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Communications to the Editor |

Salmeterol and Conventional Asthma Therapy Salmeterol and Conventional Asthma Therapy FREE TO VIEW

Brian J. Lipworth, MD
Author and Funding Information

Affiliations: Ninewells Hospital and Medical School Dundee, Scotland,  University of Texas Health Science Center San Antonio, TX

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



Chest. 2001;119(3):986-987. doi:10.1378/chest.119.3.986
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To the Editor:

I read with concern the article of Peters and colleagues in CHEST (August 2000),1 who concluded that the addition of salmeterol to conventional therapy is safe and may benefit hospitalized patients with asthma. This was based on showing greater percentage improvement in FEV1 measurements made every 12 h over a 48-h period after admission, when using salmeterol compared with placebo.,1

Unfortunately, the most important data is missing, namely how salmeterol interacts with albuterol in the first few hours after admission. This is important to know because salmeterol is a partial agonist at airway β2-adrenoceptors and has been shown in carbachol-contracted human airway, in comparison to isoproterenol (as 100%), to exhibit a relative intrinsic activity of 36%, as compared to 78% for albuterol, for its maximal relaxant effect.2 The effects of β2-agonists on contracted human airway are relevant to the setting of an acute asthma exacerbation where there is also a large increase in bronchomotor tone. Consequently, in terms of relative efficacy at airway β2-adrenoceptors, during a period of prolonged receptor occupancy by salmeterol, one would predict that it would behave as an antagonist relative to albuterol, and might therefore blunt the bronchodilator response in albuterol.3 Indeed, this has been shown in vivo in asthmatic patients, where prior treatment with either single or repeated 50-μg doses of salmeterol compared to placebo results in attenuation of the response to albuterol, 1,600 μg, in terms of overcoming methacholine-induced bronchoconstriction.5

In acute severe asthma, as in the present study, high doses of inhaled albuterol are given frequently within the first few hours of admission in order to buy time until the more delayed onset of action of acute corticosteroid therapy. During this critical initial period after admission, it is therefore imperative to know whether adding in salmeterol blunts the acute bronchodilator response to high doses of albuterol in the setting of increased bronchomotor tone. Without knowing this important information, it is surely premature to conclude that the addition of salmeterol to conventional therapy is safe in patients admitted with acute asthma.

Peters, JL, Schelledy, DC, Jones, AP, et al (2000) A randomized placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthmaChest118,313-320. [CrossRef] [PubMed]
 
Molimard, M, Naline, E, Zan Zhang, Y, et al Long- and short-acting β2-adrenoceptor agonist: interactions in human-contracted bronchiEur Respir J1998;11,583-588. [PubMed]
 
Lipworth, BJ, Grove, A Evaluation of partial β-adrenoceptor agonist activity.Br J Clin Pharmacol1997;43,9-14. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Aziz, I, Lipworth, BJ In vivoeffect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol.J Allergy Clin Immunol1999;103,816-822. [CrossRef] [PubMed]
 

Salmeterol and Conventional Asthma Therapy

To the Editor:

We appreciate the concern of Dr. Lipworth and agree that the interactions between albuterol and salmeterol during the first few hours of an acute exacerbation of asthma remain unknown. As stated in our article in CHEST (August 2000),1 one of our main objectives was to assess the safety of salmeterol as an adjunct to albuterol in the post-emergency department setting. The design of our study was established to ensure maximum safety for the patients, and measurements were obtained 12 h after each dose of salmeterol or placebo to ensure an investigator was present during each dosing interval to carefully evaluate each patient for “paradoxical” bronchospasm or any exacerbation induced by salmeterol.

We should point out that despite utilizing multiple measures to assess each patient for a paradoxical response, including FEV1, peak expiratory flow rate, severity of symptom scores, dyspnea index, respiratory rate, and oxygen saturation by pulse oximetry, we were unable to document adverse effects from the addition of salmeterol to standard therapy. It is important to realize that when patients entered our study, they still had severe bronchospasm. The mean FEV1 was 1.62 ± 0.7 L during the first 24 h for the group receiving salmeterol, and they were receiving albuterol treatments every 2 to 3 h. Despite the severity of their bronchospasms and the frequency of albuterol treatments, the addition of salmeterol led to a greater FEV1 percent improvement at each time point compared to placebo. Although these data refute the theoretic concern that salmeterol (a partial agonist) could occupy receptors and decrease the effectiveness of albuterol, we are not advocating its use in the initial therapy of an acute exacerbation of asthma. Salmeterol has not been evaluated in the emergency department treatment of asthma, and it would be dangerous to extrapolate our data to this setting.

One should not confuse the concept of bronchoprotection and bronchodilation. Attenuation of the bronchoprotective effects of salmeterol for both methacholine and exercise have been well described.23 While the observations by Aziz and Lipworth4on the effects of salmeterol on methacholine-contracted bronchi are interesting, Korosec et al5 found that salmeterol use does not compromise the bronchodilator response to albuterol during acute episodes of asthma. This study revealed that patients presenting to the emergency department who utilized salmeterol had a similar bronchodilator response when compared to the control group. Additionally, there was no difference between the control group and the salmeterol group in the duration of therapy in the emergency department or the proportion of patients admitted to the hospital. The real benefits and risks of salmeterol or formoterol in clinical settings such as the emergency department, hospital wards, and the ICU can only be determined by carefully designed clinical studies.

References
Peters, JI, Shelledy, DC, Jones, AP, et al A randomized, placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthmaChest2000;118,313-320. [CrossRef] [PubMed]
 
Lipworth, BJ, Aziz, I A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic patients receiving regular salmeterol or formoterolJ Allergy Clin Immunol1999;103,88-92. [CrossRef] [PubMed]
 
Broden, RN, Faulds, D Salmeterol xinafoate: a review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease.Drugs1991;42,895-912. [CrossRef] [PubMed]
 
Aziz, I, Lipworth, BJ In vivoeffect of albuterol of methacholine-contracted bronchi in conjunction with salmeterol and formoterol.J Allergy Clin Immunol1999;103,816-822. [CrossRef] [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. [CrossRef] [PubMed]
 

Figures

Tables

References

Peters, JL, Schelledy, DC, Jones, AP, et al (2000) A randomized placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthmaChest118,313-320. [CrossRef] [PubMed]
 
Molimard, M, Naline, E, Zan Zhang, Y, et al Long- and short-acting β2-adrenoceptor agonist: interactions in human-contracted bronchiEur Respir J1998;11,583-588. [PubMed]
 
Lipworth, BJ, Grove, A Evaluation of partial β-adrenoceptor agonist activity.Br J Clin Pharmacol1997;43,9-14. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Aziz, I, Lipworth, BJ In vivoeffect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol.J Allergy Clin Immunol1999;103,816-822. [CrossRef] [PubMed]
 
Peters, JI, Shelledy, DC, Jones, AP, et al A randomized, placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthmaChest2000;118,313-320. [CrossRef] [PubMed]
 
Lipworth, BJ, Aziz, I A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic patients receiving regular salmeterol or formoterolJ Allergy Clin Immunol1999;103,88-92. [CrossRef] [PubMed]
 
Broden, RN, Faulds, D Salmeterol xinafoate: a review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease.Drugs1991;42,895-912. [CrossRef] [PubMed]
 
Aziz, I, Lipworth, BJ In vivoeffect of albuterol of methacholine-contracted bronchi in conjunction with salmeterol and formoterol.J Allergy Clin Immunol1999;103,816-822. [CrossRef] [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. [CrossRef] [PubMed]
 
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