Drugs

, Volume 62, Issue 16, pp 2315–2332 | Cite as

Second-Line Controller Therapy for Persistent Asthma Uncontrolled on Inhaled Corticosteroids

The Step 3 Dilemma
Current Opinion

Abstract

The asthma syndrome is characterised by airway inflammation with associated bronchial hyperresponsiveness (BHR) and reversible airflow obstruction. Therapy has benefited from an enhanced understanding of the pathophysiology of asthma and the resulting guidelines that emphasise the pivotal role of anti-inflammatory inhaled corticosteroids (ICS) as first-line therapy. Most patients with mild-to-moderate asthma can be adequately controlled on low-to-medium dosages of ICS alone. For patients with moderate-to-severe asthma who are not adequately controlled by ICS, it is unclear which medication should be added on.

The two principal drugs under consideration are long-acting β2-agonists (LABAs) and leukotriene antagonists (LTAs). Although both LABAs and LTAs are both effective at improving lung function, reducing symptoms and decreasing exacerbations, important differences exist that may determine the selection of one over the other in particular circumstances. LABAs and LTAs are equally effective at reducing exacerbations and improving symptoms and quality of life when used as add-on therapy. LABAs tend to be more effective bronchodilators than LTAs. Although LABAs stabilise the airway smooth muscle, they do not affect the underlying inflammatory process. Their long-term use also leads to subsensitivity of response to both LABAs and short-acting β2-agonists (SABAs). The subsensitivity of response to SABAs is more pronounced in the presence of acute bronchoconstriction, which could be relevant during an acute attack. When combined with an ICS, LTAs provide additive non-steroidal anti-inflammatory properties and alleviate associated BHR, but do not induce subsensitivity of response. Not only is the efficacy of LTAs maintained over time, but also they do not affect the response to SABAs as reliever therapy. LTAs also have beneficial effects in patients who have concomitant allergic rhinitis, thus treating the unified airway.

The choice between LABA and LTA as add-on therapy will therefore be determined by the needs of the individual patient in terms of providing anti-inflammatory versus bronchodilatory control. For patients with poor lung function where bronchodilatation is required, then an LABA would seem to be a logical choice. For the patient whose lung function is less impaired, with evidence of ongoing BHR where bronchoprotection is needed (e.g. exercise, allergen, cold air), or when there is concomitant allergic rhinitis, then an LTA would be more suitable.

Notes

Acknowledgements

Professor Lipworth has received funding for clinical trials, second-hand equipment, attending postgraduate meetings and giving postgraduate educational lectures from: AstraZeneca, GlaxoSmithKline, Merck, Sharp and Dohme, and 3M Health Care. Dr Jackson is a GlaxoSmithKline shareholder.

References

  1. 1.
    National Asthma Education and Prevention Program Expert Panel II (NAEPP). Guidelines for the diagnosis and manage-ment of asthma. Bethesda (MD): NIH Publications; 1997. Report No.: 97-4051Google Scholar
  2. 2.
    Pavord ID, Ward R, Woltmann G, et al. Induced sputum eicosanoid concentrations in asthma. Am J Respir Crit Care Med 1999; 160: 1905–9PubMedGoogle Scholar
  3. 3.
    Louis R, Lau LC, Bron AO, et al. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 2000; 161: 9–16PubMedGoogle Scholar
  4. 4.
    Suissa S, Ernst P, Benayoun S, et al. Low-dose inhaled cortico-steroids and the prevention of death from asthma. N Engl J Med 2000; 343: 332–6PubMedCrossRefGoogle Scholar
  5. 5.
    Holt S, Suder A, Weatherall M, et al. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 2001; 323: 1–8CrossRefGoogle Scholar
  6. 6.
    Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999; 159: 941–55PubMedCrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    Wilson AM, Lipworth BJ. Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma. Am J Med 2000; 108: 269–75PubMedCrossRefGoogle Scholar
  9. 9.
    Meijer RJ, Kerstjens HA, Arends LR, et al. Effects of inhaled fluticasone and oral prednisolone on clinical and inflammatory parameters in patients with asthma. Thorax 1999; 54: 894–9PubMedCrossRefGoogle Scholar
  10. 10.
    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: 1006–11PubMedGoogle Scholar
  11. 11.
    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: 275–82PubMedCrossRefGoogle Scholar
  12. 12.
    Calhoun WJ, Hinton KL, Kratzenberg JJ. The effect of salmeterol on markers of airway inflammation following segmentai allergen challenge. Am J Respir Crit Care Med 2001; 163: 881–6PubMedGoogle Scholar
  13. 13.
    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: 1493–9PubMedGoogle Scholar
  14. 14.
    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: 79–86PubMedGoogle Scholar
  15. 15.
    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: 1047–52PubMedGoogle Scholar
  16. 16.
    Pizzichini E, Leff JA, Reiss TF, et al. Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J 1999; 14: 12–8PubMedCrossRefGoogle Scholar
  17. 17.
    Wada K, Minoguchi K, Kohno Y, et al. Effect of a leukotriene receptor antagonist, pranlukast hydrate, on airway inflammation and airway hyperresponsiveness in patients with moderate to severe asthma. Allegology International 2000; 49: 63–8CrossRefGoogle Scholar
  18. 18.
    Minoguchi K, Kohno Y, Minoguchi H, et al. Reduction of Eosinophilic inflammation in the airways of patients with asthma using montelukast. Chest 2002; 121: 732–8PubMedCrossRefGoogle Scholar
  19. 19.
    Bisgaard H, Loland L, Oj JA. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med 1999; 160: 1227–31PubMedGoogle Scholar
  20. 20.
    Wilson AM, Dempsey OJ, Sims EJ, et al. A comparison of topical budesonide and oral montelukast in seasonal allergic rhinitis and asthma. Clin Exp Allergy 2001; 31: 616–24PubMedCrossRefGoogle Scholar
  21. 21.
    Stelmach I, Jerzynska J, Kuna P. A randomized, double-blind trial of the effect of treatment with montelukast on bronchial hyperresponsiveness and serum eosinophilic cationic protein (ECP), soluble interleukin 2 receptor (sIL-2R), IL-4, and soluble intercellular adhesion molecule 1 (sICM-1) in children with asthma. J Allergy Clin Immunol 2002; 109: 257–63PubMedCrossRefGoogle Scholar
  22. 22.
    Stelmach I, Jerzynska J, Kuna P. A randomized, double-blind trial of the effect of glucocorticoid, antileukotriene and beta-agonist treatment on IL-10 serum levels in children with asthma. Clin Exp Allergy 2002; 32: 264–9PubMedCrossRefGoogle Scholar
  23. 23.
    Nakamura Y, Hoshino M, Sim JJ, et al. Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma. Thorax 1998; 53: 835–41PubMedCrossRefGoogle Scholar
  24. 24.
    Diamant Z, Grootendorst DC, Veselic-Charvat M, et al. The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma. Clin Exp Allergy 1999; 29: 42–51PubMedCrossRefGoogle Scholar
  25. 25.
    Yoshida S, Sakamoto H, Ishizaki Y, et al. Efficacy of leukotriene receptor antagonist in bronchial hyperresponsiveness and hypersensitivity to analgesic in aspirin-intolerant asthma. Clin Exp Allergy 2000; 30: 64–70PubMedCrossRefGoogle Scholar
  26. 26.
    Wilson AM, Dempsey OJ, Sims EJ, et al. Evaluation of salmeterol or montelukast as second-line therapy for asthma not controlled with inhaled corticosteroids. Chest 2001; 119: 1021–6PubMedCrossRefGoogle Scholar
  27. 27.
    Bisgaard H, Nielsen KG. Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children. Am J Respir Crit Care Med 2000; 162: 187–90PubMedGoogle Scholar
  28. 28.
    Brannan JD, Anderson SD, Gomes K, et al. Fexofenadine decreases sensitivity to and montelukast improves recovery from inhaled mannitol. Am J Respir Crit Care Med 2001; 163: 1420–5PubMedGoogle Scholar
  29. 29.
    Obase Y, Shimoda T, Tomari S, et al. Effects of pranlukast on chemical mediators in induced sputum on provocation tests in atopic and aspirin-intolerant asthmatic patients. Chest 2002; 121: 143–50PubMedCrossRefGoogle Scholar
  30. 30.
    Dempsey OJ, Kennedy G, Lipworth BJ. Comparative efficacy and anti-inflammatory profile of once-daily therapy with leukotriene antagonist or low-dose inhaled corticosteroid in patients with mild persistent asthma. J Allergy Clin Immunol 2002; 109: 68–74PubMedCrossRefGoogle Scholar
  31. 31.
    Currie GP, Lipworth BJ. Bronchoprotective effects of leukotriene receptor antagonists in asthma: a meta-analysis. Chest 2002; 122: 146–50PubMedCrossRefGoogle Scholar
  32. 32.
    D’Urzo AD, Chapman KR, Hargreave FE, et al. Effectiveness and safety of salmeterol in non specialist practice settings. Chest 2001; 119: 714–9PubMedCrossRefGoogle Scholar
  33. 33.
    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: 1108–16PubMedCrossRefGoogle Scholar
  34. 34.
    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: 783–9PubMedCrossRefGoogle Scholar
  35. 35.
    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: 1368–73PubMedCrossRefGoogle Scholar
  36. 36.
    Dahl R, Lundback B, Malo JL, et al. A dose-ranging study of fluticasone propionate in adultpatients with moderate asthma. International Study Group. Chest 1993; 104: 1352–8Google Scholar
  37. 37.
    Chervinsky P, van As A, Bronsky EA, et al. Fluticasone propionate aerosol for the treatment of adults with mild to moderate asthma. The Fluticasone Propionate Asthma Study Group. J Allergy Clin Immunol 1994; 94: 676–83Google Scholar
  38. 38.
    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: 1392–7PubMedGoogle Scholar
  39. 39.
    Lipworth BJ. Budesonide dose-response in mild persistent asthma. Am J Respir Crit Care Med 2002; 165: 1188–9PubMedGoogle Scholar
  40. 40.
    Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337: 1405–11Google Scholar
  41. 41.
    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: 1049–58PubMedCrossRefGoogle Scholar
  42. 42.
    Mclvor 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: 924–30Google Scholar
  43. 43.
    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: 996–1001PubMedGoogle Scholar
  44. 44.
    Jatakanon A, Kharitonov S, Lim S, et al. Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax 1999; 54: 108–14PubMedCrossRefGoogle Scholar
  45. 45.
    Lemanske Jr RF, Sorkness CA, Mauger EA, et al. Asthma Clinical Research Network for the National Heart, Lung, and Blood Institute. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001; 285: 2594–603Google Scholar
  46. 46.
    Fowler SJ, Lipworth BJ. Salmeterol and inhaled corticosteroids in patients with persistent asthma [letter]. JAMA 2001; 286: 3076–7PubMedGoogle Scholar
  47. 47.
    Lazarus SC, Boushey HA, Fahy JV, et al. Asthma Clinical Research Network for the National Heart, Lung, and Blood Institute. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001; 285: 2583–93Google Scholar
  48. 48.
    Barnes NC, Miller CJ. Effect of leukotriene receptor antagonist therapy on the risk of asthma exacerbations in patients with mild to moderate asthma: an integrated analysis of zafirlukast trials. Thorax 2000; 55: 478–83PubMedCrossRefGoogle Scholar
  49. 49.
    Baumgartner RA, Edelman P, Chervinsky P, et al. Comparison of the effects of oral montelukast versus inhaled beclomethasone therapy on asthma control: a meta-analysis of two randomized, double-blind, placebo-controlled, multi-center, parallel studies in adult asthmatic patients [abstract]. Eur Respir J 1999; 14: 122Google Scholar
  50. 50.
    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: 1862–8Google Scholar
  51. 51.
    Simons FE, Villa JR, Lee BW, et al. Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study. J Pediatr 2001; 138: 694–8PubMedCrossRefGoogle Scholar
  52. 52.
    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: 1088–95PubMedCrossRefGoogle Scholar
  53. 53.
    Virchow JC, 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: 578–85PubMedGoogle Scholar
  54. 54.
    Robinson OS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 2001; 357: 2007–11PubMedCrossRefGoogle Scholar
  55. 55.
    Lipworth BJ, Fowler SJ, Currie GP. Montelukast for persistent asthma [letter]. Lancet 2001; 358: 1455PubMedCrossRefGoogle Scholar
  56. 56.
    Price DB, Hernandez D, Magyar P, et al. Adding montelukast is at least as efficacious as doubling the budesonide dose in persistent asthma: results of the COMPACT study [abstract]. Am J Respir Crit Care Med 2002; 165: pA216Google Scholar
  57. 57.
    Dworski R, Fitzgerald GA, Oates JA, et al. Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am J Respir Crit Care Med 1994; 149: 953–9PubMedGoogle Scholar
  58. 58.
    O’Shaughnessy KM, Wellings R, Gillies B, et al. Differential effects of fluticasone propionate on allergen-evoked broncho-constriction and increased urinary leukotriene E4 excretion. Am Rev Respir Dis 1993; 147: 1472–6PubMedGoogle Scholar
  59. 59.
    Dempsey OJ, Fowler SJ, Wilson AM, et al. Effects of adding either a leukotriene receptor antagonist or theophylline to a low or medium dose of inhaled corticosteroid in patients with persistent asthma. Chest 2002; 122: 151–9PubMedCrossRefGoogle Scholar
  60. 60.
    Tamaoki J, Kondo M, Sakai N, et al. Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group. Am J Respir Crit Care Med 1997; 155: 1235–40Google Scholar
  61. 61.
    Lofdahl C-G, Reiss TF, Leff JA, et al. Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 1999; 319: 87–90PubMedCrossRefGoogle Scholar
  62. 62.
    Tohdu Y, Fujimura M, Taniguchi H, et al. Leukotriene receptor antagonist, montelukast, can reduce the need for inhaled steroid while mainataining clinical stability of asthmatic patients. Clin Exp Allergy 2002; 32: 1180–6CrossRefGoogle Scholar
  63. 63.
    Ducharme FM. Anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma: systematic review of current evidence. BMJ 2002; 324: 1545–62PubMedCrossRefGoogle Scholar
  64. 64.
    Busse W, Nelson H, Wolfe J, et al. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J Allergy Clin Immunol 1999; 103: 1075–80PubMedCrossRefGoogle Scholar
  65. 65.
    Lipworth BJ. Fluticasone propionate/salmeterol combination [letter]. J Allergy Clin Immunol 2001; 107: 746PubMedCrossRefGoogle Scholar
  66. 66.
    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: 423–30PubMedCrossRefGoogle Scholar
  67. 67.
    Pearlman DS, White MV, Lieberman AK, et al. Fluticasone propionate/salmeterol combination compared with montelukast for the treatment of persistent asthma. Ann Allergy Asthma Immunol 2002; 88: 227–35PubMedCrossRefGoogle Scholar
  68. 68.
    Bjermer L, Greening A, Haahtela T, et al. Addition of montelukast or salmeterol to fluticasone in patients with uncontrolled asthma: results of the IMPACT trial [abstract]. Chest 2002 Annual Meeting; 2002 Nov 2–7; San Diego (CA)Google Scholar
  69. 69.
    Sims EJ, Lipworth BJ. Sustained bronchoprotection with montelukast but not formoterol as add on therapy in asthmatics with the homozygous glycine 16 b2 adrenoceptor genotype [abstract]. J Allergy Clin Immunol 2002; 109: S157CrossRefGoogle Scholar
  70. 70.
    Lipworth BJ, Dempsey OJ, Aziz I, et al. Effects of adding a leukotriene antagonist or a long-acting beta(2)-agonist in asthmatic patients with the glycine-16 beta(2)-adrenoceptor genotype. Am J Med 2000; 109: 114–21PubMedCrossRefGoogle Scholar
  71. 71.
    Lipworth BJ. Emerging role of anti-leukotriene therapy in allergic rhinitis. Clin Exp Allergy 2001; 31: 1813–21PubMedCrossRefGoogle Scholar
  72. 72.
    Newnham DM, McDevitt DG, Lipworth BJ. Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma. Am J Med 1994; 97: 29–37PubMedCrossRefGoogle Scholar
  73. 73.
    Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995; 346: 201–6PubMedCrossRefGoogle Scholar
  74. 74.
    Newnham DM, Grove A, McDevitt DG, et al. Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Thorax 1995; 50: 497–504PubMedCrossRefGoogle Scholar
  75. 75.
    Fuglsang G, Vikre-Jorgensen J, Agertoft L, et al. Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-response to terbutaline in children with mild asthma. Pediatr Pulmonol 1998; 25: 314–21PubMedCrossRefGoogle Scholar
  76. 76.
    Ramage L, Lipworth BJ, Ingram CG, et al. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994; 88: 363–8PubMedCrossRefGoogle Scholar
  77. 77.
    Nelson JA, Strauss L, Skowronski M, et al. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med 1998; 339: 141–6PubMedCrossRefGoogle Scholar
  78. 78.
    Simons FE, Gerstner TV, Cheang MS. Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled gluco-corticoid treatment. Pediatrics 1997; 99: 655–9PubMedCrossRefGoogle Scholar
  79. 79.
    Aziz I, Tan KS, Hall IP, et al. Subsensitivity to bronchoprotection against adenosine monophosphate challenge following regular once-daily formoterol. Eur Respir J 1998; 12: 580–4PubMedCrossRefGoogle Scholar
  80. 80.
    Lipworth B, Tan S, Devlin M, et al. Effects of a treatment with formoterol on bronchoprotection against methacholine. Am J Med 1998; 104: 431–8PubMedCrossRefGoogle Scholar
  81. 81.
    Edelman JM, Turpin JA, Bronsky EA, et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction: a randomized, double-blind trial. Exercise Study Group. Ann Intern Med 2000 Jan 18; 132: 97–104Google Scholar
  82. 82.
    Villaran C, O’Neill SJ, Helbling A, et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. Montelukast/Salmeterol Exercise Study Group. J Allergy Clin Immunol 1999; 104: 547–53Google Scholar
  83. 83.
    Storms WW, Bird S, Firriolo KM, et al. The effect of rescue short-acting beta-agonist bronchodilation in patients on montelukast or salmeterol [abstract]. J Allergy Clin Immunol 2001; 107: 1032Google Scholar
  84. 84.
    Nelson HS, Berkowitz RB, Tinkelman DA, et al. Lack of subsensitivity to salbutamol after treatment with salmeterol in patients with asthma. Am J Respir Crit Care Med 1999; 159: 1556–61PubMedGoogle Scholar
  85. 85.
    Wilding P, Clark M, Coon JT, et al. Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study. BMJ 1997; 314: 1441–6PubMedCrossRefGoogle Scholar
  86. 86.
    Langley SJ, Masterson CM, Batty EP, et al. Bronchodilator response to salbutamol after chronic dosing with salmeterol or placebo. Eur Respir J 1998; 11: 1081–5PubMedCrossRefGoogle Scholar
  87. 87.
    Aziz I, Hall IP, MacFarlane LC, et al. Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J Allergy Clin Immunol 1998; 101: 337–41PubMedCrossRefGoogle Scholar
  88. 88.
    Lipworth BJ, Aziz I. Bronchodilator response to salbutamol after regular formoterol and effects of acute corticosteroid administration. Chest 2000; 117: 156–62PubMedCrossRefGoogle Scholar
  89. 89.
    van der Woude HJ, Winter TH, Aalbers R. Decreased broncho-dilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta2 agonists. Thorax 2001; 56: 529–35PubMedCrossRefGoogle Scholar
  90. 90.
    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: 953–6PubMedCrossRefGoogle Scholar
  91. 91.
    Lipworth BJ, Aziz I. A high dose of salbutamol does not overcome bronchoprotective subsensitivity in asthmatic subjects receiving regular salmeterol or formoterol. J Allergy Clin Immunol 1999; 103: 88–92PubMedCrossRefGoogle Scholar
  92. 92.
    Aziz I, Lipworth BJ. In vivo effect of salbutamol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol. J Allergy Clin Immunol 1999; 103: 816–22PubMedCrossRefGoogle Scholar
  93. 93.
    Grove A, Lipworth BJ. Evaluation of the beta 2 adrenoceptor agonist/antagonist activity of formoterol and salmeterol. Thorax 1996; 51: 54–8PubMedCrossRefGoogle Scholar
  94. 94.
    Mak JC, Nishikawa M, Barnes PJ. Glucocorticosteroids increase beta 2-adrenergic receptor transcription in human lung. Am J Physiol 1995; 268: L41–6PubMedGoogle Scholar
  95. 95.
    Tan KS, Grove A, McLean A, et al. Systemic corticosteriod rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients. Am J Respir Crit Care Med 1997; 156: 28–35PubMedGoogle Scholar
  96. 96.
    Yates DH, Kharitonov SA, Barnes PJ. An inhaled gluco-corticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist. Am J Respir Crit Care Med 1996; 154: 1603–7PubMedGoogle Scholar
  97. 97.
    Aziz I, Lipworth BJ. A bolus of inhaled budesonide rapidly reverses airway subsensitivity and beta2-adrenoceptor down-regulation after regular inhaled formoterol. Chest 1999; 115: 623–8PubMedCrossRefGoogle Scholar
  98. 98.
    Giannini D, Bacci E, Dente FL, et al. Inhaled beclomethasone dipropionate reverts tolerance to the protective effect of salmeterol on allergen challenge. Chest 1999; 115: 629–34PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Department of Clinical Pharmacology and Therapeutics, Asthma and Allergy Research Group, Ninewells University Hospital and Medical SchoolUniversity of DundeeDundeeUK
  2. 2.Tayside Centre of General PracticeUniversity of DundeeDundeeUK

Personalised recommendations