复方丹参片血清药物化学及代谢组学研究
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摘要
复方丹参片是由丹参(Radix Salviae Miltiorrhizae)、三七(Radix Notoginseng)和冰片(Borneolum Syntheticum)三味中药制成的现代中药制剂,收载于2005版中华人民共和国药典第一部,具有活血化瘀、理气止痛之功效。自20世纪70年代问世以来,复方丹参片在治疗心血管疾病方面取得了显著的成效,被广泛用来治疗心肌梗死和冠心病。临床上,关于复方丹参片改善心脏功能的机制可谓是众说纷纭,包括降低血中脂质、抑制血栓形成等。到目前为止,还没有任何一个研究能够系统地阐释复方丹参片的作用机制。另外,值得注意的是复方丹参片中化学成分众多,但并非所有的成分都是有效成分。在药效物质基础不够明确的情况下,中药复方作用机制的研究确实很难取得实质性的进展。因此,本文旨在揭示复方丹参片药效物质基础的前提下继续深入研究其治疗心肌缺血的作用机制。
众所周知,中药复方是在病证结合、方证对应、理法方药一致的条件下,通过多组分作用在多靶点,融拮抗、补充、整合、调节等多种功效于一体而起到治疗作用。由此可见,中药复方的药效作用十分注重系统性和整体性。所以,对中药药效物质基础及作用机制的研究也应从整体入手。在众多的研究方法中,血清药物化学和代谢组学都十分注重整体的研究,这与中医的整体观思维不谋而合:血清药物化学方法通过分析给药后血清中的药物移行成分,研究有效成分在体内的吸收、代谢情况,用以阐明药物的整体体内过程;代谢组学方法通过分析内源性代谢物群的改变,判别机体代谢网络所处的状态,用于疾病诊断和药物作用机制的研究。
在血清药物化学和代谢组学两大理论的指导下,本文采用液相色谱串联质谱等分析方法,通过整体动物实验,对复方丹参片药效物质基础及其治疗心肌缺血的作用机制进行了较系统的研究。主要研究内容如下:
1)在血清药物化学理论指导下,利用快速液相色谱串联四极杆飞行时间质谱(RRLC-Q-TOF/MS),检测复方丹参片的入血成分和代谢产物,即通过比较给药前后大鼠的代谢指纹图谱,寻找并鉴定给药后血清中新出现的化学成分。
2)在代谢组学理论指导下,利用超高压液相色谱串联四极杆飞行时间质谱(UPLC-Q-TOF/MS),鉴定心肌缺血的生物标志物,即通过比较造模前后大鼠的代谢指纹图谱,寻找并鉴定造模后呈现特征性改变的内源性代谢物。
3)在心肌缺血模型代谢组学研究的基础上,进一步研究常见五种常见西药(异硝酸山梨酯,普奈洛尔,维拉帕米,卡托普利,曲美他嗪)与中药(复方丹参片及其有效成分)对心肌缺血大鼠的保护作用,通过中西药对比的方式,初步阐释了复方丹参片及其有效成分(丹参酮ⅡA、丹参酚酸B)治疗心肌缺血的作用机制。
通过上述研究,本文在给药大鼠血清中检测到复方丹参片的14个原型成分和8个代谢产物,其中丹参醛、丹参新醌B、丹参素的糖结合物(M1)和丹参新醌B的甲基化产物(M8)等是利用LC-MS方法首次在大鼠体内检测到;在心肌缺血大鼠血浆中发现并最终鉴定了与疾病相关的22生物标志物,其中7个标志物同时出现在嘌呤代谢途径中,提示我们嘌呤代谢是心肌缺血后重点关注的对象;通过中西药对比研究,发现复方丹参片不同于任何一种西药具有其独特的治疗心肌缺血的机制,而丹参酮ⅡA和丹参酚酸B分别具有调节钙离子通道和抑制肾上腺素β受体的作用。
Compound Danshen Tablets (CDTs), an herbal compound preparation consisting of Radix Salviae Miltiorrhizae, Radix Notoginseng and Borneolum Syntheticum, which was officially recorded in the 2005’s edition of Chinese pharmacopoeia, holding the functions of promoting blood circulation and removing blood stasis and regulating qi-flowing to relieve pain. It has been wildly used for the treatment of cardiovascular diseases (myocardial infarction, coronary heart disease…) via decreasing blood lipids and inhibiting thrombosis since 1970s. However, mechanisms of action of CDTs are not completely understood. In addition, there are many chemical compositions in the formula, what is important, not all the compounds are active components. During the last years, the study of Chinese medicine was limited for the lack of effective methodology. In our study, we aimed to find the active components of CDTs and explore mechanisms of action of CDTs.
As we known, formulas play complex therapeutic effects through roles of multi-component on multi-target under special conditions. The efficacy of Chinese medicine attaches great importance to systematic and holistic actions. Therefore, the study of active components mechanism of Chinese medicine should start with a whole. Among the various methods, the serum pharmacochemistry and metabolomics studies are very holistic, which happens to coincide with Chinese medicine as a whole concept. Serum pharmacochemistry study aimed to explore the active components of drugs by analyzing the serum after administration to explain the whole process of drugs in vivo; metabolomics approach aimed to judge the state of body's metabolic network by analyzing endogenous metabolites to diagnose diseases and study mechanisms of action of drugs.
Based on theories of serum pharmacochemistry and metabolomics, with the help of advanced LC-MS and other modern analytical techniques, we carried out the study of pharmacodynamic material basis of CDTs and investigation of mechanisms of action for the treatment of myocardial ischemia through the animal experiment. The main content is as follows:
(1) Based on serum pharmacochemistry theory, RRLC-Q-TOF/MS analysis method was established to detect components and metabolites of CDTs in rat serum after administration, which meaned to discover novel compounds in dosed rat serum by comparing the metabolic fingerprinting between the control and dosed groups.
(2) Based on metabolomics theory, UPLC-Q-TOF/MS analysis method was established to explore the biomarkers of myocardial ischemic, which meaned to detect and identify significant changed metabolites by comparing the metabolic fingerprinting between the sham and myocardial ischemic model groups.
(3) Based on the results of metabolomic study, we further studied the protections of five western medicines with different mechanismes of action (Verapamil, Captopril, Propranolol,Isosorbide Dinitrate and Trimetazidine) and Chinese medicines (CDTs and its active components). Finally, mechanisms of CDTs and its active components (TanshinoneIIA and Salvianolic acid B) for the treatment of myocardial ischemia were explained by comparison with western medicines.
In summary, 14 components and 8 metabolites of CDTs were detected in dosed rat serum; 22 metabolites were identified as the biomarkers of myocardial ischemia; after comparative study of Chinese medicine and western medicine, CDTs has unique characteristics for the treatment of myocardial ischemia, TanshinoneIIA is a calcium antagonist and Salvianolic acid B is a beta-adrenergic blocker.
众所周知,中药复方是在病证结合、方证对应、理法方药一致的条件下,通过多组分作用在多靶点,融拮抗、补充、整合、调节等多种功效于一体而起到治疗作用。由此可见,中药复方的药效作用十分注重系统性和整体性。所以,对中药药效物质基础及作用机制的研究也应从整体入手。在众多的研究方法中,血清药物化学和代谢组学都十分注重整体的研究,这与中医的整体观思维不谋而合:血清药物化学方法通过分析给药后血清中的药物移行成分,研究有效成分在体内的吸收、代谢情况,用以阐明药物的整体体内过程;代谢组学方法通过分析内源性代谢物群的改变,判别机体代谢网络所处的状态,用于疾病诊断和药物作用机制的研究。
在血清药物化学和代谢组学两大理论的指导下,本文采用液相色谱串联质谱等分析方法,通过整体动物实验,对复方丹参片药效物质基础及其治疗心肌缺血的作用机制进行了较系统的研究。主要研究内容如下:
1)在血清药物化学理论指导下,利用快速液相色谱串联四极杆飞行时间质谱(RRLC-Q-TOF/MS),检测复方丹参片的入血成分和代谢产物,即通过比较给药前后大鼠的代谢指纹图谱,寻找并鉴定给药后血清中新出现的化学成分。
2)在代谢组学理论指导下,利用超高压液相色谱串联四极杆飞行时间质谱(UPLC-Q-TOF/MS),鉴定心肌缺血的生物标志物,即通过比较造模前后大鼠的代谢指纹图谱,寻找并鉴定造模后呈现特征性改变的内源性代谢物。
3)在心肌缺血模型代谢组学研究的基础上,进一步研究常见五种常见西药(异硝酸山梨酯,普奈洛尔,维拉帕米,卡托普利,曲美他嗪)与中药(复方丹参片及其有效成分)对心肌缺血大鼠的保护作用,通过中西药对比的方式,初步阐释了复方丹参片及其有效成分(丹参酮ⅡA、丹参酚酸B)治疗心肌缺血的作用机制。
通过上述研究,本文在给药大鼠血清中检测到复方丹参片的14个原型成分和8个代谢产物,其中丹参醛、丹参新醌B、丹参素的糖结合物(M1)和丹参新醌B的甲基化产物(M8)等是利用LC-MS方法首次在大鼠体内检测到;在心肌缺血大鼠血浆中发现并最终鉴定了与疾病相关的22生物标志物,其中7个标志物同时出现在嘌呤代谢途径中,提示我们嘌呤代谢是心肌缺血后重点关注的对象;通过中西药对比研究,发现复方丹参片不同于任何一种西药具有其独特的治疗心肌缺血的机制,而丹参酮ⅡA和丹参酚酸B分别具有调节钙离子通道和抑制肾上腺素β受体的作用。
Compound Danshen Tablets (CDTs), an herbal compound preparation consisting of Radix Salviae Miltiorrhizae, Radix Notoginseng and Borneolum Syntheticum, which was officially recorded in the 2005’s edition of Chinese pharmacopoeia, holding the functions of promoting blood circulation and removing blood stasis and regulating qi-flowing to relieve pain. It has been wildly used for the treatment of cardiovascular diseases (myocardial infarction, coronary heart disease…) via decreasing blood lipids and inhibiting thrombosis since 1970s. However, mechanisms of action of CDTs are not completely understood. In addition, there are many chemical compositions in the formula, what is important, not all the compounds are active components. During the last years, the study of Chinese medicine was limited for the lack of effective methodology. In our study, we aimed to find the active components of CDTs and explore mechanisms of action of CDTs.
As we known, formulas play complex therapeutic effects through roles of multi-component on multi-target under special conditions. The efficacy of Chinese medicine attaches great importance to systematic and holistic actions. Therefore, the study of active components mechanism of Chinese medicine should start with a whole. Among the various methods, the serum pharmacochemistry and metabolomics studies are very holistic, which happens to coincide with Chinese medicine as a whole concept. Serum pharmacochemistry study aimed to explore the active components of drugs by analyzing the serum after administration to explain the whole process of drugs in vivo; metabolomics approach aimed to judge the state of body's metabolic network by analyzing endogenous metabolites to diagnose diseases and study mechanisms of action of drugs.
Based on theories of serum pharmacochemistry and metabolomics, with the help of advanced LC-MS and other modern analytical techniques, we carried out the study of pharmacodynamic material basis of CDTs and investigation of mechanisms of action for the treatment of myocardial ischemia through the animal experiment. The main content is as follows:
(1) Based on serum pharmacochemistry theory, RRLC-Q-TOF/MS analysis method was established to detect components and metabolites of CDTs in rat serum after administration, which meaned to discover novel compounds in dosed rat serum by comparing the metabolic fingerprinting between the control and dosed groups.
(2) Based on metabolomics theory, UPLC-Q-TOF/MS analysis method was established to explore the biomarkers of myocardial ischemic, which meaned to detect and identify significant changed metabolites by comparing the metabolic fingerprinting between the sham and myocardial ischemic model groups.
(3) Based on the results of metabolomic study, we further studied the protections of five western medicines with different mechanismes of action (Verapamil, Captopril, Propranolol,Isosorbide Dinitrate and Trimetazidine) and Chinese medicines (CDTs and its active components). Finally, mechanisms of CDTs and its active components (TanshinoneIIA and Salvianolic acid B) for the treatment of myocardial ischemia were explained by comparison with western medicines.
In summary, 14 components and 8 metabolites of CDTs were detected in dosed rat serum; 22 metabolites were identified as the biomarkers of myocardial ischemia; after comparative study of Chinese medicine and western medicine, CDTs has unique characteristics for the treatment of myocardial ischemia, TanshinoneIIA is a calcium antagonist and Salvianolic acid B is a beta-adrenergic blocker.
引文
[1]田代真一,“血清药理学”と“血清药化学”—汉方の药理学がい始まつた药物血中浓度测定の新しい世界,TDM研究,1988,(5):54-57
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[3]王喜军,李廷利,孙晖,茵陈蒿汤及其血中移行成分6,7-二甲氧基香豆素的肝保护作用,中国药理学通报,2004,20 (2):239-240
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[8] I. Kjellmer, P. Andiné, H. Hagber, K. Thiringer, Extracellular increase of hypoxanthine and xanthine in the cortex and basal ganglia of fetal lambs during hypoxia–ischemia, Brain Res. 1989, 478 (2): 241-247
[9] L. Fazekas, F. Horkay, V. Kékesi, E. Huszár, E. Barát, R. Fazekas, T. Szabó, A. Juhász-Nagy, A. Naszlady, Enhanced accumulation of pericardial fluid adenosine and inosine in patients with coronary artery disease, Life Sci. 1999, 65 (10): 1005-1012
[10] S. Yard?m-Akayd?n, M. Kes?mer, E. Imren, A. Sepici, B. Simsek, M. Torum, Urate oxidation during percutaneous transluminal coronary angioplasty and thrombolysis in patients with coronary artery disease, Clin. Chim. Acta 2005, 362 (1-2): 131-137
[1] J.K. Nicholson, J. Connelly, J.C. Lindon, Metabonomies: a platform for studying drug toxicity and gene function, Nat. Rev. Drug Discov. 2002, 1 (2): 153-162
[2] K.C. Verhoeckx, S. Bijlsma, S. Jespersen, R. Ramaker, E.R. Verheij, R.F. Witkamp, J. van der Greef, R.J. Rodenburg, Characterization of anti-inflammatory compounds using transcriptomics, proteomics, and metabolomics in combination with multivariate data analysis, Int. Immunopharmacol. 2004, 4 (12): 1499-1514
[3] N. Khaper, C. Rigatto, Chronic Treatment with Propranolol Induces Antioxidant Changes and Protects Against Ischemia–Reperfusion Injury, Mol. Cell. Cardiol. 1997, 29 (12): 3335-3344
[4]宋煊赫,高丽萍,钙拮抗剂减轻大鼠皮瓣缺血再灌注损伤的效应,中国临床康复, 2006,10 (4): 78-79
[5]黄家胜,郑运江,俞国华,卡托普利对大鼠心肌缺血再灌注诱导内皮细胞损伤的保护作用,实用全科医学,2006,4 (3):251-252
[6] J. Kajstura, Y. Liu, Coronary artery constriction in rats: necrotic and apoptotic myocyte death, Am. J. Cardiol. 1998, 82 (5): 30-41
[7]徐长庆,王孝铭,范劲松,丹参酮ⅡA对豚鼠单个心室肌细胞跨膜电位及L型钙电流的影响,中国病理生理杂志,1997,13 (1):43-47
[1] J.K. Nicholson, J.C. Linebn, E. Holmes,‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiologieal stimuli via multivariate statistical analysis of biological NMR spectroscopic data, Xenobiotic 1999, 29 (11): l181-l189
[2] J.K. Nicholson, J. Connelly, J.C. Lindon, Metabonomies: a platform for studying drug toxicity and gene function, Nat. Rev. Drug Discov. 2002, (1): 153-162
[3] E. Holmes, A.W. Nicholls, J.C. Lindon, S.C. Connor, J.C. Connelly, J.N. Haselden, S.J. Damment, M. Spraul, P. Neidig, J.K. Nicholson, Chemometric models for toxicity classification based on NMR spectra of biofluids, Chem. Res. Toxieol. 2000, 13 (6): 471-478
[4] L.W. Sumner, P. Mendes, R.A. Dixon, Plant metabolomics: large-scale phytochemistry in the functional genomics era, Phytochemistry 2003, 62(6): 817-836
[5] S.G. Oliver, M.K.Winson, D.B.Kell, F. Baganz, Systematic functional analysis of the yeast genome, Trends Biotechnol. 1998, 16 (9): 373-378
[6] O. Fiehn, Metabolomics-the link between genotypes and phenotypes, Plant Mol. Biol. 2002, 48 (1-2): 155-171
[7] L.M. Raamsdonk, B. Teusink, D. Broadhurst, N.S. Zhang, A. Hayes, M.C. Walsh, A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations, Nat. Biotech. 2001, 19 (1): 45-50
[8] M.L. Anthony, B.C. Sweatman, C.R. Beddell, Pattern recognition classification of the site of nephrotoxicity based on metabolic data derived from proton nuclear magnetic resonance spectra of urine, Mol. Pharmacol. 1994, 46 (1): 199-211
[9] E. Holmes, J.K. Nicholson, A.W. Nicholls, The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine, Chemom. Intell. Lab. Syst. 1998, 44 (1-2): 245-255
[10] O. Beckonert, J. Monnerjahn, U. Bonk, Visualizing metabolic changes in breast-cancer tissue using 1H-NMR spectroscopy and self-organizing maps, NMR Biomed. 2003, 16: 1-11
[11] I. Martinez, T. Bathen, I.B. Standal, J. Halvorsen, Use of selective TOCSY NMR experiments for quantifying minor components in complex mixtures: Application to the metabonomics of amino acids in honey, Anal. Chem. 2005, 77 (8): 2455-2463
[12] O. Fiehn, J. Kopka, P. Dormann, T. Altmann, R.N. Trethewey, L. Willmitzer,Metabolite profiling for plant functional genomics, Nat. Biotechnol. 2000, 18 (11): 1157-1161
[13] C.A. Daykin, P.J.D. Foxall, S.C. Connor, The comparison of plasma deproteinization methods for the detection of low-molecular-weight metabolites by 1H nuclear magnetic resonance spectroscopy, Anal. Biochem. 2002, 304 (2): 220-230
[14] H.C. Keun, T.M.D. Ebbels, H. Antti, Analytical reproducibility in 1h-nmr-based metabonomic urinalysis, Chem. Res. Toxicol 2002, 15 (11): 1380-1386
[15] B.C.M. Potts, A.J. Deese, G.J. Stevens, NMR of biofluids and pattern recognition-assessing the impact of NMR parameters on the principal component analysis of urine from rat and mouse, J. Pharm. Boimed. Anal. 2001, 26 (3): 463-476
[16] K. Dettmer, P.A. Aronov, B.D. Hammock. Mass spectrometry based metabolomics, Mass Spectrom. Rev. 2007, 26(1): 51-78
[17] J. Yang, G.W. Xu, Y.F. Zheng, Strategy for metabonomics research based on high-performance liquid chromatography and liquid chromatography coupled with tandem mass spectrometry, J. Chromatogr. A, 2005, 1084(1-2): 214-221
[18] B.L. Ackermann, J.E. Hale, K.L. Duffin, The role of mass spectrometry in biomarker discovery and measurement, Cur. Drug Metab. 2006, 7 (5): 525-539
[19] E. Holmes, A.W. Nicholls, J.C. Lindon, Chermometric models for toxicity classification based on NMR spectra of biofluids, Chem. Res. Toxicol 2000, 13 (6): 471-478
[20] D.G. Robertson, M.D. Reily, R.E. Sigler, Metabenomies: evaluation of nuclear magnetic resonance(NMR)and pattern recognition technology for rapid in vivo screening of liver and kidney toxicants, Toxicol Sci. 2000, 57 (2): 326-337
[21] Y. Wang, M.E. Bollard, H. Keun, Spectral editing and pattern recognition methods applied to high-resolution magic-angle spinning 1H nuclear magnetic resonance spectroscopy of liver tissues, Anal. Biochem. 2003, 323 (1): 26-32
[22] F. Dieterle, G. Schlotterbeck, A. Ross, Application of metabonomics in a compound ranking study in early drug development revealing drug-induced excretion of choline into urine, Chem. Res. Toxicol 2006, 19 (9): 1175-1181
[23] F. Dieterle, A. Ross, G. Schlotterbeck, Metabolite projection analysis for fast identification of metabolites in metabonomics: application in an amiodarone study, Anal. Chem. 2006, 78 (11): 3551-3561
[24]林中营,严诗楷,戴卫星,代谢组学技术在临床诊断中的应用,中国医学科学院学报,2007,29 (6):811-817
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[27] J. Yang, G. Xu, Y. Zheng, Diagnosis of liver cancer using HPLC-based metabonomies avoiding false-positive result from hepatitis and hepatocirrhosis diseases, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2004, 813 (1-2): 59-65
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[30]田代真一,“血清药理学”と“血清药化学”—汉方の药理学がい始まつた药物血中浓度测定の新しい世界,TDM研究,1988,(5):54-57
[31]潘卫松,何希辉,张宏印,血清药理学、血清化学和中药药代动力学,世界科学技术—中药现代化基础研究,2002,4 (3):53-56
[32]王喜军,中药血清药物化学的研究动态及发展趋势,中国中药杂志,2006,31 (10):789-792
[33]王喜军,李廷利,孙晖,茵陈蒿汤及其血中移行成分6 , 72二甲氧基香豆素的肝保护作用,中国药理学通报,2004,20 (2):239-240
[34]王喜军,孙文军,孙晖,茵陈蒿汤不同配伍变化对大鼠血中移行成分的影响,中国天然药物,2008,6 (1):43-47
[35]唐泓皓,王伟,刘斌,单味中药土茯苓血清药物化学的初步研究,中华中医药杂志,2005,20 (6):342-343
[36]方建国,彭静,王文清,大青叶在大鼠中的血清药物化学研究,中国医院药学杂志,2008,28 (6):434-436
[37]王亚丽,梁逸曾,陈练,当归活性成分的血清药物化学研究,现代中药研究与实践,2004,18 (增):75-79
[38]王喜军,孙文军,张宁,六味地黄丸血中移行成分的分离及结构鉴定,中国天然药物,2007,5 (4):277-280
[39]孙健,温庆辉,李夏,黄连解毒汤及其含药血清的化学成分及抗肿瘤作用对比研究,中国中药杂志,2006,31 (18):1526-1529
[40]房方,李祥,陈建伟,中药血清药物化学的研究进展,亚太传统医药,2009,5 (1):143-145
[2]房方,李祥,陈建伟,中药血清药物化学的研究进展,亚太传统医药,2009,5 (1):143-145
[3]王喜军,李廷利,孙晖,茵陈蒿汤及其血中移行成分6,7-二甲氧基香豆素的肝保护作用,中国药理学通报,2004,20 (2):239-240
[4] J.K. Nicholson, J. Connelly, J.C. Lindon, Metabonomies: a platform for studying drug toxicity and gene function, Nat. Rev. Drug Discov. 2002, (1): 153-162
[5] C. Wang, H. Kong, Y. Guan, J. Yang, J. Gu, S. Yang, G. Xu, Plasma phospholipid metabolic profiling and biomarkers of type 2 diabetes mellitus based on high-performance liquid chromatography/electrospray mass spectrometry and multivariate statistical analysis, Anal. Chem. 2005, 77 (13): 4108-4116
[6] E. Zelena, W.B. Dunn, D. Broadhurst, S. Francis-McIntyre, K.M. Carroll, P. Begley, S. O'Hagan, J.D. Knowles, A. Halsall, I.D. Wilson, D.B. Kell, Development of a robust and repeatable UPLC-MS method for the long-term metabolomic study of human serum, Anal. Chem. 2009, 81 (4): 1357-1364
[7] G.S. Catchpole, M. Beckmann, D.P. Enot, M. Mondhe, B. Zywicki, J. Taylor, N. Hardy, A. Smith, R.D. King, D.B. Kell, O. Fiehn, J. Draper, Hierarchical metabolomics demonstrates substantial compositional similarity between genetically modified and conventional potato crops, Proc. Natl. Acad. Sci. USA 2005, 102 (40): 14458-14462
[8] K.C. Verhoeckx, S. Bijlsma, S. Jespersen, R. Ramaker, E.R. Verheij, R.F. Witkamp, J. van der Greef, R.J. Rodenburg, Characterization of anti-inflammatory compounds using transcriptomics, proteomics, and metabolomics in combination with multivariate data analysis, Int. Immunopharmacol. 2004, 4 (12): 1499-1514
[9]国家药典委员会,中华人民共和国药典(第一部),北京:化学工业出版社,2005
[10] X.C. Li, C. Yu, Y.B. Cai, G.Y. Liu, J.Y. Jia, Y.P. Wang, Simultaneous determination of six phenolic constituents of danshen in human serum using liquid chromatography/tandem mass spectrometry, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2005, 820 (1): 41-47
[11] G. Ye, C.S. Wang, Y.Y. Li, H. Ren, D.A. Guo, Simultaneous determination and pharmacokinetic studies on (3,4-Dihydroxyphenyl)-lactic acid and protocatechuicaldehyde in rat serum after oral administration of Radix Salviae miltiorrhizae extract, J. Chromatogr. Sci. 2003, 41 (6): 327-330
[12] L.C. Yu, S.C. Chen, W.C. Chang, Y.C. Huang, K.M. Lin, P.H. Lai, H.W. Sung, Stability of angiogenic agents, ginsenoside Rg1 and Re, isolated from Panax ginseng: In vitro and in vivo studies. Int. J. Pharm. 2007, 328 (2): 168-176
[13] Y.J. Wei, P. Li, B. Shu, H.J. Li, J. Chen, L. Yi, Analysis of chemical and metabolic components in traditional Chinese medicinal combined prescription containing Radix Salvia miltiorrhiza and Radix Panax notoginseng by LC-ESI-MS methods, Biomed. Chromatogr. 2007, 21 (8): 797-809
[14]朱永林,杨伟琴,复方丹参片对慢性脑缺血大鼠脑内VEGF表达的影响,中国实用神经疾病杂志,2007,10 (6):26-27
[15]朱永林,刘启强,杨伟琴,复方丹参片对慢性脑缺血大鼠脑内HIF-1Q表达的影响,实用神经疾病杂志,2005,8 (5):18-19
[16]潘文军,曾江沈,牟孝硕,复方丹参片对家兔实验性心肌梗塞和心肌酶谱的影响,沈阳药科大学学报,2005,22 (1):l 53-155
[17]吴莉,杨桂珍,黄科军,复方丹参片对糖尿病大鼠体内氧化应激的影响,宁夏医学杂志,2008,30 (5):396-398
[18]杨睿瑶,复方丹参片对血管性痴呆大鼠记忆障碍的治疗效应及其作用机理探讨,中华实用中西医杂志,2007,20 (23):2042-2044
[19]马增春,高月,谭洪玲,复方丹参片对冠心病患者血浆蛋白影响的蛋白质组学研究,中国中药杂志,2006,31:766-768
[1]田代真一,“血清药理学”と“血清药化学”—汉方の药理学がい始まつた药物血中浓度测定の新しい世界,TDM研究,1988,(5):54-57
[2]房方,李祥,陈建伟,中药血清药物化学的研究进展,亚太传统医药,2009,5 (1):143-145
[3]王喜军,李廷利,孙晖,茵陈蒿汤及其血中移行成分6,7-二甲氧基香豆素的肝保护作用,中国药理学通报,2004,20 (2):239-240
[4]唐泓皓,王伟,刘斌,单味中药土茯苓血清药物化学的初步研究,中华中医药杂志,2005,20 (6):342-343
[5]方建国,彭静,王文清,大青叶在大鼠中的血清药物化学研究,中国医院药学杂志,2008,28 (6):434-436
[6]王亚丽,梁逸曾,陈练,当归活性成分的血清药物化学研究,现代中药研究与实践,2004,18 (增):75-79
[7]王喜军,孙文军,张宁,六味地黄丸血中移行成分的分离及结构鉴定,中国天然药物,2007,5 (4):277-280
[8]孙健,温庆辉,李夏,黄连解毒汤及其含药血清的化学成分及抗肿瘤作用对比研究,中国中药杂志,2006,31 (18):1526-1529
[9] X.C. Li, C. Yu, Y.B. Cai, G.Y. Liu, J.Y. Jia, Y.P. Wang, Simultaneous determination of six phenolic constituents of danshen in human serum using liquid chromatography/tandem mass spectrometry, J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2005, 820 (1): 41-47
[10] A.J. Lau, S.O. Woo, H.L. Koh, Analysis of saponins in raw and steamed Panax notoginseng using high-performance liquid chromatography with diode array detection, J. Chromatogr. A 2003, 1011 (1-2): 77-87
[11] P. Jiang, R. Liu, S. Dou, L. Liu, W. Zhang, Z. Chen, R. Xu, J Ding, Analysis of the constituents in rat plasma after oral administration of Shexiang Baoxin pill by HPLC-ESI-MS/MS, Biomed. Chromatogr. 2009, 23 (12): 1333-1343
[12] J.H. Sun, M. Yang, X.M. Wang, M. Xu, A.H. Liu, D.A. Guo, Identification of tanshinones and their metabolites in rat bile after oral administration of TTE-50, a standardized extract of Salvia miltiorrhiza by HPLC-ESI-DAD-MSn, J. Pharm. Biomed. Anal. 2007, 44 (2): 564-574
[13] P. Hu, Q.L. Liang, G.A. Luo, Z.H. Jiang, Multi-component HPLC fingerprinting ofradix Salviae miltiorrhizae and its LC-MS-MS identification, Chem. Pharm. Bull. 2005, 53 (6): 677-683
[14] L. Li, R. Tsao, J.P. Dou, F.G. Song, Z.P. Liu, S.Y. Liu, Detection of saponins in extract of Panax notoginseng by liquid chromatography-electrospray ionization-mass spectrometry, Anal. Chim. Acta 2005, 536 (1-2): 21-28
[15] S.Y. Xiao, G.A. Luo, Y.M. Yang, Q.L.Liang, Identification of Panax notoginseng and its preparations by LC-MS, Acta Pharmacol. Sin. 2004, 39: 127-131
[16] H. Zhang, Y. Cheng, Solid-phase extraction and liquid chromatography electrospray mass spectrometric analysis of saponins in a Chinese patent medicine of formulated Salvia miltiorrhizae and Panax notoginseng, J. Pharm. Biomed. Anal. 2006, 40 (2): 429-432
[17] J.L. Zhang, M. Cui, Y. He, H.L. Yu, D.A. Guo, Chemical fingerprint and metabolic fingerprint analysis of Danshen injection by HPLC-UV and HPLC-MS methods, J. Pharm. Biomed. Anal. 2005, 36 (5): 1029-1035
[18] M. Xu, Z. Zhang, G. Fu, S. Sun, J. Sun, M. Yang, A. Liu, J. Han, D.A. Guo, Liquid chromatography–tandem mass spectrometry analysis of protocatechuic aldehyde and its phase I and II metabolites in rat, J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2007, 856 (1-2): 100-107
[19] H. Dai, M. Wang, X. Li, M. Xue, Structural elucidation of in vitro and in vivo metabolites of cryptotanshinone by HPLC-DAD-ESI-MSn, J. Pharm. Biomed. Anal. 2008, 48 (3): 885-896
[1] WHO, http://www.who.int/cardiovascular_diseases/en/. Accessed September 10, 2008
[2] J.K. Nicholson, J.C. Linebn, E. Holmes,‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiologieal stimuli via multivariate statistical analysis of biological NMR spectroscopic data, Xenobiotic 1999, 29 (11): l181-l189
[3] K. Ytrehus, Models of myocardial ischemia, Drug Discov. Today Dis. Models 2006, 3 (3): 263-271
[4] P. Madeddu, C. Emanueli, Murine models of myocardial and limb ischemia: Diagnostic end-points and relevance to clinical problems, Vascular Pharmacolo. 2006, 45 (5): 281-301
[5] S. Jun-ichi, O. Masahito, Tea catechins attenuate chronic ventricular remodeling after myocardial ischemia in rats, Mol. Cell. Cardiol. 2007, 42 (2): 432-440
[6] P. Kleihues, K. Kobayashi, K.A. Hossmann, Purine nucleotide metabolism in the cat brain after one hour of complete ischemia, J. Neurochem. 1974, 23 (2): 417-425
[7] O.D. Saugstad, H. Schrader, The determination of inosine and hypoxanthine in rat brain during normothermic and hypothermic anoxia, Acta Neurol. Scand. 1978, 57 (4): 281-288
[8] I. Kjellmer, P. Andiné, H. Hagber, K. Thiringer, Extracellular increase of hypoxanthine and xanthine in the cortex and basal ganglia of fetal lambs during hypoxia–ischemia, Brain Res. 1989, 478 (2): 241-247
[9] L. Fazekas, F. Horkay, V. Kékesi, E. Huszár, E. Barát, R. Fazekas, T. Szabó, A. Juhász-Nagy, A. Naszlady, Enhanced accumulation of pericardial fluid adenosine and inosine in patients with coronary artery disease, Life Sci. 1999, 65 (10): 1005-1012
[10] S. Yard?m-Akayd?n, M. Kes?mer, E. Imren, A. Sepici, B. Simsek, M. Torum, Urate oxidation during percutaneous transluminal coronary angioplasty and thrombolysis in patients with coronary artery disease, Clin. Chim. Acta 2005, 362 (1-2): 131-137
[1] J.K. Nicholson, J. Connelly, J.C. Lindon, Metabonomies: a platform for studying drug toxicity and gene function, Nat. Rev. Drug Discov. 2002, 1 (2): 153-162
[2] K.C. Verhoeckx, S. Bijlsma, S. Jespersen, R. Ramaker, E.R. Verheij, R.F. Witkamp, J. van der Greef, R.J. Rodenburg, Characterization of anti-inflammatory compounds using transcriptomics, proteomics, and metabolomics in combination with multivariate data analysis, Int. Immunopharmacol. 2004, 4 (12): 1499-1514
[3] N. Khaper, C. Rigatto, Chronic Treatment with Propranolol Induces Antioxidant Changes and Protects Against Ischemia–Reperfusion Injury, Mol. Cell. Cardiol. 1997, 29 (12): 3335-3344
[4]宋煊赫,高丽萍,钙拮抗剂减轻大鼠皮瓣缺血再灌注损伤的效应,中国临床康复, 2006,10 (4): 78-79
[5]黄家胜,郑运江,俞国华,卡托普利对大鼠心肌缺血再灌注诱导内皮细胞损伤的保护作用,实用全科医学,2006,4 (3):251-252
[6] J. Kajstura, Y. Liu, Coronary artery constriction in rats: necrotic and apoptotic myocyte death, Am. J. Cardiol. 1998, 82 (5): 30-41
[7]徐长庆,王孝铭,范劲松,丹参酮ⅡA对豚鼠单个心室肌细胞跨膜电位及L型钙电流的影响,中国病理生理杂志,1997,13 (1):43-47
[1] J.K. Nicholson, J.C. Linebn, E. Holmes,‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiologieal stimuli via multivariate statistical analysis of biological NMR spectroscopic data, Xenobiotic 1999, 29 (11): l181-l189
[2] J.K. Nicholson, J. Connelly, J.C. Lindon, Metabonomies: a platform for studying drug toxicity and gene function, Nat. Rev. Drug Discov. 2002, (1): 153-162
[3] E. Holmes, A.W. Nicholls, J.C. Lindon, S.C. Connor, J.C. Connelly, J.N. Haselden, S.J. Damment, M. Spraul, P. Neidig, J.K. Nicholson, Chemometric models for toxicity classification based on NMR spectra of biofluids, Chem. Res. Toxieol. 2000, 13 (6): 471-478
[4] L.W. Sumner, P. Mendes, R.A. Dixon, Plant metabolomics: large-scale phytochemistry in the functional genomics era, Phytochemistry 2003, 62(6): 817-836
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