柴胡疏肝散促胃肠动力成分的药效学和药物代谢动力学研究
|
摘要
背景和目的：功能性消化不良是指具有上腹部疼痛、上腹部胀满、早饱、嗳气、食欲不振、恶心、呕吐等上腹部不适症状,经检查排除引起这些症状的器质性疾病的一组临床综合症。柴胡疏肝散是治疗功能性消化不良的经典古方。中药复方的治疗作用是多种成分共同作用的结果。本实验的目的：①建立快速、简单、灵敏的超高效液相色谱-光电二极管阵列(UPLC-PDA)测定方法,定量分析柴胡疏肝散汤剂中没食子酸、氧化芍药苷、芍药内酯苷、芍药苷、甘草苷、阿魏酸、柚皮芸香苷、柚皮苷、橙皮苷、新橙皮苷、水合橙皮内酯、甘草素、槲皮素、苯甲酰芍药苷、异甘草素和芒柄花素16种成分。②建立液相色谱-质谱联用(LC-MS)定性测定功能性消化不良病人口服柴胡疏肝散汤剂后血浆中成分阿魏酸和水合橙皮内酯。③研究柴胡疏肝散,阿魏酸和水合橙皮内酯对大鼠胃肠运动的影响,部分阐明柴胡疏肝散治疗功能性消化不良的药效物质基础。④建立超高效液相色谱法(UPLC-PDA)研究功能性消化不良病人口服柴胡疏肝散后血浆中阿魏酸和水合橙皮内酯的药物动力学。
方法：
第一章柴胡疏肝散汤剂中16种活性成分的定量分析
采用UPLC-PDA法测定柴胡疏肝散汤剂中没食子酸、氧化芍药苷、芍药内酯苷、芍药苷、甘草苷、阿魏酸、柚皮芸香苷、柚皮苷、橙皮苷、新橙皮苷、水合橙皮内酯、甘草素、槲皮素、苯甲酰芍药苷、异甘草素和芒柄花素16种成分的含量,绘制各个成分的标准曲线,并对其最低检测浓度、精密度、回收率、样本稳定性和重现性进行验证。色谱柱：ACQUITY BEH C18柱(2.1 mm×50 mm,1.7μm),流动相：乙腈(A)-0.5%醋酸水(B),梯度洗脱,流速：0.5mL/min,柱温：40℃,检测波长：190-480nm。
第二章阿魏酸和水合橙皮内酯在功能性消化不良病人口服柴胡疏肝散汤剂后血浆中的定性分析
招募功能性消化不良病人,予一次口服柴胡疏肝散汤剂后取血。血浆经甲醇直接沉淀法去除蛋白质后,采用LC-MS法对病人血浆中阿魏酸和水合橙皮内酯进行分离分析,通过电离子喷雾(ESI)法,以选择离子反应检测(SRM)方式进行检测,阿魏酸和水合橙皮内酯离子通道m/z分别为194.8-177.0和261.1-243.0.采用Waters Xterra C18(150 mm×2.1 mm,5μm)色谱柱,流动相为10 mmol·L-1甲酸胺-乙腈(40：60,v/v),流速为0.2 mL·min-1,进样体积为20μL,柱温为40℃,样晶室温度为5℃。
第三章柴胡疏肝散及其成分阿魏酸和水合橙皮内酯促胃肠动力作用研究
采用大鼠在体胃排空和肠推进方法研究柴胡疏肝散,阿魏酸和水合橙皮内酯促胃肠动力作用；采用离体肠管实验研究阿魏酸和水合橙皮内酯对大鼠肠管收缩作用个影响。
第四章功能性消化不良病人口服柴胡疏肝散后吸收入血的阿魏酸和水合橙皮内酯药物动力学研究
用蛋白沉淀法预处理血样,UPLC法同时测定7名功能性消化不良病人口服柴胡疏肝散汤剂后13个时间点血浆样本中阿魏酸与水合橙皮内酯的血药浓度。应用3P97药动学分析软件对血药浓度-时间数据进行拟合。选用磺胺甲嗯唑为内标,阿魏酸和水合橙皮内酯检测波长分別为321nm和324nm。
结果：
第一章柴胡疏肝散汤剂中16种活性成分的定量分析
(1)建立了一个简单、快速和灵敏的能同时检测柴胡疏肝散汤剂中16种成分的UPLC-PDA法。样品分析时间：17.5min,色谱图中各成分的色谱峰分离完全,无杂峰干扰。16种成分在其线性检测范围内显示出良好的线性回归,r2>0.9992。该方法日内、日间精密度良好,其相对标准差(RSD)波动在1.87%-5.61%之间；胡疏肝散16种成分的加样回收率良好,平均加样回收率在96.13%-102.46%之间,RSD<6.74%。柴胡疏肝散汤剂样本在24小时内稳定性好,RSD波动在0.78%～2.98%。柴胡疏肝散汤剂重现性好,RSD波动于1.94%-5.36%。
(2)经UPLC-PDA方法检测后,柴胡疏肝散汤剂中没食子酸、氧化芍药苷、芍药内酯苷、芍药苷、甘草苷、阿魏酸、柚皮芸香苷、柚皮苷、橙皮苷、新橙皮苷、水合橙皮内酯、甘草素、槲皮素、苯甲酰芍药苷、异甘草素和芒柄花素16种化学成分被定量分析。
第二章阿魏酸和水合橙皮内酯在功能性消化不良病人口服柴胡疏肝散汤剂后血浆中的定性分析
通过研究阿魏酸和水合橙皮内酯主要色谱峰的质谱特征,功能性消化不良病人口服柴胡疏肝散汤剂后血浆中阿魏酸和水合橙皮内酯被成功检出。
第三章柴胡疏肝散及其成分阿魏酸和水合橙皮内酯促胃肠动力作用研究
与鼠空白对照组相比,柴胡疏肝散汤剂(20 g/kg),阿魏酸(100mg/kg)和水合橙皮内酯(14,28 mg/kg)能明显增加大鼠的胃排空率和肠推进率,P<0.05。、与大鼠空白肠相比,阿魏酸(100μmol/L)和水合橙皮内酯(10μmol/L)能明显增加大鼠空肠纵行肌和横行肌肉的收缩,P<0.05,水合橙皮内酯(30,100μmol/L)能显著增加大鼠空肠纵行肌和横行肌肉的收缩,P<0.01.
第四章功能性消化不良病人口服柴胡疏肝散后吸收入血的阿魏酸和水合橙皮内酯药物动力学研究
功能性消化不良患者(7名)口服柴胡疏肝散汤剂后,血浆中阿魏酸与水合橙皮内酯被检测。在色谱图上两种化合物分离完全,未出现其他物质干扰峰,保留时间分别为6.5 min和15.7min,内标磺胺甲嗯唑为8.0 min。阿魏酸与水合橙皮内酯的回收率分别为95.35%-102.56%和95.58%～102.09%,相对标准偏差(relative standard deviation, RSD)分别小于2.81%和3.86%。用空白血清加标准品绘制标准曲线,阿魏酸线性范围为10～320 ng/ml,信噪比为3时最低检测线为1.5 ng/ml,最低检测浓度为5 ng/ml;水合橙皮内酯范围为7.5～720ng/mL,最低检测线为2.5ng/mL,最低检测浓度7.5 ng/mL。阿魏酸与水合橙皮内酯在功能性消化不良病人体内的代谢过程被拟合为二室模型,阿魏酸与水合橙皮内酯分别在27.50 mmin和23.57 min时达到最大血药浓度0.199 mg/L和0.371 mg/L,阿魏酸的消除半衰期和AUC分别为131.27min和14.83μg·min/mL,水合橙皮内酯的消除半衰期和AUC分别为139.53 min和31.445μg·min/mL
结论：
(1)用超高效液相色谱-光电二极管阵列(UPLC-PDA)法检测柴胡疏肝散中主要有效成分快速灵敏,准确可靠、稳定且重现性好。此方法可成功用于同时检测柴胡疏肝散汤剂中16种目标成分的含量。
(2)功能性消化不良病人口服柴胡疏肝散后血浆中阿魏酸和水合橙皮内酯被的LC-MS法成功分离和定性。
(3)柴胡疏肝散及体内吸收成分阿魏酸和水合橙皮内酯均有明显促胃肠动力的作用,阿魏酸和水合橙皮内酯是柴胡疏肝散治疗功能性消化不良的主要物质基础。
(4)采用超高效液相色谱法对功能性消化不良病人服用柴胡疏肝散后血浆中的阿魏酸和水合橙皮内酯进行同步测定。柴胡疏肝散及其促胃肠动力成分阿魏酸和水合橙皮内酯的药物动力学研究将有助于监测该方的临床应用以及理解其治疗机理。
Background and objective:Functional dyspepsia is a syndrome defined by chronic or recurrent upper abdominal symptoms without any organic or biochemical abnormality. The clinical symptoms often include upper abdominal pain, upper abdominal fullness, early satiety, belching, losing of appetite, nausea, vomiting and other symptoms of upper abdominal discomfort. Chaihu-Shugan-San (CSS) is a popular traditional Chinese medicine formula to treat functional dyspepsia. It is widely accepted that the combined effect of multiple constituents of traditional Chinese medicine formula is considered to be crucial for treating diseases in clinical practice. The objective of the study are as follows:①To develop a simple, rapid and sensitive Ultra performance liquid chromatography coupled with photodiode array (UPLC-PDA) detection method for simultaneous determination of sixteen compounds in Chaihu-Shugan-San:gallic acid, oxypaeoniflora, albiflorin, paeoniflorin, liquiritin, ferulic acid (FA), narirutin, naringin, hesperidin, neohesperidin, meranzin hydrate (MH), liquiritigenin, quercimelin, benzoylpaeoniflorin, isoliquiritigenin, formononetin.②To develop a liquid chromatography-tandem mass spectrometry (LC-MS) method for the determination of FA and MH in plasmas of patients with functional dyspepsia after oral administration of Chaihu-Shugan-San decoction.③To investigated the effect of CSS, FA and MH on gastrointestinal motility in rats, partly elucidate the effective substance of CSS treating functional dyspepsia.④To develop a Ultra performance liquid churomatography coupled with photodiode array (UPLC-PDA) detection method to explore the pharmacokinetics of FA and MH in plasmas of patients with functional dyspepsia after oral administration of CSS decoction.
Method:
Part 1 The quantitative analysis of the sixteen active constituents in CSS
The analysis was performance on UPLC-PDA system with BEH C18 column (100×2.1 mm id,1.7μM). The mobile phase comprising acetonitrile (A) and 0.5% acetic acid (B) was used to elute the targets in gradient elution mode. Flow rate and detection wavelength were set at 0.5ml/min and 284nm. The sixteen constituents in CSS including gallic acid, oxypaeoniflorin, albiflorin, paeoniflorin, liquiritin, FA, narirutin, naringin, hesperidin, neohesperidin, MH, liquiritigenin, quercimelin, benzoylpaeoniflorin, isoliquiritigenin and formononetin were quantitative determinate, and the limit of determination (LOD), precision, recovery, sample stability and reproducibility of the sixteen constituents were examined in this study.
Part 2 The qualitative analysis of FA and MH in the plasma of patients with functional dyspepsia after oral administration of CSS.
The patients with functional dyspepsia were recuited and the plasmas were collected from the patients after oral administration of CSS. The plasma samples were precipitated with methanol. FA and MH were determined by LC-MS. Electrospray ionization (ESI) source was applied and operated in the positive ion mode. Selected reaction monitoring (SRM) mode with the transition of m/z 194.8-m/z 177.0 and m/z 261.1-m/z243.0 were used to detect FA and MH. Waters Xterra C18 column (150 mm×2.1 mm,5μm) was used in the experiment. The column temperature was set at 40℃.10 mmol·L-1 ammonium formate-acetonitrile (40:60, v/v) was used as mobile phase and the flow rate was 0.2mL·min-1 The sample room temperature was set at 5℃and the injection volume was 20μL.
Part 3 The effects of CSS, FA and MH on promoting gastrointestinal motility.
Gastric emptying (GE) and intestinal transit (IT) were used to study the effects of CSS, FA and MH on promoting gastrointestinal motility in vivo in rat. The intestinal muscle strips test in vitro was used to investigate the effects of FA and MH on Intestinal contraction.
Part 4 The pharmacokinetics of FA and MH in plasmas of patients with functional dyspepsia after oral administration of CSS decoction.
A total of 7 patients with functional dyspepsia were recruited in this study. The plasma samples were preprocessed by protein precipitation method. The UPLC system was used to determine the contents of FA and MH in the blood samples of 7 volunteers with functional dyspepsia, and the blood was collected through the vein at 5,10,15,30,45,60,90, 120,180,240,300,360,480 min. The dates of plasma concentration-time were fitted by using the 3P97 analytical program of pharmacokinetics. The internal standard (IS) was sulfamethoxazole. The detection wavelengths of FA and MH were set at 321 nm and 324 nm respectively.
Result:
Part1
(1) A simple, rapid and sensitive Ultra performance liquid chromatography coupled with photodiode array (UPLC-PDA) detection method was established for the simultaneous determination of sixteen compounds in CSS. The 16 marker constituents were sufficiently separated successfully in less than 17.5 min. There were no interference peaks in the vicinity of the target compounds in the chromatograms of CSS decoction. All calibration curves showed good linear regression (r2> 0.9992) within test ranges of the sixteen targets. The relative standard deviations (RSD) of intra-and inter-day precision were from 1.87% to 5.61% indicating good precision. The average recoveries of investigated sixteen targets ranged from 96.13% to 102.46%, with RSD values<6.74%, showing good recoveries. The sample of CSS decoction has good stability in 24 h, with RSD values from 0.78% to 2.98%. The RSD of the sixteen components in the reproducibility test fluctuates between 1.94% and 5.36%, indicating good reproducibility.
(2) Quantitative determination of the sixteen marker constituents in CSS decoction was made by UPLC-PDA system.
Part 2
According to the mass spectrometry analysis of main chromatogram peaks, FA and MH were successfully detected in the plasmas of patients with functional dyspepsia after oral administration of CSS.
Part 3
Compared with the control group, CSS (20g/kg), FA (100 mg/kg) and MH (14,28 mg/kg) significantly increase the rate of GE and IT in rats (P<0.05) FA (100μmol/L) and MH (10μmol/L) increased the mean amplitude of contraction in the longitudinal and circular strip compared with untreated controls (P<0.05). in addition, MH (30,100μmol/L) increased the mean amplitude of contraction in the longitudinal and circular strip compared with untreated controls (P<0.01)
Part 4
After oral administration of CSS, FA and MH were separated completely in the plasma of patients with functional dyspepsia and no other interfering peaks were found in the spectrum of the chromatograms. The retention times of FA and MH were 6.5 and 15.7 min, and that of sulfamethoxazole was 8,0 min. The recovery rates of FA and MH were from 95.35% to 102.56% with RSD< 2.81% and from 95.58% to102.09% with RSD<3.86%, respectively. The calibration curve for FA was linear over the concentration range from 10 to 320 ng/ml. The low detection limit of FA based on a signal-to-noise ratio of 3 was 1.5 ng/mL and the low concentration limit was 4.5 ng/ml. The calibration curve for MH was linear over the concentration range from 7.5 to 720 ng/mL. The low detection limit was 2.5 ng/mL and the low concentration limit was 7.5 ng/mL. The pharmacokinetics of FA and MH in patient plasma was fitted with a two-compartment model. Time to reach peak concentration of FA (0.199 mg/L) and MH (0.371 mg/L) was 27.50 min and 23.57 min, respectively. The elimination half-life and area under the concentration-time curve from t= 0 to the last time of FA and MH were 131.27 min and 14.835μg·min/mL and 139.53 min and 31.445μg·min/mL, respectively.
Conclusion:
1. A rapid, sensitive, and reliable UPLC-PDA method for the simultaneous determination of sixteen compounds in CSS was developed. The method was validated for specificity, accuracy, precision, and limits of detection and was successfully applied to determine the contents of sixteen components in CSS.
2. LC-MS is a convenient, rapid and effective method to separate and quality FA and MH in plasmas of patients with functional dyspepsia after oral administration of CSS.
3. CSS and its absorbed compound FA and MH have the significant effect on promoting gastrointestinal motility in rats. FA and MH are the effective substance of CSS to treat functional dyspepsia.
4. FA and MH in the plasmas of patients with functional dyspepsia were simultaneously determined by the UPLC method after oral administration of CSS. The pharmacokinetics of prokinetic CSS and its compounds are useful for monitoring CSS formulas in clinical practice and for understanding therapeutic mechanisms.
方法：
第一章柴胡疏肝散汤剂中16种活性成分的定量分析
采用UPLC-PDA法测定柴胡疏肝散汤剂中没食子酸、氧化芍药苷、芍药内酯苷、芍药苷、甘草苷、阿魏酸、柚皮芸香苷、柚皮苷、橙皮苷、新橙皮苷、水合橙皮内酯、甘草素、槲皮素、苯甲酰芍药苷、异甘草素和芒柄花素16种成分的含量,绘制各个成分的标准曲线,并对其最低检测浓度、精密度、回收率、样本稳定性和重现性进行验证。色谱柱：ACQUITY BEH C18柱(2.1 mm×50 mm,1.7μm),流动相：乙腈(A)-0.5%醋酸水(B),梯度洗脱,流速：0.5mL/min,柱温：40℃,检测波长：190-480nm。
第二章阿魏酸和水合橙皮内酯在功能性消化不良病人口服柴胡疏肝散汤剂后血浆中的定性分析
招募功能性消化不良病人,予一次口服柴胡疏肝散汤剂后取血。血浆经甲醇直接沉淀法去除蛋白质后,采用LC-MS法对病人血浆中阿魏酸和水合橙皮内酯进行分离分析,通过电离子喷雾(ESI)法,以选择离子反应检测(SRM)方式进行检测,阿魏酸和水合橙皮内酯离子通道m/z分别为194.8-177.0和261.1-243.0.采用Waters Xterra C18(150 mm×2.1 mm,5μm)色谱柱,流动相为10 mmol·L-1甲酸胺-乙腈(40：60,v/v),流速为0.2 mL·min-1,进样体积为20μL,柱温为40℃,样晶室温度为5℃。
第三章柴胡疏肝散及其成分阿魏酸和水合橙皮内酯促胃肠动力作用研究
采用大鼠在体胃排空和肠推进方法研究柴胡疏肝散,阿魏酸和水合橙皮内酯促胃肠动力作用；采用离体肠管实验研究阿魏酸和水合橙皮内酯对大鼠肠管收缩作用个影响。
第四章功能性消化不良病人口服柴胡疏肝散后吸收入血的阿魏酸和水合橙皮内酯药物动力学研究
用蛋白沉淀法预处理血样,UPLC法同时测定7名功能性消化不良病人口服柴胡疏肝散汤剂后13个时间点血浆样本中阿魏酸与水合橙皮内酯的血药浓度。应用3P97药动学分析软件对血药浓度-时间数据进行拟合。选用磺胺甲嗯唑为内标,阿魏酸和水合橙皮内酯检测波长分別为321nm和324nm。
结果：
第一章柴胡疏肝散汤剂中16种活性成分的定量分析
(1)建立了一个简单、快速和灵敏的能同时检测柴胡疏肝散汤剂中16种成分的UPLC-PDA法。样品分析时间：17.5min,色谱图中各成分的色谱峰分离完全,无杂峰干扰。16种成分在其线性检测范围内显示出良好的线性回归,r2>0.9992。该方法日内、日间精密度良好,其相对标准差(RSD)波动在1.87%-5.61%之间；胡疏肝散16种成分的加样回收率良好,平均加样回收率在96.13%-102.46%之间,RSD<6.74%。柴胡疏肝散汤剂样本在24小时内稳定性好,RSD波动在0.78%～2.98%。柴胡疏肝散汤剂重现性好,RSD波动于1.94%-5.36%。
(2)经UPLC-PDA方法检测后,柴胡疏肝散汤剂中没食子酸、氧化芍药苷、芍药内酯苷、芍药苷、甘草苷、阿魏酸、柚皮芸香苷、柚皮苷、橙皮苷、新橙皮苷、水合橙皮内酯、甘草素、槲皮素、苯甲酰芍药苷、异甘草素和芒柄花素16种化学成分被定量分析。
第二章阿魏酸和水合橙皮内酯在功能性消化不良病人口服柴胡疏肝散汤剂后血浆中的定性分析
通过研究阿魏酸和水合橙皮内酯主要色谱峰的质谱特征,功能性消化不良病人口服柴胡疏肝散汤剂后血浆中阿魏酸和水合橙皮内酯被成功检出。
第三章柴胡疏肝散及其成分阿魏酸和水合橙皮内酯促胃肠动力作用研究
与鼠空白对照组相比,柴胡疏肝散汤剂(20 g/kg),阿魏酸(100mg/kg)和水合橙皮内酯(14,28 mg/kg)能明显增加大鼠的胃排空率和肠推进率,P<0.05。、与大鼠空白肠相比,阿魏酸(100μmol/L)和水合橙皮内酯(10μmol/L)能明显增加大鼠空肠纵行肌和横行肌肉的收缩,P<0.05,水合橙皮内酯(30,100μmol/L)能显著增加大鼠空肠纵行肌和横行肌肉的收缩,P<0.01.
第四章功能性消化不良病人口服柴胡疏肝散后吸收入血的阿魏酸和水合橙皮内酯药物动力学研究
功能性消化不良患者(7名)口服柴胡疏肝散汤剂后,血浆中阿魏酸与水合橙皮内酯被检测。在色谱图上两种化合物分离完全,未出现其他物质干扰峰,保留时间分别为6.5 min和15.7min,内标磺胺甲嗯唑为8.0 min。阿魏酸与水合橙皮内酯的回收率分别为95.35%-102.56%和95.58%～102.09%,相对标准偏差(relative standard deviation, RSD)分别小于2.81%和3.86%。用空白血清加标准品绘制标准曲线,阿魏酸线性范围为10～320 ng/ml,信噪比为3时最低检测线为1.5 ng/ml,最低检测浓度为5 ng/ml;水合橙皮内酯范围为7.5～720ng/mL,最低检测线为2.5ng/mL,最低检测浓度7.5 ng/mL。阿魏酸与水合橙皮内酯在功能性消化不良病人体内的代谢过程被拟合为二室模型,阿魏酸与水合橙皮内酯分别在27.50 mmin和23.57 min时达到最大血药浓度0.199 mg/L和0.371 mg/L,阿魏酸的消除半衰期和AUC分别为131.27min和14.83μg·min/mL,水合橙皮内酯的消除半衰期和AUC分别为139.53 min和31.445μg·min/mL
结论：
(1)用超高效液相色谱-光电二极管阵列(UPLC-PDA)法检测柴胡疏肝散中主要有效成分快速灵敏,准确可靠、稳定且重现性好。此方法可成功用于同时检测柴胡疏肝散汤剂中16种目标成分的含量。
(2)功能性消化不良病人口服柴胡疏肝散后血浆中阿魏酸和水合橙皮内酯被的LC-MS法成功分离和定性。
(3)柴胡疏肝散及体内吸收成分阿魏酸和水合橙皮内酯均有明显促胃肠动力的作用,阿魏酸和水合橙皮内酯是柴胡疏肝散治疗功能性消化不良的主要物质基础。
(4)采用超高效液相色谱法对功能性消化不良病人服用柴胡疏肝散后血浆中的阿魏酸和水合橙皮内酯进行同步测定。柴胡疏肝散及其促胃肠动力成分阿魏酸和水合橙皮内酯的药物动力学研究将有助于监测该方的临床应用以及理解其治疗机理。
Background and objective:Functional dyspepsia is a syndrome defined by chronic or recurrent upper abdominal symptoms without any organic or biochemical abnormality. The clinical symptoms often include upper abdominal pain, upper abdominal fullness, early satiety, belching, losing of appetite, nausea, vomiting and other symptoms of upper abdominal discomfort. Chaihu-Shugan-San (CSS) is a popular traditional Chinese medicine formula to treat functional dyspepsia. It is widely accepted that the combined effect of multiple constituents of traditional Chinese medicine formula is considered to be crucial for treating diseases in clinical practice. The objective of the study are as follows:①To develop a simple, rapid and sensitive Ultra performance liquid chromatography coupled with photodiode array (UPLC-PDA) detection method for simultaneous determination of sixteen compounds in Chaihu-Shugan-San:gallic acid, oxypaeoniflora, albiflorin, paeoniflorin, liquiritin, ferulic acid (FA), narirutin, naringin, hesperidin, neohesperidin, meranzin hydrate (MH), liquiritigenin, quercimelin, benzoylpaeoniflorin, isoliquiritigenin, formononetin.②To develop a liquid chromatography-tandem mass spectrometry (LC-MS) method for the determination of FA and MH in plasmas of patients with functional dyspepsia after oral administration of Chaihu-Shugan-San decoction.③To investigated the effect of CSS, FA and MH on gastrointestinal motility in rats, partly elucidate the effective substance of CSS treating functional dyspepsia.④To develop a Ultra performance liquid churomatography coupled with photodiode array (UPLC-PDA) detection method to explore the pharmacokinetics of FA and MH in plasmas of patients with functional dyspepsia after oral administration of CSS decoction.
Method:
Part 1 The quantitative analysis of the sixteen active constituents in CSS
The analysis was performance on UPLC-PDA system with BEH C18 column (100×2.1 mm id,1.7μM). The mobile phase comprising acetonitrile (A) and 0.5% acetic acid (B) was used to elute the targets in gradient elution mode. Flow rate and detection wavelength were set at 0.5ml/min and 284nm. The sixteen constituents in CSS including gallic acid, oxypaeoniflorin, albiflorin, paeoniflorin, liquiritin, FA, narirutin, naringin, hesperidin, neohesperidin, MH, liquiritigenin, quercimelin, benzoylpaeoniflorin, isoliquiritigenin and formononetin were quantitative determinate, and the limit of determination (LOD), precision, recovery, sample stability and reproducibility of the sixteen constituents were examined in this study.
Part 2 The qualitative analysis of FA and MH in the plasma of patients with functional dyspepsia after oral administration of CSS.
The patients with functional dyspepsia were recuited and the plasmas were collected from the patients after oral administration of CSS. The plasma samples were precipitated with methanol. FA and MH were determined by LC-MS. Electrospray ionization (ESI) source was applied and operated in the positive ion mode. Selected reaction monitoring (SRM) mode with the transition of m/z 194.8-m/z 177.0 and m/z 261.1-m/z243.0 were used to detect FA and MH. Waters Xterra C18 column (150 mm×2.1 mm,5μm) was used in the experiment. The column temperature was set at 40℃.10 mmol·L-1 ammonium formate-acetonitrile (40:60, v/v) was used as mobile phase and the flow rate was 0.2mL·min-1 The sample room temperature was set at 5℃and the injection volume was 20μL.
Part 3 The effects of CSS, FA and MH on promoting gastrointestinal motility.
Gastric emptying (GE) and intestinal transit (IT) were used to study the effects of CSS, FA and MH on promoting gastrointestinal motility in vivo in rat. The intestinal muscle strips test in vitro was used to investigate the effects of FA and MH on Intestinal contraction.
Part 4 The pharmacokinetics of FA and MH in plasmas of patients with functional dyspepsia after oral administration of CSS decoction.
A total of 7 patients with functional dyspepsia were recruited in this study. The plasma samples were preprocessed by protein precipitation method. The UPLC system was used to determine the contents of FA and MH in the blood samples of 7 volunteers with functional dyspepsia, and the blood was collected through the vein at 5,10,15,30,45,60,90, 120,180,240,300,360,480 min. The dates of plasma concentration-time were fitted by using the 3P97 analytical program of pharmacokinetics. The internal standard (IS) was sulfamethoxazole. The detection wavelengths of FA and MH were set at 321 nm and 324 nm respectively.
Result:
Part1
(1) A simple, rapid and sensitive Ultra performance liquid chromatography coupled with photodiode array (UPLC-PDA) detection method was established for the simultaneous determination of sixteen compounds in CSS. The 16 marker constituents were sufficiently separated successfully in less than 17.5 min. There were no interference peaks in the vicinity of the target compounds in the chromatograms of CSS decoction. All calibration curves showed good linear regression (r2> 0.9992) within test ranges of the sixteen targets. The relative standard deviations (RSD) of intra-and inter-day precision were from 1.87% to 5.61% indicating good precision. The average recoveries of investigated sixteen targets ranged from 96.13% to 102.46%, with RSD values<6.74%, showing good recoveries. The sample of CSS decoction has good stability in 24 h, with RSD values from 0.78% to 2.98%. The RSD of the sixteen components in the reproducibility test fluctuates between 1.94% and 5.36%, indicating good reproducibility.
(2) Quantitative determination of the sixteen marker constituents in CSS decoction was made by UPLC-PDA system.
Part 2
According to the mass spectrometry analysis of main chromatogram peaks, FA and MH were successfully detected in the plasmas of patients with functional dyspepsia after oral administration of CSS.
Part 3
Compared with the control group, CSS (20g/kg), FA (100 mg/kg) and MH (14,28 mg/kg) significantly increase the rate of GE and IT in rats (P<0.05) FA (100μmol/L) and MH (10μmol/L) increased the mean amplitude of contraction in the longitudinal and circular strip compared with untreated controls (P<0.05). in addition, MH (30,100μmol/L) increased the mean amplitude of contraction in the longitudinal and circular strip compared with untreated controls (P<0.01)
Part 4
After oral administration of CSS, FA and MH were separated completely in the plasma of patients with functional dyspepsia and no other interfering peaks were found in the spectrum of the chromatograms. The retention times of FA and MH were 6.5 and 15.7 min, and that of sulfamethoxazole was 8,0 min. The recovery rates of FA and MH were from 95.35% to 102.56% with RSD< 2.81% and from 95.58% to102.09% with RSD<3.86%, respectively. The calibration curve for FA was linear over the concentration range from 10 to 320 ng/ml. The low detection limit of FA based on a signal-to-noise ratio of 3 was 1.5 ng/mL and the low concentration limit was 4.5 ng/ml. The calibration curve for MH was linear over the concentration range from 7.5 to 720 ng/mL. The low detection limit was 2.5 ng/mL and the low concentration limit was 7.5 ng/mL. The pharmacokinetics of FA and MH in patient plasma was fitted with a two-compartment model. Time to reach peak concentration of FA (0.199 mg/L) and MH (0.371 mg/L) was 27.50 min and 23.57 min, respectively. The elimination half-life and area under the concentration-time curve from t= 0 to the last time of FA and MH were 131.27 min and 14.835μg·min/mL and 139.53 min and 31.445μg·min/mL, respectively.
Conclusion:
1. A rapid, sensitive, and reliable UPLC-PDA method for the simultaneous determination of sixteen compounds in CSS was developed. The method was validated for specificity, accuracy, precision, and limits of detection and was successfully applied to determine the contents of sixteen components in CSS.
2. LC-MS is a convenient, rapid and effective method to separate and quality FA and MH in plasmas of patients with functional dyspepsia after oral administration of CSS.
3. CSS and its absorbed compound FA and MH have the significant effect on promoting gastrointestinal motility in rats. FA and MH are the effective substance of CSS to treat functional dyspepsia.
4. FA and MH in the plasmas of patients with functional dyspepsia were simultaneously determined by the UPLC method after oral administration of CSS. The pharmacokinetics of prokinetic CSS and its compounds are useful for monitoring CSS formulas in clinical practice and for understanding therapeutic mechanisms.
引文
[1]Wong SM, Chiu PY, Leung HY, et al. Myocardial post-conditioning with Danshen-Gegen decoction protects against isoproterenol induced myocardial injury via a PKCε/mKATP-mediated pathway in rats. Chin Med,2011,6(1):7-13.
[2]Lu J, Wang JS, Kong LY. Anti-inflammatory effects of Huang-Lian-Jie-Du decoction, its two fractions and four typical compounds. J Ethnopharmacol,2011, 134 (3):911-918.
[3]Wang Z, Xie S Z. The overview of the chemical composition and pharmaco-dynamics about the Compatible Granules and tradition prepared drug in pieces. Strait Pharmaceutical Journal.2004,16:78-90.
[4]Xue T. Roy R. Studying Traditional Chinese Medicine, Science.2003,300: 740-741.
[5]Ye G, Tang YH, Wang GY, et al. Characterization of the multiple absorbed constituents in rats after oral administration of Chai-Huang decoction by liquid chromatography coupled with electrospray-ionization mass spectrometry. Chem Biodivers.2010,7 (12):2917-2930.
[6]谭莲蓉.百优解加柴胡疏肝散治疗脑卒中后抑郁症疗效观察[J].中西医结合心脑血管杂志,2005,3(2)：182-183.
[7]关晓光,安春平,侣雪平.柴胡疏肝散加减治疗抑郁症30例临床观察[J].中国中医药科技,2007,14(5)：330-332.
[8]吴宇金,李振宇.柴胡疏肝散治疗功能性消化不良餐后不适综合征临床研究[J].湖北中医杂志,2009,31(7)：14-15.
[9]贺先波.柴胡疏肝散治疗功能性消化不良118例[J].山东中医杂志,2006,25(7)：460-461.
[10]Takai K, Shibenito PB, Abad MJ, et al. In vivo and in vitro anti-flammatory activity of saikosaponins. Life Sci,1998,63 (13):1147-1156.
[11]Nakamura T, Kuriyama M, Kosuge E. Effect of saiboku to (TJ296) on the production of platelet activating factor in human neutrophils. Ann N Y Acad Sci, 1993,685 (2):572-579.
[12]欧润妹,邓远辉,李伟英,等.香附不同溶剂提取物解热镇痛效应的比较[J].山东中医杂志,2004,23(12)：740-742.
[13]Sue YM, Cheng CF, Chang CC,et al. Nephrol Dial Transplant. Antioxidation and anti-inflammation by haem oxygenase-1 contribute to protection by tetrameth-ylpyrazine against gentamicin-induced apoptosis in murine renal tubular cells.2009, 24(3):769-777.
[14]高崇凯,吴雁,王勇等,白芍总苷粉针剂的抗炎镇痛作用[J].中国新药药理与临床药理,2002,13(3)：163-165.
[15]杨小军,李建军,轩原清史.白芍总甙对豚鼠结肠平滑肌作用机制的研究[J].中国中西医结合消化杂志,2002,10(3)：151-153.
[16]官福兰,王如俊,王建华.枳壳及辛弗林对小鼠胃排空和小肠推进功能的影响[J].现代中西医结合杂志,2002,11(11)：1001-1003.
[17]李伟,郑天珍,瞿颂义.陈皮对小鼠胃排空及肠推进影响[J].中药药理与临床,2002,18(2)：22-23.
[18]官福兰,王汝俊,王建华.陈皮及橙皮苷对离体肠管运动影响[J].时珍国医国药,2002,13(2)：65-67.
[19]杨春花.甘草药理活性的研究[J].长春医学,2008,6,(2)：10-12.
[20]Chen G,Zhu LX,Liu Y,et al. Isoliquiritigenin,a Flavonoid from Licorice, plays a Dual Role in regulating Gastrointestinal Motility in vitro and in vivo. Phytother Res, 2009,23:498-506.
[21]Badary OA, Awad AS, Sherief MA, et al. In vitro and in vivo effects of ferulic acid on gastrointestinal motility:Inhibition of cisplatin-induced delay in gastric empt-ying in rats. World J Gastroenterol,2006,12:5363-5367.
[22]Takeda H, Sadakane C, Hattori T, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology, 2008,134(7):2004-13.
[23]Polewski K, Kniat S, Slawinska D.Gallic acid, a natural antioxidant, in aqueous and micellar environment:spectroscopic studies.Current Topic in Biophysics,2002,26: 217-227.
[24]Zhao Z, Wang W, Guo H, et al.Antidepressant-like effect of liquiritin from Glycyrrhiza uralensis in chronic variable stress induced depression model rats, Behav Brain Res.2008,1:108-113.
[25]Aggarwal A, Gaur V, Kumar A. Nitric oxide mechanism in the protective effect of naringin against post-stroke depression (PSD) in mice.Life Sci.2010,25:928-935.
[26]Guan F L, WANG L J, WANG JH. The effect of Pericarpium Citri Reticulatae and hesperidin on gastric emptying and Intestinal transit in rat. Pharmacology and Clinics of Chinese Materia Medica,2002,3:7-9.
[27]Martin M J, Marhuenda E, Perez-Guerrero C, et al. Antiulcer effect of naringin on gastric lesions induced by ethanol in rats, Pharmacology.1994,3:144-150.
[28]Lee JH, Lee SH, Kim YS, et al. Protective effects of neohesperidin and poncirin isolated from the fruits of Poncirus trifoliata on potential gastric disease, Phytother Res.2009,12:1748-1753.
[29]Jiang WL, Chen XG, Zhu HB, et al. Paeoniflorin inhibits systemic inflammation and improves survival in experimental sepsis, Basic Clin Pharmacol Toxicol.2009, 1:64-71.
[30]Benavente-Garcia O, Castillo J. Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity, J Agric Food Chem.2008,15:6185-6205.
[31]Kim YW, Zhao RJ, Park SJ, et al. Anti-inflammatory effects of liquiritigenin as a consequence of the inhibition of NF-kappaB-dependent iNOS and proinflammatory cytokines production, Br J Pharmacol.2008,1:165-173.
[32]Lee KW, Kang NJ, Heo YS, et al. Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine, Cancer Res.2008,68:946-955.
[33]Heo HJ, Kim DO, Shin SC,et al. Effect of antioxidant flavanone, naringenin, from Citrus junoson neuroprotection, J Agric Food Chem.2004,6:1520-1525.
[34]Hirata A,Murakami Y, Shoji M, et al. Kinetics of radical-scavenging activity of hesperetin and hesperidin and their inhibitory activity on COX-2 expression, Anticancer Res.2005,5:3367-3374.
[35]Kumar A, Dogra S, Prakash A. Protective effect of naringin, a citrus flavonoid, against colchicine-induced cognitive dysfunction and oxidative damage in rats, J Med Food.2010,4:976-984.
[36]Sheu MJ, Chou PY, Cheng HC, et al. Analgesic and anti-inflammatory activities of a water extract of Trachelospermum jasminoides (Apocynaceae), J Ethnopharma-col.2009,126:332-338.
[37]Sugiyama K, Muteki T, Kano T.The Japanese herbal medicine saiko-keishi-to'activates GABAA receptors of rat sensory neurons inculture. Neuroscience Letters,1996,216(3):147-150.
[38]Kim Sun-Hee, Han Jin, Seog Dae-Hyun,et al. Antidepressant effect of Chaihu-Shugan-San extract and its constituents in rat models of depression. Life Sciences,2005,76:1297-1306.
[39]Mao QQ, Huang Z, Ip SP, et al. Antidepressant-like effect of ethanol extract from Paeonia lactiflora in mice. Phytotherapy Research,2008,22:1496-1499.
[40]Mao QQ, Ip SP, Ko KM, et al. Effects of peony glycosides on mice exposed to chronic unpredictable stress:Further evidence for antidepressant-like activity. Journal of Ethnopharmacology,2009,124:316-320.
[41]Mao QQ, Ip SP, Ko KM, et al. Peony glycosides produce antidepressant-like action in mice exposed to chronic unpredictable mild stress:Effects on hypothalamic-pituitary-adrenal function and brain-derived neurotrophic factor. Progress in Neuro-Psychopharmacology & Biological Psychiatry,2009,33:1211-1216.
[42]Mao QQ, Xiana YF, Ip SP,et al. Long-term treatment with peony glycosides reverses chronic unpredictable mild stress-induced depressive-like behavior via increasing expression of neurotrophins in rat brain. Behavioural Brain Research. 2010,210 (2):171-177.
[43]Wei XH, Cheng XM, Shen JS, et al. Antidepressant effect of Yueju-Wan ethanol extract and its fractions in mice models of despair. Journal of Ethnopharmacology, 2008,117:339-344.
[44]Zhao ZY,Wang WX,Guo HZ,et al.Anti-depressive effect of liquiritin on chronic stress depression in rats.Chin J Clin Rehabil,2006,27:69-72.
[45]Wang Weixing, Hu Xinying, Zhao Zhiyu, et al. Antidepressant-like effects of liquiritin and isoliquiritin from Glycyrrhiza uralensis in the forced swimming test and tail suspension test in mice.Progress in Neuro-Psychopharmacology & Biological Psychiatry,2008,32:1179-1184.
[46]Shigeo T, Yukio K, Mamoru T. Isolation of monoamine oxidase inhibitors from Glycyrrhiza glabra roots and the structure-activity relationship.Planta Med,1987,53: 5-8.
[47]Ainsah O, Nabishah BM, Osman CB, et al. Effects of naloxone,glycyrrhizic Acid,dexamethasone and deoxycorticosterone in repetitive stress.Clinical and Experiment-al Pharmacology and Physiology,1999,26:433-437.
[48]Zhu KY, Fu Q, Xie HQ, et al. Quality assessment of a formulated Chinese herbal decoction, Kaixinsan, by using rapid resolution liquid chromatography coupled with mass spectrometry:A chemical evaluation of different historical formulae.J Sep Sci. 2010,33(23-24):3666-3674.
[49]Guillarme D,Nguyen DT, Rudaz S, et al. Recent developments in liquid chromatography-impact on qualitative and quantitative performance, J Chromatogr A.2007,1149:20-29.
[50]Rathore AS, Parr L, Dermawan S, et al. Large scale demonstration of a process analytical technology application in bioprocessing:use of on-line high performance liquid chromatography for making real time pooling decisions for process chromatography, Biotechnol Prog.2010,26:448-457.
[51]代雪平,宋汉敏,李振国HPLC法测定不同产地芦根中阿魏酸的含量[J].中医研究,2010,23(9)：26-27
[52]胡建煜,梁煜霞.不同产地白芍中芍药苷含量比较[J].临京医学工程,2009,16(2)：89-90.
[53]Tack J, Talley NJ, Camiileri M, et al. Functional Gistroduodenal Disorders. In: Drossman DA, eds. In Rome:the functional gastrointestinal disorders,2006, 419-486.
[54]中华医学会消化病学分会胃肠动力学组.我国消化不良的诊治流程和指南.胃肠病学,2000,5(3)：141-142.
[55]陈曼湖,钟碧慧,李初俊,等.广东城镇居民消化不良的流行病学调查[J].中华内科杂志,1998,37：312-314.
[56]Malfertheiner P. Current concepts in dyspepsia:a World perspective. Eur J Gastro-enterol Hepatol,1999,11(1):25-29.
[57]Malagelada JR. Functinal dyspepsia. Insyghts on mechanisms and management strategies. Gastroenterol Clin North Am,1996,25(1):103-112.
[58]Tack J, Caenepeel P, Arts J, et al. Prevalence of acid reflux in functional dyspepsia and its association with symptom profile. Gut,2005,54(10):1370-1376.
[59]Blackshaw LA, Brookes SJ, Grundy D, et al. Sensory transmission in the gastrointestinal tract. Neurogastroenterol Motil,2007,19(1):1-19.
[60]Fock KM. Functional dyspepsia, H. pylori and post infectious FD. J Gastroenterol Hepatol,2011, (1)3:39-41.
[61]Khoo J, Rayner CK, Feinle-Bisset C, et al. Gastrointestinal hormonal dysfunction in gastroparesis and functional dyspepsia. Neurogastroenterol Motil.2010,22(12): 1270-1278.
[62]Chen TS, Luo JC, Chang FY. Psychosocial-spiritual factors in patients with functional dyspepsia:a comparative study with normal individuals having the same endoscopic features. Eur J Gastroenterol Hepatol,2010,22(1):75-80.
[63]Berstad A, Hausken T, Gilja OH, et al. ultrasonography of the human stomach.J Scand J Gastroenterol,1996,220:75-82.
[64]Erstad BL. Dyspepsia:initial evaluation and treatment. J Am Pharm Assoc (Wash), 2002,42(3):460-468.
[65]Sanaka M, Yamamoto T, Kuyama Y. Effects of proton pump inhibitors on gastric emptying:a systematic review. Dig Dis Sci,2010,55(9):2431-2440.
[66]Kandulski A, Venerito M, Malfertheiner P. Therapeutic strategies for the treatment of dyspepsia. Expert Opin Pharmacother,2010,11(15):2517-2525.
[67]Talley NJ, Herrick L, Locke GR. Antidepressants in functional dyspepsia. Expert Rev Gastroenterol Hepatol,2010,4(1):5-8.
[68]张声生,汪红兵,李乾构.功能性消化不良中医诊疗规范(草案)[J].中国中西医结合消化杂志,2002,12(6)：381-383.
[69]胡仲纯,柴胡疏肝散的临床应用.[J]现代中西医结合杂志,2008,17(18)：2909-2911.
[70]郑秀英,赵金风,温玉平.四逆散加味治疗功能性消化不良疗效观察[J].时珍国医国药,2007,18(8)：1928-1929.
[71]任平,黄熙,李双庆,等.逍遥散加味治疗肝郁脾虚型功能性消化不良56例[J]．中国中西医结合杂志,2006,26(5)：398-402.
[72]肖丽玲.加味香砂六君子汤合西沙必利治疗功能性消化不良的临床观察[J].湖南中医学院学报,2005,25(2)：41-42.
[73]李新生.保和丸加减治疗功能性消化不良临床研究[J].中医学报,2010,25(159)：965-966.
[74]胡雄丽,朱迪,周虹,等.半夏泻心汤治疗寒热错杂型功能性消化不良的临床研究[J].湖南中医学院学报,2006,26(1)：40-41.
[75]王海峰,张景,王京奇.柴胡疏肝散加味治疗功能性消化不良临床观察[J].北京中医药,2010,29(10)：781-782.
[76]张光异.柴胡疏肝散加味治疗功能性消化不良临床研究[J].长春中医药大学学报,2010,26(3)：381-382.
[77]黄熙,范荣,张海男.生物方剂分析药理：阐明方剂吸收生物活性成分的研究策略[J].中草药,2010,41(3)：337-339.
[78]Tistaert C, Dejaegher B, Heyden YV. Chromatographic separation techniques and data handling methods for herbal fingerprints:A review. Anal Chim Acta,2011, 690(2):148-161.
[79]Sabzevari O, Abdi Kh, Amini M, et al. Application of a simple and sensitive GC-MS method for determination of morphine in the hair of opium abusers. Anal Bioanal Chem,2004,379(1):120-124.
[80]Srinivas NR, Mullangi R. An overview of various validated HPLC and LC-MS/MS methods for quantitation of drugs in bile:challenges and considerations. Biomed Chromatogr,2011,25(1-2):65-81.
[81]Akira K, Mitome H, Imachi M, et al. NMR identification of a novel taurine-related metabolite observed in (1)H NMR-based metabonomics of genetically hypertensive rats. J Pharm Biomed Anal,2010,51(5):1091-1096.
[82]Douglas A, Drossm an R. The functiona lgastroin testinal disorders and the Rome process. Gastroenterology,2006,130:1377-1390.
[83]李茂玲.柴胡疏肝散应用举隅[J].实用中医药杂志,2010,26(10)：718-719.
[84]徐艳.柴胡疏肝散治疗功能性消化不良[J].中国实用医药,2010,5(22)：116-117.
[85]Steinmann D, Ganzera M. Recent advances on HPLC/MS in medicinal plant analysis. J Pharm Biomed Anal,2010,1-14.
[86]Jiang Y, David B, Tu P, Barbin Y. Recent analytical approaches in quality control of traditional Chinese medicines--a review. Anal Chim Acta,2010,657(1):9-18.
[87]张尊建,余静,杨春华,等.忍冬、山银花HPLC/UV/MS指纹图谱研究[J].中成药,2003,25(11)：863-865.
[88]Yang M, Sun J, Lu Z, et al. Phytochemical analysis of traditional Chinese medicine using liquid chromatography coupled with mass spectrometry. J Chromatogr A, 2009,1216(11):2045-2062.
[89]Qin F, Huang X, Zhang HM,et al. Pharmacokinetic comparison of puerarin after oral administration of Jiawei-Xiaoyao-San to healthy volunteers and patients with functional dyspepsia:influence of disease state. Journal of pharmacy and pharmacology,2009,61:1-5
[90]夏东亚,郭涛,潘文灏,等HPLC法测定心舒口服液中阿魏酸血浆浓度及其在大鼠体内的药动学研究[J].中草药,2004,35(1)：36-38.
[91]Li Y, Bi K. HPLC determination of ferulic acid in rat plasma after oral administration of Rhizoma Chuanxiong and its compound preparation. Biomedical chromatography,2003,17(8):543-546.
[92]王定康.半夏泻心汤治疗功能性消化不良85例[J].实用中医药杂志,2002,18(11)：16-17.
[93]王伟.参苓白术散治疗功能性消化不良80例[J].陕西中医,2007,28(1)：36-38.
[94]应瑛,何钦,徐斌.加味百合汤治疗功能性消化不良的临床观察[J].浙江中医药大学学报2007,31(6)：712-713.
[95]麦志广,陈翠环.消痞汤治疗功能性消化不良112例疗效观察[J].中国中医急症,2007,16(11)：1330-1340.
[96]陈廷卓,刘慧君.消食健脾汤治疗功能性消化不良78例[J].中外医疗,2010,35：122.
[97]许忠康.柴胡疏肝散治疗功能性消化不良66例[J].光明中医,2010,3(25)：442-443.
[98]宫照东.柴胡疏肝散加减治疗功能性消化不良86例临床观察[J].医学信息,2010,06(23)：1885.
[99]王捷虹,成凯,杜晓泉.柴胡疏肝散加味治疗动力障碍型功能性消化不良40例[J].现代中医药,2005,4(25)：23-24.
[100]Carachi R.Gastrointestinal motility disorders. Semin Pediatr Surg,2009,18(4): 193-195.
[101]Di Lorenzo C, Youssef NN. Diagnosis and management of intestinal motility disorders. Semin Pediatr Surg,2010,19(1):50-58.
[102]Torjman MC, Joseph JI, Munsick C, et al. Effects of isoflurane on gastrointestinal motility after brief exposure in rats. Int J Pharm,2005,294(1-2):65-71.
[103]Jeong SI, Kim YS, Lee MY, et al. Regulation of contractile activity by magnolol in the rat isolated gastrointestinal tracts. Pharmacol Res,2009,59(3):183-188.
[104]Perboni S, Inui A. Appetite and gastrointestinal motility:role of ghrelin-family peptides. Clin Nutr,2010,29(2):227-234.
[105]Mimaki H, Kawauchi S, Kagawa S, et al. Bicarbonate stimulatory action of nizatidine, a histamine H(2)-receptor antagonist, in rat duodenums.J Physiol Paris, 2001,95(1-6):165-171.
[106]唐文富,陈光远,黄熙.方剂代谢物组学新假说[J].中草药,2007,38(6)：801-803.
[107]黄熙.方剂体内/血清成分谱与靶成分概念的提出与意义[J].第四军医大学学报,1999,20(4)：277-279.
[108]Wang B, Ouyang J, Liu Y, et al. Sodium ferulate inhibits atherosclerogenesis in hyperlipidemia rabbits. J Cardiovasc Pharmacol.2004,43(4):549-554.
[109]Ma ZC, Hong Q, Wang YG, et al. Ferulic acid protects lymphocytes from radiation-predisposed oxidative stress through extracellular regulated kinase. Int J RadiatBiol.2011,87(2):130-140.
[110]M aurya DK, Nair CK. Preferential rad ioprotection to DNA of normal tissues by ferulic acid under exvivo and invivo conditions in tumor bearing mice. Mol Cell Biochem,2006,285:181-190.
[111]Jayap rakasam B, Van isreeM, Zhang Y, et al. Impact of alkyl esters of caffeic and ferulic acids on tumor cell proliferation, cyclo oxygenase enzym e, and lipid per oxidation. J Agric Food Chem,2006,54(15):5375-5381.
[112]Janicke B, Onning G, Oredsson SM. Differential effects of ferulic acid and p-coumaric acid on S phase distribution and length of S phase in the human colonic cell line Caco-2. J A gric Food Chem,2005,53 (17):6658-6665
[113]Badary OA, Awad AS, Sherief MA, et al. In vitro and in vivo effects of ferulic acid on gastrointestinal motility:inhibition of cisplatin-induced delay in gastric emptying in rats. World J Gastroenterol,2006,12(33):5363-5367.
[114]Pinkel, D.,1958. The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Research 18,853-856.
[115]聂琼芳.小柴胡汤加减治疗功能性消化不良38例临床观察[J].时珍国医国药,2005,16(5)：410.
[116]沈玉棠,彭丽园.逍遥散治疗功能性消化不良45例疗效观察[J].浙江中西医结合杂志,2010,20(10)：624.
[117]余江平.柴胡疏肝散治疗功能性消化不良48例观察[J].实用中医药杂志,2007,7(23)：431.
[118]赵民,齐金刚.四逆散加减治疗功能性消化不良疗效观察[J].辽宁中医杂志,2007,34(5)：599.
[119]陈明.解肝煎治疗慢性胃炎的临床观察[J].北京中医,1998,2：25-26.
[120]彭成,张磊,张利,等.四逆散治疗功能性消化不良的实验研究[J].成都中医药大学学报,1999,22(1)：39-41.
[121]黄熙,陈可冀,任平.“复方效应成分动力学”新假说的科学证据、要素、意义及前景[J].中国中药杂志,1997,22(4)：250-252.
[122]寺泽捷年.戴慧馨摘译.甘草次酸体内代谢研究Ⅱ-大鼠体内代谢[J].国外医学,中医中药分册,1987,9(2)：31.
[123]Levy G, Gibaldi M. Pharmacokinetics of drug action. Annu Rev Pharmacol, 1972,12:85-98.
[124]任平,黄熙,方剂药动学研究策略[J].山东中医药大学学报,2001,25(1)：66-68.
[125]Ma Z, Wu Q, Lee DY, et al. Determination of puerarin in human plasma by high performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci,2005,5(2):108-114.
[126]Smolen VF, Theophanous TG, Theophanous TG. Relation-ship between dose, effect, time and biophasic drug levels. Journal of Pharmaceutical Sciences,1972,61(3): 467-470.
[127]赵智强,俞晶华,陆跃呜,等.天麻钩藤饮等三方对小鼠镇痛作用的药物动力学研究[J].中国药理与临床,1999,15(3)：13-14.
[128]王尧先,赫梅先.用动物急性死亡法估测4种中成药的药动学参数[J].中成药,1991,13(5)：24-26.
[129]潘嘉,王家葵,邹文俊,等.抑菌效应法测定川芎挥发油药动学参数[J].中药药理与临床,2002,18(4)：18-19.
[130]黄熙.生物方剂分析中医药学研究的设想、背景与意义[J].中国中西医结合杂志,2002,22(4)：251-252.
[131]Li Y, Liang X, Xiao H, et al. Determination of spinosin in rat plasma by reversed-phase high-performance chromatography after oral administration ofSuanzaoren decoction. J Chromatogr B Analyt Technol Biomed Life Sci, 2003,787 (2):421-425.
[132]Li X, Li X,Wang L, et al. Simultaneous determination of danshensu, ferulic acid, cryptotanshinone and tanshinone IIA in rabbit plasma by HPLC and their pharmacokinetic application in dan xiong fang. Journal of Pharmaceutical and Biomedical Analysis,2007,44(5):1106-1112.
[133]Zafra-Gomez, A., Luzon-Toro, B., Jimenez-Diaz, I., et al. Quantification of phenolic antioxidants in rat cerebrospinal fluid by GC-MS after oral administration of compounds.Journal of Pharmaceutical and Biomedical Analysis,2010,53 (1):103-108.
[134]Li, Y., Bi, K. HPLC determination of ferulic acid in rat plasma after oral administration of Rhizoma Chuanxiong and its compound preparation. Biomedical chromatography,2003,17(8):543-546.
[135]Xu, M., Fu, G., Qiao, X.,et al. HPLC method for comparative study on tissue distribution in rat after oral administration of salvianolic acid B and phenolic acids from Salvia miltiorrhiza. Biomedical chromatography,2007,21(10):1052-1063.
[136]Qi J, Jin X, Huang L,et al. Simultaneous determination of hydroxysafflor yell-ow A and ferulic acid in rat plasma after oral administration of the co-extractum of Rhizoma chuanxiong and Flos Carthami by HPLC-diode array detector. Biomed Chromatogr,2007,21(8):816-822.
[137]何跃生,袁玲,曲树明.HPLC法测定阿魏酸钠在Beagle犬体内血浆浓度及药动学研究[J].天津医药,2007,35(9)：687-689.
[138]甘洪全,梅其炳,朱伟,等.健康志愿者口服冠心Ⅱ号煎剂后血清中阿魏酸的药动学研究[J].中国药方,2007,18(2)：109-111.
[139]Ventresca GP, Mariani L. Disease states and changes in drugpharmacokinetics. Clin Ter,1996,147:131-144.
[1]Park YJ, Kim HS, Kang HC, et al. A survey of Hwa-Byung in middle-age Korean women. Journal of Transcultural Nursing,2001,12(2):115-122
[2]王永炎,李明复,戴锡盟.《中医内科学》.上海科学技术出版社.2007.
[3]刘新光.功能性消化性不良与胃动力异常[J].中华消化杂志.2002,22(1)：44-45
[4]Thumshirn M. Pathophysiology of functional dyspepsia. Gut.2002,51:63-66
[5]谢稚晖.柴胡疏肝散加减治疗功能性消化不良42例[J].福建中医药.2007,38(5)：24-25.
[6]许忠康.柴胡疏肝散治疗功能性消化不良66例[J].光明中医.2010,3(25)：442-443
[7]冯卫,邱启霞.柴胡疏肝散加减治疗慢性消化不良症89例[J].河南中医.2008,28(4)：64-65
[8]王稹,钱屹.柴胡疏肝散加减从肝论治慢性消化不良症79例[J].现代中西医结合杂志.2005,14(23)：3117-3118
[9]贺先波.柴胡疏肝散治疗功能性消化不良118例[J].山东中医杂志.2006,7(25)：460-462
[10]宫照东.柴胡疏肝散加减治疗功能性消化不良86例临床观察[J].医学信息.2010,06(23)：1885-1886
[11]朱卫东.柴胡疏肝散加减治疗功能性消化不良64例[J].中国实用医药.2008,3(7)：79-81
[12]王捷虹,成凯,杜晓泉.察柴胡疏肝散加味治疗动力障碍型功能性消化不良40例[J].现代中医药.2005,4(25)：23-24
[13]余江平.柴胡疏肝散治疗功能性消化不良48例观察[J].实用中医药杂志.2007, 7(23)：431-432
[14]吴宇金,李振宇.柴胡疏肝散治疗功能性消化不良餐后不适综合征临床研究[J].湖北中医杂志.2009,7(31)：14-15
[15]刘纹,范萌,陈言言,周吕.柴胡疏肝散对功能性消化不良肝气郁结证患者胃动力及胃肠激素的影响[J].中医杂志.2010,51(1)：30-33
[16]董昆山,王秀琴,董一凡.现代临床中药学.北京：中国中医药出版社,1998176：292-338
[17]苗玉兰.柴胡疏肝散对实验性肝郁证小鼠胃肠功能的影响[J].国华医学实践杂志.2005(12)：12-13
[18]敖海清,徐志伟,严灿等.柴胡疏肝散及逍遥散对慢性心理应激大鼠血清皮质酮及胃肠激素的影响[J].中药新药与临床药理.2007 18(4)：288-291
[19]陈煜辉,周莺.柴胡疏肝散抗抑郁作用的药理学实验研究[J].江西中医学院学报.2004,16(4)：59-60
[20]朱清静,罗欣拉,熊振芳.柴胡疏肝散对慢性束缚应激性肝郁证大鼠下丘脑-垂体-肾上腺轴的调节作用[J].湖北中医杂志.2003,25(11)：7-8
[21]郑爱华,李家邦,蔡光先等.柴胡疏肝散、四君子汤对肝郁脾虚病人Th细胞分化信号蛋白PKC表达的影响[J].贵阳中医学院学报.2003,25(4)：14-16
[22]郑爱华,蔡光先,李家邦等.柴胡疏肝散、四君子汤对肝郁脾虚病人Th细胞蛋白激酶C表达的影响.湖南中医学院学报.2003,23(6)：15-16
[23]朱金照,冷恩仁,陈东风,等.15味中药促胃肠动力作用的筛选研究[J].第三军医大学学报.2005,22(5)：438-440
[24]骆和生.中药方剂的药理与临床研究进展.广州：华南理工大学出版社,1991,24(52)：346-345
[25]孙军,张宁,李岩.柴胡枳实水提取物对胃肠动力作用的影响[J].世界华人消化杂志.2005,13(12)：1445-1446
[26]李岩,陈苏宁,李宇权等.芍药甘草汤、四逆散对胃排空及小肠推进功能影响的拆方研究[J].中华消化杂志.1996,16(1)：18-21
[27]Kobayashi M, Ueda C, Aoki S. Anticholinergic action of Paeony root and its active constituents. Yakugaku Zasshi.1990,110(12):964-8
[28]徐优晓,苏孝共.枳壳理气作用的临床运用[J].江西中医药.2005,36(269)：57-58
[29]刘孝乐.炮制对枳壳药理作用的影响[J].中成药研究.1987,10：17-19
[30]马亚兵.枳壳的胃肠作用及炮制前后的变化[J].中药药理与临床.1996,2(6)：28-29
[31]陈惠阳.枳壳烟吸入治疗阑尾切除术后肠胀气[J].江苏中医.1993(3)：27-28
[32]官福兰,王如俊,王建华.枳壳及辛弗林对小鼠胃排空、小肠推进功能的影响.现代中西医结合杂志.2002,11(11)：1001-1003
[33]官福兰,王如俊,王建华.枳壳及辛弗林对兔离体小肠运动的影响[J].中药药理与临床.2002,18(2)：9-11
[34]Lee HT, Seo EK, Chung SJ, et al. Prokinetic activity of an aqueous extract from dried immature fruit of Poncirus trifoliata (L.) Raf. Journal of Ethnopharmacology. 2005,102:131-136
[35]Lee HT, Seo EK, Chung SJ, et al. Effect of an aqueous extract of dried immature fruit of Poncirus trifoliate (L.) Raf. On intestinal transit in rodents with experimental gastrointestinal motility dysfunctions. Journa lof Ethnopharmacology. 2005,102:302-306
[36]Choi KH, Jeong SI, Hwang BS, et al. Hexane extract of Poncirus trifoliata (L.) Raf. stimulates the motility of rat distal colon. Journal of Ethnopharmacology.2010, 127:718-724
[37]Lee HT, Seo EK, Chung SJ, et al. Prokinetic activity of an aqueous extract from dried immature fruit of Poncirus trifoliata (L.) Raf. Journal of Ethnopharmacology. 2005,102:131-136
[38]Lee HT, Seo EK, Chung SJ, et al. Effect of an aqueous extract of dried immature fruit of Poncirus trifoliate (L.) Raf. On intestinal transit in rodents with experimental gastrointestinal motility dysfunctions. Journal of Ethnopharmacology.2005,102: 302-306
[39]Keun Han Choi, Seung Il Jeong, Byung Soon Hwang, et al. Hexane extract of Poncirus trifoliata (L.) Raf. stimulates the motility of rat distal colon. Journal of Ethnopharmacology.2010,127:718-724
[40]徐彭.陈皮水提取物和挥发油的药理作用比较[J].江西中医学院学报.1998,10(4)：172-173
[41]中山医学院.药理学.人民卫生出版社,1979,478
[42]官福兰,王如俊,王建华.陈皮及橙皮甙对小鼠胃排空、小肠推进功能的影响[J].中药药理与临床.2002,18(3)：7-8
[43]李伟,郑天珍,瞿颂义等.陈皮对小鼠胃排空及肠推进的影响[J].中药药理与临床.2002,18(2)：22-23
[44]王贺玲,李岩,白菡,张健.理气中药对鼠胃肠动力的影响[J].世界华人消化杂志.2005,(5)：12-13
[45]周秋丽,张志强.柴胡皂苷和甘草甜素抑制Na+-K+-ATP酶活性的构效关系[J].药学学报.1996,31(7)：496-497
[46]韩珍,贺弋.白芍总苷的药理作用及其毒性研究进展[J].宁夏医学院学报.2008,30(4)：538-539
[47]Fang YS, Shan DM, Liu JW. Effect of constituents from Fructus Aurantii Immaturus and Radix Paeoniae Alba on gastrointestinal movement. Planta Med. 2009,75:24-31
[48]Jiang WL, Chen XG, Zhu HB. Paeoniflorin inhibits systemic inflammation and improves survival in experimental sepsis. Basic Clin Pharmacol Toxicol.2009, 105(1):64-71
[49]Asai M, Kawashima D, Katagiri K. Protective effect of a molecular chaperone inducer, paeoniflorin, on the HCl- and ethanol-triggered gastric mucosal injury. Life Sci.2011,14:88(7-8):350-7
[50]Lee JH, Lee SH, Kim YS, Jeong CS. Protective effects of neohesperidin and poncirin isolated from the fruits of Poncirus trifoliata on potential gastric disease. Phytother Res.2009,23(12):1748-53
[51]徐浩.川芎嗪的临床应用和药理作用[J].中国中西医结合杂志.2003,23：5-7
[52]Badary OA, Awad AS, Sherief MA, et al. In vitro and in vivo effects of ferulic acid on gastrointestinal motility:Inhibition of cisplatin-induced delay in gastric empt-ying in rats. World J. Gastroenterol.2006,12:5363-5367
[53]Sudheer AR, Muthukumaran S, Devipriya N, et al. Influence of ferulic acid on nicotine-induced lipid peroxidation, DNA damage and inflammation in experimental rats as compared to N-acetylcysteine. Toxicology.2008,243(3): 317-29
[54]Chen G, Zhu LX, Liu Y, et al. Isoliquiritigenin, a Flavonoid from Licorice, plays a Dual Role in regulating Gastrointestinal Motility in vitro and in vivo. Phytother. Res.2009,23:498-506
[55]Sato YJ, He JX, Nagai H, et al. Isoliquiritigenin, One of the Antispasmodic Principles of Glycyrrhiza Ularensis Roots, Acts in the Lower Part of Intestine. Biol. Pharm. Bull.2007,30(1):145-149
[56]Takeda H, Sadakane C, Hattori T, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology. 2008,134(7):2004-2013
[57]Takeda Y, Ward SM, Sanders KM, Koh SD. Effects of the gap junction blocker glycyrrhetinic acid on gastrointestinal smooth muscle cells. Am J Physiol Gastrointest Liver Physiol.2005,288(4):832-841.
[2]Lu J, Wang JS, Kong LY. Anti-inflammatory effects of Huang-Lian-Jie-Du decoction, its two fractions and four typical compounds. J Ethnopharmacol,2011, 134 (3):911-918.
[3]Wang Z, Xie S Z. The overview of the chemical composition and pharmaco-dynamics about the Compatible Granules and tradition prepared drug in pieces. Strait Pharmaceutical Journal.2004,16:78-90.
[4]Xue T. Roy R. Studying Traditional Chinese Medicine, Science.2003,300: 740-741.
[5]Ye G, Tang YH, Wang GY, et al. Characterization of the multiple absorbed constituents in rats after oral administration of Chai-Huang decoction by liquid chromatography coupled with electrospray-ionization mass spectrometry. Chem Biodivers.2010,7 (12):2917-2930.
[6]谭莲蓉.百优解加柴胡疏肝散治疗脑卒中后抑郁症疗效观察[J].中西医结合心脑血管杂志,2005,3(2)：182-183.
[7]关晓光,安春平,侣雪平.柴胡疏肝散加减治疗抑郁症30例临床观察[J].中国中医药科技,2007,14(5)：330-332.
[8]吴宇金,李振宇.柴胡疏肝散治疗功能性消化不良餐后不适综合征临床研究[J].湖北中医杂志,2009,31(7)：14-15.
[9]贺先波.柴胡疏肝散治疗功能性消化不良118例[J].山东中医杂志,2006,25(7)：460-461.
[10]Takai K, Shibenito PB, Abad MJ, et al. In vivo and in vitro anti-flammatory activity of saikosaponins. Life Sci,1998,63 (13):1147-1156.
[11]Nakamura T, Kuriyama M, Kosuge E. Effect of saiboku to (TJ296) on the production of platelet activating factor in human neutrophils. Ann N Y Acad Sci, 1993,685 (2):572-579.
[12]欧润妹,邓远辉,李伟英,等.香附不同溶剂提取物解热镇痛效应的比较[J].山东中医杂志,2004,23(12)：740-742.
[13]Sue YM, Cheng CF, Chang CC,et al. Nephrol Dial Transplant. Antioxidation and anti-inflammation by haem oxygenase-1 contribute to protection by tetrameth-ylpyrazine against gentamicin-induced apoptosis in murine renal tubular cells.2009, 24(3):769-777.
[14]高崇凯,吴雁,王勇等,白芍总苷粉针剂的抗炎镇痛作用[J].中国新药药理与临床药理,2002,13(3)：163-165.
[15]杨小军,李建军,轩原清史.白芍总甙对豚鼠结肠平滑肌作用机制的研究[J].中国中西医结合消化杂志,2002,10(3)：151-153.
[16]官福兰,王如俊,王建华.枳壳及辛弗林对小鼠胃排空和小肠推进功能的影响[J].现代中西医结合杂志,2002,11(11)：1001-1003.
[17]李伟,郑天珍,瞿颂义.陈皮对小鼠胃排空及肠推进影响[J].中药药理与临床,2002,18(2)：22-23.
[18]官福兰,王汝俊,王建华.陈皮及橙皮苷对离体肠管运动影响[J].时珍国医国药,2002,13(2)：65-67.
[19]杨春花.甘草药理活性的研究[J].长春医学,2008,6,(2)：10-12.
[20]Chen G,Zhu LX,Liu Y,et al. Isoliquiritigenin,a Flavonoid from Licorice, plays a Dual Role in regulating Gastrointestinal Motility in vitro and in vivo. Phytother Res, 2009,23:498-506.
[21]Badary OA, Awad AS, Sherief MA, et al. In vitro and in vivo effects of ferulic acid on gastrointestinal motility:Inhibition of cisplatin-induced delay in gastric empt-ying in rats. World J Gastroenterol,2006,12:5363-5367.
[22]Takeda H, Sadakane C, Hattori T, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology, 2008,134(7):2004-13.
[23]Polewski K, Kniat S, Slawinska D.Gallic acid, a natural antioxidant, in aqueous and micellar environment:spectroscopic studies.Current Topic in Biophysics,2002,26: 217-227.
[24]Zhao Z, Wang W, Guo H, et al.Antidepressant-like effect of liquiritin from Glycyrrhiza uralensis in chronic variable stress induced depression model rats, Behav Brain Res.2008,1:108-113.
[25]Aggarwal A, Gaur V, Kumar A. Nitric oxide mechanism in the protective effect of naringin against post-stroke depression (PSD) in mice.Life Sci.2010,25:928-935.
[26]Guan F L, WANG L J, WANG JH. The effect of Pericarpium Citri Reticulatae and hesperidin on gastric emptying and Intestinal transit in rat. Pharmacology and Clinics of Chinese Materia Medica,2002,3:7-9.
[27]Martin M J, Marhuenda E, Perez-Guerrero C, et al. Antiulcer effect of naringin on gastric lesions induced by ethanol in rats, Pharmacology.1994,3:144-150.
[28]Lee JH, Lee SH, Kim YS, et al. Protective effects of neohesperidin and poncirin isolated from the fruits of Poncirus trifoliata on potential gastric disease, Phytother Res.2009,12:1748-1753.
[29]Jiang WL, Chen XG, Zhu HB, et al. Paeoniflorin inhibits systemic inflammation and improves survival in experimental sepsis, Basic Clin Pharmacol Toxicol.2009, 1:64-71.
[30]Benavente-Garcia O, Castillo J. Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity, J Agric Food Chem.2008,15:6185-6205.
[31]Kim YW, Zhao RJ, Park SJ, et al. Anti-inflammatory effects of liquiritigenin as a consequence of the inhibition of NF-kappaB-dependent iNOS and proinflammatory cytokines production, Br J Pharmacol.2008,1:165-173.
[32]Lee KW, Kang NJ, Heo YS, et al. Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine, Cancer Res.2008,68:946-955.
[33]Heo HJ, Kim DO, Shin SC,et al. Effect of antioxidant flavanone, naringenin, from Citrus junoson neuroprotection, J Agric Food Chem.2004,6:1520-1525.
[34]Hirata A,Murakami Y, Shoji M, et al. Kinetics of radical-scavenging activity of hesperetin and hesperidin and their inhibitory activity on COX-2 expression, Anticancer Res.2005,5:3367-3374.
[35]Kumar A, Dogra S, Prakash A. Protective effect of naringin, a citrus flavonoid, against colchicine-induced cognitive dysfunction and oxidative damage in rats, J Med Food.2010,4:976-984.
[36]Sheu MJ, Chou PY, Cheng HC, et al. Analgesic and anti-inflammatory activities of a water extract of Trachelospermum jasminoides (Apocynaceae), J Ethnopharma-col.2009,126:332-338.
[37]Sugiyama K, Muteki T, Kano T.The Japanese herbal medicine saiko-keishi-to'activates GABAA receptors of rat sensory neurons inculture. Neuroscience Letters,1996,216(3):147-150.
[38]Kim Sun-Hee, Han Jin, Seog Dae-Hyun,et al. Antidepressant effect of Chaihu-Shugan-San extract and its constituents in rat models of depression. Life Sciences,2005,76:1297-1306.
[39]Mao QQ, Huang Z, Ip SP, et al. Antidepressant-like effect of ethanol extract from Paeonia lactiflora in mice. Phytotherapy Research,2008,22:1496-1499.
[40]Mao QQ, Ip SP, Ko KM, et al. Effects of peony glycosides on mice exposed to chronic unpredictable stress:Further evidence for antidepressant-like activity. Journal of Ethnopharmacology,2009,124:316-320.
[41]Mao QQ, Ip SP, Ko KM, et al. Peony glycosides produce antidepressant-like action in mice exposed to chronic unpredictable mild stress:Effects on hypothalamic-pituitary-adrenal function and brain-derived neurotrophic factor. Progress in Neuro-Psychopharmacology & Biological Psychiatry,2009,33:1211-1216.
[42]Mao QQ, Xiana YF, Ip SP,et al. Long-term treatment with peony glycosides reverses chronic unpredictable mild stress-induced depressive-like behavior via increasing expression of neurotrophins in rat brain. Behavioural Brain Research. 2010,210 (2):171-177.
[43]Wei XH, Cheng XM, Shen JS, et al. Antidepressant effect of Yueju-Wan ethanol extract and its fractions in mice models of despair. Journal of Ethnopharmacology, 2008,117:339-344.
[44]Zhao ZY,Wang WX,Guo HZ,et al.Anti-depressive effect of liquiritin on chronic stress depression in rats.Chin J Clin Rehabil,2006,27:69-72.
[45]Wang Weixing, Hu Xinying, Zhao Zhiyu, et al. Antidepressant-like effects of liquiritin and isoliquiritin from Glycyrrhiza uralensis in the forced swimming test and tail suspension test in mice.Progress in Neuro-Psychopharmacology & Biological Psychiatry,2008,32:1179-1184.
[46]Shigeo T, Yukio K, Mamoru T. Isolation of monoamine oxidase inhibitors from Glycyrrhiza glabra roots and the structure-activity relationship.Planta Med,1987,53: 5-8.
[47]Ainsah O, Nabishah BM, Osman CB, et al. Effects of naloxone,glycyrrhizic Acid,dexamethasone and deoxycorticosterone in repetitive stress.Clinical and Experiment-al Pharmacology and Physiology,1999,26:433-437.
[48]Zhu KY, Fu Q, Xie HQ, et al. Quality assessment of a formulated Chinese herbal decoction, Kaixinsan, by using rapid resolution liquid chromatography coupled with mass spectrometry:A chemical evaluation of different historical formulae.J Sep Sci. 2010,33(23-24):3666-3674.
[49]Guillarme D,Nguyen DT, Rudaz S, et al. Recent developments in liquid chromatography-impact on qualitative and quantitative performance, J Chromatogr A.2007,1149:20-29.
[50]Rathore AS, Parr L, Dermawan S, et al. Large scale demonstration of a process analytical technology application in bioprocessing:use of on-line high performance liquid chromatography for making real time pooling decisions for process chromatography, Biotechnol Prog.2010,26:448-457.
[51]代雪平,宋汉敏,李振国HPLC法测定不同产地芦根中阿魏酸的含量[J].中医研究,2010,23(9)：26-27
[52]胡建煜,梁煜霞.不同产地白芍中芍药苷含量比较[J].临京医学工程,2009,16(2)：89-90.
[53]Tack J, Talley NJ, Camiileri M, et al. Functional Gistroduodenal Disorders. In: Drossman DA, eds. In Rome:the functional gastrointestinal disorders,2006, 419-486.
[54]中华医学会消化病学分会胃肠动力学组.我国消化不良的诊治流程和指南.胃肠病学,2000,5(3)：141-142.
[55]陈曼湖,钟碧慧,李初俊,等.广东城镇居民消化不良的流行病学调查[J].中华内科杂志,1998,37：312-314.
[56]Malfertheiner P. Current concepts in dyspepsia:a World perspective. Eur J Gastro-enterol Hepatol,1999,11(1):25-29.
[57]Malagelada JR. Functinal dyspepsia. Insyghts on mechanisms and management strategies. Gastroenterol Clin North Am,1996,25(1):103-112.
[58]Tack J, Caenepeel P, Arts J, et al. Prevalence of acid reflux in functional dyspepsia and its association with symptom profile. Gut,2005,54(10):1370-1376.
[59]Blackshaw LA, Brookes SJ, Grundy D, et al. Sensory transmission in the gastrointestinal tract. Neurogastroenterol Motil,2007,19(1):1-19.
[60]Fock KM. Functional dyspepsia, H. pylori and post infectious FD. J Gastroenterol Hepatol,2011, (1)3:39-41.
[61]Khoo J, Rayner CK, Feinle-Bisset C, et al. Gastrointestinal hormonal dysfunction in gastroparesis and functional dyspepsia. Neurogastroenterol Motil.2010,22(12): 1270-1278.
[62]Chen TS, Luo JC, Chang FY. Psychosocial-spiritual factors in patients with functional dyspepsia:a comparative study with normal individuals having the same endoscopic features. Eur J Gastroenterol Hepatol,2010,22(1):75-80.
[63]Berstad A, Hausken T, Gilja OH, et al. ultrasonography of the human stomach.J Scand J Gastroenterol,1996,220:75-82.
[64]Erstad BL. Dyspepsia:initial evaluation and treatment. J Am Pharm Assoc (Wash), 2002,42(3):460-468.
[65]Sanaka M, Yamamoto T, Kuyama Y. Effects of proton pump inhibitors on gastric emptying:a systematic review. Dig Dis Sci,2010,55(9):2431-2440.
[66]Kandulski A, Venerito M, Malfertheiner P. Therapeutic strategies for the treatment of dyspepsia. Expert Opin Pharmacother,2010,11(15):2517-2525.
[67]Talley NJ, Herrick L, Locke GR. Antidepressants in functional dyspepsia. Expert Rev Gastroenterol Hepatol,2010,4(1):5-8.
[68]张声生,汪红兵,李乾构.功能性消化不良中医诊疗规范(草案)[J].中国中西医结合消化杂志,2002,12(6)：381-383.
[69]胡仲纯,柴胡疏肝散的临床应用.[J]现代中西医结合杂志,2008,17(18)：2909-2911.
[70]郑秀英,赵金风,温玉平.四逆散加味治疗功能性消化不良疗效观察[J].时珍国医国药,2007,18(8)：1928-1929.
[71]任平,黄熙,李双庆,等.逍遥散加味治疗肝郁脾虚型功能性消化不良56例[J]．中国中西医结合杂志,2006,26(5)：398-402.
[72]肖丽玲.加味香砂六君子汤合西沙必利治疗功能性消化不良的临床观察[J].湖南中医学院学报,2005,25(2)：41-42.
[73]李新生.保和丸加减治疗功能性消化不良临床研究[J].中医学报,2010,25(159)：965-966.
[74]胡雄丽,朱迪,周虹,等.半夏泻心汤治疗寒热错杂型功能性消化不良的临床研究[J].湖南中医学院学报,2006,26(1)：40-41.
[75]王海峰,张景,王京奇.柴胡疏肝散加味治疗功能性消化不良临床观察[J].北京中医药,2010,29(10)：781-782.
[76]张光异.柴胡疏肝散加味治疗功能性消化不良临床研究[J].长春中医药大学学报,2010,26(3)：381-382.
[77]黄熙,范荣,张海男.生物方剂分析药理：阐明方剂吸收生物活性成分的研究策略[J].中草药,2010,41(3)：337-339.
[78]Tistaert C, Dejaegher B, Heyden YV. Chromatographic separation techniques and data handling methods for herbal fingerprints:A review. Anal Chim Acta,2011, 690(2):148-161.
[79]Sabzevari O, Abdi Kh, Amini M, et al. Application of a simple and sensitive GC-MS method for determination of morphine in the hair of opium abusers. Anal Bioanal Chem,2004,379(1):120-124.
[80]Srinivas NR, Mullangi R. An overview of various validated HPLC and LC-MS/MS methods for quantitation of drugs in bile:challenges and considerations. Biomed Chromatogr,2011,25(1-2):65-81.
[81]Akira K, Mitome H, Imachi M, et al. NMR identification of a novel taurine-related metabolite observed in (1)H NMR-based metabonomics of genetically hypertensive rats. J Pharm Biomed Anal,2010,51(5):1091-1096.
[82]Douglas A, Drossm an R. The functiona lgastroin testinal disorders and the Rome process. Gastroenterology,2006,130:1377-1390.
[83]李茂玲.柴胡疏肝散应用举隅[J].实用中医药杂志,2010,26(10)：718-719.
[84]徐艳.柴胡疏肝散治疗功能性消化不良[J].中国实用医药,2010,5(22)：116-117.
[85]Steinmann D, Ganzera M. Recent advances on HPLC/MS in medicinal plant analysis. J Pharm Biomed Anal,2010,1-14.
[86]Jiang Y, David B, Tu P, Barbin Y. Recent analytical approaches in quality control of traditional Chinese medicines--a review. Anal Chim Acta,2010,657(1):9-18.
[87]张尊建,余静,杨春华,等.忍冬、山银花HPLC/UV/MS指纹图谱研究[J].中成药,2003,25(11)：863-865.
[88]Yang M, Sun J, Lu Z, et al. Phytochemical analysis of traditional Chinese medicine using liquid chromatography coupled with mass spectrometry. J Chromatogr A, 2009,1216(11):2045-2062.
[89]Qin F, Huang X, Zhang HM,et al. Pharmacokinetic comparison of puerarin after oral administration of Jiawei-Xiaoyao-San to healthy volunteers and patients with functional dyspepsia:influence of disease state. Journal of pharmacy and pharmacology,2009,61:1-5
[90]夏东亚,郭涛,潘文灏,等HPLC法测定心舒口服液中阿魏酸血浆浓度及其在大鼠体内的药动学研究[J].中草药,2004,35(1)：36-38.
[91]Li Y, Bi K. HPLC determination of ferulic acid in rat plasma after oral administration of Rhizoma Chuanxiong and its compound preparation. Biomedical chromatography,2003,17(8):543-546.
[92]王定康.半夏泻心汤治疗功能性消化不良85例[J].实用中医药杂志,2002,18(11)：16-17.
[93]王伟.参苓白术散治疗功能性消化不良80例[J].陕西中医,2007,28(1)：36-38.
[94]应瑛,何钦,徐斌.加味百合汤治疗功能性消化不良的临床观察[J].浙江中医药大学学报2007,31(6)：712-713.
[95]麦志广,陈翠环.消痞汤治疗功能性消化不良112例疗效观察[J].中国中医急症,2007,16(11)：1330-1340.
[96]陈廷卓,刘慧君.消食健脾汤治疗功能性消化不良78例[J].中外医疗,2010,35：122.
[97]许忠康.柴胡疏肝散治疗功能性消化不良66例[J].光明中医,2010,3(25)：442-443.
[98]宫照东.柴胡疏肝散加减治疗功能性消化不良86例临床观察[J].医学信息,2010,06(23)：1885.
[99]王捷虹,成凯,杜晓泉.柴胡疏肝散加味治疗动力障碍型功能性消化不良40例[J].现代中医药,2005,4(25)：23-24.
[100]Carachi R.Gastrointestinal motility disorders. Semin Pediatr Surg,2009,18(4): 193-195.
[101]Di Lorenzo C, Youssef NN. Diagnosis and management of intestinal motility disorders. Semin Pediatr Surg,2010,19(1):50-58.
[102]Torjman MC, Joseph JI, Munsick C, et al. Effects of isoflurane on gastrointestinal motility after brief exposure in rats. Int J Pharm,2005,294(1-2):65-71.
[103]Jeong SI, Kim YS, Lee MY, et al. Regulation of contractile activity by magnolol in the rat isolated gastrointestinal tracts. Pharmacol Res,2009,59(3):183-188.
[104]Perboni S, Inui A. Appetite and gastrointestinal motility:role of ghrelin-family peptides. Clin Nutr,2010,29(2):227-234.
[105]Mimaki H, Kawauchi S, Kagawa S, et al. Bicarbonate stimulatory action of nizatidine, a histamine H(2)-receptor antagonist, in rat duodenums.J Physiol Paris, 2001,95(1-6):165-171.
[106]唐文富,陈光远,黄熙.方剂代谢物组学新假说[J].中草药,2007,38(6)：801-803.
[107]黄熙.方剂体内/血清成分谱与靶成分概念的提出与意义[J].第四军医大学学报,1999,20(4)：277-279.
[108]Wang B, Ouyang J, Liu Y, et al. Sodium ferulate inhibits atherosclerogenesis in hyperlipidemia rabbits. J Cardiovasc Pharmacol.2004,43(4):549-554.
[109]Ma ZC, Hong Q, Wang YG, et al. Ferulic acid protects lymphocytes from radiation-predisposed oxidative stress through extracellular regulated kinase. Int J RadiatBiol.2011,87(2):130-140.
[110]M aurya DK, Nair CK. Preferential rad ioprotection to DNA of normal tissues by ferulic acid under exvivo and invivo conditions in tumor bearing mice. Mol Cell Biochem,2006,285:181-190.
[111]Jayap rakasam B, Van isreeM, Zhang Y, et al. Impact of alkyl esters of caffeic and ferulic acids on tumor cell proliferation, cyclo oxygenase enzym e, and lipid per oxidation. J Agric Food Chem,2006,54(15):5375-5381.
[112]Janicke B, Onning G, Oredsson SM. Differential effects of ferulic acid and p-coumaric acid on S phase distribution and length of S phase in the human colonic cell line Caco-2. J A gric Food Chem,2005,53 (17):6658-6665
[113]Badary OA, Awad AS, Sherief MA, et al. In vitro and in vivo effects of ferulic acid on gastrointestinal motility:inhibition of cisplatin-induced delay in gastric emptying in rats. World J Gastroenterol,2006,12(33):5363-5367.
[114]Pinkel, D.,1958. The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Research 18,853-856.
[115]聂琼芳.小柴胡汤加减治疗功能性消化不良38例临床观察[J].时珍国医国药,2005,16(5)：410.
[116]沈玉棠,彭丽园.逍遥散治疗功能性消化不良45例疗效观察[J].浙江中西医结合杂志,2010,20(10)：624.
[117]余江平.柴胡疏肝散治疗功能性消化不良48例观察[J].实用中医药杂志,2007,7(23)：431.
[118]赵民,齐金刚.四逆散加减治疗功能性消化不良疗效观察[J].辽宁中医杂志,2007,34(5)：599.
[119]陈明.解肝煎治疗慢性胃炎的临床观察[J].北京中医,1998,2：25-26.
[120]彭成,张磊,张利,等.四逆散治疗功能性消化不良的实验研究[J].成都中医药大学学报,1999,22(1)：39-41.
[121]黄熙,陈可冀,任平.“复方效应成分动力学”新假说的科学证据、要素、意义及前景[J].中国中药杂志,1997,22(4)：250-252.
[122]寺泽捷年.戴慧馨摘译.甘草次酸体内代谢研究Ⅱ-大鼠体内代谢[J].国外医学,中医中药分册,1987,9(2)：31.
[123]Levy G, Gibaldi M. Pharmacokinetics of drug action. Annu Rev Pharmacol, 1972,12:85-98.
[124]任平,黄熙,方剂药动学研究策略[J].山东中医药大学学报,2001,25(1)：66-68.
[125]Ma Z, Wu Q, Lee DY, et al. Determination of puerarin in human plasma by high performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci,2005,5(2):108-114.
[126]Smolen VF, Theophanous TG, Theophanous TG. Relation-ship between dose, effect, time and biophasic drug levels. Journal of Pharmaceutical Sciences,1972,61(3): 467-470.
[127]赵智强,俞晶华,陆跃呜,等.天麻钩藤饮等三方对小鼠镇痛作用的药物动力学研究[J].中国药理与临床,1999,15(3)：13-14.
[128]王尧先,赫梅先.用动物急性死亡法估测4种中成药的药动学参数[J].中成药,1991,13(5)：24-26.
[129]潘嘉,王家葵,邹文俊,等.抑菌效应法测定川芎挥发油药动学参数[J].中药药理与临床,2002,18(4)：18-19.
[130]黄熙.生物方剂分析中医药学研究的设想、背景与意义[J].中国中西医结合杂志,2002,22(4)：251-252.
[131]Li Y, Liang X, Xiao H, et al. Determination of spinosin in rat plasma by reversed-phase high-performance chromatography after oral administration ofSuanzaoren decoction. J Chromatogr B Analyt Technol Biomed Life Sci, 2003,787 (2):421-425.
[132]Li X, Li X,Wang L, et al. Simultaneous determination of danshensu, ferulic acid, cryptotanshinone and tanshinone IIA in rabbit plasma by HPLC and their pharmacokinetic application in dan xiong fang. Journal of Pharmaceutical and Biomedical Analysis,2007,44(5):1106-1112.
[133]Zafra-Gomez, A., Luzon-Toro, B., Jimenez-Diaz, I., et al. Quantification of phenolic antioxidants in rat cerebrospinal fluid by GC-MS after oral administration of compounds.Journal of Pharmaceutical and Biomedical Analysis,2010,53 (1):103-108.
[134]Li, Y., Bi, K. HPLC determination of ferulic acid in rat plasma after oral administration of Rhizoma Chuanxiong and its compound preparation. Biomedical chromatography,2003,17(8):543-546.
[135]Xu, M., Fu, G., Qiao, X.,et al. HPLC method for comparative study on tissue distribution in rat after oral administration of salvianolic acid B and phenolic acids from Salvia miltiorrhiza. Biomedical chromatography,2007,21(10):1052-1063.
[136]Qi J, Jin X, Huang L,et al. Simultaneous determination of hydroxysafflor yell-ow A and ferulic acid in rat plasma after oral administration of the co-extractum of Rhizoma chuanxiong and Flos Carthami by HPLC-diode array detector. Biomed Chromatogr,2007,21(8):816-822.
[137]何跃生,袁玲,曲树明.HPLC法测定阿魏酸钠在Beagle犬体内血浆浓度及药动学研究[J].天津医药,2007,35(9)：687-689.
[138]甘洪全,梅其炳,朱伟,等.健康志愿者口服冠心Ⅱ号煎剂后血清中阿魏酸的药动学研究[J].中国药方,2007,18(2)：109-111.
[139]Ventresca GP, Mariani L. Disease states and changes in drugpharmacokinetics. Clin Ter,1996,147:131-144.
[1]Park YJ, Kim HS, Kang HC, et al. A survey of Hwa-Byung in middle-age Korean women. Journal of Transcultural Nursing,2001,12(2):115-122
[2]王永炎,李明复,戴锡盟.《中医内科学》.上海科学技术出版社.2007.
[3]刘新光.功能性消化性不良与胃动力异常[J].中华消化杂志.2002,22(1)：44-45
[4]Thumshirn M. Pathophysiology of functional dyspepsia. Gut.2002,51:63-66
[5]谢稚晖.柴胡疏肝散加减治疗功能性消化不良42例[J].福建中医药.2007,38(5)：24-25.
[6]许忠康.柴胡疏肝散治疗功能性消化不良66例[J].光明中医.2010,3(25)：442-443
[7]冯卫,邱启霞.柴胡疏肝散加减治疗慢性消化不良症89例[J].河南中医.2008,28(4)：64-65
[8]王稹,钱屹.柴胡疏肝散加减从肝论治慢性消化不良症79例[J].现代中西医结合杂志.2005,14(23)：3117-3118
[9]贺先波.柴胡疏肝散治疗功能性消化不良118例[J].山东中医杂志.2006,7(25)：460-462
[10]宫照东.柴胡疏肝散加减治疗功能性消化不良86例临床观察[J].医学信息.2010,06(23)：1885-1886
[11]朱卫东.柴胡疏肝散加减治疗功能性消化不良64例[J].中国实用医药.2008,3(7)：79-81
[12]王捷虹,成凯,杜晓泉.察柴胡疏肝散加味治疗动力障碍型功能性消化不良40例[J].现代中医药.2005,4(25)：23-24
[13]余江平.柴胡疏肝散治疗功能性消化不良48例观察[J].实用中医药杂志.2007, 7(23)：431-432
[14]吴宇金,李振宇.柴胡疏肝散治疗功能性消化不良餐后不适综合征临床研究[J].湖北中医杂志.2009,7(31)：14-15
[15]刘纹,范萌,陈言言,周吕.柴胡疏肝散对功能性消化不良肝气郁结证患者胃动力及胃肠激素的影响[J].中医杂志.2010,51(1)：30-33
[16]董昆山,王秀琴,董一凡.现代临床中药学.北京：中国中医药出版社,1998176：292-338
[17]苗玉兰.柴胡疏肝散对实验性肝郁证小鼠胃肠功能的影响[J].国华医学实践杂志.2005(12)：12-13
[18]敖海清,徐志伟,严灿等.柴胡疏肝散及逍遥散对慢性心理应激大鼠血清皮质酮及胃肠激素的影响[J].中药新药与临床药理.2007 18(4)：288-291
[19]陈煜辉,周莺.柴胡疏肝散抗抑郁作用的药理学实验研究[J].江西中医学院学报.2004,16(4)：59-60
[20]朱清静,罗欣拉,熊振芳.柴胡疏肝散对慢性束缚应激性肝郁证大鼠下丘脑-垂体-肾上腺轴的调节作用[J].湖北中医杂志.2003,25(11)：7-8
[21]郑爱华,李家邦,蔡光先等.柴胡疏肝散、四君子汤对肝郁脾虚病人Th细胞分化信号蛋白PKC表达的影响[J].贵阳中医学院学报.2003,25(4)：14-16
[22]郑爱华,蔡光先,李家邦等.柴胡疏肝散、四君子汤对肝郁脾虚病人Th细胞蛋白激酶C表达的影响.湖南中医学院学报.2003,23(6)：15-16
[23]朱金照,冷恩仁,陈东风,等.15味中药促胃肠动力作用的筛选研究[J].第三军医大学学报.2005,22(5)：438-440
[24]骆和生.中药方剂的药理与临床研究进展.广州：华南理工大学出版社,1991,24(52)：346-345
[25]孙军,张宁,李岩.柴胡枳实水提取物对胃肠动力作用的影响[J].世界华人消化杂志.2005,13(12)：1445-1446
[26]李岩,陈苏宁,李宇权等.芍药甘草汤、四逆散对胃排空及小肠推进功能影响的拆方研究[J].中华消化杂志.1996,16(1)：18-21
[27]Kobayashi M, Ueda C, Aoki S. Anticholinergic action of Paeony root and its active constituents. Yakugaku Zasshi.1990,110(12):964-8
[28]徐优晓,苏孝共.枳壳理气作用的临床运用[J].江西中医药.2005,36(269)：57-58
[29]刘孝乐.炮制对枳壳药理作用的影响[J].中成药研究.1987,10：17-19
[30]马亚兵.枳壳的胃肠作用及炮制前后的变化[J].中药药理与临床.1996,2(6)：28-29
[31]陈惠阳.枳壳烟吸入治疗阑尾切除术后肠胀气[J].江苏中医.1993(3)：27-28
[32]官福兰,王如俊,王建华.枳壳及辛弗林对小鼠胃排空、小肠推进功能的影响.现代中西医结合杂志.2002,11(11)：1001-1003
[33]官福兰,王如俊,王建华.枳壳及辛弗林对兔离体小肠运动的影响[J].中药药理与临床.2002,18(2)：9-11
[34]Lee HT, Seo EK, Chung SJ, et al. Prokinetic activity of an aqueous extract from dried immature fruit of Poncirus trifoliata (L.) Raf. Journal of Ethnopharmacology. 2005,102:131-136
[35]Lee HT, Seo EK, Chung SJ, et al. Effect of an aqueous extract of dried immature fruit of Poncirus trifoliate (L.) Raf. On intestinal transit in rodents with experimental gastrointestinal motility dysfunctions. Journa lof Ethnopharmacology. 2005,102:302-306
[36]Choi KH, Jeong SI, Hwang BS, et al. Hexane extract of Poncirus trifoliata (L.) Raf. stimulates the motility of rat distal colon. Journal of Ethnopharmacology.2010, 127:718-724
[37]Lee HT, Seo EK, Chung SJ, et al. Prokinetic activity of an aqueous extract from dried immature fruit of Poncirus trifoliata (L.) Raf. Journal of Ethnopharmacology. 2005,102:131-136
[38]Lee HT, Seo EK, Chung SJ, et al. Effect of an aqueous extract of dried immature fruit of Poncirus trifoliate (L.) Raf. On intestinal transit in rodents with experimental gastrointestinal motility dysfunctions. Journal of Ethnopharmacology.2005,102: 302-306
[39]Keun Han Choi, Seung Il Jeong, Byung Soon Hwang, et al. Hexane extract of Poncirus trifoliata (L.) Raf. stimulates the motility of rat distal colon. Journal of Ethnopharmacology.2010,127:718-724
[40]徐彭.陈皮水提取物和挥发油的药理作用比较[J].江西中医学院学报.1998,10(4)：172-173
[41]中山医学院.药理学.人民卫生出版社,1979,478
[42]官福兰,王如俊,王建华.陈皮及橙皮甙对小鼠胃排空、小肠推进功能的影响[J].中药药理与临床.2002,18(3)：7-8
[43]李伟,郑天珍,瞿颂义等.陈皮对小鼠胃排空及肠推进的影响[J].中药药理与临床.2002,18(2)：22-23
[44]王贺玲,李岩,白菡,张健.理气中药对鼠胃肠动力的影响[J].世界华人消化杂志.2005,(5)：12-13
[45]周秋丽,张志强.柴胡皂苷和甘草甜素抑制Na+-K+-ATP酶活性的构效关系[J].药学学报.1996,31(7)：496-497
[46]韩珍,贺弋.白芍总苷的药理作用及其毒性研究进展[J].宁夏医学院学报.2008,30(4)：538-539
[47]Fang YS, Shan DM, Liu JW. Effect of constituents from Fructus Aurantii Immaturus and Radix Paeoniae Alba on gastrointestinal movement. Planta Med. 2009,75:24-31
[48]Jiang WL, Chen XG, Zhu HB. Paeoniflorin inhibits systemic inflammation and improves survival in experimental sepsis. Basic Clin Pharmacol Toxicol.2009, 105(1):64-71
[49]Asai M, Kawashima D, Katagiri K. Protective effect of a molecular chaperone inducer, paeoniflorin, on the HCl- and ethanol-triggered gastric mucosal injury. Life Sci.2011,14:88(7-8):350-7
[50]Lee JH, Lee SH, Kim YS, Jeong CS. Protective effects of neohesperidin and poncirin isolated from the fruits of Poncirus trifoliata on potential gastric disease. Phytother Res.2009,23(12):1748-53
[51]徐浩.川芎嗪的临床应用和药理作用[J].中国中西医结合杂志.2003,23：5-7
[52]Badary OA, Awad AS, Sherief MA, et al. In vitro and in vivo effects of ferulic acid on gastrointestinal motility:Inhibition of cisplatin-induced delay in gastric empt-ying in rats. World J. Gastroenterol.2006,12:5363-5367
[53]Sudheer AR, Muthukumaran S, Devipriya N, et al. Influence of ferulic acid on nicotine-induced lipid peroxidation, DNA damage and inflammation in experimental rats as compared to N-acetylcysteine. Toxicology.2008,243(3): 317-29
[54]Chen G, Zhu LX, Liu Y, et al. Isoliquiritigenin, a Flavonoid from Licorice, plays a Dual Role in regulating Gastrointestinal Motility in vitro and in vivo. Phytother. Res.2009,23:498-506
[55]Sato YJ, He JX, Nagai H, et al. Isoliquiritigenin, One of the Antispasmodic Principles of Glycyrrhiza Ularensis Roots, Acts in the Lower Part of Intestine. Biol. Pharm. Bull.2007,30(1):145-149
[56]Takeda H, Sadakane C, Hattori T, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology. 2008,134(7):2004-2013
[57]Takeda Y, Ward SM, Sanders KM, Koh SD. Effects of the gap junction blocker glycyrrhetinic acid on gastrointestinal smooth muscle cells. Am J Physiol Gastrointest Liver Physiol.2005,288(4):832-841.