0
Communications to the Editor |

Salmeterol and Tolerance FREE TO VIEW

Brian J. Lipworth, MD; Catherine M. Jackson, MD
Author and Funding Information

Affiliations: Ninewells Hospital and Medical School University of Dundee Dundee, Scotland,  Fairfax, VA

Correspondence to: Brian J. Lipworth, MD, Dept of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland DD1 9SY; e-mail: b.j.lipworth@dundee.ac.uk



Chest. 2000;117(2):609-611. doi:10.1378/chest.117.2.609
Text Size: A A A
Published online

To the Editor:

We read with interest the recent article of Rosenthal et al (September 1999),1where the use of regular twice daily salmeterol in steroid naive mild asthmatic patients was reported to show no loss of bronchoprotection against methacholine challenge between 4 weeks and 24 weeks. The authors concluded that regular treatment with salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks. We believe that this amounts to over-interpretation of the presented data for a number of reasons. According to the latest asthma management guidelines,2the use of regular long-actingβ 2-agonists such as salmeterol is advocated only for add-on therapy at step 3 for patients with moderate persistent asthma whose symptoms are suboptimally controlled on a low-to-medium dose of inhaled corticosteroid. Hence the use of regular twice daily salmeterol as monotherapy in steroid naïve asthmatic patients, as reported by Rosenthal et al, would seem to be inappropriate treatment and not consistent with accepted good clinical practice. The apparent failure to show any attenuation in bronchoprotection between 4 weeks and 24 weeks of treatment does not take into account the previous studies that have shown a rapid onset of tolerance for bronchoprotective effects with salmeterol, which occurs within the first 24 h of treatment, in either steroid-naïve or steroid-requiring patients.5 In other words, tolerance had already developed by the time of the first methacholine challenge at 4 weeks, and hence the apparent sustained bronchoprotection that was observed over the subsequent 20 weeks of evaluation.

The study of Rosenthal et al evaluated the effects of salmeterol on its own in the presence of increased airway tone due to methacholine. In this setting of increased bronchomotor tone, as might occur in an acute asthma attack, salmeterol behaves as a partialβ 2-adrenoceptor agonist and consequently might function as an antagonist in the presence of competitive receptor occupancy by albuterol, which exhibits a higher degree of intrinsic agonist activity.67 Indeed, this phenomenon has been demonstrated in vivo in asthmatic patients after single or repeated doses of salmeterol, in terms of antagonism of the protective effect of a high dose of albuterol (1600 μg) against methacholine-induced bronchoconstriction.9 In children with asthma receiving inhaled corticosteroid therapy, it has also been shown that concomitant treatment with regular salmeterol results in almost complete blunting of the bronchodilator response to repeated doses of inhaled terbutaline.10

Physicians should therefore be aware of the possibility for regular salmeterol to induce tolerance to its protection against bronchoconstrictor stimuli and of its potential for antagonism of rescue therapy with albuterol in the setting of increased airway tone. Moreover, one would predict that tolerance with salmeterol would be accentuated in 40% of asthmatic patients who exhibit the homozygous glycine-16 β2-adrenoceptor polymorphism, which predisposes to agonist induced down-regulation and desensitisation.1112

References

Rosenthal, RR, Busse, WW, Kemp, JP, et al (1999) Effect of long-term salmeterol therapy compared with as needed albuterol use on airway hyperresponsiveness.Chest116,595-602. [PubMed] [CrossRef]
 
National Asthma Education and Prevention Programme. Expert panel report II. Guidelines for the diagnosis and management of asthma. National Institutes of Health Publication 97-4051:Bethesda, MD. 1997.
 
Kalra, S, Swyston, VA, Bhagat, R, et al Inhaled steroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol.Chest1996;109,953-956. [PubMed]
 
Bhagat, R, Kalra, S, Swyston, VA, et al Rapid onset of tolerance to the bronchoprotective effect of salmeterol.Chest1995;108,1235-1239. [PubMed]
 
Drotar, DE, David, EE, Cockcroft, DW Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment.Ann Allergy Asthma Immunol1998;80,31-34. [PubMed]
 
Molimard, M, Naline, E, Zan Zhang, Y, et al Long and short-acting β2-adrenoceptor agonist: interactions in human contracted bronchi.Eur Respir J1998;11,583-588. [PubMed]
 
Kallstrom, BL, Sjober, J, Waldeck, B The interaction between salmeterol and β2-adrenoceptor agonists with higher efficacy on guinea pig trachea and human bronchus in vitro.Br J Pharmacol1994;113,676-692
 
Lipworth, BJ, Aziz, I A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic patients receiving regular salmeterol or formoterol.J Allergy Clin Immunol1999;103,88-92. [PubMed]
 
Aziz, I, Lipworth, BJ In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol.J Allergy Clin Immunol1999;103,816-822. [PubMed]
 
Fuglsang, G, Vikre-Jorgensen, J, Pedersen, S Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-response to terbutaline in children with mild asthma.Paediatr Pulmonol1998;25,314-321
 
Green, SA, Turki, J, Innis, M, et al Amino-terminal polymorphisms of the human β-adrenergic receptor impart distinct agonist-promotive regulatory properties.Biochemistry1994;33,414-419
 
Tan, KS, Hall, IP, Dewar, J, et al β2-adrenoceptor polymorphism is associated with susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics.Lancet1997;350,995-999. [PubMed]
 
To the Editor:

In response to the issues raised by Drs. Lipworth and Jackson, we would point out that ours was a study of airways hyperresponsiveness as affected by long-term treatment with the long-actingβ 2-agonist, salmeterol. It was not a treatment study of salmeterol as monotherapy, and despite the demonstrated efficacy and safety of same, there was no proposal made for its use in this way. The issue at hand is whether or not salmeterol treatment leads to clinical instability or vulnerability to asthma attacks. Clearly, a long-term salmeterol treatment study with concomitant corticosteroid added as per the guidelines would have made that assessment impossible.1Moreover, our conclusion that long-term salmeterol treatment does not lead to clinical instability even in the absence of inhaled corticosteroids is certainly not compromised by the absence of corticosteroid treatment in the study cohort. Given the results of our study, we believe that the data supports the safety of regular therapy with salmeterol per se, and lends additional support for the regular use of salmeterol in combination with inhaled corticocorticosteroids as per the guidelines.4

Studies that demonstrate tolerance to the immediate bronchoprotective effect of salmeterol were referenced in our original article (September 1999).5In these studies, a modest decrease in the initial maximal or near-maximal bronchoprotective effects of salmeterol was observed.68 In contrast to the bronchoprotective effect, the bronchodilator effect of salmeterol is fully preserved with chronic dosing, and the bronchodilator effect of albuterol is maintained in patients receiving salmeterol irrespective of their use of inhaled corticocorticosteroids.910 This lack of tolerance is likely due to high β-receptor reserve and the partial agonist property of salmeterol, which results in lower levels of desensitization and internalization of the β2 receptors relative to β-agonists with higher intrinsic efficacy.11 Regarding the notion of salmeterol as a partial antagonist in the presence of methacholine, although we did not study the response to albuterol after dosing with salmeterol, we not only reported that methacholine sensitivity was significantly less after salmeterol dosing than at baseline, but noted no difference in the spontaneous recovery from methacholine challenge after dosing. Importantly, a decrease in the magnitude of the initial bronchoprotective effect of salmeterol has only been demonstrated in experimental situations that utilize high levels of functional antagonism (eg, methacholine challenge), and the clinical relevance of these studies is unclear.12

We did not investigate the immediate bronchoprotective effects of salmeterol, but chose to investigate the protective effects at the end of the dosing period for salmeterol when the patient would be most vulnerable to a loss of protection or asthma control. With regular use for 24 weeks, the bronchoprotective effect was maintained 10 to 14 h after salmeterol dosing, with associated improvements in all measures of pulmonary function and symptom control. The bronchoprotective effect observed in our study is consistent with the long duration of protection observed after a single dose of salmeterol.13 More importantly, after washout of salmeterol (ie, 3 and 7 days posttreatment), the provocative dose of methacholine required to reduce FEV1 by 20% from baseline for patients previously receiving salmeterol remained slightly above baseline and placebo values, demonstrating that even if there was some rapidly occurring onset of tolerance to salmeterol, long-term therapy did not adversely affect airway hyperresponsiveness. Our findings are consistent with a recent study of similar design and duration that showed comparable effects of salmeterol and beclomethasone on airway responsiveness to methacholine in patients with persistent asthma.14

The genotype of patients enrolled in our study was not determined. Therefore, the response of patients exhibiting the glycine-16 polymorphism could not be measured. However, we found no evidence of a significant subset of salmeterol-treated patients who exhibited reduced bronchoprotection, a posttreatment increase in airway hyperresponsiveness, or worsening of asthma control.

References
Mak, J, Nishikawa, M, Shirasaki, H, et al Protective effects of a glucocorticoid on downregulation of pulmonary beta2-adrenergic receptor in vivo.J Clin Invest1995;96,99-106. [PubMed] [CrossRef]
 
Greening, AP, Ind, PW, Northfield, M, et al Added salmeterol versus higher-dose corticocorticosteroids in asthma patients with symptoms on existing inhaled corticocorticosteroid.Lancet1994;344,219-224. [PubMed]
 
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.Ann Allergy Asthma Immunol1999;82,383-389. [PubMed]
 
Murrary, JJ, Church, NL, Anderson, WH, et al Concurrent use of salmeterol with inhaled corticocorticosteroids is more effective than inhaled corticocorticosteroid dose increases.Allergy Asthma Proc1999;20,173-180. [PubMed]
 
Rosenthal, RR, Busse, WW, Kemp, JP, et al Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness.Chest1999;116,595-602. [PubMed]
 
Kalra, S, Swystun,, Bhagat, R, et al Inhaled corticocorticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol.Chest1996;106,953-956
 
Baghat, R, Kalra, S, Swyston, VA, et al Rapid onset of tolerance to the bronchoprotective effects of salmeterol.Chest1995;108,1235-1239. [PubMed]
 
Cheung, D, Timmers, MC, Zwinderman, AH, et al Long-term effects of a long-acting beta-agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.N Engl J Med1992;327,1198-1203. [PubMed]
 
Nelson, HS, Berkowitz, RB, Tinkelman, DA, et al Chronic therapy with salmeterol does not result in tolerance to the bronchodilator effects of albuterol.Am J Respir Crit Care Med1999;159,1556-1561. [PubMed]
 
Korosec, M, Novak, RD, Myers, E, et al Salmeterol does not compromise the bronchodilator response to albuterol during acute episodes of asthma.Am J Med1999;107,209-213. [PubMed]
 
January, B, Seibold, A, Allal, C, et al Salmeterol-induced desensitization, internalization and phosphorylation of the human β2-adrenoceptor.Br J Pharmacol1998;123,701-711. [PubMed]
 
Nathan, RA Is the tolerance to the bronchoprotective effect of salmeterol clinically relevant?Ann Allergy Asthma Immunol1998;80,1-3. [PubMed]
 
Derom, EY, Pauwels, RA, Van Der Straeten, MEF The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours.J Allergy Clin Immunol1992;89,811-815. [PubMed]
 
Nathan, RA, Pinnas, JL, Schwartz, HJ, et al A six-month, placebo-controlled comparison of the safety and efficacy of salmeterol or beclomethasone for persistent asthma.Ann Allergy Asthma Immunol1999;82,521-529. [PubMed]
 

Figures

Tables

References

Rosenthal, RR, Busse, WW, Kemp, JP, et al (1999) Effect of long-term salmeterol therapy compared with as needed albuterol use on airway hyperresponsiveness.Chest116,595-602. [PubMed] [CrossRef]
 
National Asthma Education and Prevention Programme. Expert panel report II. Guidelines for the diagnosis and management of asthma. National Institutes of Health Publication 97-4051:Bethesda, MD. 1997.
 
Kalra, S, Swyston, VA, Bhagat, R, et al Inhaled steroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol.Chest1996;109,953-956. [PubMed]
 
Bhagat, R, Kalra, S, Swyston, VA, et al Rapid onset of tolerance to the bronchoprotective effect of salmeterol.Chest1995;108,1235-1239. [PubMed]
 
Drotar, DE, David, EE, Cockcroft, DW Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment.Ann Allergy Asthma Immunol1998;80,31-34. [PubMed]
 
Molimard, M, Naline, E, Zan Zhang, Y, et al Long and short-acting β2-adrenoceptor agonist: interactions in human contracted bronchi.Eur Respir J1998;11,583-588. [PubMed]
 
Kallstrom, BL, Sjober, J, Waldeck, B The interaction between salmeterol and β2-adrenoceptor agonists with higher efficacy on guinea pig trachea and human bronchus in vitro.Br J Pharmacol1994;113,676-692
 
Lipworth, BJ, Aziz, I A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic patients receiving regular salmeterol or formoterol.J Allergy Clin Immunol1999;103,88-92. [PubMed]
 
Aziz, I, Lipworth, BJ In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol.J Allergy Clin Immunol1999;103,816-822. [PubMed]
 
Fuglsang, G, Vikre-Jorgensen, J, Pedersen, S Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-response to terbutaline in children with mild asthma.Paediatr Pulmonol1998;25,314-321
 
Green, SA, Turki, J, Innis, M, et al Amino-terminal polymorphisms of the human β-adrenergic receptor impart distinct agonist-promotive regulatory properties.Biochemistry1994;33,414-419
 
Tan, KS, Hall, IP, Dewar, J, et al β2-adrenoceptor polymorphism is associated with susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics.Lancet1997;350,995-999. [PubMed]
 
Mak, J, Nishikawa, M, Shirasaki, H, et al Protective effects of a glucocorticoid on downregulation of pulmonary beta2-adrenergic receptor in vivo.J Clin Invest1995;96,99-106. [PubMed] [CrossRef]
 
Greening, AP, Ind, PW, Northfield, M, et al Added salmeterol versus higher-dose corticocorticosteroids in asthma patients with symptoms on existing inhaled corticocorticosteroid.Lancet1994;344,219-224. [PubMed]
 
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.Ann Allergy Asthma Immunol1999;82,383-389. [PubMed]
 
Murrary, JJ, Church, NL, Anderson, WH, et al Concurrent use of salmeterol with inhaled corticocorticosteroids is more effective than inhaled corticocorticosteroid dose increases.Allergy Asthma Proc1999;20,173-180. [PubMed]
 
Rosenthal, RR, Busse, WW, Kemp, JP, et al Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness.Chest1999;116,595-602. [PubMed]
 
Kalra, S, Swystun,, Bhagat, R, et al Inhaled corticocorticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol.Chest1996;106,953-956
 
Baghat, R, Kalra, S, Swyston, VA, et al Rapid onset of tolerance to the bronchoprotective effects of salmeterol.Chest1995;108,1235-1239. [PubMed]
 
Cheung, D, Timmers, MC, Zwinderman, AH, et al Long-term effects of a long-acting beta-agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.N Engl J Med1992;327,1198-1203. [PubMed]
 
Nelson, HS, Berkowitz, RB, Tinkelman, DA, et al Chronic therapy with salmeterol does not result in tolerance to the bronchodilator effects of albuterol.Am J Respir Crit Care Med1999;159,1556-1561. [PubMed]
 
Korosec, M, Novak, RD, Myers, E, et al Salmeterol does not compromise the bronchodilator response to albuterol during acute episodes of asthma.Am J Med1999;107,209-213. [PubMed]
 
January, B, Seibold, A, Allal, C, et al Salmeterol-induced desensitization, internalization and phosphorylation of the human β2-adrenoceptor.Br J Pharmacol1998;123,701-711. [PubMed]
 
Nathan, RA Is the tolerance to the bronchoprotective effect of salmeterol clinically relevant?Ann Allergy Asthma Immunol1998;80,1-3. [PubMed]
 
Derom, EY, Pauwels, RA, Van Der Straeten, MEF The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours.J Allergy Clin Immunol1992;89,811-815. [PubMed]
 
Nathan, RA, Pinnas, JL, Schwartz, HJ, et al A six-month, placebo-controlled comparison of the safety and efficacy of salmeterol or beclomethasone for persistent asthma.Ann Allergy Asthma Immunol1999;82,521-529. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543