Original Article
Effect of Long-Term Salmeterol Treatment on Exercise-Induced Asthma
N Engl J Med 1998; 339:141-146July 16, 1998
- Abstract
Background
With long-term administration of salmeterol, the extent of protection afforded by the drug against experimental precipitants of asthma such as methacholine and adenosine may decrease. Whether this effect extends to a clinically relevant stimulus such as exercise is unknown.
Methods
We performed a random-order, double-blind, crossover trial in 20 patients with exercise-induced asthma. Each patient received inhaled salmeterol or placebo twice daily for a month, with a one-week washout period between treatments. The patients performed cycle ergometry while breathing frigid air 30 minutes after the morning dose and 9 hours later on the 1st, 14th, and 29th study days. The primary end point was the extent of the decrease in forced expiratory volume in 1 second (FEV1) 10 minutes after exertion.
Results
With placebo, significant airway narrowing developed at all times (mean [±SE] decrease from base line in FEV1, 19±2 percent in the morning and 18±2 percent in the evening). The morning dose of salmeterol attenuated the degree of bronchoconstriction at all times (decrease in FEV1 on day 1, 5±2 percent; on day 14, 10±3 percent; and on day 29, 9±3 percent; P=0.10). Its ability to act throughout the day, however, decreased with long-term administration (decrease in FEV1 from morning to evening on day 1, 6±2 percent; on day 14, 15±3 percent; and on day 29, 14±3 percent; P=0.003).
Conclusions
Protection against exercise-induced asthma is maintained with long-term administration of salmeterol, but the length of time that the drug remains active after a single dose decreases.
Media in This Article
Figure 1
Mean (±SE) Forced Expiratory Volume in One Second (FEV1) at Base Line on Each of the Test Days of Administration of Placebo and Salmeterol.Figure 3
Relative Effects of Placebo and Salmeterol on the Response to Exercise over Time.Article Activity
- Article
Selective β2-adrenergic agonists are widely used to treat acute episodes of asthma, and long-acting drugs of this type such as salmeterol are often given to prevent the bronchial narrowing that occurs at night1 or after exercise.2 However, there has been concern that long-term therapy with these agents may worsen the disease3 and minimize the body's defense against irritant stimuli.4-7 A multicenter trial showed that long-term treatment does not exacerbate asthma,8 but whether therapeutically important tachyphylaxis develops to the prophylactic action of the drugs remains to be settled.9 Unfortunately, studies reporting tachyphylaxis used provocations either that patients would not encounter in their daily lives (e.g., histamine, methacholine, and adenosine)4-6 or for which β2-adrenergic agonists would not be given as primary therapy (i.e., antigen).7 We undertook the present study to determine whether salmeterol and similar drugs lose the ability to protect against events such as exercise that initiate asthma — events for which these drugs would ordinarily be prescribed.
Methods
We studied 20 nonsmoking patients (11 women and 9 men) with exercise-induced asthma and a mean (±SD) age of 29±9 years (Table 1Table 1
Characteristics of 20 Patients with Exercise-Induced Asthma.). The patients were enrolled between November 1995 and December 1996. Exercise-induced asthma was considered to be present if a patient had symptoms of airway obstruction after exertion that were associated with a decrease in the forced expiratory volume in one second (FEV1) of 15 percent or more from the base-line value. None of the patients had upper respiratory tract infections or had taken any glucocorticoid orally in the six weeks before the study. The investigation was a random-order, double-blind, crossover trial in which the patients took two puffs (42 μg) of salmeterol (Serevent, Glaxo Wellcome, Research Triangle Park, N.C.) twice daily or a placebo from identical canisters (Glaxo Wellcome) for one month. The study phases were separated from one another by one-week washout periods. At the crossover point, the patients were reexamined to ensure that their exercise response was similar to that recorded at base line. No significant differences were found (maximal decrease [±SE] in FEV1 at the first screening, 24±2 percent; maximal decrease in FEV1 at the second screening, 26±4 percent; P=0.58).Inhaled glucocorticoid and methylxanthine therapy was permitted if the doses of these agents had been stable during the month preceding enrollment and remained constant throughout the trial. Albuterol was given to patients who had breakthrough symptoms. All treatment other than salmeterol or placebo was withheld for a minimum of 12 hours before any study day, and long-acting methylxanthine compounds were withheld for 24 hours. The protocol was approved by the institutional review board for human investigation, and all patients gave informed consent.
At base line, the patients performed four minutes of exhausting work on a cycle ergometer while breathing frigid air.10 The workloads were chosen on the basis of their ability to cause a reduction in FEV1 of 15 percent or more at any time during the first 20 minutes after exertion, and once established, they were held constant for each patient during the study. During cycling, the patient exhaled into a calibrated dry gas meter so that minute ventilation could be continuously recorded.10 The temperature of the inspired air was also measured. Recovery occurred under ambient room conditions.11
On the 1st, 14th, and 29th days of each study month, the patients came to the laboratory early in the morning without taking their study drug. Forced exhalations were performed in triplicate12 before and 30 minutes after inhalation of the morning dose. The first exercise challenge then commenced, after which spirometry was serially recorded for 60 minutes. The degree of obstruction 10 minutes after the cessation of exercise was taken as the morning response. The curves with the largest FEV1 were chosen for analysis. A second exercise challenge was undertaken nine hours later (in the evening). The second dose of salmeterol or placebo on this day was taken in the usual fashion when the patients returned home.
The data were analyzed with repeated-measures analyses of variance, paired t-tests, and chi-square tests.13 All statistical tests were two-sided. No effect of the order of treatments was found, and therefore all results were combined.
Results
The mean (±SE) FEV1 at the first visit was 93±3 percent of the predicted value, and the workload averaged 740±55 kilopond meters per minute (Table 1). At base line, 13 patients were taking nebulized albuterol as needed and 6 required both a daily β2-adrenergic agonist and an inhaled glucocorticoid; 1 of these 6 patients was also taking a methylxanthine. The remaining patient took nedocromil daily.
The mean values for minute ventilation ranged from 52±3 to 61±4 liters per minute (P=0.69), and the temperature of inspired air ranged from –5±1 to –9±3°C (P=0.11) during the study (Table 2Table 2
Minute Ventilation and Temperature of Inspired Air during Each Challenge in 20 Patients with Exercise-Induced Asthma.). Before challenge, the FEV1 ranged from 90±3 to 98±3 percent of the predicted value (P=0.91). There were no significant differences within or among the days of study or between the salmeterol or placebo period for any of the variables shown in Table 2 and Figure 1Figure 1Mean (±SE) Forced Expiratory Volume in One Second (FEV1) at Base Line on Each of the Test Days of Administration of Placebo and Salmeterol..The absolute effects of salmeterol and placebo are shown in Figure 2Figure 2
Absolute Effects of Placebo and Salmeterol on the Response to Exercise over Time., and the relative effects are shown in Figure 3Figure 3Relative Effects of Placebo and Salmeterol on the Response to Exercise over Time.. The relative effects are provided to compensate for temporal shifts in the base-line values. With placebo, the mean decrease in FEV1 was 19±2 percent in the morning and 18±2 percent in the evening (P<0.001 for all individual comparisons). There were no significant differences in results between challenges at any time (P=0.94). Salmeterol attenuated (P<0.001) but did not abolish the bronchial narrowing (P<0.01 for all comparisons with base-line values). The prophylactic benefit after the morning dose remained constant throughout the trial (decrease in FEV1 on day 1, 5±2 percent; on day 14, 10±3 percent; and on day 29, 9±3 percent; P=0.10). The duration of action of the drug, however, shortened with long-term use. By the end of the second week, the extent of protection recorded in the evening was less than that on day 1 (decrease in FEV1 from morning to evening on day 1, 6±2 percent; and on day 14, 15±3 percent; P=0.003), but it was still slightly better than the protection afforded by placebo (P=0.02). Although no further changes occurred during the subsequent two weeks (decrease in FEV1 from morning to evening with salmeterol on day 29, 14±3 percent; P=0.61 for the comparison with day 14), the differences between salmeterol and placebo disappeared (P=0.29). This overall pattern held whether we analyzed the data using the maximal response irrespective of time, the first exhalation, or the mean of the three FEV1 attempts. The number of patients for whom salmeterol did not offer protection against exercise-induced asthma later in the day (i.e., those with more than a 10 percent fall in FEV1 after exercise) increased from 2 on study day 1 to 11 on day 29 (P=0.02).Discussion
We examined whether long-term therapy with inhaled salmeterol diminished the protection afforded against a clinically important, acute precipitant of asthma. The study was designed to imitate, as closely as possible, the type of situation that would be encountered in outpatient practice; hence, we studied patients who had symptomatic exercise-induced asthma superimposed on asthma of varying severity and therapeutic requirements. In some patients, exercise was the sole active trigger of their illness, whereas in others it was only one of many stimuli that caused symptoms. This mixture of patients and the intensity of the provocation used were chosen to tax the effects of salmeterol. Generally speaking, the more aggressive the underlying asthma, the less effective any given drug is in preventing an exercise-induced component, and the more severe the challenge, the greater the opportunity for the drug to fail.14 Cold air and large workloads were used because they evoke the greatest decrements in lung function,15 yet are common natural occurrences. We found that under these circumstances the administration of standard doses of salmeterol for 30 days did not result in a clinically important decrease in protection against exertional airway obstruction.
Our findings do demonstrate, however, that the duration of action of salmeterol decreased with long-term use: by the end of the second week, the extent of protection was less in the evening, and by day 29, it no longer differed from that afforded by placebo. These observations imply that the functional activity of the airway β2-adrenergic receptors did not change over time, but that the rate of clearance of the drug from the tissue had accelerated or that some other phenomenon had occurred. Since a decrease in the rate of clearance is manifested by a diminution in the duration of bronchodilatation16 and since this has not been found with long-term administration of salmeterol in previous investigations,17 it seems an unlikely explanation. However, since the protective effects of β-adrenergic drugs against exercise are independent of airway dilatation,18 the dissociation noted suggests an as yet undefined interaction between the stimulus and the drug.
It is commonly held that a single dose of salmeterol will attenuate exercise-induced bronchoconstriction in adults for 12 hours.19-21 In most short-term trials, the post-exercise decrease in FEV1 within several hours after inhalation averages 1 to 5 percent19-21 (Figure 2 and Figure 3); however, as the effects of the drug begin to wear off, the benefits become less pronounced, and the proportion of patients in whom protection remains maximal at six hours ranges from 20 to 50 percent.19-21 It therefore seems possible that the temporal effects we observed may represent an exaggerated example of the normal pharmacology of the drug. Although direct proof of this postulate is lacking, it is well established that the duration of the prophylactic activities of sympathomimetic drugs are considerably less than the duration of their bronchodilator effects.22,23
Our study was not designed to determine how long the protection lasted throughout the day after a month of therapy. Nonetheless, we can infer from these data that for long-term therapy with salmeterol, either short-acting supplemental drugs or a change in dose schedule may be required to provide the greatest control toward the end of the dosing interval. Although such a requirement is clearly disadvantageous, it must be remembered that the effect of salmeterol lasts three to four times as long as the two hours offered by a standard dose of albuterol.22
We appreciate that our work stands in contrast to several investigations that concluded that salmeterol24 and its shorter-acting congener albuterol25 lose their effectiveness against exercise over time. Ramage and associates24 reported that the prophylaxis provided by salmeterol disappeared after a month of treatment. Unfortunately, it is unclear whether the patients actually took the drug on the test days; hence, their results are problematic. Inman and O'Byrne25 administered albuterol for one week and found a diminution in the protection against physical exertion along with an inexplicable worsening of lung function. When the fluctuations in base line in these studies are taken into account by expressing the effect as a percentage change, the purported adverse effects disappear.
In summary, we found that the extended administration of a long-acting β2-adrenergic–agonist drug such as salmeterol does not result in a loss of protection against clinically relevant precipitants of asthma, but the duration of action of the drug is shortened.
Supported in part by grants (HL-33791 and HL-07288) from the National Heart, Lung, and Blood Institute and a General Clinical Research Center Grant (MO 1 RR-00080) from the National Center for Research Resources of the National Institutes of Health, and a grant in aid from Glaxo Wellcome Corporation.
Source Information
From the Division of Pulmonary and Critical Care Medicine, University Hospitals of Cleveland, and the Department of Medicine of Case Western Reserve University School of Medicine, Cleveland.
Address reprint requests to Dr. McFadden at the Division of Pulmonary and Critical Care Medicine, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106-5067.
- References
References
1
Fitzpatrick MF ,Mackay T ,Driver H ,Douglas NJ . Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled β2-agonist. BMJ 1990;301:1365-1368
CrossRef | Web of Science | Medline2
Green CP ,Price JF . Prevention of exercise induced asthma by inhaled salmeterol xinafoate. Arch Dis Child 1992;67:1014-1017
CrossRef | Web of Science | Medline3
Sears MR ,Taylor DR ,Print CG , et al. Regular inhaled β-agonist treatment in bronchial asthma. Lancet 1990;336:1391-1396
CrossRef | Web of Science | Medline4
Vathenen AS ,Knox AJ ,Higgins BG ,Britton JR ,Tattersfield AE . Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988;1:554-558
CrossRef | Web of Science | Medline5
Cheung D ,Timmers MC ,Zwinderman AH ,Bel EH ,Dijkman JH ,Sterk PJ . Long-term effects of a long-acting β2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992;327:1198-1203
Full Text | Web of Science | Medline6
O'Connor BJ ,Aikman SL ,Barnes PJ . Tolerance to the nonbronchodilator effects of inhaled β2-agonists in asthma. N Engl J Med 1992;327:1204-1208
Full Text | Web of Science | Medline7
Cockcroft DW ,McParland CP ,Britto SA ,Swystun VA ,Rutherford BC . Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993;342:833-837
CrossRef | Web of Science | Medline8
Drazen JM ,Israel E ,Boushey HA , et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. N Engl J Med 1996;335:841-847
Full Text | Web of Science | Medline9
McFadden ER Jr . Perspectives in β2-agonist therapy: vox clamantis in deserto vel lux in tenebris? J Allergy Clin Immunol 1995;95:641-651
CrossRef | Web of Science | Medline10
Gilbert IA ,Fouke JM ,McFadden ER Jr . Intra-airway thermodynamics during exercise and hyperventilation in asthmatics. J Appl Physiol 1988;64:2167-2174
Web of Science | Medline11
McFadden ER Jr ,Lenner KA ,Strohl KP . Postexertional airway rewarming and thermally induced asthma: new insights into pathophysiology and possible pathogenesis. J Clin Invest 1986;78:18-25
CrossRef | Web of Science | Medline12
Standardization of spirometry -- 1987 update: statement of the American Thoracic Society
CrossRef | Web of Science | Medline13
Zar JH. Biostatistical analysis. 2nd ed. Englewood Cliffs, N.J.: Prentice-Hall, 1984.
14
McFadden ER Jr ,Gilbert IA . Exercise-induced asthma. N Engl J Med 1994;330:1362-1367
Full Text | Web of Science | Medline15
Repsher LH ,Anderson JA ,Bush RK , et al. Assessment of tachyphylaxis following prolonged therapy of asthma with inhaled albuterol aerosol. Chest 1984;85:34-38
CrossRef | Web of Science | Medline16
Strauss RH ,McFadden ER Jr ,Ingram RH Jr ,Jaeger JJ . Enhance-ment of exercise-induced asthma by cold air. N Engl J Med 1977;297:743-747
Full Text | Web of Science | Medline17
Pearlman DS ,Chervinsky P ,LaForce C , et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 1992;327:1420-1425
Full Text | Web of Science | Medline18
Hetzel MR ,Batten JC ,Clark TJH . Do sympathomimetic amines present exercise-induced asthma by bronchodilatation alone? Br J Dis Chest 1977;71:109-114
CrossRef | Medline19
Anderson SD ,Rodwell LT ,Du Toit J ,Young IH . Duration of protection by inhaled salmeterol in exercise-induced asthma. Chest 1991;100:1254-1260
CrossRef | Web of Science | Medline20
Kemp JP ,Dockhorn RJ ,Busse WW ,Bleecker ER ,Van As A . Prolonged effect of inhaled salmeterol against exercise-induced bronchospasm. Am J Respir Crit Care Med 1994;150:1612-1615
Web of Science | Medline21
Newnham DM ,Ingram CG ,Earnshaw J ,Palmer JBD ,Dhillon DP . Salmeterol provides prolonged protection against exercise-induced bronchoconstriction in a majority of patients with mild, stable asthma. Respir Med 1993;87:439-444
CrossRef | Web of Science | Medline22
Schoeffel RD ,Anderson SD ,Seale JP . The protective effect and duration of action of metaproterenol aerosol on exercise-induced asthma. Ann Allergy 1981;46:273-275
Medline23
Higgs CMB ,Laszlo G . The duration of protection from exercise-induced asthma by inhaled salbutamol, and a comparison with inhaled reproterol. Br J Dis Chest 1983;77:262-269
CrossRef | Medline24
Ramage L ,Lipworth BJ ,Ingram CG ,Cree IA ,Dhillon DP . Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994;88:363-368
CrossRef | Web of Science | Medline25
Inman MD ,O'Byrne PM . The effect of regular inhaled albuterol on exercise-induced bronchoconstriction. Am J Respir Crit Care Med 1996;153:65-69
Web of Science | Medline
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CrossRef2
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CrossRef5
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CrossRef6
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CrossRef7
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CrossRef8
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CrossRef9
Fanta, Christopher H., . (2009) Asthma. New England Journal of Medicine 360:10, 1002-1014
Full Text10
So-Yeon Lee, Hyo-Bin Kim, Jinho Yu, Soo-Jong Hong. (2009) Exercise-induced asthma in children. Expert Review of Clinical Immunology 5:2, 193-207
CrossRef11
Teal S. Hallstrand, William R. Henderson. (2009) Role of leukotrienes in exercise-induced bronchoconstriction. Current Allergy and Asthma Reports 9:1, 18-25
CrossRef12
Kenneth D. Fitch, Malcolm Sue-Chu, Sandra D. Anderson, Louis-Philippe Boulet, Robert J. Hancox, Donald C. McKenzie, Vibeke Backer, Kenneth W. Rundell, Juan M. Alonso, Pascale Kippelen, Joseph M. Cummiskey, Alain Garnier, Arne Ljungqvist. (2008) Asthma and the elite athlete: Summary of the International Olympic Committee's Consensus Conference, Lausanne, Switzerland, January 22-24, 2008. Journal of Allergy and Clinical Immunology 122:2, 254-260.e7
CrossRef13
Miles Weinberger. (2008) Long-acting β-agonists and exercise. Journal of Allergy and Clinical Immunology 122:2, 251-253
CrossRef14
K. H. Carlsen, S. D. Anderson, L. Bjermer, S. Bonini, V. Brusasco, W. Canonica, J. Cummiskey, L. Delgado, S. R. Del Giacco, F. Drobnic, T. Haahtela, K. Larsson, P. Palange, T. Popov, P. van Cauwenberge. (2008) Treatment of exercise-induced asthma, respiratory and allergic disorders in sports and the relationship to doping: Part II of the report from the Joint Task Force of European Respiratory Society (ERS) and European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA 2 LEN. Allergy 63:5, 492-505
CrossRef15
Hengameh H Raissy, Michelle Harkins, Franceska Kelly, H. William Kelly. (2008) Pretreatment with Albuterol versus Montelukast for Exercise-Induced Bronchospasm in Children. Pharmacotherapy 28:3, 287-294
CrossRef16
Antti Alaranta, Hannu Alaranta, Ilkka Helenius. (2008) Use of Prescription Drugs in Athletes. Sports Medicine 38:6, 449-463
CrossRef17
Richard A. Bond, Domenico Spina, Sergio Parra, Clive P. Page. (2007) Getting to the heart of asthma: Can “β blockers” be useful to treat asthma?. Pharmacology & Therapeutics 115:3, 360-374
CrossRef18
Gene L. Colice. (2007) Facing the challenge of unmet needs in asthma. Annals of Allergy, Asthma & Immunology 98:2, S16-S22
CrossRef19
E. Haydn Walters, Peter G Gibson, Toby J Lasserson, Julia AE Walters, E. Haydn Walters. 2007. Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid. .
CrossRef20
William E. Berger. (2006) The use of inhaled formoterol in the treatment of asthma. Annals of Allergy, Asthma & Immunology 97:1, 24-33
CrossRef21
V. Tsagaraki, A. Amfilochiou, S. L. Markantonis. (2006) Evidence of tachyphylaxis associated with salmeterol treatment of chronic obstructive pulmonary disease patients. International Journal of Clinical Practice 60:4, 415-421
CrossRef22
Luis Prieto, Valentina Gutiérrez, Carmen Pérez-Francés, Carlos Badiola, Amparo Lanuza, Laura Bruno, Anna Ferrer. (2005) Effect of fluticasone propionate–salmeterol therapy on seasonal changes in airway responsiveness and exhaled nitric oxide levels in patients with pollen-induced asthma. Annals of Allergy, Asthma & Immunology 95:5, 452-461
CrossRef23
John M. Weiler, Robert A. Nathan, Ned T. Rupp, Christopher J. Kalberg, Amanda Emmett, Paul M. Dorinsky. (2005) Effect of fluticasone/salmeterol administered via a single device on exercise-induced bronchospasm in patients with persistent asthma. Annals of Allergy, Asthma & Immunology 94:1, 65-72
CrossRef24
Catherine M Jackson, Brian Lipworth. (2004) Benefit-Risk Assessment of Long-Acting ??2-Agonists in Asthma. Drug Safety 27:4, 243-270
CrossRef25
Sandra D Anderson, John D Brannan. (2004) Long-Acting ??2-Adrenoceptor Agonists and Exercise-Induced Asthma. Pediatric Drugs 6:3, 161-175
CrossRef26
Sandra D Anderson. (2004) Single-Dose Agents in the Prevention of Exercise-Induced Asthma. Treatments in Respiratory Medicine 3:6, 365-379
CrossRef27
Milind P Sovani, Christopher I Whale, Anne E Tattersfield. (2004) A Benefit-Risk Assessment of Inhaled Long-Acting ??2-Agonists in the Management of Obstructive Pulmonary Disease. Drug Safety 27:10, 689-715
CrossRef28
Gaetano Caramori, Ian Adcock. (2003) Pharmacology of airway inflammation in asthma and COPD. Pulmonary Pharmacology & Therapeutics 16:5, 247-277
CrossRef29
EH Walters, JAE Walters, MDP Gibson, E. Haydn Walters. 2003. Long-acting beta2-agonists for stable chronic asthma. .
CrossRef30
P.W. IND, R. DAL NEGRO, N.C. COLMAN, C.P. FLETCHER, D. BROWNING, M.H. JAMES. (2003) Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma. Respiratory Medicine 97:5, 555-562
CrossRef31
Ellen J Dutta, James T.C Li. (2002) β-Agonists. Medical Clinics of North America 86:5, 991-1008
CrossRef32
Teal S Hallstrand, William R Henderson. (2002) Leukotriene modifiers. Medical Clinics of North America 86:5, 1009-1033
CrossRef33
Ricardo A. Tan, Sheldon L. Spector. (2002) Exercise-induced asthma: diagnosis and management. Annals of Allergy, Asthma & Immunology 89:3, 226-236
CrossRef34
Brian J. Lipworth. (2002) Antagonism of long-acting β2-adrenoceptor agonism. British Journal of Clinical Pharmacology 54:3, 231-245
CrossRef35
Kenneth R Chapman. (2002) Seretide for obstructive lung disease. Expert Opinion on Pharmacotherapy 3:3, 341-350
CrossRef36
Brian J. Lipworth, Catherine M. Jackson. (2002) Second-Line Controller Therapy for Persistent Asthma Uncontrolled on Inhaled Corticosteroids. Drugs 62:16, 2315-2332
CrossRef37
Naureckas, Edward T., Solway, Julian, . (2001) Mild Asthma. New England Journal of Medicine 345:17, 1257-1262
Full Text38
ROBERT TUCKER THOLE, ROBERT E. SALLIS, AARON L. RUBIN, GARY N. SMITH. (2001) Exercise-induced bronchospasm prevalence in collegiate cross-country runners. Medicine & Science in Sports & Exercise 33:10, 1641-1646
CrossRef39
M.R. Sears. (2001) The evolution of β2-agonists. Respiratory Medicine 95, S2-S6
CrossRef40
Carmen Vidal, Esperanza Fernández-Ovide, Juan Piñeiro, Ramón Nuñez, Arturo González-Quintela. (2001) Comparison of montelukast versus budesonide in the treatment of exercise-induced bronchoconstriction. Annals of Allergy, Asthma & Immunology 86:6, 655-658
CrossRef41
A JAMES. (2001) ASTHMA. Obstetrics and Gynecology Clinics of North America 28:2, 305-320
CrossRef42
Patrick Flood-Page, Neil C. Barnes. (2001) What are the Alternatives to Increasing Inhaled Corticosteroids for the Long Term Control of Asthma?. BioDrugs 15:3, 185-198
CrossRef43
Jean-Bruno Langdeau, Louis-Philippe Boulet. (2001) Prevalence and Mechanisms of Development of Asthma and Airway Hyperresponsiveness in Athletes. Sports Medicine 31:8, 601-616
CrossRef44
Richard Wood-Baker, Michael A. Austin, Renée Manser, Richard Wood-Baker. 2000. Combined corticosteroid and long-acting beta-agonist in one inhaler for chronic asthma. .
CrossRef45
John Kulig. (2000) ADVANCES IN MEDICAL MANAGEMENT OF ASTHMA, HEADACHES, AND FATIGUE. Medical Clinics of North America 84:4, 829-850
CrossRef46
Todd Horiuchi, Mario Castro. (2000) THE PATHOBIOLOGIC IMPLICATIONS FOR TREATMENT. Clinics in Chest Medicine 21:2, 381-395
CrossRef47
Blair Jarvis, Anthony Markham. (2000) Montelukast. Drugs 59:4, 891-928
CrossRef48
Hans Bisgaard. (2000) Long-acting ?2-agonists in management of childhood asthma: A critical review of the literature. Pediatric Pulmonology 29:3, 221-234
CrossRef49
Sherrie L. Stach. (2000) CE Forum. Improving Self-Care in Adults with Asthma Using Peak Expiratory Flow Rate Home Monitoring. Journal of the American Academy of Nurse Practitioners 12:2, 59-70
CrossRef50
Jeffrey M. Drazen. (1999) Asthma Therapy with Agents Preventing Leukotriene Synthesis or Action. Proceedings of the Association of American Physicians 111:6, 547-559
CrossRef51
Hideko Kobayashi, Kenji Minoguchi, Yasurou Kohno, Naruhito Oda, Kiyoko Wada, Kana Ueno, Masahide Miyamoto, Mitsuru Adachi, Norio Kihara. (1999) Exercise challenge in patients with asthma whose peak expiratory flow values are controlled within the green zone. Allergology International 48:2, 145-148
CrossRef52
Carolyn M. Kercsmar. (1999) Leukotriene receptor antagonist treatment of asthma: Are we there yet?. The Journal of Pediatrics 134:3, 256-259
CrossRef53
James T. Li. (1999) Inhaled corticosteroid therapy in asthma: a balancing act. Annals of Allergy, Asthma & Immunology 82:3, 229-230
CrossRef54
Johan C. Kips, Renaat A. Peleman, Romain A. Pauwels. (1999) The role of theophylline in asthma management. Current Opinion in Pulmonary Medicine 5:2, 88
CrossRef55
WILLIAM W. STORMS. (1999) Exercise-induced asthma: diagnosis and treatment for the recreational or elite athlete. Medicine & Science in Sports & Exercise 31:Supplement, S33-S38
CrossRef56
Christopher J. Clark, Lorna M. Cochrane. (1999) Physical activity and asthma. Current Opinion in Pulmonary Medicine 5:1, 68
CrossRef57
(1998) Exercise-Induced Asthma. New England Journal of Medicine 339:24, 1783-1786
Full Text58
Hansen-Flaschen, John, Schotland, Helena, . (1998) New Treatments for Exercise-Induced Asthma. New England Journal of Medicine 339:3, 192-193
Full Text
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