北京白三烯

白三烯修饰剂在哮喘、过敏性鼻炎同治中的地位,沈阳军区总医院 陈 萍,沈阳军区总医院,气道炎症与白三烯白三烯受体拮抗剂对哮喘、变应性鼻炎的治疗作用白三烯受体拮抗剂的临床应用,是一种慢性的气道炎症由多种细胞（嗜酸性粒细胞、肥大细胞、T淋巴细胞、中性粒细胞、气道上皮细胞等）及细胞组分共同参与慢性炎症导致气道高反应性的增加，通常出现广泛多变的可逆性气流受限，并引起反复发作性的喘息、气急、胸闷或咳嗽等症状，常在夜间和清晨发作、加剧多数患者可自行缓解或经治疗缓解,支气管哮喘的定义,Kardos ERS 2003,IL-3, IL-5GM-CSF,损伤,炎症,IL-4,IL-13,IL-9, IL-4,IL-3,环 境,树突状细胞,嗜酸性粒细胞,肥大细胞,嗜碱性粒细胞,平滑肌,神经,血管,成纤维母细胞,蛋白水解酶,污染 酶 病毒,粘液,重建,高反应性,气道狭窄,症状,介质,白三烯 组织胺PGs 酶,“The nose is the part of the lung” 鼻是肺的一个部分 L Lichtenstein 1982,“Asthma of the nose” 鼻哮喘Dr.Tuft 美国著名的老一辈变态反应学家 1984,“One airway , one disease”一个气道，一种疾病Allergic rhinitis and its impact on athma JACI 2001,108.,气道炎症,共同的发病机制,鼻炎同哮喘有相似的解剖和炎性细胞,大部分的哮喘患者同时患有鼻炎,近80%的哮喘病人有过敏性鼻炎,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.,Asthmaalone,Allergic rhinitisalone,Allergicrhinitis+ asthma,变应性鼻炎患者,非变应性鼻炎患者,哮喘发生率%,Brown大学在对1836名学生进行的研究中发现，曾经患有变应性鼻炎的学生日后患哮喘的百分率为10.5%，没有患变应性鼻炎的学生日后患哮喘的百分率为3.6% ，变应性鼻炎患者的哮喘发作率显著高于非鼻炎患者。Settipane RJ. Allergy Proc. 1994; 15: 21-25,一项长达23年的前瞻性研究,白三烯的表达对于其它炎症介质的作用,CysLTs appear to enhance the production and the activity of cytokines and other inflammatory mediators,CysLTs,Cytokines and Other Inflammatory Mediators(IL-4,IL-5, eotaxin, TNF, MIP, NO, superroxide radicals),其他炎症介质对于白三烯的反作用,cytokines and other inflammatory mediators appear to enhance the production and the activity of CysLTs,CysLTs,Cytokines and Other Inflammatory Mediators(IL-4,IL-5,eotaxin,TNF,MIP,NO,superroxide radicals),半胱胺酰白三烯在哮喘病理过程中的作用,Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16:304-309.,Inflammatory Cells (mast cells, eosinophils),Sensory Nerves(C fibers),CysLTs,Edema,BloodVessel,Decreased Mucus Transport,EosinophilInflux,Cationic Protein Release,Epithelial-Cell Damage,Contraction and Proliferation,Increased MucusSecretion,Airway Epithelium,气道炎症与白三烯白三烯受体拮抗剂对哮喘、变应性鼻炎的治疗作用白三烯受体拮抗剂的临床应用,哮喘控制目标的改变,05年GINA达到并维持控制1.最少(最好没有)慢性症状,包括夜间症状 2.哮喘发作次数最少3.无需因哮喘而急诊4.最少(最好不需要)按需使用2激动剂5.没有活动(包括运动)限制6.PEF昼夜变异率20%7.PEF正常或接近正常8.最少或没有药物不良反应,06年GINA达到并维持临床 控制 1.无（或最少）症状，包括活动受限2.无夜间症状3.无（最少）需接受急救治疗4.最少（很少发生）哮喘急性加重5.肺功能正常或接近正常,哮喘治疗分级,05年GINA根据疾病严重程度分级治疗,06年GINA 根据控制水平对哮喘分级治疗根据疾病严重程度分级仅用于研究目的,GINA方案轻、中、重度哮喘病人的治疗,重度持续,中度持续,轻度持续,轻度间歇,按需使用速效2受体激动剂,GINA2005,白三烯调节剂,哮喘控制水平, 出现急性加重后应重新评估维持治疗方案，以确保方案的合理性 准确的定义是：任何一周发生急性加重，该周哮喘未得到控制 肺功能对 5岁儿童不是可靠指标,06年GINA,基于控制情况的哮喘管理途径,哮喘教育环境控制,第一步,第二步,第三步,第四步,第五步,递增,递减,递增,递减,治疗步骤,白三烯修饰剂（06年GINA）,分类： 半胱氨酰白三烯（cysLT1）受体拮抗剂： 孟鲁司特、普鲁卡司特、扎鲁司特 5-脂氧酶抑制剂：齐留通,白三烯修饰剂为哮喘控制药物，其作用： 1.轻度可变的支气管扩张作用 2.减轻症状（包括咳嗽） 3.改善肺功能 4.减轻气道炎症 5.减少哮喘急性发作,1. 成人轻度哮喘的替代治疗药物2. 某些阿司匹林哮喘3. 单独作为控制药比低剂量ICS作用弱4. 对中重度哮喘可能作为减少ICS剂量的附加治疗5. 对低/高ICS未控制的哮喘患者可改善哮喘控制6. 作为ICS附加治疗不如LABA,白三烯修饰剂（06年GINA）,尽管使用激素，气道炎症依然存在,ICS=inhaled corticosteroids; OCS ICS=received oral corticosteroids with or without ICSAdapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.,20,00010,0001,000100101,Eosinophil 103/gsputum,Controlgroup,Mild to moderate,ICSlow-dose(n=10),ICShigh-dose(n=15),OCS(n=10),OCS ICS(n=7),Severe asthma,In a clinical study of 74 patients,block steroid-sensitivemediators,blocks the effects of CysLTs,Inhaled steroids,Montelukast,The slide represents an artistic rendition.Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Bisgaard H Allergy 2001;56(suppl 66):7-11.,Steroid-sensitive mediatorsplay a key role in asthmatic inflammation,CysLTsplay a key role in asthmatic inflammation,Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients,DUAL PATHWAY,半胱胺酰白三烯气道炎症的另一途径,吸入激素,炎症+气道高反应性+支气管扩张作用（长期应用）+,最佳哮喘控制,白三烯受体拮抗剂,长效受体激动剂,炎症+气道高反应性+支气管扩张作用+,炎症0气道高反应性+支气管扩张作用+,Graeme P. currie. Quarterly Journal of Medicine 2005, Vol. 98(3) 1771-82,过敏性鼻炎,哮喘,抗-白三烯,吸入性类固醇,抗组胺,b2 激动剂,避免接触过敏原,免疫治疗,鼻类固醇+ 吸入性类固醇,气道炎症与白三烯白三烯受体拮抗剂对哮喘的治疗作用白三烯受体拮抗剂(LTRA)的临床应用 LTRA作为一线治疗 LTRA与ICS联合用药 LTRA与ICS+LABA三联用药,白三烯受体拮抗剂作为哮喘一线治疗,N = 400“Mild Persistent Asthma”,Zeiger, Am J Med 2005, 118:649-657,Mild Asthma Montelukast vs Inhaled Corticosteroid StudyMIAMI,Zeiger, Am J Med 2005, 118:649-657,Mild Asthma Montelukast vs Inhaled Corticosteroid StudyMIAMI,Zeiger, Am J Med 2005, 118:649-657,Mild Asthma Montelukast vs Inhaled Corticosteroid StudyMIAMI,Zeiger, Am J Med 2005, 118:649-657,Mild Asthma Montelukast vs Inhaled Corticosteroid StudyMIAMI,Montelukast vs.Inhaled Beclomethasone孟鲁司特同吸入皮质激素对中度哮喘的对照研究,*Once daily at bedtime*200 g twice dailyAdapted from Malmstrom K et al Ann Intern Med 1999;130(6):487-495.,Montelukast vs. Inhaled Beclomethasone (12-week study)研究设计,Period ISingle-blindrun-in,Period IIDouble-blindtreatment,Period IIIDouble-blindwashout,Placebo(n=895),Montelukast 10 mg*(n=387),Placebo(n=257),Placebo,Beclomethasone 400 g*(n=251),2 0 4 8 12 15,Weeks,5040302010010,*200 g twice daily via spacer *N values refer to all patients included in the intention-to-treat analysis for morning PEFR.*Once daily at bedtimeAdapted from Malmstrom K et al Ann Intern Med 1999;130(6):487-495.,Montelukast vs. Inhaled Beclomethasone (12-week study)孟鲁司特起效速度快Change in Morning PEFR in 895 Patients Age 1585 Years,Mean + SEchangefrombaseline(L/min),Days on active treatment,1 35 7 9 11 13 15 17 1921,Beclomethasone 400 g* (n=244)*,Montelukast 10 mg* (n=372)*,Placebo(n=244)*,*Once daily at bedtime*200 g twice daily via spacerp0.05 vs. placebo for both active treatments at week 12Adapted from Malmstrom K et al Ann Intern Med 1999;130(6):487-495; Data on file, MSD.,Montelukast vs. Inhaled Beclomethasone (12-week study)外周血嗜酸性细胞数的变化,Mean SE eosinophilcount(103/l),Montelukast 10 mg* (n=387)Beclomethasone 400 g* (n=251)Placebo (n=257),Weeks,0.050.000.050.100.15,03691215,PlaceboWashout,895 Patients Age 1585 Years,Montelukast vs. Inhaled Beclomethasone (12-week study)哮喘发作的情况Time to First Asthma Attack in 895 Patients Age 1585 Years,*200 g twice daily via spacer *Once daily at bedtime*p=0.006 montelukast vs. placebo; p=0.001 beclomethasone vs. placeboNS = no significant difference between montelukast and beclomethasoneAdapted from Malmstrom K et al Ann Intern Med 1999;130(6):487-495; Data on file, MSD.,Proportionof patientswithoutan attack,Beclomethasone 400 g(n=248)*,Days after randomization,1.000.950.900.850.800.750.70,Montelukast 10 mg(n=379)*,Placebo*(n=253),0102030405060708090,P=NS,白三烯受体拮剂与吸入激素联合用药,Investigation of Montelukast as a Partner Agent for Complementary Therapy对吸入氟替卡松的哮喘病人加用孟鲁司特或沙美特罗的治疗效果的观察,治疗期间至少1次哮喘发作的病例数分析,Steroid Tapering Study孟鲁司特用于皮质激素减量的研究,*Once daily at bedtimeData on file, MSD.,Montelukast Corticosteroid-Tapering Study in Real World Setting (48-week study)激素剂量Corticosteroid dose at baseline and after 12 and 48 weeks of therapy with montelukast 10 mg* (n=580) in patients age 1571 years,Corticosteroiddose (g/day),Baseline,959,81%reduction(p0.001),0,200,400,600,800,1000,172,178,Week 12,Week 48,82%reduction(p0.001),*10 mg once daily at bedtimeData on file, MSD.,Montelukast Corticosteroid-Tapering Study in Real World Setting (48-week study)激素被完全撤除的病人数,% ofPatientswith complete tapering,Baseline,0,0,20,40,60,80,100,60,61,Week 12,Week 48,(n=581),581 Patients Age 1571 Years,(n=580),(n=580),孟鲁司特钠联合布地奈德与布地奈德倍量治疗中度哮喘的研究,研究设计,周,无哮喘症状天数(%),*Modified intention-to-treat and non-parametric approach,夜间觉醒次数(%),夜间觉醒 次数中位百分数(%),Calculations:12.3 - 2.3 x 100 = 81.3% 12.313.8 - 3.9 x 100 = 71.7% 13.8,AM PEF 的改变所有组,p=0.36,周,* Montelukast 10 mg once-daily along with budesonide 400 g twice-daily.* Budesonide 800 g twice-daily,AM PEF 的改变Asthma+AR 病人组事后分析,p0.03,* Montelukast 10 mg once-daily with budesonide 400 g twice-daily.* Budesonide 800 g twice-daily,周,AM PEF 的改变Asthma+AR 病人组,* Montelukast 10 mg once-daily along with budesonide 400 g twice-daily.* Budesonide 800 g twice-daily,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, Intranasal 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,白三烯受体拮抗剂与LABA的选用,持续哮喘每日吸入400-800ug/d BDP（或相当剂量）,评价吸入方法检查顺应性排除诱发因素,持续哮喘肺功能变化不大或合并过敏性鼻炎,加白三烯受体拮抗剂,症状控制,加LABA,no,yes,no,加LABA,制订长期随访计划,持续哮喘肺功能下降,症状控制,加白三烯受体拮抗剂,Chest 2005, 128:2954-62,白三烯受体拮抗剂与ICS+LABA三联用药,孟鲁司特降低FP/SM治疗哮喘病人的炎症指标,Graeme P. Am J Respir Crit Care Med Vol 167.1232,2003,研究流程,2w,1st随机治疗（加孟鲁司特或安慰剂）,2nd随机治疗（加孟鲁司特或安慰剂）,FP/SM头2w， FP第3w,FP/SM头2w， FP第3w,V1(d0),V2(d14),V3(d28),V5(d35),V6(d49),V6(d56),Run-in期（单用FP/SM）,