四磨汤口服液治疗肝郁气滞型IBS-C的疗效分析和机理研究
摘要
目的
1观察四磨汤口服液对便秘型肠易激综合征(IBS-C)肝气郁滞型患者的临床症状、体征的影响；研究、评价四磨汤口服液治疗便秘型肠易激综合征的临床疗效；比较四磨汤口服液与经典促胃肠动力西药莫沙比利在改善(IBS-C)肝气郁滞型患者症状方面的优劣,为指导临床医师用药提供参考。
2建立肝郁气滞证IBS-C大鼠模型,通过观察神经细胞突触可塑性的变化；检测中枢神经系统和肠神经系统两个部位中的神经递质的变化；研究脊髓、结肠中神经递质P物质、血管活性肠肽VIP在肝气郁滞型IBS-C发病中的作用和相互关系,探讨四磨汤口服液调整肠易激综合征的可能作用机理。
方法
1临床研究
在2010年3月至2012年2月期间广州中医药大学第-附属医院岭南名医诊区和消化内科门诊,选择符合纳入标准的158例中医证属肝郁气滞的便秘型肠易激综合征患者,采用随机数字法分为治疗组80例和对照组78例。分别给予四磨汤口服液和莫沙必利分散片治疗,疗程2周,治疗前、后填写临床症状评分问卷调查,统计各个症状积分的前、后增减,对比分析四磨汤口服液和莫沙比利组治疗前、后各主要症状积分变化及采用尼莫地平法评价两中药物的临床疗效。
2实验研究
选用广东省动物实验中心的SPF级SD大鼠60只,体重180-220g,雌雄各半。普通饮食,适应性喂养1周后,进行实验。随机分为模型组、正常组、四磨汤低剂量组、中剂量组和高剂量组、莫沙必利组。正常组给予常规喂养、给水,其余各组进行造模。肝郁气滞证动物模型：夹尾法加饥饱失常法。造模7天,造模后模型组给予生理盐水2m1/次,1次/日,灌胃；低、中、高剂量组分别以相当于临床等效剂量2倍、4倍、8倍的四磨汤用量灌胃给药(1.5g/kg、3g/kg、6g/kg),用药7天。给药结束后,行腹部回缩反射实验,统计大鼠台腹、拱背的压力阈值,评价IBS大鼠模型的成功与否。行胃排空及小肠推进实验,检测胃排空率及小肠推进率；透射电镜观察结肠ENS中突触的超微结构变化；运用RT-PCR检测与突触功能密切相关的突触素：mRNA的表达；通过放射免疫法和免疫组化法检测肠易激综合征大鼠脊髓及结肠神经递质VIP、 SP表达水平。
结果
1临床研究
临床研究发现中药四磨汤口服液可以明显改善肝郁气滞证IBS-C的主要临床症状：四磨汤口服液在改善腹胀,腹痛,排便艰涩不畅,大便不爽,排便不尽感,嗳气,胸胁痞满症状均优于对照组,具有统计学差异。四磨汤口服液治疗便秘型肠易激综合征(IBS-C)肝郁气滞证总有效率达92.50%,明显优于对照组阳性药物莫沙比利的总有效率84.62%；中、西药组治疗后各症状较治疗前也有显著改善,但与治疗组治疗后比较,除在改善胃纳减少方面与治疗组无差异外,其它各症状的改善都不如治疗组疗效好(P<0.05)。
2实验研究
2.1模型后大鼠精神萎靡不振,活动减少,反应减慢,纳呆,进食量、饮水量减少,腹胀,皮毛枯黄无光泽,体重增加不明显,24h排便量减少,粪便变干,粪便含水率降低,与正常组相比有显著性差异(P<0.05)。模型组胃排空及小肠推进率较正常组明显减慢,(P<0.05)。经治疗后,上述症状较模型组有明显改善,24h大便颗粒数增多,含水率增高,胃排空和小肠推进增快。与模型组比较,四磨汤高、中、低剂量组和莫沙必利组胃排空率及小肠推进率均有显著性差异(P<0.01)四磨汤高剂量组与低剂量组相比较,有统计学差异(P<0.05)。
2.2研究发现造模后大鼠结肠近端突触发生超微结构上的改变：突触囊泡数量显著增加,突触后膜电子致密物明显增厚,突触间隙变窄。这些变化：囊泡的数量的增加,PSD增厚和突触间隙的变窄,提示着囊泡释放几率增加,突触的传递效率增强。用中药四磨汤口服液高中低剂量、西药莫沙比利干预后的大鼠其结肠近端的突触突触囊泡数量较模型组减少,突触后膜电子致密物变薄,突触间隙变宽,这些变化提示这治疗后突触传递效率减低。
运用荧光定量PCR的方法检测突触素(SPY)和突触后致密物质PSD-95的表达,结果提示：与正常组比较,模型组突触素(SYP)表达水平明显提高(P<0.01)。与模型组比较,四磨汤高剂量组和西药组均显著性降低。与正常组比较,模型组PSD-95mRNA表达水平明显提高(P<0.01)。与模型组比较,四磨汤高剂量组和西药组均显著性降低。
2.3采用放免法和免疫组化法测定脊髓和结肠神经递质的变化,结果发现：模型组大鼠脊髓P物质较正常减少,两组见比较具有显著差异(P<0.01)；各组大鼠脊髓SP采用单因素方差分析分析进行数据统计,(F=2.051,P=.086),四磨汤高剂量组与模型组相比,p=0.005,具有统计学差异；此外,其余各组比较均无统计学差异(P>0.05),但就各组均数趋势而言,模型组大鼠脊髓SP含量水平较正常组有所降低,四磨汤低剂量组、四磨汤中剂量组、四磨汤高剂量组大鼠脊髓SP含量较模型组均有所增高,且呈计量相关。
各组大鼠脊髓VIP采用单因素方差分析(one-way ANOVA)分析进行数据统计,(F=0.845,P=0.524),各组间多重比较无统计学差异(P>0.05)
模型组结肠肌间神经丛SP表达水平较正常组显著降低(P<0.01),四磨汤高剂量组与莫沙必利组结肠肌间神经丛SP阳性表达较模型组增高(P<0.01),但四磨汤中、低剂量组与模型组比较无统计学差异(P>0.05),但有增高的趋势。
模型组结肠肌间神经丛VIP表达水平较正常组显著增高(P<0.01),四磨汤高剂量组与莫沙必利组结肠肌间神经丛VIP阳性表达较模型组明显降低((P<0.01),四磨汤中、低剂量组与模型组比较有统计学差异(P<0.01)。
结论
1.四磨汤口服液能够改善便秘型肠易激综合征肝气郁滞型患者的临床症状；
2.四磨汤口服液能促进肠易激综合征模型大鼠胃排空和小肠推进；
3.四磨汤能通过调节突触囊泡数量、突触间隙宽窄等来调节突触的传递效能,
4.四磨汤口服液高剂量组大鼠的脊髓P物质升高,或许与四磨汤可能促进P物质的释放有关；四磨汤口服液能促进肠易激综合征模型大鼠近端结肠P物质的释放;
5.四磨汤口服液对模型大鼠脊髓腰骶段抑制性神经递质VIP的释放无明显影响；四磨汤能抑制肠易激综合征模型大鼠近端结肠VIP的释放；
6.调节结肠突触可塑性可能是四磨汤作用于肠易激综合征大鼠的关键。
Objectives
1Observe the clinical symptoms of IBS-C. Evaluate the curative effect of Simo decoction on Stagnation of liver-Qi stagnationof IBS-C.
2Establish rat model of Stagnation of liver-Qi stagnation of IBS-C, Observe their changes in synaptic plasticity,synaptophysin,neurotransmitter,.Probe into the Function Mechanism of Simo decoction treat on Stagnation of liver-Qi stagnation of IBS-C
Methods
1Clinical research
Grouping158cases of Stagnation of liver-Qi stagnationof IBS-C patients into two parts,one were treat with Simo decoction,other Mosapride,Observe the clinical symptoms of IBS-C patients;Evaluate the curative effect of Simo decoction on Stagnation of liver-Qi stagnation of IBS-C.Filling out questionnaires before and after treating.Evaluate the curative effect of Simo decoction and Mosapride.
2Animal experiment
Grouping60SD rats into six parts.Put5of them int Stagnation of liver-Qi stagnation of IBS-C model,by the way of cliping tails and eating disorders Normal group fed conventionally,TCM-groups were intragastric infusion with Simo decoction6ml/kg,12ml/kg,24ml/kg,7days. Observe thier changes in synaptic plasticity,synaptophysin,neurotransmitter.
Results
1Clinical research Simo decoction helping patients with Stagnation of liver-Qi stagnation of IBS-C to alleviate symptoms.The difference between Simo decoction and Mosapride determined was statistically significant (P<0.05)
2Experimental research
2.1Simo decoction helping Rats with Stagnation of liver-Qi stagnation of IBS-C to alleviate symptoms.The difference between Simo decoction and Mosapride determined was statistically significant (P<0.05)
2.2The synaptic plasticity of the colon of Liver-Qi stasis model rat had changed,Simo decoction helping Rats with Stagnation of liver-Qi stagnation of IBS-C to repair. The difference between Simo decoction and Mosapride determined was statistically significant (P<0.05)
2.3The difference of the neurotransmitters of six groups rats was statistically significant.Simo decoction helping Rats with Stagnation of liver-Qi stagnation of IBS-C to getting more normal.The difference between Simo decoction and Mosapride determined was statistically significant
Conclusion
1Simo decoction helping patients with Stagnation of liver-Qi stagnation of IBS-C to alleviate symptoms.
2Simo decoction can speeding the gastric emptying and small intestine propulsion of rats with Stagnation of liver-Qi stagnation of IBS-C.
3Simo decoction helping Rats with Stagnation of liver-Qi stagnation of IBS-C to repair the synaptic plasticity.
4Simo decoction helping the neurotransmitters of rats with Stagnation of liver-Qi stagnation of IBS-C to getting more normal.
5The key point of Simo decoction to treat IBS-C may be to repair the synaptic plasticity
1观察四磨汤口服液对便秘型肠易激综合征(IBS-C)肝气郁滞型患者的临床症状、体征的影响；研究、评价四磨汤口服液治疗便秘型肠易激综合征的临床疗效；比较四磨汤口服液与经典促胃肠动力西药莫沙比利在改善(IBS-C)肝气郁滞型患者症状方面的优劣,为指导临床医师用药提供参考。
2建立肝郁气滞证IBS-C大鼠模型,通过观察神经细胞突触可塑性的变化；检测中枢神经系统和肠神经系统两个部位中的神经递质的变化；研究脊髓、结肠中神经递质P物质、血管活性肠肽VIP在肝气郁滞型IBS-C发病中的作用和相互关系,探讨四磨汤口服液调整肠易激综合征的可能作用机理。
方法
1临床研究
在2010年3月至2012年2月期间广州中医药大学第-附属医院岭南名医诊区和消化内科门诊,选择符合纳入标准的158例中医证属肝郁气滞的便秘型肠易激综合征患者,采用随机数字法分为治疗组80例和对照组78例。分别给予四磨汤口服液和莫沙必利分散片治疗,疗程2周,治疗前、后填写临床症状评分问卷调查,统计各个症状积分的前、后增减,对比分析四磨汤口服液和莫沙比利组治疗前、后各主要症状积分变化及采用尼莫地平法评价两中药物的临床疗效。
2实验研究
选用广东省动物实验中心的SPF级SD大鼠60只,体重180-220g,雌雄各半。普通饮食,适应性喂养1周后,进行实验。随机分为模型组、正常组、四磨汤低剂量组、中剂量组和高剂量组、莫沙必利组。正常组给予常规喂养、给水,其余各组进行造模。肝郁气滞证动物模型：夹尾法加饥饱失常法。造模7天,造模后模型组给予生理盐水2m1/次,1次/日,灌胃；低、中、高剂量组分别以相当于临床等效剂量2倍、4倍、8倍的四磨汤用量灌胃给药(1.5g/kg、3g/kg、6g/kg),用药7天。给药结束后,行腹部回缩反射实验,统计大鼠台腹、拱背的压力阈值,评价IBS大鼠模型的成功与否。行胃排空及小肠推进实验,检测胃排空率及小肠推进率；透射电镜观察结肠ENS中突触的超微结构变化；运用RT-PCR检测与突触功能密切相关的突触素：mRNA的表达；通过放射免疫法和免疫组化法检测肠易激综合征大鼠脊髓及结肠神经递质VIP、 SP表达水平。
结果
1临床研究
临床研究发现中药四磨汤口服液可以明显改善肝郁气滞证IBS-C的主要临床症状：四磨汤口服液在改善腹胀,腹痛,排便艰涩不畅,大便不爽,排便不尽感,嗳气,胸胁痞满症状均优于对照组,具有统计学差异。四磨汤口服液治疗便秘型肠易激综合征(IBS-C)肝郁气滞证总有效率达92.50%,明显优于对照组阳性药物莫沙比利的总有效率84.62%；中、西药组治疗后各症状较治疗前也有显著改善,但与治疗组治疗后比较,除在改善胃纳减少方面与治疗组无差异外,其它各症状的改善都不如治疗组疗效好(P<0.05)。
2实验研究
2.1模型后大鼠精神萎靡不振,活动减少,反应减慢,纳呆,进食量、饮水量减少,腹胀,皮毛枯黄无光泽,体重增加不明显,24h排便量减少,粪便变干,粪便含水率降低,与正常组相比有显著性差异(P<0.05)。模型组胃排空及小肠推进率较正常组明显减慢,(P<0.05)。经治疗后,上述症状较模型组有明显改善,24h大便颗粒数增多,含水率增高,胃排空和小肠推进增快。与模型组比较,四磨汤高、中、低剂量组和莫沙必利组胃排空率及小肠推进率均有显著性差异(P<0.01)四磨汤高剂量组与低剂量组相比较,有统计学差异(P<0.05)。
2.2研究发现造模后大鼠结肠近端突触发生超微结构上的改变：突触囊泡数量显著增加,突触后膜电子致密物明显增厚,突触间隙变窄。这些变化：囊泡的数量的增加,PSD增厚和突触间隙的变窄,提示着囊泡释放几率增加,突触的传递效率增强。用中药四磨汤口服液高中低剂量、西药莫沙比利干预后的大鼠其结肠近端的突触突触囊泡数量较模型组减少,突触后膜电子致密物变薄,突触间隙变宽,这些变化提示这治疗后突触传递效率减低。
运用荧光定量PCR的方法检测突触素(SPY)和突触后致密物质PSD-95的表达,结果提示：与正常组比较,模型组突触素(SYP)表达水平明显提高(P<0.01)。与模型组比较,四磨汤高剂量组和西药组均显著性降低。与正常组比较,模型组PSD-95mRNA表达水平明显提高(P<0.01)。与模型组比较,四磨汤高剂量组和西药组均显著性降低。
2.3采用放免法和免疫组化法测定脊髓和结肠神经递质的变化,结果发现：模型组大鼠脊髓P物质较正常减少,两组见比较具有显著差异(P<0.01)；各组大鼠脊髓SP采用单因素方差分析分析进行数据统计,(F=2.051,P=.086),四磨汤高剂量组与模型组相比,p=0.005,具有统计学差异；此外,其余各组比较均无统计学差异(P>0.05),但就各组均数趋势而言,模型组大鼠脊髓SP含量水平较正常组有所降低,四磨汤低剂量组、四磨汤中剂量组、四磨汤高剂量组大鼠脊髓SP含量较模型组均有所增高,且呈计量相关。
各组大鼠脊髓VIP采用单因素方差分析(one-way ANOVA)分析进行数据统计,(F=0.845,P=0.524),各组间多重比较无统计学差异(P>0.05)
模型组结肠肌间神经丛SP表达水平较正常组显著降低(P<0.01),四磨汤高剂量组与莫沙必利组结肠肌间神经丛SP阳性表达较模型组增高(P<0.01),但四磨汤中、低剂量组与模型组比较无统计学差异(P>0.05),但有增高的趋势。
模型组结肠肌间神经丛VIP表达水平较正常组显著增高(P<0.01),四磨汤高剂量组与莫沙必利组结肠肌间神经丛VIP阳性表达较模型组明显降低((P<0.01),四磨汤中、低剂量组与模型组比较有统计学差异(P<0.01)。
结论
1.四磨汤口服液能够改善便秘型肠易激综合征肝气郁滞型患者的临床症状；
2.四磨汤口服液能促进肠易激综合征模型大鼠胃排空和小肠推进；
3.四磨汤能通过调节突触囊泡数量、突触间隙宽窄等来调节突触的传递效能,
4.四磨汤口服液高剂量组大鼠的脊髓P物质升高,或许与四磨汤可能促进P物质的释放有关；四磨汤口服液能促进肠易激综合征模型大鼠近端结肠P物质的释放;
5.四磨汤口服液对模型大鼠脊髓腰骶段抑制性神经递质VIP的释放无明显影响；四磨汤能抑制肠易激综合征模型大鼠近端结肠VIP的释放；
6.调节结肠突触可塑性可能是四磨汤作用于肠易激综合征大鼠的关键。
Objectives
1Observe the clinical symptoms of IBS-C. Evaluate the curative effect of Simo decoction on Stagnation of liver-Qi stagnationof IBS-C.
2Establish rat model of Stagnation of liver-Qi stagnation of IBS-C, Observe their changes in synaptic plasticity,synaptophysin,neurotransmitter,.Probe into the Function Mechanism of Simo decoction treat on Stagnation of liver-Qi stagnation of IBS-C
Methods
1Clinical research
Grouping158cases of Stagnation of liver-Qi stagnationof IBS-C patients into two parts,one were treat with Simo decoction,other Mosapride,Observe the clinical symptoms of IBS-C patients;Evaluate the curative effect of Simo decoction on Stagnation of liver-Qi stagnation of IBS-C.Filling out questionnaires before and after treating.Evaluate the curative effect of Simo decoction and Mosapride.
2Animal experiment
Grouping60SD rats into six parts.Put5of them int Stagnation of liver-Qi stagnation of IBS-C model,by the way of cliping tails and eating disorders Normal group fed conventionally,TCM-groups were intragastric infusion with Simo decoction6ml/kg,12ml/kg,24ml/kg,7days. Observe thier changes in synaptic plasticity,synaptophysin,neurotransmitter.
Results
1Clinical research Simo decoction helping patients with Stagnation of liver-Qi stagnation of IBS-C to alleviate symptoms.The difference between Simo decoction and Mosapride determined was statistically significant (P<0.05)
2Experimental research
2.1Simo decoction helping Rats with Stagnation of liver-Qi stagnation of IBS-C to alleviate symptoms.The difference between Simo decoction and Mosapride determined was statistically significant (P<0.05)
2.2The synaptic plasticity of the colon of Liver-Qi stasis model rat had changed,Simo decoction helping Rats with Stagnation of liver-Qi stagnation of IBS-C to repair. The difference between Simo decoction and Mosapride determined was statistically significant (P<0.05)
2.3The difference of the neurotransmitters of six groups rats was statistically significant.Simo decoction helping Rats with Stagnation of liver-Qi stagnation of IBS-C to getting more normal.The difference between Simo decoction and Mosapride determined was statistically significant
Conclusion
1Simo decoction helping patients with Stagnation of liver-Qi stagnation of IBS-C to alleviate symptoms.
2Simo decoction can speeding the gastric emptying and small intestine propulsion of rats with Stagnation of liver-Qi stagnation of IBS-C.
3Simo decoction helping Rats with Stagnation of liver-Qi stagnation of IBS-C to repair the synaptic plasticity.
4Simo decoction helping the neurotransmitters of rats with Stagnation of liver-Qi stagnation of IBS-C to getting more normal.
5The key point of Simo decoction to treat IBS-C may be to repair the synaptic plasticity
引文
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