SEARCH

SEARCH BY CITATION

Keywords:

  • asthma;
  • extra-fine formulation;
  • methacholine;
  • nitrogen test;
  • small airways

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

To cite this article: Scichilone N, Battaglia S, Sorino C, Paglino G, Martino L, Paternò A, Santagata R, Spatafora M, Nicolini G, Bellia V. Effects of extra-fine inhaled beclomethasone/formoterol on both large and small airways in asthma. Allergy 2010; 65: 897–902.

Abstract

Background:  Airway inflammation in asthma involves both large and small airways, and the combination of inhaled corticosteroids (ICS) and long acting beta-2 agonists (LABA) is the mainstay of therapy. Available inhaled combinations differ in terms of drug delivery to the lung and the ability to reach small airways.

Aim:  To evaluate whether treatment with an extra-fine inhaled combination provides additional effects vs a nonextra-fine combination on airway function.

Methods:  After a 1- to 4-week run-in period, patients with asthma were randomized to a double blind, double dummy, 12-week treatment with either extra-fine beclomethasone/formoterol (BDP/F) 400/24 μg daily or fluticasone propionate/salmeterol (FP/S) 500/100 μg daily. Methacholine (Mch) bronchoprovocation challenge and single breath nitrogen (sbN2) test were performed.

Results:  Thirty patients with asthma (15 men), mean age 43, mean forced expiratory volume in the first second (FEV1) 71.4% of predicted, were included. A significant increase (P < 0.01) versus baseline was observed in predose FEV1 in both BDP/F and FP/S groups (0.37 ± 0.13 l and 0.36 ± 0.12 l, respectively). PD20FEV1 Mch improved significantly from 90.42 (±30.08) μg to 432.41 (±122.71) μg in the BDP/F group (P = 0.01) but not in the FP/S group. A trend toward improvement vs baseline was observed for BDP/F in closing capacity (CC), whereas no differences were recorded in other sbN2 test parameters.

Conclusion:  The findings of this pilot study suggest that an extra-fine inhaled combination for the treatment of asthma has beneficial effects on both large and small airways function as expressed by Mch and sbN2 tests.

Airway inflammation in asthma involves both large and small airways, with the term small airways meaning those airways that are <2 mm in diameter, significantly contributing to the pathogenesis of asthma in terms of bronchoconstriction and hyper-responsiveness (1). Small airways involvement has been related to asthma severity (2), and the outer wall of small airways has been recently recognized as the major site of remodeling in patients with fatal asthma (3). Moreover, early closure of these small airways, perhaps attributed to uncontrolled inflammation, has been shown to characterize patients with ‘difficult to control asthma.’ (4) Inhaled corticosteroids (ICS) are the mainstay of asthma therapy, in that, they reduce inflammation, improve pulmonary function, and lead to reductions in symptoms and exacerbations, with a negligible systemic effect. From the evidence that inflammatory and structural changes occur throughout the airways, it is clear that anti-inflammatory treatment should be targeted at both large and small airways to achieve suppression of inflammation throughout the entire bronchial tree. However, not all devices for inhaled drug formulations are efficient in targeting the small airways, with the drug being mostly deposited in the central airways. One way to overcome the limited drug delivery to the airways is to reduce the mean particle size of the inhaled drug, thus increasing the number of particles in the range of 1.5–3 μm which are needed to reach peripheral airways (5). Drugs formulated with small particle size are called extra-fine formulations, and randomized controlled studies show that extra-fine formulations of ICS as a single agent provide additional clinical benefits compared to the same nonextra-fine agents (6) or placebo (7).

International guidelines recommend the combination of a long acting beta-2-agonist (LABA) and an ICS when asthma is not fully controlled by low-dose ICS alone (8). Three fixed combinations are commercially available: budesonide/formoterol, fluticasone propionate/salmeterol (FP/S), and the recently developed beclomethasone dipropionate/formoterol (BDP/F) extra-fine combination. In patients with moderate and severe asthma, BDP/F extra-fine combination shows a comparable efficacy and safety profile to the other two fixed-dose combinations (9, 10). However, no information is available on the potential differences between ICS/LABA-fixed combinations on small airways function. BDP/F combination was developed using the Modulite® solution formulation technology (11), which provides high lung deposition and uniform distribution throughout the bronchial tree and unlike the other two fixed combinations, is the only extra-fine formulation characterized by small particle size (12, 13). Indeed, extra-fine BDP/F is the first combination showing better asthma control and a higher percentage of symptom-free days when compared to beclomethasone and formoterol given by separate inhalers (14). This finding has been suggested to be related to the lung deposition profile of BDP/F extra-fine formulation, which allows for the two drugs to target both central and peripheral airways.

Several noninvasive functional methodologies have been proposed as potentially useful tools to evaluate peripheral lung function and consequently, to establish the effect of drugs reaching the small airways (15, 16). Among these, the single breath nitrogen (sbN2) test can be used to evaluate the presence of uneven distribution of ventilation, which is indicative of functional impairments and air trapping in the periphery of the lung (16, 17). By contrast, the magnitude of airway hyper-responsiveness (AHR) to methacholine (Mch), expressed as the provocative dose able to induce a 20% fall in FEV1, mainly reflects large airways function.

On this basis, we designed an explorative study on the potential effect of extra-fine BDP/F combination on large and small airways function by comparing its effect on Mch and sbN2 tests with that obtainable with nonextra-fine FP/S combination.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Patients

Subjects were recruited prospectively from the outpatient population between August 2006 and January 2008 in the Department of Medicine and Respiratory Diseases of the University of Palermo (DIMPEFINU Palermo, Italy). Patients were included if aged between 18 and 50, with a clinical diagnosis of moderate persistent asthma for at least 6 months (8) and a forced expiratory volume in the first second (FEV1) of >60% of the predicted normal value; asthma severity was established by taking into account current treatment schedule in patients already treated. Patients were excluded if current smokers or recent (<1 year) quitters, or in case of diagnosis of chronic obstructive pulmonary disease (COPD), history of near fatal asthma, or recent severe asthma exacerbation or hospitalization. Patients who had changed their dose of ICS during the previous 4 weeks or under treatment with ICS at a daily dose >1000 μg of BDP or equivalent were also excluded. All patients had to be in stable conditions prior to the study and with no history of recent (4 weeks) upper or lower airway infections.

The study was performed in accordance with the Good Clinical Practice guidelines recommended by the International Conference on Harmonization of Technical Requirements. The protocol was approved by the institutional review board of the center, and written informed consent was obtained from each participant prior to study initiation.

Study design

This was a double blind, double dummy, randomized, parallel group study (Fig. 1). Eligible patients attended a screening visit (visit 1), and, if meeting inclusion criteria, entered a 1- to 4-week run-in period, during which time, all previous respiratory medications were discontinued. At baseline visit (visit 2), patients were randomized to a 12-week treatment period with either BDP/F 100/6 μg delivered via a pressurized metered dose inhaler (pMDI), 2 inhalations bid (Foster; Chiesi Farmaceutici, Parma, Italy), or FP/S 250/50 μg one inhalation bid (Seretide Diskus; GlaxoSmithKline, Middlesex, UK). Functional assessment included conventional spirometry, sbN2-test, and Mch bronchoprovocation. All spirometric measurements were obtained from a computerized water-sealed spirometer (Biomedin; Padua, Italy), which established compliance with criteria for acceptability and reproducibility online.

image

Figure 1.  Study design.

Download figure to PowerPoint

The sbN2-test used a 100% oxygen supplementation and a nitrogen meter connected to the mouthpiece, to allow for continuous sampling of N2 concentrations in the expired air. The N2 concentration measured during a single breath expiration was plotted against lung volume to obtain a nitrogen washout curve. The slope of the nitrogen curve (phase III), the closing volume (CV), and closing capacity (CC) were derived by the operator, and included for analysis. Conventional Mch bronchoprovocation followed standardized ERS guidelines (18), using doubling doses of the spasmogen (Lofarma, Italy). Mch was delivered through an ampul-dosimeter (Mefar Elettromedicali; Bovezzo, Italy), which was activated by an inspiratory effort for 0.5 s at a time. The provocative dose of Mch able to induce a 20% fall in FEV1 from baseline was measured by linear interpolation (PD20Mch FEV1).

Lung function was assessed at 4-week intervals, whereas sbN2 and Mch bronchoprovocation tests were performed at week 4 and 12. Coffee or tea was not allowed before the bronchoprovocations.

Statistics

Because of the explorative nature of the study, no formal sample size calculation was performed. The analysis of covariance (ancova) with treatment as factor and baseline value as a linear covariate was applied. The adjusted means for the two groups at each visit and the adjusted treatment difference between groups at each visit were recorded. All analyses were performed using sas System, Version 9.1.3 Service Pack 4 (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at 0.05 two tailed, and all analyses were performed on intention to treat population.

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Of 41 screened patients, 30 were randomized, and 27 completed the 12-week study period (two patients withdrawn for personal reasons and one because of asthma exacerbation). Demographic characteristics and baseline lung function parameters are summarized in Table 1. Study medication compliance was >90% in both groups. As expected, predose FEV1 significantly improved from the baseline mean (±SE) value of 2.27 (±0.18) l to 2.63 (±0.13) l in the BDP/F group and from 2.24 (±0.21) l to 2.61 (±0.12) l in the FP/S group at the end of treatment (P < 0.01 vs baseline for both groups; P = 0.92 between groups). Forced expiratory flow between 25% and 75% of forced vital capacity (FEF25–75%) significantly improved from the baseline mean (±SE) value of 1.28 (±0.15) l/s to 1.92 (±0.19) l/s in the BDP/F group and from 1.37 (±0.23) l/s to 1.86 (±0.17) l/s in the FP/S group at the end of treatment (P < 0.01 vs baseline for both groups; P = 0.82 between groups). Similarly, no significant differences in all other lung function parameters were recorded between treatments at the end of the study.

Table 1.   Demographic and baseline characteristics of the study groups
 BDP/F (n = 15)FP/S (n = 15)
  1. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF25–75%, forced expiratory flow between 25% and 75% of forced vital capacity; PD20 FEV1mch, Provocative dose of Mch causing a 20% fall in FEV1; BDP/F, beclomethasone dipropionate/formoterol combination; FP/S, fluticasone propionate/salmeterol combination.

Men/Women (n)8/77/8
Age (years; mean ± SD)42 ± 1244 ± 12
FEV1 (l; mean ± SE)2.27 ± 0.182.24 ± 0.21
FEV1 (%; mean ± SE)69.08 ± 2.7873.07 ± 4.19
FEV1/FVC (%; mean ± SE)64.11 ± 1.6562.65 ± 3.33
FEF25–75% (l/s; mean ± SE)1.28 ± 0.151.37 ± 0.23
PD20 FEV1mch (μg; mean ± SE)90.42 ± 30.0896.98 ± 71.20

As regards sbN2 test, a trend toward improvement from baseline was detected in CC in the BDP/F group only. CC changed from a baseline mean (±SE) value of 2.23 (±0.30) l to 1.87 (±0.18) l and 1.88 (±0.15) l after 4 and 12 weeks, respectively, in the BDP/F group (P = 0.08 at week 12; Fig 1, Table 2). In the FP/S group, CC changed from the mean (±SE) baseline value of 2.11(±0.33) l to 2.06 (±0.15) l and 2.22 (±0.12) l after 4 and 12 weeks, respectively (P = 0.58; Fig. 2, Table 2). At weeks 4 and 12, the BDP/F group showed lower adjusted means compared to the FP/S group; moreover, a difference between groups was detected at the end of treatment with a trend for significance (P = 0.09). No significant change from baseline or difference between treatment groups was detected in other sbN2 test parameters (Table 2). Data on CV and CV/vital capacity ratio had different baseline values and were not analyzed.

Table 2.   sbN2 test parameters at baseline and after treatment in the two study groups
 BDP/F (n = 15)FP/S (n = 15)
BaselineWeek 12BaselineWeek 12
  1. CC, closing capacity; CC/TLC, closing capacity/total lung capacity ratio; VC, vital capacity; DN2%/L, slope of phase III of the washout curve; BDP/F, beclomethasone dipropionate/formoterol combination; FP/S, fluticasone propionate/salmeterol combination; #P = 0.08 vs. baseline; $P = 0.09 between treatments.

CC (l; mean ± SE)2.23 ± 0.301.88 ± 0.15#$2.11 ± 0.332.22 ± 0.12
CC/TLC (%; mean ± SE)37.00 ± 5.4133.11 ± 3.0237.31 ± 3.5239.31 ± 1.97
VC (l; mean ± SE)3.09 ± 0.383.58 ± 0.303.23 ± 0.253.53 ± 0.23
DN2 (%/l; mean ± SE)3.38 ± 0.763.07 ± 1.273.51 ± 0.503.77 ± 0.98
image

Figure 2.  Mean change from baseline in closing capacity (CC) in BDP/F (black columns) and FP/S (gray columns) groups; BDP/F, beclomethasone dipropionate/formoterol combination; FP/S, fluticasone propionate/salmeterol combination; bars are SE; #P = 0.08 vs baseline for BDP/F.

Download figure to PowerPoint

The Mch provocative dose causing 20% reduction in FEV1 (PD20mchFEV1) significantly increased from the mean (±SE) baseline value of 90.42 (±30.08) μg to 416.96 (±122.42) μg and 432.41 (±122.71) μg after 4 and 12 weeks in the BDP/F arm (P = 0.01), but not in the FP/S group [96.98 (±71.20) μg, 185.62 (±127.87) μg and 208.16 (±122.71) μg at baseline and after 4 and 12 weeks, respectively] (Fig. 3). However, the difference between groups did not reach statistical significance (P = 0.21 at the end of treatment).

image

Figure 3.  Mean values of provocative dose of Mch causing a 20% fall in FEV1 in the BDP/F (closed circles, continuous line) and FP/S (open squares, dotted line) groups during the study; BDP/F, beclomethasone dipropionate/formoterol combination; FP/S, fluticasone propionate/salmeterol combination; bars are SE; *= 0.01 vs baseline for BDP/F.

Download figure to PowerPoint

No significant difference was found between groups in vital signs, treatment emergent adverse events, and as needed salbutamol use during the study period.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The present pilot study provides evidence of effects on both large and small airways function with BDP/F extra-fine formulation, in terms of a greater effect in increasing the provocative concentration of Mch causing a 20% fall in FEV1 and reducing CC, when compared to the FP/S combination.

As regards standard spirometry, a significant improvement in lung function parameters in both treatment groups was observed. This was expected as FEV1 mainly measures large airway function, and FEF25–75% may indicate small airways function in some instances, but it is not considered a definitive measure of small airways involvement (5). Nevertheless, the improvement from baseline in spirometric measures confirms that enrolled patients had room for improvement during treatment.

The efficacy of extra-fine ICS on peripheral inflammation and airway function has already been demonstrated (19–22). Recently, Cohen et al. (7) showed improvements in small airway function after treatment with ciclesonide, formulated in small particles, in 16 mild to moderate patients with asthma who participated in a double blind, randomized, placebo-controlled pilot study. The novelty of our study consists in testing two currently available inhaled drug combinations with the specific aim of assessing the effect on parameters reflective of both large and small airways function.

One of the main issues in the assessment of small airway involvement is the lack of a physiological measurement representing the gold standard for the functional evaluation of the distal lung. Nevertheless, the test that was used in our study is employed in other research protocols as reflective of small airway abnormalities. A body of evidence indicates that the sbN2 test can efficiently detect small airway dysfunction (7, 15–17). Bourdin et al. (17) showed that ventilation dishomogeneities were significantly associated with poor asthma control, irrespective of FEV1. In another study carried out in individuals with poor control of their asthma, the sbN2 parameters were significantly associated with recurrent asthma exacerbations (16). Thongngarm et al. (23) demonstrated that in 30 poorly controlled moderate to severe patients with asthma, the addition of extra-fine BDP provided greater benefits than the equivalent dose of nonextra-fine FP on small airway function evaluated with sbN2 test, associated with improvements in asthma control. The additional effect of extra-fine BDP has also been confirmed by imaging computed tomography techniques (20), with reduction in regional air trapping in the small airways. The reduction in CC in patients treated with BDP/F extra-fine combination in the present study is consistent with a reduction in air trapping.

Gardini et al. (24) recently presented the results of a study comparing the same inhaled combinations that were employed in our study, showing an improvement in sbN2 phase III slope and CV only after treatment with extra-fine BDP/F. In addition, our findings are consistent with the reduction in air trapping highlighted by the significantly greater improvement in FVC with BDP/F combination when compared to FP/S combination which was previously shown in a larger randomized controlled trial (9).

The current study also investigated the effect of the two inhaled combinations on AHR. ICS have been demonstrated to reduce the degree of AHR, likely by suppressing inflammation. The addition of a LABA further lowers the airway response to Mch, presumably by stabilizing the airway smooth muscle, which confers protection against the spasmogen (25). In our study, both treatments caused a decrease in the magnitude of AHR, which became significant only in the extra-fine BDP/F group. This is in keeping with the observations by Micheletto et al. (19), who showed a significantly greater effect of extra-fine BDP on the airway response to Mch than the corresponding nonextra-fine BDP formulation for a period of 12 weeks. The explanation for the different effect of the two treatments on AHR could lie on the different time-course of the response of clinical and functional parameters to treatment; indeed, AHR needs longer time to be significantly affected (26), and there is no long-term study comparing extra-fine with nonextra-fine treatments. Even if Mch bronchoprovocation test is not considered as a marker of small airways dysfunction, different studies found a greater effect of extra-fine formulations on this parameter, confirming that extra-fine formulations can target both large and small airways. Our results are in agreement with the recently published study by Yamaguchi and coworkers (27) comparing an extra-fine formulation of BDP with the same drug in a nonextra-fine formulation. In that study, only the extra-fine formulation significantly attenuated airway sensitivity and resistance of small airways measured by impulse oscillometry system. Notably, a strong correlation was found between the improvement of airway sensitivity and baseline resistance in the small airways, suggesting that patients with more severe small airway impairment may gain greater additional benefits from extra-fine treatments.

The major limit of our study is that we did not select subjects on the basis of compromised sbN2 test and/or severe AHR, thus lowering the potential for treatment effect. Moreover, the difference in sbN2 test showed only a trend for significance, and this can be attributed to the small number of patients who cannot exclude a type II error in between group comparisons. The alternative hypotheses are that the two treatments are equally effective on large and small airways, or the parameters we chose are not sensitive enough to detect differences between treatments.

The conclusion of our study is that improvements shown in the BDP/F group and not in the FP/S group suggest an additional effect of extra-fine formulation on both large and small airways and raise the possibility that sbN2 test can be employed to evaluate small airways. Further studies are needed to confirm the clinical relevance of these observations.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The study was supported by Chiesi Farmaceutici S.p.A.; G. Nicolini is an employee of the sponsor Company.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  • 1
    Hamid Q, Song Y, Kotsimbos TC, Minshall E, Bai TR, Hegele RG et al. Inflammation of small airways in asthma. J Allergy Clin Immunol 1997;100:4451.
  • 2
    Wenzel SE, Busse WW; the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Severe asthma: lessons from the Severe Asthma Research Program. J Allergy Clin Immunol 2007;119:1421.
  • 3
    Dolhnikoff M, Da Silva LF, De Araujo BB, Gomes HA, Fernezlian S, Mulder A et al. The outer wall of small airways is a major site of remodeling in fatal asthma. J Allergy Clin Immunol 2009;123:10901097.
  • 4
    Burgel PR, De Blic J, Chanez P, Delacourt C, Devillier P, Didier A et al. Update on the roles of distal airways in asthma. Eur Respir Rev 2009;18:8095.
  • 5
    Bjermer L. History and future perspectives of treating asthma as a systemic and small airways disease. Respir Med 2001;95:703719. Review.
  • 6
    Vanden Burgt JA, Busse WW, Martin RJ, Szefler SJ, Donnell D. Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma. J Allergy Clin Immunol 2000;106:12091226.
  • 7
    Cohen J, Douma WR, Ten Hacken NH, Vonk JM, Oudkerk M, Postma DS. Ciclesonide improves measures of small airway involvement in asthma. Eur Respir J 2008;31:12131220.
  • 8
    Global INitiative for Asthma (GINA). Global strategy for asthma management and prevention: NHLBI/WHO workshop report. Bethesda, MD: National Heart, Lung and Blood Institute, Updated 2006.
  • 9
    Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma. Allergy 2007;62:11821188.
  • 10
    Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J 2007;29:682689.
  • 11
    Acerbi D, Brambilla G, Kottakis I. Advances in asthma and COPD management: delivering CFC-free inhaled therapy using Modulite technology. Pulm Pharmacol Ther 2007;20:290303.
  • 12
    Nicolini G, Scichilone N, Bizzi A, Papi A, Fabbri LM. Beclomethasone/formoterol fixed combination for the management of asthma: patient considerations. Ther Clin Risk Manag 2008;4:855864.
  • 13
    Fabbri LM, Nicolini G, Olivieri D, Papi A. Inhaled beclometasone dipropionate/formoterol extra-fine fixed combination in the treatment of asthma: evidence and future perspectives. Expert Opin Pharmacother 2008;9:479490.
  • 14
    Huchon G, Magnussen H, Chuchalin A, Dymek L, Gonod FB, Bousquet J. Lung function and asthma control with beclomethasone and formoterol in a single inhaler. Respir Med 2009;103:4149.
  • 15
    Battaglia S, Den Hertog H, Timmers MC, Lazeroms SP, Vignola AM, Rabe KF et al. Small airways function and molecular markers in exhaled air in mild asthma. Thorax 2005;60:639644.
  • 16
    In‘t Veen JC, Beekman AJ, Bel EH, Sterk PJ. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000;161:19021906.
  • 17
    Bourdin A, Paganin F, Prefaut C, Kieseler D, Godard P, Chanez P. Nitrogen washout slope in poorly controlled asthma. Allergy 2006;61:8589.
  • 18
    Sterk PJ, Fabbri LM, Quarnier PhH, Cockcroft DW, O’Byrne PM, Anderson SD et al. Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur Respir J 1993;6(Suppl. 16):5383.
  • 19
    Micheletto C, Guerriero M, Tognella S, Dal Negro RW. Effects of HFA- and CFC-beclomethasone dipropionate on the bronchial response to methacholine (MCh) in mild asthma. Respir Med 2005;99:850855.
  • 20
    Goldin JG, Tashkin DP, Kleerup EC, Greaser LE, Haywood UM, Sayre JW et al. Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipropionate inhalation on small airways: assessment with functional helical thin-section computed tomography. J Allergy Clin Immunol 1999;104:S258S267.
  • 21
    Hauber H, Taha R, Bergeron C, Migounov V, Hamid Q, Olivenstein R. Effects of hydrofluoroalkane and dry powder-formulated corticosteroids on sputum inflammatory markers in asthmatic patients. Can Respir J 2006;13:7378.
  • 22
    Verbanck S, Schuermans D, Meysman M, Paiva M, Vincken W. Noninvasive assessment of airway alterations in smokers: the small airways revisited. Am J Respir Crit Care Med 2004;15:170.
  • 23
    Thongngarm T, Silkoff PE, Kossack WS, Nelson HS. Hydrofluoroalkane-134A beclomethasone or chlorofluorocarbon fluticasone: effect on small airways in poorly controlled asthma. J Asthma 2005;42:257263.
  • 24
    Gardini G, Corda L, Guerini M, La Piana GE, Taranto Montemurro L, Tantucci C. Effect on small airway obstruction of two different long-term LABA+ics treatments in asthmatic patients. Eur Respir J 2009;34(Suppl. 53):P1985.
  • 25
    Currie GP, Stenback S, Lipworth BJ. Effects of fluticasone vs. fluticasone/salmeterol on airway calibre and airway hyperresponsiveness in mild persistent asthma. Br J Clin Pharmacol 2003;56:1117.
  • 26
    Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW et al. 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 2009;180:5999.
  • 27
    Yamaguchi M, Niimi A, Ueda T, Takemura M, Matsuoka H, Jinnai M et al. Effect of inhaled corticosteroids on small airways in asthma: investigation using impulse oscillometry. Pulm Pharmacol Ther 2009;22:326332.