Treatments in Respiratory Medicine

, Volume 3, Issue 5, pp 279–289 | Cite as

Combination Therapy of Long-Acting β2-Adrenoceptor Agonists and Corticosteroids for Asthma

Leading Article


Twice-daily combination therapy of inhaled corticosteroids and long-acting β2-adrenoceptor agonists (LABA) is now established as a most effective treatment for moderate to severe asthma and is available in a combined single inhaler. The benefits of combination therapy include better day-to-day control and a reduction in exacerbations compared with monotherapy with inhaled corticosteroids at a lower dose.

Total control of asthma, defined as no daytime or night-time symptoms, no use of rescue β2-adrenoceptor agonists (β2-agonists), no exacerbations and a peak flow rate of >80% predicted, may be achieved with the use of combined salmeterol/fluticasone in up to 41% of patients with moderate to severe asthma, compared with only 28% of patients treated with fluticasone alone. Adjustable maintenance dosing with budesonide/formoterol may provide better control when compared with fixed-dosing combination regimens. Other therapies combining effectively with inhaled corticosteroids include slow-release theophylline and leukotriene inhibitors, montelukast and zafirlukast, but LABA are the most efficacious.

Molecular interactions between corticosteroids and β2-adrenoceptors may underlie the clinical added benefits of combination therapy. Corticosteroids may increase the number of β2-adrenoceptors and their coupling with Gs proteins, while β2-agonists may induce glucocorticoid receptor nuclear translocation, activate transcription factor/enhancer binding protein C/EBPα together with corticosteroids, or phosphorylate corticosteroid receptors. The combination of corticosteroids and LABA potentiates inhibition of interleukin-8 and eotaxin release from human airway smooth muscle cells and granulocyte-macrophage colony-stimulating factor release from epithelial cells, and also the inhibition of airway smooth muscle cell proliferation.

It is important to determine whether there is a potentiating effect of combination therapy compared with corticosteroid treatment alone on airway inflammation and airway wall remodelling. Improvements in combination therapy include a once-daily preparation and possible combination of inhaled corticosteroids with newer drugs such as phosphodiesterase IV inhibitors.



No external source of funding or assistance was obtained for the preparation or writing of this review. Both authors have received funding from various pharmaceutical companies to research into the clinical effects of the compounds reviewed in this article.


  1. 1.
    Greening AP, Ind PW, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344: 219–24PubMedCrossRefGoogle Scholar
  2. 2.
    Busse WW, Chervinsky P, Condemi J, et al. Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma. J Allergy Clin Immunol 1998; 101: 457–63PubMedCrossRefGoogle Scholar
  3. 3.
    Dahl R, Lundback B, Malo J, et al. A dose-ranging study of fluticasone propionate in adult patients with moderate asthma. Chest 1998; 104: 352–8Google Scholar
  4. 4.
    Woolcock A, Lundback B, Ringdal N, et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153(5): 1481–8PubMedGoogle Scholar
  5. 5.
    Pauwels RA, Lofdahl C, Postma D, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 337: 1405–11PubMedCrossRefGoogle Scholar
  6. 6.
    Tattersfield AE, Postma DS, Barnes PJ, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. Am J Respir Crit Care Med 1999; 160(2): 594–9PubMedGoogle Scholar
  7. 7.
    Juniper EF, Svensson K, O’Byrne PM, et al. Asthma quality of life during 1 year of treatment with budesonide with or without formoterol. Eur Respir J 1999; 14(5): 1038–43PubMedCrossRefGoogle Scholar
  8. 8.
    Matz J, Emmett A, Rickard K, et al. Addition of salmeterol to low-dose fluticasone versus higher-dose fluticasone: an analysis of asthma exacerbations. J Allergy Clin Immunol 2001; 107(5): 783–9PubMedCrossRefGoogle Scholar
  9. 9.
    Condemi JJ, Goldstein S, Kalberg C, et al. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma: Salmeterol Study Group. Ann Allergy Asthma Immunol 1999; 82(4): 383–9PubMedCrossRefGoogle Scholar
  10. 10.
    Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ 2000; 320(7246): 1368–73PubMedCrossRefGoogle Scholar
  11. 11.
    van Noord JA, Schreurs AJ, Mol SJ, et al. Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax 1999; 54(3): 207–12PubMedCrossRefGoogle Scholar
  12. 12.
    Price D, Dutchman D, Mawson A, et al. Early asthma control and maintenance with eformoterol following reduction of inhaled corticosteroid dose. Thorax 2002; 57(9): 791–8PubMedCrossRefGoogle Scholar
  13. 13.
    O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164 (8 Pt 1): 1392–7PubMedGoogle Scholar
  14. 14.
    Taylor DR, Town GI, Herbison GP, et al. Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998; 53(9): 744–52PubMedCrossRefGoogle Scholar
  15. 15.
    Byrnes C, Shrewsbury S, Barnes PJ, et al. Salmeterol in paediatric asthma. Thorax 2000; 55(9): 780–4PubMedCrossRefGoogle Scholar
  16. 16.
    Aldridge RE, Hancox RJ, Robin TD, et al. Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma. Am J Respir Crit Care Med 2000; 161(5): 1459–64PubMedGoogle Scholar
  17. 17.
    Tattersfield AE, Lofdahl CG, Postma DS, et al. Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomised trial. Lancet 2001; 357(9252): 257–61PubMedCrossRefGoogle Scholar
  18. 18.
    Bateman ED, Britton M, Carrillo J. Salmeterol/fluticasone combination inhlaer: a new, effective and well-tolerated treatment for asthma. Clin Drug Invest 1998; 16: 193–201CrossRefGoogle Scholar
  19. 19.
    Aubier M, Pieters WR, Schlosser NJ, et al. Salmeterol/fluticasone propionate (50/500 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Respir Med 1999; 93(12): 876–84PubMedCrossRefGoogle Scholar
  20. 20.
    Chapman KR, Ringdal N, Backer V, et al. Salmeterol and fluticasone propionate (50/250 microg) administered via combination Diskus inhaler: as effective as when given via separate Diskus inhalers. Can Respir J 1999; 6(1): 45–51PubMedGoogle Scholar
  21. 21.
    Pearlman DS, Stricker W, Weinstein S, et al. Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma. Ann Allergy Asthma Immunol 1999; 82(3): 257–65PubMedCrossRefGoogle Scholar
  22. 22.
    Kavuru M, Melamed J, Gross G, et al. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2000; 105 (6 Pt 1): 1108–16PubMedCrossRefGoogle Scholar
  23. 23.
    Shapiro G, Lumry W, Wolfe J, et al. Combined salmeterol 50 microg and fluticasone propionate 250 microg in the diskus device for the treatment of asthma. Am J Respir Crit Care Med 2000; 161 (2 Pt 1): 527–34PubMedGoogle Scholar
  24. 24.
    Van den Berg NJ, Ossip MS, Hederos CA, et al. Salmeterol/fluticasone propionate (50/100 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in children with asthma. Pediatr Pulmonol 2000; 30(2): 97–105PubMedCrossRefGoogle Scholar
  25. 25.
    Jenkins C, Woolcock AJ, Saarelainen P, et al. Salmeterol/fluticasone propionate combination therapy 50/250 microg twice daily is more effective than budesonide 800 microg twice daily in treating moderate to severe asthma. Respir Med 2000; 94(7): 715–23PubMedCrossRefGoogle Scholar
  26. 26.
    Zetterstrom O, Buhl R, Meilern H, et al. Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone. Eur Respir J 2001; 18(2): 262–8PubMedCrossRefGoogle Scholar
  27. 27.
    Lalloo UG, Malolepszy J, Kozma D, et al. Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild-to-moderate asthma. Chest 2003; 123(5): 1480–7PubMedCrossRefGoogle Scholar
  28. 28.
    Tal A, Simon G, Vermeulen JH, et al. Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma. Pediatr Pulmonol 2002; 34(5): 342–50PubMedCrossRefGoogle Scholar
  29. 29.
    Markham A, Jarvis B. Inhaled salmeterol/fluticasone propionate combination: a review of its use in persistent asthma. Drugs 2000; 60(5): 1207–33PubMedCrossRefGoogle Scholar
  30. 30.
    McGavin JK, Goa KL, Jarvis B. Inhaled budesonide/formoterol combination. Drugs 2001; 61(1): 71–8PubMedCrossRefGoogle Scholar
  31. 31.
    Pyke S, Frith L, Drake F, et al. Synergy between fluticasone propionate and salmeterol from a single combination inhaler (AdvairTM/SeretideTM) vs delivery via separate inhalers. Am J Respir Crit Care Med 2001; 163: A864Google Scholar
  32. 32.
    Bateman ED, Bousquet J, Braunstein GL. Is overall asthma control being achieved? A hypothesis-generating study. Eur Respir J 2001; 17(4): 589–95PubMedCrossRefGoogle Scholar
  33. 33.
    Bateman ED, Boushey HA, Bousquet J, et al. The GOAL investigators group. Can guideline-defined asthma control be achieved? the gaining asthma control study. Am J Respir Crit Care Med. In pressGoogle Scholar
  34. 34.
    Jenkins C, Woolcock AJ, Saarelainen P, et al. Salmeterol/fluticasone propionate combination therapy 50/250 microg twice daily is more effective than budesonide 800 microg twice daily in treating moderate to severe asthma. Respir Med 2000; 94(7): 715–23PubMedCrossRefGoogle Scholar
  35. 35.
    Ukena D, Harnest U, Sakalauskas R, et al. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J 1997; 10(12): 2754–60PubMedCrossRefGoogle Scholar
  36. 36.
    Evans DJ, Taylor DA, Zetterstrom O, et al. Theophylline plus low dose inhaled steroid is as effective as high dose inhaled steroid in the control of asthma. N Engl J Med 1997; 337: 1412–8PubMedCrossRefGoogle Scholar
  37. 37.
    Davies B, Brooks G, Devoy M. The efficacy and safety of salmeterol compared to theophylline: meta-analysis of nine controlled studies. Respir Med 1998; 92(2): 256–63PubMedCrossRefGoogle Scholar
  38. 38.
    Laviolette M, Malmstrom K, Lu S, et al. Montelukast added to inhaled beclomethasone in treatment of asthma: Montelukast/Beclomethasone Additivity Group. Am J Respir Crit Care Med 1999; 160(6): 1862–8PubMedGoogle Scholar
  39. 39.
    Virchow CJ, Prasse A, Naya I, et al. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000; 162 (2 Pt 1): 578–85PubMedGoogle Scholar
  40. 40.
    Nelson HS, Busse WW, Kerwin E, et al. Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol 2000; 106(6): 1088–95PubMedCrossRefGoogle Scholar
  41. 41.
    Fish JE, Israel E, Murray JJ, et al. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest 2001; 120(2): 423–30PubMedCrossRefGoogle Scholar
  42. 42.
    Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 2001; 357(9273): 2007–11PubMedCrossRefGoogle Scholar
  43. 43.
    Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids: new developments. Am J Respir Crit Care Med 1998; 157: S1–53PubMedGoogle Scholar
  44. 44.
    Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids: new developments. Am J Respir Crit Care Med 1998; 157: 51–3Google Scholar
  45. 45.
    Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann Intern Med 2003; 139: 359–70PubMedGoogle Scholar
  46. 46.
    Ogryzko VV, Schiltz RL, Russanova V, et al. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 1996; 87(5): 953–9PubMedCrossRefGoogle Scholar
  47. 47.
    Ray A, Laforge KS, Sehgal PB. On the mechanisms of effecient repression of the interleukin-6 promotor by glucocorticoids: enhancer TATA box and RNA start site occlusion. Mol Cell Biochem 1990; 10: 5736–46Google Scholar
  48. 48.
    Schule R, Rangarajan P, Kliewer S, et al. Functional antagonism between oncoprotein C-Jun and glucocorticoid receptor. Cell 1990; 62: 1217–26PubMedCrossRefGoogle Scholar
  49. 49.
    Manolitsas ND, Wang J, Devalia JL, et al. Regular albuterol, nedocromil sodium, and bronchial inflammation in asthma. Am J Respir Crit Care Med 1995; 151(6): 1925–30PubMedGoogle Scholar
  50. 50.
    Gardiner PV, Ward C, Booth H, et al. Effect of eight weeks of treatment with salmeterol on bronchoalveolar lavage inflammatory indices in asthmatics. Am J Respir Crit Care Med 1994; 150(4): 1006–11PubMedGoogle Scholar
  51. 51.
    Roberts JA, Bradding P, Britten KM, et al. The long-acting beta2-agonist salmeterol xinafoate: effects on airway inflammation in asthma. Eur Respir J 1999; 14(2): 275–82PubMedCrossRefGoogle Scholar
  52. 52.
    Jeffery PK, Venge P, Gizycki MJ, et al. Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study. Eur Respir J 2002; 20(6): 1378–85PubMedCrossRefGoogle Scholar
  53. 53.
    Kraft M, Wenzel SE, Bettinger CM, et al. The effect of salmeterol on nocturnal symptoms, airway function, and inflammation in asthma. Chest 1997; 111(5): 1249–54PubMedCrossRefGoogle Scholar
  54. 54.
    Turner MO, Johnston PR, Pizzichini E, et al. Anti-inflammatory effects of salmeterol compared with beclomethasone in eosinophilic mild exacerbations of asthma: a randomized, placebo controlled trial. Can Respir J 1998; 5(4): 261–8PubMedGoogle Scholar
  55. 55.
    Wallin A, Sandstrom T, Soderberg M, et al. The effects of regular inhaled formoterol, budesonide, and placebo on mucosal inflammation and clinical indices in mild asthma. Am J Respir Crit Care Med 1999; 159(1): 79–86PubMedGoogle Scholar
  56. 56.
    Wallin A, Sandstrom T, Cioppa GD, et al. The effects of regular inhaled formoterol and budesonide on preformed Th-2 cytokines in mild asthmatics. Respir Med 2002; 96(12): 1021–5PubMedCrossRefGoogle Scholar
  57. 57.
    Wilson SJ, Wallin A, Della-Cioppa G, et al. Effects of budesonide and formoterol on NF-kappaB, adhesion molecules, and cytokines in asthma. Am J Respir Crit Care Med 2001; 164(6): 1047–52PubMedGoogle Scholar
  58. 58.
    Li X, Ward C, Thien F, et al. An antiinflammatory effect of salmeterol, a long-acting beta (2) agonist, assessed in airway biopsies and bronchoalveolar lavage in asthma. Am J Respir Crit Care Med 1999; 160 (5 Pt 1): 1493–9PubMedGoogle Scholar
  59. 59.
    Orsida BE, Ward C, Li X, et al. Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma. Am J Respir Crit Care Med 2001; 164(1): 117–21PubMedGoogle Scholar
  60. 60.
    Dente FL, Bancalari L, Bacci E, et al. Effect of a single dose of salmeterol on the increase in airway eosinophils induced by allergen challenge in asthmatic subjects. Thorax 1999; 54(7): 622–4PubMedCrossRefGoogle Scholar
  61. 61.
    Calhoun WJ, Hinton KL, Brick JJ, Vachinich J. Effects of salmeterol on eosinophil recruitment in the airway following segemental allergen challenge in atopic asthmatics. International Respiratory Forum: acute and chronic inflammation in the respiratory tract. London: Calwood House, 1995: 62Google Scholar
  62. 62.
    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(4): 1049–58PubMedCrossRefGoogle Scholar
  63. 63.
    Aziz I, Lipworth BJ. In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol. J Allergy Clin Immunol 1999; 103 (5 Pt 1): 816–22PubMedCrossRefGoogle Scholar
  64. 64.
    Rosenthal RR, Busse WW, Kemp JP, et al. Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness. Chest 1999; 116(3): 595–602PubMedCrossRefGoogle Scholar
  65. 65.
    Meijer GG, Postma DS, Mulder PG, et al. Long-term circadian effects of salmeterol in asthmatic children treated with inhaled corticosteroids. Am J Respir Crit Care Med 1995; 152 (6 Pt 1): 1887–92PubMedGoogle Scholar
  66. 66.
    Booth H, Bish R, Walters J, et al. Salmeterol tachyphylaxis in steroid treated asthmatic subjects. Thorax 1996; 51(11): 1100–4PubMedCrossRefGoogle Scholar
  67. 67.
    van der Woude HJ, Winter TH, Aalbers R. Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta2 agonists. Thorax 2001; 56(7): 529–35PubMedCrossRefGoogle Scholar
  68. 68.
    Truss M, Beato M. Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocr Rev 1993; 14(4): 459–79PubMedGoogle Scholar
  69. 69.
    Adcock IM, Ito K. Molecular mechanisms of corticosteroid actions. Monaldi Arch Chest Dis 2000; 55(3): 256–66PubMedGoogle Scholar
  70. 70.
    Barnes PJ. Beta-adrenergic receptors and their regulation. Am J Respir Crit Care Med 1995; 152(3): 838–60PubMedGoogle Scholar
  71. 71.
    Irusen E, Matthews JG, Takahashi A, et al. p38 Mitogen-activated protein kinaseinduced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol 2002; 109(4): 649–57PubMedCrossRefGoogle Scholar
  72. 72.
    Hsu SC, Qi M, DeFranco DB. Cell cycle regulation of glucocorticoid receptor function. EMBO J 1992; 11(9): 3457–68PubMedGoogle Scholar
  73. 73.
    Montminy MR, Gonzalez GA, Yamamoto KK. Regulation of cAMP-inducible genes by CREB. Trends Neurosci 1990; 13(5): 184–8PubMedCrossRefGoogle Scholar
  74. 74.
    Mak JC, Hisada T, Salmon M, et al. Glucocorticoids reverse IL-1 beta-induced impairment of beta-adrenoceptor-mediated relaxation and up-regulation of G-protein-coupled receptor kinases. Br J Pharmacol 2002; 135(4): 987–96PubMedCrossRefGoogle Scholar
  75. 75.
    Mak JC, Nishikawa M, Shirasaki H, et al. Protective effects of a glucocorticoid on downregulation of pulmonary beta 2-adrenergic receptors in vivo. J Clin Invest 1995; 96(1): 99–106PubMedCrossRefGoogle Scholar
  76. 76.
    Davies AO, Lefkowitz RJ. Regulation of beta-adrenergic receptors by steroid hormones. Ann Rev Physiol 1984; 46: 119–30CrossRefGoogle Scholar
  77. 77.
    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: 1420–5PubMedCrossRefGoogle Scholar
  78. 78.
    Cheung D, Timmers CM, Zwinderman AH, et al. Long-term effects of a long-acting β2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992; 327: 1198–203PubMedCrossRefGoogle Scholar
  79. 79.
    Kalra S, Swystun VA, Bhagat R, et al. Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol. Chest 1996; 109(4): 953–6PubMedCrossRefGoogle Scholar
  80. 80.
    Yates DH, Kharitonov SA, Barnes PJ. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist. Am J Respir Crit Care Med 1996; 154 (6 Pt 1): 1603–7PubMedGoogle Scholar
  81. 81.
    Grootendorst DC, Sterk PJ, Heijerman HG. Effect of oral prednisolone on the bronchoprotective effect of formoterol in patients with persistent asthma. Eur Respir J 2001; 17(3): 374–9PubMedCrossRefGoogle Scholar
  82. 82.
    Eickelberg O, Roth M, Lorx R, et al. Ligand-independent activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells. J Biol Chem 1999; 274(2): 1005–10PubMedCrossRefGoogle Scholar
  83. 83.
    Usmani O, Maneechotesuwan K, Adcock IM, et al. Glucocorticoid receptor activation following inhlaed fluticasone and salmeterol [abstract]. Am J Respir Crit Care Med 2002; 165: A616Google Scholar
  84. 84.
    Roth M, Johnson PR, Rudiger JJ, et al. Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002; 360(9342): 1293–9PubMedCrossRefGoogle Scholar
  85. 85.
    Rudiger JJ, Roth M, Bihl MP, et al. Interaction of C/EBPalpha and the glucocorticoid receptor in vivo and in nontransformed human cells. FASEB J 2002; 16(2): 177–84PubMedCrossRefGoogle Scholar
  86. 86.
    Pang L, Knox AJ. Regulation of TNF-alpha-induced eotaxin release from cultured human airway smooth muscle cells by beta2-agonists and corticosteroids. FASEB J 2001; 15(1): 261–9PubMedCrossRefGoogle Scholar
  87. 87.
    Silvestri M, Fregonese L, Sabatini F, et al. Fluticasone and salmeterol downregulate in vitro, fibroblast proliferation and ICAM-1 or H-CAM expression. Eur Respir J 2001; 18(1): 139–45PubMedCrossRefGoogle Scholar
  88. 88.
    Korn SH, Jerre A, Brattsand R. Effects of formoterol and budesonide on GM-CSF and IL-8 secretion by triggered human bronchial epithelial cells. Eur Respir J 2001; 17(6): 1070–7PubMedCrossRefGoogle Scholar
  89. 89.
    Farmer P, Pugin J. Beta-adrenergic agonists exert their “anti-inflammatory” effects in monocytic cells through the IkappaB/NF-kappaB pathway. Am J Physiol Lung Cell Mol Physiol 2000; 279(4): L675–82PubMedGoogle Scholar
  90. 90.
    Canonica GW, Castellani P, Cazzola M, et al. Adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma symptom control at a lower dose that fixed maintenance dosing. Pulm Pharmaco Ther 2004; 17: 239–47CrossRefGoogle Scholar
  91. 91.
    Markham A, Adkins JC. Inhaled salmeterol/fluticasone propionate combination: a pharmacoeconomic review of its use in the management of asthma. Pharmacoeconomics 2000; 18(6): 591–608PubMedCrossRefGoogle Scholar
  92. 92.
    Andersson F, Stahl E, Barnes PJ, et al. Adding formoterol to budesonide in moderate asthma: health economic results from the FACET study. Respir Med 2001; 95(6): 505–12PubMedCrossRefGoogle Scholar
  93. 93.
    British Thoracic Society. British guideline on the management of asthma. Thorax 2003; 58Suppl. 1: i1–94Google Scholar
  94. 94.
    Global Initiative for Asthma. Global strategy for asthma management and prevention: NHLBI/WHO Workshop Report. Maryland. National Institutes of Health NHLBI, 2002Google Scholar
  95. 95.
    Wong CS, Wahedna I, Pavord ID, et al. Effect of regular terbutaline and budesonide on bronchial reactivity to allergen challenge. Am J Respir Crit Care Med 1994; 150 (5 Pt 1): 1268–73PubMedGoogle Scholar
  96. 96.
    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 (5 Pt 1): 1485–9PubMedGoogle Scholar
  97. 97.
    Sears MR, Taylor RD, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391–6PubMedCrossRefGoogle Scholar
  98. 98.
    Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma: Asthma Clinical Research Network. N Engl J Med 1996; 335(12): 841–7PubMedCrossRefGoogle Scholar
  99. 99.
    Dennis SM, Sharp SJ, Vickers MR, et al. Regular inhaled salbutamol and asthma control: the TRUST randomised trial. Therapy Working Group of the National Asthma Task Force and the MRC General Practice Research Framework. Lancet 2000 May 13; 355(9216): 1675–9PubMedCrossRefGoogle Scholar
  100. 100.
    Bijl-Hofland ID, Cloosterman SG, Folgering HT, et al. Inhaled corticosteroids, combined with long-acting beta (2)-agonists, improve the perception of bronchoconstriction in asthma. Am J Respir Crit Care Med 2001; 164(5): 764–9PubMedGoogle Scholar
  101. 101.
    Kips JC, O’Connor BJ, Inman MD, et al. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. Am J Respir Crit Care Med 2000; 161 (3 Pt 1): 996–1001PubMedGoogle Scholar
  102. 102.
    Mcivor RA, Pizzichini E, Turner MO, et al. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998; 158(3): 924–30PubMedGoogle Scholar
  103. 103.
    Nielsen LP, Pedersen B, Faurschou P, et al. Salmeterol reduces the need for inhaled corticosteroid in steroid-dependent asthmatics. Respir Med 1999; 93(12): 863–8PubMedCrossRefGoogle Scholar
  104. 104.
    Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001; 285(20): 2583–93PubMedCrossRefGoogle Scholar
  105. 105.
    Verberne AAPH, Frost C, Roorda RJ, et al. One year treatment with salmeterol compared with beclomethasone in children with asthma. Am J Respir Crit Care Med 1997; 156: 688–95PubMedGoogle Scholar
  106. 106.
    Lemanske Jr RF, Sorkness CA, Mauger EA, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001; 285(20): 2594–603PubMedCrossRefGoogle Scholar
  107. 107.
    Rickard KA. 2003 Safety Alert-Serevent (salmeterol xinafoate): important new safety information. Available from URL: [Accessed 2003 Oct 23]
  108. 108.
    Heuck C, Heickendorff L, Wolthers OD. A randomised controlled trial of short term growth and collagen turnover in asthmatics treated with inhaled formoterol and budesonide. Arch Dis Child 2000; 83(4): 334–9PubMedCrossRefGoogle Scholar
  109. 109.
    Palmqvist M, Arvidsson P, Beckman O, et al. Onset of bronchodilation of budesonide/formoterol vs salmeterol/fluticasone in single inhalers. Pulm Pharmacol Ther 2001; 14(1): 29–34PubMedCrossRefGoogle Scholar
  110. 110.
    Aalbers R, Backer V, Kara TT, et al. Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol/fluticasone in moderate-to-severe asthma. Curr Med Res Opin 2004; 20: 225–40PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Imperial CollegeNational Heart and Lung InstituteLondonUK
  2. 2.Royal Brompton HospitalLondonUK

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