顺尔宁在儿童哮喘中应用

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asthma@163.com北京哮喘病临床研究所BurdenofAsthmainChildren~6.3million

18yearsofage~14millionmissedschooldaysannually

~3.5millionphysicianvisits*~1/3ofpediatricasthmadeathsinthoseclassifiedwithmildasthma~203

000Hospitalizations*~658

000emergency

departmentvisits**Includes1999or2000annualestimatesforchildren<15yearsofage.AmericanLungAssociation.2003;Manninoetal.MMWR.2002;51:1-13.asthma@163.com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asthma@163.com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asthma@163.com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asthma@163.com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4asthma@163.com北京哮喘病临床研究所达到肺部的剂量(%)23212128051015202530定量吸入装置(n=18)定量吸入装置+储雾罐(n=18*)呼吸启动的定量吸入装置(n=18)干粉吸入(n=10)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):542-550Ref6,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5asthma@163.com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,p1052B02040608010095.458.431.8报告的应用数实际应用数正确时间的应用数(n=24)选自MilgromHetal.JAllergyClin

Immunol1996;98(6,part1);151-10576

报告的依从性并不一定能反映实际应用状况asthma@163.com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.JAllergyClin

Immunol

1998;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%缓解期哮喘儿童(n=16)需要口服激素救急治疗的儿童(n=8)02040608010068.2%依从性p=0.00813.7%依从性7asthma@163.com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0102030405060708090100Cromolyn8mg**12Montelukast5mg*88Percent

expressingpreferences(n=249)p<0.00112-WeekStudyin266Childrenasthma@163.com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asthma@163.com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P<0.00110,0001,000100101P<0.001P<0.01P<0.05对照组

n=22间歇哮喘

n=19轻中度哮喘

n=38重度哮喘

n=17100,000LouisRetal.AmJRespir

CritCareMed.2000;161:9–16,©AmericanThoracicSociety.asthma@163.com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;OCS±ICS=receivedoralcorticosteroidswithorwithoutICSAdaptedfromLouisRetalAmJRespirCritCareMed2000;161:9-16.

Ref3,p14,Figure3;p10,¶1,L120,00010,0001,000100101Eosinophil

103/g

sputumControl

groupMildtomoderateICS

low-dose(n=10)ICS

high-dose(n=15)OCS

(n=10)OCS±ICS

(n=7)Severeasthmap<0.01p<0.001p<0.001p<0.01Inaclinicalstudyof74patientsasthma@163.com北京哮喘病临床研究所block

steroid-

sensitive

mediatorsblocksthe

effectsof

CysLTsInhaledsteroidsMontelukastThesliderepresentsanartisticrendition.AdaptedfromPeters-GoldenM,SampsonAPJAllergyClinImmunol2003;111(1suppl):S37-S42;BisgaardHAllergy2001;56(suppl66):7-11.Steroid-sensitive

mediators

playakeyrole

inasthmatic

inflammationCysLTs

playakeyrole

inasthmatic

inflammationSteroidsdoNOTinhibitCysLTformationintheairwaysofasthmaticpatients两条路径半胱氨酰白三烯---气道炎症的另一路径asthma@163.com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)Sensory

Nerves

(Cfibers)CysLTsEdemaBlood

VesselDecreasedMucusTransportEosinophilInfluxCationicProteinRelease,Epithelial-CellDamageContractionandProliferationAirwaySmoothMuscleIncreased

MucusSecretionAirway

Epitheliumasthma@163.com北京哮喘病临床研究所每天吸入激素量:1,444mcg933mcg6.4P<0.02*13P<0.05*11.4P<0.02*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;160:1905–1909.asthma@163.com北京哮喘病临床研究所每天吸入激素的剂量:1,444mcg933mcg6.4P<0.02*13P<0.05*11.4P<0.02*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;160:1905–1909.asthma@163.com北京哮喘病临床研究所p=NSbetweengroupsAdaptedfromO’ShaughnessyKMetalAmRevRespirDis1993;147:1472-1476.

18.7201612840UrinaryLTE4

excretion(ng/mmol

creatinine)18.4PlaceboFluticasone

propionate氟替卡松对尿LTE4水平没有影响asthma@163.com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。asthma@163.com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.JAllergyClin

Immunol.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

接触的途径

免疫反应的程度靶器官的反应气道上皮功能障碍asthma@163.com北京哮喘病临床研究所FigueroaD,etalAJRCCM2001;163:226–233DistributionofCysLT1Receptor(includinghard-to-reachsmallairways)andBiologicalEffectsinInflammation

CENTRALAIRWAYSPERIPHERALAIRWAYSEvansJ,FigueroaDJClinExpAllergyRev2001asthma@163.com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

一级间歇发作病情严重度分级每日的哮喘控制药物其他治疗选择不需任何药物低剂量吸入型糖皮质激素二级轻度持续茶碱缓释片，或色甘酸钠，或白三烯受体调节剂三级中度持续中剂量吸入型糖皮质激素中剂量吸入型糖皮质激素加茶碱缓释片，或中剂量吸入型糖皮质激素加吸入长效ß2激动剂，或高剂量吸入型糖皮质激素，或中剂量吸入型糖皮纸激素加白三烯受体调节剂四级重度持续高剂量吸入型糖皮质激素，如果需要时可加入以下一种或多种治疗：茶碱缓释片吸入长效ß2激动剂白三烯受体调节剂口服糖皮质激素asthma@163.com北京哮喘病临床研究所ReprintedfromJAMA1998,Volume279

ORIGINALINVESTIGATIONMontelukastforChronicAsthmain

6-to14-Year-OldChildren:ARandomized,Double-BlindTrialKnorrB,MatzJ,BernsteinJAetalforthePediatricMontelukastStudyGroup.MontelukastinthePreventionofBronchoconstriction(Cold,DryAir)inChildren3-5YearsofAge.AmJRespir

CritCareMed2000;162:187-190ReprintedfromPediatrics2001,Volume108

ORIGINALINVESTIGATIONMontelukast,aLeukotrieneReceptorAntagonist,fortheTreatmentofPersistentAsthmainChildrenAged2to5YearsKnorrB,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asthma@163.com北京哮喘病临床研究所研究设计*One5mgchewabletabletoncedailyatbedtimeShort-actingbeta2agonistswereusedasneeded.AdaptedfromKnorrBetalJAMA1998;279(15):1181-1186;Dataonfile,MSD.InhaledcorticosteroidsMontelukast*

(n=201)0224WeeksPeriodI

Run-inSingle-blindPeriodIIEfficacyTrial(8weeks)

Double-blindPeriodIII

SafetyExtension(14weeks)Open-label

10Placebo(n=135)MontelukastPlaceboInhaledcorticosteroidsMontelukastasthma@163.com北京哮喘病临床研究所肺功能（FEV1)改变

*One5mgchewabletabletoncedailyatbedtime**BetweengroupsovereightweeksoftreatmentAdaptedfromKnorrBetalJAMA1998;279(15):1181-1186;Dataonfile,MSD.02468101220468Montelukast*(n=196)Placebo(n=131)MeanchangeinFEV1(%)Weeksinactivetreatmentp<0.001**8-WeekStudyin336Childrenasthma@163.com北京哮喘病临床研究所生活质量*One5mgchewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalJAMA1998;279(15):1181-1186andDataonfile,MSD.1.080.60.50.580.190.100.20.40.60.81.01.2ActivitySymptomsEmotionsMontelukast*(n=162)Placebo(n=106)Changefrombaselineinquality-of-lifescore

(LSmean)p<0.001p=0.007p=0.0028-WeekStudyin336Childrenasthma@163.com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)–0.10–0.050.000.0520468Weeksinactivetreatmentp=0.02**8-WeekStudyin336Childrenasthma@163.com北京哮喘病临床研究所延伸研究资料－同吸入激素对照

*One5mgchewabletabletoncedailyatbedtime**Beclomethasone84µgthreetimesdailyoragentusedinPrimaryStudyDataonfile,MSD.01234567FEV1

(change

from

baselinein%

predicted)Primarystudy(8weeks)Extensiondata(48weeks)Montelukast*(n=182)5.27Placebo

(n=122)2.19Montelukast*

(n=200)6.01Inhaled

corticosteroid**(n=38)5.55p<0.0548-WeekExtensionStudyin245Childrenasthma@163.com北京哮喘病临床研究所MontelukastMontelukast4mg*

(n=461)Numbersrepresentpatientsenteringeachperiod.InPeriodIII:montelukast(n=288);usualcare(n=119)Short-actingbeta2agonistswereusedasneededinbothgroups.*Onechewabletabletoncedailyatbedtime;patientsintheextensionstudywhobecamesixyearsofage

wereswitchedtomontelukast5mg(onechewabletabletoncedailyatbedtime).**Inhaled/nebulizedcorticosteroidsorcromolynaccordingtotheusualclinicalpracticeoftheinvestigatorAdaptedfromKnorrBetalPediatrics2001;108(3):1-10;Dataonfile,MSD.Slide220250WeeksPeriodI

Run-inSingle-blindPeriodIIActiveTreatment(12weeks)

Double-blindPeriodIII

TolerabilityExtension(36weeks)

Open-label14Placebo(n=228)MontelukastPlaceboUsualCare**UsualCare**MontelukastChronicAsthmaStudy(2–5years)

StudyDesignasthma@163.com北京哮喘病临床研究所*One4mgchewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalPediatrics2001;108(3):1-10;Dataonfile,MSD.Slide25MontelukastChronicAsthmaStudy(2–5years)

DaytimeAsthmaSymptomScoresDaytime

asthma

symptom

score

(changefrom

baseline)–0.40–0.35–0.30–0.25–0.20–0.15–0.10–0.050Montelukast*

(n=458)Placebo

(n=227)–0.37–0.26p=0.00312-WeekStudyin689Childrenasthma@163.com北京哮喘病临床研究所Slide31

OnsetofAction:DaytimeSymptoms

*ImprovedfromDay1*Posthocanalysisofthefirst21daysoftreatment;first7daysshownonslide.Short-actingbeta2agonistswereusedasneededinbothgroups.*OnechewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalPediatrics2001;108(3):1-10.DaysonactivetreatmentPlacebo(n=227)Montelukast4mg*(n=458)Mean±SEchangein

daytimesymptom

score1467–0.4–0.10.00.1–0.2–0.353212-WeekStudyin689Childrenasthma@163.com北京哮喘病临床研究所5MontelukastChronicAsthmaStudy(2–5years)

MontelukastSignificantlyImproved

IndividualDaytimeSymptomScores353942422628282301015202530354045Coughingp=0.003Wheezingp=0.042Troublebreathingp=0.007Activitiesp<0.001Montelukast4mg*(n=458)Placebo(n=227)Posthocanalysisbasedon0-to5-pointdiaryscale(nosymptomstoverysevere)Short-actingbeta2agonistswereusedasneededinbothgroups.*OnechewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalPediatrics2001;108(3):1-10.Slide26Mean

improvement

frombaseline(%)12-WeekStudyin689Childrenasthma@163.com北京哮喘病临床研究所*One4mgchewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalPediatrics2001;108(3):1-10.Slide27MontelukastChronicAsthmaStudy(2–5years)

Beta2-AgonistUsePercentage

ofdayswithbeta2-agonistuse464850525456Montelukast*

(n=461)Placebo

(n=228)4955p=0.00112-WeekStudyin689Childrenasthma@163.com北京哮喘病临床研究所MontelukastChronicAsthmaStudy(2–5years)

ReductioninPeripheralBloodEosinophilsSlide32–25–20–15–10–50Least-squares

mean%changefrombaselinePlacebo

(n=221)Montelukast4mg*

(n=