順爾寧在兒童哮喘中應(yīng)用

白三烯受體拮抗劑---孟魯司特(順爾寧)

在兒童哮喘治療中的作用asthma@163.com北京哮喘病臨床研究所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北京哮喘病臨床研究所哮喘長(zhǎng)期控制目標(biāo)(GINA2002)哮喘癥狀得到控制哮喘的急性發(fā)作得到預(yù)防肺功能正?；蚪咏１３终５捏w力活動(dòng),包括運(yùn)動(dòng)避免治療哮喘藥物的副作用預(yù)防不可逆的氣道阻塞預(yù)防因哮喘死亡asthma@163.com北京哮喘病臨床研究所哮喘控制藥物(GINA2002)吸入皮質(zhì)激素抗白三烯藥物長(zhǎng)效吸入

2受體激動(dòng)劑長(zhǎng)效口服2受體激動(dòng)劑全身皮質(zhì)激素色苷酸鈉和尼多克羅米鈉甲基黃嘌呤第二代抗組胺藥（H1拮抗劑）其他口服抗過敏藥物全身激素減量療法變應(yīng)原特異性免疫療法asthma@163.com北京哮喘病臨床研究所真實(shí)世界的實(shí)際效果

兒童哮喘治療尤需關(guān)注的問題實(shí)際效果=療效x順應(yīng)性口服vs吸入服用次數(shù)副作用花費(fèi)病人受教育程度起效速度吸入技術(shù)asthma@163.com北京哮喘病臨床研究所與目前治療相關(guān)的主要問題

兒童應(yīng)用吸入治療的困難4asthma@163.com北京哮喘病臨床研究所達(dá)到肺部的劑量(%)23212128051015202530定量吸入裝置(n=18)定量吸入裝置+儲(chǔ)霧罐(n=18*)呼吸啟動(dòng)的定量吸入裝置(n=18)干粉吸入(n=10)資料源自10個(gè)研究中的179名患者*兩項(xiàng)獨(dú)立研究總共18名患者選自CochraneMGetal.Chest2000;117(2):542-550Ref6,pp547A,548A輸送至肺部的藥物與目前治療相關(guān)的主要問題

吸入皮質(zhì)激素藥物輸送的困難5asthma@163.com北京哮喘病臨床研究所與目前治療相關(guān)的主要問題

吸入皮質(zhì)激素的依從性問題應(yīng)用皮質(zhì)激素吸入治療的平均數(shù)

(%)Ref8,p1052B02040608010095.458.431.8報(bào)告的應(yīng)用數(shù)實(shí)際應(yīng)用數(shù)正確時(shí)間的應(yīng)用數(shù)(n=24)選自MilgromHetal.JAllergyClin

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

報(bào)告的依從性并不一定能反映實(shí)際應(yīng)用狀況asthma@163.com北京哮喘病臨床研究所與目前治療相關(guān)的主要問題

依從性是控制哮喘的一項(xiàng)基本要素選自MilgromHetal.JAllergyClin

Immunol

1998;98(6,part1):1051-1057.Ref8,p1055A哮喘緩解期與需要口服皮質(zhì)激素救急治療的發(fā)作期小兒的依從性比較依從性不良可導(dǎo)致治療效果不佳依從性%緩解期哮喘兒童(n=16)需要口服激素救急治療的兒童(n=8)02040608010068.2%依從性p=0.00813.7%依從性7asthma@163.com北京哮喘病臨床研究所

*Onechewabletabletoncedailyatbedtime

**Two1mgpuffsfourtimesdailyAdaptedfromVolovitzBetalCurrTherRes2000;61(7):490-506.同吸入治療相比

家長(zhǎng)及監(jiān)護(hù)人更喜歡口服的藥物0102030405060708090100Cromolyn8mg**12Montelukast5mg*88Percent

expressingpreferences(n=249)p<0.00112-WeekStudyin266Childrenasthma@163.com北京哮喘病臨床研究所選擇另一種方法使藥物到達(dá)靶器官asthma@163.com北京哮喘病臨床研究所嗜酸粒細(xì)胞,X103/gSputum氣道炎癥：痰中嗜酸粒細(xì)胞增多和疾病嚴(yán)重度P<0.00110,0001,000100101P<0.001P<0.01P<0.05對(duì)照組

n=22間歇哮喘

n=19輕中度哮喘

n=38重度哮喘

n=17100,000LouisRetal.AmJRespir

CritCareMed.2000;161:9–16,?AmericanThoracicSociety.asthma@163.com北京哮喘病臨床研究所盡管使用激素，氣道炎癥依然存在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北京哮喘病臨床研究所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兩條路徑半胱氨酰白三烯---氣道炎癥的另一路徑asthma@163.com北京哮喘病臨床研究所我們知道:

半胱氨酰白三烯在哮喘病理過程中扮演重要作用

皮質(zhì)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北京哮喘病臨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):

在誘導(dǎo)痰液中與疾病嚴(yán)重度*vscontrol. AdaptedfromPavordIDetal.AmJRespirCritCareMed.1999;160:1905–1909.asthma@163.com北京哮喘病臨床研究所每天吸入激素的劑量: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):

在誘導(dǎo)痰液中與疾病嚴(yán)重度*vscontrol. AdaptedfromPavordIDetal.AmJRespirCritCareMed.1999;160:1905–1909.asthma@163.com北京哮喘病臨床研究所p=NSbetweengroupsAdaptedfromO’ShaughnessyKMetalAmRevRespirDis1993;147:1472-1476.

18.7201612840UrinaryLTE4

excretion(ng/mmol

creatinine)18.4PlaceboFluticasone

propionate氟替卡松對(duì)尿LTE4水平?jīng)]有影響asthma@163.com北京哮喘病臨床研究所我們了解關(guān)鍵性概念有關(guān)哮喘發(fā)病的現(xiàn)代研究工作提示哮喘的臨床表現(xiàn)是全身免疫反應(yīng)性炎癥的結(jié)果病情的嚴(yán)重度與吸入和/或口服激素的使用并無依賴關(guān)系，炎癥仍可持續(xù)存在。LTs

是一種重要的介質(zhì)參與炎癥形成。CysLT1受體（CysLT1-R）廣泛分布于全身，已確定在前炎細(xì)胞及哮喘相關(guān)的特殊位置上均有受體存在。CysLTs作為一個(gè)效應(yīng)分子,在哮喘進(jìn)程中發(fā)揮直接或間接的效應(yīng)作用。asthma@163.com北京哮喘病臨床研究所

平滑肌功能障礙炎癥細(xì)胞的激活身性炎癥表現(xiàn)中呼吸系統(tǒng)的參與因素AdaptedfromSichererSHetal.JAllergyClin

Immunol.2000;106:S251-S257.基因易感性環(huán)境暴露免疫反應(yīng)的Homing

免疫反應(yīng)的類型

接觸的途徑

免疫反應(yīng)的程度靶器官的反應(yīng)氣道上皮功能障礙asthma@163.com北京哮喘病臨床研究所FigueroaD,etalAJRCCM2001;163:226–233DistributionofCysLT1Receptor(includinghard-to-reachsmallairways)andBiologicalEffectsinInflammation

CENTRALAIRWAYSPERIPHERALAIRWAYSEvansJ,FigueroaDJClinExpAllergyRev2001asthma@163.com北京哮喘病臨床研究所我們關(guān)注白三烯受體拮抗劑應(yīng)用定位代替低劑量吸入皮質(zhì)激素作為一線預(yù)防性單藥治療,尤其是嬰幼兒哮喘(依從性較差)對(duì)3級(jí)、4級(jí)病人,與低劑量吸入皮質(zhì)激素合并使用作為預(yù)防運(yùn)動(dòng)性哮喘的治療

一級(jí)間歇發(fā)作病情嚴(yán)重度分級(jí)每日的哮喘控制藥物其他治療選擇不需任何藥物低劑量吸入型糖皮質(zhì)激素二級(jí)輕度持續(xù)茶堿緩釋片，或色甘酸鈉，或白三烯受體調(diào)節(jié)劑三級(jí)中度持續(xù)中劑量吸入型糖皮質(zhì)激素中劑量吸入型糖皮質(zhì)激素加茶堿緩釋片，或中劑量吸入型糖皮質(zhì)激素加吸入長(zhǎng)效?2激動(dòng)劑，或高劑量吸入型糖皮質(zhì)激素，或中劑量吸入型糖皮紙激素加白三烯受體調(diào)節(jié)劑四級(jí)重度持續(xù)高劑量吸入型糖皮質(zhì)激素，如果需要時(shí)可加入以下一種或多種治療：茶堿緩釋片吸入長(zhǎng)效?2激動(dòng)劑白三烯受體調(diào)節(jié)劑口服糖皮質(zhì)激素asthma@163.com北京哮喘病臨床研究所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.各種臨床研究顯示了順而寧在兒童哮喘治療中的作用尤其是小年齡兒童以及運(yùn)動(dòng)又誘發(fā)的支氣管收縮的作用asthma@163.com北京哮喘病臨床研究所研究設(shè)計(jì)*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北京哮喘病臨床研究所肺功能（FEV1)改變

*One5mgchewabletabletoncedailyatbedtime**BetweengroupsovereightweeksoftreatmentAdaptedfromKnorrBetalJAMA1998;279(15):1181-1186;Dataonfile,MSD.02468101220468Montelukast*(n=196)Placebo(n=131)MeanchangeinFEV1(%)Weeksinactivetreatmentp<0.001**8-WeekStudyin336Childrenasthma@163.com北京哮喘病臨床研究所生活質(zhì)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北京哮喘病臨床研究所外周血嗜酸性細(xì)胞記數(shù)

*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北京哮喘病臨床研究所延伸研究資料－同吸入激素對(duì)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北京哮喘病臨床研究所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北京哮喘病臨床研究所*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北京哮喘病臨床研究所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北京哮喘病臨床研究所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北京哮喘病臨床研究所*One4mgchewabletabletoncedailyatbedtimeAdaptedfromKnorrBetalPediatrics2001;108(3):1-10.Slide27MontelukastChronicAsthmaStudy(2–5years)

Beta2-AgonistUsePercentage

ofdayswithbeta2-agonistuse464850525456Montelukast*

(n=461)Placebo

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

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

mean%changefrombaselinePlacebo

(n=221)Montelukast4mg*

(n=