过敏性鼻炎及其对哮喘的影响.ppt

北京中医药大学,*,*,过敏性鼻炎及对哮喘的影响,Asthma and rhinitis,are common,co-morbidities,suggesting the concept of,“one airway,one disease”,鼻炎,=,鼻部的炎症,症状,=,流鼻涕,鼻塞,鼻痒,打喷嚏,鼻炎的病因,变态反应,感染性因素,其他原因,-,药物相关的原因，,PCD,，囊性纤维化，免疫缺陷性因素，,GORD,血管运动性，激素性，肉芽肿性,过敏性鼻炎,由,IgE,介导的鼻黏膜变应性炎症,在,ARIA,发表之前分为,-,季节性过敏性鼻炎,(,枯草热,),户外空气中的变应原引起特别是花粉,常年性过敏性鼻炎,由室内变应原,(,主要是尘螨、真菌和动物皮屑、职业性变应原,),IL-10,Basic proteins,Enzymes,Lipid mediators,Cytokines,Chemokines,IL-5,IL-3,GM-CSF,Th0,Th2,Eosinophil,Mast cell,Histamine,Lipid mediators,Enzymes,Cytokines,Chemokines,IL-3,IL-4,Recruitment,activation,APC,Selection,Expansion,+,Allergen,Cellular mechanisms of allergic rhinitis,IgE,Allergen,Nasal blockage,Loss of smell,Nasalhyperreactivity,Itch,sneezing,Watery discharge,Nasal congestion,Symptomsof allergicinflammation,Acute,Chronic,Holt PG,et al,.Nature 1999,B-cell,鼻炎和哮喘患者的生活质量,62,57,General health perception,50,55,Change in health(1 yr),77,74,Pain,55,59,Energy/fatigue,65,66,Mental health,64,70,Role limitation(emotional),61,66,Role limitation(physical),73,84,Social functioning,89,80,Physical functioning,Rhinitis(n=111),Asthma(n=252),Health concept,Mean quality of life score(scale,1-100),Am J Respir Crit Care Med 1994;149:373,J Allergy Clin Immunol 1994;94:186,肺,鼻,中耳,气道,平滑肌,鼻旁窦,鼻炎和气道高反应性,鼻炎导致气道高反应性,过敏性鼻炎患者对组胺和乙酰胆碱具有支气管高反应性,(Townley,1975;Ramsdale 1984),季节性过敏性鼻炎患者在花粉季节发展为无症状的支气管收缩,(Gerblich,1986),鼻内使用糖皮质激素或色苷酸钠能够逆转支气管高反应性，提示支气管反应性受鼻部炎症的影响,Lowhagen O,Rak S.JACI 1985,Dorward AJ et al Clin.Allergy 1986,Sotomayer H et al ARRD 1984,Prieto L et al Eur.Respir.J.1994,Boulet LP et al JACI 1993,鼻炎和气道高反应性,流行病学,过敏性鼻炎,过敏性鼻炎和哮喘相关的流行病学,过敏性鼻炎和哮喘有相似的流行病模式,在,463,，,801,个,13-14,岁的儿童中进行遗传过敏症世界范围的发病率研究。超过,12,个月的儿童自述症状的问卷调查,Adapted from,t,he International Study of Asthma and Allergies in Childhood(ISAAC)Steering Committee.,Lancet,1998;351:1225-1232.,英国,澳大利亚,加拿大,巴西,美国,南非,德国,法国,阿根廷,阿尔及利亚,中国,俄国,0,5,10,15,20,25,30,35,40,%,发病率,英国,澳大利亚,加拿大,巴西,美国,南非,德国,法国,阿根廷,阿尔及利亚,中国,俄国,0,5,10,15,20,25,30,35,40,%,发病率,哮喘,过敏性鼻炎和哮喘相关的流行病学,大多数哮喘病人合并过敏性鼻炎,大约有,80%,的哮喘病人合并过敏性鼻炎,Adapted from,The Workshop Expert Panel.,Management of Allergic Rhinitis and its Impact on Asthma(ARIA)Pocket Guide.A Pocket Guide for Physicians and Nurses.,2001;Bousquet J and the ARIA Workshop Group,J Allergy Clin Immunol,2001;108(5):S147-S334;Sibbald B,Rink E,Thorax,1991;46:895-901;Leynaert B et al,Am J Respir Crit Care Med,2000;162:1391-1396.,仅有哮喘,仅有过敏性鼻炎,过敏性鼻炎,+,哮喘,过敏性鼻炎和哮喘相关的流行病学,过敏性鼻炎是哮喘的高危因素,过敏性鼻炎使哮喘的风险增加了,3,倍,接受过敏试验的大学新生的,23,年的跟踪研究,；数据亦来源于,738,名（,69%,为男性）平均年龄为,40,岁的研究对象。,Adapted from Settipane RJ et al,Allergy Proc,1994;15:21-25.,12,10,8,6,4,2,0,发展为哮喘的病人数,%,10.5,研究开始有过敏性鼻炎,(n=162),3.6,研究开始无过敏性鼻炎,(n=528),p0.002,过敏性鼻炎和哮喘相关的流行病学,过敏性鼻炎合并哮喘病人身心双方的损害,对照组,(n=448),过敏性鼻炎组,(n=297),哮喘,+,过敏性鼻炎组,(n=76),对性别，年龄，抽烟状况等因素进行偏倚调节的,20-44,岁的患者的多中心研究。,Adapted from Leynaert B et al,Am J Respir Crit Care Med,2000;162:1391-1396.,p0.001,60,50,40,30,20,10,0,评分均值,身体损害,精神损害,p0.001,p0.001,p0.001,过敏性鼻炎和哮喘相关的流行病学,哮喘合并过敏性鼻炎的病人有极大的经济支出,每年总的医疗费用*在过敏性鼻炎合并哮喘的人群中增加,34%,对低于,65,岁的目标人群的流行病学及过敏性鼻炎合并哮喘所需费用增长的普查。数据提供从,1987,1996.,*,除去药费,n=,人,-,年,Adapted from Yawn BP et al,J Allergy Clin Immunol,1999;103:54-59.,350,300,250,200,150,100,50,0,平均美元,/,每人每年,哮喘,(n=3821),哮喘,+,过敏性鼻炎,(n=4743),$249.89,$335.82,p0.0001,0.9,过敏性鼻炎和哮喘相关的流行病学,过敏性鼻炎治疗减少了哮喘治疗相关医疗资源利用,该群病人（,12-60,岁过敏性鼻炎合并哮喘）一年内医疗费用的回顾。,Adapted from Crystal-Peters J et al,J Allergy Clin Immunol,2002;109(1):57-62.,2.5,2.0,1.5,1.0,0.5,0,病人数,%,未被治疗过敏性鼻炎的病人,(n=1357),被治疗过敏性鼻炎的病人,(n=3587),2.3,p0.01,治疗组病人的住院率减少了,61%,过敏性鼻炎和哮喘相关的流行病学,总 结,过敏性鼻炎和哮喘在世界范围内有相似的流行模式,过敏性鼻炎患者发展为哮喘的风险增加了,3,倍,大约有,80%,的哮喘病人合并过敏性鼻炎,过敏性鼻炎合并哮喘的病人降低了生活质量,哮喘合并过敏性鼻炎的病人治疗了过敏性鼻炎可以减少医疗费用,病理生理学,IL-10,Basic proteins,Enzymes,Lipid mediators,Cytokines,Chemokines,IL-5,IL-3,GM-CSF,Th0,Th2,Eosinophil,Mast cell,Histamine,Lipid mediators,Enzymes,Cytokines,Chemokines,IL-3,IL-4,Recruitment,activation,APC,Selection,Expansion,+,allergen,B-cell,Cellular mechanisms of allergic asthma,Bronchialhyper-responsiveness(BHR),Cough,Chest tightness,Wheeze,Dyspnea,Symptomsof allergicinflammation,Acute,Chronic,IgE,Allergen,Holt PG,et al,.Nature 1999,过敏性鼻炎和哮喘共同的病理学特点,过敏性鼻炎和哮喘有同样的诱因,非类固醇类消炎药（如阿司匹林）,室内的过敏原,/,刺激因子,屋尘螨,动物皮屑,昆虫（如蟑螂）,烟草的烟,室外的过敏原,花粉,霉菌,Adapted from National Institutes of Health,Global Initiative for Asthma:Global Strategy for Asthma Management and Prevention:A Pocket Guide for Physicians and Nurses.,Publication No.95-3659B.Bethesda,MD:National Institutes of Health,1998;Workshop Expert Panel,Management of Allergic Rhinitis and its Impact on Asthma(ARIA)Pocket Guide.A Pocket Guide for Physicians and Nurses.,2001.,过敏性鼻炎和哮喘共同的病理学特点,过敏性鼻炎和哮喘有相同的免疫病理学,CysLTs=,半胱酰胺白三烯,;PGs=,前列腺素,;PAF=,血小板活化因子,Based on and modified from Casale TB,Amin BV,Clin Rev Allergy Immunol,2001;21(1):27-49;Kay AB,N Engl J Med,2001;344:30-37.,膜上的,IgE,急性过敏反应,包括早发相应答,慢性过敏反应,包括迟发相应答,肥大细胞,T,细胞,过敏原,细胞因子,组胺前体,新形成的介质,CysLTs,、,PGs,，,PAF,Eosinophils,过敏性鼻炎和哮喘共同的病理学特点,过敏性鼻炎和哮喘有相似的早发相和晚发相应答,Adapted from Varner AE,Lemanske RF Jr.In:,Asthma and Rhinitis.,2nd ed.Oxford:Blackwell Science,2000:1172-1185;Togias A,J Allergy Clin Immunol,2000;105(6 pt 2):S599-S604.,哮喘,过敏性鼻炎,症状评分,刺激后时间（小时）,1,过敏原刺激,34,812,24,早发相,晚发相,FEV1,（变化率,%,）,时间（小时）,1,10,24,0,2,3,4,5,6,7,8,9,0,50,100,100,50,0,过敏性鼻炎和哮喘共同的病理学特点,过敏性鼻炎和哮喘都是嗜酸性细胞增多性炎症疾病,Eos=,嗜酸性细胞,neut=,嗜中性白细胞,MC=,肥大细胞,Ly=,淋巴细胞,MP=,巨噬细胞,Adapted from Bousquet J et al,J Allergy Clin Immunol,Suppl,2001;108(5):S148-S149.,嗜酸性细胞浸润,过敏性鼻炎,哮喘,Adapted from Togias A,Allergy,1999;54(suppl 57):94-105.,炎性分泌物的吸入从上呼吸道到下呼吸道,鼻到嘴的交替呼吸,鼻支气管反射,鼻和下呼吸道系统炎症对整个系统的影响,过敏性鼻炎和哮喘共同的病理学特点,过敏性鼻炎和哮喘：互相作用的机制,过敏性鼻炎和哮喘共同的病理学特点,结 论,过敏性鼻炎和哮喘有相同的多种病理学特点,相同的诱因,暴露在过敏原下的相似的炎症连锁反应,相似的早发相和晚发相应答模式,相同的炎症细胞浸润（嗜酸性细胞）,各种潜在的相关途径包括炎症介质的全身传送,Adapted from National Institutes of Health,Global Initiative for Asthma:Global Strategy for Asthma Management and Prevention:A Pocket Guide for Physicians and Nurses.,Publication No.95-3659B.Bethesda,MD:National Institutes of Health,1998;Workshop Expert Panel,Management of Allergic Rhinitis and its Impact on Asthma(ARIA)Pocket Guide.A Pocket Guide for Physicians and Nurses.,2001;Kay AB,N Engl J Med,2001;344:30-37;Varner AE,Lemanske RF Jr.In:,Asthma and Rhinitis,.2nd ed.Oxford,UK:Blackwell Science,2000:1172-1185;Togias A,J Allergy Clin Immunol,2000;105(6 pt 2):S599-S604;Togias A,Allergy,1999;54(suppl 57):94-105.,支气管高反应性的发生率*,过敏性鼻炎和哮喘临床上的联系,花粉季节里过敏性鼻炎病人支气管高反应性增加,有关枯草热的病人（平均年龄,20,岁）的支气管高反应性的研究；在每年秋季和约,6,个月后进行刺激。,*,刺激物剂量,1mg,导致,FEV1,下降,20%,Adapted from Madonini E et al,J Allergy Clin Immunol,1987;79:358-363,.,60,50,40,30,20,10,0,病人数,%,季节外,季节内,(n=27),11,48,p0.02,Chemoattractants,Eosinophil activation,Mediator,release,Chemotaxis,Adhesion,Blood vessel,Airway epithelium,Bone marrow,嗜酸性粒细胞在哮喘炎症中发挥重要作用,IL-5generation,Pluripotentstem cells,Eosinophils,沉默炎症,哮喘患者鼻部存在炎症,(,Gaga et al Cli.Exp.Allergy,),鼻炎患者支气管存在炎症,(,DjukanovicR et al Eur.Respir.J.1992,Chakir et al JACI 2000,),过敏性鼻炎和哮喘临床上的联系,鼻和支气管的炎症改变是相关的,对无论是否合并过敏性鼻炎的哮喘病人是否存在鼻黏膜炎症的研究，研究对象年龄,20-66,岁。,Adapted from Gaga M et al,Clin Exp Allergy,2000;20:663-669.,40,35,30,25,20,15,10,5,0,哮喘者鼻黏膜的嗜酸性细胞,0,r=0.851,p15,岁的哮喘病人，孟鲁司特和安慰剂对比，多中心，随机，,12,周双盲试验。,*p0.001,孟鲁司特与安慰剂比较,Adapted from Reiss TF et al,Arch Intern Med,1998;158:1213-1220;Malmstrom K et al.Poster presentation at the 57th AAAAI Annual Meeting,March 16,21,2001.,3,15,10,5,0,0,6,9,12,15,安慰剂,(n=273),哮喘,均值,SE FEV1*,0,0.1,0.2,0.3,0.4,0.5,每晚临睡前,10mg,孟鲁司特,(n=348),过敏性鼻炎,白天鼻症状评分*,安慰剂,(n=352),每天,10mg,孟鲁司特,(n=408),基础评分的改变（,LS,均值）,晨,FEV1,均值,%,改变,周,过敏性鼻炎和哮喘临床上的联系,结 论,证实过敏性鼻炎病人增加了,BHR,。,鼻过敏原刺激增加了哮喘合并过敏性鼻炎病人的,BHR,哮喘病人的鼻嗜酸性细胞明显增加,鼻嗜酸性细胞增加与支气管嗜酸性细胞增加相关,支气管过敏原刺激增加了鼻、肺及全身组织的炎症,相同的药物治疗对两种疾病均有疗效,过敏性鼻炎的治疗可更好控制哮喘,抗白三烯治疗已证明对,2,种疾病均有疗效,Adapted from Madonini E et al,J Allergy Clin Immunol,1987;79:358-363;Corren J et al,J Allergy Clin Immunol,1992;89:611-618;Gaga M et al,Clin Exp Allergy,2000;20:663-669;Braunstahl G-J et al,Am J Respir Crit Care Med,2000;161:2051-2057;Welsh PW et al,Mayo Clin Proc,1987;62(2):125-134;Reiss TF et al,Arch Intern Med,1998;158:1213-1220;Malstrom K et al.Poster presentation at the 57th AAAAI Annual Meeting,March 1621,2001.,结 论,过敏性鼻炎和哮喘是炎症性疾病，在流行病学、病理学和治疗方法上都显示是,“,同一气道，同一疾病,”,ARIA,推荐哮喘合并过敏性鼻炎的病人应采用联合管理的策略,Adapted from National Institutes of Health,Global Initiative for Asthma:Global Strategy for Asthma Management and Prevention:A Pocket Guide for Physicians and Nurses,.Publication No.95-3659B.Bethesda,MD:National Institutesof Health,1998;Bousquet J et al,J Allergy Clin Immunol,Suppl,2001;108(5):S148-S149;Casale TB,Amin BV,Clin Rev Allergy Immunol,2001;21(1):27-49.,半胱酰胺白三烯在过敏性鼻炎中的作用,假设：如以下问题能得到肯定的回答，就可证明半胱酰胺白三烯在过敏性鼻炎中的作用,过敏性鼻炎患者的半胱酰胺白三烯浓度是否增加？,在体外试验中，半胱酰胺白三烯是否也能引发过敏性鼻炎症状？,祛除半胱酰胺白三烯是否能减少过敏性鼻炎症状？,Adapted from,Dale HH,Bull Johns Hopkins Hosp,1933;53(6):297-347.,采用,Dale,基本条件,Ref 20,p 1628,Fig 1,C1,L1,患过敏性鼻炎时半胱酰胺白三烯浓度增加,*,与基础值对比,;*,与之前的花粉量及基础值的对比,Adapted from,Creticos PS et al,N Engl J Med,1984;31:1626-1630.,p=0.01*,6,5,4,3,2,1,0,半胱酰胺白三烯总量,（,ng/ml,）,刺激前,10,(n=17),豚草花粉粒,/,刺激量,稀释液刺激,100,1000,5000,p=0.03*,p=0.004*,p=0.02*,Adapted from Volovitz B et al,J Allergy Clin Immunol,1988;82(3 pt 1):414-418.,LTC,4,浓度,(n=16),LTC,4,平均值,(ng/ml),节前,节中,节后,12,10,8,6,4,2,0,豚草季节,症状平均评分,节前,节中,节后,12,10,8,6,4,2,0,豚草季节,症状,(n=16),半胱酰胺白三烯浓度增加与症状严重度的关系,p0.001,p0.05,1.87,0.43,5.52,0.7,4.45,1.04,6.8,1.6,10.61,1.5,7.8,2.1,建立,LTC,4,在过敏性鼻炎中作用,:,假设,1,过敏性鼻炎患者的半胱酰胺白三烯浓度是否增加？,在体外试验中，半胱酰胺白三烯是否也能引发过敏性鼻炎症状？,祛除半胱酰胺白三烯是否能减少过敏性鼻炎症状？,YES,半胱酰胺白三烯刺激增加了鼻气道的阻力,*,与基础值比较,p0.05NAR=,鼻气道的阻塞,Adapted from,Okuda M et al,Ann Allergy,1988;60:537-540.,NAR,的改变,%,刺激,*,*,*,*,*,小时,150,125,100,1/2 1 3 57 9 11,LTC4,在诱发鼻免疫应答时的作用比组胺大,5000,倍,(n=7),半胱酰胺白三烯刺激增加了流涕,Adapted from,Okuda M et al,Ann Allergy,1988;60:537-540.,鼻分泌物,(10,-2,g/min),0,5,10,15,20,时间,(,分钟,),1.00,0.75,0.50,0.25,0,(n=8),建立,LTC,4,在过敏性鼻炎中作用,:,假设,1,和,2,过敏性鼻炎患者的半胱酰胺白三烯浓度是否增加？,在体外试验中，半胱酰胺白三烯是否也能引发过敏性鼻炎症状？,祛除半胱酰胺白三烯是否能减少过敏性鼻炎症状？,YES,YES,孟鲁司特钠改善春季过敏性鼻炎白昼症状评分,最小面积均值,*,与安慰剂相比,Adapted from Malmstrom K et al.,Poster presentation at the American Academy of Allergy,Asthma,and Immunology 57th Annual Meeting,March 2001,New Orleans,Louisiana,USA;Philip G et al.Poster presentation at the European Academy of Allergy and Clinical Immunology,May 2001,Berlin,Germany;Data on file,MSD.,0.24,0,0.1,0.2,0.3,0.4,0.5,基础评分改变,0.37,p,0.001*,0.47,p,0.001*,0.14,0.27,p,0.001*,0.23,p,0.01,*,安慰剂,(n=352),孟鲁司特,(n=348),氯雷他啶,(n=602),白天症状评分,夜间症状评分,0,0.05,0.10,0.15,0.20,0.25,0.30,嗜酸性细胞计数基础值：,0.20*103,细胞数,/ul,（每个治疗组）,.,Adapted from Philip G et al.Poster presentation at the European Academy of Allergy and Clinical Immunology,May 2001,Berlin,Germany.,0.01,0.01,0,0.005,0.015,0.025 0.035,基础值改变,最小面积均值,（,103/ul,）,0.03,无变化,孟鲁司特钠减少季节性（春季）过敏性鼻炎周围血嗜酸性细胞计数,安慰剂,(n=352),孟鲁司特,10 mg(n=348),氯雷他啶,10 mg(n=602),p,0.001,总结和结论,得到以下关键问题的肯定回答才能确定半胱酰胺白三烯,在过敏性鼻炎中的作用：,Adapted from,Creticos PS et al,N Engl J Med,1984;31:1626-1630;Okuda M et al,Ann Allergy,1988;60:537-540;Knapp HR,N Engl J Med,1990;323(25):1745-1748;Donnelly AL et al,Am J Respir Crit Care Med,1995;151(6):1734-1739;Drazen JM,.In:,Asthma and Rhinitis,vol.2,2nd ed.London:Blackwell Science,2000,:10,14-1026;Volovitz B et al,J Allergy Clin Immunol,1988;82(3 pt 1):414-418.,过敏性鼻炎患者的半胱酰胺白三烯浓度是否增加？,在体外试验中，半胱酰胺白三烯是否也能引发过敏性鼻炎症状？,祛除半胱酰胺白三烯是否能减少过敏性鼻炎症状？,YES,YES,YES,白三烯受体拮抗剂在,ARIA,的地位,过敏性鼻炎及其对哮喘的影响（,ARIA,）的倡议*,ARIA,倡议的目标*,更新临床医生关于过敏性鼻炎的知识,突出过敏性鼻炎对哮喘的影响,提供诊断和治疗方法的循证医学依据,描述过敏性鼻炎的阶梯式管理,*,与世界卫生组织（,WHO,）合作发展,Adapted from the Workshop Expert Panel,Management of Allergic Rhinitis and its Impact on Asthma(ARIA)Pocket Guide.A Pocket Guide for Physicians and Nurses,.2001.,过敏性鼻炎及其对哮喘的影响（,ARIA,）的倡议*,ARIA,指南建议上、下气道管理同时进行,对持续性过敏性鼻炎患者应进行哮喘评估,哮喘患者应对过敏性鼻炎进行评估,根据安全性、有效性，应采用上下气道联合治疗的策略,Adapted from Bousquet J et al,J Allergy Clin Immunol,Suppl,2001;108(5):S148-S149.,哮喘合并过敏性鼻炎鼻炎的药物治疗,同时有哮喘和鼻炎的治疗,哮喘的治疗应遵循全球哮喘防治小组,GINA,指南,Bousquet J,Van Cauwenberge P,Khaltaev N,ARIA Workshop Group,World Health Organization.Allergic rhinitis and its impact on asthma.J Allergy Clin Immunol 2001;108:S147-S334.,哮喘,鼻炎,白三烯受体拮抗剂,Yes,Yes,糖皮质激素,Yes,Yes,受体激动剂,No,Yes,2,受体激动剂,Yes,No,H,1,型抗组胺药,No,Yes,哮喘合并过敏性鼻炎鼻炎的药物治疗,同时有哮喘和鼻炎的治疗,经由口服给予药物，将同时影响鼻腔及支气管的症状,糖皮质激素鼻喷剂安全性已被建立。然而，大剂量吸入性（支气管内）皮质激素使用，可能引发副作用。同时经由这二重途径给予药物，副作用可能叠加,过敏性鼻炎的预防及早期治疗，将有助于避免哮喘及严重支气管症状的发生，此假说已被提出，但仍需要更多的资料来证实,1,Bousquet J,Van Cauwenberge P,Khaltaev N,ARIA Workshop Group,World Health Organization.Allergic rhinitis and its impact on asthma.J Allergy Clin Immunol 2001;108:S147-S334.,孟鲁司特钠对哮喘合并过敏性鼻炎的治疗,分类,:,白三烯受体拮抗剂,非糖皮质激素类抗炎药,“,白三平”,通用名：孟鲁司特钠,孟鲁司特钠的作用机理,花生四烯酸（,AA,）,5-HPETE,膜磷脂,LTB,4,LTC,4,LTD,4,LTE,4,CysLTs,LTA,4,CysLTR,5-,脂氧化酶抑制剂,PLA,2,水解酶,双肽酶,GGT,GGL,孟鲁司特钠,孟鲁司特钠联合吸入布地奈德治疗慢性哮喘的临床研究,（,C,linical,O,bservation of,M,ontelu,kast as a,P,artner,A,gent for,C,omplementary,T,herapy,）,Price DB,Hernandez D,Magyar P et al.,Thorax,2003;58:211-216,鼻炎的理想控制能改善同时存在的哮喘,1,孟鲁司特用于哮喘治疗，被批准用于过敏性鼻炎,亚洲国家和地区：新加坡，韩国，台湾，香港,阿根廷,捷克,墨西哥,新西兰,美国等,.,1.Bousquet J and the ARIA Workshop Group,J Allergy Clin Immunol,2001;108(5):S147-S334,背 景,COMPACT,研究入组标准,男女病人，年龄,15-70,，慢性哮喘病史至少1年,进入研究前至少吸入皮质激素,12,周,:,剂量范围,600,到,1200,g/,天（或相同剂量的激素）,哮喘未达到最佳控制(由研究者判断),在随访1和随访3，基础,FEV1,或,PEF,值,50%,预计值,在随机入组时，吸入-激动剂,FEV1,可逆性,12%,或,PEF,可逆性,15%,，,或预计,PEF,变异率,20%,在第一阶段的后两周里日间症状评分和-激动剂用量达到预定要求,研究设计,孟鲁司特,钠,10 mg,qd,+,布地奈德,400 g,bid,布地奈德,800 g,bid,布地奈德,400g bid,第一阶段,筛选期,(4,周,),单盲,第二阶段,治疗期,(12,周,),双盲,0,4,16,周,1,n=448,n=441,8,12,分析目的,确定并比较分析,吸入布地奈德(,800,g,/日)和孟鲁司特钠,（10,mg/,日）,合用,与,吸入双倍剂量布地奈德(由,800g,/日增加至1600,g,/日),对哮喘合并过敏性鼻炎的病人带来的额外益处,AM PEF,的改变所有组,p=0.36,0.0,10.0,20.0,30.0,40.0,50.0,4,8,12,Change from Baseline,(L/Min,LS Mean SEM),Montelukast*(N=433),Budesonide*(N=425),周,*Montelukast 10 mg once-daily along with budesonide 400,g twice-daily.,*Budesonide 800 g twice-daily,AM PEF,值,Montelukast*,N=433,Budesonide*,N=425,基线值,(L/min),391.0,388.5,增长的绝对值,(L/min),33.5,30.1,增长的百分比,(%),8.6%,7.7%,MontelukastBudesonide,组,的差异,(L/min),最小面积均值,(95%CI),4.2(-4.7,13.0),P=0.357,*Montelukast 10 mg once-daily along with budesonide 400,g twice-daily.,*Budesonide 800 g twice-daily,AM PEF,的改变所有组,AM PEF,的改变,Asthma+AR,病人组事后分析,p0.03,0.0,10.0,20.0,30.0,40.0,50.0,0,4,8,12,Changes from Baseline,(L/Min,LS Mean+SEM),*Montelukast 10 mg once-daily with budesonide 400,g twice-daily.,*Budesonide 800 g twice-daily,周,Montelukast*(N=433),Budesonide*(N=425),AM PEF,的改变,Asthma+AR,病人组,AM PEF,值,Montelukast*,N=216,Budesonide*,N=184,基线值,(L/min),394.7,403.4,增长的绝对值,(L/min),36.4,24.1,增长的百分比,(%),9.2%,6.0%,MontelukastBudesonide,组,的差异,(L/min),最小面积均值,(95%CI),14.2 (1.58,26.84),P=0.028,*Montelukast 10 mg once-daily along with budesonide 400,g twice-daily.,*Budesonide 800 g twice-daily,-20.0,-10.0,0.0,10.0,20.0,30.0,40.0,50.0,60.0,70.0,4,8,12,Changes from Baseline,(L/Min,LS Mean+SEM),AM PEF,的改变,Asthma+AR,病人,:,使用治疗过敏性鼻炎的药物,事后分析,I,ntranasal steroids or antihistamines or other treatments for rhinitis,p0.02,周,*Montelukast 10 mg once-daily along with budesonide 400,g twice-daily.,*Budesonide 800 g twice-daily,Montelukast*(N=433),Budesonide*(N=425),AM PEF,的改变,Asthma+AR,病人,:,使用鼻炎药物,AM PEF,值,Montelukast*,N=33,Budesonide*,N=23,基线值,(L/min),431.1,411.9,增长的绝对值,(L/min),52.1,7.8,增长的百分比,(%),12.1%,1.9%,MontelukastBudesonide,组,的差异,(L/min),Least Squares Mean(95%CI),44.3 (8.35,80.25),P=0.017,I,ntranasal steroids or antihistamines or other treatments for rhinitis,*Montelukast 10 mg once-daily along with budesonide 400,g twice