Abstract
The use of a regular long-acting β2-adrenoceptor agonists (β2-agonists; LABA) is now established in asthma guidelines as the preferred option for second-line controller therapy in addition to inhaled corticosteroids. This has been driven by data showing beneficial effects of LABAs on exacerbation rates, in turn suggesting a putative corticosteroid-sparing effect. As LABAs are devoid of any clinically meaningful anti-inflammatory activity in vivo, their effects on exacerbations are presumably due to a diurnal stabilising effect on airway smooth muscle.
LABAs have marked effects on symptoms and lung function, and this may make it difficult to assess anti-inflammatory control with inhaled corticosteroids when used in a combination inhaler such as fluticasone propionate/salmeterol or budesonide/formoterol. The use of fixed-dose combination inhalers is in many respects counter-intuitive to conventional teaching regarding flexible dosage titration with inhaled corticosteroids. It would therefore seem prudent first to gain optimal control of inflammation with inhaled corticosteroids before considering adding a LABA. Increasing the dosage of inhaled corticosteroids will have a relatively greater effect on exacerbations than on symptoms and lung function, whereas the converse applies when adding a LABA. Another option is to add a leukotriene receptor antagonist, which confers additional anti-inflammatory activity and is as effective on exacerbations as adding a LABA.
Despite in vitro and ex vivo data showing a ligand-independent effect of LABAs on glucocorticoid receptor activation, clinical data do not indicate any relevant synergy between LABAs and inhaled corticosteroids when used together in the same inhaler. In particular, there is no evidence of potentiation by LABAs of the in vivo anti-inflammatory activity of inhaled corticosteroids that would suggest any genuine corticosteroid-sparing activity. Nonetheless, the data support the additive effects of inhaled corticosteroids and LABAs when used together due to their separate effects on inflammation and smooth muscle, respectively.
Tolerance with LABAs is a predictable pharmacological phenomenon that occurs despite concomitant therapy with inhaled corticosteroids. Moreover, cross-tolerance also develops to short-acting β2-agonists used for protection against bronchoconstrictor stimuli as a result of LABA-induced down-regulation, desensitisation and prolonged occupancy of β2-adrenoceptors. The exact role of β2-adrenoceptor polymorphism in determining tolerance with LABAs requires further prospective clinical studies evaluating long-term effects on outcomes such as exacerbations in patients with relevant genotypes and haplotypes.
The next decade will provide challenging issues for clinicians with respect to defining further the role of LABAs as add-on controller therapy, particularly in evaluating the long-term effects of combination inhalers on inflammatory outcomes and airway remodelling.
Similar content being viewed by others
References
British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 2003; 58 Suppl. 1: 1–83
Suissa S, Ernst P, Benayoun S, et al. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000; 343: 332–6
Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003; 361: 1071–6
Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999; 159: 941–55
Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391–6
Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992; 326: 501–6
Vathenen AS, Know AJ, Higgins BG, et al. Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988; I: 554–7
Cockroft DW, McParland CP, Britto SA, et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993; 342: 833–7
Haahtela T, Jarvinen M, Kava T, et al. Comparison of a β2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991; 325: 388–92
Chapman KR, Kesten S, Szalai JP. Regular vs as-needed inhaled salbutamol in asthma control. Lancet 1994; 343: 1379–82
Dennis SM, Sharp SJ, Vickers MR, et al. Regular inhaled salbutamol and asthma control: the TRUST randomised trial: Therapy Working Group of the National Asthma Task Force and the MRC General Practice Research Framework. Lancet 2000; 355: 1675–9
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: 1420–5
Lundback B, Rawlinson DW, Palmer JB. Twelve month comparison of salmeterol and salbutamol as dry powder formulations in asthmatic patients: European Study Group. Thorax 1993; 48: 148–53
Greening AP, Ind PW, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid: Allen and Hanburys Limited UK Study Group. Lancet 1994; 344: 219–24
Woolcock A, Lundback B, Ringdal N, et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153: 1481–8
Van Noord JA, Schreurs AJ, Mol SJ, et al. Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax 1999; 54: 207–12
Condemi JJ, Goldstein S, Kalberg C, et al. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma: Salmeterol Study Group. Ann Allergy Asthma Immunol 1999; 82: 383–9
Lipworth BJ, Jackson CM. Second-line controller therapy for persistent asthma uncontrolled on inhaled corticosteroids: the 3 step dilemma. Drugs 2002; 62(16): 2315–32
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: 1006–11
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: 275–82
Li X, Ward C, Thien F, et al. An anti-inflammatory 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: 1493–9
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: 79–86
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: 1047–52
Wallin A, Sue-Chu M, Bjermer L, et al. Effect of inhaled fluticasone with and without salmeterol on airway inflammation in asthma. J Allergy Clin Immunol 2003; 112: 72–8
Calhoun WJ, Hinton KL, Kratzenberg JJ. The effect of salmeterol on markers of airway inflammation following segmental allergen challenge. Am J Respir Crit Care Med 2001; 163: 881–6
Kips JC, O’Connor BJ, Inman MD, et al. A long-term study of the anti-inflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. Am J Respir Crit Care Med 2000; 161: 996–1001
Vanacker NJ, Palmans E, Pauwels RA, et al. Effect of combining salmeterol and fluticasone on the progression of airway remodelling. Am J Respir Crit Care Med 2002; 166: 1128–34
Spoelstra FM, Postma DS, Hovenga H, et al. Additive anti-inflammatory effect of formoterol and budesonide on human lung. Thorax 2002; 57: 237–41
Greiff L, Wollmer P, Andersson M, et al. Effects of formoterol on histamine induced plasma exudation in induced sputum from normal subjects. Thorax 1998; 53: 1010–3
Green RH, Brightling CE, McKenna S, et al. A placebo controlled comparison of formoterol, montelukast or higher dose of inhaled corticosteroids in subjects with symptomatic asthma despite treatment with low dose inhaled corticosteroids [abstract]. Thorax 2002; 57Suppl. 3: 11
Currie GP, Bates CE, Lee DK, et al. Effects of fluticasone plus salmeterol versus twice the dose of fluticasone in asthmatic patients. Eur J Clin Pharmacol 2003; 59: 11–5
Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360: 1715–21
Leuppi JD, Salome CM, Jenkins CR, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001; 163: 406–12
McIvor RA, Pizzichini E, Turner MO, et al. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998; 158: 924–30
Fowler SJ, Currie GP, Lipworth BJ. Step-down therapy with low-dose fluticasone-salmeterol combination or medium-dose hydrofluoroalkane 134a-beclomethasone alone. J Allergy Clin Immunol 2002; 109: 929–35
Currie GP, Jackson CM, Ogston SA, et al. Airway stabilising effects on long acting beta-2-agonists as add on therapy to inhaled corticosteroids. Q J Med 2003; 96: 001–6
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: 1392–7
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: 1405–11
Tattersfield AE, Postma DS, Barnes PJ, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations: The FACET International Study Group. Am J Respir Crit Care Med 1999; 160: 594–9
Lemanske Jr RF, Sorkness CA, Mauger EA, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001; 285(20): 2594–603
Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001; 285: 2583–93
Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma. BMJ 2000; 320: 1368–73
Rickard KA. SMART Safety Study. Research Triangle Park (NC), USA: GlaxoSmithKline, 2003 (Data on file). Also online. Available from URL: http://www.fda.gov/medwatch/SAFETY/2003/serevent_deardoc.pdf
Castle W, Fuller R, Hall J, et al. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993; 306: 1034–7
Mann RD, Kubota K, Pearce G, et al. Salmeterol: a study by prescription-event monitoring in a UK cohort of 15,407 patients. J Clin Epidemiol 1996; 49(2): 247–50
Lipworth BJ, McDevitt DG, Struthers AD. Prior treatment with diuretic augments the hypokalaemic and electrocardiographic effects of inhaled albuterol. Am J Med 1989; 86: 653–7
Linden A, Bergendal A, Ullman A, et al. Salmeterol, formoterol, and salbutamol in the isolated guinea pig trachea: differences in maximum relaxant effect and potency but not in functional antagonism. Thorax 1993; 48: 547–53
Molimard M, Naline E, Zhang Y, et al. Long- and short-acting beta2 adrenoceptor agonists: interactions in human contracted bronchi. Eur Respir J 1998; 11: 583–8
Kallstrom BL, Sjoberg J, Waldeck B. The interaction between salmeterol and beta 2-adrenoceptor agonists with higher efficacy on guinea-pig trachea and human bronchus in vitro. Br J Pharmacol 1994; 113: 687–92
Guhan AR, Cooper S, Oborne J, et al. Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects. Thorax 2000; 55: 650–6
Tranfa CM, Pelaia G, Grembiale RD, et al. Short-term cardiovascular effects of salmeterol. Chest 1998; 113: 1272–6
Chervinsky P, Goldberg P, Galant S, et al. Long-term cardiovascular safety of salmeterol powder pharmacotherapy in adolescent and adult patients with chronic persistent asthma: a randomized clinical trial. Chest 1999; 115: 642–8
Lipworth BJ. Revisiting interactions between hypoxaemia and beta2 agonists in asthma. Thorax 2001; 56: 506–7
Cazzola M, Imperatore F, Salzillo A, et al. Cardiac effects of formoterol and salmeterol in patients suffering from COPD with pre-exisiting cardiac arrhythmias and hypoxemia. Chest 1998; 114: 411–5
Ferguson GT, Funck-Brentano C, Fischer T, et al. Cardiovascular safety of salmeterol in COPD. Chest 2003; 123: 1817–24
Aziz I, McFarlane LC, Lipworth BJ. Concomitant inhaled corticosteroid resensitises cardiac β2-adrenoceptors in the presence of long-acting β2-agonist therapy. Eur J Clin Pharmacol 1998; 54: 377–81
Tan KS, McFarlane LC, Lipworth BJ. Concomitant administration of low dose prednisolone protects against in vivo β2-adrenoceptor subsensitivity induced by regular formoterol. Chest 1998; 113: 34–41
Nishikawa M, Mak JC, Barnes PJ. Effect of short- and long-acting beta 2-adrenoceptor agonists on pulmonary beta 2-adrenoceptor expression in human lung. Eur J Pharmacol 1996; 318: 123–9
Hanania NA, Sharafkhaneh A, Barber R, et al. Beta-agonist intrinsic efficacy: measurement and clinical significance. Am J Respir Crit Care Med 2002; 165: 1353–8
Zetterstrom O, Buhl R, Mellem H, et al. Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone. Eur Respir J 2001; 18: 262–8
Mahler RA, Wire P, Hortsman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via a Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166: 1084–91
Newnham DM, McDevitt DG, Lipworth BJ. Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma. Am J Med 1994; 97: 29–37
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: 497–504
O’Connor BJ, Aikman SL, Barnes PJ. Subsensitivity to the non-bronchodilator effects of inhaled beta 2-agonists in asthma. N Engl J Med 1992; 327: 1204–8
Cheung D, Timmers MC, Zwinderman AH, et al. Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992; 327: 1198–203
Booth H, Bish R, Walters J, et al. Salmeterol tachyphylaxis in steroid treated asthmatic subjects. Thorax 1996; 51: 1100–4
Verberne AA, Hop WC, Creyghton FB, et al. Airway responsiveness after a single dose of salmeterol and during four months of treatment in children with asthma. J Allergy Clin Immunol 1996; 97: 938–46
Meijer GG, Postma DS, Mulder PG, et al. Long-term circadian effects of salmeterol in asthmatic children treated with inhaled corticosteroids. Am J Respir Crit Care Med 1995; 152: 1887–92
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: 953–6
Bhagat R, Kalra S, Swystun VA, et al. Rapid onset of tolerance to the bronchoprotective effect of salmeterol. Chest 1995; 108: 1235–9
Drotar DE, Davis EE, Cockcroft DW. Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment. Ann Allergy Asthma Immunol 1998; 80: 31–4
Ramage L, Lipworth BJ, Ingram CG, et al. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994; 88: 363–8
Nelson JA, Strauss L, Skowronski M, et al. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med 1998; 339: 141–6
Giannini D, Carletti A, Dente FL, et al. Tolerance to the protective effect of salmeterol on allergen challenge. Chest 1996; 110: 1452–7
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: 547–53
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; 132: 97–104
Lipworth B, Tan S, Devlin M, et al. Effects of treatment with formoterol on bronchoprotection against methacholine. Am J Med 1998; 104: 431–8
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: 580–4
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: 655–9
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: 1021–6
Sims EJ, Jackson CM, Lipworth BJ. Add on therapy with montelukast or formoterol in patients with the glycine-16 β2-receptor genotype. Br J Clin Pharmacol 2003; 56: 104–11
Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995; 346: 201–6
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: 314–21
Nelson HS, Berkowitz RB, Tinkelman DA, et al. Lack of subsensitivity to albuterol after treatment with salmeterol in patients with asthma. Am J Respir Crit Care Med 1999; 159: 1556–61
Lipworth BJ, Jackson C. Lack of subsensitivity to albuterol after treatment with salmeterol in patients with asthma. Am J Respir Crit Care Med 1999; 160: 2125–6
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: 1441–6
Korosec M, Novak RD, Myers E, et al. Salmeterol does not compromise the bronchodilator response to albuterol during acute episodes of asthma. Am J Med 1999; 107: 209–13
Peters JI, Shelledy DC, Jones Jr AP, et al. A randomized, placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthma. Chest 2000; 118: 313–20
Lipworth BJ. Salmeterol and conventional asthma therapy. Chest 2001; 119: 986–7
Yates DH, Kharitonov SA, Barnes PJ. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist. Am J Respir Crit Care Med 1996; 154: 1603–7
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: 88–92
Aziz I, Lipworth BJ. In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol. J Allergy Clin Immunol 1999; 103: 816–22
Van der Woude HJ, Winter TH, Aalbers R. Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta2 agonists. Thorax 2001; 56: 529–35
Lee DKC, Jackson CM, Currie GP, et al. Comparison of combination inhalers versus inhaled corticosteroid alone in moderate persistent asthma. Br J Clin Pharmacol 2003 Nov; 56(5): 494–500
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 Ther 2003; 16: 153–61
Storms WW, Bird S, Firriolo KM, et al. The effect of rescue short-acting beta-agonist bronchodilatation in patients on montelukast or salmeterol [abstract]. J Allergy Clin Immunol 2001; 107: S316
Tan KS, Grove A, McLean A, et al. Systemic corticosteroid rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients. Am J Respir Crit Care Med 1997; 156: 28–35
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: 623–8
Lipworth BJ, Aziz I. Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration. Chest 2000; 117: 156–62
Green SA, Turki J, Bejarano P, et al. Influence of beta 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995; 13: 25–33
Green SA, Turki J, Innis M, et al. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–9
Liggett SB. The pharmacogenetics of beta2-adrenergic receptors: relevance to asthma. J Allergy Clin Immunol 2000; 105(2 Pt 2): S487–92
Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000; 97(19): 10483–8
Turki J, Green SA, Newman KB, et al. Human lung cell beta 2-adrenergic receptors desensitize in response to in vivo administered beta-agonist. Am J Physiol 1995; 269: L709–14
Lima JJ, Thomason DB, Mohamed MH, et al. Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 1999; 65: 519–25
Martinez FD, Graves PE, Baldini M, et al. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 1997; 100: 3184–8
Lee DKC, Bates CE, Lipworth BJ. Acute systematic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous β2-adrenoceptor haplotypes at positions 16 and 27. Br J Clin Pharmacol 2004 Jan; 57(1): 100–4
Tan S, Hall IP, Dewar J, et al. Association between beta 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350: 995–9
Lipworth BJ, Dempsey OJ, Aziz I. Functional antagonism with formoterol and salmeterol in asthmatic patients expressing the homozygous glycine-16 beta(2)-adrenoceptor polymorphism. Chest 2000; 118: 321–8
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: 253–9
Lipworth BJ, Hall IP, Tan S, et al. Effects of genetic polymorphism on ex vivo and in vivo function of beta2-adrenoceptors in asthmatic patients. Chest 1999; 115: 324–8
Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000; 162: 75–80
Taylor DR, Drazen JM, Herbison GP, et al. Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism. Thorax 2000; 55: 762–7
Dishy V, Sofowora GG, Xie HG, et al. The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med 2001; 345(14): 1030–5
Lee DKC, Currie GP, Hall IP, et al. The arginine-16 beta-2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol 2004 Jan; 57(1): 68–75
Ellul-Micallef R, Fenech FF. Effect of intravenous prednisolone in asthmatics with diminished adrenergic responsiveness. Lancet 1975; II: 1269–71
Holgate ST, Baldwin CJ, Tattersfield AE. Beta-adrenergic agonist resistance in normal human airways. Lancet 1977; II: 375–7
Brodde OE, Brinkmann M, Schemuth R, et al. Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors: accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen. J Clin Invest 1985; 76: 1096–101
Brodde OE, Howe U, Egerszegi S, et al. Effect of prednisolone and ketotifen on beta 2-adrenoceptors in asthmatic patients receiving beta 2-bronchodilators. Eur J Clin Pharmacol 1988; 34: 145–50
Hui KK, Conolly ME, Tashkin DP. Reversal of human lymphocyte beta-adrenoceptor desensitization by glucocorticoids. Clin Pharmacol Ther 1982; 32: 566–71
Collins S, Caron MG, Lefkowitz RJ. Beta-adrenergic receptors in hamster smooth muscle cells are transcriptionally regulated by glucocorticoids. J Biol Chem 1988; 263: 9067–70
Davies AO, Lefkowitz RJ. Agonist-promoted high affinity state of the beta-adrenergic receptor in human neutrophils: modulation by corticosteroids J Clin Endocrinol Metab 1981; 53: 703–8
Davies AO, Lefkowitz RJ. In vitro desensitization of beta adrenergic receptors in human neutrophils: attenuation by corticosteroids. J Clin Invest 1983; 71: 565–71
Hadcock JR, Williams DL, Malbon CC. Physiological regulation at the level of mRNA: analysis of steady-state levels of specific mRNAs by DNA-excess solution hybridisation. Am J Physiol 1989; 256: c457–65
Eickelberg O, Roth M, Lorx R, et al. Ligand-independent activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells. J Biol Chem 1999; 274: 1005–10
Roth M, Johnson PR, Rudiger JJ, et al. Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002; 360: 1293–9
Usmani OS, Maneechotesuwan K, Adcock IM, et al. Glucocorticoid receptor activation in induced sputum following inhaled long-acting beta 2 agonist and glucocorticoid treatment [abstract]. Thorax 2002; 57Suppl. 3: S27
Yanagawao H, Adcock IM, Hewitt AL, et al. Effects of long acting beta agonists and steroids on cytokine expression [abstract]. Thorax 2002; 57Suppl. 3: S18
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: 1049–58
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 2002; 105: 1108–16
Shapiro G, Lumry W, Wolfe J, et al. Combined salmeterol 50 microg and fluticasone propionate 250 microg in the Diskus device for the treatment of asthma. Am J Respir Crit Care Med 2000; 161(2 Pt 1): 527–34
Aubier M, Pieters WR, Schlosser NJ, et al. Salmeterol/fluticasone propionate (50/500 micrograms) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Respir Med 1999; 93: 876–84
Pearlman DS, Stricker W, Weinstein S, et al. Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma. Ann Allergy Asthma Immunol 1999; 82: 257–65
Nelson HS, Chapman KR, Pike SD, et al. Enhanced synergy between fluticasone propionate and salmeterol inhaled from a single inhaler versus separate inhalers. J Allergy Clin Immunol 2003; 112: 29–36
Lipworth BJ, Fardon TC. Enhanced synergy between fluticasone propionate and salmeterol inhaled from a single inhaler versus separate inhalers [letter]. J Allergy Clin Immunol 2004; 113: 178
Currie GP, Lee DKC, Haggart K, et al. Effects of montelukast on surrogate inflammatory markers in corticosteroid treated patients with asthma. Am J Respir Crit Care Med 2003; 167: 1232–8
Bjermer L, Bisgaard H, Bousquet J, et al. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial. BMJ 2003; 327: 891
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: 1088–95
Busse W, Koenig SM, Oppenheimer J, et al. Steroid-sparing effects of fluticasone propionate 100 microgram and salmeterol 50 microgram administered twice daily in a single product in patients previously controlled with fluticasone propionate 250 microg administered twice daily. J Allergy Clin Immunol 2003; 111: 57–65
Lalloo UG, Malolepszy J, Kozma D, et al. Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild-to-moderate asthma. Chest 2003; 123: 1480–7
Acknowledgments
The authors wish to thank Ms Kara Robertson for secretarial assistance in preparing the manuscript. Dr Jackson is a member of the National Institute for Clinical Excellence (NICE).
Professor Lipworth, as part of the Asthma and Allergy Research Group, has received financial support from GlaxoSmithKline (who make salmeterol and fluticasone propionate/salmeterol combination), Novartis (who make formoterol), AstraZeneca (who make formoterol and budesonide/formoterol combination), and Merck Sharp and Dohme (who make montelukast) for performing clinical trials, for attending and talking at postgraduate educational meetings, for providing equipment and for staff development resources.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Jackson, C.M., Lipworth, B. Benefit-Risk Assessment of Long-Acting β2-Agonists in Asthma. Drug-Safety 27, 243–270 (2004). https://doi.org/10.2165/00002018-200427040-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-200427040-00003