三黄方抗内毒素活性的药代动力学和药效学研究

成都中医药大学博士学位论文三黄方抗内毒素活性的药代动力学和药效学研究姓名：邓翀申请学位级别：博士专业：中药学指导教师：张艺2008-05LPSDASTNONOLPSBeaglet1/2kaKaMRT0-8CmaxTmaxT1/2KaKAbstractSan-HuangFormulawasfirstlyrecordedinJinguiChamber,composedbyRadixetRhizomaRhei,RhizomaCoptidisandRadixScutellariae,withthefunctionofclearingheat-fire,removingdampnessandremovingtoxin,forthetreatmentofheat-toxinsyndrome,whichissimilartoendotoxemia.Accordingtothecharacteristicsoftheprincipleofthetreatmentofheat-toxinsyndrome,themethodofclearingheatandremovingtoxinisconstantlyapplied.UndertheguidanceofTCMtheory,thispaperisbasedontheresearchideasthatSan-HuangFormulacantreatendotoxemia,obeyedtheprinciplesofthecombinationofdiseaseandsyndrome,therelevanceofformulaandsyndrome,thecorrespondenceofdrugandsyndrome,andtheunificationoftheory,method,formulaanddrug.OBJECTIVERegardingtheanti-toxinactivityasthebreakthroughpoint,thisarticlehadstudiedpharmacokineticsandpharmacodynamicsofanti-endotoxemiaofseriesofSan-Huangpreparations,andalsocomparedanti-endotoxinactivity,inordertorevealtherelationshipbetweeneffectivecomponentsandeffectofSan-HuangFormula,elucidateitsmechanismandprovidescientificbasisfortheclinicalapplication.METHODS1San-HuangFormulaanti-endotoxinactivityinvitroandchemicalfingerprintsComparedwiththeanti-endotoxinactivityinvitroofthedifferentprescriptionsof12manufacturersofSan-HuangFormula,andpreliminarilystudiedchemicalfingerprintsaswell,allthemajorpeakshadbeenconfirmedbythemethodofthedynamicturbidity,withclusteranalysisandprincipalcomponentanalysistoprocessstatisticaldata.2thepharmacokineticandpharmacodyamicresearchofYiqingCapsuleforanti-endotoxemiaAccordingtopreliminaryresultscombinedwithTCMtheory,thisexperimenthadbeenchosenYiqingCapsule,oneofSan-Huangpreparationswithcomparativeanti-endotoxinactivityinvitro.WiththeindexofthecontentofendotoxinintheserumandNO,peripheralhemodynamics,histomorphologyandsoon,YiqingCapsulehadbeenstudiedthepharmacodyamicsofLPS-inducedBeagleendotoxemia,thepharmacokineticsoftreatmentgroupandblanktreatmentgroupwithbaicalinandrheinastheindex,andthedeterminationofplasmaconcentrationofbaicalinandrheinwhichthepharmacokineticparametersofhadbeenanalyzedbyDAS.TreatmentgroupandblanktreatmentgrouphadbeencomparedthepharmacokineticparametersbyT-test.Onthebasisofthepharmacodynamicexperimentsofanti-endotoxemiaofYiqingCapsule,therelevanceofthepharmacodynamicandpharmacokinetictargetshadbeeninvestigatedwitheffectiveindexofhemodynamics,theremovalrateofanti-endotoxinandtheinhibitingrateofNO.RESULTS1San-HuangFormulaanti-endotoxinactivityinvitroandChemicalfingerprintsTheresultsshowedthatthechemicalcompositionsofSan-Huangpreparationswereofgreatdifferencewiththemainfactorsofbaicalin,rheinandemodinthataffectedthequalityofpreparations.Thechemicalcompositions,suchasberberine,,baicalin,rhein,emodin,chrysophanol,andaloe-emodin,werecorrelatedwithanti-endo-toxininvitro.2thepharmacokineticandpharmacodyamicresearchofYiqingCapsuleforanti-endotoxemiaYiqingCapsuleremovedplasmaendotoxin,inhibitedtheexcessivereleaseofNO,positivelyeffectedtheperipheralhemodynamicsparameters,apparentlyimprovedthepathologicchangeofhistomorphologyofLPS-inducedBeagleendotoxemia,andalsorelievedtheinflammationcausedbyendotoxemia.Contrastedthepharmacokineticparametersbetweentreatmentgroupandblanktreatmentgroup,t1/2ka,KaandMRT(0-8)ofbaicalinandCmax,Tmax,T1/2,KaandKofrheinwereofconspicuousdisparity,andthevelocityofresorptionandmetabolismofbaicalinandRheinoftreatmentgroupwasnotablelyslowerblanktreatmentgroup.Bothofbloodconcentration-effectcurveappearedsignificantlyhysteresisloopthatthepeakofeffectapparentlylaggedbehindthepeakofbloodconcentration,andtheeffectroomwasnotinthebloodroomwhichappearedthephenomenonthattheeffectlaggedbehindthebloodconcentration.CONCLUSIONThroughthecombinationofinvitroandinvivo,thechemicalfingerprintsandeffects,andpharmacokineticsandefficacy,San-HuangFormulawasprovedthatcouldremoveendotoxinsandreducetheinflammatorycausedbyendotoxins,withtheeffectivecomponentsofbaicalin,rhein,emodin,chrysophanol,andaloe-emodin.INNOVATION1InitiallyraisedSan-HuangFormulacantreatmentendotoxemia,forSan-HuangFormulatreatmentendotoxemiaprovidescientificbasis.2Establishmentofchemicalfingerprint-pharmacodynamics(invitroandinvivo)-pharmacokineticcombiningofthemethodtoevaluationSan-HuangFormulaqualityandefficacy.Keywords:San-HuangFormula;YiqingCapsule;fingerprint;Anti-LPSactivityPharmacodynamics;pharmacokineticsLPSlipopolysaccharidePKPharmacokineticsPDPharmacodynamicsCMC-Nacarboxycmc-nacmccelluloseMethylHPLCHighperformanceLiquidChromatographyODSOctadectlsilaneSDSSodiumdodecylsulfatePCAPrincipalComponentAnalysisETMEndotoeamiaHRHeartrateSP/SBPSystolicpressureDP/DBPDiastolicpressureMAPMeanarterialpressureNONitricOxideKeEliminationrateconstantT1/2HalflifetimeCmaxTheconcentrationprofileTmaxTheconcentration-timeprofileAUCAreaunderthecurveMRTMeanResidenceTime139111.12181.1.1101543[1]12g42g10g2,,San-HuangFormulapreparationsprescriptionlist1.1.230%50%[1][2]31.27521.5[6][7][8]-a-1[7]1.34[7][8][9]G-G-[11]1.4[12]5[13]pH[14][15][16][17][18][19]