Basic Researchs On The TCM Incompatibility Theory Based On Eighteen Incompatible Medicament

This work was supported by National Basic Research Program of China(973 Program)(No.2011CB505303).This dissertation is divided into five chapters.Chapter 1 was literature research.Recent progress in the effects and mechanisms of compatibining Glycyrrhizae Radix et Rhizoma {Gancao)with Sargassum(Haizao),Euphorbiae Pekinensis Radix(Daji),Kansui Radix(Gansui)or Genkwa Flos(Yuanhua)on gastrointestinal function.To explore the possible characteristics and mechanisms of incompatibility,this review is based on traditional Chinese medicine theory,revolve around the toxic effects characterizations of toxicity caused and enhanced or effect reduced,open a new perspective on gastrointestinal function,then clarify the modern pharmacology researchs of anti-drugs.Chapter 2 was the introduction of the technology system of gastrointestinal function.Evaluation of the gastrointestinal tract system function is a very important part for studying incompatibility of traditional Chinese medicine.This article focuses on gastrointestinal motility,secretion and barriers,seeks to establish an evaluation system on gastrointestinal tract function which in accordance with the characteristics of Chinese herbal medicine incompatibility.Chapter 3 was effects of anti-drug combination on gastrointestinal motility.The effects of anti-drug combination were researched on different in vitro and in vivo models of gastrointestinal motility.Section I,Effects of anti-drugs on gastrointestinal transit in the mouse in vivo.Using a mice gastric emptying and intestinal propulsive model,a single gavage administration,Haizao decoction(0.78 g/kg,1.56 g/kg,3.12 g/kg)can significantly increase the rate of intestinal propulsive,Gancao decoction(0.78 g/kg,1.56 g/kg,3.12 g/kg)can inhibit intestinal propulsion.Haizao-Gancao co-decoction solution(1:1)of the small intestine propulsion rate had no significant effect.Daji(0.195 g/kg,0.39 g/kg,0.78 g/kg),Gansui(0.0975 g/kg,0.195 g/kg,0.39 g/kg)and Yuanhua(0.195 g/kg,0.39 g/kg,0.78 g/kg)aqueous solution of powder could significantly increase the rate of intestinal propulsive,when combined with Gancao decoction,the intestinal propulsion-promoting effect significantly reduced.Section II,Effects of anti-drugs on the spontaneous contractions of rat ileum in vitro.Using model of isolated rat ileum,single Gancao decoction(0.1～2 mg/mL)significantly inhibited the spontaneous contractions of rat ileal smooth muscle,while each single decoction of Haizao(0.1 to 2 mg/mL),Daji(0.3 to 2 mg/mL),Gansui(0.1 to 2 mg/mL)and Yuanhua(0.3～2 mg/mL)could promote the ileal contraction to a certain degree.The effect of Haizao,Daji,Gansui or Yuanhua would be weakened when it was mixed with Gancao.The contraction-promoting effect of each co-decoction was weaker than the single decoction.And the effect of Gancao-Gansui co-decoction was weaker than the mixed decoction,whereas the effects of another three co-decoctions were stronger than the mixed decoction.Section Ⅲ,Mechanisms underlying Haizao,Daji,Gansui,Yuanhua and Gancao aqueous extracts on the contractions of rat ileum in vitroUsing model of isolated rat ileum,GRRAE induced the relaxant effect by possible muscarinic receptors antagonism and Ca2+ channel blockade in the rat ileum.The regulatory effect of GFAE on rat ileal contraction are medicated possibly through activation of muscarinic receptor and β-adrenoceptors,augmentation of Ca2+ influx through L-type Ca2+ channel,and Ca2+ release from the intracellular stores.The regulatory effect of HZAE are medicated possibly through activation of α-adrenoceptors,augmentation of Ca2+ influx through L-type Ca2+ channel,and Ca2+ release from the intracellular stores.The regulatory effect of DJAE are medicated possibly through activation of muscarinic receptor and a-adrenoceptors and augmentation of Ca2+ influx through L-type Ca2+ channel.The regulatory effect of GSAE are medicated possibly through activation of muscarinic receptor and β-adrenoceptors,augmentation of Ca2+ influx through L-type Ca2+ channel,and Ca2+ release from the intracellular stores.Section IV,Chemical Substances underlying Yuanhua aqueous extract-induced contraction of rat ileum in vitroThe active substances from Yuanhua promoting rat isolated ileal contraction might be in the PE and DCM fractions.And Yuanhuacine(5μM)can promote ileal contraction.The n-BuOH and H2O fractions played a role in promoting ileal contraction at high concentrations(3～30 mg crude drug/ml).The flavonoid glycosides from Yuanhua aqueous extract might be one of the ingredients of promoting ileal contraction.Chapter 4 was effects of anti-drug combination on gastrointestinal secretion function.Section I,Effects of anti-drugs on the secretion by mice colon intestinal mucosa.PAS staining was observed in mice with a single gavage anti-drugs decoction on intestinal mucus secretion.Haizao decoction(1.56 g/kg,3.12 g/kg)can significantly increase intestinal mucus secretion,Gancao decoction can inhibit the intestinal mucus secretion,and Haizao-Gancao co-decoction solution(1:1)of the intestinal mucus secretion had no significant effect.Daji,Gansui and Yuanhua aqueous solution of powder could increase the intestinal mucus secretion,when combined with Gancao decoction,the intestinal secretion-promoting effect significantly reduced.Section H,Effects of anti-drugs on Na+-K+-ATPase activity in mice.The results showed that Haizao,Daji and Yuanhua single oral administration had no significant effect on intestinal Na+-K+-ATPase activity,while Gansui(0.195g/kg)can significantly reduce the Na+-K+-ATPase activity(P<0.05).when combined with Gancao,Na+-K+-ATPase activity of each group was significantly increased.Chapter 5 was effects of anti-drug combination on gastrointestinal barriers function.Section I,Effects of anti-drugs on the mice intestinal barriers.HE staining was observed in mice with a single gavage anti-drugs decoction on the intestinal barrier.In the pharmacopoeia dose range,Daji and Yuanhua had no significant intestinel injury of mice,when combined with Gancao,the intestinal appeared inflammatory infiltrate.Individual mice of Gansui group also showed inflammatory infiltrate,and the inflammatory infiltrate was aggravated at 0.0975g/kg when combined with Gancao.Section Ⅱ,Effects of anti-drugs on IEC-6 cell migration.In the early stages of mucosal injury,the intestinal mucosa mainly through epithelial cells migration to cover the damage quickly,rebuilding the mucosal barrier.Gancao aqueous extracts(100mg/L)promoted the migration of IEC-6.Haizao,Daji,Gansui and Yuanhua could inhibitIEC-6 cell migration at differeent degree.When combined with Gancao,the inhibition degree of IEC-6 cell migration was stronger.Comprehensive analysis of each role of the above areas can draw conclusions:(1)Haizao,Daji,Gansui and Yuanhua could significantly promote intestinal motility and secretion,playing a "LI SHUI","RUN XIA" or "XIE SHUI ZHU YIN "role.Gancao can inhibit intestinal motility and secretion.The effects of anti-drugs groups may be reduced.(2)Gancao is"YI QI JIAN PI" traditional Chinese medicine,protecting the intestinal mucosa and repairing the barrier quickly,by promoting epithelial cell migration.Haizao,Daji,Gansui and Yuanhua could inhibit cell migration,when combined with Gancao,the effect was stronger,indicating anti-drugs groups could not quickly repair the intestinal barrier.In addition,Gancao could not relieve symptoms in patients with bloating caused by Gansui and Yuanhua.In other words,anti-drugs groups failed to treat the adverse gastrointestinal reactions,and failed to rapid repair the intestinal barrier by promoting cell migration.