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Effects of Treatment with Formoterol on Bronchoprotection against Methacholine

      Abstract

      PURPOSE: In addition to their bronchodilatory effects, β2-agonists protect against bronchoconstriction, such as that caused by methacholine challenge. However, tachyphylaxis to this beneficial effect develops after chronic use of β2-agonists. We studied whether the frequency or dose of treatment with a long-acting β2-agonist (formoterol) affects the degree of bronchoprotection afforded against methacholine challenge and to compare this with the effects of a short-acting β2-agonist (terbutaline).
      PATIENTS AND METHODS: In a randomized, parallel group, double-blind study at two centers, patients with stable asthma of mild to moderate severity who were treated with inhaled corticosteroids were treated with formoterol 6 μg twice daily, 24 μg twice daily, 12 μg once daily; terbutaline 500 μg four times daily; or placebo. Treatments were given by dry powder inhaler for a period of 2 weeks. Of the 72 patients who were enrolled, 67 completed the study. Methacholine challenge was performed to calculate the provocative dose that caused a 20% fall in forced expiratory volume in 1 second at baseline (unprotected) after an initial 1-week run-in without β2-agonists, 1 hour after the first dose of study treatment, and again 1 hour after 7 and 14 days of study treatment.
      RESULTS: Each of the four active treatments exhibited significant tachyphylaxis (P <0.05) to protection against methacholine challenge when comparing first/last dose (as geometric mean protection ratio versus baseline): formoterol 24 μg twice daily (9.6-fold/1.6-fold), 12 μg once daily (7.1-fold/2.2-fold), 6 μg twice daily (6.2-fold/2.3-fold), and terbutaline 500 μg four times daily (2.9-fold/2.0-fold). There were no significant differences among treatments after 2 weeks in bronchoprotection against methacholine challenge. For all formoterol regimens, the bronchodilator response 1 hour after inhalation was maintained over the 2-week treatment period. Diurnal control of morning and evening peak flow was significantly better with formoterol 24 μg twice daily than with terbutaline.
      CONCLUSIONS: Tachyphylaxis to bronchoprotection against methacholine challenge develops after 2 weeks of therapy with formoterol, a long-acting β2-agonist, at all three dosage regimens that were tested. In contrast, the bronchodilator effects of formoterol were maintained during the 2 weeks of treatment.
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      References

        • National Asthma Education and Prevention Program
        Expert Panel Report II. National Institutes of Health, Publication No. 97-4051, Bethesda, Md1997
        • Greening A.P
        • Ind P.W
        • Northfield M
        • Shore G
        Added salmeterol versus higher dose corticosteroid in asthma patients with symptoms on existing inhaled steroid.
        Lancet. 1994; 344: 219-224
        • Woolcock A
        • Lundback B
        • Rnngdal N
        • Jacqes L
        Comparison and addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids with doubling of the dose of inhaled steroids.
        Am J Respir Crit Care Med. 1996; 153: 1481-1488
        • Pauwels R.A
        • Lofdahl C.G
        • Postma D.S
        • et al.
        Effect of inhaled formoterol and budesonide on exacerbations of asthma.
        NEJM. 1997; 337: 1405-1411
        • Cockcroft D.W
        • Swystun V.A
        Functional antagonism tolerance produced by inhaled beta 2-agonists.
        Thorax. 1996; 51: 1051-1056
        • American Thoracic Society
        Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease and asthma.
        Am Rev Respir Dis. 1987; 36: 225-244
        • Connolly M.J
        • Avery A.J
        • Walters E.H
        • Hendrick D.J
        The relationship between bronchial responsiveness to methacholine and bronchial responsiveness to histamine in asthmatic patients.
        Pulm Pharmacol. 1988; 1: 53-58
        • Beach J.R
        • Jung C.L
        • Avery H.A
        • et al.
        Measurement of airway responsiveness to methacholine.
        Thorax. 1993; 48: 239-243
        • Newnham D.M
        • Grove A
        • McDevitt D.G
        • Lipworth B.J
        Subsensitivity of bronchodilator and systemic β2-adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients.
        Thorax. 1995; 50: 497-504
        • Rabe K.F
        • Jorres R
        • Nowak D
        • et al.
        Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness over 24 hours in bronchial asthma.
        Am Rev Respir Dis. 1997; 147: 1436-1441
        • Lipworth B.J
        • Aziz I
        • Tan K.S
        Subsensitivity to bronchoprotection against adenosine monophosphate challenge following regular once daily formoterol.
        Eur Respir J. 1997; 10: 11S-12S
        • Lipworth B.J
        Airway subsensitivity with long-acting 2-agonists.
        Drug Safety. 1997; 16: 295-308
        • Booth H
        • Bish R
        • Walatons J
        • et al.
        Salmeterol tachyphylaxis in steroid treated asthmatic patients.
        Thorax. 1996; 51: 1100-1104
        • Grove A
        • Lipworth B.J
        Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients.
        Lancet. 1995; 346: 210-216
        • Kalra S
        • Swystun V.A
        • Bahagat R
        • Cockcroft D.W
        Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol.
        Chest. 1996; 109: 953-956
        • Yates D.H
        • Kaharitonov S.A
        • Barnes P.J
        An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting β2-agonists.
        Am J Respir Crit Care Med. 1996; 154: 1603-1607
        • Mak J.C.W
        • Nishikawa S
        • Shirasiki H
        • et al.
        Protective effects of a glucocorticoid on down-regulation on pulmonary β2-adrenergic receptors in vivo.
        J Clin Invest. 1995; 96: 99-106
        • Samuelson W.N
        • Davis A.O
        Hydrocortisone induced reversal of β-adrenergic receptor uncoupling.
        Am Rev Respir Dis. 1984; 130: 1023-1026
        • Tan K.S
        • 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