1、,LTRA在Guidelines中的地位,王永清,常州市第一人民医院,MK说明书外应用,1 commonly associated with asthma: exercise induced asthma, rhinitis, chronic obstructive pulmonary disease, interstitial lung disease, chronic urticaria, atopic dermatitis, allergic fungal disease, nasal polyposis, and paranasal sinus diseasenot connected
2、 to asthma: migraine, respiratory syncytial virus postbronchiolitis, systemic mastocytosis, cystic fibrosis, pancreatitis, vulvovaginal candidiasis, cancer, atherosclerosis, eosinophils cystitis, otitis media, capsular contracture, and eosinophilic gastrointestinal disorders,-Riccioni G, Curr Med Ch
3、em. 2007,目录contents,01,哮喘,02,哮喘合并AR,03,病毒诱发哮喘或喘息,04,运动诱发哮喘,05,阿司匹林哮喘,01,哮喘,PRACTALL2014 日本儿童哮喘指南2016 中国儿童哮喘指南2012 ICON2016 GINA2014 BTS,01,全球成人及儿童轻度哮喘的发病率约为40%70%在美国一项含826未经治疗的哮喘儿童研究发现，5岁以下的儿童更易患轻度哮喘 (间歇性41%，持续性10%)美国指南允许5岁以上儿童轻度哮喘，可以MK、色酮或茶碱替用ICS，或MK、LABA、茶碱联用ICS英国指南内容与美国者类似,British Thoracic Societ
4、y and Scottish Intercollegiate Guidelines Network. 2007 British Guideline on the Management of Asthma. http:/www.sign.ac.uk/ guidelines/fulltext/63/index.html,儿童轻度间歇和轻度持续性哮喘,LTRAs对各型哮喘疗效,01,01,01,LTRA在哮喘治疗中的作用,抑制气道嗜酸粒细胞炎症抑制炎症介质和细胞因子释放降低FeNO (4周后)抑制气道LTC4释放长程（3月）可部分降低血IgE水平改善肺功能，降低AHR抑制气道重塑,Stelmach
5、I et al.J Allergy Clin Immunol 2002;109: 2572263 Wu AY,et al. Clin Exp Allergy 2003;33: 359-366 Bratton DL,et al. Pediatr Pulmonol 1999;28: 402-407Volovitz B,et al. J Allergy Clin Immunol 1999;104: 1162-1167 Henderson WR, et al. Am J Respir Crit Care Med 2002;165: 108-116 Peters-Golden M ,et al. N E
6、ngl J Med 2007;357:1841-54 Henderson WR Jr, et al. Am J Respir Crit Care Med. 2006;173(7):718-28.,NS,OVA,mk,小鼠哮喘模型，显示MK可抑制平滑肌增厚及胶原沉积,半胱氨酰白三烯与炎症介质相互作用,Peters-Golden M, et al. Clin Exp Allergy. 2006;36(6):689-703.,a,b,c,半胱氨酰白三烯可调控这些炎症介质,这些炎症介质可调控半胱氨酰白三烯,a 研究证实，白三烯与这些炎症介质可相互调节活性；b 白三烯可调节这些炎症介质的活性；c 这些炎
7、症介质可调节白三烯的活性。,IL=白介素，GMCSF=粒性细胞-巨噬细胞集落剌激因子，IFN=干扰素，TNF=肿瘤坏死因子，PAF=血小板活化因子，PAI=纤溶酶原激活物抑制剂，ICAM=细胞间粘附分子，MIP=巨噬细胞炎性蛋白，MMP=基质金属蛋白酶，EDN=嗜酸性粒细胞衍生的神经毒素，Eos Prot X=嗜酸性粒细胞蛋白X，RANTES=调节激活正常T细胞表达和分泌细胞因子，ECP=嗜酸性粒细胞阳离子蛋白，NF-B=核转录因子-B，EGF=上皮生长因子，Mac=巨噬细胞分化抗原,01,01,PRACTALL-LTRA为轻度哮喘一线治疗,PRACTALL-P18,01,PRACTALL-大
8、于2岁儿童,PRACTALL-P15,常规控制剂治疗的主要目标是减少气道炎症,LTRA持续性哮喘可选的一线治疗有证据显示口服孟鲁司特是儿童轻度哮喘的首选控制剂，它可提供气道保护的作用，在过敏性哮喘的学龄前儿童中通过检测一氧化氮证实LTRA可减少气道炎症较小的年龄（10岁）和高水平的尿白三烯支持使用LTRA治疗患者不能或不愿意使用ICS因为作用机制不同，联合ICS治疗可互补治疗2-5岁患儿的病毒诱发喘息可以减少急性发作频率对于6个月患儿也显示有益处,01,2014 日本儿童哮喘指南,P346,可抑制支气管收缩和气道炎症，在长程控制中有效大多数研究显示，LTRAs应用1-2周内即改善肺功能、降低发
9、作频率轻持型哮喘，LTRAs与ICSs同样有效作为ICSs的附加治疗，LTRAs证实同样有效,01,2014 日本儿童哮喘指南-2岁儿童,01,2014 日本儿童哮喘指南-2-5岁儿童,01,2014 日本儿童哮喘指南-6-15岁儿童,2016 中国儿童支气管哮喘诊断与防治指南:LTRA,01,01,2016 中国儿童支气管哮喘诊断与防治指南-6岁儿童,01,2016 中国儿童支气管哮喘诊断与防治指南-6岁儿童,01,LTRA可以改善各年龄段患者的临床症状、肺功能水平以及减少急性发作次数初级治疗方案中，可作为低剂量ICS后的第二治疗选择，或为一线治疗的备选药物升级治疗中，也可作为联合用药PRA
10、CTALL中建议，LTRA可能特别适用于合并鼻炎的患者,International Consensus On (ICON) Pediatric Asthma 2012,2012ICON 对儿童哮喘应用LTRA的评价,01,2012 ICON,Figure 4 The stepwise approach to asthma treatment in childhood aims at disease control.,GINA 2016, Box 6-5,Infrequentviral wheezing and no or few interval symptoms,Symptom patter
11、n consistent with asthma and asthma symptoms not well-controlled, or 3 exacerbations per year Symptom pattern not consistent with asthma but wheezing episodes occur frequently, e.g. every 68 weeks. Give diagnostic trial for 3 months.,Asthma diagnosis, and not well-controlled on low dose ICS,Not well
12、-controlled on double ICS,First check diagnosis, inhaler skills, adherence, exposures,CONSIDER THIS STEP FOR CHILDREN WITH:,RELIEVER,Other controller options,PREFERRED CONTROLLER CHOICE,As-needed short-acting beta2-agonist (all children),Leukotriene receptor antagonist (LTRA)Intermittent ICS,Low dos
13、e ICS + LTRA,Add LTRA Inc. ICSfrequencyAdd intermitt ICS,Daily low dose ICS,Double low dose ICS,Continue controller & refer for specialist assessment,STEP 1,STEP 2,STEP 3,STEP 4,01,2016 GINA- 5岁儿童,01,2016 GINA,GINA 2016, page43,01,2014 BTS英国哮喘管理指南,01,2014 BTS英国哮喘管理指南,2014 BTS-P63,Step 2,01,2014 BTS英
14、国哮喘管理指南,2014 BTS-P64,Step 3,01,2014 BTS英国哮喘管理指南,2014 BTS-P66,Step 4,01,2014 BTS英国哮喘管理指南-Summary of stepwise management in children aged 5-12 years,2014 BTS-P73,01,2014 BTS英国哮喘管理指南- Summary of stepwise management in children less than 5 years,2014 BTS-P74,01,南非儿童哮喘工作组指南,哮喘轻度急性发作后，早期口服孟鲁司特可以有效缓解哮喘症状，并
15、降低后续医疗需求。,British Thoracic Society and Scottish Intercollegiate Guidelines Network (SIGN). British guideline on the management of asthma. A national clinical guideline. (SIGN publication no. 101). http:/www.sign.ac.uk/guidelines/fulltext/101/index.html (accessed 10 Sep 2012).,不可以将孟鲁司特作为急救药物。,2012 BT
16、S英国哮喘管理指南,01,2014 BTS英国哮喘管理指南,01,哮喘轻度急性发作，2岁者,01,哮喘：何时更适合用LTRAs？,Fitzgerald DA, Treat Respir Med, 2006;5:407-411,02,哮喘+AR,PRACTALL2010 AIRA2016 中国儿童哮喘指南2016 GINA,02,PRACTALL-伴随鼻炎的哮喘患者,PRACTALL-P15,LTRA may be particularly useful if the patient has concomitant rhinitis.LTRA对伴随鼻炎的患者尤其有效,02,2010-ARIA,4
17、5.白三烯受体拮抗剂能否用于AR合并哮喘的患者？推荐,AIRA-P474,02,2016 中国儿童支气管哮喘诊断与防治指南-白三烯调节剂,目前应用于儿童临床的主要为白三烯受体拮抗剂（LTRA）孟鲁司特，可单独应用于轻度持续性哮喘的治疗，尤其适用于无法应用或不愿使用ICS，或伴变应性鼻炎的患儿。,P177,02,2016 GINA,2016 GINA-P45,03,病毒诱发哮喘或喘息,PRACTALL2016 中国儿童哮喘指南2016 GINA,03,PRACTALL-LTRA治疗病毒喘,PRACTALL-P18,每日使用LTRA作为控制剂治疗病毒喘（长期或短期治疗）,03,2016 中国儿童支
18、气管哮喘诊断与防治指南,LTRA对6岁儿童持续性喘息、反复病毒诱发喘息及间歇性喘息部分有效，并可降低气道高反应性有证据表明，在呼吸道感染早期服用LTRA，可以减少学龄前间歇性哮喘患儿的病毒诱发性喘息发作，并可能降低后续医疗需求,P177,03,2016 GINA- 5岁儿童,Step 2 (children 5 years) initial controller+ as-needed SABA,IndicationChild with symptom pattern consistent with asthma, and symptoms not well-controlled, or 3 e
19、xacerbations per yearMay also be used as a diagnostic trial for children with frequent wheezing episodesPreferred option: regular daily low dose ICS + as-needed inhaled SABAGive for 3 months to establish effectiveness, and review responseOther options depend on symptom pattern(Persistent asthma) reg
20、ular leukotriene receptor antagonist (LTRA) leads to modest reduction in symptoms and need for OCS compared with placebo (Intermittent viral-induced wheeze) regular LTRA improves some outcomes but does not reduce risk of exacerbations(Frequent viral-induced wheeze with interval symptoms) consider ep
21、isodic or as-needed ICS, but give a trial of regular ICS first,2016GINA-P107,04,运动诱发哮喘,PRACTALL2014 日本儿童哮喘指南2012 ICON2016 GINA2014 BTS,04,PRACTALL,PRACTALL-P18,近来有研究显示LTRA可作为ICS的替代治疗运动诱发哮喘，因LTRA对运动诱发引起的FEV1下降有快速、持续、长期的作用常规使用不会产生耐药作用影响保护效应,04,2014 日本儿童哮喘指南-EIA的治疗,EIA: exercise-induced asthma,P352,04,
22、2012 ICON,ICON-P987,孟鲁司特治疗运动诱发哮喘有独特的疗效，优于其他治疗,04,2016 GINA- Exercise-induced bronchoconstriction (EIB),2016 GINA-P65,04,2014 BTS英国哮喘管理指南,2014 BTS-P76,05,阿司匹林哮喘,2016 GINA2014 BTS,05,2016 GINA- Aspirin-exacerbated respiratory disease,2016 GINA-P68,05,2014 BTS英国哮喘管理指南,2014 BTS-P77,症状为基础的定位 -合并AR -1-2级/
23、0-1级年龄为基础的定位 -年幼儿基因药理学定位尿LTE4/FeNO定位,也是小结：LTRA治疗儿童哮喘定位,PC20: provocation concentration. 使FEV1下降20%时累计吸入激发物的浓度,哮喘Step2治疗：ICS vs MK,Pijnenburg MW, Paediatr Respir Rev, 2015;16:101-107,12-80岁患者,也算小结：来自真实世界的哮喘研究,Price D, N Engl J Med, 2011;364:1695-707,05,12-80岁患者,哮喘：来自真实世界的研究,Price D, N Engl J Med, 201
24、1;364:1695-707,医疗补助项目（n=7804）,健康计划（n=11334）,也算小结：PEAL Network 哮喘患儿LTRA/ICS用药12个月亚组分析,Wu AC, et al. Use of Leukotriene Receptor Antagonists Are Associated with a Similar Risk of Asthma Exacerbations as Inhaled Corticosteroids. Allergy Clin Immunol Pract. 2014 ;2(5):607-13.,p0.001,p0.001,PEAL Network (population-based Effectiveness in Asthma and Lung Disease)2004.1.1-2010.12.31资料，4-17岁儿童被纳入。结论：真实世界中预防哮喘急发，LTRA和ICS同样有效；合并AR初始用LTRA者因哮喘急发去ED者更少,THANK YOU!,THANK YOU FOR WATCHING,
