顺尔宁在儿童哮喘中应用PPT课件.ppt

白三烯受体拮抗剂-孟鲁司特(顺尔宁)在儿童哮喘治疗中的作用,.,BurdenofAsthmainChildren,6.3million18yearsofage,14millionmissedschooldaysannually,3.5millionphysicianvisits*,1/3ofpediatricasthmadeathsinthoseclassifiedwithmildasthma,203000Hospitalizations*,658000emergencydepartmentvisits*,*Includes1999or2000annualestimatesforchildren15yearsofage.AmericanLungAssociation.2003;Manninoetal.MMWR.2002;51:1-13.,北京哮喘病临床研究所,哮喘长期控制目标(GINA2002),哮喘症状得到控制哮喘的急性发作得到预防肺功能正常或接近正常保持正常的体力活动,包括运动避免治疗哮喘药物的副作用预防不可逆的气道阻塞预防因哮喘死亡,北京哮喘病临床研究所,哮喘控制药物(GINA2002),吸入皮质激素抗白三烯药物长效吸入2受体激动剂长效口服2受体激动剂,全身皮质激素色苷酸钠和尼多克罗米钠甲基黄嘌呤第二代抗组胺药（H1拮抗剂）其他口服抗过敏药物全身激素减量疗法变应原特异性免疫疗法,北京哮喘病临床研究所,真实世界的实际效果儿童哮喘治疗尤需关注的问题,实际效果=疗效x顺应性,口服vs吸入,服用次数,副作用,花费,病人受教育程度,起效速度,吸入技术,北京哮喘病临床研究所,与目前治疗相关的主要问题儿童应用吸入治疗的困难,4,北京哮喘病临床研究所,达到肺部的剂量(%),资料源自10个研究中的179名患者*两项独立研究总共18名患者选自CochraneMGetal.Chest2000;117(2):542-550,Ref6,pp547A,548A,输送至肺部的药物,与目前治疗相关的主要问题吸入皮质激素药物输送的困难,5,北京哮喘病临床研究所,与目前治疗相关的主要问题吸入皮质激素的依从性问题,应用皮质激素吸入治疗的平均数(%),Ref8,p1052B,选自MilgromHetal.JAllergyClinImmunol1996;98(6,part1);151-1057,6,报告的依从性并不一定能反映实际应用状况,北京哮喘病临床研究所,与目前治疗相关的主要问题依从性是控制哮喘的一项基本要素,选自MilgromHetal.JAllergyClinImmunol1998;98(6,part1):1051-1057.,Ref8,p1055A,哮喘缓解期与需要口服皮质激素救急治疗的发作期小儿的依从性比较,依从性不良可导致治疗效果不佳,依从性%,7,北京哮喘病临床研究所,*Onechewabletabletoncedailyatbedtime*Two1mgpuffsfourtimesdailyAdaptedfromVolovitzBetalCurrTherRes2000;61(7):490-506.,同吸入治疗相比家长及监护人更喜欢口服的药物,0,10,20,30,40,50,60,70,80,90,100,Cromolyn8mg*,12,Montelukast5mg*,88,Percentexpressingpreferences,(n=249),p0.001,12-WeekStudyin266Children,北京哮喘病临床研究所,选择另一种方法使药物到达靶器官,北京哮喘病临床研究所,嗜酸粒细胞,X103/gSputum,气道炎症：痰中嗜酸粒细胞增多和疾病严重度,P0.001,10,000,1,000,100,10,1,P0.001,P0.01,P0.05,对照组n=22,间歇哮喘n=19,轻中度哮喘n=38,重度哮喘n=17,100,000,LouisRetal.AmJRespirCritCareMed.2000;161:916,AmericanThoracicSociety.,北京哮喘病临床研究所,尽管使用激素，气道炎症依然存在,ICS=inhaledcorticosteroids;OCSICS=receivedoralcorticosteroidswithorwithoutICSAdaptedfromLouisRetalAmJRespirCritCareMed2000;161:9-16.,Ref3,p14,Figure3;p10,1,L1,20,00010,0001,000100101,Eosinophil103/gsputum,Controlgroup,Mildtomoderate,ICSlow-dose(n=10),ICShigh-dose(n=15),OCS(n=10),OCSICS(n=7),Severeasthma,p0.01,p0.001,p0.001,p0.01,Inaclinicalstudyof74patients,北京哮喘病临床研究所,blocksteroid-sensitivemediators,blockstheeffectsofCysLTs,Inhaledsteroids,Montelukast,Thesliderepresentsanartisticrendition.AdaptedfromPeters-GoldenM,SampsonAPJAllergyClinImmunol2003;111(1suppl):S37-S42;BisgaardHAllergy2001;56(suppl66):7-11.,Steroid-sensitivemediatorsplayakeyroleinasthmaticinflammation,CysLTsplayakeyroleinasthmaticinflammation,SteroidsdoNOTinhibitCysLTformationintheairwaysofasthmaticpatients,两条路径,半胱氨酰白三烯-气道炎症的另一路径,北京哮喘病临床研究所,我们知道:半胱氨酰白三烯在哮喘病理过程中扮演重要作用皮质不能抑制其作用,AdaptedfromHayDWPetalTrendsPharmacolSci1995;16:304-309.,InflammatoryCells(mastcells,eosinophils),SensoryNerves(Cfibers),CysLTs,Edema,BloodVessel,DecreasedMucusTransport,EosinophilInflux,CationicProteinRelease,Epithelial-CellDamage,ContractionandProliferation,IncreasedMucusSecretion,AirwayEpithelium,北京哮喘病临床研究所,每天吸入激素量:1,444mcg933mcg,6.4,P0.02*13,P0.05*11.4,P0.02*9.4,半胱氨酰白三烯在痰液中,ng/mL,半胱氨酰白三烯(LTC4,LTD4,LTE4):在诱导痰液中与疾病严重度,*vscontrol.AdaptedfromPavordIDetal.AmJRespirCritCareMed.1999;160:19051909.,北京哮喘病临床研究所,每天吸入激素的剂量:1,444mcg933mcg,6.4,P0.02*13,P0.05*11.4,P0.02*9.4,半胱氨酰白三烯在痰液中,ng/mL,半胱氨酰白三烯(LTC4,LTD4,LTE4):在诱导痰液中与疾病严重度,*vscontrol.AdaptedfromPavordIDetal.AmJRespirCritCareMed.1999;160:19051909.,北京哮喘病临床研究所,p=NSbetweengroupsAdaptedfromOShaughnessyKMetalAmRevRespirDis1993;147:1472-1476.,18.7,201612840,UrinaryLTE4excretion(ng/mmolcreatinine),18.4,Placebo,Fluticasonepropionate,氟替卡松对尿LTE4水平没有影响,北京哮喘病临床研究所,我们了解关键性概念,有关哮喘发病的现代研究工作提示哮喘的临床表现是全身免疫反应性炎症的结果病情的严重度与吸入和/或口服激素的使用并无依赖关系，炎症仍可持续存在。LTs是一种重要的介质参与炎症形成。CysLT1受体（CysLT1-R）广泛分布于全身，已确定在前炎细胞及哮喘相关的特殊位置上均有受体存在。CysLTs作为一个效应分子,在哮喘进程中发挥直接或间接的效应作用。,北京哮喘病临床研究所,平滑肌功能障碍,炎症细胞的激活,身性炎症表现中呼吸系统的参与因素,AdaptedfromSichererSHetal.JAllergyClinImmunol.2000;106:S251-S257.,基因易感性,环境暴露,免疫反应的Homing,免疫反应的类型,免疫反应的程度,靶器官的反应,气道上皮功能障碍,北京哮喘病临床研究所,FigueroaD,etalAJRCCM2001;163:226233,DistributionofCysLT1Receptor(includinghard-to-reachsmallairways)andBiologicalEffectsinInflammation,CENTRALAIRWAYS,PERIPHERALAIRWAYS,EvansJ,FigueroaDJClinExpAllergyRev2001,北京哮喘病临床研究所,我们关注白三烯受体拮抗剂应用定位,代替低剂量吸入皮质激素作为一线预防性单药治疗,尤其是婴幼儿哮喘(依从性较差)对3级、4级病人,与低剂量吸入皮质激素合并使用作为预防运动性哮喘的治疗,北京哮喘病临床研究所,ReprintedfromJAMA1998,Volume279,MontelukastforChronicAsthmain6-to14-Year-OldChildren:ARandomized,Double-BlindTrial,KnorrB,MatzJ,BernsteinJAetalforthePediatricMontelukastStudyGroup.,MontelukastinthePreventionofBronchoconstriction(Cold,DryAir)inChildren3-5YearsofAge.AmJRespirCritCareMed2000;162:187-190,ReprintedfromPediatrics2001,Volume108,Montelukast,aLeukotrieneReceptorAntagonist,fortheTreatmentofPersistentAsthmainChildrenAged2to5Years,KnorrB,BranchiLM,BisgaardHetal.,各种临床研究显示了顺而宁在儿童哮喘治疗中的作用尤其是小年龄儿童以及运动又诱发的支气管收缩的作用,北京哮喘病临床研究所,研究设计,*One5mgchewabletabletoncedailyatbedtimeShort-actingbeta2agonistswereusedasneeded.AdaptedfromKnorrBetalJAMA1998;279(15):1181-1186;Dataonfile,MSD.,Inhaledcorticosteroids,Montelukast*(n=201),0,2,24,Weeks,PeriodIRun-inSingle-blind,PeriodIIEfficacyTrial(8weeks)Double-blind,PeriodIIISafetyExtension(14weeks)Open-label,10,Placebo(n=135),Montelukast,Placebo,Inhaledcorticosteroids,Montelukast,北京哮喘病临床研究所,肺功能（FEV1)改变,*One5mgchewabletabletoncedailyatbedtime*BetweengroupsovereightweeksoftreatmentAdaptedfromKnorrBetalJAMA1998;279(15):1181-1186;Dataonfile,MSD.,0,2,4,6,8,10,12,2,0,4,6,8,Montelukast*(n=196)Placebo(n=131),MeanchangeinFEV1(%),Weeksinactivetreatment,p0.001*,8-WeekStudyin336Children,北京哮喘病临床研究所,生活质量,*One5mgchewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalJAMA1998;279(15):1181-1186andDataonfile,MSD.,1.08,0.6,0.5,0.58,0.19,0.1,0,0.2,0.4,0.6,0.8,1.0,1.2,Activity,Symptoms,Emotions,Montelukast*(n=162),Placebo(n=106),Changefrombaselineinquality-of-lifescore(LSmean),p0.001,p=0.007,p=0.002,8-WeekStudyin336Children,北京哮喘病临床研究所,外周血嗜酸性细胞记数,*One5mgchewabletabletoncedailyatbedtime*BetweengroupsovereightweeksoftreatmentAdaptedfromKnorrBetalJAMA1998;279(15):1181-1186andDataonfile,MSD.,Montelukast*(n=197)Placebo(n=133),Meaneosinophilcount(no.ofcells109/L),0.10,0.05,0.00,0.05,2,0,4,6,8,Weeksinactivetreatment,p=0.02*,8-WeekStudyin336Children,北京哮喘病临床研究所,延伸研究资料同吸入激素对照,*One5mgchewabletabletoncedailyatbedtime*Beclomethasone84gthreetimesdailyoragentusedinPrimaryStudyDataonfile,MSD.,0,1,2,3,4,5,6,7,FEV1(changefrombaselinein%predicted),Primarystudy(8weeks),Extensiondata(48weeks),Montelukast*(n=182),5.27,Placebo(n=122),2.19,Montelukast*(n=200),6.01,Inhaledcorticosteroid*(n=38),5.55,p0.05,48-WeekExtensionStudyin245Children,北京哮喘病临床研究所,Montelukast,Montelukast4mg*(n=461),Numbersrepresentpatientsenteringeachperiod.InPeriodIII:montelukast(n=288);usualcare(n=119)Short-actingbeta2agonistswereusedasneededinbothgroups.*Onechewabletabletoncedailyatbedtime;patientsintheextensionstudywhobecamesixyearsofagewereswitchedtomontelukast5mg(onechewabletabletoncedailyatbedtime).*Inhaled/nebulizedcorticosteroidsorcromolynaccordingtotheusualclinicalpracticeoftheinvestigatorAdaptedfromKnorrBetalPediatrics2001;108(3):1-10;Dataonfile,MSD.,Slide22,0,2,50,Weeks,PeriodIRun-inSingle-blind,PeriodIIActiveTreatment(12weeks)Double-blind,PeriodIIITolerabilityExtension(36weeks)Open-label,14,Placebo(n=228),Montelukast,Placebo,UsualCare*,UsualCare*,MontelukastChronicAsthmaStudy(25years)StudyDesign,北京哮喘病临床研究所,*One4mgchewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalPediatrics2001;108(3):1-10;Dataonfile,MSD.,Slide25,MontelukastChronicAsthmaStudy(25years)DaytimeAsthmaSymptomScores,Daytimeasthmasymptomscore(changefrombaseline),0.40,0.35,0.30,0.25,0.20,0.15,0.10,0.05,0,Montelukast*(n=458),Placebo(n=227),0.37,0.26,p=0.003,12-WeekStudyin689Children,北京哮喘病临床研究所,Slide31,OnsetofAction:DaytimeSymptoms*ImprovedfromDay1*,Posthocanalysisofthefirst21daysoftreatment;first7daysshownonslide.Short-actingbeta2agonistswereusedasneededinbothgroups.*OnechewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalPediatrics2001;108(3):1-10.,Daysonactivetreatment,Placebo(n=227)Montelukast4mg*(n=458),MeanSEchangeindaytimesymptomscore,1,4,6,7,0.4,0.1,0.0,0.1,0.2,0.3,5,3,2,12-WeekStudyin689Children,北京哮喘病临床研究所,5,MontelukastChronicAsthmaStudy(25years)MontelukastSignificantlyImprovedIndividualDaytimeSymptomScores,35,39,42,42,26,28,28,23,0,10,15,20,25,30,35,40,45,Coughing,p=0.003,Wheezing,p=0.042,Troublebreathing,p=0.007,Activities,p0.001,Montelukast4mg*(n=458),Placebo(n=227),Posthocanalysisbasedon0-to5-pointdiaryscale(nosymptomstoverysevere)Short-actingbeta2agonistswereusedasneededinbothgroups.*OnechewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalPediatrics2001;108(3):1-10.,Slide26,Meanimprovementfrombaseline(%),12-WeekStudyin689Children,北京哮喘病临床研究所,*One4mgchewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalPediatrics2001;108(3):1-10.,Slide27,MontelukastChronicAsthmaStudy(25years)Beta2-AgonistUse,Percentageofdayswithbeta2-agonistuse,46,48,50,52,54,56,Montelukast*(n=461),Placebo(n=228),49,55,p=0.001,12-WeekStudyin689Children,北京哮喘病临床研究所,MontelukastChronicAsthmaStudy(25years)ReductioninPeripheralBloodEosinophils,Slide32,25,20,15,10,5,0,Least-squaresmean%changefrombaseline,Placebo(n=221),Montelukast4mg*(n=448)