复方丹参滴丸干预心肌缺血大鼠的代谢组学研究
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摘要
冠心病是由动脉粥样硬化造成冠状动脉管腔狭窄,使冠状动脉供血不足和心肌缺血,并引起心脏病变。目前已成为我国城市人口死亡原因中的第三位。西医常采用硝酸脂类、钙拮抗剂及β受体阻断剂等进行治疗,但存在头晕、面红、血压低等不良反应。因此副作用小、疗效显著的复方中药的研究越来越受人关注。
复方丹参滴丸是根据中医的传统理论与现代药学新技术相结合研制成的滴丸剂,具有多组分、多环节、多靶点的心血管保护作用特点,已成为预防与治疗冠心病心绞痛的临床一线药物,但目前缺乏整体反映其作用的评价体系和标准。代谢组学的出现为这一问题的解决提供了契机。
本文利用代谢组学技术研究冠脉结扎对心肌缺血大鼠内源性代谢物的影响,从整体代谢网络调控角度阐释心肌缺血对机体的影响机制,评价复方丹参滴丸干预心肌缺血大鼠的作用。结合常规药理学方法,尝试从代谢图谱角度全面认识心肌缺血的危害,阐明复方丹参滴丸干预心肌缺血的作用机制,建立以代谢组学方法评价药物疗效的方法。主要内容与结果如下:
本研究采用与临床最为相似的冠脉结扎方法建立并复制―心肌缺血‖大鼠模型,通过测定体重、心脏重量及脏器比、血浆CK水平、心肌组织中MDA、SOD含量,心肌组织形态情况等,考察冠脉结扎对机体缺血损伤的影响,同时给予复方丹参滴丸进行干预,并尝试从抗自由基、抗氧化方面阐释复方丹参滴丸的作用机制,结果表明复方丹参滴丸疗效肯定,具有良好的抗氧自由基、抗氧化损伤、保护心肌的作用。在此基础上,我们采用大鼠血浆和尿液的代谢组学方法研究心肌缺血大鼠内源性代谢物的变化。结果发现通过对假手术组、模型组及模型给药不同组间,造模给药三天及二十八天不同时间点的比较,冠脉结扎导致大鼠心肌缺血与生物体的能量代谢、糖代谢、谷胱甘肽代谢、乳糖代谢、ABC转运蛋白等代谢途径都有密切关系。心肌缺血大鼠血浆中延胡索酸、琥珀酸、葡萄糖、柠檬酸、乳酸、尿素、天门冬氨酸、苏氨酸及肌酐等内源性代谢物有差异性变化,在尿液中葡萄糖、果糖、脯氨酸、苏氨酸、甘氨酸、丙二酸、尿酸、十四酸、硬脂酸等有差异性变化,而通过造模给药后,复方丹参滴丸给药的大鼠这些内源性代谢物都有不同程度的回调,说明复方丹参滴丸的有效成分能够通过改变机体代谢物的变化,改善机体代谢网络,从而发挥降低心肌耗氧、改善心肌能量代谢、保护心肌细胞能力等调节作用。
Coronary heart disease(CHD) is caused by atherosclerotic coronary artery stenosis, leading to insufficient blood supply of coronary and myocardial ischemia which will result in heart attack. Currently, CHD has become the third cause of death in China. Western medicine usually treat it with nitric acid lipids, calcium antagonists and beta-blockers, but there are some side-effects, such as dizziness, flushing and low blood pressure. With little side effects and significant effect, Traditional Chinese Medicine(TCM) is getting increasing attention in current researches.
Compound Danshen dripping pills(CDDP) are developed based TCM theory and modern preparation technologies. With its multi-component, multi-link and multi-target characters, CDDP got tremendous employment in the prevention and treatment of CHD in clinic. The evaluation of the whole effect of CDDP, however, still lack a overall system and standards to reflect. The appearance of metabolomics has provided an opportunity for the resolution of this issue.
With the technology of metabolomics, this paper studied the change of endogenous metabolites by ischemic myocardium resulted from coronary ligation in rats. By explaining the mechanism of myocardial ischemia on the body from the perspective of the overall metabolic network, the CDDP are evaluated. Combined with conventional pharmacological approaches, we tried a comprehensive understanding of the hazards of myocardial ischemia from the perspective of metabolic pathway, clarified the mechanism of CDDP interfering myocardial ischemia, and established a metabolomics approach to evaluate drug effect. The main content and the results are as follows:
In this study, we made coronary artery ligation to establish and copy the rat model of myocardial ischemia, which is similar to the clinical disease. By measuring body weight, heart weight, heart-body ratio, CK in plasma, MDA and SOD in tissue, as well as the myocardial morphology, we investigated the influences on myocardial ischemia caused by coronary artery ligation. We also treated rats with CDDP, and evaluated its effect on the mechanism of anti-oxidative and anti-free radical. The result showed that CDDP have excellent effects: anti-oxygen-radicals, anti-oxidative-damage and protection of myocardial cells. Based on this, we studies the endogenous metabolites in the plasma and urine of rats with metabolomics. By the comparison of sham group, model group and model+CDDP group, and the difference between the 3rd day and the 28th day after modeling and treating, we found that myocardial ischemia leaded by ligation is closely related to energy metabolism, glucose metabolism, glutathione metabolism, lactose metabolism and ABC transporter, etc. In the plasma of rats, 2-butenedioic acid, succinic acid, l-threonine, creatinine, l-aspartic acid, l-isoleucine, citric acid, d-glucose, urea and so on had significant changes before and after myocardial ischemia. In the urine of rats, glycine, tetradecanoic acid, d-glucose, octadecanoic acid, uric acid, l-proline, d-fructose, aminomalonic acid, l-threonine and others made differences. However, with the administration of CDDP, rat endogenous metabolites have different degrees of correction, which shows that the active ingredient of the CDDP helped to change the level of metabolites and improve the metabolism networks, which leads to decreasing myocardial oxygen consumption, regulating myocardial energy metabolism, and protecting myocardial cells.
复方丹参滴丸是根据中医的传统理论与现代药学新技术相结合研制成的滴丸剂,具有多组分、多环节、多靶点的心血管保护作用特点,已成为预防与治疗冠心病心绞痛的临床一线药物,但目前缺乏整体反映其作用的评价体系和标准。代谢组学的出现为这一问题的解决提供了契机。
本文利用代谢组学技术研究冠脉结扎对心肌缺血大鼠内源性代谢物的影响,从整体代谢网络调控角度阐释心肌缺血对机体的影响机制,评价复方丹参滴丸干预心肌缺血大鼠的作用。结合常规药理学方法,尝试从代谢图谱角度全面认识心肌缺血的危害,阐明复方丹参滴丸干预心肌缺血的作用机制,建立以代谢组学方法评价药物疗效的方法。主要内容与结果如下:
本研究采用与临床最为相似的冠脉结扎方法建立并复制―心肌缺血‖大鼠模型,通过测定体重、心脏重量及脏器比、血浆CK水平、心肌组织中MDA、SOD含量,心肌组织形态情况等,考察冠脉结扎对机体缺血损伤的影响,同时给予复方丹参滴丸进行干预,并尝试从抗自由基、抗氧化方面阐释复方丹参滴丸的作用机制,结果表明复方丹参滴丸疗效肯定,具有良好的抗氧自由基、抗氧化损伤、保护心肌的作用。在此基础上,我们采用大鼠血浆和尿液的代谢组学方法研究心肌缺血大鼠内源性代谢物的变化。结果发现通过对假手术组、模型组及模型给药不同组间,造模给药三天及二十八天不同时间点的比较,冠脉结扎导致大鼠心肌缺血与生物体的能量代谢、糖代谢、谷胱甘肽代谢、乳糖代谢、ABC转运蛋白等代谢途径都有密切关系。心肌缺血大鼠血浆中延胡索酸、琥珀酸、葡萄糖、柠檬酸、乳酸、尿素、天门冬氨酸、苏氨酸及肌酐等内源性代谢物有差异性变化,在尿液中葡萄糖、果糖、脯氨酸、苏氨酸、甘氨酸、丙二酸、尿酸、十四酸、硬脂酸等有差异性变化,而通过造模给药后,复方丹参滴丸给药的大鼠这些内源性代谢物都有不同程度的回调,说明复方丹参滴丸的有效成分能够通过改变机体代谢物的变化,改善机体代谢网络,从而发挥降低心肌耗氧、改善心肌能量代谢、保护心肌细胞能力等调节作用。
Coronary heart disease(CHD) is caused by atherosclerotic coronary artery stenosis, leading to insufficient blood supply of coronary and myocardial ischemia which will result in heart attack. Currently, CHD has become the third cause of death in China. Western medicine usually treat it with nitric acid lipids, calcium antagonists and beta-blockers, but there are some side-effects, such as dizziness, flushing and low blood pressure. With little side effects and significant effect, Traditional Chinese Medicine(TCM) is getting increasing attention in current researches.
Compound Danshen dripping pills(CDDP) are developed based TCM theory and modern preparation technologies. With its multi-component, multi-link and multi-target characters, CDDP got tremendous employment in the prevention and treatment of CHD in clinic. The evaluation of the whole effect of CDDP, however, still lack a overall system and standards to reflect. The appearance of metabolomics has provided an opportunity for the resolution of this issue.
With the technology of metabolomics, this paper studied the change of endogenous metabolites by ischemic myocardium resulted from coronary ligation in rats. By explaining the mechanism of myocardial ischemia on the body from the perspective of the overall metabolic network, the CDDP are evaluated. Combined with conventional pharmacological approaches, we tried a comprehensive understanding of the hazards of myocardial ischemia from the perspective of metabolic pathway, clarified the mechanism of CDDP interfering myocardial ischemia, and established a metabolomics approach to evaluate drug effect. The main content and the results are as follows:
In this study, we made coronary artery ligation to establish and copy the rat model of myocardial ischemia, which is similar to the clinical disease. By measuring body weight, heart weight, heart-body ratio, CK in plasma, MDA and SOD in tissue, as well as the myocardial morphology, we investigated the influences on myocardial ischemia caused by coronary artery ligation. We also treated rats with CDDP, and evaluated its effect on the mechanism of anti-oxidative and anti-free radical. The result showed that CDDP have excellent effects: anti-oxygen-radicals, anti-oxidative-damage and protection of myocardial cells. Based on this, we studies the endogenous metabolites in the plasma and urine of rats with metabolomics. By the comparison of sham group, model group and model+CDDP group, and the difference between the 3rd day and the 28th day after modeling and treating, we found that myocardial ischemia leaded by ligation is closely related to energy metabolism, glucose metabolism, glutathione metabolism, lactose metabolism and ABC transporter, etc. In the plasma of rats, 2-butenedioic acid, succinic acid, l-threonine, creatinine, l-aspartic acid, l-isoleucine, citric acid, d-glucose, urea and so on had significant changes before and after myocardial ischemia. In the urine of rats, glycine, tetradecanoic acid, d-glucose, octadecanoic acid, uric acid, l-proline, d-fructose, aminomalonic acid, l-threonine and others made differences. However, with the administration of CDDP, rat endogenous metabolites have different degrees of correction, which shows that the active ingredient of the CDDP helped to change the level of metabolites and improve the metabolism networks, which leads to decreasing myocardial oxygen consumption, regulating myocardial energy metabolism, and protecting myocardial cells.
引文
[1]陈敏生,刘世明,罗健东.心血管病学前沿[M].广州:广东科技出版社2011.62-75.
[2]孙勤国,王建久,郑云,等.冠心病[M].北京:中国医药科技出版社, 2010.20-22;38-40.
[3]黄政德,周德生.中西医结合冠心病学[M].长沙:湖南科学技术出版社, 2009.1-98.
[4]柯元南,曾玉杰.冠心病临床实用对策[M].北京:北京科学技术出版社, 2010.99-188.
[5]胡大一.冠心病[M].北京:化学工业出版社, 2009.37-58.
[6]孙勤国,王建久,郑云,等.冠心病[M].北京:中国医药科技出版社, 2010.215-327.
[7]陈明哲.心脏病学[M].北京:北京医科大学出版社, 2000.1058-1067.
[8]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:中国医药科技出版社, 2010.961.
[9]袁如玉,李广平.复方丹参滴丸在心血管疾病防治中的多靶点作用[J].中国新药杂志, 2009,18 (5):337-380.
[10]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:中国医药科技出版社, 2010.70-71.
[11]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:中国医药科技出版社, 2010.11.
[12]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:中国医药科技出版社, 2010.136-137.
[13]冉桦.复方丹参滴丸在心血管方面的药理与临床研究.家庭医药[J]·医药论坛, 2010,10:734-736.
[14]李全凤,王孝铭,朱世军,等.复方丹参滴丸对缺氧心肌细胞内钙离子平均荧光强度的影响[J].中国病理生理杂志, 2001,17 (7):690-691.
[15]赵雅君,朱世军,史从宁,等.大鼠心肌缺血再灌注时能量代谢及脂质过氧化变化及复方丹参滴丸的保护作用[J].哈尔滨医科大学学报, 2003,37 (4):290-293.
[16]赵明中,汪家瑞,魏嘉平,等.复方丹参滴丸对大鼠心肌缺血再灌注时心肌细胞凋亡及凋亡相关基因表达的影响[J].中国临床药理学杂志, 1999,15 (4):288-291.
[17]徐曼,李全凤,张伟华,等.复方丹参滴丸对培养的乳鼠心肌细胞缺氧及缺氧/复氧时Fas/FasL蛋白表达的影响[J].中国病理生理杂志, 2003,19 (4):499-502.
[18]赵娜,刘育英,卫晓红,等.复方丹参滴丸一次性预给药对缺血再灌注后大鼠心脏血流量和心肌损伤的改善作用[J].世界科学技术-中医药现代化, 2008,10 (3):94-98,122.
[19]冯洁,王嗣岑.复方丹参滴丸对大鼠血小板聚集功能的影响[J].中国误诊学杂志, 2006,6 (12):2261-2263.
[20]王山岭,王丽霞,孙月和.复方丹参滴丸对不稳定型心绞痛患者血小板活化及纤溶活性的影响[J].中国心血管杂志, 2003,8 (5):354- 356.
[21]陈良,张梅,李长江,等.复方丹参滴丸对动脉粥样硬化粘附因子的作用[J].中国动脉硬化杂志, 2007,15 (2):101-104.
[22]王东霞,王孝铭,许晶兰.复方丹参滴丸对人血管内皮细胞功能及形态保护作用的研究[J].中国病理生理杂志, 2006,22 (5):933-937.
[23]许晶兰,王孝铭,王东霞.复方丹参滴丸对过氧化氢损伤的人脐静脉血管内皮细胞的保护作用[J].中国病理生理杂志, 2006,22 (5):929- 932.
[24]诸葛丽敏,吴清,楼正家.复方丹参滴丸对急性冠脉综合征患者CRP及血管内皮功能的影响[J].浙江中医学院学报, 2005,29 (4):13-15.
[25]叶武,叶美颜,冯培芳,等.复方丹参滴丸对自发性高血压大鼠血管壁重建的干预及可能机制[J].中国动脉硬化杂志, 2007,15 (3):181-184.
[26]陈建宗,田季雨,顾宜,等.复方丹参滴丸对动脉粥样硬化家兔颈动脉血管壁血管细胞黏附分子-1表达的影响[J].中国临床康复, 2004,8 (24):5048-5049.
[27]韩晶岩,秋叶保忠,堀江义则,等.复方丹参滴丸及其主要成分丹参、三七对缺血再灌注引起的大鼠肠系膜微循环障碍的多环节改善作用[J].世界科学技术-中医药现代化, 2008,10 (3):99-105.
[28]乔成栋,孙玉瑛,蒋生祥.复方丹参滴丸治疗胸痹的临床观察[J].兰州大学学报(医学版), 2006,32 (1):41-44.
[29]邱宏,马军.复方丹参滴丸治疗冠心病82例疗效观察[J].中国医师杂志, 2006,1:294.
[30]陈开地.复方丹参滴丸治疗冠心病心绞痛84例临床分析[J].中国社区医师, 2011,1:17.
[31]解金洪,郁晓群.复方丹参滴丸治疗高血压左心室肥厚55例[J].现代中西医结合杂志, 2007,16 (18):2545-2546.
[32]鲁永菊,周蜜.复方丹参滴丸治疗顽固性高血压[J].中西医结合心脑血管病杂志, 2007,5 (4):291-292.
[33]杨学平,凌和水.复方丹参滴丸治疗急性脑梗死73例疗效观察[J].江西医药, 2005,40 (10):633-635.
[34]王永升.复方丹参滴丸治疗早期脑梗塞40例[J].陕西中医, 2006,6 (9):1093-1094.
[35]邱奉林,万国琳.复方丹参滴丸治疗糖尿病视网膜病变的临床观察[J].天津药学, 2006,18 (6):33-34.
[36]郭玉洁.复方丹参滴丸治疗早期糖尿病肾病的临床观察.中国民康医学, 2007,19 (2):117-118.
[37]张月萍,魏世芳.复方丹参滴丸治疗肝硬化疗效分析[J].实用肝脏病杂志, 2005,8 (1):45-46.
[38]翟穗燕,陈锐,吴学红.复方丹参滴丸治疗偏头痛41例观察[J].实用中医药杂志, 2006,22 (1):26.
[39]张诗军,陈泽雄,林佑武,等.复方丹参滴丸治疗痰瘀型高脂血症的临床研究[J].中国中药杂志, 2007,32 (5):440-443.
[40]梁启廉,陈小东,李小英,等.复方丹参滴丸加化疗治疗肝癌的临床疗效评价[J].中医药学刊, 2006,24 (1):186-188.
[41]陈小东,梁启廉,李小英,等.复方丹参滴丸在41例中晚期胰腺癌化疗中的应用[J].肿瘤学杂志, 2005,11 (1):46-48.
[42]潘桂湘,高秀梅,张伯礼,等. HPLC法测定复方丹参方中三七皂苷类成分的含量[J].中药新药临床药理, 2003,12 (3):112.
[43] Liu A-H, Lin Y-H, Guo H. Development of the fingerprints for the quality of the roots of Salvia miltiorrhiza and its related preparations by HPLC-DAD and LC–MSn[J].Journal of Chromatography B, 2007,846:32
[44]高秀梅,王怡,商洪才,等.复方丹参方抗大鼠心肌缺血作用研究[J].天津中医药, 2003,20 (1):23.
[45] Edward G K O, Lynn, Vazhappilly R, et al. Siow Magnesium tanshinoate B (MTB) inhibits low density lipoprotein oxidation[J].Life Sciences, 2001,68:903.
[46]赵雅君,朱世军,史从宁,等.大鼠心肌缺血再灌注时能量代谢及脂质过氧化变化及复方丹参滴丸的保护作用[J].哈尔滨医科大学学报, 2003,37 (4):290.
[47] Peia W-J, Zhao X-F, Zhuc Z-M, et al. Study of the determination and pharmacokinetics of Compound Danshen Dripping Pills in human serum by column switching liquid chromatography electrospray ion trap mass spectrometry[J].Journal of Chromatography B, 2004,809:237.
[48]李晓莉,李晓蓉,王丽娟,等.单用与复方给药后隐丹参酮在家兔体内的药物动力学比较[J].中国药理学通报, 2007,23 (8):1102.
[49]王宁生,宓穗卿,洪馨,等.口服复方丹参滴丸血清中丹参相关成分的LC/ MS检测[J].中药新药与临床药理, 2000,11 (3):141.
[50]史昕云,夏正远,方建国,等.复方丹参注射液对心内直视手术心肌缺血再灌注后血清内皮素及前列环素/血栓素A-2比值的影响[J].中国中西医结合杂志, 2000,12:9.
[51] Nicholson J K, Lindon J C, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data[J].Xenobiotica, 1999,29 (11):1181-1189.
[52]贾伟.医学代谢组学[M].上海:上海科学技术出版社, 2011.1.
[53] German J B, Bauman D E, Burrin D G, et al. Metabolomics in the opening decade of the 21st century: building the roads to individualized health[J].The journal of nutrition, 2004,134 (10):2729-2732.
[54] Taylor J, King R D, Altmann T, et al. Application of metabolomics to plantgenotype discrimination using statistics and machine learning [J].Bioinformatics, 2002,18 (2):241-248.
[55]严士海,朱萱萱.代谢组学在疾病诊断中的应用研究进展[J].现代中西医结合杂志, 2007,16 (5):711-712.
[56] Plumb R S, Stumpf C L, Gorenstein M V, et al. Metabonomics: the use of electrospray mass spectrometry coupled to reversed-phase liquid chromatography shows potential for the screening of rat urine in drug development.Rapid Commun[J] Mass Spectrom. 2002;16(20):1991-1996.
[57] Qiu Y, Su M, Liu Y, et al. Application of ethyl chloroformate derivatization for gas chromatography–mass spectrometry based metabonomic profiling[J].Analytica Chimica Acta, 2007,583 (2):277-283.
[58] Watkins S M, Reifsnyder P R, Pan H J, et al. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone[J] Journal of lipid research, 2002,43 (11):1809-1817.
[59] Castle A L, Carver M P, Mendrick D L. Toxicogenomics: a new revolution in drug safety[J].Drug Discovery Today, 2002,7 (13):728-736.
[60] Howells S L, Maxwell R J, Peet A C, et al. An investigation of tumor 1H nuclear magnetic resonance spectra by the application of chemometric techniques[J]. Magnetic Resonance In Medicine, 1992,28 (2):214-236.
[61] Oliver S G. Yeast as a navigational aid in genome analysis[J].Microbiology-Uk, 1997,143:1483-1487.
[62] Dalluge J J, Smith S, Sanchez-Riera F, et al. Potential of fermentation profiling via rapid measurement of amino acid metabolism by liquid chromatography-tandem mass spectrometry[J].Journal of Chromatography A, 2004,1043 (1):3-7.
[63] Sabatine M S. Metabolomic Identification of Novel Biomarkers of Myocardial Ischemia[J].Circulation, 2005,112 (25):3868-3875.
[64] BATHEN T F, ENGAN T, KRANE J. Principal component analysis of proton nuclear magnetic resonance spectra of lipoprotein fractions from patients with coronary heart disease and healthy subjects[J].Scandinavian Journal Of Clinical And Laboratory Investigation, 1999,59:349-360.
[65] Lewis G D, Wei R, Liu E, et al. Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardialinjury[J].Journal of Clinical Investigation, 2008,118 (10):3503-3512.
[66] 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.
[67] Barba I, de Leon G, Martin E, et al. Nuclear magnetic resonance-based metabolomics predicts exercise-induced ischemia in patients with suspected coronary artery disease[J]. Magnetic Resonance In Medicine, 2008,60 (1):27-32.
[68] Shah S H, Bain J R, Muehlbauer M J, et al. Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events[J].Circulation: Cardiovascular Genetics, 2010,3 (2):207-214.
[69]王广基,阿基业,严蓓,等.代谢组学研究冠心病中医分型的体内物质基础[J].世界科学技术(中医药现代化), 2009,11 (1):127-133.
[70]朱萱萱,王广基,阿基业,等.冠心病中医辨证分型的代谢组学研究[J].中华中医药学刊, 2009,27 (06):1267-1269.
[71]严蓓,阿基业,郝海平,等.心血瘀阻与气阴两虚证心肌缺血大鼠模型的代谢组学表征与辨识[J].中国科学(C辑:生命科学), 2008 (12):1143-1151.
[72]简维雄,袁肇凯,黄献平,等.冠心病心血瘀阻证血浆代谢组学的检测分析[J].中国中西医结合杂志, 2010,30 (6):579-584.
[73] Steffens D C, Jiang W, Krishnan K R R, et al. Metabolomic Differences in Heart Failure Patients With and Without Major Depression[J].Journal of Geriatric Psychiatry and Neurology, 2010,23 (2):138-146.
[74] Drenos F, Talmud P J, Casas J P, et al. Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk[J]. Human Molecular Genetics, 2009,18 (12):2305-2316.
[75] Lv Y H, Liu X R, Yan S K, et al. Metabolomic study of myocardial ischemia and intervention effects of Compound Danshen Tablets in rats using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry[J].Journal of Pharmaceutical and Biomedical Analysis, 2010,52 (1):129-135.
[76] Liang X P, Chen X, Liang Q L, et al. Metabonomic Study of Chinese Medicine Shuanglong Formula as an Effective Treatment for MyocardialInfarction in Rats[J].Journal of Proteome Research, 2011,10 (2):790-799.
[77]刘昌孝.代谢物组学在中药现代研究中的意义[J].中草药, 2004,35 (6):601-605.
[78] http://www.moh.gov.cn/publicfiles/business/htmLfiles/zwgkzt/ptjnj/year2010 /index2010.htmL. 2010中国卫生统计年鉴, 2010.
[79]邱明丰.国家自然科学基金面上项目―基于代谢网络变化的复方丹参滴丸整体疗效评价方法的研究‖, 2007-2010,项目批准号30772789.
[80]高谦,杜军保,张清友,等.二磷酸果糖对慢性心肌缺血大鼠脑损伤的保护作用[J].中国临床康复, 2005,9 (29):96-98.
[81]黄秀兰,张雪静,王伟,等.淫羊藿总黄酮注射液对垂体后叶素致大鼠心肌缺血的影响[J].中华中医药杂志, 2005,20 (9):533-534.
[82]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:化学工业出版社, 2005.528.
[83]刘涛.气虚血瘀证(心肌缺血)动物模型及蛋白质组学研究[D].北京中医药大学, 2007:28-32.
[84]倪新海,郜朝晖,张宇清,等.提高心肌梗塞—心衰大鼠模型动物存活率的实验研究[J].中国实验动物学杂志, 1999,9 (4):206-210.
[85]周文武,林玲,陈军,等.冠脉结扎法制做大鼠心肌缺血模型[J].中国实验动物学报, 2004,12 (4):226-230.
[86] Loscher W, Cramer S, Ebert U. Differences in kindling development in seven outbred and inbred rat strains[J]. Experimental Neurology, 1998,154 (2):551-559.
[87]张润峰,魏毅东,张晓刚,等.提高大鼠心肌梗死模型成功率的方法研究[J].同济大学学报(医学版), 2005,26 (4):67-69.
[88] JohnsTNP, BJ O. Experimental myocardial infarction:A method of coronary occlusion in small animals[J]. Annals of Surgery, 1994,10 (5):675-682.
[89]徐叔云,卞如濂,陈修.药理实验方法学.北京:人们卫生出版社, 2005:1043-1046.
[90]样小玲.气相色谱衍生试剂的研究进展[J].中国科技信息, 2005,7:25.
[91] Zhang Z, Qiu Y, Hua Y, et al. Serum and urinary metabonomic study of human osteosarcoma[J].J Journal Of Proteome Research, 2010,9 (9):4861-4868.
[92] Zhang Q, Wang G, Du Y, et al. GC/MS analysis of the rat urine for metabonomic research[J].Journal of Chromatography B, 2007,854 (1-2):20-25.
[93]简维雄,袁肇凯,黄献平,等.冠心病心血瘀阻证尿液代谢组学的检测分析.中医杂志[J], 2010,51 (8):729-732.
[94]王华丙,张振义,包锐,等. ABC转运蛋白的结构与转运机制[J].生命的化学, 2007,27 (3):208-210.
[95] Zhang H-y, Chen X, Hu P, et al. Metabolomic profiling of rat serum associated with isoproterenol-induced myocardial infarction using ultra-performance liquid chromatography/time-of-flight mass spectrometry and multivariate analysis[J].Talanta, 2009,79 (2):254-259.
[96]吕永海.复方丹参片血清药物化学及代谢组学研究[D],第二军医大学, 2010: 50.
[1]庞明.中国老年心血管病流行现状.广西医学,2007,29 (1):139-140.
[2]王淼,王薇,赵冬,等.北京地区青年人群心血管病危险因素10年变化趋势.心肺血管病杂志, 2005,24 (2):65-70.
[3]杨艺.浅析冠心病的病因及治疗.中外医疗, 2010,14:182.
[4]国家―九五‖科技攻关课题协作组.我国中年人群心血管病主要危险因素流行现状及从80年代初至90年代末的变化趋势.中华心血管病杂志, 2001,29 (2):74-79.
[5]刘昌孝,贾伟.代谢组学与中药现代研究.中草药, 2006,37:2-7.
[6]隆琦,陈楠.代谢组学在疾病中的应用进展.医学综述, 2010,16 (9):1300-1302.
[7] Nicholson J K, Lindon J C, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica, 1999,29:1181-1189.
[8] Watkins S M, Reifsnyder P R, Pan H J, et al. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. The Journal of Lipid Research, 2002,43:1809-1817.
[9] Castle A L, Carver M P, Mendrick D L. Toxicogenomics: a new revolution in drug safety.Drug Discovery Today, 2002,7:728-736.
[10] Howells S L, Maxwell R J, Peet A C, et al. An investigation of tumor 1H nuclear magnetic resonance spectra by the application of chemometric techniques.Magnetic Resonance in Medicine, 1992,28:214-236.
[11] Oliver S. Yeast as a navigational aid in genome analysis.Microbiology, 1997,143:1483-1487.
[12] Dalluge J J, Smith S, Sanchez-Riera F, et al. Potential of fermentation profiling via rapid measurement of amino acid metabolism by liquid chromatography-tandem mass spectrometry.Journal of Chromatograohy A, 2004,1043:3-7.
[13]席宏巍,金立伟,刘军鲁.冠状动脉造影与冠心病临床分析.医药论坛杂志, 2008,29 (22):54-55.
[14] Otvos J D, Jeyarajah E J, Bennett D W. Quantification of plasma lipoproteins by proton nuclear magnetic resonance spectroscopy.Clinical Chemistry, 1991,37:377-386.
[15] Bathen T F, Engan T, Krane J. Principal component analysis of proton nuclear magnetic resonance spectra of lipoprotein fractions from patients with coronary heart disease and healthy subjects. Scandinavian Journal Of ClinicalAnd Laboratory Investigation, 1999,59:349-360.
[16] Kuller L, Arnold A, Tracy R, et al. Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the Cardiovascular Health Study.Arteriosclerosis, Thrombosis and Vascular Biology, 2002,22:1175-1180.
[17] Brindle J T, Antti H, Holmes E, et al. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics.Nature Medicine, 2002,8(4):1439-1444.
[18] Kirschenlohr H L, Griffin J L, Clarke S C, et al. Proton NMR analysis of plasma is a weak predictor of coronary artery disease.Nature Medicine, 2006,12 (7):705-710.
[19] Roussel R, Mentre F, Bouchemal N, et al. NMR-based prediction of cardiovascular risk in diabetes.Nature Medicine, 2007,13 (4):399-400.
[20] Barba I, Jaimez-Auguets E, Rodriguez-Sinovas A. 1 H NMR-based metabolomic identification of at-risk areas after myocardial infarction in swine.Magnetic Resonance Materials in Physics, Biology and Medicine, 2007,20 (5):265-271.
[21] Barba I, de Leon G, Martin E, et al. Nuclear magnetic resonance-based metabolomics predicts exercise-induced ischemia in patients with suspected coronary artery disease.Magnetic Resonance in Medicine, 2008,60 (1):27-32.
[22] Bernini P, Bertini I, Luchinat C, et al. The Cardiovascular Risk of Healthy Individuals Studied by NMR Metabonomics of Plasma Samples.Journal of Proteome Research, 2011:111003103121002.
[23] Sabatine M, Liu E, Morrow D, et al. Metabolomic identification of novel biomarkers of myocardial ischemia.Circulation, 2005,112 (25):3868.
[24] Dunn W B, Broadhurst D I, Deepak S M, et al. Serum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2-oxoglutarate.Metabolomics, 2007,3 (4):413-426.
[25] Lewis G D, Wei R, Liu E, et al. Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury.Journal of Clinical Investigation, 2008,118 (10):3503-3512.
[26] Zhang H-y, Chen X, Hu P, et al. Metabolomic profiling of rat serum associated with isoproterenol-induced myocardial infarction using ultra-performance liquid chromatography/ time-of-flight mass spectrometry and multivariate analysis.Talanta, 2009,79 (2):254-259.
[27] Shah S H, Bain J R, Muehlbauer M J, et al. Association of a Peripheral Blood Metabolic Profile With Coronary Artery Disease and Risk of Subsequent Cardiovascular Events.Circulation: Cardiovascular Genetics, 2010,3 (2):207-214.
[28]刘萍,王平,陈刚,等.应用代谢组学探讨中医药复杂理论体系的研究思路和方法.中华中医药杂志, 2011,26 (5):993-998.
[29] Chen M, Zhao L, Jia W. Metabonomic study on the biochemical profiles of a hydrocortisone-induced animal model. Journal of Proteome Research, 2005,4:2391-2396.
[30]罗和古,丁杰,岳广欣,等.大鼠肝郁脾虚证的代谢组学研究.中西医结合学报,2007 (03):307-313.
[31]李林,王建农,任建勋,等.气虚血瘀证大鼠尿液的核磁共振谱代谢组学.科学通报,2007 (15):1758-1762.
[32] Lu Y, Hao H, Wang G. Metabolomics approach to the biochemical differentiation of Traditional Chinese Medicine syndrome types of hypertension.Chinese Journal of Clinical Pharmacology and Therapeutics, 2007.,12 (10):1144-1150.
[33]李霞.浅谈中医对冠心病的分型与治疗.中国医疗前沿, 2008,3 (23):74.
[34]朱浩.心律失常中医证治研究进展.中国中医急症, 2008,17 (6):828-829,880.
[35]张红栓,贾钰华,华何与,等.冠心病心绞痛痰浊证、血瘀证的尿液代谢组学研究.中国中医基础医学杂志, 2010,16 (2):126-128.
[36]张红栓,贾钰华,华何与,等.冠心病心绞痛痰浊证、血瘀证的血浆代谢组学研究.新中医, 2010,42 (6):12-14.
[37]华何与,贾钰华,张红栓,等.冠心病心绞痛三种血瘀证的血浆代谢组学研究.热带医学杂志, 2010,10 (3):258-260,279.
[38]简维雄,袁肇凯,黄献平,等.冠心病心血瘀阻证尿液代谢组学的检测分析.中医杂志, 2010,51 (8):729-732.
[39]简维雄,袁肇凯,黄献平,等冠心病心血瘀阻证血浆代谢组学的检测分析.中国中西医结合杂志, 2010,30 (6):579-584.
[40]严蓓,阿基业,郝海平,等.心血瘀阻与气阴两虚证心肌缺血大鼠模型的代谢组学表征与辨识.中国科学(C辑:生命科学), 2008 (12):1143-1151.
[41]王广基,阿基业,严蓓,等.代谢组学研究冠心病中医分型的体内物质基础.世界科学技术(中医药现代化), 2009,11 (01):127-133.
[42]朱萱萱,王广基,阿基业,等.冠心病中医辨证分型的代谢组学研究.中华中医药学刊, 2009,27 (06):1267-1269.
[43] Steffens D C, Wei J, Krishnan K R R, et al. Metabolomic Differences in Heart Failure Patients With and Without Major Depression.Journal of Geriatric Psychiatry and Neurology, 2010,23 (2):138-146.
[44] Drenos F, Talmud P J, Casas J P, et al. Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk.Human Molecular Genetics, 2009,18 (12):2305-2316.
[45] Lv Y, Liu X, Yan S, et al. Metabolomic study of myocardial ischemia and intervention effects of Compound Danshen Tablets in rats using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.Journal of Pharmaceutical and Biomedical Analysis, 2010,52 (1):129-135.
[46] Liang X, Chen X, Liang Q, et al. Metabonomic study of Chinese medicine Shuanglong formula as an effective treatment for myocardial infarction in rats.Journal of Proteome Research, 2011,10:790–799.
[47] Lu Y, Liu X, Liang X, et al. Metabolomic strategy to study therapeutic and synergistic effects of tanshinone IIA, salvianolic acid B and ginsenoside Rb1 in myocardial ischemia rats.Journal of Ethnopharmacology, 2011,134 (1):45-49.
[2]孙勤国,王建久,郑云,等.冠心病[M].北京:中国医药科技出版社, 2010.20-22;38-40.
[3]黄政德,周德生.中西医结合冠心病学[M].长沙:湖南科学技术出版社, 2009.1-98.
[4]柯元南,曾玉杰.冠心病临床实用对策[M].北京:北京科学技术出版社, 2010.99-188.
[5]胡大一.冠心病[M].北京:化学工业出版社, 2009.37-58.
[6]孙勤国,王建久,郑云,等.冠心病[M].北京:中国医药科技出版社, 2010.215-327.
[7]陈明哲.心脏病学[M].北京:北京医科大学出版社, 2000.1058-1067.
[8]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:中国医药科技出版社, 2010.961.
[9]袁如玉,李广平.复方丹参滴丸在心血管疾病防治中的多靶点作用[J].中国新药杂志, 2009,18 (5):337-380.
[10]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:中国医药科技出版社, 2010.70-71.
[11]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:中国医药科技出版社, 2010.11.
[12]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:中国医药科技出版社, 2010.136-137.
[13]冉桦.复方丹参滴丸在心血管方面的药理与临床研究.家庭医药[J]·医药论坛, 2010,10:734-736.
[14]李全凤,王孝铭,朱世军,等.复方丹参滴丸对缺氧心肌细胞内钙离子平均荧光强度的影响[J].中国病理生理杂志, 2001,17 (7):690-691.
[15]赵雅君,朱世军,史从宁,等.大鼠心肌缺血再灌注时能量代谢及脂质过氧化变化及复方丹参滴丸的保护作用[J].哈尔滨医科大学学报, 2003,37 (4):290-293.
[16]赵明中,汪家瑞,魏嘉平,等.复方丹参滴丸对大鼠心肌缺血再灌注时心肌细胞凋亡及凋亡相关基因表达的影响[J].中国临床药理学杂志, 1999,15 (4):288-291.
[17]徐曼,李全凤,张伟华,等.复方丹参滴丸对培养的乳鼠心肌细胞缺氧及缺氧/复氧时Fas/FasL蛋白表达的影响[J].中国病理生理杂志, 2003,19 (4):499-502.
[18]赵娜,刘育英,卫晓红,等.复方丹参滴丸一次性预给药对缺血再灌注后大鼠心脏血流量和心肌损伤的改善作用[J].世界科学技术-中医药现代化, 2008,10 (3):94-98,122.
[19]冯洁,王嗣岑.复方丹参滴丸对大鼠血小板聚集功能的影响[J].中国误诊学杂志, 2006,6 (12):2261-2263.
[20]王山岭,王丽霞,孙月和.复方丹参滴丸对不稳定型心绞痛患者血小板活化及纤溶活性的影响[J].中国心血管杂志, 2003,8 (5):354- 356.
[21]陈良,张梅,李长江,等.复方丹参滴丸对动脉粥样硬化粘附因子的作用[J].中国动脉硬化杂志, 2007,15 (2):101-104.
[22]王东霞,王孝铭,许晶兰.复方丹参滴丸对人血管内皮细胞功能及形态保护作用的研究[J].中国病理生理杂志, 2006,22 (5):933-937.
[23]许晶兰,王孝铭,王东霞.复方丹参滴丸对过氧化氢损伤的人脐静脉血管内皮细胞的保护作用[J].中国病理生理杂志, 2006,22 (5):929- 932.
[24]诸葛丽敏,吴清,楼正家.复方丹参滴丸对急性冠脉综合征患者CRP及血管内皮功能的影响[J].浙江中医学院学报, 2005,29 (4):13-15.
[25]叶武,叶美颜,冯培芳,等.复方丹参滴丸对自发性高血压大鼠血管壁重建的干预及可能机制[J].中国动脉硬化杂志, 2007,15 (3):181-184.
[26]陈建宗,田季雨,顾宜,等.复方丹参滴丸对动脉粥样硬化家兔颈动脉血管壁血管细胞黏附分子-1表达的影响[J].中国临床康复, 2004,8 (24):5048-5049.
[27]韩晶岩,秋叶保忠,堀江义则,等.复方丹参滴丸及其主要成分丹参、三七对缺血再灌注引起的大鼠肠系膜微循环障碍的多环节改善作用[J].世界科学技术-中医药现代化, 2008,10 (3):99-105.
[28]乔成栋,孙玉瑛,蒋生祥.复方丹参滴丸治疗胸痹的临床观察[J].兰州大学学报(医学版), 2006,32 (1):41-44.
[29]邱宏,马军.复方丹参滴丸治疗冠心病82例疗效观察[J].中国医师杂志, 2006,1:294.
[30]陈开地.复方丹参滴丸治疗冠心病心绞痛84例临床分析[J].中国社区医师, 2011,1:17.
[31]解金洪,郁晓群.复方丹参滴丸治疗高血压左心室肥厚55例[J].现代中西医结合杂志, 2007,16 (18):2545-2546.
[32]鲁永菊,周蜜.复方丹参滴丸治疗顽固性高血压[J].中西医结合心脑血管病杂志, 2007,5 (4):291-292.
[33]杨学平,凌和水.复方丹参滴丸治疗急性脑梗死73例疗效观察[J].江西医药, 2005,40 (10):633-635.
[34]王永升.复方丹参滴丸治疗早期脑梗塞40例[J].陕西中医, 2006,6 (9):1093-1094.
[35]邱奉林,万国琳.复方丹参滴丸治疗糖尿病视网膜病变的临床观察[J].天津药学, 2006,18 (6):33-34.
[36]郭玉洁.复方丹参滴丸治疗早期糖尿病肾病的临床观察.中国民康医学, 2007,19 (2):117-118.
[37]张月萍,魏世芳.复方丹参滴丸治疗肝硬化疗效分析[J].实用肝脏病杂志, 2005,8 (1):45-46.
[38]翟穗燕,陈锐,吴学红.复方丹参滴丸治疗偏头痛41例观察[J].实用中医药杂志, 2006,22 (1):26.
[39]张诗军,陈泽雄,林佑武,等.复方丹参滴丸治疗痰瘀型高脂血症的临床研究[J].中国中药杂志, 2007,32 (5):440-443.
[40]梁启廉,陈小东,李小英,等.复方丹参滴丸加化疗治疗肝癌的临床疗效评价[J].中医药学刊, 2006,24 (1):186-188.
[41]陈小东,梁启廉,李小英,等.复方丹参滴丸在41例中晚期胰腺癌化疗中的应用[J].肿瘤学杂志, 2005,11 (1):46-48.
[42]潘桂湘,高秀梅,张伯礼,等. HPLC法测定复方丹参方中三七皂苷类成分的含量[J].中药新药临床药理, 2003,12 (3):112.
[43] Liu A-H, Lin Y-H, Guo H. Development of the fingerprints for the quality of the roots of Salvia miltiorrhiza and its related preparations by HPLC-DAD and LC–MSn[J].Journal of Chromatography B, 2007,846:32
[44]高秀梅,王怡,商洪才,等.复方丹参方抗大鼠心肌缺血作用研究[J].天津中医药, 2003,20 (1):23.
[45] Edward G K O, Lynn, Vazhappilly R, et al. Siow Magnesium tanshinoate B (MTB) inhibits low density lipoprotein oxidation[J].Life Sciences, 2001,68:903.
[46]赵雅君,朱世军,史从宁,等.大鼠心肌缺血再灌注时能量代谢及脂质过氧化变化及复方丹参滴丸的保护作用[J].哈尔滨医科大学学报, 2003,37 (4):290.
[47] Peia W-J, Zhao X-F, Zhuc Z-M, et al. Study of the determination and pharmacokinetics of Compound Danshen Dripping Pills in human serum by column switching liquid chromatography electrospray ion trap mass spectrometry[J].Journal of Chromatography B, 2004,809:237.
[48]李晓莉,李晓蓉,王丽娟,等.单用与复方给药后隐丹参酮在家兔体内的药物动力学比较[J].中国药理学通报, 2007,23 (8):1102.
[49]王宁生,宓穗卿,洪馨,等.口服复方丹参滴丸血清中丹参相关成分的LC/ MS检测[J].中药新药与临床药理, 2000,11 (3):141.
[50]史昕云,夏正远,方建国,等.复方丹参注射液对心内直视手术心肌缺血再灌注后血清内皮素及前列环素/血栓素A-2比值的影响[J].中国中西医结合杂志, 2000,12:9.
[51] Nicholson J K, Lindon J C, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data[J].Xenobiotica, 1999,29 (11):1181-1189.
[52]贾伟.医学代谢组学[M].上海:上海科学技术出版社, 2011.1.
[53] German J B, Bauman D E, Burrin D G, et al. Metabolomics in the opening decade of the 21st century: building the roads to individualized health[J].The journal of nutrition, 2004,134 (10):2729-2732.
[54] Taylor J, King R D, Altmann T, et al. Application of metabolomics to plantgenotype discrimination using statistics and machine learning [J].Bioinformatics, 2002,18 (2):241-248.
[55]严士海,朱萱萱.代谢组学在疾病诊断中的应用研究进展[J].现代中西医结合杂志, 2007,16 (5):711-712.
[56] Plumb R S, Stumpf C L, Gorenstein M V, et al. Metabonomics: the use of electrospray mass spectrometry coupled to reversed-phase liquid chromatography shows potential for the screening of rat urine in drug development.Rapid Commun[J] Mass Spectrom. 2002;16(20):1991-1996.
[57] Qiu Y, Su M, Liu Y, et al. Application of ethyl chloroformate derivatization for gas chromatography–mass spectrometry based metabonomic profiling[J].Analytica Chimica Acta, 2007,583 (2):277-283.
[58] Watkins S M, Reifsnyder P R, Pan H J, et al. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone[J] Journal of lipid research, 2002,43 (11):1809-1817.
[59] Castle A L, Carver M P, Mendrick D L. Toxicogenomics: a new revolution in drug safety[J].Drug Discovery Today, 2002,7 (13):728-736.
[60] Howells S L, Maxwell R J, Peet A C, et al. An investigation of tumor 1H nuclear magnetic resonance spectra by the application of chemometric techniques[J]. Magnetic Resonance In Medicine, 1992,28 (2):214-236.
[61] Oliver S G. Yeast as a navigational aid in genome analysis[J].Microbiology-Uk, 1997,143:1483-1487.
[62] Dalluge J J, Smith S, Sanchez-Riera F, et al. Potential of fermentation profiling via rapid measurement of amino acid metabolism by liquid chromatography-tandem mass spectrometry[J].Journal of Chromatography A, 2004,1043 (1):3-7.
[63] Sabatine M S. Metabolomic Identification of Novel Biomarkers of Myocardial Ischemia[J].Circulation, 2005,112 (25):3868-3875.
[64] BATHEN T F, ENGAN T, KRANE J. Principal component analysis of proton nuclear magnetic resonance spectra of lipoprotein fractions from patients with coronary heart disease and healthy subjects[J].Scandinavian Journal Of Clinical And Laboratory Investigation, 1999,59:349-360.
[65] Lewis G D, Wei R, Liu E, et al. Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardialinjury[J].Journal of Clinical Investigation, 2008,118 (10):3503-3512.
[66] 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.
[67] Barba I, de Leon G, Martin E, et al. Nuclear magnetic resonance-based metabolomics predicts exercise-induced ischemia in patients with suspected coronary artery disease[J]. Magnetic Resonance In Medicine, 2008,60 (1):27-32.
[68] Shah S H, Bain J R, Muehlbauer M J, et al. Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events[J].Circulation: Cardiovascular Genetics, 2010,3 (2):207-214.
[69]王广基,阿基业,严蓓,等.代谢组学研究冠心病中医分型的体内物质基础[J].世界科学技术(中医药现代化), 2009,11 (1):127-133.
[70]朱萱萱,王广基,阿基业,等.冠心病中医辨证分型的代谢组学研究[J].中华中医药学刊, 2009,27 (06):1267-1269.
[71]严蓓,阿基业,郝海平,等.心血瘀阻与气阴两虚证心肌缺血大鼠模型的代谢组学表征与辨识[J].中国科学(C辑:生命科学), 2008 (12):1143-1151.
[72]简维雄,袁肇凯,黄献平,等.冠心病心血瘀阻证血浆代谢组学的检测分析[J].中国中西医结合杂志, 2010,30 (6):579-584.
[73] Steffens D C, Jiang W, Krishnan K R R, et al. Metabolomic Differences in Heart Failure Patients With and Without Major Depression[J].Journal of Geriatric Psychiatry and Neurology, 2010,23 (2):138-146.
[74] Drenos F, Talmud P J, Casas J P, et al. Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk[J]. Human Molecular Genetics, 2009,18 (12):2305-2316.
[75] Lv Y H, Liu X R, Yan S K, et al. Metabolomic study of myocardial ischemia and intervention effects of Compound Danshen Tablets in rats using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry[J].Journal of Pharmaceutical and Biomedical Analysis, 2010,52 (1):129-135.
[76] Liang X P, Chen X, Liang Q L, et al. Metabonomic Study of Chinese Medicine Shuanglong Formula as an Effective Treatment for MyocardialInfarction in Rats[J].Journal of Proteome Research, 2011,10 (2):790-799.
[77]刘昌孝.代谢物组学在中药现代研究中的意义[J].中草药, 2004,35 (6):601-605.
[78] http://www.moh.gov.cn/publicfiles/business/htmLfiles/zwgkzt/ptjnj/year2010 /index2010.htmL. 2010中国卫生统计年鉴, 2010.
[79]邱明丰.国家自然科学基金面上项目―基于代谢网络变化的复方丹参滴丸整体疗效评价方法的研究‖, 2007-2010,项目批准号30772789.
[80]高谦,杜军保,张清友,等.二磷酸果糖对慢性心肌缺血大鼠脑损伤的保护作用[J].中国临床康复, 2005,9 (29):96-98.
[81]黄秀兰,张雪静,王伟,等.淫羊藿总黄酮注射液对垂体后叶素致大鼠心肌缺血的影响[J].中华中医药杂志, 2005,20 (9):533-534.
[82]中华人民共和国药典委员会.中华人民共和国药典(一部)[S].北京:化学工业出版社, 2005.528.
[83]刘涛.气虚血瘀证(心肌缺血)动物模型及蛋白质组学研究[D].北京中医药大学, 2007:28-32.
[84]倪新海,郜朝晖,张宇清,等.提高心肌梗塞—心衰大鼠模型动物存活率的实验研究[J].中国实验动物学杂志, 1999,9 (4):206-210.
[85]周文武,林玲,陈军,等.冠脉结扎法制做大鼠心肌缺血模型[J].中国实验动物学报, 2004,12 (4):226-230.
[86] Loscher W, Cramer S, Ebert U. Differences in kindling development in seven outbred and inbred rat strains[J]. Experimental Neurology, 1998,154 (2):551-559.
[87]张润峰,魏毅东,张晓刚,等.提高大鼠心肌梗死模型成功率的方法研究[J].同济大学学报(医学版), 2005,26 (4):67-69.
[88] JohnsTNP, BJ O. Experimental myocardial infarction:A method of coronary occlusion in small animals[J]. Annals of Surgery, 1994,10 (5):675-682.
[89]徐叔云,卞如濂,陈修.药理实验方法学.北京:人们卫生出版社, 2005:1043-1046.
[90]样小玲.气相色谱衍生试剂的研究进展[J].中国科技信息, 2005,7:25.
[91] Zhang Z, Qiu Y, Hua Y, et al. Serum and urinary metabonomic study of human osteosarcoma[J].J Journal Of Proteome Research, 2010,9 (9):4861-4868.
[92] Zhang Q, Wang G, Du Y, et al. GC/MS analysis of the rat urine for metabonomic research[J].Journal of Chromatography B, 2007,854 (1-2):20-25.
[93]简维雄,袁肇凯,黄献平,等.冠心病心血瘀阻证尿液代谢组学的检测分析.中医杂志[J], 2010,51 (8):729-732.
[94]王华丙,张振义,包锐,等. ABC转运蛋白的结构与转运机制[J].生命的化学, 2007,27 (3):208-210.
[95] Zhang H-y, Chen X, Hu P, et al. Metabolomic profiling of rat serum associated with isoproterenol-induced myocardial infarction using ultra-performance liquid chromatography/time-of-flight mass spectrometry and multivariate analysis[J].Talanta, 2009,79 (2):254-259.
[96]吕永海.复方丹参片血清药物化学及代谢组学研究[D],第二军医大学, 2010: 50.
[1]庞明.中国老年心血管病流行现状.广西医学,2007,29 (1):139-140.
[2]王淼,王薇,赵冬,等.北京地区青年人群心血管病危险因素10年变化趋势.心肺血管病杂志, 2005,24 (2):65-70.
[3]杨艺.浅析冠心病的病因及治疗.中外医疗, 2010,14:182.
[4]国家―九五‖科技攻关课题协作组.我国中年人群心血管病主要危险因素流行现状及从80年代初至90年代末的变化趋势.中华心血管病杂志, 2001,29 (2):74-79.
[5]刘昌孝,贾伟.代谢组学与中药现代研究.中草药, 2006,37:2-7.
[6]隆琦,陈楠.代谢组学在疾病中的应用进展.医学综述, 2010,16 (9):1300-1302.
[7] Nicholson J K, Lindon J C, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.Xenobiotica, 1999,29:1181-1189.
[8] Watkins S M, Reifsnyder P R, Pan H J, et al. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. The Journal of Lipid Research, 2002,43:1809-1817.
[9] Castle A L, Carver M P, Mendrick D L. Toxicogenomics: a new revolution in drug safety.Drug Discovery Today, 2002,7:728-736.
[10] Howells S L, Maxwell R J, Peet A C, et al. An investigation of tumor 1H nuclear magnetic resonance spectra by the application of chemometric techniques.Magnetic Resonance in Medicine, 1992,28:214-236.
[11] Oliver S. Yeast as a navigational aid in genome analysis.Microbiology, 1997,143:1483-1487.
[12] Dalluge J J, Smith S, Sanchez-Riera F, et al. Potential of fermentation profiling via rapid measurement of amino acid metabolism by liquid chromatography-tandem mass spectrometry.Journal of Chromatograohy A, 2004,1043:3-7.
[13]席宏巍,金立伟,刘军鲁.冠状动脉造影与冠心病临床分析.医药论坛杂志, 2008,29 (22):54-55.
[14] Otvos J D, Jeyarajah E J, Bennett D W. Quantification of plasma lipoproteins by proton nuclear magnetic resonance spectroscopy.Clinical Chemistry, 1991,37:377-386.
[15] Bathen T F, Engan T, Krane J. Principal component analysis of proton nuclear magnetic resonance spectra of lipoprotein fractions from patients with coronary heart disease and healthy subjects. Scandinavian Journal Of ClinicalAnd Laboratory Investigation, 1999,59:349-360.
[16] Kuller L, Arnold A, Tracy R, et al. Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the Cardiovascular Health Study.Arteriosclerosis, Thrombosis and Vascular Biology, 2002,22:1175-1180.
[17] Brindle J T, Antti H, Holmes E, et al. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics.Nature Medicine, 2002,8(4):1439-1444.
[18] Kirschenlohr H L, Griffin J L, Clarke S C, et al. Proton NMR analysis of plasma is a weak predictor of coronary artery disease.Nature Medicine, 2006,12 (7):705-710.
[19] Roussel R, Mentre F, Bouchemal N, et al. NMR-based prediction of cardiovascular risk in diabetes.Nature Medicine, 2007,13 (4):399-400.
[20] Barba I, Jaimez-Auguets E, Rodriguez-Sinovas A. 1 H NMR-based metabolomic identification of at-risk areas after myocardial infarction in swine.Magnetic Resonance Materials in Physics, Biology and Medicine, 2007,20 (5):265-271.
[21] Barba I, de Leon G, Martin E, et al. Nuclear magnetic resonance-based metabolomics predicts exercise-induced ischemia in patients with suspected coronary artery disease.Magnetic Resonance in Medicine, 2008,60 (1):27-32.
[22] Bernini P, Bertini I, Luchinat C, et al. The Cardiovascular Risk of Healthy Individuals Studied by NMR Metabonomics of Plasma Samples.Journal of Proteome Research, 2011:111003103121002.
[23] Sabatine M, Liu E, Morrow D, et al. Metabolomic identification of novel biomarkers of myocardial ischemia.Circulation, 2005,112 (25):3868.
[24] Dunn W B, Broadhurst D I, Deepak S M, et al. Serum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2-oxoglutarate.Metabolomics, 2007,3 (4):413-426.
[25] Lewis G D, Wei R, Liu E, et al. Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury.Journal of Clinical Investigation, 2008,118 (10):3503-3512.
[26] Zhang H-y, Chen X, Hu P, et al. Metabolomic profiling of rat serum associated with isoproterenol-induced myocardial infarction using ultra-performance liquid chromatography/ time-of-flight mass spectrometry and multivariate analysis.Talanta, 2009,79 (2):254-259.
[27] Shah S H, Bain J R, Muehlbauer M J, et al. Association of a Peripheral Blood Metabolic Profile With Coronary Artery Disease and Risk of Subsequent Cardiovascular Events.Circulation: Cardiovascular Genetics, 2010,3 (2):207-214.
[28]刘萍,王平,陈刚,等.应用代谢组学探讨中医药复杂理论体系的研究思路和方法.中华中医药杂志, 2011,26 (5):993-998.
[29] Chen M, Zhao L, Jia W. Metabonomic study on the biochemical profiles of a hydrocortisone-induced animal model. Journal of Proteome Research, 2005,4:2391-2396.
[30]罗和古,丁杰,岳广欣,等.大鼠肝郁脾虚证的代谢组学研究.中西医结合学报,2007 (03):307-313.
[31]李林,王建农,任建勋,等.气虚血瘀证大鼠尿液的核磁共振谱代谢组学.科学通报,2007 (15):1758-1762.
[32] Lu Y, Hao H, Wang G. Metabolomics approach to the biochemical differentiation of Traditional Chinese Medicine syndrome types of hypertension.Chinese Journal of Clinical Pharmacology and Therapeutics, 2007.,12 (10):1144-1150.
[33]李霞.浅谈中医对冠心病的分型与治疗.中国医疗前沿, 2008,3 (23):74.
[34]朱浩.心律失常中医证治研究进展.中国中医急症, 2008,17 (6):828-829,880.
[35]张红栓,贾钰华,华何与,等.冠心病心绞痛痰浊证、血瘀证的尿液代谢组学研究.中国中医基础医学杂志, 2010,16 (2):126-128.
[36]张红栓,贾钰华,华何与,等.冠心病心绞痛痰浊证、血瘀证的血浆代谢组学研究.新中医, 2010,42 (6):12-14.
[37]华何与,贾钰华,张红栓,等.冠心病心绞痛三种血瘀证的血浆代谢组学研究.热带医学杂志, 2010,10 (3):258-260,279.
[38]简维雄,袁肇凯,黄献平,等.冠心病心血瘀阻证尿液代谢组学的检测分析.中医杂志, 2010,51 (8):729-732.
[39]简维雄,袁肇凯,黄献平,等冠心病心血瘀阻证血浆代谢组学的检测分析.中国中西医结合杂志, 2010,30 (6):579-584.
[40]严蓓,阿基业,郝海平,等.心血瘀阻与气阴两虚证心肌缺血大鼠模型的代谢组学表征与辨识.中国科学(C辑:生命科学), 2008 (12):1143-1151.
[41]王广基,阿基业,严蓓,等.代谢组学研究冠心病中医分型的体内物质基础.世界科学技术(中医药现代化), 2009,11 (01):127-133.
[42]朱萱萱,王广基,阿基业,等.冠心病中医辨证分型的代谢组学研究.中华中医药学刊, 2009,27 (06):1267-1269.
[43] Steffens D C, Wei J, Krishnan K R R, et al. Metabolomic Differences in Heart Failure Patients With and Without Major Depression.Journal of Geriatric Psychiatry and Neurology, 2010,23 (2):138-146.
[44] Drenos F, Talmud P J, Casas J P, et al. Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk.Human Molecular Genetics, 2009,18 (12):2305-2316.
[45] Lv Y, Liu X, Yan S, et al. Metabolomic study of myocardial ischemia and intervention effects of Compound Danshen Tablets in rats using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.Journal of Pharmaceutical and Biomedical Analysis, 2010,52 (1):129-135.
[46] Liang X, Chen X, Liang Q, et al. Metabonomic study of Chinese medicine Shuanglong formula as an effective treatment for myocardial infarction in rats.Journal of Proteome Research, 2011,10:790–799.
[47] Lu Y, Liu X, Liang X, et al. Metabolomic strategy to study therapeutic and synergistic effects of tanshinone IIA, salvianolic acid B and ginsenoside Rb1 in myocardial ischemia rats.Journal of Ethnopharmacology, 2011,134 (1):45-49.