Ji W., Gong B.Q.. Hypolipidemic activity and mechanism of purified herbal extract of Salvia miltiorrhiza in hyperlipidemic rats[J]. Journal of Ethnopharmacology,2008, 119(2):291-298.
[95]Qian Shuhong, Huo Dongxia, Wang Shijin, et al. Inhibition of glucose-induced vascular endothelial growth factor expression by Salvia miltiorrhiza hydrophilic extract in human microvascular endothelial cells:Evidence for mitochondrial oxidative stress[J]. Journal of Ethnopharmacology,2011,137(2):985-991.
[96]Dong Juane, Wan Guowei, Liang Zongsuo. Accumulation of salicylic acid-induced phenolic compounds and raised activities of secondary metabolic and antioxidative enzymes in Salvia miltiorrhiza cell culture[J]. Journal of Biotechnology,2010,148(2-3): 99-104.
[97]Zhou Yongqiang, Li Weize, Xu Lei, et al. In Salvia miltiorrhiza, phenolic acids possess protective properties against amyloid β-induced cytotoxicity, and tanshinones act as acetylcholinesterase inhibitors [J]. Environmental Toxicology and Pharmacology,2011, 31(3):443-452.
[98]Hung Yuchiang, Wang Peiwen, Pan Tailong. Functional proteomics reveal the effect of Salvia miltiorrhiza aqueous extract against vascular atherosclerotic lesions [J]. Biochimica et Biophysica Acta (BBA)-Proteins & Proteomics,2010,1804(6):1310-1321.
[99]Wenlin W., Yuanting Z., Li Z., et al. Extraction, preliminary structural characterization, and antioxidant activities of polysaccharides from Salvia miltiorrhiza Bunge[J]. Carbohydrate Polymers,2012,87(2):1348-1353.
[100]Adam M., Sylwia Z., Jan O., et al. Antioxidant activity of extracts from leaves and roots of Salvia miltiorrhiza Bunge, S. przewalskii Maxim., and S. verticillata L.[J]. Bioresource Technology,2008,99(16):7892-7896.
[101]Zhang Yuan, Li Xing, Wang Zhezhi. Antioxidant activities of leaf extract of Salvia miltiorrhiza Bunge and related phenolic constituents [J]. Food and Chemical Toxicology, 2010,48(10):2656-2662.
[102]Wen-Chi Hou, Hsin-Sheng Tsay, Hong-Jen Liang, et al. Improving abnormal hemorheological parameters in aging guinea pigs by water-soluble extracts of Salvia miltiorrhiza Bunge[J]. Journal of Ethnopharmacology,2007,111(3):483-489.
[103]Chen Yuancheng, Cao Wanwen, Cao Yuan, et al. Using neural networks to determine the contribution of danshensu to its multiple cardiovascular activities in acute myocardial infarction rats [J]. Journal of Ethnopharmacology,2011,138(1):126-134.
[104]Shou-bao Wang, Shuo Tian, Fan Yang, et al. Cardioprotective effect of salvianolic acid A on isoproterenol-induced myocardial infarction in rats[J]. European Journal of Pharmacology,2009,615(1-3):125-132.
[105]Hu-Quan Yin, You-Jin Choi, Youn-Chul Kim, et al. Salvia miltiorrhiza Bunge and its active component cryptotanshinone protects primary cultured rat hepatocytes from acute ethanol-induced cytotoxicity and fatty infiltration [J]. Food and Chemical Toxicology, 2009,47(1):98-103.
[106]Francis F.Y.L., John H.K.Y., Kam M.C., et al. Dihydrotanshinone, a lipophilic component of Salvia miltiorrhiza (danshen), relaxes rat coronary artery by inhibition of calcium channels[J]. Journal of Ethnopharmacology,2008,119(2):318-321.
[107]Jing-Yan H., Jing-Yu F., Yoshinori H., et al. Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion[J]. Pharmacology & Therapeutics,2008,117(2): 280-295.
[108]Chun-Mei Cao, Qiang Xia, Xiong Zhang, et al. Salvia miltiorrhiza attenuates the changes in contraction and intracellular calcium induced by anoxia and reoxygenation in rat cardiomyocytes[J]. Life Sciences,2003,72(22):2451-2463.
[109]Jian Sun, Shan Hong Huang, Benny K.H. Tan, et al. Effects of purified herbal extract of Salvia miltiorrhiza on ischemic rat myocardium after acute myocardial infarction [J]. Life Sciences,2005,76(24):2849-2860.
[110]邓婧,张岱尊,杨文静.醇取丹参液对几种口腔致病菌的体外抑菌作用[J].上海口腔医学,2006,2：107-109.
[111]Bok Yun Kang, Su Wol Chung, Seung Hyun Kim, et al. Inhibition of interleukin-12 and interferon-y production in immune cells by tanshinones from Salvia miltiorrhiza[J]. Immunopharmacology,2000,49(3):355-361.
[112]Ming-Jaw Don, Chien-Chang Shen, Wan-Jr Syu, et al. Cytotoxic and aromatic constituents from Salvia miltiorrhiza[J]. Phytochemistry,2006,67(5):497-503.
[113]Shanhong Ling, Ruizhi Luo, Aozhi Dai, et al. A pharmaceutical preparation of Salvia miltiorrhiza protects cardiac myocytes from tumor necrosis factor-induced apoptosis and reduces angiotensin Ⅱ-stimulated collagen synthesis in fibroblasts[J]. Phytomedicine, 2009,16(1):56-64.
[114]Lee W.Y.W., Chiu L.C.M., Yeung J.H.K.. Cytotoxicity of major tanshinones isolated from Danshen (Salvia miltiorrhiza) on HepG2 cells in relation to glutathione perturbation[J]. Food and Chemical Toxicology,2008,46(1):328-338.
[115]Seung Eun Lee, Seong Ⅱ Jeong, Hana Yang, et al. Extract of Salvia miltiorrhiza (Danshen) induces Nrf2-mediated heme oxygenase-1 expression as a cytoprotective action in RAW 264.7 macrophages[J]. Journal of Ethnopharmacology,2012,139(2): 541-548.
[116]李如冰,吴强,徐素娟.二氢丹参酮Ⅰ对QGY-7703细胞和TSC-A-1细胞放射敏感性影响[J].辐射研究与辐射工艺学报,1998,16(1)：29.
[117]王国中,冯化杰,孙凤侠,等.丹参抗大鼠乙酸十二指肠溃疡的实验研究[J].齐齐哈尔医学院学报,2001,22(6)：601-602.
[118]王国中,陈志伟,潘洪明,等.丹参抗大鼠乙醇性胃黏膜损伤的作用及机制[J].中 国中西医结合消化杂志,2002,10(6)：340-341.
[119]Jennifer Man-Fan Wan, Wai-Hung Sit, Cheuk-Lun Lee, et al. Protection of lethal toxicity of endotoxin by Salvia miltiorrhiza Bunge is via reduction in tumor necrosis factor alpha release and liver injury[J]. International Immunopharma-cology,2006,6(5): 750-758.
[120]Eun-Jeon Park, Yu-Zhe Zhao, Youn-Chul Kim, et al. Preventive effects of a purified extract isolated from Salvia miltiorrhiza enriched with tanshinone I, tanshinone IIA and cryptotanshinone on hepatocyte injury in vitro and in vivo[J]. Food and Chemical Toxicology,2009,47(11):2742-2748.
[121]Xin-Jian Wang, Zhi-Bo Wang, Jian-Xing Xu. Effect of salvianic acid A on lipid peroxidation and membrane permeability in mitochondria[J]. Journal of Ethnopharma-cology,2005,97(3):441-445.
[122]Lin Yunlian, Wu Chiahung, Luo Miaohua, et al. In vitro protective effects of salvianolic acid B on primary hepatocytes and hepatic stellate cells[J]. Journal of Ethnopharmacology,2006,105(1-2):215-222.
[123]国家药典委员会.中华人民共和国药典(一部)[M].北京：中国医药科技出版社,2010：56.
[124]国家药典委员会.中华人民共和国药典(一部)[M].北京：中国医药科技出版社,2010：82.
[125]李凝,王永梅.α-蒎烯BPO催化法合成冰片的动力学研究[J].桂林工学院学报,2001,3(21)：280-283.
[126]国家药典委员会.中华人民共和国药典(一部)[M].北京：中国医药科技出版社,2010：136.
[127]周志彬.几种冰片的区分[J].中国药业,2006,15(9)：57.
[128]班炳坤,王建,王洋,等.麝香与冰片及其不同配比对脑冷冻伤大鼠血清ET、NO的影响[J].中药药理与临床,2011,27(1)：61-63.
[129]林竹贞,姚美村,蓝明雄,等.冰片对阿魏酸钠在小鼠血浆和脑区中分布的影响[J].中草药,2008,39(4)：551-556.
[130]王平,王晨,楼一层.冰片、川芎对复方舒郁健脑方剂透过血脑屏障的作用研究[J].湖北中医药大学学报,2011,13(5)：21-23.
[131]史卫忠,赵志刚.冰片作用下尼莫司汀透过血脑屏障的药动学[J].中国医院药学杂志,2008,8(22)：1933-1936.
[132]刘启德,梁美蓉,陈芝喜,等.冰片对庆大霉素透血脑屏障的影响[J].广州中医学院学报,1994,11(1)：37.
[133]冯宏业,葛朝莉.冰片对癫痫患者血清及脑脊液卡马西平药物浓度的作用[J].海南医学,2005,16(6)：11.
[134]吴雪,欧阳丽娜,向大位,等.冰片及石菖蒲促进羟基红花黄色素A透过血脑屏障的实验研究[J].中草药,2011,42(4)：734-737.
[135]陈瑞玲,赵志刚,张星虎,等.冰片对丙戊酸钠透过血脑屏障的影响[J].中国康复理论与实践,2007,13(2)：151.
[136]褚建波,王玮,赵文霞,等.冰片对克林霉素透过小鼠血-脑脊液屏障的促进作用,医药导报[J].2008,27(7)：35.
[137]Xiao Y.Y., Ping Q.N., Chen Z.P.. The enhancing effect of synthetical borneol on the absorption of tetramethylpyrazine phosphate in mouse[J]. International Journal of Pharmaceutics,2007,337(1-2):74-79.
[138]Lai Xiaojuan, Zhang Liang, Li Junsong, et al. Comparative pharmacokinetic and bioavailability studies of three salvianolic acids after the administration of Salviae miltiorrhizae alone or with synthetical borneol in rats[J]. Fitoterapia,2011,82(6): 883-888.
[139]石森林,吴瑾瑾,葛卫红,等.冰片对灯盏花素鼻腔给药在大鼠体内药动学的影响[J].浙江中医药大学学报,2010,34(2)：148-150.
[140]胡慧玲,王战国,蒋学华,等.冰片对盐酸小檗碱在大鼠小肠吸收的影响[J].中国医院药学杂志,2009,29(4)：281-284.
[141]Zhou Yongqiang, Li Weize, Chen Lvyi, et al. Enhancement of intestinal absorption of akebia saponin D by borneol and probenecid in situ and in vitro [J]. Environmental Toxicology and Pharmacology,2010,29(3):229-234.
[142]杨洪滨,李志坚,于楠楠.冰片对血眼屏障通透性的影响[J].国际眼科杂志,2008,8(8)：1576-1578.
[143]郑晓晖,赵欣,房敏峰,等.复方丹参方中使药冰片对君药丹参药代动力学的影响[J].西安交通大学学报(医学版),2007,28(2)：170-173.
[144]刘洁,李霞,胡珊珊,等.复方丹参方中使药冰片对君药中的丹参素在家兔组织分布中的影响[J].药物分析杂志,2008,28(10)：1612-1615.
[145]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.
[146]陈林,张丽,戴云,等.使药郁金对君药丹参药代动力学的影响研究[J].中国民族医药杂志,2007,(7)：55-57.
[147]杨荣,卫引茂,李霞,等LC-MS/MS法研究活血化瘀方中丹参素在兔体内的组织分布[J].中国药科大学学报,2008,39(2)：155-158.
[148]范菲,王世祥,房敏峰,等.降香对丹参素兔药代动力学及组织分布的影响[J].第四军医大学学报,2008,29(24)：2284-2287.
[149]梁杨静,桑柏,申旭霁,等.檀香对广枣中原儿茶酸和没食子酸的药代动力学影响.第二军医大学学报,2010,31(8)：870-873.
[150]桑柏,王世祥,兰薇,等.RP-HPLC研究冰片对广枣中没食子酸在家兔体内的药动学影响.中国药学杂志,2010,45(7)：548-550.
[151]杨洁,王世祥,兰薇,等.冰片对原儿茶酸在家兔体内药动学的影响[J].中国中药杂志,2009,34(9)：1141-1143.
[152]杨洁.“广枣-降香”君-使对药体内效应物质的研究[D].西安：西北大学,2009年.
[153]张伯礼,高秀梅,商洪才,等.复方丹参方的药效物质及作用机理研究[J].世界科学技术-中医药现代化,2003,5(5)：14-17.
[154]罗晓健,毕开顺,周书余,等.复方丹参片的研究概况[J].中成药,2001,23(5)：371-374.
[155]刘小清,罗宪堂,欧阳小安.复方丹参剂型研究简况[J].时珍国医国药,2001,12(5)：474-475.
[156]郑晓晖,张群正,王世祥,等.β-(3,4-二二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途[P].中国：ZL200610041787.3,2006-10-4.
[157]郑晓晖,张群正,王世祥,等.取代p-苯基-α-羟基丙酸衍生物的合成及应用[P].国际发明专利：PCT/CN2007/0011550,2007-07-15.
[158]张雪.丹参及其复方制剂多指标成分质量控制方法研究[D].石家庄：河北医科大学,2010年.
[159]张前.“丹参-降香”君-使对药药代动力学及作用物质基础研究[D].西安：西北大学,2010年.
[160]Tsui-Hwa Tseng, Chau-Jong Wang, Erl-Shyh Kao, et al. Hibiscus protocatechuic acid protects against oxidative damage induced by tert-butylhydroperoxide in rat primary hepatocytes[J]. Chemico-Biological Interactions,1996,101(2):137-148.
[161]Mei-chin Yin, Che-yi Chao. Anti-Campylobacter, anti-aerobic, and anti-oxidative effects of roselle calyx extract and protocatechuic acid in ground beef[J]. International Journal of Food Microbiology,2008,127(1-2):73-77.
[162]Sung-Won Min, Su-Noh Ryu, Dong-Hyun Kim. Anti-inflammatory effects of black rice, cyanidin-3-O-β-d-glycoside, and its metabolites, cyanidin and protocatechuic acid[J]. International Immunopharmacology,2010,10(8):959-966.
[163]Suqin H., Erbao L., Hua L.. On-line chemiluminescence determination protocatechuic aldehyde and protocatechuic acid in pharmaceutical preparations by capillary electrophoresis[J]. Journal of pharmaceutical and biomedical analysis,2005,37(4): 733-738.
[164]Xu Man, Zhang Zichuan, Fu Gang, et al. Liquid chromatography-tandem mass spectrometry analysis of protocatechuic aldehyde and its phase Ⅰ and Ⅱ metabolites in rat[J]. Journal of Chromatography B,2007,856:100-107.
[165]Cao Yanguang, Zhang Lin, Ma Chen, et al. Metabolism of protocatechuic acid influences fatty acid oxidation in rat heart:New anti-angina mechanism implication[J]. Biochemical pharmacology,2009,77:1096-1104.
[166]Zhou Zhe, Liu Yong, Miao Aidong, et al. Protocatechuic aldehyde suppresses TNF-a-induced ICAM-1 and VCAM-1 expression in human umbilical vein endothelial cells[J]. European journal of pharmacology.2005,513(1-2):1-8.
[167]王敬良,杨砚华,朱莉,等.原儿茶酸片(心电安)对冠心病的疗效观察(摘要)[J].江苏医药,1981,(6)：39.
[168]Shui Guan, Yongming Bao, Bo Jiang, et al. Protective effect of protocatechuic acid from Alpinia oxyphylla on hydrogen peroxide-induced oxidative PC 12 cell death[J]. European journal of pharmacology,2006,538(1-3):73-79.
[169]Takuji T., Takahiro T., Mayu T.. Potential Cancer Chemopreventive Activity of Protocatechuic Acid[J]. Journal of Experimental & Clinical Medicine,2011,3(1):27-33.
[170]Guan Shui. Ge Dan, Liu Tianqing, et al. Protocatechuic acid promotes cell proliferation and reduces basal apoptosis in cultured neural stem cells[J]. Toxicology in Vitro,2009,23(2):201-208.
[171]Wang Han, Liu Tianqing, Guan Shui, et al. Protocatechuic acid from Alpinia oxyphylla promotes migration of human adipose tissue-derived stromal cells in vitro[J]. European Journal of Pharmacology,2008,599(1-3):24-31.
[172]潘琪,王玲,王俊俊,等.拉米夫定与原儿茶酸药物组合体内抗鸭乙肝病毒[J].中华中医药杂志,2011,26(11)：2500-2504.
[173]吴文华,张晓雷,韩凤梅.原儿茶酸与拉米夫定体外联合抗HBV药效学研究[J].湖北大学学报(自然科学版),2011,33(2)：193-196.
[174]Guan S., Jiang B., Bao Y.M., et al. Protocatechuic acid suppresses MPP+-induced mitochondrial dysfunction and apoptotic cell death in PC 12 cells[J]. Food and Chemical Toxicology,2006,44(10):1659-1666.
[175]王秋娟,后德辉,洪善云,等.原儿茶酸衍生物对实验性心律失常的作用[J].1988,19(1)：70-72.
[176]张遵仪,韩鹏飞,梁满达,等.原儿茶酸衍生物的化学结构与冠脉流量、心肌耗氧量关系的探讨[J].1980,15(11)：641-647.
[177]刘睿,谢跃生,潘桂湘,等.药物血浆蛋白结合率测定方法的研究进展[J].天津中医药,2007,24(6)：526-528.
[178]卢来春,蒋学华,杨俊毅,等.阿莫西林对格列美脲血浆蛋白结合率的影响[J].华西药学杂志,2003,18(4)：246-250.
[179]张群正,董岩,南叶飞,等.β-(3,4-二羟基苯基)-a-羟基丙酸异丙酯/冰片酯合成研究[J].有机化学,2009,29(9)：1466-1469.
[180]曹振华,尹军祥,田金洲,等.源于冷刺激的血液与血管病理变化研究[J].北京中医药,2009,28(4)：308-311.
[181]国家药典委员会.中华人民共和国药典(一部)[M].北京：化学工业出版社,2005：314.
[182]Cao Yanguang, Zhang Lin, Ma Chen, et al. Metabolism of protocatechuic acid influences fatty acid oxidation in rat heart:New anti-angina mechanism implication[J]. Biochemical Pharmacology,2009,77:1096-1104.
[183]Emil F., Max B., Werner L.. New synthesis of digallic acid, and migration of acyl in the partial hydrolysis of acylated phenolcarboxylic acids[J]. Berichte der Deutschen Chemischen Gesellschaft,1918,51:45-79.
[184]Zhang Qunzheng, Li Zhongjin, Zhao Xinfeng, et al. Analysis of isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate, a metabolite of danshensu, from Salvia miltiorrhiza, in rabbit plasma[J]. Chromatographia,2008,68(11-12):1067-1070.
[2]Alan L.H.. Medicines from nature:are natural products still relevant to drug discovery[J]? Trends in pharmacological sciences,1999,20(5):196-198.
[3]于德泉.展望从天然产物创新药物研究[J].中国医学科学院学报,2002,24(4)：335-338.
[4]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.
[5]杜冠华,胡娟娟,夏丽娟,等.药物筛选的发展与现状[J].药学学报,1998,33(11)：876-879.
[6]Chan K.C., Muschik G.M., Issaq H.J., et al. High-speed screening of polymerase chain reaction products by capillary electrophoresis[J]. Analytical Biochemistry,1996,243(1): 133-139.
[7]Dias J.M., Go N.F., Hart C.P., et al. Genetic recombination as a reporter for screening steroid receptor agonists and antagonists[J]. Analytical Biochemistry,1998,258(1): 96-102.
[8]Game S.M., Rajapurohit P.K., Clifford M., et al. Scintillation proximity assay for E-, P-, and L-selectin utilizing polyacrylamide-based neoglycoconjugates as ligands[J]. Analytical Biochemistry,1998,258(1):127-135.
[9]Shuber A.P., Michalowsky L.A., Nass G.S., et al. High throughput parallel analysis of hundreds of patient samples for more than 100 mutations in multiple disease genes[J]. Human Molecular Genetics,1997,6(3):337-347.
[10]Jayawickreme C.K., Kost T.A.. Gene expression systems in the development of high-throughput screens[J]. Current Opinion in Biotechnology,1997,8(5):629-634.
[11]Von S.O.D., Thies W.G., Hofmann M.. A high throughput screening for rarely transcribed differentially expressed genes[J]. Nucleic Acids Research,1997,25(13): 2598-2602.
[12]Hegde S., Schmidt M.. To Market, To Market-2007[J]. Annual Reports in Medicinal Chemistry,2008,43:455-497.
[13]Hegde S., Schmidt M.. To Market, To Market-2008[J]. Annual Reports in Medicinal Chemistry,2009,44:577-632.
[14]Hegde S., Schmidt M.. To Market, To Market-2009[J]. Annual Reports in Medicinal Chemistry,2010,45:466-537.
[15]Graul A.I., Sorbera L., Pina P., et al. The year's new drugs and biologies-2009[J]. Drug News Perspect,2010,23(1):7-36.
[16]于国安.我国新药研发问题与出路[J].创新科技,2008,(1)：20-21.
[17]周群,陈伟,王方敏,等.中国新药研发现状及药品审评模式探讨[J].中国药事,2004,18(3)：172-174.
[18]赵芳,徐立,许立.中药复方作用物质基础研究思路与方法[J].中国中西医结合杂志,2007,27(1)：80-82.
[19]王阶,张林国,孟淑环.中药复方配伍规律研究的思考[J].中国中药杂志,2001,26(12)：799-801.
[20]裘索.中药西药新药研究的异同点及开发的独特性[J].中医药学刊,2005,23(2)：01.
[21]宋军,陈可冀.中药新药开发若干重要问题的思考[J].中国处方药,2005,8(41)：17-21.
[22]吴文博.中药与新药开发的思考[J].中医药研究,2000,16(2)：52-53.
[23]Wani M.C., Taylor H.L., Wall M.E., et al. Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia [J]. Journal of the American Chemical Society,1971,93(9):2325-2327.
[24]Holton R.A., Somoza C., Kim H.B., et al. First total synthesis of taxol.1. functionalization of the B ring [J]. Journal of the American Chemical Society,1994, 116(4):1597-1598.
[25]Nicolaou K.C., Yang Z., Liu J.J., et al. Total synthesis of taxol.[J]. Nature,1994,367: 630-634.
[26]王淑月,王洪亮.前药原理与新药设计[J].河北工业科技,2003,20(1)：54-57.
[27]王介庆,吉民.兽用原料药的化学结构修饰[J].兽药与饲料添加剂,2001,6(1)：11-12.
[28]Denmeade S.R., Jakobsen C.M., Janssen S., et al. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer[J]. Journal of the National Cancer Institute,2003,95(13):990-1000.
[29]Dubowchik G.G., Mosure K., Knipe J.O., et al. Cathepsin B-sensitive dipeptide prodrugs. 2. models of anticancer drugs paclitaxel (taxol), mitomycin C and doxorubicin[J]. Bioorg Med Chem,1998,8(23):3347-3352.
[30]Bradley M.O., Swindell C.S., Anthony F.H., et al. Tumor targeting by conjugation of DHA to paclitaxel[J]. Journal of Controlled Release,2001,74(1-3):233-236.
[31]Walko C.M., Lindley C.. Capecitabine:a Review[J]. Clinical Therapeutics,2005,27(1): 23-44.
[32]Ouchi T., Tada M., Matsumoto M., et al. Design of macromolecular prodrug of sfluorouracil using N-acetylpolygalactosamine as a targeting carrier to hepatoma[J]. Reactive Functional Polymers,1998,37(1-3):235-244.
[33]Jensen B.D., Schmitt T.C., Slezak S.E.. Labeling of mammalian cells for in vivo tracking by a fluorescence method[J]. Progress in Clinical and Biological Research,1990, 355:199-207.
[34]Baker M.A., Gray B.D., Ohlsson-Wilhelm BM, et al. Zyn-Linked colchicines: Controlled-release lipophilic prodrugs with enhanced antitumor efficacy[J]. Journal of Controlled Release,1996,40(1):89-100.
[35]郭鲁宏.单宁酶的制备及酶法制取没食子酸及其丙酯研究[D].沈阳：中国科学院沈阳应用生态研究所,2000年.
[36]喻晓蔚.有机介质体系单宁酶生物合成酸酯键的研究[D].杭州：浙江大学,2006年.
[37]晏仁义,陈若芸.天然产物中先导化合物的发现与优化[J].中国天然药物,2005,3(6)：332-335.
[38]仉文升,李安良.药物化学[M].北京：高等教育出版社,1999,114-118.
[39]Zhang X., Li Y., Chen X., et al. Synthesis and characterization of the paclitaxel/MPEG-PLA block copolymer conjugate[J]. Biomaterials,2005,26 (14): 2121-2128.
[40]Greenwald R.B.. PEG drugs:an overview[J]. Journal of Controlled Release,2001, 74(1-3):159-171.
[41]Lundberg B.B., Risovic V., Ramaswamy M., et al. A lipophilic paclitaxel derivative incorporated in a lipid emulsion for parenteral administration [J]. Journal of Controlled Release,2003,86(1):93-100.
[42]Bundgaard H., Nielsen N.M.. Prodrugs as drug delivery systems.74. Facile hydrolysis of N-(acyloxymethyl) amide derivatives and implications for the design of prodrugs of NH-acidic compounds and of carboxylic acids [J]. Acta Pharmaceutica Suecica,1987, 24(5):233-246.
[43]Jolimatre P., Andr B.C., Malet M.M., et al. A new method for the synthesis of 5-fluorouracil prodrugs[J]. Synlett,1999,11(1):1829-1831.
[44]Jolimaitre P., Malet M.M, Martino R.. Fluorouracil prodrugs for the treatment of proliferative vitreoretinopathy:formulation in silicone oil and in vitro release of fluorouracil[J]. International Journal of Pharmaceutics,2003,259 (1-2):181-192.
[45]Deutsch H.M., Glinski J.A., Hermandez M., et al. Synthesis of congeners and prodrugs. 3. Water-soluble prodrugs of taxol with potent antitumor activity[J]. Journal of Medicinal Chemistry,1989,32 (4):788-792.
[46]Zhao Z.Y., David G., Kingston I.. Modified taxols 6 preparation of water-soluble prodrugs of taxol[J]. Journal of Natural Products,1991,54 (6):1607-1611.
[47]Mathew A.E., Mejillano M.R., Nath J.P., et al. Synthesis and evaluation of some water-soluble prodrugs and derivatives of paclitaxel with antitumor activity [J]. Journal of Medicinal Chemistry,1992,35 (1):145-151.
[48]Moosavi M.A.A., Hakimelahi S., Chamani J., et al. Design, synthesis, and anticancer activity of phosphonic acid diphosphate derivative of adenine-containing butenolide and its water-soluble derivatives of paclitaxel with high antitumor activity [J]. Bioorganic & Medicinal Chemistry,2003,11(20):4303-4313.
[49]Vrudhula V.M., Macmaster J.F., Li Z.G., et al. Reductively activated disulfide prodrugs of paclitaxel [J]. Bioorganic & Medicinal Chemistry Letters,2002,12(24):3591-3594.
[50]Greenwald R.B., Gibert C.W., Pendri A., et al. Drug delivery systems:water soluble taxol 2'-poly (ethylene glycol) ester prodrugs-design and in vivo effectiveness [J]. Journal of Medicinal Chemistry,1996,39(2):424-431.
[51]Schmidt F., Monneret C.. Prodrug. Prodrug Mono Therapy:synthesis and biological evaluation of an etoposide glucuronide-prodrug[J]. Bioorganic & Medicinal Chemistry, 2003,11(10):2277-2283.
[52]陈福伟.噻托溴铵联合沙丁胺醇治疗慢性阻塞性肺病30例[J].中国医药科学,2012,2(1)：111.
[53]平天洲.川芎嗪联合奥扎格雷钠治疗急性脑梗死的临床观察[J].西南军医,2012,14(1)：74-75.
[54]陈缓,周枚.自由基医学[M].北京：人民军医出版社,1991：465-466.
[55]张大平,陆伟根.新药开发中药物的盐型选择[J].中国医药工业杂志,2011,42(8)：631-635.
[56]Berge S.M., Bighley L.D., Monkhouse D.C.. Pharmaceutical salts[J]. Journal of Pharmaceutical Sciences,1977,66(1):1-19.
[57]Banerjee R., Bhatt P.M., Ravindra N.V., et al. Saccharin salts of active pharmaceutical ingredients, their crystal structure, and increased water solubilities[J]. Crystal Growth & Design,2005,5(6):2299-2309.
[58]Bastin R.J., Bowker M.J., Slater B.J.. Salt selection and optimisation procedures for pharmaceutical new chemical entities [J]. Organic Progress Research & Development, 2000,4(5):427-435.
[59]Lam K.W., Xu J., Ng K.M., et al. Pharmaceutical salt formation guided by phase diagram[J]. Industrial & Engineering Chemistry Research,2010,49(24):12503-12512.
[60]Li S., Doyle P., Metz S., et al. Effect of chloride ion on dissolution of different salt forms of haloperidol, a model basic drug[J]. Journal of Pharmaceutical Sciences,2005, 94(10):2224-2231
[61]曹观坤.成酯反应[J].药学进展,1986,3：41-47.
[62]陈道仁,王夏炎,胡绍渝.小檗碱9-为脱甲基及成酯的一种简便方法[J].现代应用药学,1988,5(3)：25-26.
[63]计榆,陶淑娟,徐莉英.(E)-3-苯基丙烯酸衍生物的合成及抗炎活性考察[J].沈阳药科大学学报,2007,24(2)：82-85.
[64]国家药典委员会.中华人民共和国药典(一部)[M].北京：中国医药科技出版社,2010,70.
[65]郭宝林,冯毓秀,赵杨景.丹参种质资源研究进展[J].中国中药杂志,2002,27(7)：492-495.
[66]郑国樨,柿浑宽.丹参化学成分的研究概况[J].中国药学杂志,1989,24(1)：6.
[67]Honda G., Koezuke Y., Tabata M., et al. Isolation of an antiderm atophytic substance from the root of Salvia miltiorrhiza. Chemical and Pharmaceutical Bulletin,1988,36(1): 408-411.
[68]Hiroshi K., Teruo H., Toshiko Y. Structures of isotanshinones. Tetrahedron Letters,1969, (5):301-304.
[69]钱名堃,杨保津,顾文华,等.丹参有效成分的研究[J].化学学报,1978,36(3)：199-206.
[70]徐任生.丹参——生物学及其应用[M].北京：科学出版社,1990：81.
[71]杨东,罗厚蔚.丹参二萜醌的结构修饰[J].中国药科大学学报,1998,29(4)：255-258.
[72]Tetsugo H., Hiroshi K., Hong Y.H., et al. Structure of miltirone, a new diterpenoid quinone[J]. Journal of the Chemical Society [Section] D:Chemical Communications, 1970, (5):299.
[73]Nasipuri D., Mitra A.K.. Synthetic studies in the diterpene series. VIII. Synthesis of miltirone, a diterpenoid quinone[J]. Journal of the Chemical Society, Perkin Transactions 1:Organic and Bio-Organic Chemistry,1973, (3):285-287.
[74]Fumika A., Takenori K., Guozhi Z.. Cryptoacetalide and epicryptoacetalide, novel spirolactone diterpenoids from Salvia miltiorrhiza[J]. Chemistry Letters,1990, (10): 1885-1888.
[75]Haro G., Hiroshi K.. Miltipolone, a new diterpenoid tropolone possessing cytotoxic activities from Salvia miltiorrhiza Bunge[J]. Chemistry Letters,1990, (9):1599-1602.
[76]Hiroshi K. Tetsugo H, Handa T, et al. Structure of salviol, a new phenolic diterpene[J]. Journal of the Chemical Society [Section] D:Chemical Communications,1971, (11): 541-542.
[77]杨保津,钱名堃,泰国伟,等.丹参有效成分的研究[J].药学学报,1981,16(11)：837-841.
[78]Haro G., Takenori K., Ishitsuka M.O., et al. Salviolone, a cytotoxic bisnorditerpene with a benzotropolone chromophore from a Chinese drug Dan-Shen (Salvia miltiorrhiza)[J). Tetrahedron Letters,1988,29(36):4603-4606.
[79]Masahito M., Yoshinobu I., Hiroshi K.. Synthesis of salviolone, a cytotoxic benzotropolonoid bisnorditerpene from Salvia miltiorrhiza[J].Chemistry Letters,1989, (6):1021-1022.
[80]Haro G, Mori M., Ishitsuka M.O., et al. Structures of diterpenoid tropolones, salviolone and miltipolone, from the root of Salvia miltiorrhiza Bunge[J]. Bulletin of the Chemical Society of Japan,1991,64(11):3422-3426.
[81]陈政雄,顾文华,黄慧珠,等.丹参中水溶性酚酸成分的研究[J].中国药学杂志,1981,16(9)：536-537.
[82]余世春,琚小龙,段广勋.丹参的化学成分和药理活性研究概况[J].安徽卫生职业技术学院学报,2002,1(2)：43-47.
[83]赵淑娟,章国瑛,刘涤,等.丹参水溶性酚酸类化合物药理及生物合成途径研究进展[J].中草药,2004,35(3)：341-344.
[84]周长新,罗厚蔚,丹羽正武.丹参水溶性化学成分的研究[J].中国药科大学学报, 1999,30(6)：411-416.
[85]Li L.N., Tan R., Chen W.M.. Salvianolic acid A, a new depside from Salvia miltiorrhiza[J]. Planta Medica,1984,50:227-231.
[86]Ai C.B., Li L.N.. Stereo structure of salvianolic acid B and isolation of salvianolic acid C from Salvia miltiorrhiza[J]. Journal of Natural Products,1988,51(1):145-149.
[87]Ai C.B., Li L.N.. Salvianolic acid D and E:Two new depsides from Salvia miltiorrhiza[J]. Planta Medica,1992,58:197-202.
[88]Guo Y.X., Han J., Zhang D.Y., et al. An ammonium sulfate/ethanol aqueous two-phase system combined with ultrasonication for the separation and purification of lithospermic acid B from Salvia miltiorrhiza Bunge[J]. Ultrasonics Sonochemistry,2012,19(4): 719-724.
[89]关昕.注射用丹参化学对照品的制备、提取工艺及所用药材丹参质量标准研究[D].沈阳：沈阳药科大学,2005年.
[90]钱名堃,杨保津,顾文华,等.丹参有效成分的研究[J].化学学报,1978,36(3)：199-206.
[91]郭济贤.丹参的研究与临床应用[M].北京：中国医药科技出版社,1992,39.
[92]Yang Y, Yang S., Chen M.Z., et al. Compound Astragalus and Salvia miltiorrhiza extract exerts anti-fibrosis by mediating TGF-(3/S mad signaling in myofibroblasts[J]. Journal of Ethnopharmacology,2008,118(2):264-270.
[93]Francis F.Y.L., John H.K.Y., Yiu W.K., et al. Salvianolic acid B, an aqueous component of danshen (Salvia miltiorrhiza), relaxes rat coronary artery by inhibition of calcium channels[J]. European Journal of Pharmacology,2006,553(1-3):240-245.
[94]Ji W., Gong B.Q.. Hypolipidemic activity and mechanism of purified herbal extract of Salvia miltiorrhiza in hyperlipidemic rats[J]. Journal of Ethnopharmacology,2008, 119(2):291-298.
[95]Qian Shuhong, Huo Dongxia, Wang Shijin, et al. Inhibition of glucose-induced vascular endothelial growth factor expression by Salvia miltiorrhiza hydrophilic extract in human microvascular endothelial cells:Evidence for mitochondrial oxidative stress[J]. Journal of Ethnopharmacology,2011,137(2):985-991.
[96]Dong Juane, Wan Guowei, Liang Zongsuo. Accumulation of salicylic acid-induced phenolic compounds and raised activities of secondary metabolic and antioxidative enzymes in Salvia miltiorrhiza cell culture[J]. Journal of Biotechnology,2010,148(2-3): 99-104.
[97]Zhou Yongqiang, Li Weize, Xu Lei, et al. In Salvia miltiorrhiza, phenolic acids possess protective properties against amyloid β-induced cytotoxicity, and tanshinones act as acetylcholinesterase inhibitors [J]. Environmental Toxicology and Pharmacology,2011, 31(3):443-452.
[98]Hung Yuchiang, Wang Peiwen, Pan Tailong. Functional proteomics reveal the effect of Salvia miltiorrhiza aqueous extract against vascular atherosclerotic lesions [J]. Biochimica et Biophysica Acta (BBA)-Proteins & Proteomics,2010,1804(6):1310-1321.
[99]Wenlin W., Yuanting Z., Li Z., et al. Extraction, preliminary structural characterization, and antioxidant activities of polysaccharides from Salvia miltiorrhiza Bunge[J]. Carbohydrate Polymers,2012,87(2):1348-1353.
[100]Adam M., Sylwia Z., Jan O., et al. Antioxidant activity of extracts from leaves and roots of Salvia miltiorrhiza Bunge, S. przewalskii Maxim., and S. verticillata L.[J]. Bioresource Technology,2008,99(16):7892-7896.
[101]Zhang Yuan, Li Xing, Wang Zhezhi. Antioxidant activities of leaf extract of Salvia miltiorrhiza Bunge and related phenolic constituents [J]. Food and Chemical Toxicology, 2010,48(10):2656-2662.
[102]Wen-Chi Hou, Hsin-Sheng Tsay, Hong-Jen Liang, et al. Improving abnormal hemorheological parameters in aging guinea pigs by water-soluble extracts of Salvia miltiorrhiza Bunge[J]. Journal of Ethnopharmacology,2007,111(3):483-489.
[103]Chen Yuancheng, Cao Wanwen, Cao Yuan, et al. Using neural networks to determine the contribution of danshensu to its multiple cardiovascular activities in acute myocardial infarction rats [J]. Journal of Ethnopharmacology,2011,138(1):126-134.
[104]Shou-bao Wang, Shuo Tian, Fan Yang, et al. Cardioprotective effect of salvianolic acid A on isoproterenol-induced myocardial infarction in rats[J]. European Journal of Pharmacology,2009,615(1-3):125-132.
[105]Hu-Quan Yin, You-Jin Choi, Youn-Chul Kim, et al. Salvia miltiorrhiza Bunge and its active component cryptotanshinone protects primary cultured rat hepatocytes from acute ethanol-induced cytotoxicity and fatty infiltration [J]. Food and Chemical Toxicology, 2009,47(1):98-103.
[106]Francis F.Y.L., John H.K.Y., Kam M.C., et al. Dihydrotanshinone, a lipophilic component of Salvia miltiorrhiza (danshen), relaxes rat coronary artery by inhibition of calcium channels[J]. Journal of Ethnopharmacology,2008,119(2):318-321.
[107]Jing-Yan H., Jing-Yu F., Yoshinori H., et al. Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion[J]. Pharmacology & Therapeutics,2008,117(2): 280-295.
[108]Chun-Mei Cao, Qiang Xia, Xiong Zhang, et al. Salvia miltiorrhiza attenuates the changes in contraction and intracellular calcium induced by anoxia and reoxygenation in rat cardiomyocytes[J]. Life Sciences,2003,72(22):2451-2463.
[109]Jian Sun, Shan Hong Huang, Benny K.H. Tan, et al. Effects of purified herbal extract of Salvia miltiorrhiza on ischemic rat myocardium after acute myocardial infarction [J]. Life Sciences,2005,76(24):2849-2860.
[110]邓婧,张岱尊,杨文静.醇取丹参液对几种口腔致病菌的体外抑菌作用[J].上海口腔医学,2006,2：107-109.
[111]Bok Yun Kang, Su Wol Chung, Seung Hyun Kim, et al. Inhibition of interleukin-12 and interferon-y production in immune cells by tanshinones from Salvia miltiorrhiza[J]. Immunopharmacology,2000,49(3):355-361.
[112]Ming-Jaw Don, Chien-Chang Shen, Wan-Jr Syu, et al. Cytotoxic and aromatic constituents from Salvia miltiorrhiza[J]. Phytochemistry,2006,67(5):497-503.
[113]Shanhong Ling, Ruizhi Luo, Aozhi Dai, et al. A pharmaceutical preparation of Salvia miltiorrhiza protects cardiac myocytes from tumor necrosis factor-induced apoptosis and reduces angiotensin Ⅱ-stimulated collagen synthesis in fibroblasts[J]. Phytomedicine, 2009,16(1):56-64.
[114]Lee W.Y.W., Chiu L.C.M., Yeung J.H.K.. Cytotoxicity of major tanshinones isolated from Danshen (Salvia miltiorrhiza) on HepG2 cells in relation to glutathione perturbation[J]. Food and Chemical Toxicology,2008,46(1):328-338.
[115]Seung Eun Lee, Seong Ⅱ Jeong, Hana Yang, et al. Extract of Salvia miltiorrhiza (Danshen) induces Nrf2-mediated heme oxygenase-1 expression as a cytoprotective action in RAW 264.7 macrophages[J]. Journal of Ethnopharmacology,2012,139(2): 541-548.
[116]李如冰,吴强,徐素娟.二氢丹参酮Ⅰ对QGY-7703细胞和TSC-A-1细胞放射敏感性影响[J].辐射研究与辐射工艺学报,1998,16(1)：29.
[117]王国中,冯化杰,孙凤侠,等.丹参抗大鼠乙酸十二指肠溃疡的实验研究[J].齐齐哈尔医学院学报,2001,22(6)：601-602.
[118]王国中,陈志伟,潘洪明,等.丹参抗大鼠乙醇性胃黏膜损伤的作用及机制[J].中 国中西医结合消化杂志,2002,10(6)：340-341.
[119]Jennifer Man-Fan Wan, Wai-Hung Sit, Cheuk-Lun Lee, et al. Protection of lethal toxicity of endotoxin by Salvia miltiorrhiza Bunge is via reduction in tumor necrosis factor alpha release and liver injury[J]. International Immunopharma-cology,2006,6(5): 750-758.
[120]Eun-Jeon Park, Yu-Zhe Zhao, Youn-Chul Kim, et al. Preventive effects of a purified extract isolated from Salvia miltiorrhiza enriched with tanshinone I, tanshinone IIA and cryptotanshinone on hepatocyte injury in vitro and in vivo[J]. Food and Chemical Toxicology,2009,47(11):2742-2748.
[121]Xin-Jian Wang, Zhi-Bo Wang, Jian-Xing Xu. Effect of salvianic acid A on lipid peroxidation and membrane permeability in mitochondria[J]. Journal of Ethnopharma-cology,2005,97(3):441-445.
[122]Lin Yunlian, Wu Chiahung, Luo Miaohua, et al. In vitro protective effects of salvianolic acid B on primary hepatocytes and hepatic stellate cells[J]. Journal of Ethnopharmacology,2006,105(1-2):215-222.
[123]国家药典委员会.中华人民共和国药典(一部)[M].北京：中国医药科技出版社,2010：56.
[124]国家药典委员会.中华人民共和国药典(一部)[M].北京：中国医药科技出版社,2010：82.
[125]李凝,王永梅.α-蒎烯BPO催化法合成冰片的动力学研究[J].桂林工学院学报,2001,3(21)：280-283.
[126]国家药典委员会.中华人民共和国药典(一部)[M].北京：中国医药科技出版社,2010：136.
[127]周志彬.几种冰片的区分[J].中国药业,2006,15(9)：57.
[128]班炳坤,王建,王洋,等.麝香与冰片及其不同配比对脑冷冻伤大鼠血清ET、NO的影响[J].中药药理与临床,2011,27(1)：61-63.
[129]林竹贞,姚美村,蓝明雄,等.冰片对阿魏酸钠在小鼠血浆和脑区中分布的影响[J].中草药,2008,39(4)：551-556.
[130]王平,王晨,楼一层.冰片、川芎对复方舒郁健脑方剂透过血脑屏障的作用研究[J].湖北中医药大学学报,2011,13(5)：21-23.
[131]史卫忠,赵志刚.冰片作用下尼莫司汀透过血脑屏障的药动学[J].中国医院药学杂志,2008,8(22)：1933-1936.
[132]刘启德,梁美蓉,陈芝喜,等.冰片对庆大霉素透血脑屏障的影响[J].广州中医学院学报,1994,11(1)：37.
[133]冯宏业,葛朝莉.冰片对癫痫患者血清及脑脊液卡马西平药物浓度的作用[J].海南医学,2005,16(6)：11.
[134]吴雪,欧阳丽娜,向大位,等.冰片及石菖蒲促进羟基红花黄色素A透过血脑屏障的实验研究[J].中草药,2011,42(4)：734-737.
[135]陈瑞玲,赵志刚,张星虎,等.冰片对丙戊酸钠透过血脑屏障的影响[J].中国康复理论与实践,2007,13(2)：151.
[136]褚建波,王玮,赵文霞,等.冰片对克林霉素透过小鼠血-脑脊液屏障的促进作用,医药导报[J].2008,27(7)：35.
[137]Xiao Y.Y., Ping Q.N., Chen Z.P.. The enhancing effect of synthetical borneol on the absorption of tetramethylpyrazine phosphate in mouse[J]. International Journal of Pharmaceutics,2007,337(1-2):74-79.
[138]Lai Xiaojuan, Zhang Liang, Li Junsong, et al. Comparative pharmacokinetic and bioavailability studies of three salvianolic acids after the administration of Salviae miltiorrhizae alone or with synthetical borneol in rats[J]. Fitoterapia,2011,82(6): 883-888.
[139]石森林,吴瑾瑾,葛卫红,等.冰片对灯盏花素鼻腔给药在大鼠体内药动学的影响[J].浙江中医药大学学报,2010,34(2)：148-150.
[140]胡慧玲,王战国,蒋学华,等.冰片对盐酸小檗碱在大鼠小肠吸收的影响[J].中国医院药学杂志,2009,29(4)：281-284.
[141]Zhou Yongqiang, Li Weize, Chen Lvyi, et al. Enhancement of intestinal absorption of akebia saponin D by borneol and probenecid in situ and in vitro [J]. Environmental Toxicology and Pharmacology,2010,29(3):229-234.
[142]杨洪滨,李志坚,于楠楠.冰片对血眼屏障通透性的影响[J].国际眼科杂志,2008,8(8)：1576-1578.
[143]郑晓晖,赵欣,房敏峰,等.复方丹参方中使药冰片对君药丹参药代动力学的影响[J].西安交通大学学报(医学版),2007,28(2)：170-173.
[144]刘洁,李霞,胡珊珊,等.复方丹参方中使药冰片对君药中的丹参素在家兔组织分布中的影响[J].药物分析杂志,2008,28(10)：1612-1615.
[145]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.
[146]陈林,张丽,戴云,等.使药郁金对君药丹参药代动力学的影响研究[J].中国民族医药杂志,2007,(7)：55-57.
[147]杨荣,卫引茂,李霞,等LC-MS/MS法研究活血化瘀方中丹参素在兔体内的组织分布[J].中国药科大学学报,2008,39(2)：155-158.
[148]范菲,王世祥,房敏峰,等.降香对丹参素兔药代动力学及组织分布的影响[J].第四军医大学学报,2008,29(24)：2284-2287.
[149]梁杨静,桑柏,申旭霁,等.檀香对广枣中原儿茶酸和没食子酸的药代动力学影响.第二军医大学学报,2010,31(8)：870-873.
[150]桑柏,王世祥,兰薇,等.RP-HPLC研究冰片对广枣中没食子酸在家兔体内的药动学影响.中国药学杂志,2010,45(7)：548-550.
[151]杨洁,王世祥,兰薇,等.冰片对原儿茶酸在家兔体内药动学的影响[J].中国中药杂志,2009,34(9)：1141-1143.
[152]杨洁.“广枣-降香”君-使对药体内效应物质的研究[D].西安：西北大学,2009年.
[153]张伯礼,高秀梅,商洪才,等.复方丹参方的药效物质及作用机理研究[J].世界科学技术-中医药现代化,2003,5(5)：14-17.
[154]罗晓健,毕开顺,周书余,等.复方丹参片的研究概况[J].中成药,2001,23(5)：371-374.
[155]刘小清,罗宪堂,欧阳小安.复方丹参剂型研究简况[J].时珍国医国药,2001,12(5)：474-475.
[156]郑晓晖,张群正,王世祥,等.β-(3,4-二二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途[P].中国：ZL200610041787.3,2006-10-4.
[157]郑晓晖,张群正,王世祥,等.取代p-苯基-α-羟基丙酸衍生物的合成及应用[P].国际发明专利：PCT/CN2007/0011550,2007-07-15.
[158]张雪.丹参及其复方制剂多指标成分质量控制方法研究[D].石家庄：河北医科大学,2010年.
[159]张前.“丹参-降香”君-使对药药代动力学及作用物质基础研究[D].西安：西北大学,2010年.
[160]Tsui-Hwa Tseng, Chau-Jong Wang, Erl-Shyh Kao, et al. Hibiscus protocatechuic acid protects against oxidative damage induced by tert-butylhydroperoxide in rat primary hepatocytes[J]. Chemico-Biological Interactions,1996,101(2):137-148.
[161]Mei-chin Yin, Che-yi Chao. Anti-Campylobacter, anti-aerobic, and anti-oxidative effects of roselle calyx extract and protocatechuic acid in ground beef[J]. International Journal of Food Microbiology,2008,127(1-2):73-77.
[162]Sung-Won Min, Su-Noh Ryu, Dong-Hyun Kim. Anti-inflammatory effects of black rice, cyanidin-3-O-β-d-glycoside, and its metabolites, cyanidin and protocatechuic acid[J]. International Immunopharmacology,2010,10(8):959-966.
[163]Suqin H., Erbao L., Hua L.. On-line chemiluminescence determination protocatechuic aldehyde and protocatechuic acid in pharmaceutical preparations by capillary electrophoresis[J]. Journal of pharmaceutical and biomedical analysis,2005,37(4): 733-738.
[164]Xu Man, Zhang Zichuan, Fu Gang, et al. Liquid chromatography-tandem mass spectrometry analysis of protocatechuic aldehyde and its phase Ⅰ and Ⅱ metabolites in rat[J]. Journal of Chromatography B,2007,856:100-107.
[165]Cao Yanguang, Zhang Lin, Ma Chen, et al. Metabolism of protocatechuic acid influences fatty acid oxidation in rat heart:New anti-angina mechanism implication[J]. Biochemical pharmacology,2009,77:1096-1104.
[166]Zhou Zhe, Liu Yong, Miao Aidong, et al. Protocatechuic aldehyde suppresses TNF-a-induced ICAM-1 and VCAM-1 expression in human umbilical vein endothelial cells[J]. European journal of pharmacology.2005,513(1-2):1-8.
[167]王敬良,杨砚华,朱莉,等.原儿茶酸片(心电安)对冠心病的疗效观察(摘要)[J].江苏医药,1981,(6)：39.
[168]Shui Guan, Yongming Bao, Bo Jiang, et al. Protective effect of protocatechuic acid from Alpinia oxyphylla on hydrogen peroxide-induced oxidative PC 12 cell death[J]. European journal of pharmacology,2006,538(1-3):73-79.
[169]Takuji T., Takahiro T., Mayu T.. Potential Cancer Chemopreventive Activity of Protocatechuic Acid[J]. Journal of Experimental & Clinical Medicine,2011,3(1):27-33.
[170]Guan Shui. Ge Dan, Liu Tianqing, et al. Protocatechuic acid promotes cell proliferation and reduces basal apoptosis in cultured neural stem cells[J]. Toxicology in Vitro,2009,23(2):201-208.
[171]Wang Han, Liu Tianqing, Guan Shui, et al. Protocatechuic acid from Alpinia oxyphylla promotes migration of human adipose tissue-derived stromal cells in vitro[J]. European Journal of Pharmacology,2008,599(1-3):24-31.
[172]潘琪,王玲,王俊俊,等.拉米夫定与原儿茶酸药物组合体内抗鸭乙肝病毒[J].中华中医药杂志,2011,26(11)：2500-2504.
[173]吴文华,张晓雷,韩凤梅.原儿茶酸与拉米夫定体外联合抗HBV药效学研究[J].湖北大学学报(自然科学版),2011,33(2)：193-196.
[174]Guan S., Jiang B., Bao Y.M., et al. Protocatechuic acid suppresses MPP+-induced mitochondrial dysfunction and apoptotic cell death in PC 12 cells[J]. Food and Chemical Toxicology,2006,44(10):1659-1666.
[175]王秋娟,后德辉,洪善云,等.原儿茶酸衍生物对实验性心律失常的作用[J].1988,19(1)：70-72.
[176]张遵仪,韩鹏飞,梁满达,等.原儿茶酸衍生物的化学结构与冠脉流量、心肌耗氧量关系的探讨[J].1980,15(11)：641-647.
[177]刘睿,谢跃生,潘桂湘,等.药物血浆蛋白结合率测定方法的研究进展[J].天津中医药,2007,24(6)：526-528.
[178]卢来春,蒋学华,杨俊毅,等.阿莫西林对格列美脲血浆蛋白结合率的影响[J].华西药学杂志,2003,18(4)：246-250.
[179]张群正,董岩,南叶飞,等.β-(3,4-二羟基苯基)-a-羟基丙酸异丙酯/冰片酯合成研究[J].有机化学,2009,29(9)：1466-1469.
[180]曹振华,尹军祥,田金洲,等.源于冷刺激的血液与血管病理变化研究[J].北京中医药,2009,28(4)：308-311.
[181]国家药典委员会.中华人民共和国药典(一部)[M].北京：化学工业出版社,2005：314.
[182]Cao Yanguang, Zhang Lin, Ma Chen, et al. Metabolism of protocatechuic acid influences fatty acid oxidation in rat heart:New anti-angina mechanism implication[J]. Biochemical Pharmacology,2009,77:1096-1104.
[183]Emil F., Max B., Werner L.. New synthesis of digallic acid, and migration of acyl in the partial hydrolysis of acylated phenolcarboxylic acids[J]. Berichte der Deutschen Chemischen Gesellschaft,1918,51:45-79.
[184]Zhang Qunzheng, Li Zhongjin, Zhao Xinfeng, et al. Analysis of isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate, a metabolite of danshensu, from Salvia miltiorrhiza, in rabbit plasma[J]. Chromatographia,2008,68(11-12):1067-1070.