基于“良”关系的丹参—红花药对效应物质研究
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摘要
道德经日“道生一,一生二,二生三,三生万物,万物负阴而抱阳,冲气以为和”,人体是一个阴阳平衡的整体,为“和”的状态,而患病的病机是外界及机体本身的种种病因造成了阴阳的失衡,恢复“和”的平衡,是为医之道。用药治病,是利用药物的阴阳偏性,即药物的“四气五味、升降沉浮”之性等,有针对性地来协助调整恢复人体的平衡,对此中医谓之“正治法”,为“道生一”；用有阴阳二种属性之药谓之“一生二”,这里的“二”即“药对”；据君臣佐使之理组成方剂谓之“二生三”,即由“药对”形成“复方”；针对“证候”病机加减组成千变万化变方药,谓之“三生万”。可见,“药对”作为从单味药发展到复方的关键节点,其配伍规律的研究能提纲挈领、驭繁就简,已成为方剂配伍规律研究的一个重点方向；而药对配伍中,以“良”关系最为重要。本论文基于“良”关系,选择常见活血化瘀的丹参-红花为研究对象,采用药代动力学及代谢组学方法对该药对及其体内效应物质进行了系统地研究。该研究可为创新药物的发现提供借鉴,亦可为临床用药提供参考。全文共分5章,作者的主要贡献如下：
1.基于《神农本草经》“当用相须、相使者良”,提出“良”关系概念；并基于该“良”关系,选择常见活血化瘀的丹参-红花为“药对”。
2.制作寒凝血瘀模型,并分别给正常、寒凝血瘀模型以丹参、红花及丹参红花配伍药物；采用建立的丹参-红花中酚酸类指标性成分丹参素、原儿茶醛、原儿茶酸及羟基红花黄色素A的分析的方法,从药代动力学角度对上述指标性成分在各给药组大鼠体内之药代动力学特征差异性进行了研究。结果表明,丹参与红花均能提高各药在大鼠体内的吸收与分布。
3.采用长期给药方式分别给予模型大鼠丹参、红花及丹参-红花配伍药物,运用高效液相-质谱联用代谢组学技术对大鼠尿样进行分析,考察各给药组药物体内应答物质群及相应生理途径之异同,从药物有效物质及内源性应答物质群角度阐释丹参-红花药对组成之“良”关系。研究结果表明：寒凝血瘀模型制作成功后,相比正常组,模型大鼠体内酪氨酸、色氨酸、精氨酸、脯氨酸、嘌呤等代谢通路及三羧酸循环过程均发生了异常,推断连续冷应激后糖皮质激素上调,去甲肾上腺素能系统活动加强；同时,三羧酸循环发挥自身能量补偿作用,以适应寒冷环境。通过给大鼠一周的药物治疗,模型大鼠症状有所改观,丹参、红花、丹参-红花药对均有改善作用,且发现上述三组药物体内体内应答物质及相应代谢途径的异同点。
4.考察了“良”关系在丹参、红花为主药的复杂组方配伍中的推广。以中药注射剂血必净注射液中酚酸类指标成分丹参素、原儿茶醛、原儿茶醛及羟基红花黄色素A为研究对象,建立高效液相-离子液体-纳米金-电化学分析体系,考察了不同加入量离子液体及纳米金对该体系色谱分离行为及电化学检测性能的影响,在此基础上,对血必净注射液中上述成分在大鼠体内(血样、尿样及粪样)代谢进行了研究。结果发现：离子液体的加入使得待测化合物的保留时间均发生了前移,理论塔板数及峰面积也得到了改善,相比无离子液体,0.4%离子液体加入时,丹参素、原儿茶酸、原儿茶醛和羟基红花黄色素A分别减少2.851,1.532,1.53及0.818min,电化学响应值分别是无离子液体的：丹参素772%,原儿茶酸628%,原儿茶醛584%,羟基红花黄色素A703%;纳米金溶胶的引入使得其电化学响应及工作电压在加入离子液体的基础上亦发生了显著变化：丹参素增大5.74倍,原儿茶醛为6.21倍,其中原儿茶酸面积增大倍数为66.48倍,且两种添加剂的影响均与加入比例有关。
5.运用微透析-高效液相-电化学在线实时检测手段,进行了丹参-红花药对在大鼠海马区的代谢研究。实验发现,代谢产物丹参素异丙酯为该药对的体内效应物质。
As The Expression Goes in 'Moral Classics''Dao Sheng Yi, Yi Sheng Er, Er Sheng San, San Sheng Wanwu, Wanwu Fu Yin Er Bao Yang, Chong Qi Yi Wei He'. Generally, human body is in the state of'He'which is the equilibrium between yin and yang. Illness always cause the disequilibrium of body between yin and yang, and recovering its balance of'He'is the'dao'of medicament。 Treating the illness with medicine is actually utilizing the properties of yin and yan, the nature of Siqi, Wuwei and ShengJiangChenFu, thereby helping to make the human body to restore the balance of yin and yang, that is called "Zhengzhifa" in the culture of Traditional Chinese Medicine, and it is defined as "Dao Sheng Yi"; Utilizing herb-pair with the properties of yin and yang is defined as "Yi Sheng Er"; Forming the prescription according to the principles of Monarch,Minister,Assistant and Guide is called"Er Sheng San"; and the composition of prescription changing aiming at pathogenesis of illness is called"San Sheng Wanwu". Herb-pair is the key joint of the development of Traditional Chinese Medicine, the study on the compatibility of herb-pair have already to be become a key point of investigation on the compatibility of medicines in prescription. The sentence of "It's better to utilize the herb-pair with compatibility of Xiangxu and Xiangshi'is recorded in 'Shen Nong Materia Medica'.'Liang'relationship is the core of'Zhengzhifa' and guides the long-term clinical medication. Under the guidance of the theories of'Liang'relationship in'Shen Nong Materia Medica',Salvia miltiorrhiza-Carthamus tinctorius was selected as the research object, the methods of pharmacokinetics and metabonomics were employed in studying the effector substance of Salvia miltiorrhiza-Carthamus tinctorius to explore the'Liang'relationship within the perspective of the changes and interaction between the group of medicinal compositions and endogenous substance. This study provides an important approach to enrich the Compatibility Theory of Chinese Traditional Medicine. This dissertation has five chapters, and the chief contributions of the author are as follows:
1. Under the guidance of'Shen Nong Materia Medica', we proposed a new concept,'Liang'relationship. Taking Salvia miltiorrhiza-Carthamus tinctorius as the research object, for the reason of Salvia miltiorrhiza-Carthamus tinctorius is a common herb-pair in the TCM formulae with activating blood circulation to dissipate blood stasis, and then summrized the research progress of the herb-pair above。
2. Taking Salvia miltiorrhiza-Carthamus tinctorius as the study object, analytical system was developed in this study for simultaneously detecting danshensu(DSS), protocatechuic acid (PA), protocatechuic aldehyde (PAH) and hydroxy safflower yellow A (HSYA) in the injection and plasma. After administration of Salvia miltiorrhiza, Salvia miltiorrhiza-Carthamus tinctorius and Carthamus tinctorius for the normal and model group, their plasma were analyzed utilizing the analytical system above, and then the variation of DSS, PA, PAH and HSYA and mutual influential action were studied from the point of pharmacokinetics. Meanwhile, urines of rats in normal and model group were investigated so as to acquire the flag of pathology by means of metabonomics with LC-MS. After administration of Salvia miltiorrhiza, Salvia miltiorrhiza-Carthamus tinctorius and Carthamus tinctorius, the similarities and differences in endogenous substances and their relative metabolism pathways were studied based on the urinary metobonomics with the aim to explore the 'Liang' relationship from the angle of endogenous substances. It is proved that both Salvia miltiorrhiza and Carthamus tinctorius could improve the absorption and distribution in vivo each other; meanwhile, comparing to the normal group, the tyrosine metabolic pathway, tryphan metabolic pathway, arginine metabolic pathway, proline metabolic pathway, purine metabolic pathway and tricarboxylic acid cycle(TCA cycle) in model rats were abnormal, and it can be inferred that the lever of glucocorticoid was up-regulation, noradrenergic system activity was strengthened owning to the long-time cold stress; Simultaneously, TCA cycle took effect in compensating acticn for the cold environment. After treatment of Salvia miltiorrhiza and Carthamus tinctorius, illness of the model rats was relieved by means of same responsive substances and metabolic pathways as Salvia miltiorrhiza-Carthamus tinctorius effected.
3. The phenolic acids of DSS, PA,PAH and HSYA in Xuebijing injection which contains Salvia miltiorrhiza-Carthamus tinctorius were selected as research targets, and a novel high performance liquid chromatography-electrochemical detector (HPLC-ECD) analytical system was developed in this study by integratedly utilizing ionic liquid (IL) of1-butyl-3-methylimidazolium bromide and an additive of gold nanoparticles. The resulted pilot study was first performed to assess the effects of1-butyl-3-methylimidazolium bromide and gold nanoparticles on the chromatographic characteristics of four phenolic acids in Xuebijing injection, including DSS, PA, PAH and HSYA. It was notable to observe that retainability of the phenolic acids were markly lowered by IL addition. Compared with the cases without IL addition, the retention times of DSS, PA, PAH and HSYA have decreased2.851,1.532,1.53and0.818min, respectively when0.4%IL in the mobile phase. In addition, the corresponding theoretical plate numbers and peak areas for these compounds were significantly increased. Area response for DSS, PA, PAH and HSYA were enhanced by772%,628%,584%and703%, respectively. It was observed that nano-gold catalysis power enabled peak areas of DSS, PAH and PA to enhance5.7,6.2and66.5times relative to the case with addition of IL. Altogether, the optimized HPLC-ECD system was successfully applied to the pharmacokinetics study of Xuebijing injection with underlying applicability to in vivo and in vitro analysis of a variety of natural product from Chinese medicine plants, TCM formulae and associated patent TCM preparation.
Furthermore, the metabolic study of Salvia miltiorrhiza-Carthamus tinctorius in hippocampus area of rats were carried out utilizing the Microdialysis-HPLC-ECD analytical method with properties of real time detecting on line, the characteristic metabolic of IDHP was found.
1.基于《神农本草经》“当用相须、相使者良”,提出“良”关系概念；并基于该“良”关系,选择常见活血化瘀的丹参-红花为“药对”。
2.制作寒凝血瘀模型,并分别给正常、寒凝血瘀模型以丹参、红花及丹参红花配伍药物；采用建立的丹参-红花中酚酸类指标性成分丹参素、原儿茶醛、原儿茶酸及羟基红花黄色素A的分析的方法,从药代动力学角度对上述指标性成分在各给药组大鼠体内之药代动力学特征差异性进行了研究。结果表明,丹参与红花均能提高各药在大鼠体内的吸收与分布。
3.采用长期给药方式分别给予模型大鼠丹参、红花及丹参-红花配伍药物,运用高效液相-质谱联用代谢组学技术对大鼠尿样进行分析,考察各给药组药物体内应答物质群及相应生理途径之异同,从药物有效物质及内源性应答物质群角度阐释丹参-红花药对组成之“良”关系。研究结果表明：寒凝血瘀模型制作成功后,相比正常组,模型大鼠体内酪氨酸、色氨酸、精氨酸、脯氨酸、嘌呤等代谢通路及三羧酸循环过程均发生了异常,推断连续冷应激后糖皮质激素上调,去甲肾上腺素能系统活动加强；同时,三羧酸循环发挥自身能量补偿作用,以适应寒冷环境。通过给大鼠一周的药物治疗,模型大鼠症状有所改观,丹参、红花、丹参-红花药对均有改善作用,且发现上述三组药物体内体内应答物质及相应代谢途径的异同点。
4.考察了“良”关系在丹参、红花为主药的复杂组方配伍中的推广。以中药注射剂血必净注射液中酚酸类指标成分丹参素、原儿茶醛、原儿茶醛及羟基红花黄色素A为研究对象,建立高效液相-离子液体-纳米金-电化学分析体系,考察了不同加入量离子液体及纳米金对该体系色谱分离行为及电化学检测性能的影响,在此基础上,对血必净注射液中上述成分在大鼠体内(血样、尿样及粪样)代谢进行了研究。结果发现：离子液体的加入使得待测化合物的保留时间均发生了前移,理论塔板数及峰面积也得到了改善,相比无离子液体,0.4%离子液体加入时,丹参素、原儿茶酸、原儿茶醛和羟基红花黄色素A分别减少2.851,1.532,1.53及0.818min,电化学响应值分别是无离子液体的：丹参素772%,原儿茶酸628%,原儿茶醛584%,羟基红花黄色素A703%;纳米金溶胶的引入使得其电化学响应及工作电压在加入离子液体的基础上亦发生了显著变化：丹参素增大5.74倍,原儿茶醛为6.21倍,其中原儿茶酸面积增大倍数为66.48倍,且两种添加剂的影响均与加入比例有关。
5.运用微透析-高效液相-电化学在线实时检测手段,进行了丹参-红花药对在大鼠海马区的代谢研究。实验发现,代谢产物丹参素异丙酯为该药对的体内效应物质。
As The Expression Goes in 'Moral Classics''Dao Sheng Yi, Yi Sheng Er, Er Sheng San, San Sheng Wanwu, Wanwu Fu Yin Er Bao Yang, Chong Qi Yi Wei He'. Generally, human body is in the state of'He'which is the equilibrium between yin and yang. Illness always cause the disequilibrium of body between yin and yang, and recovering its balance of'He'is the'dao'of medicament。 Treating the illness with medicine is actually utilizing the properties of yin and yan, the nature of Siqi, Wuwei and ShengJiangChenFu, thereby helping to make the human body to restore the balance of yin and yang, that is called "Zhengzhifa" in the culture of Traditional Chinese Medicine, and it is defined as "Dao Sheng Yi"; Utilizing herb-pair with the properties of yin and yang is defined as "Yi Sheng Er"; Forming the prescription according to the principles of Monarch,Minister,Assistant and Guide is called"Er Sheng San"; and the composition of prescription changing aiming at pathogenesis of illness is called"San Sheng Wanwu". Herb-pair is the key joint of the development of Traditional Chinese Medicine, the study on the compatibility of herb-pair have already to be become a key point of investigation on the compatibility of medicines in prescription. The sentence of "It's better to utilize the herb-pair with compatibility of Xiangxu and Xiangshi'is recorded in 'Shen Nong Materia Medica'.'Liang'relationship is the core of'Zhengzhifa' and guides the long-term clinical medication. Under the guidance of the theories of'Liang'relationship in'Shen Nong Materia Medica',Salvia miltiorrhiza-Carthamus tinctorius was selected as the research object, the methods of pharmacokinetics and metabonomics were employed in studying the effector substance of Salvia miltiorrhiza-Carthamus tinctorius to explore the'Liang'relationship within the perspective of the changes and interaction between the group of medicinal compositions and endogenous substance. This study provides an important approach to enrich the Compatibility Theory of Chinese Traditional Medicine. This dissertation has five chapters, and the chief contributions of the author are as follows:
1. Under the guidance of'Shen Nong Materia Medica', we proposed a new concept,'Liang'relationship. Taking Salvia miltiorrhiza-Carthamus tinctorius as the research object, for the reason of Salvia miltiorrhiza-Carthamus tinctorius is a common herb-pair in the TCM formulae with activating blood circulation to dissipate blood stasis, and then summrized the research progress of the herb-pair above。
2. Taking Salvia miltiorrhiza-Carthamus tinctorius as the study object, analytical system was developed in this study for simultaneously detecting danshensu(DSS), protocatechuic acid (PA), protocatechuic aldehyde (PAH) and hydroxy safflower yellow A (HSYA) in the injection and plasma. After administration of Salvia miltiorrhiza, Salvia miltiorrhiza-Carthamus tinctorius and Carthamus tinctorius for the normal and model group, their plasma were analyzed utilizing the analytical system above, and then the variation of DSS, PA, PAH and HSYA and mutual influential action were studied from the point of pharmacokinetics. Meanwhile, urines of rats in normal and model group were investigated so as to acquire the flag of pathology by means of metabonomics with LC-MS. After administration of Salvia miltiorrhiza, Salvia miltiorrhiza-Carthamus tinctorius and Carthamus tinctorius, the similarities and differences in endogenous substances and their relative metabolism pathways were studied based on the urinary metobonomics with the aim to explore the 'Liang' relationship from the angle of endogenous substances. It is proved that both Salvia miltiorrhiza and Carthamus tinctorius could improve the absorption and distribution in vivo each other; meanwhile, comparing to the normal group, the tyrosine metabolic pathway, tryphan metabolic pathway, arginine metabolic pathway, proline metabolic pathway, purine metabolic pathway and tricarboxylic acid cycle(TCA cycle) in model rats were abnormal, and it can be inferred that the lever of glucocorticoid was up-regulation, noradrenergic system activity was strengthened owning to the long-time cold stress; Simultaneously, TCA cycle took effect in compensating acticn for the cold environment. After treatment of Salvia miltiorrhiza and Carthamus tinctorius, illness of the model rats was relieved by means of same responsive substances and metabolic pathways as Salvia miltiorrhiza-Carthamus tinctorius effected.
3. The phenolic acids of DSS, PA,PAH and HSYA in Xuebijing injection which contains Salvia miltiorrhiza-Carthamus tinctorius were selected as research targets, and a novel high performance liquid chromatography-electrochemical detector (HPLC-ECD) analytical system was developed in this study by integratedly utilizing ionic liquid (IL) of1-butyl-3-methylimidazolium bromide and an additive of gold nanoparticles. The resulted pilot study was first performed to assess the effects of1-butyl-3-methylimidazolium bromide and gold nanoparticles on the chromatographic characteristics of four phenolic acids in Xuebijing injection, including DSS, PA, PAH and HSYA. It was notable to observe that retainability of the phenolic acids were markly lowered by IL addition. Compared with the cases without IL addition, the retention times of DSS, PA, PAH and HSYA have decreased2.851,1.532,1.53and0.818min, respectively when0.4%IL in the mobile phase. In addition, the corresponding theoretical plate numbers and peak areas for these compounds were significantly increased. Area response for DSS, PA, PAH and HSYA were enhanced by772%,628%,584%and703%, respectively. It was observed that nano-gold catalysis power enabled peak areas of DSS, PAH and PA to enhance5.7,6.2and66.5times relative to the case with addition of IL. Altogether, the optimized HPLC-ECD system was successfully applied to the pharmacokinetics study of Xuebijing injection with underlying applicability to in vivo and in vitro analysis of a variety of natural product from Chinese medicine plants, TCM formulae and associated patent TCM preparation.
Furthermore, the metabolic study of Salvia miltiorrhiza-Carthamus tinctorius in hippocampus area of rats were carried out utilizing the Microdialysis-HPLC-ECD analytical method with properties of real time detecting on line, the characteristic metabolic of IDHP was found.
引文
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