治咳川贝枇杷滴丸药效物质组学及作用机制的评价研究
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摘要
治咳川贝枇杷滴丸是以现代科技提取枇杷叶、平贝母、桔梗和半夏中的有效成分与薄荷脑精制而成的滴丸制剂，具有服用方便、生物利用度高及无明显毒副作用等特点，具有宣肺降气、清热化痰的功效。临床上主要用于痰热郁肺所致咳嗽及支气管炎等症。作为一个蕴含着科学配伍和独特辩证规律的现代中药复方，以整体系统生物学为指导对其进行药效物质组学及机理评价的研究可以解决困扰其国际化推广的技术瓶颈。
在质量控制方面：采用UPLC/Q-TOF技术建立了35种成分的多维多息质量控制指纹图谱；并同时对六个指标成分进行了定量分析；采用聚类分析最小二乘法（PLS-DA）对不同批次滴丸的质量进行评价，确定了影响质量的关键点为挥发性成分，并通过全二维气相质谱联用技术对其74种成分进行了较为全面地信息表征。
在有效性评价方面：通过枸橼酸引咳豚鼠模型、豚鼠离体平滑肌组织模型和NF-κB炎症通路荧光素酶筛选评价体系对滴丸按极性萃取的子物质组分进行药效学评价，筛选出二氯甲烷层具有止咳平喘的功效，而正丁醇层具有抗炎作用；并对其进行化学成分信息表征，并通过网络生物信息学与在线细胞快速筛选技术相结合的手段，对药效指标成分的作用机制进行阐释与验证。
在配伍协同评价方面：采用计算机虚拟计算（in Silico）对可被机体吸收的成分进行预测；分别采用Caco-2单层细胞实验、外翻肠囊实验和肝微粒体酶代谢等体外研究（in vitro）方法，在细胞水平和离体器官水平对滴丸的吸收代谢进行研究，并探讨处方配伍机制；在活体动物水平采用体内（in vivo）研究的方法，对大鼠灌胃给药前后的血浆、尿液和粪便总成分进行指纹图谱分析，表征其代谢产物及途径。
通过本项目研究，基本明确了治咳川贝枇杷滴丸的药效物质基础和作用机制，对质量控制手段进行合理的完善和丰富，从吸收代谢角度初步探讨了其吸收、代谢和复方配伍的规律，为指导其临床合理准确有效安全用药提供实验依据。
Chuanbeipipa dropping pills(CBPP), a traditional Chinese medicine, consistingof Eriobotrya japonica leaf, Platycodon grandiflorum, Pinellia ternate, Fritillariaussuriensis and volatile oilextracts from Menthahaplocalyxis exclusively developedby employing modern technology. CBPP is widely used in clinicalon the treatment ofchronic obstructive lung disease and cough caused by bronchial catarrh, whichpossesses the advantage of small dosage, convenience, high bioavailability, littlegastrointestinal irritation, toxic and side-effect. However, the limited acknowledgmentof its chemical material basis and mechanism of action resisted theinternationalization of traditionalChinese medicine. And a holistic methodology,chemomics-integrated global systems biology, was performed to study on the globalchemome and mechanism appreciation to solve the problem above.
Quality control: a rapid and comprehensive fingerprint method was establishedby using the UPLC/Q-TOF mass spectrum and six index components were analyzedquantitatively. And partial least squares discriminant analysis (PLS-DA) was appliedto quality assessment of diverse batches of CBPPs. The scores plot clearly revealedthe volatile oil was the key point of quality control. GC×GC-TOF-MAStechnique wasalso used to comprehensively analyze the sample batches of CBPPs.
Validity assessment: CBPPs were extracted consequencely of dichloromethane,ethyl acetate, and butanol. Screening for effective compounds and assessment ofpharmacodynamics was respectivelyon the model of citric acid-induced coughing inguinea pigs, the concentration-response curves of acetylcholine chloride (ACh) aswell as bypGL4/NF-κB luciferase reporter vectors assay. The main bioactivecomponents of the DME were identified and analyzedto have effects on cough andasthma, meanwhile, butanolextract (BUE) was conformed anti inflammatory activities.A new technic bioinformatics researches in regulatory networks conjunct with onlinecell screening was also applied.
Safety evaluation: The absorbable compounds were profiled by using threecomplementary: a computational prediction method in silico, a Caco-2cell monolayerin vitro experiment and an improved everted gut sac in vitro experiment. While themetabolites of CBPP, collected from serum, urine and feces afteroral administation in rat in vivo experiment, were analyzed by fingerprint methods.
The current study aimed to establish a reliable and effective method for screeningthe potentially bioactive components of CBPP, report for the first time the basis ofCBPP pharmacology, and provide useful information for further studies on the CBPPmechanism of action.
在质量控制方面：采用UPLC/Q-TOF技术建立了35种成分的多维多息质量控制指纹图谱；并同时对六个指标成分进行了定量分析；采用聚类分析最小二乘法（PLS-DA）对不同批次滴丸的质量进行评价，确定了影响质量的关键点为挥发性成分，并通过全二维气相质谱联用技术对其74种成分进行了较为全面地信息表征。
在有效性评价方面：通过枸橼酸引咳豚鼠模型、豚鼠离体平滑肌组织模型和NF-κB炎症通路荧光素酶筛选评价体系对滴丸按极性萃取的子物质组分进行药效学评价，筛选出二氯甲烷层具有止咳平喘的功效，而正丁醇层具有抗炎作用；并对其进行化学成分信息表征，并通过网络生物信息学与在线细胞快速筛选技术相结合的手段，对药效指标成分的作用机制进行阐释与验证。
在配伍协同评价方面：采用计算机虚拟计算（in Silico）对可被机体吸收的成分进行预测；分别采用Caco-2单层细胞实验、外翻肠囊实验和肝微粒体酶代谢等体外研究（in vitro）方法，在细胞水平和离体器官水平对滴丸的吸收代谢进行研究，并探讨处方配伍机制；在活体动物水平采用体内（in vivo）研究的方法，对大鼠灌胃给药前后的血浆、尿液和粪便总成分进行指纹图谱分析，表征其代谢产物及途径。
通过本项目研究，基本明确了治咳川贝枇杷滴丸的药效物质基础和作用机制，对质量控制手段进行合理的完善和丰富，从吸收代谢角度初步探讨了其吸收、代谢和复方配伍的规律，为指导其临床合理准确有效安全用药提供实验依据。
Chuanbeipipa dropping pills(CBPP), a traditional Chinese medicine, consistingof Eriobotrya japonica leaf, Platycodon grandiflorum, Pinellia ternate, Fritillariaussuriensis and volatile oilextracts from Menthahaplocalyxis exclusively developedby employing modern technology. CBPP is widely used in clinicalon the treatment ofchronic obstructive lung disease and cough caused by bronchial catarrh, whichpossesses the advantage of small dosage, convenience, high bioavailability, littlegastrointestinal irritation, toxic and side-effect. However, the limited acknowledgmentof its chemical material basis and mechanism of action resisted theinternationalization of traditionalChinese medicine. And a holistic methodology,chemomics-integrated global systems biology, was performed to study on the globalchemome and mechanism appreciation to solve the problem above.
Quality control: a rapid and comprehensive fingerprint method was establishedby using the UPLC/Q-TOF mass spectrum and six index components were analyzedquantitatively. And partial least squares discriminant analysis (PLS-DA) was appliedto quality assessment of diverse batches of CBPPs. The scores plot clearly revealedthe volatile oil was the key point of quality control. GC×GC-TOF-MAStechnique wasalso used to comprehensively analyze the sample batches of CBPPs.
Validity assessment: CBPPs were extracted consequencely of dichloromethane,ethyl acetate, and butanol. Screening for effective compounds and assessment ofpharmacodynamics was respectivelyon the model of citric acid-induced coughing inguinea pigs, the concentration-response curves of acetylcholine chloride (ACh) aswell as bypGL4/NF-κB luciferase reporter vectors assay. The main bioactivecomponents of the DME were identified and analyzedto have effects on cough andasthma, meanwhile, butanolextract (BUE) was conformed anti inflammatory activities.A new technic bioinformatics researches in regulatory networks conjunct with onlinecell screening was also applied.
Safety evaluation: The absorbable compounds were profiled by using threecomplementary: a computational prediction method in silico, a Caco-2cell monolayerin vitro experiment and an improved everted gut sac in vitro experiment. While themetabolites of CBPP, collected from serum, urine and feces afteroral administation in rat in vivo experiment, were analyzed by fingerprint methods.
The current study aimed to establish a reliable and effective method for screeningthe potentially bioactive components of CBPP, report for the first time the basis ofCBPP pharmacology, and provide useful information for further studies on the CBPPmechanism of action.
引文
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