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Additive Bronchoprotective and Bronchodilator Effects With Single Doses of Salmeterol and Montelukast in Asthmatic Patients Receiving Inhaled Corticosteroids^*

^* From the Asthma and Allergy Research Group, Department of Clinical Pharmacology & Therapeutics, Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland, UK.

Correspondence to: Brian J. Lipworth, Department of Clinical Pharmacology & Therapeutics, Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland, UK, DD1 9SY; e-mail: b.j.lipworth{at}dundee.ac.uk

	Abstract

TOP Abstract Introduction Patients Materials and Methods Results Discussion References

 
Objective: We wished to evaluate whether the combination of a leukotriene receptor antagonist and long-acting ß₂-agonist might confer additive beneficial effects in terms of bronchoprotection and bronchodilatation, in mild to moderate asthmatic patients who were suboptimally controlled on inhaled corticosteroids alone.

Methods: Twelve asthmatic patients were enrolled into a single-blind, placebo-controlled, crossover study, receiving additive therapy as either of the following: (1) montelukast alone, 10 mg (ML₁₀); (2) inhaled salmeterol alone, 50 µg (SM₅₀); (3) ML₁₀ and SM₅₀; (4) ML₁₀ and inhaled salmeterol, 100 µg (SM₁₀₀); or (5) placebo inhaler and tablet. Trough measurements were made of adenosine monophosphate (AMP) bronchial challenge (the provocative concentration of a drug [AMP] causing a fall of 20% in FEV₁ [PC₂₀]) as the primary end point, and spirometry, following single doses of either placebo or active treatments (12 h after salmeterol, and 24 h after monteleukast, respectively).

Results: Compared to placebo, all active treatments led to significant improvements (p < 0.05) in geometric mean AMP-PC₂₀: placebo, 42 mg/mL; ML₁₀, 106 mg/mL; SM₅₀, 115 mg/mL; ML₁₀ and SM₅₀, 183 mg/mL; and ML₁₀ and SM₁₀₀, 247 mg/mL. The effects of montelukast and salmeterol were numerically additive, with ML₁₀ and SM₁₀₀ being significantly different (p < 0.05) from ML₁₀ alone. For mean FEV₁ and forced expiratory flow rate between 25% and 75% of vital capacity, there were significant differences (p < 0.05) between both combination therapies vs ML₁₀ alone.

Conclusions: Our results suggest additive benefits of a single dose of a long-acting ß₂-agonist and leukotriene antagonist, in terms of bronchoprotection and bronchodilation. Further studies in more severe asthmatics are required to evaluate long-term clinical effects.

Key Words: adenosine monophosphate • asthma • ß₂-adrenoceptor • bronchial hyperrreactivity • leukotriene receptor • montelukast • salmeterol

	Introduction

TOP Abstract Introduction Patients Materials and Methods Results Discussion References

 
Current asthma guidelines emphasize the importance of inhaled corticosteroids as first-line anti-inflammatory therapy.¹ For patients who are suboptimally controlled on inhaled corticosteroids, there is the option of adding in second-line therapy with oral leukotriene receptor antagonist or inhaled long-acting ß₂-agonist. Since leukotriene receptor antagonists and long-acting ß₂-agonists act at different parts of the inflammatory cascade,² we wished to evaluate whether the combination of leukotriene receptor antagonist and long-acting ß₂-agonist treatment in patients who are suboptimally controlled on inhaled corticosteroids, as monotherapy might confer additive beneficial effects in terms of bronchoprotection (adenosine monophosphate [AMP] challenge) and bronchodilatation (spirometry). We decided to evaluate trough effects at the end of a 12-h dosing interval for salmeterol and after 24 h for montelukast, as this is the period when the airway would be most vulnerable to bronchoconstrictor stimuli.

	Patients

TOP Abstract Introduction Patients Materials and Methods Results Discussion References

 
Twelve asthmatic patients (6 males) were recruited into the study. They had the following characteristics: mean (SEM) age, 33.6 (2.6) years; FEV₁, 75.3 (4.0) percent predicted; and forced expiratory flow rate between 25% and 75% of vital capacity (FEF_25–75), 49.7 (5.0) percent predicted. All patients had persistent asthma of mild to moderate severity and were suboptimally controlled despite taking > 400 µg/d of inhaled corticosteroids as monotherapy (median dose, 500 µg/d; interquartile range, 400 to 800 µg/d): beclomethasone dipropionate (n = 10), budesonide (n = 1), or fluticasone propionate (n = 1). Patients were eligible for inclusion if they were symptomatic (day or night), requiring at least 2 puffs/d of reliever therapy with their usual short-acting ß₂-agonist, and had at least 10% diurnal variability between their morning and evening peak expiratory flow rates. All patients were required to be responsive to AMP challenge testing with a provocation concentration of drug producing 20% fall in FEV₁ (PC₂₀) < 100 mg/mL (geometric mean, 20.2 ± 7.8) at the screening visit. All patients were nonsmokers, and none had received oral corticosteroids or antibiotics for 6 months prior to the study. Approval for the study was obtained from the Tayside medical ethics committee, and all patients gave written informed consent.

	Materials and Methods

TOP Abstract Introduction Patients Materials and Methods Results Discussion References

 
The study had a randomized, placebo-controlled, single (investigator)-blind, crossover design. Patients continued on their usual maintenance dose of inhaled corticosteroid throughout the study. Patients were randomized to receive single doses of the following: (1) 10 mg of montelukast sodium [ML₁₀] (tablet) and placebo inhaler; (2) 50 µg of salmeterol xinafoate [SM₅₀] (via Accuhaler; Glaxo Wellcome; Middlesex, UK; 50 µg per actuation) and placebo tablet; (3) ML₁₀ and SM₅₀; (4) ML₁₀ and 100 µg of salmeterol xinafoate (SM₁₀₀); and (5) placebo inhaler and placebo tablet. All inhalers and tablets were taken 12 h (9:00 PM) and 24 h (9:00 AM, respectively) before each laboratory visit the next day (9:00 AM), in order that measurements coincided with trough levels of each drug. Each treatment was separated by a minimum of 4 days.

AMP Challenge
AMP bronchial challenge testing was performed as previously described,³ after patients had withheld their rescue bronchodilator medication for at least 12 h. In brief, AMP was administered in doubling cumulative doses given at 90-s intervals until a fall in FEV₁ 20% was recorded. The PC₂₀ was calculated using a computer-assisted curve fitting package (Biolab Assistant 1.1; University of Dundee; Dundee, Scotland) and interpolation of the steep part of the log dose-response curve. A value of 1,600 mg/mL was assigned if the FEV₁ did not fall below 20% of baseline value.

Spirometry
Spirometry was performed according to best test criteria using a Vitalograph compact spirometer (Vitalograph Ltd.; Buckinghamshire, UK) with a pneumotachograph head and pressure transducer that was calibrated daily using a precision syringe (Vitalograph Ltd.).

Statistical Analysis
The study was designed with sample size of 12, with at least 80% power to detect a 1.0 doubling-dilution difference (twofold) in AMP-PC₂₀ (the primary end point), with the error set at 0.05 (two-tailed). The data for AMP-PC₂₀ were log-transformed in order to normalize their distribution prior to analysis. FEV₁ data were normally distributed. Overall comparisons between active and placebo treatments were made by multifactorial analysis of variance using subject, treatment, and period as factors, followed by Duncan’s multiple-range testing (set at 95% confidence interval [CI]) in order to obviate multiple pair-wise comparisons. Consequently, comparisons are only denoted as being significant (p < 0.05) or not significant in order to not confound the error. The analysis was performed using Statgraphics statistical software package (STSC Software Publishing Group; Rockville, MD).

	Results

TOP Abstract Introduction Patients Materials and Methods Results Discussion References

 
Compared to placebo treatment, all active treatments led to significant (p < 0.05) improvement in AMP-PC₂₀ (Fig 1 and Table 1 ). Furthermore, the combination of ML₁₀ and SM₁₀₀ significantly (p < 0.05) improved AMP-PC₂₀ compared to ML₁₀ treatment alone. For FEV₁ and FEF_25–75, there were significant differences (p < 0.05) between both combination therapies as compared to placebo or ML₁₀ treatment alone (Table 1) . There was a similar trend for FEF_25–75.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Geometric mean (SEM) are shown on a log2 scale (as doubling dilutions) for AMP-PC20. Values are shown after treatment with ML10, SM50, and SM100 given alone or in combination. Asterisk denotes p < 0.05 vs placebo. Cross denotes p < 0.05 vs ML10.

	Discussion

TOP Abstract Introduction Patients Materials and Methods Results Discussion References

Our results are perhaps not surprising, as both drugs affect different points in the inflammatory cascade that results ultimately in bronchoconstriction and bronchial hyperresponsiveness.² Long-acting ß₂-agonists act predominantly at the bottom of this cascade at the site of smooth muscle, as bronchodilatory agents, although it has been suggested they may also possess weak anti-inflammatory properties.^{5 6} Leukotriene receptor antagonists attenuate the proinflammatory effects of leukotrienes, such as increased microvascular permeability, eosinophil chemotaxis, mucus secretion, as well as blocking leukotriene-induced smooth muscle constriction and proliferation.⁷

AMP hyperresponsiveness is increasingly recognized as being a noninvasive surrogate marker of airway inflammation in asthmatic patients.⁸ Inhaled AMP is believed to cause bronchoconstriction indirectly secondary to primed mast cell mediator release. This may be more sensitive than challenges such as methacholine, which act directly on smooth muscle. The bronchoprotective properties of ß₂-agonists on AMP challenge are partly due to functional antagonism of smooth muscle ß₂-adrenoceptors, as well as a component due to direct inhibition of mast cell ß₂-adrenoceptors.⁹ In one study by Taylor et al,¹⁰ using a Diskhaler, peak bronchoprotection (at 2 h) with salmeterol was similar for effects on histamine and AMP challenge, whereas albuterol exhibited significantly greater protection (at 30 min) on AMP challenge. In another study from the same group, using a Turbuhaler, peak protection (at 30 min) with formoterol was significantly greater on AMP than histamine, while albuterol showed similar protection for both challenges.¹¹ However, it is probably not valid to compare the study of Taylor et al¹⁰ looking at peak bronchoprotection with salmeterol (at 2 h) with the present study looking at trough effects (at 12 h). In our study, there were significant bronchoprotective and bronchodilator effects at trough, suggesting that these effects are not dissociated with time. Leukotriene receptor antagonists are recognized as having bronchoprotective properties with allergen, exercise, and other challenges, although there are no previous data regarding their effects on AMP challenge.⁷

There were limitations to our study, which are important to consider. Although we found a clear numerical trend toward additive bronchoprotection with salmeterol and montelukast, statistical significance was attained only with the combination containing the highest dose of salmeterol, in comparison to montelukast alone. With a larger sample size, it is likely that this trend would have reached statistical significance with the lower dose of salmeterol as combination therapy. FEV₁ and FEF_25–75 were not primary end points, although a similar trend was seen, reaching significance with combination therapy containing low- or high-dose salmeterol. Our results pertain only to a single dose of each drug, and it is known that tachyphylaxis to bronchoprotection occurs with regular salmeterol in steroid-treated patients, although there is a significant degree of residual protection after chronic dosing.^{12 13} It was evident that the difference in AMP-PC₂₀ between low-dose combination therapy (ML₁₀ and SM₅₀) and monotherapy amounted to less than one doubling dilution, and so this effect may not be clinically relevant. It is also possible that further improvements in bronchial hyperreactivity and lung function may have been achieved by increasing the dose of inhaled corticosteroid, but this was not evaluated in the present study. It is also unclear whether the current findings can be extrapolated to more severe asthmatics, although bronchial challenge may be more hazardous in such patients. Further studies are indicated to examine the effect of chronic dosing in more severe asthmatics with leukotriene receptor antagonist and long-acting ß₂-agonist.

	Acknowledgements

 
The authors would like to thank Mrs. W. Coutie for her help in data collection and assistance with the bronchial challenge test.

	Footnotes

 
Abbreviations: AMP = adenosine monophosphate; CI = confidence interval; FEF_25–75 = forced expiratory flow rate between 25% and 75% of vital capacity; ML₁₀ = 10 mg of oral montelukast sodium; PC₂₀ = provocative concentration of drug causing a fall 20% in FEV₁; SM₅₀ = 50 µg of inhaled salmeterol xinafoate; SM₁₀₀ = 100 µg of inhaled salmeterol xinafoate

Study funded by a University of Dundee research grant.

Received for publication July 7, 1999. Accepted for publication November 23, 1999.

	References

TOP Abstract Introduction Patients Materials and Methods Results Discussion References

 

1. National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, 1997; Publication No. 97–4051
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4. Hui, KP, Barnes, NC (1991) Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist. Lancet 337,1002-1003
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9. O’Connor, BJ, Ridge, SM, Barnes, PJ, et al (1992) Greater effect of inhaled budesonide on adenosine 5'-monophosphate-induced than on sodium-metabisulfite-induced bronchoconstriction in asthma. Am Rev Respir Dis 146,560-564[ISI][Medline]
10. Taylor, DA, Jensen, MW, Aikmann, SL, et al (1997) Comparison of salmeterol and albuterol induced bronchoprotection against adenosine monophosphate and histamine in mild asthma. Am J Respir Crit Care Med 156,1731-1737[Abstract/Free Full Text]
11. Nightingale, JA, Rogers, DF, Barnes, PJ (1999) Differential effect of formoterol on adenosine monophosphate and histamine reactivity in asthma. Am J Respir Crit Care Med 159,1786-1790[Abstract/Free Full Text]
12. Booth, H, Bish, R, Walters, J, et al (1996) Salmeterol tachyphylaxis in steroid treated asthmatic subjects. Thorax 51,1100-1104[Abstract]
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