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Drug Safety

, Volume 11, Issue 4, pp 259–283 | Cite as

The β2-Agonist Controversy

Observations, Explanations and Relationship to Asthma Epidemiology
  • Malcolm R. Sears
  • D. Robin Taylor
Review Articles Pharmacoepidemiology

Summary

Links between frequent use of inhaled β2-agonists and morbidity and mortality from asthma appear probable. Two mortality epidemics followed the marketing of potent inhaled adrenergic agents. Case-control studies in New Zealand linked mortality with prescription of fenoterol, especially in severe asthma. A Saskatchewan case-control study confirmed an association of mortality with fenoterol, and also with frequent use of salbutamol (albuterol). Cardiac effects of β2-agonists do not cause mortality, but frequent use of these agents may increase the chronic severity of asthma, hence increasing the number of asthmatic patients at risk of death in an acute attack. Frequent use of β2-agonists may reduce lung function, increasing airway responsiveness, and impair control of asthma, despite use of inhaled corticosteroids. Mechanisms for this effect may include tachyphylaxis to nonbronchodilator effects, increased responsiveness to allergen, interaction with corticosteroid receptors, altered mucociliary function, differential effects of enantiomers, and masking of symptoms by β2-agonist use. The withdrawal of fenoterol from New Zealand in 1990 was associated with a substantial decline in morbidity and mortality.

Overall, the evidence suggests that frequent use of inhaled β2-agonists has a deleterious effect on the control of asthma. Epidemics of mortality are explained by an increase in chronic severity of asthma following introduction of more potent β2-agonists. While β2-agonists remain essential for relief of breakthrough symptoms, long term use, particularly with high doses of potent agents, appears to be detrimental.

Keywords

Asthma Adis International Limited Salbutamol Budesonide Asthmatic Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case-control study. Lancet 1989; 1: 918–22Google Scholar
  2. 2.
    Spitzer WO, Suissa S, Ernst P, et al. The use of β-agonists and the risk of death and near death from asthma. N Engl J Med 1992; 326: 501–6PubMedGoogle Scholar
  3. 3.
    Pearce N, Crane J, Burgess C, et al. Beta agonists and asthma mortality: deja vu. Clin Exp Allergy 1991; 21: 401–10PubMedGoogle Scholar
  4. 4.
    Sears MR, Taylor DR. Regular beta-agonist therapy — the quality of the evidence. Eur Respir J 1992; 5: 896–7PubMedGoogle Scholar
  5. 5.
    Speizer FE, Doll R, Heaf P. Observations on recent increase in mortality from asthma. BMJ 1968; 1: 335–9PubMedGoogle Scholar
  6. 6.
    Fraser PM, Speizer FE, Waters SDM, et al. The circumstances preceding death from asthma in young people in 1968 to 1969. Br J Dis Chest 1971; 65: 71–84PubMedGoogle Scholar
  7. 7.
    Inman WHW, Adelstein AM. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet 1969; 2: 279–85PubMedGoogle Scholar
  8. 8.
    Stolley PD, Schinnar R. Association between asthma mortality and isoproterenol aerosols: a review. Prev Med 1978; 7: 519–38PubMedGoogle Scholar
  9. 9.
    Bradford Hill A. The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295–300Google Scholar
  10. 10.
    Skarpaas UK, Gulsvik A. Prevalence of bronchial asthma and respiratory symptoms in schoolchildren in Oslo. Allergy 1984; 40: 295–9Google Scholar
  11. 11.
    Asher MI, Pattemore PK, Harrison AC, et al. International comparison of the prevalence of asthma symptoms and bronchial hyperresponsiveness. Am Rev Respir Dis 1988; 138: 524–9PubMedGoogle Scholar
  12. 12.
    Sears MR. Epidemiology. In: Barnes PJ, Rodger IW, Thomson NC, editors. Asthma: basic mechanisms and clinical management. London: Academic Press, 1992: 1–19Google Scholar
  13. 13.
    McWhorter WP, Polis MA, Kaslow RA. Occurrence, predictors, and consequences of adult asthma in NHANESI and follow-up survey. Am Rev Respir Dis 1989; 139: 721–4PubMedGoogle Scholar
  14. 14.
    Woolcock AJ, Peat JK, Salome CM, et al. Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population. Thorax 1987; 42: 361–8PubMedGoogle Scholar
  15. 15.
    Jackson R, Sears MR, Beaglehole R, et al. International trends in asthma mortality: 1970 to 1985. Chest 1988; 94: 914–8PubMedGoogle Scholar
  16. 16.
    Sly RM. Mortality from asthma, 1979–1984. J Allergy Clin Immunol 1988; 82: 705–17PubMedGoogle Scholar
  17. 17.
    Wilson JD, Sutherland DC, Thomas AC. Has the change to beta-agonists combined with oral theophylline increased cases of fatal asthma? Lancet 1981; 1: 1235–7PubMedGoogle Scholar
  18. 18.
    Sears MR, Rea HH, Beaglehole R, et al. Asthma mortality in New Zealand: a two year national study. NZ Med J 1985; 98: 271–5Google Scholar
  19. 19.
    Sears MR, Rea HH, de Boer G, et al. Accuracy of certification of deaths due to asthma: a national study. Am J Epidemiol 1986; 124: 1004–11PubMedGoogle Scholar
  20. 20.
    Sears MR, Rea HH, Fenwick J, et al. 75 deaths in asthmatics prescribed home nebulisers. BMJ 1987; 294: 477–80PubMedGoogle Scholar
  21. 21.
    Sears MR, Rea HH, Rothwell RPG, et al. Asthma mortality: comparison between New Zealand and England. BMJ 1986; 293: 1342–5PubMedGoogle Scholar
  22. 22.
    Rea HH, Sears MR, Beaglehole R, et al. Lessons from the national asthma mortality study: circumstances surrounding death. NZ Med J 1987; 100: 10–3Google Scholar
  23. 23.
    Sears MR. The short- and long-term effects of ß2-agonists. In: Holgate ST, Austen KF, Lichtenstein LM, et al., editors. Asthma: physiology, immunopharmacology, and treatment. London: Academic Press, 1993; 359–74Google Scholar
  24. 24.
    Crane J, Burgess C, Pearce N, et al. Asthma deaths in New Zealand. BMJ 1992; 304: 1307PubMedGoogle Scholar
  25. 25.
    Schenker MB, Goldf EB, Lopez RL, et al. Asthma mortality in California, 1960–1989. Am Rev Respir Dis 1993; 147: 1454–60PubMedGoogle Scholar
  26. 26.
    Sears MR. Worldwide trends in asthma mortality. Bull Int Union Tuberc Lung Dis 1991; 66: 79–83PubMedGoogle Scholar
  27. 27.
    BTA Subcommittee. Accuracy of death certificates in bronchial asthma. Thorax 1984; 39: 505–9Google Scholar
  28. 28.
    Weiss KB, Gergen PJ, Wagener DK. Breathing better or wheezing worse? The changing epidemiology of asthma morbidity and mortality. Annu Rev Public Health 1993; 14: 491–513PubMedGoogle Scholar
  29. 29.
    Sears MR. Epidemiology of asthma. In: O’Byrne PM, editor. Asthma as an inflammatory disease. New York: Marcel Dekker, 1990; 15–48Google Scholar
  30. 30.
    Mao Y, Semenciw R, Morrison H, et al. Increased rates of illness and death from asthma in Canada. Can Med Assoc J 1987; 137: 620–4Google Scholar
  31. 31.
    Weiss KB, Wagener DK. Geographic variations in US asthma mortality: small-area analyses of excess mortality, 1981–1985. Am J Epidemiol 1990; 132 Suppl. 1: S107–15PubMedGoogle Scholar
  32. 32.
    Kaplan KM. Epidemiology of deaths from asthma in Pennsylvania, 1978-87. Public Health Rep 1993; 108: 66–9PubMedGoogle Scholar
  33. 33.
    Carr W, Zeitel L, Weiss K. Variations in asthma hospitalizations and deaths in New York City. Am J Public Health 1992; 82: 59–65PubMedGoogle Scholar
  34. 34.
    Marder D, Targonski P, Orris P, et al. Effect of racial and socioeconomic factors on asthma mortality in Chicago. Chest 1992; 101: 426–9Google Scholar
  35. 35.
    Speight ANP, Lee DA, Hey EN. Underdiagnosis and undertreatment of asthma in childhood. BMJ 1983; 286: 1253–6PubMedGoogle Scholar
  36. 36.
    Barnes PJ. Anti-inflammatory therapy for asthma. Ann Rev Med 1993; 44: 229–42PubMedGoogle Scholar
  37. 37.
    Laitinen LA, Laitinen A, Heino M, et al. Eosinophilic airway inflammation during exacerbation of asthma and its treatment with inhaled corticosteroid. Am Rev Respir Dis 1991; 143: 423–7PubMedGoogle Scholar
  38. 38.
    Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993; 148: S1–26PubMedGoogle Scholar
  39. 39.
    Paterson JW, Woolcock AJ, Shenfield GM. Bronchodilator drugs. Am Rev Respir Dis 1979; 120: 1149–88PubMedGoogle Scholar
  40. 40.
    Price AH, Clissold SP. Salbutamol in the 1980s. A reappraisal of its clinical efficacy. Drugs 1989; 38: 77–122PubMedGoogle Scholar
  41. 41.
    Keating G, Mitchell EA, Jackson R, et al. Trends in sales of drugs for asthma in New Zealand, Australia and the United Kingdom 1975-81. BMJ 1984; 289: 348–51PubMedGoogle Scholar
  42. 42.
    Bosco LA, Knapp DE, Gerstman B, et al. Asthma drug therapy in the United States, 1972 to 1985. J Allergy Clin Immunol 1987; 80: 398–402PubMedGoogle Scholar
  43. 43.
    British Thoracic Association. Death from asthma in two regions of England. BMJ 1982; 285: 1251–4Google Scholar
  44. 44.
    Johnson AJ, Nunn AJ, Somner AR, et al. Circumstances of death from asthma. BMJ 1984; 288: 1870–2PubMedGoogle Scholar
  45. 45.
    Wilson JD. Selective prescribing of fenoterol and salbutamol in New Zealand general practice. Post Marketing Surveillance 1991; 5: 105–18Google Scholar
  46. 46.
    Petri H, Urquhart J, Herings R, et al. Characteristics of patients prescribed three different inhalation beta2 agonists: an example of the channeling phenomenon. Post Marketing Surveillance 1991; 5: 57–66Google Scholar
  47. 47.
    Beasley R, Crane J, Burgess C, et al. Fenoterol and severe asthma mortality. NZ Med J 1989; 102: 294–6Google Scholar
  48. 48.
    Committee on Safety of Medicines. Beta agonist use in asthma: report from the CSM Working Party. London: CSM, 1992: Report no. 33Google Scholar
  49. 49.
    Costello J. Asthma — the problem and the paradox. Postgrad Med J 1991; 67 Suppl. 4: S1–5PubMedGoogle Scholar
  50. 50.
    Taylor DR, Sears MR. Debate in print. Regular inhaled ß-agonists — evidence, not reassurance, is what is needed. Chest 1994; 106: 552–9PubMedGoogle Scholar
  51. 51.
    Rea HH, Scragg R, Jackson R, et al. A case-control study of deaths from asthma. Thorax 1986; 41: 833–9PubMedGoogle Scholar
  52. 52.
    O’Donnell TV, Rea HH, Holst PE, et al. Fenoterol and fatal asthma. Lancet 1989; 1: 1070–1Google Scholar
  53. 53.
    Buist AS, Burney PGJ, Feinstein AR, et al. Fenoterol and fatal asthma. Lancet 1989; 1: 1071Google Scholar
  54. 54.
    Poole C, Lanes SF, Walker AM. Fenoterol and fatal asthma. Lancet 1990; 335: 920PubMedGoogle Scholar
  55. 55.
    Sackett DL, Shannon HS, Browman GW. Fenoterol and fatal asthma. Lancet 1990; 335: 45–6PubMedGoogle Scholar
  56. 56.
    Pearce N, Grainger J, Atkinson M, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-81. Thorax 1990; 45: 170–5PubMedGoogle Scholar
  57. 57.
    Grainger J, Woodman K, Pearce N, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study. Thorax 1991; 46: 105–11PubMedGoogle Scholar
  58. 58.
    Horwitz RI, Spitzer W, Buist S, et al. Clinical complexity and epidemiologic uncertainty in case-control research. Fenoterol and asthma management. Chest 1991; 100: 1586–91PubMedGoogle Scholar
  59. 59.
    Paterson JW, Conolly ME, Davies DS, et al. Isoprenaline resistance and the use of pressurised aerosols in asthma. Lancet 1968; 2: 426–9PubMedGoogle Scholar
  60. 60.
    Lipworth BJ, Struthers AD, McDevitt DG. Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. Am Rev Respir Dis 1989; 140: 586–92PubMedGoogle Scholar
  61. 61.
    Lehr D. Isoproterenol and sudden death of asthmatic patients in ventricular fibrillation. N Engl J Med 1972; 287: 987–8PubMedGoogle Scholar
  62. 62.
    Al-Hillawi AH, Hayward R, Johnson NM. Incidence of cardiac arrhythmias in patients taking slow release salbutamol and slow release terbutaline for asthma. BMJ 1984; 288: 367PubMedGoogle Scholar
  63. 63.
    Lipworth BJ. Risks versus benefits of inhaled β2-agonists in the management of asthma. Drug Saf 1992; 7: 54–70PubMedGoogle Scholar
  64. 64.
    Haalboom JRE, Deenstra M, Struyvenberg A. Hypokalaemia induced by inhalation of fenoterol. Lancet 1985; 1: 1125–7PubMedGoogle Scholar
  65. 65.
    Scheinin M, Koulu M, Laurikainen E, et al. Hypokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled dose-response study in healthy volunteers. Br J Clin Pharmacol 1987; 24: 645–53PubMedGoogle Scholar
  66. 66.
    Kelly WH, Menendez R, Voyles W. Lack of significant arrhythmogenicity from chronic theophylline and beta-2-adrenergic combination therapy in asthmatic subjects. Ann Allergy 1985; 54: 405–10PubMedGoogle Scholar
  67. 67.
    Taylor GJ, Harris WS. Cardiac toxicity of aerosol propellants. JAMA 1970; 214: 81–5PubMedGoogle Scholar
  68. 68.
    Sly RM. Adverse effects and complications of treatment with beta-adrenergic agonist drugs. J Allergy Clin Immunol 1985; 75: 443–9Google Scholar
  69. 69.
    Belej MA, Aviado DM. Cardiopulmonary toxicity of propellants for aerosols. J Clin Pharmacol 1975; 15: 105–15PubMedGoogle Scholar
  70. 70.
    Aviado DM. Toxicity of aerosols. J Clin Pharmacol 1975; 15: 86–104PubMedGoogle Scholar
  71. 71.
    Molfino NA, Nannini LJ, Martelli AN, et al. Respiratory arrest in near-fatal asthma. N Engl J Med 1991; 324: 285–8PubMedGoogle Scholar
  72. 72.
    Crane J, Burgess C, Beasley R. Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline. Thorax 1989; 44: 136–40PubMedGoogle Scholar
  73. 73.
    Smyth ET, Pavord ID, Wong CS, et al. Interaction and dose equivalence of salbutamol and salmeterol in patients with asthma. BMJ 1993; 306: 543–5PubMedGoogle Scholar
  74. 74.
    Guideri G, Barletta MA, Lehr D. Extraordinary potentiation of isoproterenol cardiotoxicity by corticoid pretreatment. Cardiovasc Res 1974; 8: 775–86PubMedGoogle Scholar
  75. 75.
    Taylor DR, Wilkins GT, Herbison GP, et al. Interaction between corticosteroid and β-agonist drugs: biochemical and cardiovascular effects in normal subjects. Chest 1992; 102: 519–24PubMedGoogle Scholar
  76. 76.
    Bonnin AJ, Richmond GW, Musto PK, et al. Repeated inhalation of nebulized albuterol did not induced arrhythmias in a patient with Wolff-Parkison-White syndrome and asthma. Chest 1993; 103: 1892–4PubMedGoogle Scholar
  77. 77.
    Seider N, Abinader EG, Oliven A. Cardiac arrhythmias after inhaled bronchodilators in patients with COPD and ischaemic heart disease. Chest 1993; 104: 1070–4PubMedGoogle Scholar
  78. 78.
    Ziment I. Infrequent cardiac deaths occur in bronchial asthma. Chest 1992; 101: 1703–5PubMedGoogle Scholar
  79. 79.
    Robin ED, McCauley R. Sudden cardiac death in bronchial asthma, and inhaled beta-adrenergic agonists. Chest 1992; 101: 1699–702PubMedGoogle Scholar
  80. 80.
    Miller BD, Strunk RC. Circumstances surrounding the deaths of children due to asthma. A case-control study. Am J Dis Child 1989; 143: 1294–9PubMedGoogle Scholar
  81. 81.
    Bremner P, Burgess CD, Crane J, et al. Cardiovascular effects of fenoterol under conditions of hypoxaemia. Thorax 1992; 47: 814–7PubMedGoogle Scholar
  82. 82.
    Anderson HR. Increase in hospital admissions for childhood asthma: trends in referral, severity, and readmissions from 1970 to 1985 in a health region of the United Kingdom. Thorax 1989; 44: 614–9PubMedGoogle Scholar
  83. 83.
    Evans R III, Mullally DI, Wilson RW, et al. National trends in the morbidity and mortality of asthma in the US. Prevalence, hospitalization and death from asthma over two decades: 1965–1984. Chest 1987; 91: 65S–74SPubMedGoogle Scholar
  84. 84.
    Dawson KP. The severity of asthma in children admitted to hospital: a 20 year review. NZ Med J 1987; 100: 520–1Google Scholar
  85. 85.
    Rea H, Sears M, Mitchell E, et al. Is asthma becoming more severe? Thorax 1987; 42: 736Google Scholar
  86. 86.
    US Department of Health and Human Services, National Institutes of Health. International consensus report on diagnosis and management of asthma. NIH Publication no. 92-3091, June 1992Google Scholar
  87. 87.
    Van As A. Beta-adrenergic stimulant bronchodilators. In: Stein M, editor. New directions in asthma. Lund: American College of Chest Physicians, printed by Rahms 1974; 415–32Google Scholar
  88. 88.
    Vanderwalker ML, Kray KT, Weber RW, et al. Addition to terbutaline to optimal theophylline therapy. Double blind crossover study in asthmatic patients. Chest 1986; 90: 198–203Google Scholar
  89. 89.
    Smith JA, Weber RW, Nelson HS. Theophylline and aerosolized terbutaline in the treatment of bronchial asthma. Double-blind comparison of optimal doses. Chest 1980; 78: 816–8PubMedGoogle Scholar
  90. 90.
    Bennati D, Piacentini GL, Peroni DG, et al. Changes in bronchial reactivity in asthmatic children after treatment with beclomethasone alone or in association with salbutamol. J Asthma 1989; 26: 359–64PubMedGoogle Scholar
  91. 91.
    Horn CR, Clark TJH, Cochrane GM. Inhaled therapy reduces morning dips in asthma. Lancet 1984; 1: 1143–5PubMedGoogle Scholar
  92. 92.
    Haahtela T, Alanko K, Muittari A, et al. The superiority of combination beclomethasone and salbutamol over standard dosing of salbutamol in the treatment of chronic asthma. Ann Allergy 1989; 62: 63–6PubMedGoogle Scholar
  93. 93.
    Prior JG, Nowell RV, Cochrane GM. High-dose inhaled terbutaline in the management of chronic severe asthma: comparison of wet nebulisation and tube-spacer delivery. Thorax 1992; 37: 300–3Google Scholar
  94. 94.
    O’Driscoll BRC, Ruffles SP, Ayres JG, et al. Long term treatment of severe asthma with subcutaneous terbutaline. Br J Dis Chest 1988; 82: 360–7PubMedGoogle Scholar
  95. 95.
    Cluzel M, Bousquet J, Daures JP, et al. Ambulatory long-term subcutaneous salbutamol infusion in chronic severe asthma. J Allergy Clin Immunol 1990; 85: 599–605PubMedGoogle Scholar
  96. 96.
    Horn CR, Clark TJH, Cochrane GM. Can the morbidity of asthma be reduced by high dose inhaled therapy? A prospective study. Respir Med 1990; 84: 61–6PubMedGoogle Scholar
  97. 97.
    Van Schayck CP, Dompeling E, Van Herwaarden CLA, et al. Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study. BMJ 1991; 303: 1426–31PubMedGoogle Scholar
  98. 98.
    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: 1420–5PubMedGoogle Scholar
  99. 99.
    Haahtela T, Ahokas I, Ahonen A, et al. Inhaled bronchodilators in asthma: low or high dose? Ann Allergy 1991; 66: 175–80PubMedGoogle Scholar
  100. 100.
    Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391–6PubMedGoogle Scholar
  101. 101.
    Taylor DR, Sears MR, Herbison GP, et al. Regular inhaled beta-agonist: effects on lung function and exacerbations. Thorax 1993; 48: 134–8PubMedGoogle Scholar
  102. 102.
    Nelson HS, Szefler SJ, Martin RJ. Regular inhaled beta-adrenergic agonists in the treatment of bronchial asthma: beneficial or detrimental? Am Rev Respir Dis 1991; 144: 249–50PubMedGoogle Scholar
  103. 103.
    Lofdahl C-G, Svedmyr N. Beta-agonists — friends or foes? Eur Respir J 1991; 4: 1161–5PubMedGoogle Scholar
  104. 104.
    Cochrane GM. Regular versus intermittent inhaled bronchodilator therapy in the treatment of asthma. Res Clin Forums 1984; 6: 55–9Google Scholar
  105. 105.
    Shepherd GL, Hetzel MR, Clark TJH. Regular versus symptomatic aerosol bronchodilator treatment of asthma. Br J Dis Chest 1981; 75: 215–7PubMedGoogle Scholar
  106. 106.
    Zellweger JP, Clottu R, Crittin A, et al. Etude comparee des effets de l’inhalation de salbutamol regulierement ou a la demande dans le traitement de l’asthme. Schweiz Med Wochenschr 1986; 116: 1260–3PubMedGoogle Scholar
  107. 107.
    Wahedna I, Wong CS, Wisniewski AFZ, et al. Asthma control during and after cessation of regular beta2 agonist treatment. Am Rev Respir Dis 1993; 148: 707–12PubMedGoogle Scholar
  108. 108.
    Trembath PW, Greenacre JK, Anderson M, et al. Comparison of four weeks’ treatment with fenoterol and terbutaline aerosols in adult asthmatics. J Allergy Clin Immunol 1979; 63: 395–400PubMedGoogle Scholar
  109. 109.
    Patakas D, Maniki E, Tsara V, et al. Intermittent and continuous salbutamol rotacaps inhalation in asthmatic patients. Respiration 1988; 54: 174–8PubMedGoogle Scholar
  110. 110.
    Van Arsdel Jr PP, Schaffrin RM, Rosenblatt J, et al. Evaluation of oral fenoterol in chronic asthmatic patients. Chest 1978; 73 Suppl.: 997–8Google Scholar
  111. 111.
    Van Schayck CP, Van Herwaarden CLA. Do bronchodilators adversely affect the prognosis of bronchial hyperresponsiveness? Thorax 1993; 48: 470–3PubMedGoogle Scholar
  112. 112.
    Taylor DR, Sears MR. Bronchodilators and bronchial hyperresponsiveness. Thorax 1994; 49: 190PubMedGoogle Scholar
  113. 113.
    Vathenen AS, Higgins BG, Knox AJ, et al. Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988; 1: 554–8PubMedGoogle Scholar
  114. 114.
    Van Schayck CP, Graafsma SJ, Visch MB, et al. Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol. J Allergy Clin Immunol 1990; 86: 793–800PubMedGoogle Scholar
  115. 115.
    Kraan J, Koeter GH, v d Mark ThW, et al. Changes in bronchia hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J Allergy Clin Immunol 1985; 76: 628–36PubMedGoogle Scholar
  116. 116.
    Raes M, Mulder P, Kerrebijn KF. Long-term effect of ipratropium bromide and fenoterol on the bronchial hyperresponsiveness to histamine in children with asthma. J Allergy Clin Immunol 1989; 84: 874–9PubMedGoogle Scholar
  117. 117.
    Town I, O’Donnell TV, Purdie G. Bronchial responsiveness during regular fenoterol therapy: a 4 months prospective study. NZ Med J 1991; 104: 3–5Google Scholar
  118. 118.
    Kerrebijn KF, van Essen-Zandvliet EEM, Neijens HJ. Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma. J Allergy Clin Immunol 1987; 79: 653–9PubMedGoogle Scholar
  119. 119.
    Haahtela T, Jarvinen M, Kava T, et al. Comparison of β2-ago-nist, terbutaline with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991; 325: 388–92PubMedGoogle Scholar
  120. 120.
    Kerstjens HAM, Brand PLP, Hughes MD, et al. A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. N Engl J Med 1992; 327: 1413–9PubMedGoogle Scholar
  121. 121.
    Peel ET, Gibson GJ. Effects of long-term inhaled salbutamol therapy on the provocation of asthma by histamine. Am Rev Respir Dis 1980; 121: 973–8PubMedGoogle Scholar
  122. 122.
    Mitchell EA. Is current treatment increasing asthma mortality and morbidity? Thorax 1989; 44: 81–4PubMedGoogle Scholar
  123. 123.
    Van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, et al. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. Am Rev Respir Dis 1992; 146: 547–54PubMedGoogle Scholar
  124. 124.
    Hargreave FE, Ryan G, Thomson NC, et al. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clin Immunol 1981; 68: 347–55PubMedGoogle Scholar
  125. 125.
    Cutrera R, Filtchev SI, Merolla R, et al. Analysis of expiratory pattern for monitoring bronchial obstruction in school-age children. Pediatr Pulmonol 1991; 10: 6–10PubMedGoogle Scholar
  126. 126.
    Conolly ME, Davies DS, Dollery CT, et al. Resistance to β-ad-renoeptor stimulants (a possible explanation for the rise in asthma deaths). Br J Pharmacol 1971; 43: 389–402PubMedGoogle Scholar
  127. 127.
    Conolly ME, Greenacre JK. The lymphocyte β-adrenoceptor in normal subjects and patients with bronchial asthma. J Clin Invest 1976; 58: 1307–16PubMedGoogle Scholar
  128. 128.
    Galant SP, Duriseti L, Underwood S, et al. Decreased betaadrenergic receptors on polymorphonuclear leucocytes after adrenergic therapy. N Engl J Med 1978; 299: 933–6PubMedGoogle Scholar
  129. 129.
    Harvey JE, Baldwin CJ, Wood PJ, et al. Airway and metabolic responsiveness to intravenous salbutamol in asthma: effect of regular inhaled salbutamol. Clin Sci 1981; 60: 579–85PubMedGoogle Scholar
  130. 130.
    Lipworth BJ, Clark RA, Dhillon DP, et al. Comparison of the effects of prolonged treatment with low and high doses of inhaled terbutaline on beta-adrenoceptor responsiveness in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1990; 142: 338–42PubMedGoogle Scholar
  131. 131.
    Harvey JE, Tattersfield AE. Airway response to salbutamol: effect of regular salbutamol inhalations in normal, atopic and asthmatic subjects. Thorax 1982; 37: 280–7PubMedGoogle Scholar
  132. 132.
    Tashkin DP, Conolly ME, Deutsch RI, et al. Subsensitization of beta-adrenoceptors in airways and lymphocytes of healthy and asthmatic subjects. Am Rev Respir Dis 1982; 125: 185–93PubMedGoogle Scholar
  133. 133.
    Nelson HS, Raine D, Doner CH, et al. Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Am Rev Respir Dis 1988; 16: 871–8Google Scholar
  134. 134.
    Jenne JW, Chick TW, Strickland RD, et al. Subsensitivity of beta responses during therapy with a long-acting beta-2 preparation. J Allergy Clin Immunol 1977; 49: 383–90Google Scholar
  135. 135.
    Weber RW, Smith JA, Nelson HS. Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration. J Allergy Clin Immunol 1982; 70: 417–22PubMedGoogle Scholar
  136. 136.
    Larsson K, Martinsson A, Hjemdahl P. Influence of β-adrenergic receptor function during terbutaline treatment on allergen sensitivity and bronchodilator response to terbutaline in asthmatic subjects. Chest 1992; 101: 953–60PubMedGoogle Scholar
  137. 137.
    Svedmyr N, Larsson S, Thiringer G. Studies of resistance to long-acting adrenergic beta-stimulators in asthmatic patients. BMJ 1974; 2: 668–9PubMedGoogle Scholar
  138. 138.
    Larsson S, Svedmyr N, Thiringer G. Lack of bronchial beta adrenoceptor resistance in asthmatics during long term treatment with terbutaline. J Allergy Clin Immunol 1977; 59: 93–100PubMedGoogle Scholar
  139. 139.
    Repsher LH, Anderson JA, Bush RK, et al. Assessment of tachyphylaxis following prolonged therapy of asthma with inhaled albuterol aerosol. Chest 1984; 85: 34–8PubMedGoogle Scholar
  140. 140.
    Hauck RW, Böhm M, Gengenbach S, et al. ß2-adrenoceptors in human and peripheral mononuclear lymphocytes of untreated and terbutaline treated patients. Chest 1990; 98: 376–81PubMedGoogle Scholar
  141. 141.
    Gibson GJ, Greenacre JK, Konig P, et al. Use of exercise challenge to investigate possible tolerance to beta-adrenoceptor stimulation in asthma. Br J Dis Chest 1978; 72: 199–206PubMedGoogle Scholar
  142. 142.
    O’Connor BJ, Aikman SL, Barnes PJ. Tolerance to the non-bronchodilator effects of inhaled ß2-agonists in asthma. N Engl J Med 1992; 327: 1204–8PubMedGoogle Scholar
  143. 143.
    Bel EH, Zwinderman AH, Timmers MC, et al. The protective effect of a beta2 agonist against excessive airway narrowing in the response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease. Thorax 1991; 46: 9–14PubMedGoogle Scholar
  144. 144.
    Wong CS, Wahedna I, Pavord ID, et al. The effect of regular terbutaline and budesonide on bronchial reactivity to allergen challenge. Am J Respir Crit Care Med. In pressGoogle Scholar
  145. 145.
    Cockcroft DW, McParland CP, Britto SA, et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993; 342: 833–7PubMedGoogle Scholar
  146. 146.
    Swystun V, Bhagat R, O’Byrne PM, et al. Regular inhaled salbutamol increases allergen-induced late asthmatic responsiveness. J Allergy Clin Immunol 1994; 93: 260Google Scholar
  147. 147.
    Morley J, Sanjar S, Newth C. Viewpoint: untoward effects of beta-adrenoceptor agonists in asthma. Eur Respir J 1990; 3: 226–33Google Scholar
  148. 148.
    Lai CKW, Twentyman OP, Holgate ST. The effect of an increase in inhaled allergen dose after rimiterol hydrobromide on the occurrence and magnitude of the late asthmatic response and the associated change in nonspecific bronchial responsiveness. Am Rev Respir Dis 1989; 140: 917–23PubMedGoogle Scholar
  149. 149.
    O’Hollaren MT, Yunginger JW, Offord KP, et al. Exposure to an aeroallergen as a possible precipitating factor in respiratory arrest in young patients with asthma. N Engl J Med 1991; 324: 359–63PubMedGoogle Scholar
  150. 150.
    Svedmyr N. Action of corticosteroids on beta-adrenergic receptors: clinicals aspects. Am Rev Respir Dis 1990; 141: S31–8PubMedGoogle Scholar
  151. 151.
    Ihara I, Nakanishi S. Selective inhibition of expression of substance P receptor mRNA in pancreatic acinar AR42J cells by glucocorticoids. J Biol Chem 1990; 26: 22441–5Google Scholar
  152. 152.
    Schule R, Rangarajan P, Kliewer S, et al. Functional antagonism between oncoprotein c-JUN and the glucocorticoid receptor. Cell 1990; 62: 1217–26PubMedGoogle Scholar
  153. 153.
    Peters MJ, Adcock IM, Brown CR, et al. β-agonist inhibition of steroid-receptor DNA binding activity in human lung [abstract]. Am Rev Respir Dis 1993; 147: A772Google Scholar
  154. 154.
    Waalkens HJ, Gerritsen J, Koeter GH, et al. Budesonide and terbutaline or terbutaline alone in children with mild asthma: effects on bronchial hyperresponsiveness and diurnal variation in peak flow. Thorax 1991; 46: 499–503PubMedGoogle Scholar
  155. 155.
    Selroos GO, Nyholm JE. Infuence of a budesonide-terbutaline combination on bronchial hyper-reactivity. Clin Exp Allergy 1990; 20 Suppl. 1: 76Google Scholar
  156. 156.
    Cochrane GM, Horn CR. The management of asthma in the community: problems of compliance with treatment. Q J Med 1991; 294: 797–8Google Scholar
  157. 157.
    Arvidsson P, Larsson S, Lofdahl C-G, et al. Inhaled formoterol during one year in asthma: a comparison with salbutamol. Eur Respir J 1991; 4: 1168–73PubMedGoogle Scholar
  158. 158.
    Messina MS, O’Riordan TG, Smaldone GC. Changes in mucociliary clearance during acute exacerbations of asthma. Am Rev Respir Dis 1991; 143: 993–7PubMedGoogle Scholar
  159. 159.
    Bateman JRM, Pavia D, Shehan NF, et al. Impaired mucociliary clearance in patients with mild stable asthma. Thorax 1984; 38: 463–7Google Scholar
  160. 160.
    Pavia D, Bateman JRM, Sheahan NF, et al. Tracheobronchial mucociliary clearance in asthma: impairment during remission. Thorax 1985; 40: 171–5PubMedGoogle Scholar
  161. 161.
    Dunnill MS. Pathological changes in the airways in asthma. J Clin Pathol 1960; 13: 27–33PubMedGoogle Scholar
  162. 162.
    Iravani J, Melville GN. Mucociliary function of the respiratory tract as influenced by drugs. Respiration 1974; 31: 350–7PubMedGoogle Scholar
  163. 163.
    Foster WM, Bergofsky E, Bohning DE, et al. Effect of adrenergic agents and their mode of action on mucociliary clearance. J Appl Physiol 1976; 41: 146–52PubMedGoogle Scholar
  164. 164.
    Kean WF, Lock CJL, Howard-Lock HE. Chirality in antirheumatic drugs. Lancet 1991; 338: 1565–8PubMedGoogle Scholar
  165. 165.
    Sanjar S, Kristersson A, Mazzoni L, et al. Increased airway reactivity in the guinea-pig follows exposure to intravenous isoprenaline. J Physiol 1909; 425: 43–54Google Scholar
  166. 166.
    Galland BC, Blackman JG. Enhancement of airway reactivity to histamine by isoprenaline and related β-adrenoceptor agonists in the guinea pig. Br J Pharmacol 1993; 108: 1016–23PubMedGoogle Scholar
  167. 167.
    Hartley D, Middlemiss D. Absolute configuration of the optical isomers of salbutamol. J Med Chem 1971; 14: 895–6Google Scholar
  168. 168.
    Brittain RT, Farmer JB, Marshall RJ. Some observations on the β-adrenoceptor agonist properties of the isomers of salbutamol. Br J Pharmacol 1973; 48: 144–7PubMedGoogle Scholar
  169. 169.
    Hawkins CJ, Klease GT. Relative potency of (−) and (±) salbutamol on guinea pig trachéal tissue. J Med Chem 1973; 16: 856–7PubMedGoogle Scholar
  170. 170.
    Tan YK, Soldin SJ. Analysis of salbutamol enantiomers in human urine by chiral high performance liquid chromatography and preliminary studies related to the stereoselective disposition kinetics in man. J Chromatogr 1987; 422: 187–96PubMedGoogle Scholar
  171. 171.
    Keighley JF. Iatrogenic asthma associated with adrenergic aerosols. Ann Intern Med 1966; 65: 985–95PubMedGoogle Scholar
  172. 172.
    Eisenstadt WS, Nicholas SS. The adverse effect of adrenergic aerosols in bronchial asthma. Ann Allergy 1969; 27: 283–8PubMedGoogle Scholar
  173. 173.
    Reisman RE. Asthma induced by adrenergic aerosols. J Allergy 1970; 46: 162–77PubMedGoogle Scholar
  174. 174.
    Trautlein J, Allegra J, Field J, et al. Paradoxic bronchospasm after inhalation of isoproterenol. Chest 1976; 70: 711–4PubMedGoogle Scholar
  175. 175.
    Hansel TT, Schwarz F, Villiger B, et al. Anomolous bronchospasm following inhalation of (+) isoprenaline by asthmatics. New Drugs Allergy Asthma 1993; 281-8Google Scholar
  176. 176.
    Suissa S, Ernst P, Spitzer WO. Asthma deaths in New Zealand. BMJ 1992; 305: 889PubMedGoogle Scholar
  177. 177.
    Garrett JE, Kolbe J, Richards GN, et al. Asthma in New Zealand: trends in drug treatment, hospital admission and mortality rates, 1981–1991 [abstract]. Am Rev Respir Dis 1993; 147: A798Google Scholar
  178. 178.
    Benson RL, Perlman F. Clinical effects of epinephrine by inhalation. J Allergy 1948; 19: 129–40PubMedGoogle Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Malcolm R. Sears
    • 1
  • D. Robin Taylor
    • 2
  1. 1.Firestone Regional Chest and Allergy UnitSt Joseph’s Hospital and McMaster UniversityHamiltonCanada
  2. 2.University of Otago Medical SchoolDunedinNew Zealand

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