BACKGROUND. Asthma is characterized by hyperresponsiveness of the airways to bronchoconstrictive stimuli. Long-acting beta 2-adrenoceptor agonists have been introduced as a new therapeutic approach, but there is growing concern about whether control of asthma may deteriorate with the regular use of these agents. We investigated the long-term effects of the beta 2 agonist salmeterol on bronchodilation and on airway hyperresponsiveness to the bronchoconstrictive agent methacholine in mild asthma. METHODS. In a parallel, double-blind study, 24 patients with mild asthma were randomly assigned to treatment with either inhaled salmeterol (50 micrograms, twice daily) (n = 12) or placebo (n = 12) during an eight-week trial. Methacholine challenge was performed before, during, and after the treatment period. Methacholine responsiveness was measured as the provocative concentration (PC20) that caused a 20 percent decrease in the forced expiratory volume in one second (FEV1). RESULTS. There was a significant increase in FEV1 one hour after the inhalation of salmeterol (P = 0.006), which did not differ significantly on days 0, 28, and 56 of the treatment period (increase, 9.8, 9.4, and 8.8 percent of predicted FEV1, respectively; P = 0.91). On the first treatment day, salmeterol afforded significant protection against methacholine-induced bronchoconstriction, as shown by a 10-fold increase in the PC20 as compared with the value at entry (P less than 0.001). After four and eight weeks of treatment, however, the salmeterol-induced change in the PC20 was significantly attenuated (P less than 0.001) to only a twofold increase. Two and four days after treatment ended, the PC20 was not significantly different from the value before treatment (P = 0.15). CONCLUSIONS. Regular treatment of patients with mild asthma with salmeterol leads to tolerance to its protective effects against a bronchoconstrictor stimulus, in this case inhaled methacholine, despite well-maintained bronchodilation. This finding raises concern about the effectiveness of prolonged therapy with long-acting beta 2-adrenoceptor agonists in asthma.
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Department of Pulmonology, University Hospital Leiden, The Netherlands.
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117: 609-611
[Full Text]
Billington, C. K., Hall, I. P., Mundell, S. J., Parent, J.-L., Panettieri, R. A. Jr., Benovic, J. L., Penn, R. B.
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[Abstract][Full Text]
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160: 1493-1499
[Abstract][Full Text]
AHRENS, R. C., HENDELES, L., CLARKE, W. R., DOCKHORN, R. J., HILL, M. R., VAUGHAN, L. M., LUX, C., HAN, S.-H.
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160: 1238-1243
[Abstract][Full Text]
Borst, M. M., Beuthien, W., Schwencke, C., LaRosee, P., Marquetant, R., Haass, M., Kubler, W., Strasser, R. H.
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34: 848-856
[Abstract][Full Text]
Rosenthal, R. R., Busse, W. W., Kemp, J. P., Baker, J. W., Kalberg, C., Emmett, A., Rickard, K. A.
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116: 595-602
[Abstract][Full Text]
PALMQVIST, M., IBSEN, T., MELLÉN, A., LÖTVALL, J.
(1999). Comparison of the Relative Efficacy of Formoterol and Salmeterol in Asthmatic Patients. Am. J. Respir. Crit. Care Med.
160: 244-249
[Abstract][Full Text]
NELSON, H. S., BERKOWITZ, R. B., TINKELMAN, D. A., EMMETT, A. H., RICKARD, K. A., YANCEY, S. W.
(1999). Lack of Subsensitivity to Albuterol After Treatment with Salmeterol in Patients with Asthma. Am. J. Respir. Crit. Care Med.
159: 1556-1561
[Abstract][Full Text]
Aziz, I., Lipworth, B. J.
(1999). A Bolus of Inhaled Budesonide Rapidly Reverses Airway Subsensitivity and {beta}2-Adrenoceptor Down-regulation After Regular Inhaled Formoterol. Chest
115: 623-628
[Abstract][Full Text]
Giannini, D., Bacci, E., Dente, F. L., Di Franco, A., Vagaggini, B., Testi, R., Paggiaro, P.
(1999). Inhaled Beclomethasone Dipropionate Reverts Tolerance to the Protective Effect of Salmeterol on Allergen Challenge. Chest
115: 629-634
[Abstract][Full Text]
Lockey, R. F., DuBuske, L. M., Friedman, B., Petrocella, V., Cox, F., Rickard, K.
(1999). Nocturnal Asthma: Effect of Salmeterol on Quality of Life and Clinical Outcomes. Chest
115: 666-673
[Abstract][Full Text]
van Noord, J A, Schreurs, A J M, Mol, S J M, Mulder, P G H
(1999). Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax
54: 207-212
[Abstract][Full Text]
WALLIN, A., SANDSTRÖM, T., SÖDERBERG, M., HOWARTH, P., LUNDBÄCK, B., DELLA-CIOPPA, G., WILSON, S., JUDD, M., HOLGATE, S., LINDBERG, A., LARSSEN, L., Judd, M., Melander, B.
(1999). The Effects of Regular Inhaled Formoterol, Budesonide, and Placebo on Mucosal Inflammation and Clinical Indices in Mild Asthma. Am. J. Respir. Crit. Care Med.
159: 79-86
[Abstract][Full Text]
BARNES, P. J.
(1998). Pharmacology of Airway Smooth Muscle. Am. J. Respir. Crit. Care Med.
158: S123-S132
[Abstract][Full Text]
CHEUNG, D., WEVER, A. M. J., de GOEIJ, J. A., de GRAAFF, C. S., STEEN, H., STERK, P. J.
(1998). Effects of Theophylline on Tolerance to the Bronchoprotective Actions of Salmeterol in Asthmatics In Vivo. Am. J. Respir. Crit. Care Med.
158: 792-796
[Abstract][Full Text]
Taylor, D R., Town, G I., Herbison, G P., Boothman-Burrell, D., Flannery, E. M, Hancox, B., Harré, E., Laubscher, K., Linscott, V., Ramsay, C. M, Richards, G.
(1998). Asthma control during long term treatment with regular inhaled salbutamol and salmeterol. Thorax
53: 744-752
[Abstract][Full Text]
Nelson, J. A., Strauss, L., Skowronski, M., Ciufo, R., Novak, R., McFadden, E.R.
(1998). Effect of Long-Term Salmeterol Treatment on Exercise-Induced Asthma. NEJM
339: 141-146
[Abstract][Full Text]
Taylor, D., Jensen, M., Aikman, S., Harris, J., Barnes, P., O'Connor, B.
(1997). Comparison of salmeterol and albuterol-induced bronchoprotection against adenosine monophosphate and histamine in mild asthma. Am. J. Respir. Crit. Care Med.
156: 1731-1737
[Abstract][Full Text]
Pauwels, R. A., Lofdahl, C.-G., Postma, D. S., Tattersfield, A. E., O'Byrne, P., Barnes, P. J., Ullman, A., The Formoterol and Corticosteroids Establishing Th,
(1997). Effect of Inhaled Formoterol and Budesonide on Exacerbations of Asthma. NEJM
337: 1405-1411
[Abstract][Full Text]
YATES, D. H., WORSDELL, M., BARNES, P. J.
(1997). Effect of Regular Salmeterol Treatment on Albuterol-induced Bronchoprotection in Mild Asthma. Am. J. Respir. Crit. Care Med.
156: 988-991
[Abstract][Full Text]
TAN, K. S., GROVE, A., LEAN, A. M., GNOSSPELIUS, Y., HALL, I. P., LIPWORTH, B. J.
(1997). Systemic Corticosteriod Rapidly Reverses Bronchodilator Subsensitivity Induced by Formoterol in Asthmatic Patients. Am. J. Respir. Crit. Care Med.
156: 28-35
[Abstract][Full Text]
Simons, F. E. R., Gerstner, T. V., Cheang, M. S.
(1997). Tolerance to the Bronchoprotective Effect of Salmeterol in Adolescents With Exercise-induced Asthma Using Concurrent Inhaled Glucocorticoid Treatment. Pediatrics
99: 655-659
[Abstract][Full Text]
Weinberger, M., Hendeles, L.
(1996). Theophylline in Asthma. NEJM
334: 1380-1388
[Full Text]
Nelson, H. S.
(1995). {beta}-Adrenergic Bronchodilators. NEJM
333: 499-507
[Full Text]
Weinberger, S. E.
(1993). Recent Advances in Pulmonary Medicine- First of Two Parts. NEJM
328: 1389-1397
[Full Text]
Hoshiko, K., Chapman, I.D., Morley, J., Cheung, D., Sterk, P.J., O'Connor, B. J., Barnes, P. J.
(1993). Sympathomimetic Agents and Airway Hyperreactivity. NEJM
328: 665-666
[Full Text]
(1992). TOLERANCE TO BETA-AGONISTS ERODES THEIR BENEFIT IN ASTHMA. JWatch General
1992: 5-5
[Full Text]
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