胃肠安丸药理学研究及止泻功效新探
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摘要
目的
腹泻是胃肠道机能障碍时常见的一种症状。我国全人口的腹泻发病率为0.17-0.70次/人年,5岁以下儿童2.50-3.38次/人年。非特异性腹泻的治疗仍是临床需要解决的问题。中医药治疗腹泻具有疗效迅速、费用低廉等优势。胃肠安丸是治疗腹泻的要药,全方芳香化浊,理气止痛,健胃导滞。临床多用于消化不良引起的腹泻,脘腹胀满,腹痛等疗效肯定。但方中巴豆霜有大毒,限制了该方的非处方应用,因此寻找合理的巴豆霜替代药物被列为天津市科委科技创新专项基金项目《胃肠安大品种系统开发项目》的主攻课题之一。本研究拟从中医学理论及已知药理学研究出发,提出元明粉可以替代巴豆霜的假设,试图通过现代药理学研究自替代与原味单品、组合及复方三阶段,逐一比较巴豆霜与元明粉、与大黄组合以及新方对肠道动力、肠吸收以及肠分泌的影响,以期明确各实验药物对腹泻动物模型的药理作用及作用机制,为寻找胃肠安丸中巴豆霜的合理替代药物提供必需的理论依据。
方法
1.以番泻叶(FXY)灌胃诱导功能性腹泻大鼠模型。
2.通过观察梯度浓度元明粉与巴豆霜、二者并用大黄对兔回肠水液代谢的影响,比较单品及与大黄合用后两药的药效学异同,确定替代用量。
3.以前一实验为基础,通过观察有效浓度单味药、组合药及复方药对模型大鼠稀便率、结肠吸收功能及结肠运动功能的影响,比较元明粉与巴豆霜的异同,找寻替代依据。
4.以前一实验为基础,通过观察原药与替代药单品、组合及成方对模型大鼠血清电解质、结肠上皮细胞Na+-K+-ATPase活力的影响,探讨二者改善结肠水、电解质吸收作用靶点的异同,寻找单品、组合可替代,复方不可替代的原因。
5.以第三部分实验为基础,从肠动力学角度,通过观察结肠组织SP、VIP含量变化,探寻单品、大黄组合及复方对结肠运动影响的差异,阐明可否予以替代作用机制,进一步明确胃肠安复方止泻药理机制
结果
1.成功建立功能性腹泻模型。5g/kg体重FXY致泻大鼠平均稀便率达85.54%,结肠吸收功能降低(P<0.01)。
2.实验剂量元明粉与巴豆霜对回肠水液代谢影响趋势相同(P>0.05),在低浓度时表现出可以促进回肠水液吸收的作用(P<0.01)；当终浓度增加到各自作为泻下药10倍浓度时,其表现出促进回肠大量水液分泌的作用(P<0.01)。二者合用大黄后作用趋势亦相同(P>0.05),但在中、高浓度时表现出促进回肠水液吸收的作用(P<0.01,P<0.05)。
3.等浓度的单品巴豆霜及元明粉可降低模型大鼠稀便率,改善其结肠吸收功能(P<0.05)；二者分别合用大黄后,该作用亦存在；但两种组合在全方中体现的作用不同,胃肠安方可以降低模型稀便率,改善模型大鼠结肠吸收功能(P<0.05),而胃肠安新方无此作用(P>0.05)。巴豆霜、并用大黄均可延缓腹泻模型结肠运动(P<0.05),胃肠安全方作用相同(P<0.05)。而元明粉、并用大黄对腹泻模型结肠运动无影响(P>0.05),与之相反,胃肠安新方可以减缓腹泻模型结肠运动(P<0.05)。
4.单品巴豆霜能增加模型大鼠血清钠、钾、氯浓度(P<0.01,P<0.05,P<0.05),提高模型大鼠结肠上皮细胞Na+-K+-ATPase活力(P<0.05)。元明粉仅可增加模型大鼠血清钠、氯浓度(P<0.01,P<0.05)。二大黄组合均能增加模型大鼠血清钾、钠、氯浓度(P<0.01,P<0.05,P<0.05),提高模型大鼠结肠上皮细胞Na+-K+-ATPase活力(P<0.05)。胃肠安方能增加模型大鼠血清钠、钾、氯浓度(P<0.01,P<0.05,P<0.05),且对血清钠的调整优于巴豆霜与大黄组合(P<0.05)；提高模型大鼠结肠上皮细胞Na+-K+-ATPase活力(P<0.05),优于单品巴豆霜(P<0.05)。而胃肠安新方仅增加血清钠浓度(P<0.01)。
5.低浓度巴豆霜、并用大黄可降低模型大鼠结肠SP、VIP(P<0.01)。而中浓度巴豆霜只降低VIP(P<0.01)。元明粉、并用大黄对模型大鼠结肠SP、VIP无影响(P>0.05)。胃肠安原方、新方均可降低模型大鼠结肠SP、VIP(P<0.01)。
结论
1.胃肠安中巴豆霜不能被元明粉替代,新方不可替代原方,原因：小剂量单品、不同大黄组合虽能改善结肠水、电解质吸收,但二单品作用靶点不同；小剂量巴豆霜、配伍大黄可降低结肠SP、VIP含量,调整结肠运动,而元明粉无此作用。
2.巴豆霜、配伍大黄只在小量应用时有止泻作用
3.胃肠安止泻功效重在调整脾胃功能,调理中焦气机,而非以往认识的“通因通用”祛除积滞而止泻。
Objective:
Diarrhea is one of common clinical symptoms of gastrointestinal dysfunction. The incidence of diarrhea is very high.The latest statistics show the incidence of diarrhea of whole population is 0.17-0.7 times per person per year in China, and it is 2.50-3.38 times per person per year in the children under 5 years old. At present, the treatment of nonspecific diarrhea is still a clinical issue needs to be studied. Wei Chang An pills can treat diarrhea effectively. In TCM it can aromatic herbs resolving turbidity, regulating qi to alleviate pain, strengthening stomach to relieve stagnation. In clinic it is used to treat diarrhea, fullness and pain of stomach and abdomen, indigestion and infantile dyspepsia. But this prescription includes poisonous Semen Crotonis Pulveratum, which restrict the clinical using of Wei Chang An pills. So removing Semen Crotonis Pulveratum from Wei Chang An pills or finding a substitute of Semen Crotonis Pulveratum had be a item of Tianjin Science and Technology Innovation funds. This study advanced a hypothesis that Natrii Sulfas could be the substitute of Semen Crotonis Pulveratum in Wei Chang An pills. The purpose of this research is to compare Semen Crotonis Pulveratum with Natrii Sulfas on intestinal movement, intestinal absorption and secretion, in order to elucidate the pharmacological effect and mechanism of all experimental drugs on diarrhea model. This study will find the necessary evidence to probe into the substitute of Semen Crotonis Pulveratum in Wei Chang An pills.
Methods:
1. Diarrhea rats model is established by administrating Folium Cassiae.
2. Groups with different concentrations of BDS,YMF,BDS+DH and YMF+DH were established. Through testing the ileum liquid water metabolism of rabbit compared BDS with YMF and BDS+DH with YMF+DH on pharmacodynamic effects, in order to find the doses of Natrii Sulfas to substitute Semen Crotonis Pulveratum.
3. Based on the results of test 2, through testing the rate of loose stools, colon movement and colon absorption compared BDS with YMF and BDS+DH with YMF+DH and WCA with TDF. we try to explore the evidence to probe into the substitute of Semen Crotonis Pulveratum in Wei Chang An pills.
4. Based on the results of test 3, through testing the activity of Na+-K+-ATPase in the colonic epithelial cell and the serum electrolyte compared BDS with YMF and BDS+DH with YMF+DH and WCA with TDF. we tried to compare Natrii Sulfas with Semen Crotonis Pulveratum on the mechanisms of regulating the colon absorption.
5. Based on the results of test 3, we tested the level of SP and VIP to compare BDS with YMF and BDS+DH with YMF+DH and WCA with TDF.
Results:
1. Diarrhea rats resulted by 5g/kg FXY showed the rate of loose stools reached 85.54%, the serum D-xylose content and the activity of Na+-K+-ATPase in the colonic epithelial cell decreased(P<0.01).
2. Test dose of YMF and BDS had the same effects on the ileum liquid water metabolism(P>0.05).1.11 mg/ml and 2.22 mg/ml of YMF and BDS could accelerate the ileum liquid water absorption(P<0.01).22.2 mg/ml of BDS and 1g/ml of YMF can result the ileum liquid water increase(P<0.01). When the YMF and BDS combined with DH, the effect was same as the single-drug.3.33 mg/ml and 4.44 mg/ml combination with DH could accelerate the ileum liquid water absorption(P<0.01, P<0.05).
3. The BDS can reduce the rate of loose stools and improve the colonic absorption(P<0.05), there was no difference in the same concentration YMF(P>0.05). When the YMF and BDS combined with DH, the action was same as the single-drug(P>0.05) and there were no different between YMF+DH and BDS+DH(P>0.05). But the effect of two combinations was different in the formula. The WCA could reduce the rate of loose stools and improve the colonic absorption(P<0.05), the TDF had not these action(P>0.05).
4. BDS, BDS+DH and WCA could slower colon movement(P<0.05). YMF and YMF+DH had not effect on colon movement(P>0.05), but the TDF could slower colon movement(P<0.05).
5. BDS could improve serum Na+, K+, Cl- (P<0.01, P<0.05, P<0.05) and the activity of Na+-K+-ATPase in the colonic epithelial cell (P<0.05).YMF could increase serum Na+, Cl- (P<0.01, P<0.05). BDS+DH could improve serum Na+, K+, Cl- (P<0.01, P<0.05, P<0.05) and the activity of Na+-K+-ATPase in the colonic epithelial cell (P<0.05).YMF+DH had the same action as BDS+DH(P>0.05).
6. WCA could improve serum Na+, K+, Cl- (P<0.01, P<0.05, P<0.05)and the activity of Na+-K+-ATPase in the colonic epithelial cell (P<0.05).The function of adjusting serum Na+was better than BDS+DH(P<0.05). The function of adjusting the activity of Na+-K+-ATPase was better than BDS(P<0.05).TDF just can improve serum Na+(P<0.01).
7. Lower concentration of BDS and BDS+DH debase the level of SP and VIP(P<0.01). Middle concentration of BDS just debase the level of VIP(P<0.01).YMF and YMF+DH had no effect on the level of SP and VIP(P>0.05).Both of the WCA and TDF could debase the level of SP and VIP(P<0.01).
Conclusions:
1. All of the BDS, BDS+DH, and WCA are able to improve the colon absorption, promote colonic water and electrolyte metabolism, adjust of the colon movement, and reduce the colon secretion. Low-dose of YMF improve intestinal water and electrolyte absorption,witch is similar to BDS. But the mechanism of YMF is not same as the BDS. Combined with DH, the acting target of two complex tends to similar. However, the action of YMF+DH is antagonized by WCA. BDS of WCA can not be substituted by YMF.
2. Low dose BDS and BDS+DH can treat diarrhea.
3. Through activating spleen and resolving dampness, harmonizing functional activities of qi,the WCA can stop the diarrhea. The therapeutic principles of WCA belong to treating diarrhea with regulating functions of zang and fu organs.
腹泻是胃肠道机能障碍时常见的一种症状。我国全人口的腹泻发病率为0.17-0.70次/人年,5岁以下儿童2.50-3.38次/人年。非特异性腹泻的治疗仍是临床需要解决的问题。中医药治疗腹泻具有疗效迅速、费用低廉等优势。胃肠安丸是治疗腹泻的要药,全方芳香化浊,理气止痛,健胃导滞。临床多用于消化不良引起的腹泻,脘腹胀满,腹痛等疗效肯定。但方中巴豆霜有大毒,限制了该方的非处方应用,因此寻找合理的巴豆霜替代药物被列为天津市科委科技创新专项基金项目《胃肠安大品种系统开发项目》的主攻课题之一。本研究拟从中医学理论及已知药理学研究出发,提出元明粉可以替代巴豆霜的假设,试图通过现代药理学研究自替代与原味单品、组合及复方三阶段,逐一比较巴豆霜与元明粉、与大黄组合以及新方对肠道动力、肠吸收以及肠分泌的影响,以期明确各实验药物对腹泻动物模型的药理作用及作用机制,为寻找胃肠安丸中巴豆霜的合理替代药物提供必需的理论依据。
方法
1.以番泻叶(FXY)灌胃诱导功能性腹泻大鼠模型。
2.通过观察梯度浓度元明粉与巴豆霜、二者并用大黄对兔回肠水液代谢的影响,比较单品及与大黄合用后两药的药效学异同,确定替代用量。
3.以前一实验为基础,通过观察有效浓度单味药、组合药及复方药对模型大鼠稀便率、结肠吸收功能及结肠运动功能的影响,比较元明粉与巴豆霜的异同,找寻替代依据。
4.以前一实验为基础,通过观察原药与替代药单品、组合及成方对模型大鼠血清电解质、结肠上皮细胞Na+-K+-ATPase活力的影响,探讨二者改善结肠水、电解质吸收作用靶点的异同,寻找单品、组合可替代,复方不可替代的原因。
5.以第三部分实验为基础,从肠动力学角度,通过观察结肠组织SP、VIP含量变化,探寻单品、大黄组合及复方对结肠运动影响的差异,阐明可否予以替代作用机制,进一步明确胃肠安复方止泻药理机制
结果
1.成功建立功能性腹泻模型。5g/kg体重FXY致泻大鼠平均稀便率达85.54%,结肠吸收功能降低(P<0.01)。
2.实验剂量元明粉与巴豆霜对回肠水液代谢影响趋势相同(P>0.05),在低浓度时表现出可以促进回肠水液吸收的作用(P<0.01)；当终浓度增加到各自作为泻下药10倍浓度时,其表现出促进回肠大量水液分泌的作用(P<0.01)。二者合用大黄后作用趋势亦相同(P>0.05),但在中、高浓度时表现出促进回肠水液吸收的作用(P<0.01,P<0.05)。
3.等浓度的单品巴豆霜及元明粉可降低模型大鼠稀便率,改善其结肠吸收功能(P<0.05)；二者分别合用大黄后,该作用亦存在；但两种组合在全方中体现的作用不同,胃肠安方可以降低模型稀便率,改善模型大鼠结肠吸收功能(P<0.05),而胃肠安新方无此作用(P>0.05)。巴豆霜、并用大黄均可延缓腹泻模型结肠运动(P<0.05),胃肠安全方作用相同(P<0.05)。而元明粉、并用大黄对腹泻模型结肠运动无影响(P>0.05),与之相反,胃肠安新方可以减缓腹泻模型结肠运动(P<0.05)。
4.单品巴豆霜能增加模型大鼠血清钠、钾、氯浓度(P<0.01,P<0.05,P<0.05),提高模型大鼠结肠上皮细胞Na+-K+-ATPase活力(P<0.05)。元明粉仅可增加模型大鼠血清钠、氯浓度(P<0.01,P<0.05)。二大黄组合均能增加模型大鼠血清钾、钠、氯浓度(P<0.01,P<0.05,P<0.05),提高模型大鼠结肠上皮细胞Na+-K+-ATPase活力(P<0.05)。胃肠安方能增加模型大鼠血清钠、钾、氯浓度(P<0.01,P<0.05,P<0.05),且对血清钠的调整优于巴豆霜与大黄组合(P<0.05)；提高模型大鼠结肠上皮细胞Na+-K+-ATPase活力(P<0.05),优于单品巴豆霜(P<0.05)。而胃肠安新方仅增加血清钠浓度(P<0.01)。
5.低浓度巴豆霜、并用大黄可降低模型大鼠结肠SP、VIP(P<0.01)。而中浓度巴豆霜只降低VIP(P<0.01)。元明粉、并用大黄对模型大鼠结肠SP、VIP无影响(P>0.05)。胃肠安原方、新方均可降低模型大鼠结肠SP、VIP(P<0.01)。
结论
1.胃肠安中巴豆霜不能被元明粉替代,新方不可替代原方,原因：小剂量单品、不同大黄组合虽能改善结肠水、电解质吸收,但二单品作用靶点不同；小剂量巴豆霜、配伍大黄可降低结肠SP、VIP含量,调整结肠运动,而元明粉无此作用。
2.巴豆霜、配伍大黄只在小量应用时有止泻作用
3.胃肠安止泻功效重在调整脾胃功能,调理中焦气机,而非以往认识的“通因通用”祛除积滞而止泻。
Objective:
Diarrhea is one of common clinical symptoms of gastrointestinal dysfunction. The incidence of diarrhea is very high.The latest statistics show the incidence of diarrhea of whole population is 0.17-0.7 times per person per year in China, and it is 2.50-3.38 times per person per year in the children under 5 years old. At present, the treatment of nonspecific diarrhea is still a clinical issue needs to be studied. Wei Chang An pills can treat diarrhea effectively. In TCM it can aromatic herbs resolving turbidity, regulating qi to alleviate pain, strengthening stomach to relieve stagnation. In clinic it is used to treat diarrhea, fullness and pain of stomach and abdomen, indigestion and infantile dyspepsia. But this prescription includes poisonous Semen Crotonis Pulveratum, which restrict the clinical using of Wei Chang An pills. So removing Semen Crotonis Pulveratum from Wei Chang An pills or finding a substitute of Semen Crotonis Pulveratum had be a item of Tianjin Science and Technology Innovation funds. This study advanced a hypothesis that Natrii Sulfas could be the substitute of Semen Crotonis Pulveratum in Wei Chang An pills. The purpose of this research is to compare Semen Crotonis Pulveratum with Natrii Sulfas on intestinal movement, intestinal absorption and secretion, in order to elucidate the pharmacological effect and mechanism of all experimental drugs on diarrhea model. This study will find the necessary evidence to probe into the substitute of Semen Crotonis Pulveratum in Wei Chang An pills.
Methods:
1. Diarrhea rats model is established by administrating Folium Cassiae.
2. Groups with different concentrations of BDS,YMF,BDS+DH and YMF+DH were established. Through testing the ileum liquid water metabolism of rabbit compared BDS with YMF and BDS+DH with YMF+DH on pharmacodynamic effects, in order to find the doses of Natrii Sulfas to substitute Semen Crotonis Pulveratum.
3. Based on the results of test 2, through testing the rate of loose stools, colon movement and colon absorption compared BDS with YMF and BDS+DH with YMF+DH and WCA with TDF. we try to explore the evidence to probe into the substitute of Semen Crotonis Pulveratum in Wei Chang An pills.
4. Based on the results of test 3, through testing the activity of Na+-K+-ATPase in the colonic epithelial cell and the serum electrolyte compared BDS with YMF and BDS+DH with YMF+DH and WCA with TDF. we tried to compare Natrii Sulfas with Semen Crotonis Pulveratum on the mechanisms of regulating the colon absorption.
5. Based on the results of test 3, we tested the level of SP and VIP to compare BDS with YMF and BDS+DH with YMF+DH and WCA with TDF.
Results:
1. Diarrhea rats resulted by 5g/kg FXY showed the rate of loose stools reached 85.54%, the serum D-xylose content and the activity of Na+-K+-ATPase in the colonic epithelial cell decreased(P<0.01).
2. Test dose of YMF and BDS had the same effects on the ileum liquid water metabolism(P>0.05).1.11 mg/ml and 2.22 mg/ml of YMF and BDS could accelerate the ileum liquid water absorption(P<0.01).22.2 mg/ml of BDS and 1g/ml of YMF can result the ileum liquid water increase(P<0.01). When the YMF and BDS combined with DH, the effect was same as the single-drug.3.33 mg/ml and 4.44 mg/ml combination with DH could accelerate the ileum liquid water absorption(P<0.01, P<0.05).
3. The BDS can reduce the rate of loose stools and improve the colonic absorption(P<0.05), there was no difference in the same concentration YMF(P>0.05). When the YMF and BDS combined with DH, the action was same as the single-drug(P>0.05) and there were no different between YMF+DH and BDS+DH(P>0.05). But the effect of two combinations was different in the formula. The WCA could reduce the rate of loose stools and improve the colonic absorption(P<0.05), the TDF had not these action(P>0.05).
4. BDS, BDS+DH and WCA could slower colon movement(P<0.05). YMF and YMF+DH had not effect on colon movement(P>0.05), but the TDF could slower colon movement(P<0.05).
5. BDS could improve serum Na+, K+, Cl- (P<0.01, P<0.05, P<0.05) and the activity of Na+-K+-ATPase in the colonic epithelial cell (P<0.05).YMF could increase serum Na+, Cl- (P<0.01, P<0.05). BDS+DH could improve serum Na+, K+, Cl- (P<0.01, P<0.05, P<0.05) and the activity of Na+-K+-ATPase in the colonic epithelial cell (P<0.05).YMF+DH had the same action as BDS+DH(P>0.05).
6. WCA could improve serum Na+, K+, Cl- (P<0.01, P<0.05, P<0.05)and the activity of Na+-K+-ATPase in the colonic epithelial cell (P<0.05).The function of adjusting serum Na+was better than BDS+DH(P<0.05). The function of adjusting the activity of Na+-K+-ATPase was better than BDS(P<0.05).TDF just can improve serum Na+(P<0.01).
7. Lower concentration of BDS and BDS+DH debase the level of SP and VIP(P<0.01). Middle concentration of BDS just debase the level of VIP(P<0.01).YMF and YMF+DH had no effect on the level of SP and VIP(P>0.05).Both of the WCA and TDF could debase the level of SP and VIP(P<0.01).
Conclusions:
1. All of the BDS, BDS+DH, and WCA are able to improve the colon absorption, promote colonic water and electrolyte metabolism, adjust of the colon movement, and reduce the colon secretion. Low-dose of YMF improve intestinal water and electrolyte absorption,witch is similar to BDS. But the mechanism of YMF is not same as the BDS. Combined with DH, the acting target of two complex tends to similar. However, the action of YMF+DH is antagonized by WCA. BDS of WCA can not be substituted by YMF.
2. Low dose BDS and BDS+DH can treat diarrhea.
3. Through activating spleen and resolving dampness, harmonizing functional activities of qi,the WCA can stop the diarrhea. The therapeutic principles of WCA belong to treating diarrhea with regulating functions of zang and fu organs.
引文
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