Protective effect of budesonide/formoterol compared with formoterol, salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised, double-blind, cross-over study

René Aalbers, Martin Boorsma, Hanneke J van der Woude, René E Jonkers, René Aalbers, Martin Boorsma, Hanneke J van der Woude, René E Jonkers

Abstract

Background: The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear.

Methods: The acute protective effect of inhaled budesonide was tested in a model of temporarily increased airway inflammation with repeated indirect airway challenges, mimicking an acute asthma exacerbation. A randomised, double-blind, cross-over study design was used. Asthmatic patients (n = 17, mean FEV1 95% of predicted) who previously demonstrated a > or = 30% fall in forced expiratory volume in 1 second (FEV1) after inhaling adenosine 5'-monophosphate (AMP), were challenged on four consecutive test days, with the same dose of AMP (at 09:00, 12:00 and 16:00 hours). Within 1 minute of the maximal AMP-induced bronchoconstriction at 09:00 hours, the patients inhaled one dose of either budesonide/formoterol (160/4.5 microg), formoterol (4.5 microg), salbutamol (2 x 100 microg) or placebo. The protective effects of the randomised treatments were assessed by serial lung function measurements over the test day.

Results: In the AMP provocations at 3 and 7 hours after inhalation, the budesonide/formoterol combination provided a greater protective effect against AMP-induced bronchoconstriction compared with formoterol alone, salbutamol and placebo. In addition all three active treatments significantly increased FEV1 within 3 minutes of administration, at a time when inhaled AMP had induced the 30% fall in FEV1.

Conclusions: A single dose of budesonide/formoterol provided a greater protective effect against inhaled AMP-induced bronchoconstriction than formoterol alone, both at 3 and at 7 hours after inhalation. The acute protection against subsequent bronchoconstrictor stimuli such as inhaled AMP and the rapid reversal of airway obstruction supports the use of budesonide/formoterol for both relief and prevention in the treatment of asthma.

Trial registration: ClinicalTrials.gov NCT00272753.

Figures

Figure 1
Figure 1
Study design of the Test Days.
Figure 2
Figure 2
Mean FEV1 over the test day with three AMP provocations followed by a single dose of budesonide/formoterol 160/4.5 μg (open diamonds), formoterol 4.5 μg (open squares), salbutamol 2 × 100 μg (filled triangles) or placebo (crosses) immediately after the first AMP provocation.
Figure 3
Figure 3
Mean FEF25-75 over the Test Day with three AMP provocations followed by a single dose of budesonide/formoterol 160/4.5 μg (open diamonds), formoterol 4.5 μg (open squares), salbutamol 2 × 100 μg (filled triangles) or placebo (crosses) immediately after the first AMP provocation.
Figure 4
Figure 4
Mean Borg score over the Test Day with three AMP provocations followed by a single dose of budesonide/formoterol 160/4.5 μg (open diamonds), formoterol 4.5 μg (open squares), salbutamol 2 × 100 μg (filled triangles) or placebo (crosses) immediately after the first AMP provocation.

References

    1. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA); 2008. Global Initiative for Asthma.
    1. Politiek MJ, Boorsma M, Aalbers R. Comparison of formoterol, salbutamol and salmeterol in methacholine-induced severe bronchoconstriction. Eur Respir J. 1999;13:988–992. doi: 10.1034/j.1399-3003.1999.13e10.x.
    1. Tattersfield AE, Lofdahl C-G, Postma DS, Eivindson A, Schreurs AG, Rasidakis A. Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomised trial. Lancet. 2001;357:257–261. doi: 10.1016/S0140-6736(00)03611-4.
    1. Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A. Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. Eur Respir J. 2003;22:787–794. doi: 10.1183/09031936.03.00055803.
    1. Cheung D, van Klink HCJ, Aalbers R. for the OZON study group. Improved lung function and symptom control with formoterol on demand in asthma. Eur Respir J. 2006;27:504–510. doi: 10.1183/09031936.06.00006805.
    1. Zetterström O, Buhl R, Mellem H, Hedman J, O'Neill S, Ekstrom T. Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone. Eur Respir J. 2001;18:262–268. doi: 10.1183/09031936.01.00065801.
    1. Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centanni S, Boulet LP, Naya IP, Hultquist C. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Curr Med Res Opin. 2004;20:1403–1418. doi: 10.1185/030079904X2051.
    1. Boonsawat W, Charoenratanakul S, Pothirat C, Sawanyawisuth K, Seearamroongruang T, Bengtsson T, Brander R, Selroos O. Formoterol (OXIS) Turbuhaler as a rescue therapy compared with salbutamol pMDI plus spacer in patients with acute severe asthma. Respir Med. 2003;97:1067–1074. doi: 10.1016/S0954-6111(03)00139-2.
    1. Woude HJ Van der, Boorsma M, Bergqvist PBF, Winter TH, Aalbers R. Budesonide/formoterol in a single inhaler rapidly relieves methacholine-induced moderate-to-severe bronchoconstriction. Pulm Pharm Ther. 2004;17:89–95. doi: 10.1016/j.pupt.2003.11.001.
    1. O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med. 2005;171:129–136. doi: 10.1164/rccm.200407-884OC.
    1. Rabe KF, Pizzichini E, Ställberg B, Romero S, Balanzat AM, Atienza T. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Chest. 2006;129:246–256. doi: 10.1378/chest.129.2.246.
    1. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet. 2006;368:744–753. doi: 10.1016/S0140-6736(06)69284-2.
    1. Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martínez-Jimenez NE, Buhl R. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract. 2007;61:725–736. doi: 10.1111/j.1742-1241.2007.01338.x.
    1. Bousquet J, Boulet LP, Peters MJ, Magnussen H, Quiralte J, Martinez-Aguilar NE, Carlsheimer A. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med. 2007;101:2437–2446. doi: 10.1016/j.rmed.2007.07.014.
    1. Gibson PG. Teaching old drugs new tricks: asthma therapy adjusted by patient perception or noninvasive markers. Eur Respir J. 2005;25:397–399. doi: 10.1183/09031936.05.00002805.
    1. Gibson PG, Saltos N, Fakes K. Acute anti-inflammatory effects of inhaled budesonide in asthma. A randomized controlled trial. Am J Respir Crit Care Med. 2001;163:32–36.
    1. Essen-Zandvliet EE, Hop WC, de Jong H, Ferwerda A, Kerrebijn KF. Minor acute effect of an inhaled corticosteroid (budesonide) on bronchial hyperresponsiveness to methacholine in children with asthma. Eur Respir J. 1993;6:383–386.
    1. Mendes ES, Pereira A, Danta I, Duncan RC, Wanner A. Comparative bronchial vasoconstrictive efficacy of inhaled corticosteroids. Eur Respir J. 2003;21:989–993. doi: 10.1183/09031936.03.00072402.
    1. Aalbers R, Kauffman HF, Koëter GH, Postma DS, de Vries K, de Monchy JGR. Dissimilarity in methacholine and adenosine 5'-monophosphate responsiveness 3 and 24 h after allergen challenge. Am Rev Respir Dis. 1991;144:352–357.
    1. Polosa R, Holgate ST. Adenosine bronchoprovocation: a promising marker of allergic inflammation in asthma? Thorax. 1997;52:919–923. doi: 10.1136/thx.52.10.919.
    1. Ketchell RI, Jensen MW, Spina D, O'Connor BJ. Dose-related effects of formoterol on airway responsiveness to adenosine 5'-monophosphate and histamine. Eur Respir J. 2002;19:611–616. doi: 10.1183/09031936.02.00332001.
    1. Aziz I, Wilson AM, Lipworth BJ. Effects of once-daily formoterol and budesonide given alone or in combination on surrogate inflammatory markers in asthmatic adults. Chest. 2000;118:1049–1058. doi: 10.1378/chest.118.4.1049.
    1. Dahlén B, Lantz AS, Ihre E, Skedinger M, Henriksson E, Jörgensen L, Ekström T, Dahlén SE, Larsson K. Effect of formoterol with or without budesonide in repeated low-dose allergen challenge. Eur Respir J. 2009;33(4):747–53. doi: 10.1183/09031936.00095508.
    1. O'Connor BJ, Ridge SM, Barnes PJ, Fuller RW. Greater effect of inhaled budesonide on adenosine 5'-monophosphate-induced than on sodium-metabisulfite-induced bronchoconstriction in asthma. Am Rev Respir Dis. 1992;146:560–564.
    1. Ketchell RI, Jensen MW, Lumley P, Wright AM, Allenby MI, O'Connor BJ. Rapid effect of inhaled fluticasone propionate on airway responsiveness to adenosine 5'-monophosphate in mild asthma. J Allergy Clin Immunol. 2002;110:603–606. doi: 10.1067/mai.2002.128486.
    1. Luijk B, Kempsford RD, Wright AM, Zanen P, Lammers JWJ. Duration of effect of single-dose inhaled fluticasone propionate on AMP-induced bronchoconstriction. Eur Respir J. 2004;23:559–564. doi: 10.1183/09031936.04.00043504.
    1. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14:377–381.
    1. Quanjer PhH, Tammeling GJ, Cotes JE, Pedersen OF, Yernault JC. Lung volumes and forced ventilatory flows. Report working party: Standardisation 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.
    1. Vilsvik J, Ankerst J, Palmqvist M, Persson G, Schaanning J, Schwabe G. Protection against cold air and exercise-induced bronchoconstriction while on regular treatment with Oxis. Respir Med. 2001;95:484–490. doi: 10.1053/rmed.2001.1074.
    1. Duong ML, Gauvreau G, Watson R, Obminski G, Strinich T, Evans M. The effects of inhaled budesonide and formoterol in combination and alone when given directly after allergen challenge. J Allergy Clin Immunol. 2007;119:322–327. doi: 10.1016/j.jaci.2006.10.018.
    1. Boschetto P, Rogers DF, Fabbri LM, Barnes PJ. Corticosteroid inhibition of airway microvascular leakage. Am Rev Respir Dis. 1991;143:605–609.
    1. Horvath G, Wanner A. Inhaled corticosteroids: effects on the airway vasculature in bronchial asthma. Eur Respir J. 2006;27:172–187. doi: 10.1183/09031936.06.00048605.
    1. Horvath G, Vasas S, Wanner A. Inhaled corticosteroids reduce asthma-associated airway hyperperfusion through genomic and non-genomic mechanisms. Pulm Pharm Ther. 2007;20:157–162. doi: 10.1016/j.pupt.2006.03.009.
    1. Balanag VM, Yunus F, Yang PC, Jorup C. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulm Pharm Ther. 2005;19:139–147. doi: 10.1016/j.pupt.2005.04.009.
    1. Bateman ED, Fairal L, Lombardi DM, English R. Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol. Respir Res. 2006;7:13. doi: 10.1186/1465-9921-7-13.

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