王 永，楊雅淳，劉 勇

·藥物與臨床·

孟魯司特片聯(lián)合沙美特羅替卡松粉吸入劑治療咳嗽變異性哮喘的臨床療效

王 永，楊雅淳，劉 勇

221400江蘇省新沂市，鐵路醫(yī)院呼吸科(王永，劉勇)，藥劑科(楊雅淳)

【摘要】目的觀察孟魯司特片聯(lián)合沙美特羅替卡松粉吸入劑治療咳嗽變異性哮喘(CVA)的臨床療效。方法選取2011—2014年新沂市鐵路醫(yī)院收治的CVA患者112例，按就診順序分為對(duì)照組與觀察組，每組56例。對(duì)照組患者予以沙丁胺醇?xì)忪F劑治療，觀察組患者予以孟魯司特片聯(lián)合沙美特羅替卡松粉吸入劑治療；兩組患者均連續(xù)治療8周。比較兩組患者臨床療效、治療前后肺功能指標(biāo)〔第1秒用力呼氣容積(FEV1)、第1秒用力呼氣容積占用力肺活量的百分比(FEV1/FVC)、最大呼氣流量(PEF)〕、咳嗽緩解時(shí)間(CRT)，咳嗽消失時(shí)間(CDT)、復(fù)發(fā)率(RR)及不良反應(yīng)發(fā)生情況。結(jié)果觀察組患者臨床療效優(yōu)于對(duì)照組(P<0.05)。治療前兩組患者FEV1、FEV1/FVC、PEF比較，差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；治療后觀察組患者FEV1、FEV1/FVC、PEF高于對(duì)照組(P<0.05)。觀察組患者CRT、CDT短于對(duì)照組，RR低于對(duì)照組(P<0.05)。對(duì)照組患者出現(xiàn)頭痛3例，手指震顫2例；觀察組患者未出現(xiàn)嚴(yán)重不良反應(yīng)。結(jié)論孟魯司特片聯(lián)合沙美特羅替卡松粉吸入劑治療CVA的臨床療效確切，可改善患者肺功能，縮短患者咳嗽緩解時(shí)間及消失時(shí)間，降低復(fù)發(fā)率，且安全性較高。

【關(guān)鍵詞】哮喘；孟魯司特片；沙美特羅替卡松粉吸入劑；治療結(jié)果

王永，楊雅淳，劉勇.孟魯司特片聯(lián)合沙美特羅替卡松粉吸入劑治療咳嗽變異性哮喘的臨床療效[J].實(shí)用心腦肺血管病雜志，2016，24(4)：118-120.[www.syxnf.net]

Wang Y，Yang YC，Liu Y.Clinical effect of montelukast combined with salmeterol and fluticas inhalant on cough variant asthma[J].Practical Journal of Cardiac Cerebral Pneumal and Vascular Disease，2016，24(4)：118-120.

咳嗽變異性哮喘(cough variant asthma，CVA)是呼吸內(nèi)科常見(jiàn)病、多發(fā)病，臨床表現(xiàn)為慢性或持續(xù)性發(fā)作的咳嗽，是一種特殊類型哮喘[1]，嚴(yán)重影響患者的身心健康及生活質(zhì)量，其臨床癥狀、體征與上呼吸道感染、支氣管炎、咽炎等相似，易造成誤診、漏診[2]，其占慢性咳嗽病因的14%～42%[3]。近年來(lái)，隨著大氣及環(huán)境污染加劇，CVA發(fā)病率及復(fù)發(fā)率呈逐年上升趨勢(shì)。CVA常因誤診而導(dǎo)致治療不當(dāng)，療程不足，治療效果不佳，病情反復(fù)，給患者造成較大的壓力，故CVA需早期診斷，并積極進(jìn)行干預(yù)治療。目前，CVA尚無(wú)統(tǒng)一的臨床治療方案[4]，治療方法和藥物與典型哮喘基本相同[5]。本研究旨在探討孟魯司特片聯(lián)合沙美特羅替卡松粉吸入劑治療CVA的臨床療效，現(xiàn)報(bào)道如下。

1資料與方法

1.1納入與排除標(biāo)準(zhǔn)納入標(biāo)準(zhǔn)：(1)符合中華醫(yī)學(xué)會(huì)呼吸病學(xué)分會(huì)哮喘學(xué)組制定的CVA診斷標(biāo)準(zhǔn)[6]；(2)年齡≥16歲；(3)胸部X線、CT檢查未見(jiàn)異常。排除標(biāo)準(zhǔn)：(1)嚴(yán)重心、肝、腎功能障礙者；(2)妊娠期及哺乳期婦女；(3)精神病者；(4)合并呼吸道感染者；(5)合并其他呼吸道疾病者；(6)不能或不愿配合治療者。

1.2一般資料選取2011—2014年新沂市鐵路醫(yī)院收治的CVA患者112例，本研究獲得醫(yī)院倫理委員會(huì)批準(zhǔn)，患者及其家屬簽署知情同意書。按就診順序?qū)⑺谢颊叻譃橛^察組與對(duì)照組，各56例。兩組患者性別、年齡、病程比較，差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05，見(jiàn)表1)，具有可比性。

表1　兩組患者一般資料比較

注：a為t值

1.3方法對(duì)照組患者予以沙丁胺醇?xì)忪F劑(葛蘭素史克集團(tuán)公司生產(chǎn)，批準(zhǔn)文號(hào)：H20090514；規(guī)格：100 μg/噴)治療， 1～2噴/次，4次/d。觀察組患者予以孟魯司特片(杭州默沙東制藥有限公司生產(chǎn)，批準(zhǔn)文號(hào)：J20070070；規(guī)格：5 mg/片)聯(lián)合沙美特羅替卡松粉吸入劑(葛蘭素史克集團(tuán)公司生產(chǎn)，批準(zhǔn)文號(hào)：H20090240；規(guī)格：50/250 μg/噴) 治療，孟魯司特片10 mg/次，口服，1次/d；沙美特羅替卡松粉吸入劑1噴/次，2次/d。兩組患者均連續(xù)治療8周。

1.4觀察指標(biāo)觀察兩組患者臨床療效、治療前后肺功能指標(biāo)〔第1秒用力呼氣容積(FEV1)、第1秒用力呼氣容積占用力肺活量的百分比(FEV1/FVC)、最大呼氣流量(PEF)〕、咳嗽緩解時(shí)間(CRT)，咳嗽消失時(shí)間(CDT)、復(fù)發(fā)率(RR)及不良反應(yīng)發(fā)生情況。采用日本捷斯特HI-101型肺功能儀檢測(cè)肺功能指標(biāo)；隨訪6個(gè)月記錄患者復(fù)發(fā)情況，計(jì)算RR，RR=復(fù)發(fā)例數(shù)/總例數(shù)×100%。

1.5臨床療效判定標(biāo)準(zhǔn)治愈：治療后患者咳嗽消失，肺功能恢復(fù)正常；顯效：治療后患者咳嗽發(fā)作次數(shù)及程度明顯好轉(zhuǎn)，肺功能明顯改善；有效：治療后患者咳嗽發(fā)作次數(shù)及程度有所好轉(zhuǎn)，肺功能有所改善；無(wú)效：治療后患者咳嗽發(fā)作次數(shù)及程度無(wú)好轉(zhuǎn)或出現(xiàn)加重，肺功能改善不明顯或未改善。

2結(jié)果

2.1臨床療效觀察組患者臨床療效優(yōu)于對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義(u=2.378，P<0.05，見(jiàn)表2)。

表2　兩組患者臨床療效比較〔n(%)〕

2.2肺功能指標(biāo)治療前兩組患者FEV1、FEV1/FVC、PEF比較，差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；治療后觀察組患者FEV1、FEV1/FVC、PEF高于對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義(P<0.05，見(jiàn)表3)。

Table3Comparisonoflungfunctionindexbetweenthetwogroupsbeforeandaftertreatment

組別例數(shù)FEV1(L)治療前 治療后FEV1/FVC(%)治療前 治療后PEF(L)治療前 治療后對(duì)照組561.54±0.121.84±0.1264.99±3.0777.57±2.763.01±0.343.32±0.30觀察組561.53±0.102.24±0.1165.29±2.7779.48±2.782.99±0.323.72±0.29t值0.08818.1420.5423.6520.4007.193P值0.9300.0000.5890.0000.6900.000

注：FEV1=第1秒用力呼氣容積，F(xiàn)EV1/FVC=第1秒用力呼氣容積占用力肺活量的百分比，PEF=最大呼氣流量

2.3CRT、CDT、RR觀察組患者CRT、CDT短于對(duì)照組，RR低于對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義(P<0.05，見(jiàn)表4)。

表4　兩組患者CRT、CDT、RR比較

注：CRT=咳嗽緩解時(shí)間，CDT=咳嗽消失時(shí)間，RR=復(fù)發(fā)率；a為χ2值

2.4不良反應(yīng)對(duì)照組患者出現(xiàn)頭痛3例，手指震顫2例，藥物減量后不良反應(yīng)消失；觀察組患者未出現(xiàn)嚴(yán)重不良反應(yīng)。

3討論

CVA屬于一種特殊類型的哮喘，也是一種隱匿型哮喘，以慢性、持續(xù)性、頑固性咳嗽為主要臨床特征[7]，其臨床癥狀常不典型，缺乏特異性，易誤診為支氣管炎或上呼吸道感染，而誤診、誤治會(huì)貽誤最佳治療時(shí)機(jī)，使患者病情反復(fù)發(fā)作，部分患者會(huì)發(fā)展成典型性哮喘[8-9]。CVA的病理基礎(chǔ)是氣道高反應(yīng)性(airway hyper reactivity,AHR)、氣道炎癥、肺動(dòng)靜脈擴(kuò)張及氣道痙攣等，是由肥大細(xì)胞、嗜酸粒細(xì)胞(eosinophil，EOS)及T細(xì)胞等炎性細(xì)胞參與，白三烯(leukotrienes，LTs)介導(dǎo)的慢性非特異性變態(tài)反應(yīng)性呼吸道炎癥[10]。LTs是體內(nèi)非常重要的炎性遞質(zhì)，可使支氣管平滑肌收縮、支氣管變窄、增強(qiáng)AHR、支氣管黏膜水腫、增加支氣管黏膜分泌黏液、降低纖毛清除能力，導(dǎo)致氣道重構(gòu)[11]。白三烯受體拮抗劑(leukotrienes receptor antagonist，LTRAs)可通過(guò)與體內(nèi)受體競(jìng)爭(zhēng)結(jié)合，對(duì)半胱氨酰白三烯(cysteinyl leukotrienes，Cys-LTs)導(dǎo)致的炎癥發(fā)揮作用，LTRAs對(duì)于哮喘的治療具有重要作用，且耐受性較好[12]。

沙美特羅替卡松粉吸入劑是一種長(zhǎng)效β2腎上腺素受體激動(dòng)劑聯(lián)合糖皮質(zhì)激素的吸入劑[13]；沙美特羅可擴(kuò)張支氣管平滑肌，解除支氣管痙攣，可長(zhǎng)時(shí)間保持支氣管舒張，降低AHR，激活糖皮質(zhì)激素受體，與氟替卡松聯(lián)合具有協(xié)同作用，可增加氟替卡松受體的敏感性，提高氟替卡松的抗炎活性[14]；吸入激素主要作用于肺部，無(wú)口服激素的不良反應(yīng)，已成為治療肺部疾病的主要給藥途徑[15]。

孟魯司特片是一種常用的新型高選擇性半胱氨酰白三烯受體拮抗劑(cysteinyl leukotrienes receptor antagonist，Cys-LTRAs)，是目前最強(qiáng)效的LTRAs，已廣泛應(yīng)用于CVA的治療中[16]。孟魯司特片可競(jìng)爭(zhēng)性抑制氣道平滑肌中Cys-LTs多肽的活性，阻斷Cys-LTs與其受體特異性結(jié)合，減輕CVA速發(fā)和遲發(fā)相變態(tài)反應(yīng)，降低毛細(xì)血管通透性，減少EOS在氣道聚集、浸潤(rùn)及活化[4]；抑制炎性細(xì)胞成熟、黏附、聚集，減輕氣道的局部炎性反應(yīng)，減少呼吸道黏膜分泌量；抑制肥大細(xì)胞與LTs產(chǎn)生的致喘、致炎作用[17]，減輕氣管炎癥，抑制支氣管痙攣及AHR，擴(kuò)張支氣管[4]，從而達(dá)到治療、控制病情及減少?gòu)?fù)發(fā)的目的[18-19]。孟魯司特片可控制大多數(shù)CVA患者的臨床癥狀，且臨床療效確切[20]。有研究表明，孟魯司特片聯(lián)合沙美特羅替卡松對(duì)CVA的臨床癥狀緩解效果優(yōu)于單獨(dú)用藥，且治愈時(shí)間短[21]。

本研究結(jié)果顯示，觀察組患者臨床療效優(yōu)于對(duì)照組，F(xiàn)EV1、FEV1/FVC、PEF高于對(duì)照組，CRT、CDT短于對(duì)照組，RR低于對(duì)照組。表明孟魯司特片聯(lián)合沙美特羅替卡松粉吸入劑治療CVA的臨床療效確切，可有效改善患者肺功能，縮短患者CRT及CDT，降低復(fù)發(fā)率，且安全性較高，值得臨床推廣應(yīng)用。

參考文獻(xiàn)

[1]Niimi A.Cough and Asthma[J].Current Respiratory Medicine Reviews,2011,7(1):47-54.

[2]Tajiri T,Niimi A,Matsumoto H,et al.Prevalence and clinical relevance of allergic rhinitis in patients with classic asthma and cough variant asthma[J].Respiration,2014,87(3):211-218.

[3]Ohta K,Yamaguchi M,Akiyama K,et al.Japanese guideline for adult asthma[J].Allergol Int,2011,60(2):115-145.

[4]Takemura M,Niimi A,Matsumoto H,et al.Clinical,physiological and anti-inflammatory effect of montelukast in patients with cough variant asthma[J].Respiration,2012,83(4):308-315.

[5]Okunishi K,Peters-Golden M.Leukotrienes and airway inflammation[J].Biochimica Et Biophysica Acta,2011,1810(11):1096-1102.

[6]中華醫(yī)學(xué)會(huì)呼吸病學(xué)分會(huì)哮喘學(xué)組.咳嗽的診斷與治療指南(2009版)[J].中華結(jié)核和呼吸雜志,2009,7(5):407-413.

[7]Ohkura N,Fujimura M,Nakade Y,et al.Heightened cough response to bronchoconstriction in cough variant asthma[J].Respirology,2012,17(6):964-968.

[8]Krishnan JA,Bender BG,Wamboldt FS,et al.Adherence to inhaled corticosteroids:an ancillary study of the Childhood Asthma Management Program clinical trial[J].J Allergy Clin Immunol,2012,129(1):112-118.

[9]Lougheed MD,Turcotte SE,Fisher T.Cough variant asthma:lessons learned from deep inspirations[J].Lung,2012,190(1):17-22.

[10]Lipińska-Ojrzanowska A,Wiszniewska M,Walusiak-Skorupa J.Cough-variant asthma:a diagnostic dilemma in the occupational setting[J].Occup Med (Lond),2015,65(2):165-168.

[11]Rely K,McQuire SE,Alexandre PK,et al.Cost effectiveness of treatment with salmeterol/fluticasone compared to montelukast for the control of persistent asthma in children[J].Value Health,2011,14(5 Suppl 1):S43-S47.

[12]Pedersen SE,Hurd SS,Lemanske RF J,et al.Global strategy for the diagnosis and management of asthma in children 5 years and younger[J].Pediatr Pulmonol,2011,46(1):1-17.

[13]Paggiaro P,Patel S,Nicolini G,et al.Stepping down from high dose fluticasone/salmeterol to extrafine BDP/F in asthma is cost-effective[J].Respir Med,2013,107(10):1531-1537.

[14]Liu ZW,Yue F,Gao FY,et al.Research on the molecular mechanism of Seretide treatment to asthma disease[J].Eur Rev Med Pharmacol Sci,2012,16(12):1701-1706.

[15]Kagohashi K,Satoh H,Ohara G,et al.Long-term safety of budesonide/formoterol for the treatment of elderly patients with bronchial asthma[J].Exp Ther Med,2014,7(4):1005-1009.

[16]Ilarraza R,Wu Y,Adamko DJ.Montelukast inhibits leukotriene stimulation of human dendritic cells in vitro[J].Int Arch Allergy Immunol,2012,159(4):422-427.

[17]Fujimura M.Pathophysiology,diagnosis and treatment of cough variant asthma[J].Rinsho Byori，2014，62(5)：464-470.

[18]Souza FC,Gobbato NB,Maciel RG,et al.Effects of corticosteroid,montelukast and iNOS inhibition on distal lung with chronic inflammation[J].Respir Physiol Neurobiol,2013,185(2):435-445.

[19]Tamaoki J,Yokohori N,Tagaya E,et al.Comparable effect of a leukotriene receptor antagonist and long-acting beta2-adrenergic agonist in cough variant asthma[J].Allergy Asthma Proc,2010,31(5):78-84.

[20]Keast SL,Thompson D,Farmer K，et al.Impact of a prior authorization policy for montelukast on clinical outcomes for asthma and allergic rhinitis among children and adolescents in a state Medicaid program[J].J Manag Care Spec Pharm,2014,20(6):612-621.

[21]Saito N,Itoga M,Tamaki M，et al.Cough variant asthma patients are more depressed and anxious than classic asthma patients[J].J Psychosom Res,2015,79(1):18-26.

(本文編輯：李潔晨)

Clinical Effect of Montelukast Combined With Salmeterol and Fluticas Inhalant on Cough Variant Asthma

WANGYong，YANGYa-chun，LIUYong.

DepartmentofRespiratoryMedicine，RailwayHospitalofXinyi，Xinyi221400，China

【Abstract】ObjectiveTo observe the clinical effect of montelukast combined with salmeterol and fluticas inhalant on cough variant asthma.MethodsA total of 112 patients with cough variant asthma were selected in the Railway Hospital of Xinyi from 2011 to 2014，and they were divided into control group and observation group according to visiting sequence，each of 56 cases.Patients of control group received salbutamol aerosol after admission，while patients of observation group received montelukast combined with salmeterol and fluticas inhalant；both groups continuously treated for 8 weeks.Clinical effect，index of lung function(including FEV1，F(xiàn)EV1/FVC and PEF)，cough relief time(CRT)，cough disappearance time(CDT)，recurrence rate and incidence of adverse reactions were compared between the two groups.ResultsThe clinical effect of observation group was statistically significantly better than that of control group(P<0.05).No statistically significant differences of FEV1，F(xiàn)EV1/FVC or PEF was found between the two groups before treatment(P>0.05)，while FEV1，F(xiàn)EV1/FVC and PEF of observation group were statistically significantly higher than those of control group(P<0.05).CRT and CDT of observation group were statistically significantly shorter than those of control group，and recurrence rate of observation group was statistically significantly lower than that of control group(P<0.05).Of control group，3 cases occurred headache，2 cases occurred finger fremitus；no one of observation group occurred any serious adverse reactions.ConclusionMontelukast combined with salmeterol and fluticas inhalant has certain clinical effect in treating cough variant asthma，can effectively improve the lung function，shorten the CRT and CDT，reduce the recurrence rate，and is safe.

【Key words】Asthma;Montelukast;Salmeterol and fluticas inhalant;Treatment outcome

【中圖分類號(hào)】R 562.25

【文獻(xiàn)標(biāo)識(shí)碼】B

doi:10.3969/j.issn.1008-5971.2016.04.035

(收稿日期：2016-01-10；修回日期：2016-04-15)