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Published ahead of print on August 15, 2002, doi:10.1164/rccm.200206-509OC
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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 1212-1217, (2002)
© 2002 American Thoracic Society

Original Article

Effects of Montelukast and Budesonide on Airway Responses and Airway Inflammation in Asthma

Richard Leigh, Dilini Vethanayagam, Makoto Yoshida, Richard M. Watson, Tracy Rerecich, Mark D. Inman and Paul M. O'Byrne

Asthma Research Group, Firestone Institute for Respiratory Health and Department of Medicine, St. Joseph's Healthcare–McMaster University, Hamilton, Ontario, Canada

Correspondence and requests for reprints should be addressed to Paul M. O'Byrne, M.B., E. J. Moran Campbell Professor, Firestone Institute for Respiratory Health, Room 113, St. Joseph's Hospital, 50 Charlton Avenue East, Hamilton, ON, L8N 4A6 Canada. E-mail: obyrnep{at}mcmaster.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Inhaled corticosteroids are effective antiinflammatory therapy for asthma; however, they do not completely abolish allergen-induced airway inflammation. Leukotriene modifiers attenuate both early and late allergen responses and have antiinflammatory properties. We reasoned that treatment with budesonide and montelukast in combination might provide greater antiinflammatory effects than either drug alone, and the purpose of this study was to compare the effects of treatment with budesonide and montelukast, alone or in combination, on outcome variables after allergen inhalation. Ten subjects with asthma with dual responses after allergen inhalation were included in this randomized, double-blind, crossover study. Outcomes included early and late asthmatic responses, and changes in airway responsiveness and sputum eosinophilia, measured before and after challenge. Treatment with montelukast attenuated the maximal early asthmatic response compared with placebo (p < 0.001) and budesonide (p = 0.002). Both budesonide and montelukast, alone and in combination, attenuated the maximal late asthmatic response compared with placebo (p < 0.01). Budesonide and montelukast, alone and in combination, afforded protection against allergen-induced airway hyperresponsiveness (p < 0.05), although the treatment effect of budesonide was greater than that of montelukast (p < 0.05). Treatment with budesonide and montelukast, alone and in combination, also attenuated allergen-induced sputum eosinophilia. Thus, montelukast and budesonide attenuated allergen-induced asthmatic responses, airway hyperresponsiveness, and sputum eosinophilia, although combination treatment did not provide greater antiinflammatory effects than either drug alone.

Key Words: asthma • allergen challenge • airway inflammation • glucocorticosteroids • cysteinyl leukotrienes


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Inhaled corticosteroids (ICSs) are regarded as the cornerstone of effective antiinflammatory therapy for the treatment of asthma (1). Regular long-term ICS therapy significantly reduces asthma mortality (2), asthma exacerbations (3, 4), airway inflammation, and asthma symptoms (5, 6) and significantly improves lung function in subjects with asthma (7).

Although regular ICS treatment inhibits allergen-induced late airway responses and attenuates allergen-induced airway hyperresponsiveness (AHR), it does not completely abolish allergen-induced increases in sputum eosinophils (8, 9). Furthermore, a recent study from the Asthma Clinical Research Network (10) has demonstrated that there is significant intersubject variability in response to low–medium dose ICS treatment, suggesting that at least in subjects demonstrating a poor response to ICS, there are ongoing inflammatory mechanisms that are relatively insensitive to the antiinflammatory effects of ICS.

Among the various proinflammatory mediators involved in the pathophysiology of asthma, cysteinyl leukotrienes have a causative role in mediating bronchoconstriction and allergic airway inflammation (11–13). Cysteinyl leukotrienes are released from inflammatory cells in the airways and induce bronchoconstriction (14), inflammatory cell infiltration (15–16), smooth muscle proliferation (17), mucous secretion, and increased vascular permeability (12, 18, 19). However, in vivo studies have shown that the synthesis and release of cysteinyl leukotrienes into the airways of patients with asthma are not blocked by corticosteroid therapy (20), suggesting that the inflammatory effects of cysteinyl leukotrienes are not inhibited by corticosteroid treatment.

Montelukast sodium (Singulair) is a potent, oral, specific cysteinyl leukotriene D4-receptor antagonist that inhibits bronchoconstrictor response to exercise (21) and early and late airway responses to allergen (22). Furthermore, montelukast has been shown to attenuate airway eosinophilia in subjects with asthma having eosinophilic bronchitis (23), whereas the related leukotriene-modifying compounds, zafirlukast and zileuton, reduce airway eosinophilia in bronchoalveolar lavage fluid after segmental allergen challenge (24, 25).

We reasoned that the combination of a low dose of ICS and a cysteinyl leukotriene receptor antagonist (montelukast) may provide greater antiinflammatory effects against allergen-induced airway inflammation than either drug alone. Therefore, the primary purpose of this study was to evaluate the effects of budesonide and montelukast, alone and in combination, on allergen-induced early and late bronchoconstrictor responses, AHR, and airway inflammation in subjects with mild, stable asthma.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Ten nonsmoking subjects (seven males, three females) (Table 1 ) with stable, mild atopic asthma were included in the study. All subjects had symptoms of asthma for more than a year, and their inclusion in the study was based on their having a provocative concentration producing a 20% reduction in FEV1 (PC20) of less than 16 mg/ml methacholine (MCh) and allergen-induced early and late bronchoconstrictor responses of at least 15% reduction in FEV1 during screening challenges. Subjects who had been treated with any asthma medication other than inhaled ß2-agonists, or who used inhaled ß2-agonists more frequently than once daily during the 4-week period before screening, were not permitted to participate in the study. One subject failed to complete all treatment arms of the study due to a protocol violation, and the analysis was thus based on data from nine subjects. The study protocol was approved by the Ethics Committee at the McMaster University Health Sciences Centre, and all subjects gave written, informed consent to participate in the study.


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  		TABLE 1. Subject characteristics

 
Study Design and Protocol
The study was performed using a prospective, double-blind, double-dummy, placebo-controlled, randomized, four-period crossover design. After successful screening, subjects were randomized to receive one of four different treatment regimens of 10 days each, separated by washout periods of at least 21 days (Figure 1) . The four treatment regimens were (1) montelukast (Singulair) 10 mg, received orally once daily in the evening and placebo Turbuhaler; (2) inhaled budesonide (Pulmicort Turbuhaler) 200 µg, one inhalation taken in the morning and evening (total daily dose, 400 µg) and placebo tablet; (3) active montelukast and active budesonide in dosages described previously; and (4) placebo tablet and placebo Turbuhaler.



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  		Figure 1. The protocol used within each treatment period of the study. The four treatment periods were each separated by a washout period of at least 21 days.

 
On the first day of each treatment period, an MCh inhalation challenge and sputum induction were performed to determine baseline pretreatment airway responsiveness and airway inflammatory status, respectively (Day 1). Subjects began receiving their study medications on the evening of Day 1, continued thereafter, and on Day 8, the MCh challenge and sputum induction were repeated to establish preallergen baseline levels. On Day 9, after receiving the morning dose of study medication, subjects underwent an allergen inhalation challenge; spirometry was monitored throughout the day to check for early and late asthmatic responses. Seven hours after allergen inhalation, sputum induction was repeated to assess airway inflammation. The final dose of study medication was received on the morning of Day 10, after which MCh challenge and sputum induction were performed, 24 hours after allergen inhalation. All measurements for each subject were made at the same time of the day (± 2 hours) at baseline and after each treatment period. Study subjects were allowed to use inhaled ß2-agonists on an as-needed basis throughout the treatment and washout periods but were asked to refrain from doing so 8 hours before any study visit.

Randomization and Allocation Concealment
Randomization was performed by using computer-generated randomization codes, which were maintained by a research pharmacist at McMaster University who was independent of the study. Treatment allocation was concealed from the investigators and participants for the duration of the study. All study medications were independently packaged and labeled by the hospital pharmacy. Placebo tablets were identical in appearance and labeling to montelukast tablets, both of which were supplied by Merck Research Laboratories (Merck Frosst Canada & Co., Montreal, PQ, Canada). Placebo Turbuhalers were identical in appearance and labeling to budesonide Turbuhalers (Pulmicort Turbuhaler, 200 µg/dose), both of which were supplied by AstraZeneca (AstraZeneca Canada Inc., Mississauga, ON, Canada). At the start of a treatment period, each subject was given a new coded container with sufficient study tablets and a new coded Turbuhaler. Inhaler technique was checked at each visit and corrected if necessary. At the end of each treatment period, study medication was returned, and compliance was monitored by counting the number of tablets and Turbuhaler doses remaining.

Outcome Measurements
The primary outcome was the effect of treatment on allergen-induced airway eosinophilia. Secondary outcomes were the effects of treatment on allergen-induced early and late bronchoconstrictor responses and on allergen-induced AHR. The sample size was considered sufficient because previous studies have shown that a group of eight or more subjects has sufficient power to demonstrate differences in allergen-induced airway eosinophilia and in allergen-induced early and late asthmatic responses, using the same methodologies used in this study (8, 26).

Laboratory Procedures
MCh inhalation challenge.
MCh inhalation challenge was performed using the method described by Cockcroft and colleagues (27). Subjects inhaled through a mouthpiece attached to a Wright nebulizer (Roxon Medi-Tech, Montreal, PQ, Canada). Normal saline, followed by doubling concentration increases in MCh were nebulized for 2 minutes each. FEV1 was measured at 30, 90, 180, and 300 seconds after each inhalation using a Collins water-sealed spirometer (Warren E. Collins, Braintree, MA) and kymograph. The test was terminated when FEV1 had fallen to a level at least 20% below the postsaline measurement. The concentration of MCh required to achieve a decrease in FEV1 of 20% (MCh PC20) was calculated through linear interpolation of percent fall in FEV1 against the log-transformed MCh concentration (27).

Allergen inhalation challenge.
Allergen challenge was performed according to the method described by O'Byrne and colleagues (28). The allergen producing the largest skin wheal diameter after skin prick testing was used for subsequent airway challenges. Allergens used were house dust mite (n = 5), cat (n = 4), and tree mix (combination of tree allergens indigenous to North America; viz., Ash, Birch, Hazelnut, Poplar, Oak mix, Willow, Maple, American Beech, Sycamore, and Elm) (n = 1). The concentration of allergen extract for inhalation was determined using a formula derived by Cockcroft and colleagues (29) using the results from skin test titrations and the MCh PC20. During the screening allergen challenge, the starting concentration of allergen extract for inhalation was two doubling concentrations below that predicted to cause a 20% decrease in FEV1. Doubling increases in allergen concentration were inhaled every 10 minutes until a 15% reduction in FEV1 was achieved. FEV1 was then measured at 10, 20, 30, 45, 60, 90, and 120 minutes after allergen inhalation, then each hour until 7 hours after allergen inhalation. The early bronchoconstrictor response was taken to be the largest percent fall in FEV1 within 2 hours after allergen inhalation, and the late bronchoconstrictor response was taken to be the largest percent fall in FEV1 in the period beginning 3 hours and ending 7 hours after allergen inhalation. Maximal decreases in FEV1 were chosen to quantify the early and late response magnitudes based on earlier studies from our group, indicating that these measurements have utility in detecting treatment effects (30). Only subjects who achieved a 15% or greater early and late decline in FEV1 on the allergen screening challenge were randomized, and the same allergen concentrations were used on all subsequent allergen inhalation challenges.

Sputum induction and analysis.
Sputum induction was performed after MCh challenge on Days 1, 8, and 10, and 7 hours after allergen challenge on Day 9 of each treatment period. MCh challenge performed before sputum induction does not significantly alter the cellular and biochemical constituents of sputum (31). Sputum was induced as described by Pin and colleagues (32) and modified as described by Pizzichini and colleagues (33). Briefly, after pretreatment with inhaled albuterol (200 µg), subjects inhaled an aerosol of 3, 4, and 5% hypertonic saline for 7 minutes each from a Medix ultrasonic nebulizer (Clement Clarke, Harlow, Essex, UK). After each inhalation period, subjects expectorated sputum into a container. Sputum was processed within 2 hours of collection as described by Pizzichini and colleagues (34). Total cell counts were performed using a hemocytometer and were expressed as the number of cells per milliliter of sputum. Cells were resuspended in Dulbecco's phosphate buffered saline at 0.75 to 1.0 x 106/ml, and cytospins were prepared using a Shandon III cytocentrifuge (Shandon Southern Instruments, Sewickly, PA). Slides were stained using Diff-Quik (American Scientific Products, Mcgaw Park, IL), and a 400 nonsquamous differential cell count was performed on all slides by a single observer blind to the clinical data; the mean count from two slides per subject was used for analysis.

Statistical Analysis
Statistica software, version 5 (StatSoft, Inc., Tulsa, OK) was used to analyze the data. Measurement variability was expressed using the SD for baseline subject characteristics and SEM for outcome variables. MCh PC20 measurements were log2-transformed to normalize the data and are reported as geometric means (35). The choice of base 2 for the logarithmic transformation allows differences between PC20 values to be expressed as doubling concentrations. Comparisons between treatment periods with respect to early and late asthmatic responses, AHR, and sputum eosinophils were made using two-factor repeated-measures analysis of variance to analyze the effect of the two independent variables, treatment and time, on the outcome variables described previously. Comparisons of treatment effects of placebo and the three active treatment regimens on allergen-induced airway responses were made using separate analyses of variance to compare the largest percent fall in FEV1 during the early and late bronchoconstrictor responses. Similar comparisons were also made by analyzing area under the curve (26). Comparisons between treatment effects of placebo and the three treatment regimens on allergen-induced changes in MCh PC20 and sputum eosinophilia were made using separate analyses of variance. In the case of MCh PC20, the pre- to postallergen delta ({Delta}) PC20 was calculated using the log2-transformed data and is therefore expressed in the text as doubling concentration changes. Appropriate post hoc testing was performed using Duncan's test to assess for significant effects while controlling for multiple comparisons. All comparisons were two-tailed, and p values less than 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Early and Late Responses
There were no significant differences between the preallergen challenge FEV1 values in each treatment arm, being 3.0 ± 0.38 L after placebo, 3.2 ± 0.38 L after budesonide, 3.1 ± 0.45 L after montelukast, and 3.1 ± 0.41 L after combination treatment with both drugs. The maximal early percent fall in FEV1 after placebo treatment was 28.4 ± 4.3% (mean ± SEM), which was not significantly attenuated by treatment with budesonide (25.3 ± 7.0%), although it was significantly reduced by montelukast treatment alone to 12.4 ± 3.9% (p < 0.01) and by combination treatment with budesonide and montelukast to 11.0 ± 3.7% (p < 0.01). Whereas both montelukast treatment alone (p = 0.02) and the combination of montelukast and budesonide (p = 0.01) resulted in a significant attenuation of the maximal early percent fall in FEV1 when compared with budesonide treatment alone, there were no significant differences between treatment with montelukast alone and in combination with budesonide on the maximal early percent fall in FEV1 (Figure 2) .



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  		Figure 2. Time course of the mean decline in FEV1 (expressed as percent below the prechallenge values), after allergen challenge in each treatment period. There was significant attenuation of the maximal early response after treatment with either montelukast or the combination of budesonide and montelukast when compared with placebo (p < 0.01). There was also significant attenuation of the maximal late response by all three active treatment regimens when compared with placebo (p <= 0.01).

 
The maximal late percent fall in FEV1 after placebo treatment was 17.8 ± 4.6%. This was significantly reduced by all three treatments, to 3.4 ± 3.0% after budesonide (p < 0.001), 7.8 ± 3.3% after montelukast (p = 0.01), and 3.0 ± 2.6% after the combination of montelukast and budesonide (p < 0.001). There were no significant differences in the degree of attenuation between budesonide and montelukast, either alone or in combination, on the maximal late percent fall in FEV1 (Figure 2). Similar significant differences between treatment groups were observed for both the early and late responses when the data were analyzed using the area under the curve.

Airway Responsiveness
After treatment, but before allergen inhalation (Day 8), the MCh PC20 increased relative to pretreatment values by 0.82 ± 0.45 doubling concentrations after treatment with budesonide, by 0.52 ± 0.29 doubling concentrations after treatment with montelukast, and by 0.32 ± 0.29 doubling concentrations after treatment with the combination of budesonide and montelukast. However, these increases were not significantly different from the 0.27 ± 0.25 doubling concentration increase after placebo treatment (p > 0.05) (Figure 3) . The allergen-induced decreases in MCh PC20 after treatment with budesonide, montelukast, and the combination of budesonide and montelukast were 0.46 ± 0.39, 0.81 ± 0.28, and 0.47 ± 0.33 doubling concentrations, respectively, which were all significantly less than the 1.49 ± 0.38 doubling concentration decrease after allergen challenge in the placebo treatment phase (p < 0.05) (Figure 3). Furthermore, the allergen-induced decrease in MCh PC20 after treatment with budesonide alone (0.46 ± 0.39) was significantly less than the allergen-induced decrease observed after treatment with montelukast alone (0.81 ± 0.28) (p < 0.05).



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  		Figure 3. Airway responsiveness, as measured by MCh PC20, before and after treatment and allergen challenge in each treatment period of the study. *Indicates a significant difference from pre-allergen value in the same treatment group (p < 0.001). #Indicates a significant difference from placebo at the same time point (p < 0.05). +Indicates that budesonide was significantly different from montelukast at the same time point (p < 0.05).

 
Sputum Eosinophilia
The percentage of sputum eosinophils was not significantly different at the pretreatment visit or at the preallergen visit, being 1.95 ± 0.94% after treatment with placebo, 0.86 ± 0.28% with budesonide, 0.96 ± 0.47% with montelukast, and 0.74 ± 0.88% after combination treatment with both drugs (p > 0.05) (Figure 4) . A significant increase in sputum eosinophilia was measured 7 hours after allergen inhalation (8.10 ± 3.01%) after treatment with placebo (p < 0.01). This allergen-induced sputum eosinophilia was attenuated by treatment with budesonide (2.95 ± 1.24%), montelukast (3.80 ± 1.35%), and by treatment with montelukast and budesonide in combination (4.17 ± 1.55%), all of which were significantly different when compared with placebo (p < 0.05) (Figure 4). Similarly, a significant increase in sputum eosinophilia was measured 24 hours after allergen inhalation after placebo treatment (12.94 ± 4.72%) (p < 0.001), and this was again attenuated by treatment with budesonide (4.85 ± 1.60%), montelukast (3.21 ± 1.62%), and by the combination of montelukast and budesonide (3.72 ± 1.05%), all of which were significantly different from placebo (p < 0.001) (Figure 4). There were no significant differences in the ability of budesonide or montelukast, either alone or in combination, to attenuate sputum eosinophilia at either 7 hours or 24 hours after allergen challenge (p > 0.05). Similar differences were observed when sputum eosinophils were expressed as absolute cell counts.



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  		Figure 4. The percentage of sputum eosinophils before and after treatment and allergen challenge in each treatment period of the study. *Indicates significant difference from preallergen value in the same treatment group (p < 0.01). Filled triangles indicate a significant difference from placebo at the same time point (p < 0.05).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we have observed that montelukast treatment significantly reduced the magnitude of allergen-induced early and late asthmatic responses, allergen-induced AHR, and allergen-induced increases in sputum eosinophilia. In contrast, inhaled budesonide treatment had no significant effect on the early asthmatic response, but did, like montelukast, significantly reduce the late asthmatic response, allergen-induced AHR, and allergen-induced increases in sputum eosinophilia. Using the two drugs in combination offered no significant additional benefit in further attenuating the allergen-induced early asthmatic response, allergen-induced AHR, or allergen-induced increases in sputum eosinophilia compared with either drug alone. Furthermore, the combination did not completely abrogate allergen-induced airway eosinophilia.

This study is the first to directly compare the protection afforded by an ICS with that afforded by montelukast against allergen-induced airway responses and inflammation. The results are consistent with the observations of other investigators who have shown that leukotriene modifiers, including montelukast, significantly reduce bronchoconstriction during the early and late asthmatic responses (22, 36–38). However, the study is the first to demonstrate that montelukast has antiinflammatory properties in significantly attenuating allergen-induced sputum eosinophilia. The only other study to evaluate the effect of montelukast on allergen-induced sputum eosinophilia (22) was unable to demonstrate any treatment effect on this outcome. Possible explanations for this difference include the fact that in that study there was a much smaller allergen-induced increase in sputum eosinophilia in the placebo-treated group and that montelukast was given for an insufficient duration.

Montelukast treatment also significantly attenuated allergen-induced AHR. This result is consistent with the findings of a previous study by our group, in which we demonstrated that treatment with the leukotriene modifier, pranlukast, significantly protected against allergen-induced AHR when compared with treatment with placebo (39). In addition, the current study also demonstrates that budesonide afforded significantly greater protection against allergen-induced AHR than did montelukast, whereas the magnitude of the effect on allergen-induced eosinophilia was similar in all three treatment groups.

If, as we have proposed, budesonide and montelukast attenuate different components of the inflammatory pathway, then the combination of budesonide and montelukast might have been expected to show enhanced attenuation of allergen-induced hyperresponsiveness compared with either drug alone. Although an explanation for this lack of additive effect is uncertain, we speculate that the etiology of AHR is multifactorial and relatively independent of acute, leukotriene-mediated inflammatory events. Although leukotrienes are chemotactic for eosinophils (15, 40), eosinophilic airway inflammation can occur in the absence of AHR (41, 42), and studies using maneuvers to abrogate eosinophilic airway inflammation have shown little effect in attenuating AHR (43, 44). Other inflammatory cells and mediators present in the asthmatic airway are likely to play an important role in the pathogenesis of AHR, and we have recently provided evidence to support the notion that a component of AHR results from chronic structural changes that occur as a consequence of allergen-induced acute airway inflammation (45). It may be that budesonide, with broader antiinflammatory actions that potentially affect these chronic structural changes, is likely to have a greater effect in attenuating allergen-induced AHR compared with montelukast, which blocks leukotriene-mediated eosinophilic inflammation.

The lack of clinical benefit from inhaled budesonide, in terms of improvement in FEV1, between the pretreatment and preallergen phases in the current study, likely relates to the relatively short duration of treatment compared with randomized controlled trials in which 12 months of inhaled budesonide resulted in improvement in lung function (3, 4). Although the current study design was adequately powered (> 90%) to observe a 50% attenuation of the maximum percent late fall in FEV1 and a 50% attenuation of allergen-induced eosinophilia (46), it was not sufficiently powered to detect clinically significant differences in the bronchoprotective effects of the study medications (47); thus, a change of 0.82 doubling doses in MCh PC20 after budesonide treatment compared with a 0.32 doubling dose change after treatment with the combination of budesonide and montelukast likely reflects the variability of the test.

It is perhaps surprising that both budesonide and montelukast had similar effects on attenuating the allergen-induced sputum eosinophilia, although we have performed several allergen challenge studies in our laboratory, and the results from this study are consistent with previous studies in terms of the magnitudes of attenuation of the early and late asthmatic responses, the allergen-induced AHR, and allergen-induced sputum eosinophilia. A possible explanation for the apparently similar antiinflammatory effects of inhaled budesonide and montelukast may relate to the relatively low dose of inhaled budesonide used in the current study (400 µg/day). It is apparent that there is a dose-attenuating effect of inhaled steroids on allergen-induced sputum eosinophilia; in a study by our group (9), mometasone furoate in doses of 200 and 800 µg/day attenuated the 7-hour allergen-induced sputum eosinophilia by approximately 60 and 85%, respectively. Similar dose-effects were seen on 24-hour allergen-induced sputum eosinophilia. Similarly, a study by Gauvreau and colleagues (48) showed that 1 week of treatment with 200 µg budesonide twice a day significantly attenuated the allergen-induced sputum eosinophilia at 24 hours after challenge, from 28.8 ± 4.3% after placebo to 12.6 ± 2.9% after budesonide treatment. Thus, the magnitude of attenuation was similar to that seen in our study, in which we used the same dose of budesonide for the same duration of treatment. The antiinflammatory effects of montelukast on allergen-induced sputum eosinophilia have only been examined in one previous study (22), as discussed earlier. However, two previous studies in our laboratory (39, 49) showed that leukotriene modifiers attenuated early and late asthmatic responses, as well as allergen-induced AHR, by similar magnitudes as montelukast did in our current study, and we are thus satisfied that the magnitude of attenuation in sputum eosinophils after treatment with montelukast is valid.

Although both budesonide and montelukast treatment, alone and in combination, significantly attenuated allergen-induced airway eosinophilia, none of the three active treatment regimens completely abrogated airway inflammation. This suggests that at least some chemoattractants responsible for recruiting eosinophils into the asthmatic airway act independently of leukotriene-mediated, or steroid-sensitive, inflammatory events. Such pathways might also explain why both montelukast and budesonide were similar in inhibiting sputum eosinophilia to equivalent baseline levels. Whereas there has been some recent controversy as to the functional role of eosinophils in the pathogenesis of asthma (43, 50), our results indicate that if in fact, eosinophils do play a central role in asthma, then budesonide and montelukast, either alone or in combination, may be insufficient to optimally control the airway inflammation observed in asthma.

In summary, we have demonstrated that treatment with either budesonide or montelukast had significant antiinflammatory effects when compared with placebo, although treatment with budesonide and montelukast in combination did not provide greater antiinflammatory effects than either drug alone. However, the fact that montelukast was able to attenuate the early asthmatic response and that budesonide and montelukast, either alone or in combination, were able to attenuate the late asthmatic response, allergen-induced AHR, and allergen-induced sputum eosinophilia indicates that these two compounds act on different mediators within the inflammatory pathways that mediate allergen-induced airway inflammation.


   Acknowledgments
 
The authors thank Joceline Otis and Russ Ellis for their expert technical assistance.


   FOOTNOTES
 
Supported by a grant-in-aid from Merck Frosst Canada & Co. R.L. is a Canadian Institutes of Health Research Fellow, and M.I. is the Harbinger Fellow in Respiratory Medicine.

Received in original form June 4, 2002; accepted in final form August 12, 2002


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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