倡议树立方剂“主效应”研究的新思路——对中药复方作用机制与配伍机制研究的新思考
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摘要
中药对机体的调节杂泛性和机体处置中药的复杂差异性,仍是科学阐释中药作用机制和提高疗效的障碍,新近"多成分单靶点叠加作用"假说,认为中药多成分多靶点协同作用网络中局部靶点可存在相似多成分的药效叠加作用。该文作者进而认为,中药多成分只能在有限条件/浓度下起叠加作用,由于中药-机体系统杂泛性,在药效单靶点上更多显现的是多成分叠加与竞争/拮抗并存的复杂作用,此复杂作用可能是影响中药多靶点协同作用的关键,理论上,选择和创造单靶点叠加作用,可实现中药的科学配伍、疗效提高与毒性减弱。该文根据中药多成分、多靶点协同作用特点,及"叠加作用"假说等,提出方剂"主效应"研究思路——中药(复方)作用多样、复杂,如何更好地研究中药复方配伍机制和提高疗效?应该从中药复杂多样的作用中筛选与临床具体病证相关的某一或某几个"作用效应"作为方剂"主效应",方剂"主效应"是中药复方多成分多靶点协同作用的宏观体现,方剂"主效应"研究至少可以包含2个方面,一是方剂"主效应"的药动学应用研究,二是方剂"主效应"的药效作用研究:在某一具体临床使用中,仅仅是应用方剂治疗某一临床病证的作用,那么这一作用可视为当下该方剂的主效应,此时,如能研究得出该"主效应"的药动学规律(如主效应时间曲线,主效应-剂量相关性等),可制定此方剂治疗该病证的临床优化用药方案;主效应的作用研究上,主要有2个要素,其一,机体的哪些药物靶点与"主效应"直接相关,也即找出"主效应"的靶点网络,其二,"主效应"靶点网络中单个靶点受哪些药物成分调控(正相关、负相关),调控的成分浓度或数量变化会引起单靶点药效的何种变化,进而会引起多靶点协同作用的何种变化。此两要素将是最终阐释中药作用机制和配伍机制的研究关键。通过对方剂"主效应"的研究,可以提高具体病证应用下方剂的临床疗效和阐释其配伍机制与作用机制。
This article proposes a new thought on the study of " main effect" of traditional Chinese medicine( TCM) formulae. The blood concentrations of the pharmacodynamic substances of Chinese material medica( CMM) are usually very low,with lower toxic and side effects than western medicine. Therefore,according to a recent hypothesis of additive effect of multiple components for a single target,local targets in multi-component multi-target synergistic effect network of TCM may have the additive effect of similar components.Studies on the disposition of CMM showed that a constituent could bebio-transformed to many metabolites; these compounds with a similar structure are likely to have the same pharmacological effects on the same target,which could provide experimental evidences for the hypothesis of " additive effect". The authors of this article further believe that additive effect of TCM multi-components only comes up under a limited conditions/concentration. Because of the complexity of TCM-organism system,the complex effect of multicomponent addition and competition/antagonism is more likely to appear in single targets of drug effect. This complex effect may be the key to impact the synergistic effect of TCM multi-targets. In theory,choose and create a single target additive effect could realize the scientific compatibility of TCM and improve the curative effect and attenuate toxicity. According to the clinical demand and under the guidance of the above thought,we proposed the " main effect" of TCM formulae. Because traditional Chinese medicine( compounds) have diverse and complex effects,how to better study TCM formulae compatibility mechanism and improve the curative effect? Efforts shall be made to select one or several effects relating to clinical specific syndromes from the complex and diverse effects of TCM as the " main effect".The " main effect" of TCM formulae is the macroscopic manifestation of the synergistic effect of multi-component/multi-target. The study of the Formulae " main effect" can contain at least two aspects: one is the study of pharmacokinetic application of TCM formulae,and another is the study for pharmacodynamics effect. In the study of main effect,there are two main elements. First,which drug targets are directly related to the main effect? This requires identifying the target network. Second,which drug components positively or negatively control the single target of the target network? And what change in single target effect as well as the multi-target synergistic effect will be caused by the regulatory component concentration or the change in number? These two elements is the key to elucidate the mechanism of compound action and compatibility mechanism of Chinese herbal compound formulae. Through the study of the main effect,the clinical curative effect and the mechanism of the TCM formulae shall be improved.
This article proposes a new thought on the study of " main effect" of traditional Chinese medicine( TCM) formulae. The blood concentrations of the pharmacodynamic substances of Chinese material medica( CMM) are usually very low,with lower toxic and side effects than western medicine. Therefore,according to a recent hypothesis of additive effect of multiple components for a single target,local targets in multi-component multi-target synergistic effect network of TCM may have the additive effect of similar components.Studies on the disposition of CMM showed that a constituent could bebio-transformed to many metabolites; these compounds with a similar structure are likely to have the same pharmacological effects on the same target,which could provide experimental evidences for the hypothesis of " additive effect". The authors of this article further believe that additive effect of TCM multi-components only comes up under a limited conditions/concentration. Because of the complexity of TCM-organism system,the complex effect of multicomponent addition and competition/antagonism is more likely to appear in single targets of drug effect. This complex effect may be the key to impact the synergistic effect of TCM multi-targets. In theory,choose and create a single target additive effect could realize the scientific compatibility of TCM and improve the curative effect and attenuate toxicity. According to the clinical demand and under the guidance of the above thought,we proposed the " main effect" of TCM formulae. Because traditional Chinese medicine( compounds) have diverse and complex effects,how to better study TCM formulae compatibility mechanism and improve the curative effect? Efforts shall be made to select one or several effects relating to clinical specific syndromes from the complex and diverse effects of TCM as the " main effect".The " main effect" of TCM formulae is the macroscopic manifestation of the synergistic effect of multi-component/multi-target. The study of the Formulae " main effect" can contain at least two aspects: one is the study of pharmacokinetic application of TCM formulae,and another is the study for pharmacodynamics effect. In the study of main effect,there are two main elements. First,which drug targets are directly related to the main effect? This requires identifying the target network. Second,which drug components positively or negatively control the single target of the target network? And what change in single target effect as well as the multi-target synergistic effect will be caused by the regulatory component concentration or the change in number? These two elements is the key to elucidate the mechanism of compound action and compatibility mechanism of Chinese herbal compound formulae. Through the study of the main effect,the clinical curative effect and the mechanism of the TCM formulae shall be improved.
引文
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[10]翁小刚,李玉洁,杨庆,等.戊己丸不同配伍组方体内对CYP1A2酶活性的影响及其临床意义[J].世界科学技术——中医药现代化,2011,13(1):193.
[11]Chen Y,Li Y,Wang Y,et al.Comparative pharmacokinetics of active alkaloids after oral administration of Rhizoma Coptidis extract and Wuji Wan formulas in rat using a UPLC-MS/MS method[J].Eur J Drug Metab Pharmacokinet,2015,40(1):67.
[12]王怡薇,王彦礼,李玉洁,等.戊己丸不同配伍对代表成分吸收及肝脏摄取的影响[J].中华中医药杂志,2012(4):793.
[2]徐风,杨东辉,尚明英,等.中药药效物质的“显效形式”、“叠加作用”和“毒性分散效应”——由中药体内代谢研究引发的思考[J].世界科学技术——中医药现代化,2014,16(4):688.
[3]薛燕,雷跻九.中药复方霰弹理论——论中药复方现代研究方法[M].北京:中国环境科学出版社,1996.
[4]薛燕.以现代科学阐明中药复方作用机理的霰弹理论及其重要意义[C].北京:97中医药博士论坛,1997.
[5]张伯礼,高秀梅,商洪才,等.复方丹参方的药效物质及作用机理研究[J].世界科学技术——中医药现代化,2003(5):14.
[6]白毅.中药药效物质新假说诠释中药未解之谜[N].中国医药报,2014-07-29(008).
[7]王爱云,沈颖,陈文星,等.中药发挥效应的核心作用方式的科学思考[J].世界科学技术——中医药现代化,2017,19(10):1692.
[8]辛萍,匡海学,李晓亮,等.蛋白质组学技术及其在中药作用机制研究中的应用[J].中国中药杂志,2018,43(5):904.
[9]Weng X,Gao Y,Li Y,et al.Studies on efficacy mechanism of Chinese herbal combination based on drug metabolizing enzyme[J].J Thermodyn Catal,2016,7:160.
[10]翁小刚,李玉洁,杨庆,等.戊己丸不同配伍组方体内对CYP1A2酶活性的影响及其临床意义[J].世界科学技术——中医药现代化,2011,13(1):193.
[11]Chen Y,Li Y,Wang Y,et al.Comparative pharmacokinetics of active alkaloids after oral administration of Rhizoma Coptidis extract and Wuji Wan formulas in rat using a UPLC-MS/MS method[J].Eur J Drug Metab Pharmacokinet,2015,40(1):67.
[12]王怡薇,王彦礼,李玉洁,等.戊己丸不同配伍对代表成分吸收及肝脏摄取的影响[J].中华中医药杂志,2012(4):793.