“广枣—檀香”君—使对药的效应物质研究
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摘要
复方配伍是在中医理论的指导下,在辨证审因、决定治法之后,选择适当的中药,按组方原则,酌定用量、用法,妥善配伍而成,是中医理论的重要组成部分。因为中药组成及其复杂性在临床应用上讲究辨证治疗,所以很难用现代科学技术准确的阐明中药配伍理论。因此,如何科学,有效的阐明复方配伍理论一直是中医药理论研究的难点。复方配伍研究,应以中医药理论为指导,有效成分研究和药理研究相结合；通过拆方研究,确定复方中主要药物或活性物质、从复方中寻找有效成分的最佳组合而从整体经过还原研究回归整体。“君-使”药物是复方中的核心对药,在中药理论中具有相互增效的作用,所以研究这种关键的配伍关系,既可以简化复方药物研究的复杂性,同样又能抓住复方药的核心重点,对发现体内效应物质,丰富并发展复方配伍理论,并且进一步认识中药引经实质有着重要的意义。本论文选择经典藏药方“三味檀香散”中“广枣-檀香”为研究对象,研究了使药檀香对君药广枣中没食子酸和原儿茶酸药代动力学,以及广枣中效应物质在大鼠体内代谢行为过程的影响。全文分四章,其主要内容如下：
1.建立了大鼠血浆中没食子酸(GA)和原儿茶酸(PA)的高效液相色谱分析方法,结果显示：高、中、低三个浓度的方法回收率、精密度和稳定性等指标均符合生物样品分析要求。没食子酸在0.02～1.25 mg·L-1,原儿茶酸在0.03～1.75 mg·L-1范围内具有良好的线性关系,为君-使对药体内的药动学研究奠定了方法学基础,可作为广枣体内效应物质研究的方法。
2.制作了病证结合的气滞血瘀动物模型,采用上述分析方法研究了广枣中没食子酸和原儿茶酸在正常组和模型组大鼠体内的药代动力学过程；并配伍使药檀香研究其对广枣中没食子酸和原儿茶酸药代动力学方面的影响。研究发现没食子酸和原儿茶酸在模型大鼠体内的有效含量增加,达峰时间滞后；与檀香配伍后,可促进原儿茶酸由血液向组织中分布,提高原儿茶酸的生物利用度,提示檀香可能增强了广枣在治疗心血管疾病方面的疗效,为分析檀香增效-导向作用提供了理论依据。
3.用SPSS主成分分析法并结合药时曲线的变化规律,筛选色谱数据进行分析,确定了3个未知成分为“广枣-檀香”的体内效应物质。并且进一步通过高效液相色谱质谱联用技术(HPLC-MS)初步进行了定性分析,测定其中三个效应物质的离子峰为：m／z 120.4,m／z 231.4,和m／z 231.4。建立了“君-使”对药体内效应物质研究新模式,为创新药物的开发提供了新途径。
Compound compatibility theory is a important part of TCM.It is formed using the guidance of TCM theory, and after the decision of treatment method select the appropriate medicine and use Appropriate drug dosage and proper drug compatibility.But, for the complex composition and clinical application with philosophic thoughts, it's very difficult to express the mechanism of prescription compatibility by modern science and technology. Therefore, how to express the principle of prescription compatibility according to modern science and technology is a hotspot and a tough problem all the time. Compound compatibility study should be guided by Chinese medicine theory, research and pharmacology of active ingredient combination; by separate components studied to determine the drug or active compound of main material, from the compound to find the best combination of active ingredients through the reduction from the overall of regression as a whole. Monarch-guide compatible herbal medicine is the core of TCM. An important approach to enrich the theories of Traditional Chinese Medicine by simplify the compound drugs, and develop highly effective new drugs is to find the key compatibility relationship through the studies of efficacious prescriptions and find their bioactive substances.
This paper chose "Guang zao-sandalwood" of Classical Tibetan side"San wei tan xiang san" as the research object to systematically study the mechanism of monarch-guide herbal medicine in the body through metabolomics. The influence of guide herb (sandalwood) was revealed through investigating the pharmacokinetical (PK) changes of bioactive substances in monarch herb(Guangzao,GZ); The main contents are as follows:
1. A new high performance liquid chromatography (HPLC) method for analysis of the gallic acid (GA) and protocatechuic acid (PA) of Guangzao in plasma is established. The results showed that the linear range of GA is 0.02～1.25 mg·L/-1 and PA is 0.03～1.75. The relative recovery and absolute recovery of low, medium and high concentration, relative standard deviations (RSD) of precision and stability experiments are consistent with the requirements of biological sample analysis.
2. After intragastric administration of Guangzao and Guangzao-sandalwood, the PK parameters of GA and PA in plasma of Stagnancy of Qi and Blood Stasis (SQBS) model rats are compared with those in normal rats. The results indicated that sandalwood could change the pharmacokinetics of GA and PA, also could increase the biological availability of GA and PA. Further, it might indicate that the the sandalwood enhance curative effect of Guangzao in the cardiovascular diseases, which will provide evidences of sandalwood's synergism and explaination of the theory of prescription compatibility by modern science and technology.
3. With the SPSS PCA method and considering the change of concentration-time curves,3 unkown substances were ascertained to be the bioactive substances of Guangzao-sandalwood. An initial qualitative analysis on them was carried out by HPLC-MS, then the fragmentions corresponded with 3 unknown bioactive substances were supposed to be:m/z 120.4, m/z 231.4 and m/z 231.4. A new mode to investigate the bioactive substances of monarch-guide compatible herb was established, which could provide new pathway to develop highly effective new drugs.
1.建立了大鼠血浆中没食子酸(GA)和原儿茶酸(PA)的高效液相色谱分析方法,结果显示：高、中、低三个浓度的方法回收率、精密度和稳定性等指标均符合生物样品分析要求。没食子酸在0.02～1.25 mg·L-1,原儿茶酸在0.03～1.75 mg·L-1范围内具有良好的线性关系,为君-使对药体内的药动学研究奠定了方法学基础,可作为广枣体内效应物质研究的方法。
2.制作了病证结合的气滞血瘀动物模型,采用上述分析方法研究了广枣中没食子酸和原儿茶酸在正常组和模型组大鼠体内的药代动力学过程；并配伍使药檀香研究其对广枣中没食子酸和原儿茶酸药代动力学方面的影响。研究发现没食子酸和原儿茶酸在模型大鼠体内的有效含量增加,达峰时间滞后；与檀香配伍后,可促进原儿茶酸由血液向组织中分布,提高原儿茶酸的生物利用度,提示檀香可能增强了广枣在治疗心血管疾病方面的疗效,为分析檀香增效-导向作用提供了理论依据。
3.用SPSS主成分分析法并结合药时曲线的变化规律,筛选色谱数据进行分析,确定了3个未知成分为“广枣-檀香”的体内效应物质。并且进一步通过高效液相色谱质谱联用技术(HPLC-MS)初步进行了定性分析,测定其中三个效应物质的离子峰为：m／z 120.4,m／z 231.4,和m／z 231.4。建立了“君-使”对药体内效应物质研究新模式,为创新药物的开发提供了新途径。
Compound compatibility theory is a important part of TCM.It is formed using the guidance of TCM theory, and after the decision of treatment method select the appropriate medicine and use Appropriate drug dosage and proper drug compatibility.But, for the complex composition and clinical application with philosophic thoughts, it's very difficult to express the mechanism of prescription compatibility by modern science and technology. Therefore, how to express the principle of prescription compatibility according to modern science and technology is a hotspot and a tough problem all the time. Compound compatibility study should be guided by Chinese medicine theory, research and pharmacology of active ingredient combination; by separate components studied to determine the drug or active compound of main material, from the compound to find the best combination of active ingredients through the reduction from the overall of regression as a whole. Monarch-guide compatible herbal medicine is the core of TCM. An important approach to enrich the theories of Traditional Chinese Medicine by simplify the compound drugs, and develop highly effective new drugs is to find the key compatibility relationship through the studies of efficacious prescriptions and find their bioactive substances.
This paper chose "Guang zao-sandalwood" of Classical Tibetan side"San wei tan xiang san" as the research object to systematically study the mechanism of monarch-guide herbal medicine in the body through metabolomics. The influence of guide herb (sandalwood) was revealed through investigating the pharmacokinetical (PK) changes of bioactive substances in monarch herb(Guangzao,GZ); The main contents are as follows:
1. A new high performance liquid chromatography (HPLC) method for analysis of the gallic acid (GA) and protocatechuic acid (PA) of Guangzao in plasma is established. The results showed that the linear range of GA is 0.02～1.25 mg·L/-1 and PA is 0.03～1.75. The relative recovery and absolute recovery of low, medium and high concentration, relative standard deviations (RSD) of precision and stability experiments are consistent with the requirements of biological sample analysis.
2. After intragastric administration of Guangzao and Guangzao-sandalwood, the PK parameters of GA and PA in plasma of Stagnancy of Qi and Blood Stasis (SQBS) model rats are compared with those in normal rats. The results indicated that sandalwood could change the pharmacokinetics of GA and PA, also could increase the biological availability of GA and PA. Further, it might indicate that the the sandalwood enhance curative effect of Guangzao in the cardiovascular diseases, which will provide evidences of sandalwood's synergism and explaination of the theory of prescription compatibility by modern science and technology.
3. With the SPSS PCA method and considering the change of concentration-time curves,3 unkown substances were ascertained to be the bioactive substances of Guangzao-sandalwood. An initial qualitative analysis on them was carried out by HPLC-MS, then the fragmentions corresponded with 3 unknown bioactive substances were supposed to be:m/z 120.4, m/z 231.4 and m/z 231.4. A new mode to investigate the bioactive substances of monarch-guide compatible herb was established, which could provide new pathway to develop highly effective new drugs.
引文
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