Pediatric Drugs

, Volume 6, Issue 3, pp 161–175 | Cite as

Long-Acting β2-Adrenoceptor Agonists and Exercise-Induced Asthma

Lessons to Guide Us in the Future
Review Article


The safety and efficacy of long-acting β2-adrenoceptor agonists (LABAs) taken intermittently for the prevention of exercise-induced asthma (EIA) in children is well established. However, the safety and efficacy of LABAs taken twice daily, either alone or in combination with inhaled corticosteroids, for the prevention of EIA is not as clear because of issues of tolerance (defined as being less responsive to the influence of LABAs).

There have been many observations on short-acting β2-adrenoceptor agonists (SABAs) and EIA that should have alerted us to the potential for tolerance and desensitization to occur with LABAs. For example, we expected that the use of LABAs for EIA would overcome the problem of the short duration of protection of SABAs, and to some extent they have. The protective period of a LABA is two to three times longer in duration than that of a SABA. However, when a LABA is taken daily it is apparent that the duration of its protective effect is reduced and there is a risk of EIA occurring well within the 12-hour administration schedules. Furthermore, daily use of LABAs attenuates the bronchodilator effect of SABAs, an effect that is greater the more severe the bronchoconstriction. This ‘tolerance’ increases both the time and the amount of therapy that is needed to recover from bronchoconstriction, and thus, could potentially impact on the success of rescue therapy should severe EIA occur. The daily use of LABAs also increases the sensitivity of the bronchial smooth muscle to contractile agents. This increase in sensitivity is almost equivalent to the extent to which inhaled corticosteroids reduce sensitivity to the same contractile agents. The increased sensitivity to contractile agents may occur either by a reduction in the inhibitory effect of β2-adrenoceptor agonists on release of mediators from mast cells or by a direct effect on the bronchial smooth muscle. These unwanted effects of LABAs are not necessarily reduced by concomitant treatment with inhaled corticosteroids.

As the number of children being treated with LABAs increases, it is predicted that problems with breakthrough EIA will also increase. We need to know the percentage of children taking a LABA daily who are requiring either extra doses of a β2-adrenoceptor agonist to prevent (or reverse) EIA or other provocative stimuli. If this percentage is significant then we may need to reconsider the position of LABAs in the treatment of children with asthma who regularly perform strenuous physical activity.



John Brannan is supported by a grant from the National Health & Medical Research Council of Australia. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Jones RS, Wharton MJ, Buston MH. Place of physical exercise and bronchodilator drugs in the assessment of the asthmatic child. Arch Dis Child 1963; 38: 539–45PubMedGoogle Scholar
  2. 2.
    Silverman M, Andrea T. Time course of effect of disodium cromoglycate on exercise-induced asthma. Arch Dis Child 1972; 47(253): 419–22PubMedGoogle Scholar
  3. 3.
    Godfrey S, Silverman M, Anderson SD. The use of the treadmill for assessing exercise-induced asthma and the effect of varying the severity and the duration of exercise. Paediatrics 1975; 56 (5 Pt 2): 893S–8SGoogle Scholar
  4. 4.
    Anderson SD, Silverman M, Walker SR. Metabolic and ventilatory changes in asthmatic patients during and after exercise. Thorax 1972; 27: 718–25PubMedGoogle Scholar
  5. 5.
    Anderson SD, McEvoy JDS, Bianco S. Changes in lung volumes and airway resistance after exercise in asthmatic subjects. Am Rev Respir Dis 1972; 106: 30–7PubMedGoogle Scholar
  6. 6.
    Bye PTP, Anderson SD, Daviskas E, et al. Plasma cyclic AMP levels in response to exercise and terbutaline sulphate aerosol in normal and asthmatic patients. Eur J Respir Dis 1980; 61: 287–97PubMedGoogle Scholar
  7. 7.
    Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing: 1999. Am J Respir Crit Care Med 2000; 161: 309–29PubMedGoogle Scholar
  8. 8.
    Roca J, Whipp BJ, Agusti AGN, et al. Clinical exercise testing with reference to lung diseases: indications, standardization and interpretation strategies. Position document of the European Respiratory Society. Eur Respir J 1997; 10: 2662–89Google Scholar
  9. 9.
    Anderson SD, Lambert S, Brannan JD, et al. Laboratory protocol for exercise asthma to evaluate salbutamol given by two devices. Med Sci Sports Exerc 2001; 33(6): 893–900PubMedGoogle Scholar
  10. 10.
    Hofstra WB, Sterk PJ, Neijens HJ, et al. Prolonged recovery from exercise-induced asthma with increasing age in childhood. Pediatr Pulmonol 1995; 20(3): 177–83PubMedGoogle Scholar
  11. 11.
    Godfrey S, Konig P. Suppression of exercise-induced asthma by salbutamol, theophylline, atropine, cromolyn, and placebo in a group of asthmatic children. Pediatrics 1975; 56: 930–4PubMedGoogle Scholar
  12. 12.
    Godfrey S, Konig P. Inhibition of exercise-induced asthma by different pharmacological pathways. Thorax 1976; 31(2): 137–43PubMedGoogle Scholar
  13. 13.
    Silverman M, Konig P, Godfrey S. The use of serial exercise test to assess the efficacy and duration of action of drugs in asthma. Thorax 1973; 28: 574–8PubMedGoogle Scholar
  14. 14.
    Poppius H, Sovijarvi ARA, Tammilehto L. Lack of protective effect of high-dose ipratropium on bronchoconstriction following exercise with cold air breathing in patients with mild asthma. Eur J Respir Dis 1986; 68: 319–25PubMedGoogle Scholar
  15. 15.
    Anderson SD. Exercise-induced asthma: the state of the art. Chest 1985; 87S: 191S–5SGoogle Scholar
  16. 16.
    Silverman M, Turner-Warwick M. Exercise-induced asthma: response to disodium cromoglycate in skin-test positive and skin-test negative subjects. Clin Allergy 1972; 2: 137–42PubMedGoogle Scholar
  17. 17.
    Jonasson G, Carlsen KH, Hultquist C. Low-dose budesonide improves exercise-induced bronchospasm in schoolchildren. Pediatr Allergy Immunol 2000; 11(2): 120–5PubMedGoogle Scholar
  18. 18.
    Anderson SD, Rozea PJ, Dolton R, et al. Inhaled and oral bronchodilator therapy in exercise-induced asthma. Aust N Z J Med 1975; 5: 544–50PubMedGoogle Scholar
  19. 19.
    Anderson SD, Seale JP, Rozea P, et al. Inhaled and oral salbutamol in exercise-induced asthma. Am Rev Respir Dis 1976; 114: 493–500PubMedGoogle Scholar
  20. 20.
    Anderson SD, Seale JP, Ferris L, et al. An evaluation of pharmacotherapy for exercise-induced asthma. J Allergy Clin Immunol 1979; 64: 612–24PubMedGoogle Scholar
  21. 21.
    König P, Eggleston PA, Serby CW. Comparison of oral and inhaled metaproterenol for prevention of exercise-induced asthma. Clin Allergy 1981; 11: 597–604PubMedGoogle Scholar
  22. 22.
    Anderson SD, Spiroglou M, Lindsay DA. An evaluation of oral hexoprenaline sulphate (ipradol) in exercise-induced asthma. Med J Aust 1977; 2: 825–7PubMedGoogle Scholar
  23. 23.
    Laursen LC, Johannesson N, Weeke B. Effects of enprophylline and theophylline on exercise-induced asthma. Allergy 1985; 40: 506–9PubMedGoogle Scholar
  24. 24.
    Seale JP, Anderson SD, Lindsay DA. A comparison of oral theophylline and oral salbutamol in exercise-induced asthma. Aust N Z J Med 1977; 7: 270–4PubMedGoogle Scholar
  25. 25.
    Anderson SD, Rodwell LT, Du Toit J, et al. Duration of protection by inhaled salmeterol in exercise-induced asthma. Chest 1991; 100: 1254–60PubMedGoogle Scholar
  26. 26.
    Schoeffel RE, Anderson SD, Seale JP. The protective effect and duration of action of metaproteronol aerosol on exercise-induced asthma. Ann Allergy 1981; 46: 273–5PubMedGoogle Scholar
  27. 27.
    Woolley M, Anderson SD, Quigley B. Duration of protective effect of terbutaline sulphate and cromolyn sodium alone and in combination on exercise-induced asthma. Chest 1990; 97: 39–45PubMedGoogle Scholar
  28. 28.
    Anderson SD. Exercise-induced asthma. In: Middleton E, Reed C, Ellis E, et al., editors. Allergy: principles and practice. 3rd ed. St Louis (MA): CV Mosby Company, 1988: 1156–75Google Scholar
  29. 29.
    Smith CM, Anderson SD, Seale JP. The duration of action of the combination of fenoterol hydrobromide and ipratropium bromide in protecting against asthma provoked by hyperpnea. Chest 1988; 94: 709–17PubMedGoogle Scholar
  30. 30.
    Schoeffel RE, Anderson SD, Lindsay DA. Sodium cromoglycate as a pressurized aerosol (Vicrom) in exercise-induced asthma. Aust N Z J Med 1983; 13: 157–61PubMedGoogle Scholar
  31. 31.
    Henriksen JM, Dahl R. Effects of inhaled budesonide alone and in combination with low-dose terbutaline in children with exercise-induced asthma. Am Rev Respir Dis 1983; 128: 993–7PubMedGoogle Scholar
  32. 32.
    Henriksen JM. Effect of inhalation of corticosteroids on exercise induced asthma: randomised double blind crossover study of budesonide in asthmatic children. BMJ 1985; 291: 248–9PubMedGoogle Scholar
  33. 33.
    Yoshikawa T, Shoji S, Fujii T, et al. Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthma. Eur Respir J 1998; 12: 879–84PubMedGoogle Scholar
  34. 34.
    Jonasson G, Carlsen KH, Jonasson C, et al. Low-dose inhaled budesonide once or twice daily for 27 months in children with mild asthma. Allergy 2000; 55(8): 740–8PubMedGoogle Scholar
  35. 35.
    Hofstra WB, Neijens HJ, Duiverman EJ, et al. Dose-response over time to inhaled fluticasone propionate: treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma. Pediatr Pulmonol 2000; 29(6): 415–23PubMedGoogle Scholar
  36. 36.
    Thio BJ, Slingerland GLM, Nagelkerke AF, et al. Effects of single-dose fluticasone on exercise-induced asthma in asthmatic children: a pilot study. Pediatr Pulmonol 2001; 32: 115–21PubMedGoogle Scholar
  37. 37.
    Edmunds A, Tooley M, Godfrey S. The refractory period after exercise-induced asthma: its duration and relation to the severity of exercise. Am Rev Respir Dis 1978; 117: 247–54PubMedGoogle Scholar
  38. 38.
    Schoeffel RE, Anderson SD, Gillam I, et al. Multiple exercise and histamine challenge in asthmatic patients. Thorax 1980; 35: 164–70PubMedGoogle Scholar
  39. 39.
    Juniper EF, Latimer KM, Morris MM, et al. Airway responses to hyperventilation of cold dry air: duration of protection by cromolyn sodium. J Allergy Clin Immunol 1986; 78: 387–91PubMedGoogle Scholar
  40. 40.
    Grönneröd TA, Von Berg A, Schwabe G, et al. Formoterol via Turbuhaler® gave better protection than terbutaline against repeated exercise challenge for up to 12 hours in children and adolescents. Respir Med 2000; 94: 661–7PubMedGoogle Scholar
  41. 41.
    Anderson SD, Silverman M, Konig P, et al. Exercise-induced asthma: a review. Br J Dis Chest 1975; 69: 1–39PubMedGoogle Scholar
  42. 42.
    Albazzaz MK, Neale MG, Patel KR. Dose duration of nebulized nedocromil sodium in exercise-induced asthma. Eur Respir J 1992; 5: 967–9PubMedGoogle Scholar
  43. 43.
    O’Byrne PM, Jones GL. The effect of indomethacin on exercise-induced bronchoconstriction and refractoriness after exercise. Am Rev Respir Dis 1986; 134: 69–72PubMedGoogle Scholar
  44. 44.
    Wilson BA, Bar-Or O, O’Byrne PM. The effects of indomethacin on refractoriness following exercise both with and without bronchoconstriction. Eur Respir J 1994; 12: 2174–8Google Scholar
  45. 45.
    O’Sullivan S, Roquet A, Dahlén B, et al. Evidence for mast cell activation during exercise-induced bronchoconstriction. Eur Respir J 1998; 12: 345–50PubMedGoogle Scholar
  46. 46.
    Reiss TF, Hill JB, Harman E, et al. Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 1997; 52(12): 1030–5PubMedGoogle Scholar
  47. 47.
    Manning PJ, Watson RM, O’Byrne PM. Exercise-induced refractoriness in asthmatic subjects involves leukotriene and prostaglandin interdependent mechanisms. Am Rev Respir Dis 1993; 148: 950–4PubMedGoogle Scholar
  48. 48.
    Dessanges J-F, Prefaut C, Taytard A, et al. The effect of zafirlukast on repetitive exercise-induced bronconstriction: the possible role of leukotrienes in exercise-induced refractoriness. J Allergy Clin Immunol 1999; 104(6): 1155–66PubMedGoogle Scholar
  49. 49.
    Hancox RJ, Subbarao P, Kamada D, et al. β2-agonist tolerance and exercise-induced bronchospasm. Am J Respir Crit Care Med 2002; 165(8): 1068–70PubMedGoogle Scholar
  50. 50.
    Inman MD, O’Byrne PM. The effect of regular inhaled albuterol on exercise-induced bronchoconstriction. Am J Respir Crit Care Med 1996; 153: 65–9PubMedGoogle Scholar
  51. 51.
    Henriksen JM, Agertoft L, Pedersen S. Protective effect and duration of action of inhaled formoterol and salbutamol on exercise-induced asthma in children. J Allergy Clin Immunol 1992; 89: 1176–82PubMedGoogle Scholar
  52. 52.
    Boner AL, Spezia E, Piovesan P, et al. Inhaled formoterol in the prevention of exercise-induced bronchoconstriction in asthmatic children. Am J Respir Crit Care Med 1994; 149: 935–8PubMedGoogle Scholar
  53. 53.
    Nielsen KG, Skov M, Klug B, et al. Flow dependent effect of formoterol dry-powder inhaled from the Aeroliser®. Eur Respir J 1997; 10: 2105–9PubMedGoogle Scholar
  54. 54.
    Green CP, Price JF. Prevention of exercise induced asthma by inhaled salmeterol zinofoate. Arch Dis Child 1992; 67: 1014–7PubMedGoogle Scholar
  55. 55.
    Carlsen KH, Roksund O, Olsholt K, et al. Overnight protection by inhaled salmeterol on exercise-induced asthma in children. Eur Respir J 1995; 8: 1852–5PubMedGoogle Scholar
  56. 56.
    de Benedictis FM, Tuteri G, Pazzelli P, et al. Salmeterol in exercise-induced bronchoconstriction in asthmatic children: comparison of two doses. Eur Respir J 1996; 9: 2099–103PubMedGoogle Scholar
  57. 57.
    Nielsen KG, Auk IL, Bojsen K, et al. Clinical effect of Diskus™ dry-powder inhaler at low and high inspiratory flow rates in children. Eur Respir J 1998; 11: 350–4PubMedGoogle Scholar
  58. 58.
    Daugbjerg P, Nielsen KG, Skov M, et al. Duration of action of formoterol and salbutamol dry-powder inhalation in prevention of exercise-induced asthma in children. Acta Paediatr 1996; 85: 684–7PubMedGoogle Scholar
  59. 59.
    Patessio A, Podda A, Carone M, et al. Protective effect and duration of action of formoterol aerosol on exercise-induced asthma. Eur Respir J 1991; 4: 296–300PubMedGoogle Scholar
  60. 60.
    Shapiro GS, Yegen Ü, Xiang J, et al. A randomized, double-blind, single-dose, crossover clinical trial of the onset and duration of protection from exercise-induced bronchoconstriction by formoterol and albuterol. Clin Ther 2002; 24(12): 2077–87PubMedGoogle Scholar
  61. 61.
    Bronsky EA, Yegen Ü, Yeh CM, et al. Formoterol provides long-lasting protection against exercise-induced bronchospasm. Ann Allergy Asthma Immunol 2002; 89: 407–12PubMedGoogle Scholar
  62. 62.
    Blake KV, Pearlman DS, Scott C, et al. Prevention of exercise-induced broncho-spasm in pediatric asthma patients: a comparison of salmeterol powder with albuterol. Ann Allergy Asthma Immunol 1999; 82(2): 205–11PubMedGoogle Scholar
  63. 63.
    Bisgaard H. Long-acting beta2-agonists in management of childhood asthma: a critical review of the literature. Pediatr Pulmonol 2000; 29(3): 221–34PubMedGoogle Scholar
  64. 64.
    Anderson GP, Rabe KF. Bronchodilators: an overview. In: Hansel TT, Barnes PJ, editors. New drugs for asthma, allergy and COPD. Basel: Karger, 2000: 54–9Google Scholar
  65. 65.
    Richter K, Janicki S, Jorres RA, et al. Acute protection against exercise-induced bronchoconstriction by formoterol, salmeterol and terbutaline. Eur Respir J 2002; 19: 865–71PubMedGoogle Scholar
  66. 66.
    Ferrari M, Segattini C, Zanon R, et al. Comparison of the protective effect of salmeterol against exercise-induced bronchospasm when given immediately before a cycloergometric test. Respiration 2002; 69(6): 509–12PubMedGoogle Scholar
  67. 67.
    Newnham DM, Ingram CG, Earnshaw J, et al. Salmeterol provides prolonged protection against exercise-induced bronchoconstriction in a majority of subjects with mild, stable asthma. Respir Med 1993; 87: 439–44PubMedGoogle Scholar
  68. 68.
    O’Connor BJ, Aikman S, Barnes PJ. Tolerance to the non-bronchodilator effects of inhaled beta-agonists in asthma. N Engl J Med 1992; 327: 1204–8PubMedGoogle Scholar
  69. 69.
    Solér M, Joos L, Bolliger CT, et al. Bronchoprotection by salmeterol: cell stabilization or functional antagonism? Comparative effects on histamine- and AMP-induced bronchoconstriction. Eur Respir J 1994; 7: 1973–7PubMedGoogle Scholar
  70. 70.
    Giannini D, Carlett A, Dente FL, et al. Tolerance to the protective effect of salmeterol on allergen challenge. Chest 1996; 110: 1452–7PubMedGoogle Scholar
  71. 71.
    Cockcroft DW, Swystun VA, Bhagat R, et al. Salmeterol and airway response to allergen. Can Respir J 1997; 4: 37–40Google Scholar
  72. 72.
    Ramage L, Ingram C, Cree IA, et al. Chronic dosing with inhaled salmeterol in exercise induced asthma (EIA) [abstract]. Thorax 1991; 47(3): 255PGoogle Scholar
  73. 73.
    Ramage L, Lipworth BJ, Ingram CG, et al. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994; 88: 363–8PubMedGoogle Scholar
  74. 74.
    Simons FE, Gerstner TV, Cheang MS. Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics 1997; 99(5): 655–9PubMedGoogle Scholar
  75. 75.
    Villarin C, O’Neill J, Heibling A, et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. J Allergy Clin Immunol 1999; 104: 547–53Google Scholar
  76. 76.
    Nelson JA, Strauss L, Skowronski M, et al. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med 1998; 339(3): 141–6PubMedGoogle Scholar
  77. 77.
    Edelman JM, Turpin JA, Bronsky EA. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. Ann Intern Med 2000; 132: 97–104PubMedGoogle Scholar
  78. 78.
    Anderson SD. Exercise-induced asthma in children: a marker of airway inflammation. Med J Aust 2002; 177: S61–3PubMedGoogle Scholar
  79. 79.
    Garcia R, Guerra P, Feo F, et al. Tachyphylaxis following regular use of formoterol in exercise-induced bronchospasm. J Investig Allergol Clin Immunol 2001; 11(3): 176–82PubMedGoogle Scholar
  80. 80.
    Vilsvik J, Ankerst J, Palmqvist M, et al. Protection against cold air and exercise-induced bronchoconstriction while on regular treatment with Oxis®. Respir Med 2001; 95: 484–90PubMedGoogle Scholar
  81. 81.
    Davis BE, Reid JK, Cockcroft DW. Formoterol thrice weekly does not result in the development of tolerance to bronchoprotection. Can Respir J 2003; 10(1): 23–6PubMedGoogle Scholar
  82. 82.
    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: 953–6PubMedGoogle Scholar
  83. 83.
    Booth H, Bish R, Walters J, et al. Salmeterol tachyphylaxis in steroid treated asthmatic subjects. Thorax 1996; 51(11): 1100–4PubMedGoogle Scholar
  84. 84.
    Boulet LP, Cartier A, Milot J, et al. Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids. Eur Respir J 1998; 11(5): 1091–7PubMedGoogle Scholar
  85. 85.
    Meijer GG, Postma DS, Mulder PGH, et al. Long-term circadian effects of salmeterol in asthmatic children treated with inhaled corticosteroids. Am J Respir Crit Care Med 1995; 152: 1887–92PubMedGoogle Scholar
  86. 86.
    Aldridge RE, Hancox RJ, Robin Taylor D, et al. Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma. Am J Respir Crit Care Med 2000; 161: 1459–64PubMedGoogle Scholar
  87. 87.
    van Veen A, Weller FR, Wierenga EA, et al. A comparison of salmeterol and formoterol in attenuating airway responses to short-acting beta2-agonists. Pulm Pharmacol 2003; 16(3): 153–61Google Scholar
  88. 88.
    Lim S, Jatakanan A, John M, et al. Effect of inhaled budesonide on lung function and airway inflammation. Am J Respir Crit Care Med 1999; 159: 22–30PubMedGoogle Scholar
  89. 89.
    Sont JK, Willems LN, Bel EH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999; 159 (4 Pt 1): 1043–51PubMedGoogle Scholar
  90. 90.
    Wraight JM, Hancox RJ, Herbison GP, et al. Bronchodilator tolerance: the impact of increasing bronchoconstriction. Eur Respir J 2003; 21(5): 810–5PubMedGoogle Scholar
  91. 91.
    Anja AP, Verberne PH, Froct C, et al. One year treatment with salmeterol compared with beclomethasone in children with asthma. Am J Respir Crit Care Med 1997; 156: 688–95Google Scholar
  92. 92.
    Dorinsky P, Kalberg C, Emmett A, et al. Sustained protection against activity-induced bronchospasm during chronic treatment with the fluticasone proprionate/salmeterol combination (poster no. 1932) [abstract]. Eur Respir J 2002; 20Suppl. 38: 308sGoogle Scholar
  93. 93.
    Hancox RJ, Aldridge EE, Cowan JO, et al. Tolerance to beta-agonists during acute bronchoconstriction. Eur Respir J 1999; 14(2): 283–7PubMedGoogle Scholar
  94. 94.
    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 β2 agonists. Thorax 2001; 56: 529–35PubMedGoogle Scholar
  95. 95.
    Jones CL, Cowan JO, Flannery EM, et al. Reversing the acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol. Eur Respir J 2001; 17(3): 368–73PubMedGoogle Scholar
  96. 96.
    Lee DK, Jackson CM, Currie GP, et al. Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma. Br J Clin Pharmacol 2003; 56(5): 494–500PubMedGoogle Scholar
  97. 97.
    Scola AM, Chong LK, Suvarna SK, et al. Desensitisation of mast cell β2-adrenoceptor-mediated responses by salmeterol and formoterol. Br J Pharmacol 2004; 141(1): 163–71PubMedGoogle Scholar
  98. 98.
    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: 32–6PubMedGoogle Scholar
  99. 99.
    Johnson M. The β-adrenoceptor. Am J Respir Crit Care Med 1998; 158: S146–53PubMedGoogle Scholar
  100. 100.
    Chong LK, Suvarna K, Chess-Williams R, et al. Desensitization of β2-adre-noceptor-mediated responses by short-acting β2-adrenoceptor agonists in human lung mast cells. Br J Pharmacol 2003; 138: 512–20PubMedGoogle Scholar
  101. 101.
    Barnes PJ. Beta-adrenergic receptors and their regulation. Am J Respir Crit Care Med 1995; 152: 838–60PubMedGoogle Scholar
  102. 102.
    Ferguson SG. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 2001; 53(1): 1–24PubMedGoogle Scholar
  103. 103.
    Giembycz MA. Phosphodiesterase-4 and tolerance to β2-adrenoceptor agonists in asthma. Trends Pharmacol Sci 1996; 17: 331–6PubMedGoogle Scholar
  104. 104.
    Finney PA, Belvisi MG, Donnelly LE, et al. Albuterol-induced down-regulation of G accounts for pulmonary β2-adrenoceptor desensitization in vivo. J Clin Invest 2000; 106: 125–35PubMedGoogle Scholar
  105. 105.
    Finney PA, Donnelly LE, Belvisi MG, et al. Chronic systemic administration of salmeterol to rats promotes pulmonary β2-adrenoceptor desensitization and down-regulation of G. Br J Pharmacol 2001; 132: 1261–70PubMedGoogle Scholar
  106. 106.
    Hayes MJ, Qing F, Rhodes CG, et al. In vivo quantification of human pulmonary beta-adrenoceptors: effect of beta-agonist therapy. Am J Respir Crit Care Med 1996; 154(5): 1277–83PubMedGoogle Scholar
  107. 107.
    Torphy TJ, Zhou H-L, Foley JJ, et al. Salbutamol up-regulates PDE4 activity and induces a heterologous desensitization of U937 cells to prostaglandin E2. J Biol Chem 1995; 270(40): 23598–604PubMedGoogle Scholar
  108. 108.
    Timmer W, Lecher V, Birraux G, et al. The phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-α ex vivo. J Clin Pharmacol 2002; 42: 297–303PubMedGoogle Scholar
  109. 109.
    McGraw DW, Liggett SB. Heterogeneity of beta adrenergic receptor kinase expression in the lung accounts for cell-specific desensitisation of the beta adrenergic receptor. J Biol Chem 1997; 272: 7338–44PubMedGoogle Scholar
  110. 110.
    Taylor DR, Hancox RJ, McRae W, et al. The influence of polymorphism at position 16 of the beta2-adrenoceptor on the development of tolerance to beta-agonist. J Asthma 2000; 37(8): 691–700PubMedGoogle Scholar
  111. 111.
    Lipworth BJ, Hall IP, Aziz I, et al. Beta2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short-and long-acting beta2-agonist therapy. Clin Sci 1999; 96(3): 253–9PubMedGoogle Scholar
  112. 112.
    Israel E, Drazen JM, Liggett SB, et al. Effect of polymorphism of the beta2-adrenergic receptor on response to regular use of albuterol in asthma. Int Arch Allergy Immunol 2001; 124(1): 183–6PubMedGoogle Scholar
  113. 113.
    Tan S, Hall IP, Dewar J, et al. Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350: 995–9PubMedGoogle Scholar
  114. 114.
    Lee DKC, Currie GP, Hall IP, et al. The arginine-16 β2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol 2004; 57(1): 68–75PubMedGoogle Scholar
  115. 115.
    Daviskas E, Shaw JG, Anderson SD, et al. Effects of beta2 agonists on mucociliary clearance (MCC) in patients with asthma: association to polymorphisms of the beta2 receptor [abstract]. Eur Respir J 2003; 22Suppl. 45: P3013Google Scholar
  116. 116.
    Boucher RC. Human airway ion transport. Am J Respir Crit Care Med 1994; 150 (Pt 1, 2): 271–81, 581–93PubMedGoogle Scholar
  117. 117.
    Daviskas E, Anderson SD, Gonda I, et al. Mucociliary clearance during and after isocapnic hyperventilation with dry air in the presence of furosemide. Eur Respir J 1996; 9: 716–24PubMedGoogle Scholar
  118. 118.
    Anderson SD. Is there a unifying hypothesis for exercise-induced asthma? J Allergy Clin Immunol 1984; 73: 660–5PubMedGoogle Scholar
  119. 119.
    Anderson SD, Daviskas E. The mechanism of exercise-induced asthma is … J Allergy Clin Immunol 2000; 106(3): 453–9PubMedGoogle Scholar
  120. 120.
    Anderson SD, Daviskas E, Smith CM. Exercise-induced asthma: a difference in opinion regarding the stimulus. Allergy Proc 1989; 10: 215–26PubMedGoogle Scholar
  121. 121.
    Anderson SD, Daviskas E. The airway microvasculature and exercise-induced asthma. Thorax 1992; 47: 748–52PubMedGoogle Scholar
  122. 122.
    Brannan JD, Gulliksson M, Anderson SD, et al. Evidence of mast cell activation and leukotriene release after mannitol inhalation. Eur Respir J 2003; 22(3): 491–6PubMedGoogle Scholar
  123. 123.
    Leuppi JD, Brannan JD, Belousova E, et al. Questionnaire responses that predict airway response to hypertonic saline [abstract]. Eur Respir J 2002; 20Suppl. 38: 188SGoogle Scholar
  124. 124.
    Evans DW, Salome CM, King GG, et al. Effect of regular inhaled salbutamol on airway responsiveness and airway inflammation in rhinitic non-asthmatic subjects. Thorax 1997; 52: 136–42PubMedGoogle Scholar
  125. 125.
    Leff AR. Role of leukotrienes in bronchial hyperresponsiveness and cellular responses in airways. Thorax 2000; 55Suppl. 2: 32S–7SGoogle Scholar
  126. 126.
    Anderson SD, Bye PTP, Schoeffel RE, et al. Arterial plasma histamine levels at rest, during and after exercise in patients with asthma: effects of terbutaline aerosol. Thorax 1981; 36: 259–67PubMedGoogle Scholar
  127. 127.
    Joos GF, O’Connor B, Anderson SD, et al. Indirect airway challenges. Eur Respir J 2003; 21: 1050–68PubMedGoogle Scholar
  128. 128.
    Van Schoor J, Joos GF, Pauwels RA. Indirect bronchial hyperresponsiveness in asthma: mechanisms, pharmacology and implications for clinical research. Eur Respir J 2000; 16: 514–33PubMedGoogle Scholar
  129. 129.
    Mussaffi H, Springer C, Godfrey S. Increased bronchial responsiveness to exercise and histamine after allergen challenge in children with asthma. J Allergy Clin Immunol 1986; 77: 48–52PubMedGoogle Scholar
  130. 130.
    Swystun VA, Gordon JR, Davis EB, et al. Mast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol. J Allergy Clin Immunol 2000; 106: 57–64PubMedGoogle Scholar
  131. 131.
    Johnson PRA, Ammit AJ, Carlin SM, et al. Mast cell tryptase potentiates histamine induced contraction in human sensitised bronchi. Eur Respir J 1996; 10: 38–43Google Scholar
  132. 132.
    Ammit AJ, Bekir SS, Johnson PR, et al. Mast cell numbers are increased in the smooth muscle of human sensitized isolated bronchi. Am J Respir Crit Care Med 1997; 155(3): 1123–9PubMedGoogle Scholar
  133. 133.
    Brightling CE, Bradding P, Symon FA, et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002; 346(22): 1699–705PubMedGoogle Scholar
  134. 134.
    Carroll NG, Mutavdzic S, James AL. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur Respir J 2002; 19: 879–85PubMedGoogle Scholar
  135. 135.
    Page S, Ammit AJ, Black JL, et al. Human mast cells and airway smooth muscle cell interactions: implications for asthma. Am J Physiol Lung Cell Mol Physiol 2001; 281(6): L1313–23PubMedGoogle Scholar
  136. 136.
    Crummy F, Livingston M, deCourcey F, et al. Endobronchial AMP challenge causes mast cell mediator release in non-atopic non-asthmatic subjects (poster G8). Am J Respir Crit Care Med 2003; 167(7 Suppl.): A62Google Scholar
  137. 137.
    Mannix ET, Farber MO, Palange P, et al. Exercise-induced asthma in figure skaters. Chest 1996; 109: 312–5PubMedGoogle Scholar
  138. 138.
    Rundell KW, Im J, Mayers LB, et al. Self-reported symptoms and exercise-induced asthma in the elite athlete. Med Sci Sports Exerc 2001; 33(2): 208–13PubMedGoogle Scholar
  139. 139.
    Holzer K, Anderson SD, Chan H-K, et al. Mannitol as a challenge test to identify exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 2003; 167(4): 534–47PubMedGoogle Scholar
  140. 140.
    Helenius IJ, Tikkanen HO, Haahtela T. Occurrence of exercise induced bronchospasm in elite runners: dependence on atopy and exposure to cold air and pollen. Br J Sports Med 1998; 32: 125–9PubMedGoogle Scholar
  141. 141.
    Turcotte H, Langdeau JB, Thibault G, et al. Prevalence of respiratory symptoms in an athlete population. Respir Med 2003; 97(8): 955–63PubMedGoogle Scholar
  142. 142.
    Helenius I, Haahtela T. Allergy and asthma in elite summer sport athletes. J Allergy Clin Immunol 2000; 106(3): 444–52PubMedGoogle Scholar
  143. 143.
    Holzer K, Anderson SD, Douglass J. Exercise in elite summer athletes: challenges for diagnosis. J Allergy Clin Immunol 2002; 110(3): 374–80PubMedGoogle Scholar
  144. 144.
    Anderson SD, Fitch K, Perry CP, et al. Responses to bronchial challenge submitted for approval to use inhaled beta2 agonists prior to an event at the 2002 Winter Olympics. J Allergy Clin Immunol 2003; 111(1): 44–9Google Scholar
  145. 145.
    Official website of the Olympic movement [online]. Available from URL: and [Accessed 2004 Feb 15]
  146. 146.
    Briffa P, Perry C, Camps J, et al. 2003: bronchial responsiveness in applicants to the NSW police force with a history or symptoms suggestive of asthma [online]. Available from URL [Accessed 2004 Jan 13]
  147. 147.
    Anderson SD, Brannan J, Trevillion L, et al. Lung function and bronchial provocation tests for intending divers with a history of asthma. SPUMS J 1995; 25: 233–48Google Scholar
  148. 148.
    Bensch G, Berger WE, Blokhin BM, et al. One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma. Ann Allergy Asthma Immunol 2002; 89: 180–90PubMedGoogle Scholar
  149. 149.
    Mann M, Chowdhury B, Sullivan E, et al. Serious asthma exacerbations in asthmatics treated with high-dose formoterol. Chest 2003; 124(1): 70–4PubMedGoogle Scholar
  150. 150.
    Wooltorton E. Salmeterol (Serevent) asthma trial halted early [letter]. CMAJ 2003; 168(6): 738PubMedGoogle Scholar
  151. 151.
    US Food and Drug Administration website [online]. Available from URL: [Accessed 2003 Sep 8]
  152. 152.
    Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J 2002; 19(1): 182–91PubMedGoogle Scholar
  153. 153.
    Lemière C, Becker A, Boulet L-P, et al. Should combination therapy with inhaled corticosteroids and long-acting β2-agonists be prescribed as initial maintenance treatment for asthma? CMAJ 2002; 67(9): 1008–9Google Scholar
  154. 154.
    Lipworth BJ. Airway subsensitivity with long-acting beta2-agonists: is there a cause for concern? Drug Saf 1997; 16(5): 295–308PubMedGoogle Scholar
  155. 155.
    Lipworth BJ, Aziz I. A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic subjects receiving regular salmeterol or formoterol. J Allergy Clin Immunol 1999; 103(1): 88–92PubMedGoogle Scholar
  156. 156.
    Shore SA, Drazen JM. Beta-agonists and asthma: too much of a good thing. J Clin Invest 2003; 112: 495–7PubMedGoogle Scholar
  157. 157.
    Bisgaard H. Effect of long-acting beta2 agonists on exacerbation rates of asthma in children. Pediatr Pulmonol 2003; 36(5): 391–8PubMedGoogle Scholar
  158. 158.
    Korn SH, Jerre A, Brattsand R. Effect of formoterol and budesonide on GM-CSF and IL-8 secretion by triggered human bronchial epithelial cells. Eur Respir J 2001; 17: 1070–7PubMedGoogle Scholar
  159. 159.
    Roth M, Johnson PR, Rudiger IJ, et al. Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002; 360(9342): 1293–9PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Department of Respiratory MedicineRoyal Prince Alfred HospitalCamperdown, SydneyAustralia

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