Clinical Investigations

Comparison of the Protective Effect of Formoterol and of Salmeterol against Exercise-Induced Bronchospasm when Given Immediately before a Cycloergometric Test
Marcello Ferrari, Carlo Segattini, Roberto Zanon, Mariano Bertaiola, Filippo Balestreri, Emanuele Brotto, Vincenzo Lo Cascio

Dipartimento di Scienze Biomediche e Chirurgiche, Servizio di Fisiopatologia Respiratoria, University of Verona, Verona, Italy

Address of Corresponding Author

Respiration 2002;69:509-512 (DOI: 10.1159/000066458)

 Outline

• Key Words
• Abstract
• Introduction
• Patients and Methods
• Results
• Discussion
• Acknowledgements
• References

• Author Contacts
• Article Information
• Publication Details
• Drug Dosage / Copyright

  Key Words

• Long-acting ₂-agonist
• Formoterol
• Salmeterol
• Exercise-induced bronchospasm

  Abstract

Background: Salmeterol and formoterol, two long-acting ₂-adrenergic agonists, have been shown to be effective against exercise-induced bronchospasm (EIB) several hours after inhalation, but no study has yet compared their protective effect immediately after administration. Objectives: To compare the protective effect of inhaled formoterol and salmeterol against EIB immediately and 4 h after administration. Methods: Double-blind, two-period cross-over study of 11 EIB-positive asthmatic subjects (mean age 21.2 years) administered formoterol 24 µg and salmeterol 50 µg by means of metered-dose inhalers (MDIs) on 2 days separated by an interval of 72 h; the subjects performed two cycloergometric exercise tests immediately and 4 h after dosing. Forced expiratory volume (FEV₁) measurements were made before and at the end of exercise, and then after 3, 5, 10, 15, 20, 25 and 30 min. The maximum percentage decrease in FEV₁ in the 30 min following exercise was considered. Results: Immediately after drug administration, but not 4 h later, formoterol provided significantly better protection against EIB than salmeterol (p = 0.02). The number of formoterol-treated subjects protected against EIB (i.e. with a <15% decrease in FEV₁ after treatment) was 10/11 after the first exercise test and 7/8 after the second; the corresponding figures after salmeterol treatment were 5/11 and 7/8. Conclusions: Our results show that formoterol inhaled via an MDI is effective in preventing EIB as early as within a few minutes of administration, whereas salmeterol does not offer any appreciable protection. On the contrary, the protective effect of the two drugs is clinically equivalent 4 h after administration.

Copyright © 2002 S. Karger AG, Basel

 Introduction

Exercise-induced bronchospasm (EIB) frequently affects patients with asthma, and can be effectively prevented by means of the inhalation of a ₂-adrenergic agonist before the exercise [1]. However, the duration of action of the most widely used ₂-adrenergic agonists, such as salbutamol, is short when they are used as bronchodilators and even shorter when they are used to provide protection against EIB [2]. Salmeterol and formoterol are two ₂-adrenergic agonists whose bronchodilating effects persist for at least 12 h [3]. Formoterol has a significantly faster onset of action than salmeterol, and leads to greater bronchodilatation within 2 h of administration [3, 4, 5, 6]. It has been shown that both salmeterol and formoterol are effective against EIB several hours after their inhalation by adult asthmatics [7, 8, 9], but no study has yet compared their protective effect immediately after administration.

The aim of this study was to assess the degree of protection against EIB provided by salmeterol and formoterol administered by means of metered-dose inhalers (MDIs) immediately before a 7-min cycloergometric exercise test.

 Patients and Methods

Twelve patients with bronchial asthma [10] were enrolled in the study. The inclusion criteria were a baseline forced expiratory volume in 1 s (FEV₁) of 70% the predicted value, and a fall in FEV₁ of at last 15% after a pretrial exercise challenge. The exclusion criteria were the presence of respiratory infection during the month preceding the study or any clinically significant condition that contraindicated exercise or interfered with the evaluation of the drug. No subject was taking inhaled steroids or long-acting ₂-agonists on a regular basis. The patients had access to rescue medication consisting of short-acting ₂-adrenergic agonists, which were withheld 12 h before the study days. Informed consent was obtained from all of the subjects or their parents before participation.

The subjects attended the laboratory on two occasions at the same time of day, with at least 72 h between each visit. FEV₁ was measured in triplicate using a turbine spirometer (Cosmed, Rome, Italy), the best recording being used for the analysis. Baseline FEV₁ was recorded on arrival at the laboratory, after which formoterol 24 µg (Novartis Farma, Italy) or salmeterol 50 µg (Glaxo Wellcome, Italy) were randomly administered under double-blind conditions by means of indistinguishable MDIs. A cycloergometric exercise test was performed immediately after drug administration and repeated 4 h later.

The exercise was performed for 7 min in a room at constant temperature (21 ± 1°C) with the subject inhaling dehumidified air, as previously described [11]. Briefly, the test consisted of a 1-min spell of rapidly increasing workload aimed at inducing a target heart rate of 85% of the maximum predicted value [12] and 6 min of constant work. FEV₁ measurements were taken before and at the end of exercise, and then after 3, 5, 10, 15, 20 and 30 min. The bronchial response to exercise was calculated as the maximum percentage fall in FEV₁:

FEV₁%fall = (baseline FEV₁ - lowest FEV₁ after exercise)

× 100/baseline FEV₁.

Efficacy was assessed by means of analysis of variance according to a two-treatment cross-over design, using the patient, period and treatment as factors. It was assumed that the washout period between the treatment days was adequate, and no attempt was made to evaluate any possible carry-over effects. The statistical tests were two-sided at a 5% level of significance. All of the calculations were made using the SAS package. The data are given as mean values ± standard deviation (SD).

 Results

One patient developed a pneumonia 2 days after the first test with salmeterol and was excluded from the study. Three patients underwent the first exercise test immediately after the administration of the two ₂-adrenergic agonists, but refused to repeat the second test 4 h later. In the study group (11 patients) there were 8 males and 3 females with a mean age of 21.2 ± 9.1 (range 11-39 years). The mean FEV₁ value at the pretrial visit was 3.0 ± 0.7 liters (85.4 ± 10.0% of predicted). At the same time, the mean maximum percent fall in FEV₁ after an exercise test was 39.4 ±18.0%.

The mean FEV₁ values recorded before formoterol and salmeterol administrations (i.e. before the first test) were respectively 2.9 ± 0.6 and 3.0 ± 0.7 liters; 4 h after dosing, before the start of the second exercise test, they were respectively 3.3 ± 0.91 and 3.2 ± 0.8 liters. Before both tests, there was no between-treatment or between-time difference in FEV₁ values.

The mean FEV₁ values over the 30 min following the first exercise test are shown in figure 1. The maximal percentage fall in FEV₁ for each patient is reported in figure 2. FEV₁ measured at the end of the 7-min exercise test was slightly increased by formoterol (3.1 ± 0.6 liters) but was decreased after salmeterol (2.7 ± 0.7 liters). At the subsequent time after formoterol treatment, the maximum percent fall in FEV₁ was negligible (1.5 ± 16.1%) in all of the subjects but 1, in whom it was 39%. On the contrary, FEV₁ decreased after salmeterol administration by a mean maximum of 21.7 ± 14.8%. The difference between the treatments was significant (p = 0.02), with formoterol providing better protection than salmeterol.

Fig. 1. Mean values of FEV1 with standard error, at baseline and during the 30 min following exercise tests performed immediately (first test) and 4 h after (second test) the administration of formoterol 24 µg () and salmeterol 50 µg () by means of MDI. After the first challenge, the difference between the treatments was significant (p = 0.02), with formoterol providing better protection than salmeterol.

Fig. 2. Maximal percent fall in FEV1 for each patient, after the first challenge (immediately after the administration of formoterol and salmeterol; 11 patients), and the second challenge (performed 4 h later; 8 patients). After the first challenge, the difference between the treatments was significant (p = 0.02), with formoterol providing better protection than salmeterol.

The mean maximum percent fall in FEV₁ following the second test (i.e. 4 h after dosing) (fig. 1, 2) was 6.9 ± 4.8% after formoterol and 9.5 ± 5.6% after salmeterol. The between-treatment difference was not statistically significant (p > 0.05).

The number of formoterol-treated subjects protected against EIB (i.e. with a <15% decrease in FEV₁ after treatment) was 10/11 after the first exercise test and 7/8 after the second; the corresponding figures after salmeterol treatment were 5/11 and 7/8. It is worth noting that 3 patients experienced a decrease in FEV₁ of >25% following the test performed immediately after salmeterol administration.

No clinically significant side effect was observed in either treatment group.

 Discussion

Formoterol is a long-acting ₂-adrenergic agonist whose rapid onset of action is comparable with that of short-acting ₂-adrenergic agonists [6], but no studies have previously examined whether it can provide equally rapid protection against EIB. In this study, inhaled formoterol led to rapid bronchodilation (about 7 min after administration), and proved to be highly effective in protecting against EIB. This is the first study showing that formoterol can prevent EIB as early as within a few minutes after administration, and extends the results of our group's recent study of athletes with asthma [11].

A number of studies comparing the effects of formoterol with salmeterol on lung function and bronchial reactivity in patients with asthma have been published recently [3, 4, 5]. They have shown that salmeterol and formoterol have similar bronchodilatatory effects that persist for at least 12 h, but that the onset of action of formoterol is significantly faster [5]. This study adds the further information that inhaled formoterol has a more rapid protective effect than salmeterol against exercise-induced asthma. Immediately after administration, the protective effect of the two ₂-adrenergic agents was very different not only statistically but also clinically. Following formoterol administration, post-exercise FEV₁ tends to increase rather than decrease, and all but 1 of the subjects were protected against exertional asthma. On the contrary, inhaled salmeterol did not prevent EIB: the mean fall in FEV₁ of 21.7% was only slightly different from that observed after the pretrial exercise test. It is also worth noting that 45% of the patients (5/11) showed a decrease in FEV₁ of >15%, thus further indicating the lack of efficacy of salmeterol in preventing EIB when administered just before an exercise challenge.

Four hours after administration, both drugs provided similar protection against EIB, a finding that confirms their long-lasting action [7, 8, 9].

The fact that formoterol is not only long-lasting but also offers rapid protection against EIB has some practical consequences. The drug can be taken minutes or hours before exercise without any substantial variation in its protective effect. Furthermore, the fact that formoterol can protect subjects from EIB for several hours removes the need for repeated administrations before every exercise.

In conclusion, our results show that formoterol given by means of an MDI is effective in preventing EIB as early as within a few minutes of administration, whereas salmeterol does not provide any appreciable protection. On the contrary, the two long-acting ₂-agonists are similarly effective against exertional asthma 4 h after administration. The rapid and long-lasting protective effect of formoterol gives it a significant advantage over salmeterol in the management of asthmatic subjects with EIB.

 Acknowledgements

We thank Virginio Oldani (Novartis Farma S.p.A., Italy) for statistical contributions and for his assistance in writing and editing the manuscript.

  References

1.

Anderson SD, Seale JP, Ferris L, Schoeffel RE, Lindsay DA: An evaluation of pharmacotherapy for exercise-induced asthma. J Allergy Clin Immunol 1979;64:612-624. 

2.

Konig P, Hardnik BS, Serely CV: Fenoterol in exercise-induced asthma. Effect of dose on efficacy and duration of action. Chest 1984;85:462-464. 

3.

Palmqvist M, Persson G, Lazer L, Rosenborg J, Larsson P, Lötwall J: Inhaled dry-powder formoterol and salmeterol in asthmatic patients: Onset of action, duration of effect and potency. Eur Respir J 1997;10:2484-2489. 

4.

Van Noord JA, Smeets JJ, Raaijmakers JAM, Bommer AM, Maesen FPV: Salmeterol versus formoterol in patients with moderately severe asthma: Onset and duration of action. Eur Respir J 1996;9:1684-1688. 

5.

Politiek MJ, Boorsma M, Aalbers R: Comparison of formoterol, salbutamol and salmeterol in methacholine-induced severe bronchoconstriction. Eur Respir J 1999;13:988-992. 

6.

Wagener T, Hedenström H, Melander B: Rapid onset of action of inhaled formoterol in asthmatic patients. Chest 1992;102:535-538. 

7.

Patessio A, Podda A, Carone M, Trombetta N, Donner CF: Protective effect and duration of action of formoterol aerosol on exercise-induced asthma. Eur Respir J 1991;4:296-300. 

8.

Kemp JP, Dockhorn RJ, Busse WW, Bleeker ER, Van As A: Prolonged effect of inhaled salmeterol against exercise-induced bronchospasm. Am J Respir Crit Care Med 1994;150:1612-1615. 

9.

Anderson SD, Rodwell LT, Du Toit J, Young IH: Duration of protection by inhaled salmeterol in exercise-induced asthma. Chest 1991;100:1254-1260. 

10.

American Thoracic Society: Guidelines for the diagnosis and care of patients with chronic pulmonary diseases (COPD) and asthma. Am Rev Respir Dis 1987;136:225-244. 

11.

Ferrari M, Balestreri M, Baratieri S, Biasin C, Oldani V, Lo Cascio V: Evidence of the rapid protective effect of formoterol dry-powder inhalation against exercise-induced bronchospasm in athletes with asthma. Respiration 2000;67:510-513. 

12.

Jones NL, Makrides L, Hitchoch C, Chypchar T, McCartney N: Normal standards for incremental progressive cycle ergometer test. Am Rev Respir Dis 1985;131:700-708. 

  Author Contacts

Dr. Marcello Ferrari
Medicina Interna D, Policlinico G.B. Rossi
I-37134 Verona (Italy)
Tel. +39 045 8074262, Fax +39 045 583041, E-Mail ferrari@medicinad.univr.it

  Article Information

Received: Received: January 23, 2002
Accepted after revision: July 16, 2002
Number of Figures : 2, Number of Tables : 0, Number of References : 12

  Publication Details

Respiration (International Review of Thoracic Diseases)
Founded 1944 as 'Schweizerische Zeitschrift für Tuberkulose und Pneumonologie' by E. Bachmann, M. Gilbert, F. Häberlin, W. Löffler, P. Steiner and E. Uehlinger, continued 1962-1967 as 'Medicina Thoracalis' as of 1968 as 'Respiration', H. Herzog (1962-1997)
Official Journal of the European Association for Bronchology and Interventional Pulmonology

Vol. 69, No. 6, Year 2002 (Cover Date: November-December 2002)

Journal Editor: C.T. Bolliger, Cape Town
ISSN: 0025-7931 (print), 1423-0356 (Online)

For additional information: http://www.karger.com/journals/res

  Drug Dosage / Copyright

Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.