Effect of Inhaled Formoterol and Budesonide on Exacerbations of Asthma
Romain A. Pauwels, M.D., Claes-Göran Löfdahl, M.D., Dirkje S. Postma, M.D., Anne E. Tattersfield, M.D., Paul O'Byrne, M.B., Peter J. Barnes, D.M., Anders Ullman, M.D., for The Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group
Background The role of long-acting, inhaled 2-agonists in treatingasthma is uncertain. In a double-blind study, we evaluated theeffects of adding inhaled formoterol to both lower and higherdoses of the inhaled glucocorticoid budesonide.
Methods After a four-week run-in period of treatment with budesonide(800 µg twice daily), 852 patients being treated withglucocorticoids were randomly assigned to one of four treatmentsgiven twice daily by means of a dry-powder inhaler (Turbuhaler):100 µg of budesonide plus placebo, 100 µg of budesonideplus 12 µg of formoterol, 400 µg of budesonide plusplacebo, or 400 µg of budesonide plus 12 µg of formoterol.Terbutaline was permitted as needed. Treatment continued forone year; we compared the frequency of exacerbations of asthma,symptoms, and lung function in the four groups. A severe exacerbationwas defined by the need for oral glucocorticoids or a decreasein the peak flow to more than 30 percent below the base-linevalue on two consecutive days.
Results The rates of severe and mild exacerbations were reducedby 26 percent and 40 percent, respectively, when formoterolwas added to the lower dose of budesonide. The higher dose ofbudesonide alone reduced the rates of severe and mild exacerbationsby 49 percent and 37 percent, respectively. Patients treatedwith formoterol and the higher dose of budesonide had the greatestreductions — 63 percent and 62 percent, respectively.Symptoms of asthma and lung function improved with both formoteroland the higher dose of budesonide, but the improvements withformoterol were greater.
Conclusions In patients who have persistent symptoms of asthmadespite treatment with inhaled glucocorticoids, the additionof formoterol to budesonide therapy or the use of a higher doseof budesonide may be beneficial. The addition of formoterolto budesonide therapy improves symptoms and lung function withoutlessening the control of asthma.
Inhaled glucocorticoids are considered the first-line treatmentfor patients with moderate-to-severe, persistent asthma.1,2,3However, many patients taking an inhaled glucocorticoid continueto have symptoms and need additional treatment. Inhaled 2-agonistsare widely used for symptomatic relief in patients with asthma,but their regular use has been the subject of recent controversy.4,5,6Treatment with the long-acting, inhaled 2-agonists formoteroland salmeterol provides better control of symptoms and improveslung function more than short-acting 2-agonists.7,8 Combininga long-acting, inhaled 2-agonist with an inhaled glucocorticoidled to a greater improvement in the control of symptoms andin lung function than doubling the dose of the inhaled glucocorticoid.9,10However, some studies have suggested that long-term treatmentwith long-acting, inhaled 2-agonists might result in toleranceto its effects or mask an increase in airway inflammation.11,12,13,14,15,16,17,18,19,20
We studied the hypothesis that the addition of regular treatmentwith the long-acting, inhaled 2-agonist formoterol to a loweror higher dose of the inhaled glucocorticoid budesonide wouldresult in improved control of symptoms and lung function, withoutany long-term deterioration in the control of asthma over a12-month period. The primary outcomes evaluated were the ratesof severe and mild exacerbations of asthma. Secondary outcomesincluded lung function, symptoms, and the need for 2-agonistsfor rescue therapy.
Methods
Patients
Patients 18 to 70 years old, who had had asthma for at leastsix months and had been treated with an inhaled glucocorticoidfor at least three months were enrolled. The forced expiratoryvolume in one second (FEV1) at base line had to be at least50 percent of the predicted value,21 with an increase of atleast 15 percent in FEV1 from the base-line value after theinhalation of 1 mg of terbutaline. Patients taking more than2000 µg of beclomethasone or 1600 µg of budesonidedaily by pressurized metered-dose inhaler, 800 µg of budesonidedaily by Turbuhaler dry-powder inhaler (Astra, Södertällje,Sweden), or 800 µg of fluticasone daily were excluded.They were also excluded if they had had three or more coursesof oral glucocorticoids or had been hospitalized for asthmaduring the previous six months.
Study Design
The study was a double-blind, randomized, parallel-group studywith four treatment groups. It was carried out at 71 centersin nine countries (Belgium, Canada, the Netherlands, Israel,Italy, Luxembourg, Norway, Spain, and the United Kingdom). Approvalfrom regulatory agencies and ethics committees was obtainedin all countries and at all centers. All patients gave witnessedoral or written informed consent.
The study had a 4-week run-in period, followed by 12 monthsof randomized treatment. There were nine scheduled visits tothe clinic: at the start of the run-in period, at the startof treatment, and after 2 weeks and 1, 2, 3, 6, 9, and 12 monthsof treatment. In addition, telephone contacts were scheduledwith the patients after 2 weeks of the run-in period, after2 to 5 days of treatment, and after 4, 5, 7, 8, 10, and 11 monthsof treatment.
All patients entering the run-in phase received inhaled budesonide(Pulmicort, Astra Draco, Lund, Sweden) at a dose of 800 µgtwice daily (total daily dose, 1600 µg), plus 250 µgof inhaled terbutaline (Bricanyl, Astra Draco) as needed. Atthe end of the run-in period, patients were eligible for randomizationif they had complied with the run-in treatment and had stableasthma. Compliance was defined as the use of 75 to 125 percentof the recommended number of doses of inhaled budesonide, asindicated on a hidden mechanical counter built into the dry-powderinhaler that could be read only by the investigators. Asthmawas defined as stable if none of the following occurred duringthe last 10 days of the run-in period: diurnal variation ofmore than 20 percent in the peak expiratory flow on 2 consecutivedays; use of four or more inhalations of 2-agonist per day on2 consecutive days; awakening due to asthma on 2 consecutivenights; or the need to use oral glucocorticoids.
Eligible patients were randomly assigned to receive one of thefollowing treatments (each dose was given twice daily) for aperiod of 12 months: 100 µg of budesonide (total dailydose, 200 µg) plus placebo; 100 µg of budesonideplus 12 µg of formoterol (Oxis, Astra Draco; total dailydose, 24 µg); 400 µg of budesonide (total dailydose, 800 µg) plus placebo; or 400 µg of budesonideplus 12 µg of formoterol. Terbutaline (250 µg perinhalation) was used as rescue medication. All medications wereinhaled by means of a multidose Turbuhaler. The stated dosesof budesonide, formoterol, and terbutaline are the metered doses.The patients were randomly assigned to treatment groups in balancedblocks of four at each center.
Outcome Measures
Exacerbations of Asthma
The primary outcomes studied were the rates of severe and mildexacerbations of asthma per patient per year. A severe exacerbationwas defined as one requiring treatment with oral glucocorticoids,as judged by the investigator, or a decrease in the peak expiratoryflow as measured in the morning to more than 30 percent belowthe base-line value on two consecutive days. Seventy-three percentof severe exacerbations were identified clinically by the investigators.The base-line peak expiratory flow was defined as the mean peakexpiratory flow in the morning during the last 10 days of therun-in period. All severe exacerbations had to be treated witha 10-day course of oral glucocorticoids (30 mg of prednisoloneor prednisone or 24 mg of methylprednisolone per day). Patientswho had three severe exacerbations within three months or atotal of five severe exacerbations were withdrawn from the study.Days with mild exacerbations were defined as days when one ofthe following occurred: a peak expiratory flow in the morningthat was more than 20 percent below the base-line value; theuse of more than three additional inhalations of terbutalineper 24 hours as compared with the base-line period; or awakeningat night due to asthma. Single, isolated days of mild exacerbationswere not counted. The base-line value was the mean value forthe variable during the last 10 days of the run-in period. Daysincluded in a severe exacerbation were excluded from the countof days with mild exacerbations.
Diary-Card Data
Patients filled in a daily diary during the run-in and treatmentperiods, recording the best of three measurements of peak expiratoryflow made with a Vitalograph Peak Flow Meter (Vitalograph, Buckingham,United Kingdom) in the morning and evening before medication;symptoms of asthma during the night or the daytime (accordingto a 4-point scale, with 0 indicating no symptoms and 3 incapacitatingsymptoms); awakening due to asthma; use of inhalations of terbutalinefor rescue therapy (at night or during the day); and the useof oral glucocorticoids.
Clinic Visits
At scheduled clinic visits, clinical measures, adverse events,withdrawals, or changes in medication were recorded, diary cardswere reviewed, and FEV1 was measured.
Episode-Free Days
An episode-free day was defined as a day with optimally controlledasthma — that is, no need for rescue therapy with inhaled2-agonists, an asthma-symptom score of 0, a morning peak expiratoryflow that was 80 percent or more of the base-line value, andno adverse events.
Statistical Analysis
The data analysis followed a factorial design, and pairwisecomparisons were made by appropriate contrasts. Rates of exacerbationwere analyzed by applying a Poisson regression model. Othervariables were analyzed with use of analysis of covariance,with base-line variables as covariates. For data from the diaries,mean values for the last 10 days before each visit were used.The analysis included all randomized patients (intention-to-treatapproach). Data for patients who withdrew or discontinued therapywere included up to the time of their withdrawal. The numberof days when treatment was received was entered as a covariate.
Results
From April 1994 to April 1995, consecutive potentially eligiblepatients were identified at the participating institutions.Of the 1114 patients entering the run-in period, 262 were excludedbefore randomization because they were determined to be ineligible.The remaining 852 patients (436 women and 416 men) were randomlyassigned to treatment groups. Base-line demographic and spirometriccharacteristics and diary-card data are presented in Table 1.The differences in base-line data among the groups were minorand nonsignificant. Of the 852 patients randomly assigned toreceive treatment, 694 (81 percent) completed the 12-month study.Of the 158 patients who did not complete the study, 44 did notfulfill the entry criteria and were incorrectly randomized,30 had worsening of asthma, 29 had adverse events, and 55 leftthe study for other reasons (13 because of noncompliance withstudy procedures, 5 because they intended to become pregnant,5 because they relocated, 20 for personal reasons, and 12 becausethey were lost to follow-up). Most of the incorrectly randomizedpatients were withdrawn in the initial part of the study aftera visit to the clinic for monitoring. Only three remained inthe study for more than 90 days.
Table 1. Base-Line Characteristics of the Study Patients.
Exacerbations of Asthma
Table 2 shows the two primary outcome variables, the rate ofsevere exacerbations and the rate of mild exacerbations, accordingto treatment group. The lowest rates were among the patientswho received the higher dose of budesonide plus formoterol.There was no significant interaction between budesonide andformoterol in terms of either severe or mild exacerbations.Formoterol and the higher dose of budesonide produced additivereductions in severe and mild exacerbations.
The rate of severe exacerbations was reduced by 26 percent whenformoterol was added to the lower dose of budesonide and by49 percent when the higher dose of budesonide was given alone.The combination of formoterol and the higher dose of budesonidereduced the estimated rate of severe exacerbations by 63 percent,from 0.91 per year per patient to 0.34 (P<0.001). Givingthe higher dose of budesonide resulted in a greater reductionin the rate of severe exacerbations than did the addition offormoterol (P = 0.03). Altogether, 80.8 percent of the patientsreceiving both formoterol and the higher dose of budesonidewere free of severe exacerbations during the study, as comparedwith 61.4 percent of the patients receiving the lower dose ofbudesonide without formoterol. Of the 30 patients who left thestudy because their asthma worsened, 21 were withdrawn becausethey had frequent severe exacerbations: 10 receiving the lowerdose of budesonide alone, 7 receiving the lower dose of budesonideplus formoterol, 4 receiving only the higher dose of budesonide,and none receiving the higher dose of budesonide plus formoterol(P = 0.01 for the difference among the treatment groups).
The rate of mild exacerbations was reduced by 37 percent whenthe higher dose of budesonide, rather than the lower dose, wasgiven and by 40 percent when formoterol was added to the lowerdose of budesonide. The combination of budesonide and the higherdose of formoterol reduced the estimated rate of mild exacerbationsby 62 percent, from 35.4 per patient per year to 13.4 (P<0.001).There was no significant change in the rate of severe or mildexacerbations in any treatment group during the course of thestudy.
Symptoms
At the end of the run-in period, when patients received 800µg of budesonide twice a day, clinical-symptom scores,the rate of use of rescue medication, and the frequency of nighttimeawakening were low in all four groups (Table 1). The additionof formoterol to budesonide therapy was associated with a significantfurther improvement in both daytime and nighttime symptom scores(Table 2). The higher dose of budesonide was significantly betterthan the lower dose in controlling symptoms during the day,but patients in both treatment groups that received budesonidewithout formoterol had a slight increase in symptom scores ascompared with the run-in period.
The need for rescue medication was reduced significantly byadding formoterol, during both the day and the night, and bythe use of the higher dose of budesonide, during the night butnot during the day. The addition of formoterol to budesonidetherapy was associated with a significantly increased numberof episode-free days; the higher dose of budesonide was notassociated with a significant increase (Table 2).
Lung Function
FEV1 increased significantly in all groups during the run-inperiod and increased further with the addition of formoterol(Figure 1). The higher dose of budesonide was associated witha significantly higher FEV1 than the lower dose. Peak expiratoryflow in the morning and evening increased considerably whenformoterol was added (Figure 2). The higher dose of budesonidewas associated with a significant increase in peak expiratoryflow, although less than that associated with the addition offormoterol.
Figure 1. Forced Expiratory Volume in One Second (FEV1) during the Study.
FEV1 is shown as a mean percentage of the predicted value during the run-in period (shaded area) and the treatment period. The bars indicate 2 SE. During the run-in period, all patients received 800 µg of budesonide twice daily. Patients were then randomly assigned to twice-daily treatment with 100 µg of budesonide, 100 µg of budesonide plus 12 µg of formoterol, 400 µg of budesonide, or 400 µg of budesonide plus 12 µg of formoterol.
Figure 2. Changes in Mean Peak Expiratory Flow (PEF) in the Morning during the Run-in Period, on Days 1 through 14 of Treatment, and at Months 1 through 12 of Treatment.
During the run-in period all patients received 800 µg of budesonide twice daily. Patients were then randomly assigned to twice-daily treatment with 100 µg of budesonide, 100 µg of budesonide plus 12 µg of formoterol, 400 µg of budesonide, or 400 µg of budesonide plus 12 µg of formoterol.
In the formoterol groups, the peak expiratory flow in the morningwas higher during the first days of treatment than subsequently(i.e., after day 3; P<0.001). For the rest of the 12-monthtreatment period, the peak expiratory flow remained stable andconsiderably higher than the value in the groups treated withbudesonide alone (Figure 2).
Adverse Events
All treatments were well tolerated throughout the study. Theproportion of patients reporting adverse events was similarin the four treatment groups. Eleven patients were hospitalizedbecause of asthma: three receiving the lower dose of budesonideplus placebo, one receiving the lower dose of budesonide plusformoterol, five receiving the higher dose of budesonide plusplacebo, and two receiving the higher dose of budesonide plusformoterol. Twenty-nine patients withdrew because of adverseevents: six receiving lower-dose budesonide plus placebo, sixreceiving lower-dose budesonide plus formoterol, eight receivinghigher-dose budesonide plus placebo, and nine receiving higher-dosebudesonide plus formoterol. Seven withdrawals were due to pharmacologicallypredictable adverse events: three in the group receiving lower-dosebudesonide plus formoterol (one with headache and two with tremor)and four in the group receiving higher-dose budesonide plusformoterol (two with tremor, one with tachycardia, and one withoral candidiasis). The other 22 withdrawals were due to throatirritation (2 patients), gastrointestinal effects (5), and miscellaneousside effects (15).
Discussion
We examined the hypothesis that adding regular treatment withthe long-acting inhaled 2-agonist formoterol to therapy withthe inhaled glucocorticoid budesonide would improve symptomsof asthma without a long-term worsening of the disease, as indicatedby the rates of severe and mild exacerbations. We found no evidenceof deterioration in the control of asthma over the course ofa year when formoterol was added to budesonide therapy. In fact,the addition of formoterol decreased the incidence of both severeand mild exacerbations. This effect was independent of the doseof budesonide. The rates of severe and mild exacerbations werealso lower among the patients given the higher dose of budesonide;this effect was independent of the addition of formoterol. Forsevere exacerbations, the effect of the higher dose of budesonidewas significantly more pronounced than the effect of formoterol.
Regular treatment with long-acting, inhaled 2-agonists has notbeen shown to modify chronic airway inflammation in patientswith asthma.22,23 The reason for the reduction in the rate ofsevere exacerbations with formoterol is not clear. Possibleexplanations include an inhibitory effect on the acute inflammatorychanges that occur during a severe exacerbation; an inhibitoryeffect on airway smooth-muscle contraction, plasma extravasation,or both — assuming that these are important to the developmentof severe acute exacerbations; and an increased deposition ofbudesonide in the airways after the inhalation of formoterol.Acute exacerbations of asthma are associated with an influxof eosinophils, neutrophils, or both.24,25 Formoterol has beenshown to inhibit the influx of inflammatory cells in animalmodels of acute airway inflammation.26 Formoterol is a potentfunctional antagonist of airway smooth-muscle stimulants andinhibits plasma extravasation.27,28,29,30
In our study, the addition of formoterol to either the loweror the higher dose of budesonide also improved asthma-symptomscores and lung function and reduced the need for rescue medications.The improvement in the control of symptoms is in agreement withthe results of other studies, which have shown better controlof symptoms when long-acting, inhaled 2-agonists are added tothe treatment regimen.7,8,9,10,31,32
The control of asthma symptoms and lung function were betterin the higher-dose budesonide groups than in the lower-dosegroups, although the effect of increasing the dose of budesonideon these measures was less marked than that of adding formoterol.The relative effects of adding formoterol or giving a higherdose of budesonide on the control of symptoms and on lung functionin this study are in keeping with observations made with salmeterol.9,10
Regular treatment with formoterol combined with budesonide didnot cause any long-term loss of control of asthma. There wereno signs of worsening of disease or tolerance to the effectsof medication with regard to any clinical or functional variableexamined, except for a decrease in the effect of formoterolon peak expiratory flow in the morning after the first two daysof treatment. The addition of formoterol resulted in a substantialincrease in peak expiratory flow in the morning during the firstone to two days of treatment, followed by a slight decreasein both budesonide groups. The peak expiratory flow then remainedstable and significantly higher than in the budesonide-onlygroups for the rest of the one-year study period. One possibleexplanation is the development of limited tolerance to the bronchodilatingeffect of formoterol during the early phase of regular treatment,as demonstrated in other studies.11,12,13,14,15,16,18,19 Ourfindings suggest that such tolerance has little or no clinicalsignificance.
It is important to emphasize that our conclusions may applyonly when formoterol is given with an inhaled glucocorticoid.33Another limitation of our study is that patients underwent randomizationonly if they had stable asthma during the last 10 days of therun-in period, when all patients were treated with 1600 µgof budesonide daily. This is a relatively high dose of budesonide,considering that inhalation from a Turbuhaler delivers twiceas much budesonide to the airways as inhalation from pressurizedmetered-dose inhalers.34,35
Our results support therapeutic guidelines that recommend theaddition of a long-acting inhaled 2-agonist to low doses ofinhaled glucocorticoids in patients with persistent symptomsof asthma or less than optimal lung function.3 Increasing themaintenance dose of inhaled glucocorticoids might be a moreappropriate initial therapeutic step in patients with repeatedsevere exacerbations of asthma.
Supported by a grant from Astra Draco, Lund, Sweden.
* The members of the study group are listed in the Appendix.
Source Information
From the Department of Respiratory Diseases, University Hospital, Ghent, Belgium (R.A.P.); the Department of Respiratory Medicine, University Hospital, Lund, Sweden (C.-G.L.); the Division of Respiratory Disease, University Hospital, Groningen, the Netherlands (D.S.P.); the Division of Respiratory Medicine, City Hospital, Nottingham, United Kingdom (A.E.T.); the Department of Respirology, McMaster University, Hamilton, Ont., Canada (P.O.); the National Heart and Lung Institute, Imperial College, London (P.J.B.); and Clinical Research and Development, Astra Draco, Lund, Sweden (A.U.).
Address reprint requests to Dr. Pauwels at the Department of Respiratory Diseases, University Hospital, De Pintelaan 185, B9000 Ghent, Belgium.
References
Haahtela T, Järvinen M, Kava T, et al. Comparison of a 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-392. [Abstract]
van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiverman EJ, Pocock SJ, Kerrebijn KF. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. Am Rev Respir Dis 1992;146:547-554. [Medline]
Global Initiative for Asthma. Global strategy for asthma management and prevention. Washington, D.C.: National Heart, Lung, and Blood Institute, 1995. (Publication no. 95-3659.)
Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990;336:1391-1396. [CrossRef][Medline]
Spitzer WO, Suissa S, Ernst P, et al. The use of -agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501-506. [Abstract]
Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. N Engl J Med 1996;335:841-847. [Free Full Text]
Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 1992;327:1420-1425. [Abstract]
Kesten S, Chapman KR, Broder I, et al. A three-month comparison of twice daily inhaled formoterol versus four times daily inhaled albuterol in the management of stable asthma. Am Rev Respir Dis 1991;144:622-625. [Medline]
Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344:219-224. [CrossRef][Medline]
Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996;153:1481-1488. [Abstract]
Kalra S, Swystun VA, Bhagat R, Cockcroft DW. Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol. Chest 1996;109:953-956. [Free Full Text]
Bhagat R, Kalra S, Swystun VA, Cockcroft DW. Rapid onset of tolerance to the bronchoprotective effect of salmeterol. Chest 1995;108:1235-1239. [Erratum, Chest 1996;109:592.] [Free Full Text]
Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijkman JH, Sterk PJ. Long-term effects of a long-acting 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992;327:1198-1203. [Abstract]
Ramage L, Lipworth BJ, Ingram CG, Cree IA, Dhillon DP. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994;88:363-368. [CrossRef][Medline]
Newnham DM, McDevitt DG, Lipworth BJ. Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma. Am J Med 1994;97:29-37. [CrossRef][Medline]
O'Connor BJ, Aikman SL, Barnes PJ. Tolerance to the nonbronchodilator effects of inhaled 2-agonists in asthma. N Engl J Med 1992;327:1204-1208. [Abstract]
Tattersfield AE. Clinical pharmacology of long-acting beta-receptor agonists. Life Sci 1993;52:2161-2169. [Medline]
Cockcroft DW, Swystun VA, Bhagat R. Interaction of inhaled beta 2 agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine. Am J Respir Crit Care Med 1995;152:1485-1489. [Abstract]
Yates DH, Sussman HS, Shaw MJ, Barnes PJ, Chung KF. Regular formoterol treatment in mild asthma: effect on bronchial responsiveness during and after treatment. Am J Respir Crit Care Med 1995;152:1170-1174. [Abstract]
Lofdahl CG, Svedmyr N. Beta-agonists -- friends or foes? Eur Respir J 1991;4:1161-1165. [Medline]
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows: report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal: official statement of the European Respiratory Society. Eur Respir J 1993;6:Suppl 16:5-40. [Medline]
Roberts JA, Bradding P, Walls AF, et al. The influence of salmeterol xinafoate on mucosal inflammation in asthma. Am Rev Respir Dis 1992;145:Suppl:A418-A418.abstract
Gardiner PV, Ward C, Booth H, Allison A, Hendrick DJ, Walters EH. Effect of eight weeks of treatment with salmeterol on bronchoalveolar lavage inflammatory indices in asthmatics. Am J Respir Crit Care Med 1994;150:1006-1011. [Abstract]
Turner MO, Hussack P, Sears MR, Dolovich J, Hargreave FE. Exacerbations of asthma without sputum eosinophilia. Thorax 1995;50:1057-1061. [Free Full Text]
Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995;95:843-852. [CrossRef][Medline]
Whelan CJ, Johnson M, Vardey CJ. Comparison of the anti-inflammatory properties of formoterol, salbutamol and salmeterol in guinea-pig skin and lung. Br J Pharmacol 1993;110:613-618. [Medline]
Erjefalt I, Persson CG. Long duration and high potency of antiexudative effects of formoterol in guinea-pig tracheobronchial airways. Am Rev Respir Dis 1991;144:788-791. [Medline]
Advenier C, Qian Y, Koune JD, Molimard M, Candenas ML, Naline E. Formoterol and salbutamol inhibit bradykinin- and histamine-induced airway microvascular leakage in guinea-pig. Br J Pharmacol 1992;105:792-798. [Medline]
Baluk P, McDonald DM. The beta 2-adrenergic receptor agonist formoterol reduces microvascular leakage by inhibiting endothelial gap formation. Am J Physiol 1994;266:L461-L468. [Free Full Text]
Kallstrom BL, Sjoberg J, Waldeck B. The interaction between salmeterol and beta 2-adrenoceptor agonists with higher efficacy on guinea-pig trachea and human bronchus in vitro. Br J Pharmacol 1994;113:687-692. [Medline]
Britton MG, Earnshaw JS, Palmer JBD. A twelve month comparison of salmeterol with salbutamol in asthmatic patients. Eur Respir J 1992;5:1062-1067. [Erratum, Eur Respir J 1993;6:150.] [Abstract]
Kesten S, Chapman KR, Broder I, et al. Sustained improvement in asthma with long-term use of formoterol fumarate. Ann Allergy 1992;69:415-420. [Medline]
Verberne AAPH, Frost C, Roorda RJ, van der Laag H, Kerrebijn KF, Dutch Paediatric Asthma Study Group. One year treatment with salmeterol compared with beclomethasone in children with asthma. Am J Respir Crit Care Med 1997;156:688-695. [Free Full Text]
Thorsson L, Edsbacker S, Conradson TB. Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI. Eur Respir J 1994;7:1839-1844. [Abstract]
Borgstrom L, Derom E, Stahl E, Wahlin-Boll E, Pauwels R. The inhalation device influences lung deposition and bronchodilating effect of terbutaline. Am J Respir Crit Care Med 1996;153:1636-1640. [Abstract]
Appendix
The following physicians, listed according to country, enrolledpatients: Belgium — W. DeBacker, M. Decramer, P.-M. Mengeot,L. Siemons, J. Verhaert, and W. Vinken; Canada — M. Alexander,J. Bouchard, A. Day, A. Knight, J.-L. Malo, D. Marciniuk, J.G.Martin, S. Peters, B. Sanders, B. Sproule, and D. Stubbing;the Netherlands — A. Baas, T.A. Bantje, J. Creemers, H.Sinninghe Damsté, W. Evers, S. Gans, A. Greefhorst, H.Hassing, F. Maesen, M.J. Möllers, H.R. Pasma, Z. Pelikan,P.E. Postmus, J. Prins, B.M. Santana, M. Schrijver, A.P. Sips,R. Stallaert, L. van der Maas, and A.J. van Harreveld; Israel— J. Greif, D. Heimer, A.H. Rubin, and A. Wollner; Italy— F. Bariffi, F. Bonifazi, V. Brusasco, G. D'Amato, L.Fabbri, C. Franco, L. Gandola, C. Giuntini, E. Gramiccioni,V. Grassi, L. Marazzini, A. Rossi, A.M. Santolicandro, and C.Sturani; Luxembourg — J.-P. Parini; Norway — L.Bjermer and N. Ringdal; Spain — J.L. Alvarez Sala, P.L.Cabrera Navarro, S. Romero, J. Sanchis, V. Sobradillo, and H.Verea; United Kingdom — G. Basran, L.M. Campbell, D. Franklin,G.J. Gibson, R.C. Joshi, A. Knox, A.B. MacLean, R. Scott, R.Smith, A. Tattersfield, and J.P. Vernon. The following Astraemployees were involved in the study: C.-A. Bauer (project leader),M. Best (data entry), C. Hultquist (medical advisor), F. Jackson(safety evaluation), A. Lennon (medical coordinator), S. Lindgren(safety evaluation), H. MacFarlane (computing), A. McLean (deputyproject leader), M. Nevinson (medical coordinator), M.-Å.Persson (computing), and K. Svensson (statistician). The nationalmedical monitors were: F. Bellemans, T. Ben-Or, S. Bordonaro,M. Chiesa, I. Garcia, J. Haddon, S. Holthe, M. Huybrechts, A.Ning, H. Rijskamp, F. Stafford, and M. van den Dobbelsteen.
Wijesinghe, M., Weatherall, M., Perrin, K., Harwood, M., Beasley, R.
(2009). Risk of mortality associated with formoterol: a systematic review and meta-analysis. Eur Respir J
34: 803-811
[Abstract][Full Text]
Oborne, J., Mortimer, K., Hubbard, R. B., Tattersfield, A. E., Harrison, T. W.
(2009). Quadrupling the Dose of Inhaled Corticosteroid to Prevent Asthma Exacerbations: A Randomized, Double-blind, Placebo-controlled, Parallel-Group Clinical Trial. Am. J. Respir. Crit. Care Med.
180: 598-602
[Abstract][Full Text]
Lommatzsch, M, Lindner, Y, Edner, A, Bratke, K, Kuepper, M, Virchow, J C
(2009). Adverse effects of salmeterol in asthma: a neuronal perspective. Thorax
64: 763-769
[Abstract][Full Text]
Montuschi, P., Pagliari, G., Fuso, L.
(2009). Pharmacotherapy of asthma: regular treatment or on demand?. Ther Adv Respir Dis
3: 175-191
[Abstract]
Reddel, H. K., Taylor, D. R., Bateman, E. D., Boulet, L.-P., Boushey, H. A., Busse, W. W., Casale, T. B., Chanez, P., Enright, P. L., Gibson, P. G., de Jongste, J. C., Kerstjens, H. A. M., Lazarus, S. C., Levy, M. L., O'Byrne, P. M., Partridge, M. R., Pavord, I. D., Sears, M. R., Sterk, P. J., Stoloff, S. W., Sullivan, S. D., Szefler, S. J., Thomas, M. D., Wenzel, S. E., on behalf of the American Thoracic Society/Europea,
(2009). An Official American Thoracic Society/European Respiratory Society Statement: Asthma Control and Exacerbations: Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice. Am. J. Respir. Crit. Care Med.
180: 59-99
[Abstract][Full Text]
Plint, A. C., Johnson, D. W., Patel, H., Wiebe, N., Correll, R., Brant, R., Mitton, C., Gouin, S., Bhatt, M., Joubert, G., Black, K. J.L., Turner, T., Whitehouse, S., Klassen, T. P., Pediatric Emergency Research Canada (PERC),
(2009). Epinephrine and Dexamethasone in Children with Bronchiolitis. NEJM
360: 2079-2089
[Abstract][Full Text]
Drazen, J. M., O'Byrne, P. M.
(2009). Risks of Long-Acting Beta-Agonists in Achieving Asthma Control. NEJM
360: 1671-1672
[Full Text]
Dahlen, B., Lantz, A-S., Ihre, E., Skedinger, M., Henriksson, E., Jorgensen, L., Ekstrom, T., Dahlen, S-E., Larsson, K.
(2009). Effect of formoterol with or without budesonide in repeated low-dose allergen challenge. Eur Respir J
33: 747-753
[Abstract][Full Text]
Fanta, C. H.
(2009). Asthma. NEJM
360: 1002-1014
[Full Text]
Kelly, H W.
(2009). Comparison of Inhaled Corticosteroids: An Update. The Annals of Pharmacotherapy
43: 519-527
[Abstract][Full Text]
Sears, M. R., Ottosson, A., Radner, F., Suissa, S.
(2009). Long-acting {beta}-agonists: a review of formoterol safety data from asthma clinical trials. Eur Respir J
33: 21-32
[Abstract][Full Text]
O'Byrne, P. M., Pedersen, S., Lamm, C. J., Tan, W. C., Busse, W. W., on behalf of the START Investigators Group,
(2009). Severe Exacerbations and Decline in Lung Function in Asthma. Am. J. Respir. Crit. Care Med.
179: 19-24
[Abstract][Full Text]
O'Byrne, P. M., Naya, I. P., Kallen, A., Postma, D. S., Barnes, P. J.
(2008). Increasing Doses of Inhaled Corticosteroids Compared to Adding Long-Acting Inhaled {beta}2-Agonists in Achieving Asthma Control. Chest
134: 1192-1199
[Abstract][Full Text]
Southam, D. S., Ellis, R., Wattie, J., Glass, W., Inman, M. D.
(2008). Goblet Cell Rebound and Airway Dysfunction with Corticosteroid Withdrawal in a Mouse Model of Asthma. Am. J. Respir. Crit. Care Med.
178: 1115-1122
[Abstract][Full Text]
Johnson, J. R., Pacitto, S. R., Wong, J., Archer, E. W., Eirefelt, S., Miller-Larsson, A., Jordana, M.
(2008). Combined budesonide/formoterol therapy in conjunction with allergen avoidance ameliorates house dust mite-induced airway remodeling and dysfunction. Am. J. Physiol. Lung Cell. Mol. Physiol.
295: L780-L788
[Abstract][Full Text]
Rank, M. A., Volcheck, G. W., Li, J. T. C., Patel, A. M., Lim, K. G.
(2008). Formulating an Effective and Efficient Written Asthma Action Plan. Mayo Clin Proc.
83: 1263-1270
[Abstract][Full Text]
Pinnock, H.
(2008). A man with poorly controlled asthma and exercise induced symptoms. BMJ
337: a1963-a1963
[Full Text]
Message, S. D., Laza-Stanca, V., Mallia, P., Parker, H. L., Zhu, J., Kebadze, T., Contoli, M., Sanderson, G., Kon, O. M., Papi, A., Jeffery, P. K., Stanciu, L. A., Johnston, S. L.
(2008). Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc. Natl. Acad. Sci. USA
105: 13562-13567
[Abstract][Full Text]
Sykes, A., Seemungal, T., ICEAD contributors,
(2008). Recent advances in exacerbations of asthma. Thorax
63: 758-760
[Full Text]
Bjermer, L.
(2008). Review: Evaluating combination therapies for asthma: pros, cons, and comparative benefits. Ther Adv Respir Dis
2: 149-161
[Abstract]
Greening, A. P., Stempel, D., Bateman, E. D., Virchow, J. C.
(2008). Managing asthma patients: which outcomes matter?. ERR
17: 53-61
[Abstract][Full Text]
Sears, M. R., Boulet, L-P., Laviolette, M., Fitzgerald, J. M., Bai, T. R., Kaplan, A., Smiljanic-Georgijev, N., Lee, J. S-M.
(2008). Budesonide/formoterol maintenance and reliever therapy: impact on airway inflammation in asthma. Eur Respir J
31: 982-989
[Abstract][Full Text]
Liu, K., Gualano, R. C., Hibbs, M. L., Anderson, G. P., Bozinovski, S.
(2008). Epidermal Growth Factor Receptor Signaling to Erk1/2 and STATs Control the Intensity of the Epithelial Inflammatory Responses to Rhinovirus Infection. J. Biol. Chem.
283: 9977-9985
[Abstract][Full Text]
Mehuys, E., Van Bortel, L., De Bolle, L., Van Tongelen, I., Annemans, L., Remon, J. P., Brusselle, G.
(2008). Effectiveness of pharmacist intervention for asthma control improvement. Eur Respir J
31: 790-799
[Abstract][Full Text]
Bateman, E. D., Hurd, S. S., Barnes, P. J., Bousquet, J., Drazen, J. M., FitzGerald, M., Gibson, P., Ohta, K., O'Byrne, P., Pedersen, S. E., Pizzichini, E., Sullivan, S. D., Wenzel, S. E., Zar, H. J.
(2008). Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J
31: 143-178
[Abstract][Full Text]
Kaur, M., Chivers, J. E., Giembycz, M. A., Newton, R.
(2008). Long-Acting 2-Adrenoceptor Agonists Synergistically Enhance Glucocorticoid-Dependent Transcription in Human Airway Epithelial and Smooth Muscle Cells. Mol. Pharmacol.
73: 203-214
[Abstract][Full Text]
D'Urzo, A. D.
(2007). {beta}-Agonists: all the facts please. cfp
53: 1884-1886
[Full Text]
Salpeter, S. R.
(2007). Response. cfp
53: 1886-1886
[Full Text]
Loven, J., Svitacheva, N., Jerre, A., Miller-Larsson, A., Korn, S. H.
(2007). Anti-inflammatory activity of {beta}2-agonists in primary lung epithelial cells is independent of glucocorticoid receptor. Eur Respir J
30: 848-856
[Abstract][Full Text]
Cazzola, M., Matera, M. G.
(2007). Review: Safety of long-acting {beta}2 -agonists in the treatment of asthma. Ther Adv Respir Dis
1: 35-46
[Abstract]
Nuijsink, M., Hop, W. C. J., Sterk, P. J., Duiverman, E. J., de Jongste, J. C., on behalf of the Children Asthma Therapy Optimal (,
(2007). Long-term asthma treatment guided by airway hyperresponsiveness in children: a randomised controlled trial. Eur Respir J
30: 457-466
[Abstract][Full Text]
Tai, A., Ranganathan, S.
(2007). Optimizing Medications for Poorly Controlled Asthma. Am. J. Respir. Crit. Care Med.
176: 520-521
[Full Text]
Shaw, D. E., Berry, M. A., Thomas, M., Green, R. H., Brightling, C. E., Wardlaw, A. J., Pavord, I. D.
(2007). The Use of Exhaled Nitric Oxide to Guide Asthma Management: A Randomized Controlled Trial. Am. J. Respir. Crit. Care Med.
176: 231-237
[Abstract][Full Text]
Johnston, S. L.
(2007). Innate Immunity in the Pathogenesis of Virus-induced Asthma Exacerbations. Proc Am Thorac Soc
4: 267-270
[Abstract][Full Text]
Shaheen, S. O, Newson, R. B, Rayman, M. P, Wong, A. P-L, Tumilty, M. K, Phillips, J. M, Potts, J. F, Kelly, F. J, White, P. T, Burney, P. G J
(2007). Randomised, double blind, placebo-controlled trial of selenium supplementation in adult asthma. Thorax
62: 483-490
[Abstract][Full Text]
Edwards, M. R., Haas, J., Panettieri, R. A. Jr., Johnson, M., Johnston, S. L.
(2007). Corticosteroids and beta2 Agonists Differentially Regulate Rhinovirus-induced Interleukin-6 via Distinct Cis-acting Elements. J. Biol. Chem.
282: 15366-15375
[Abstract][Full Text]
Papi, A., Canonica, G. W., Maestrelli, P., Paggiaro, P., Olivieri, D., Pozzi, E., Crimi, N., Vignola, A. M., Morelli, P., Nicolini, G., Fabbri, L. M., the BEST Study Group,
(2007). Rescue Use of Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma. NEJM
356: 2040-2052
[Abstract][Full Text]
Beeh, K. M., Derom, E., Kanniess, F., Cameron, R., Higgins, M., van As, A.
(2007). Indacaterol, a novel inhaled {beta}2-agonist, provides sustained 24-h bronchodilation in asthma. Eur Respir J
29: 871-878
[Abstract][Full Text]
Bell, A. D., McIvor, R. A.
(2007). The SMART study. cfp
53: 687-688
[Full Text]
Papi, A., Paggiaro, P. L., Nicolini, G., Vignola, A. M., Fabbri, L. M., on behalf of the Inhaled Combination Asthma Treatm,
(2007). Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J
29: 682-689
[Abstract][Full Text]
Cox, G., Thomson, N. C., Rubin, A. S., Niven, R. M., Corris, P. A., Siersted, H. C., Olivenstein, R., Pavord, I. D., McCormack, D., Chaudhuri, R., Miller, J. D., Laviolette, M., the AIR Trial Study Group,
(2007). Asthma Control during the Year after Bronchial Thermoplasty. NEJM
356: 1327-1337
[Abstract][Full Text]
Naline, E., Trifilieff, A., Fairhurst, R. A., Advenier, C., Molimard, M.
(2007). Effect of indacaterol, a novel long-acting {beta}2-agonist, on isolated human bronchi. Eur Respir J
29: 575-581
[Abstract][Full Text]
Enderby, B., Doull, I.
(2007). Hypertonic saline inhalation in cystic fibrosis--salt in the wound, or sweet success?. Arch. Dis. Child.
92: 195-196
[Full Text]
Travers, J., Marsh, S., Williams, M., Weatherall, M., Caldwell, B., Shirtcliffe, P., Aldington, S., Beasley, R.
(2007). External validity of randomised controlled trials in asthma: to whom do the results of the trials apply?. Thorax
62: 219-223
[Abstract][Full Text]
Erin, E. M., Kon, O. M., Barnes, P. J., Hansel, T. T.
(2007). . Am. J. Respir. Crit. Care Med.
175: 288a-289
[Full Text]
Moore, R. H., Millman, E. E., Godines, V., Hanania, N. A., Tran, T. M., Peng, H., Dickey, B. F., Knoll, B. J., Clark, R. B.
(2007). Salmeterol Stimulation Dissociates beta2-Adrenergic Receptor Phosphorylation and Internalization. Am. J. Respir. Cell Mol. Bio.
36: 254-261
[Abstract][Full Text]
Bisgaard, H., Le Roux, P., Bjamer, D., Dymek, A., Vermeulen, J. H., Hultquist, C.
(2006). Budesonide/Formoterol Maintenance Plus Reliever Therapy: A New Strategy in Pediatric Asthma. Chest
130: 1733-1743
[Abstract][Full Text]
Ernst, P., McIvor, A., Ducharme, F. M., Boulet, L.-P., FitzGerald, M., Chapman, K. R., Bai, T., for the Canadian Asthma Guideline Group,
(2006). Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids.. ANN INTERN MED
145: 692-694
[Abstract][Full Text]
Salpeter, S. R.
(2006). Safety of Long-Acting {beta}-Agonists.. ANN INTERN MED
145: 708-710
[Full Text]
Lindberg, M. J.
(2006). Safety of long-acting beta-agonists.. ANN INTERN MED
145: 706-707
[Full Text]
FitzGerald, J M, Gibson, P G
(2006). Asthma exacerbations {middle dot} 4: Prevention.. Thorax
61: 992-999
[Abstract][Full Text]
Erin, E. M., Leaker, B. R., Nicholson, G. C., Tan, A. J., Green, L. M., Neighbour, H., Zacharasiewicz, A. S., Turner, J., Barnathan, E. S., Kon, O. M., Barnes, P. J., Hansel, T. T.
(2006). The Effects of a Monoclonal Antibody Directed against Tumor Necrosis Factor-{alpha} in Asthma. Am. J. Respir. Crit. Care Med.
174: 753-762
[Abstract][Full Text]
Bell, A., McIvor, R. A.
(2006). SMART therapy.. CMAJ
175: 276-277
[Full Text]
Johnston, N W, Sears, M R
(2006). Asthma exacerbations {middle dot} 1: Epidemiology.. Thorax
61: 722-728
[Abstract][Full Text]
Reddel, H. K., Barnes, D. J.
(2006). Pharmacological strategies for self-management of asthma exacerbations.. Eur Respir J
28: 182-199
[Abstract][Full Text]
Green, R. H., Brightling, C. E., McKenna, S., Hargadon, B., Neale, N., Parker, D., Ruse, C., Hall, I. P., Pavord, I. D.
(2006). Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness. Eur Respir J
27: 1144-1151
[Abstract][Full Text]
Williams, D. M.
(2006). Considerations in the long-term management of asthma in ambulatory patients. Am J Health Syst Pharm
63: S14-S21
[Abstract][Full Text]
Wouters, E. F. M.
(2006). Approaches to Improving Health Status in Chronic Obstructive Pulmonary Disease: One or Several?. Proc Am Thorac Soc
3: 262-269
[Abstract][Full Text]
Edwards, M. R., Johnson, M. W., Johnston, S. L.
(2006). Combination Therapy: Synergistic Suppression of Virus-Induced Chemokines in Airway Epithelial Cells. Am. J. Respir. Cell Mol. Bio.
34: 616-624
[Abstract][Full Text]
Rubinfeld, A. R., Scicchitano, R., Hunt, A., Thompson, P. J., Van Nooten, A., Selroos, O.
(2006). Formoterol Turbuhaler as reliever medication in patients with acute asthma. Eur Respir J
27: 735-741
[Abstract][Full Text]
Rees, J.
(2006). Asthma control in adults.. BMJ
332: 767-771
[Full Text]
Koopmans, J G, Lutter, R, Jansen, H M, van der Zee, J S
(2006). Adding salmeterol to an inhaled corticosteroid: long term effects on bronchial inflammation in asthma. Thorax
61: 306-313
[Abstract][Full Text]
(2006). Endpoints in asthma drug trials - what do they mean?. DTB
44: 21-24
[Abstract][Full Text]
Jayaram, L., Pizzichini, M. M., Cook, R. J., Boulet, L-P., Lemiere, C., Pizzichini, E., Cartier, A., Hussack, P., Goldsmith, C. H., Laviolette, M., Parameswaran, K., Hargreave, F. E.
(2006). Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations.. Eur Respir J
27: 483-494
[Abstract][Full Text]
Cheung, D., van Klink, H. C. J., Aalbers, R., for the OZON study group,
(2006). Improved lung function and symptom control with formoterol on demand in asthma.. Eur Respir J
27: 504-510
[Abstract][Full Text]
Wechsler, M. E., Lehman, E., Lazarus, S. C., Lemanske, R. F. Jr., Boushey, H. A., Deykin, A., Fahy, J. V., Sorkness, C. A., Chinchilli, V. M., Craig, T. J., DiMango, E., Kraft, M., Leone, F., Martin, R. J., Peters, S. P., Szefler, S. J., Liu, W., Israel, E., for the National Heart Lung and Blood Institute's,
(2006). beta-Adrenergic Receptor Polymorphisms and Response to Salmeterol. Am. J. Respir. Crit. Care Med.
173: 519-526
[Abstract][Full Text]
Parameswaran, K.
(2006). Treatment Strategy for Asthma: One for All and All for One?. Chest
129: 221-223
[Full Text]
Rabe, K. F., Pizzichini, E., Stallberg, B., Romero, S., Balanzat, A. M., Atienza, T., Lier, P. A., Jorup, C.
(2006). Budesonide/Formoterol in a Single Inhaler for Maintenance and Relief in Mild-to-Moderate Asthma: A Randomized, Double-Blind Trial.. Chest
129: 246-256
[Abstract][Full Text]
O'Byrne, P. M., Adelroth, E.
(2006). {beta}2 Deja Vu. Chest
129: 3-5
[Full Text]
Todorova, L., Gurcan, E., Miller-Larsson, A., Westergren-Thorsson, G.
(2006). Lung Fibroblast Proteoglycan Production Induced by Serum Is Inhibited by Budesonide and Formoterol. Am. J. Respir. Cell Mol. Bio.
34: 92-100
[Abstract][Full Text]
Miller, M., Cho, J. Y., McElwain, K., McElwain, S., Shim, J. Y., Manni, M., Baek, J. S., Broide, D. H.
(2006). Corticosteroids prevent myofibroblast accumulation and airway remodeling in mice. Am. J. Physiol. Lung Cell. Mol. Physiol.
290: L162-L169
[Abstract][Full Text]
Harle, P, Straub, R H, Wiest, R, Mayer, A, Scholmerich, J, Atzeni, F, Carrabba, M, Cutolo, M, Sarzi-Puttini, P
(2006). Increase of sympathetic outflow measured by neuropeptide Y and decrease of the hypothalamic-pituitary-adrenal axis tone in patients with systemic lupus erythematosus and rheumatoid arthritis: another example of uncoupling of response systems. Ann Rheum Dis
65: 51-56
[Abstract][Full Text]
Barnes, P., Virchow, J. C., Sanchis, J., Welte, T., Pedersen, S.
(2005). Asthma management: important issues. ERR
14: 147-151
[Abstract][Full Text]
Vogelmeier, C., D'Urzo, A., Pauwels{dagger}, R., Merino, J. M., Jaspal, M., Boutet, S., Naya, I., Price, D.
(2005). Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option?. Eur Respir J
26: 819-828
[Abstract][Full Text]
Donohue, J. F.
(2005). Combination Therapy for Chronic Obstructive Pulmonary Disease: Clinical Aspects. Proc Am Thorac Soc
2: 272-281
[Abstract][Full Text]
Baouz, S., Giron-Michel, J., Azzarone, B., Giuliani, M., Cagnoni, F., Olsson, S., Testi, R., Gabbiani, G., Canonica, G. W.
(2005). Lung myofibroblasts as targets of salmeterol and fluticasone propionate: inhibition of {alpha}-SMA and NF-{kappa}B. Int Immunol
17: 1473-1481
[Abstract][Full Text]
Currie, G. P., Lee, D. K. C., Srivastava, P.
(2005). Long-Acting Bronchodilator or Leukotriene Modifier as Add-on Therapy to Inhaled Corticosteroids in Persistent Asthma?. Chest
128: 2954-2962
[Abstract][Full Text]
Usmani, O. S., Ito, K., Maneechotesuwan, K., Ito, M., Johnson, M., Barnes, P. J., Adcock, I. M.
(2005). Glucocorticoid Receptor Nuclear Translocation in Airway Cells after Inhaled Combination Therapy. Am. J. Respir. Crit. Care Med.
172: 704-712
[Abstract][Full Text]
Calverley, P., Pauwels{dagger}, R., Lofdahl, C-G., Svensson, K., Higenbottam, T., Carlsson, L-G., Stahl, E.
(2005). Relationship between respiratory symptoms and medical treatment in exacerbations of COPD. Eur Respir J
26: 406-413
[Abstract][Full Text]
Overbeek, S. E., Mulder, P. G., Baelemans, S. M., Hoogsteden, H. C., Prins, J.-B.
(2005). Formoterol Added to Low-Dose Budesonide Has No Additional Antiinflammatory Effect in Asthmatic Patients. Chest
128: 1121-1127
[Abstract][Full Text]
Littner, M. R., Leung, F. W., Ballard, E. D. II, Huang, B., Samra, N. K., on behalf of the Lansoprazole Asthma Study Group,
(2005). Effects of 24 Weeks of Lansoprazole Therapy on Asthma Symptoms, Exacerbations, Quality of Life, and Pulmonary Function in Adult Asthmatic Patients With Acid Reflux Symptoms. Chest
128: 1128-1135
[Abstract][Full Text]
Tattersfield, A E
(2005). When should a long acting {beta} agonist be added to an inhaled corticosteroid?. Thorax
60: 710-710
[Full Text]
Masoli, M, Weatherall, M, Holt, S, Beasley, R
(2005). Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma. Thorax
60: 730-734
[Abstract][Full Text]
Silkoff, P. E., Corbetta, L., Fabbri, L. M., Currie, G. P., Lee, D. K.C., Smith, A. D., Taylor, D. R.
(2005). Exhaled Nitric Oxide and Asthma. NEJM
353: 732-733
[Full Text]
Gaga, M., Papageorgiou, N., Zervas, E., Gioulekas, D., Konstantopoulos, S.
(2005). Control of Asthma Under Specialist Care: Is It Achieved?. Chest
128: 78-84
[Abstract][Full Text]
Nie, M., Knox, A. J., Pang, L.
(2005). {beta}2-Adrenoceptor Agonists, Like Glucocorticoids, Repress Eotaxin Gene Transcription by Selective Inhibition of Histone H4 Acetylation. J. Immunol.
175: 478-486
[Abstract][Full Text]
Peek, E. J., Richards, D. F., Faith, A., Lavender, P., Lee, T. H., Corrigan, C. J., Hawrylowicz, C. M.
(2005). Interleukin-10-Secreting "Regulatory" T Cells Induced by Glucocorticoids and {beta}2-Agonists. Am. J. Respir. Cell Mol. Bio.
33: 105-111
[Abstract][Full Text]
Jayaram, L, Pizzichini, E, Lemiere, C, Man, S F P, Cartier, A, Hargreave, F E, Pizzichini, M M M
(2005). Steroid naive eosinophilic asthma: anti-inflammatory effects of fluticasone and montelukast. Thorax
60: 100-105
[Abstract][Full Text]
O'Byrne, P. M., Bisgaard, H., Godard, P. P., Pistolesi, M., Palmqvist, M., Zhu, Y., Ekstrom, T., Bateman, E. D.
(2005). Budesonide/Formoterol Combination Therapy as Both Maintenance and Reliever Medication in Asthma. Am. J. Respir. Crit. Care Med.
171: 129-136
[Abstract][Full Text]
Reddel, H.K.
(2004). Goals of asthma treatment: how high should we go?. Eur Respir J
24: 715-717
[Full Text]
Calverley, P. M. A.
(2004). Effect of Corticosteroids on Exacerbations of Asthma and Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc
1: 161-166
[Abstract][Full Text]
Lee, D K C, Jackson, C M, Bates, C E, Lipworth, B J
(2004). Cross tolerance to salbutamol occurs independently of {beta}2 adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol. Thorax
59: 662-667
[Abstract][Full Text]
Larj, M. J., Bleecker, E. R.
(2004). Therapeutic Responses in Asthma and COPD: Corticosteroids. Chest
126: 138S-149S
[Abstract][Full Text]
Sin, D. D., Man, J., Sharpe, H., Gan, W. Q., Man, S. F. P.
(2004). Pharmacological Management to Reduce Exacerbations in Adults With Asthma: A Systematic Review and Meta-analysis. JAMA
292: 367-376
[Abstract][Full Text]
Gaga, M.
(2004). Fixed obstruction in severe asthma: not just a matter of time. Eur Respir J
24: 8-10
[Full Text]
Stempel, D. A., Roberts, C. S., Stanford, R. H.
(2004). Treatment Patterns in the Months Prior to and After Asthma-Related Emergency Department Visit. Chest
126: 75-80
[Abstract][Full Text]
Cazzola, M., Dahl, R.
(2004). Inhaled Combination Therapy With Long-Acting {beta}2-Agonists and Corticosteroids in Stable COPD. Chest
126: 220-237
[Abstract][Full Text]
Busse, W W, Lemanske, R F Jr
(2004). Management of asthma exacerbations. Thorax
59: 545-546
[Full Text]
Perng, D.-W., Huang, H.-Y., Lee, Y.-C., Perng, R.-P.
(2004). Leukotriene Modifier vs Inhaled Corticosteroid in Mild-to-Moderate Asthma: Clinical and Anti-inflammatory Effects. Chest
125: 1693-1699
[Abstract][Full Text]
A correction has been published: N Engl J Med 1998;338(2):139.
2-agonists in treating asthma is uncertain. In a double-blind study, we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide. 
