(Chest. 2001;119:402-408.)
© 2001
American College of Chest Physicians
Anti-inflammatory and Lung Function Effects of Montelukast in Asthmatic Volunteers Exposed to Sulfur Dioxide*
Henry Gong, Jr., MD, FCCP;
William S. Linn, MA;
Sheryl L. Terrell, BA;
Karen R. Anderson, BS and
Kenneth W. Clark, MA
*
From the Environmental Health Service (Mss. Terrell and Anderson, and Mr. Clark), Rancho Los Amigos, National Rehabilitation Center, Downey, CA; and the Departments of Medicine (Dr. Gong) and Preventive Medicine (Mr. Linn), Keck School of Medicine, University of Southern California, Los Angeles, CA.
Correspondence to: Henry Gong, Jr., MD, FCCP, 51 Medical Science Building, Rancho Los Amigos National Rehabilitation Center, 7601 East Imperial Hwy, Downey, CA 90242; e-mail: hgong{at}dhs.co.la.ca.us
 |
Abstract
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Background: Sulfur dioxide (SO2) gas may
induce acute asthmatic responses when inhaled by individuals in the
setting of community or occupational air pollution during
exercise. Some asthma medications mitigate the SO2
response, which is not fully understood but appears to involve multiple
mechanisms.
Objective: We tested the hypothesis that
pretreatment with the cysteinyl-leukotriene inhibitor montelukast
sodium protects against the inflammatory and bronchoconstrictive
effects of SO2 in the airways of asthmatic subjects.
Methods: Asthmatic volunteers (enrolled, 12 subjects;
completed study, 11 subjects) were exposed to 0.75 ppm SO2
for 10-min periods during exercise (mean ventilation, 35 L/min) and
were exposed similarly to filtered air (control condition) after
double-blinded pretreatments with montelukast (10 mg/d for 3 days) and
placebo.
Results: After montelukast pretreatment,
specific airways resistance, FEV1, symptoms, and eosinophil
counts in induced sputum showed statistically and clinically
significant improvements in preexposure measurements and/or decreased
responses to SO2 exposure or exercise. The mean
FEV1 immediately after exposure was 95% of baseline
FEV1 with montelukast pretreatment vs 82% with
placebo.
Conclusion: Montelukast significantly
protects against airways eosinophilic inflammation and
bronchoconstriction from SO2 exposure during
exercise. This implies a role for leukotrienes in
SO2-induced lung effects.
Key Words: air pollutants • airway resistance • asthma • leukotrienes • montelukast • spirometry • sputum induction • sulfur dioxide
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Introduction
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Sulfur
dioxide (SO2) is a common irritant pollutant gas
in community and workplace air. Many individuals with asthma (even very
mild asthma) are highly sensitive to SO2,
experiencing clinically significant airways constriction and symptoms
after a few minutes of moderate exercise in SO2
concentrations as low as 0.25 ppm,1
which is within the
range of community and workplace exposures. The
SO2 response resembles exercise-induced
bronchoconstriction in its rapid onset (ie, within 1 to 3
min) and spontaneous reversal (ie, within 1 to 2 h
while resting in clean air). However, exercise is not necessary to
induce the response if the inhaled dose rate of
SO2 is sufficiently high (eg, at
concentrations of several parts per million). Among standard
pharmacologic agents, inhaled {beta}2-agonists are
highly (but < 100%) effective in blocking the
SO2-induced bronchoconstrictive response, while
ipratropium, cromolyn, and theophylline block the airway response to a
lesser degree.1
The role of airways inflammation and the
efficacy of anti-inflammatory medications in the asthmatic response to
SO2 have not been investigated extensively.
The recent development of a new class of pharmacologic agents,
cysteinyl-leukotriene receptor antagonists, offers possibilities for
clinical management and for exploring mechanisms of the asthmatic
response to SO2. These medications exhibit both
anti-inflammatory and bronchodilator activity, and appear to be
generally safe and effective with once-daily or twice-daily oral
dosing.2
3
4
5
Lazarus et al6
investigated the
effect of one such agent, zafirlukast, on the SO2
response by challenging asthmatic volunteers with increasing
concentrations of SO2 during eucapnic
hyperventilation at rest. The investigators found that pretreatment
with a single 20-mg dose of zafirlukast approximately doubled the
SO2 concentration required to provoke a given
degree of bronchoconstriction, and they concluded that
SO2-induced bronchoconstriction involves the
release of leukotrienes. Montelukast, another leukotriene receptor
antagonist, has been found to reduce airway eosinophilic inflammation
in patients with asthma, as measured by cell counts of induced
sputum,7
and to mitigate bronchoconstriction induced by
exercise8
9
or allergen challenge.10
On the basis of the above evidence, we hypothesized that montelukast
would block inflammatory effects and bronchoconstrictive effects in
asthmatic subjects exposed to SO2 with exercise
under conditions representative of outdoor or occupational air
pollution exposures. Effective protection by montelukast would strongly
imply that leukotrienes play a major causative role in
SO2-induced lung effects, would reveal another
therapeutic dimension of leukotriene receptor antagonists in protection
against pollution effects, and would motivate further mechanistic
studies with other pollutants. To test our hypothesis, we exposed adult
asthmatic volunteers, pretreated with montelukast sodium (Singulair;
Merck & Co; West Point, PA) or placebo, to filtered air (control
condition) and to 0.75 ppm SO2 in filtered air
for 10-min periods with continuous moderate exercise. We measured their
responses in terms of symptoms, lung function, and counts of
inflammatory cells from induced sputum.
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Materials and Methods
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Subject Recruitment and Screening
Twelve adult volunteers aged 20 to 48 years with comparatively
mild asthma were recruited by word of mouth or advertisements. Each
subject gave written informed consent and was paid a participation fee.
The protocol was reviewed and approved by the institutional review
board for Rancho Los Amigos National Rehabilitation Center. Inclusion
criteria were the following: asthma of > 1 year duration that had
been treated primarily with an inhaled bronchodilator (either regularly
or intermittently as needed) and had been clinically stable for > 4
weeks prior to entrance into the study; the ability to withhold
treatment with respiratory medications prior to each laboratory visit;
pretreatment FEV1 of 
70% of the predicted
value; and 15% FEV1 decline after a
screening SO2 challenge (see below). Exclusion
criteria were the following: the use of a corticosteroid or a
leukotriene antagonist medication within 4 weeks of entrance into the
study; smoking within 1 year of study; an allergy to the study drug or
to inhaled {beta}-agonists; clinically significant cardiopulmonary or
metabolic disease other than asthma; an inability to exercise on a
cycle ergometer; and pregnancy or nursing. Women with child-bearing
potential had negative results for pregnancy tests at the outset and
were required to practice effective contraception during the study.
During a screening evaluation, subjects gave medical histories
(including medications and allergies) and underwent routine physical
examinations, spirometry to determine FVC and
FEV1, 12-lead resting ECGs, urinary pregnancy
tests (women only), and 10-min exposures to 0.75 ppm
SO2 in filtered air at 22°C and 60% relative
humidity in a previously prepared environmentally controlled
chamber.11
The test gas was metered into the chamber from
a cylinder of 5% SO2 in nitrogen. The
SO2 exposure concentration was monitored by a
pulsed fluorescent SO2 analyzer (Meloy;
Springfield, VA), which was calibrated with a permeation-tube
apparatus. During the challenge, the subject exercised continuously
(for 10 min) on a cycle ergometer to achieve a minute ventilation of 25
to 30 L/min (a work intensity that should not elicit clinically
significant exercise-induced bronchoconstriction). A 15% loss in
FEV1 was required at 5, 10, 15, or 30 min
postchallenge to qualify for further participation in the study.
Experimental Protocol
Each subject was scheduled for four laboratory visits, at
approximately the same time of day and not < 14 days apart, to
undergo challenges with the following four pretreatment/exposure
conditions: placebo/filtered air; placebo/SO2;
montelukast/filtered air; and
montelukast/SO2. The order of presentation
was counterbalanced and randomly assigned. Nominally double-blind
conditions were maintained, although we could not rule out the
possibility that some subjects distinguished active drug from placebo
by their symptom levels, and/or distinguished SO2
from filtered air by odor, taste, or symptom responses. Tablets of
montelukast (10 mg per tablet) and identically appearing placebo, with
coded labels, were supplied by Merck & Co. For pretreatment, the
subject took one tablet at 8 PM on each of the 3 days
immediately preceding each scheduled laboratory visit/exposure. Thus,
with 14 days between visits, the washout interval between
successive pretreatments was 11 days.
On arrival at the laboratory on the morning of an exposure, the subject
underwent a brief cardiopulmonary examination and gave an interval
medical history, and underwent ECG electrode application and
preexposure measurements of specific airways resistance (SRaw),
FEV1 (required to be within 10% of screening
value), and FVC, as well as respiratory and nonrespiratory symptoms
scored on a standardized questionnaire (scoring details are given in
Table 2 ). SRaw measurements employed a constant-volume whole-body
plethysmograph (locally manufactured), which was calibrated daily by
applying known pressure, volume, and flow signals. Four successive
measurements were made at each time of testing, and the result was
expressed as the mean. Forced expiratory measurements were made using a
pneumotachograph-based spirometer (Vmax System; Sensormedics, Inc;
Yorba Linda, CA), which was certified to meet American Thoracic Society
standards for accuracy12
and was calibrated daily with a
volumetric syringe according to the manufacturer’s procedure. Three
blows meeting American Thoracic Society criteria12
were
recorded at each time of testing, and the result was expressed as the
largest of the three FEV1 values. Experimental
exposures employed the same facilities and 10-min protocol used in the
screening SO2 challenges. The individual
ergometer workloads that evoked the target ventilation rate of 25 to 30
L/min in the screening examinations were maintained in all exposures;
however, exercise ventilation rates during exposures averaged higher
(see "Results" section). The subject was continuously monitored by
direct observation and ECG telemetry. Breathing was unencumbered
throughout exposure, except when ventilation was measured via
mouthpiece during the final 2 min. The SRaw measurement was repeated
immediately (ie, at approximately 1 min) after the
completion of exposure and at 1 h and 2 h later. Symptoms
were recorded at the time of each SRaw measurement, and
FEV1 was measured immediately afterward
(ie, approximately 5 min after exposure ended for the
initial postexposure measurement). Additional
FEV1 measurements were made 10 min, 15 min, and
30 min after the end of the exposure. No subject required
bronchodilator medication to relieve symptoms postexposure.
Sputum induction13
14
was performed 2 h after
completion of the exposure. The subject rested in a filtered-air
environment in the interim. After the 2-h postexposure measurements of
SRaw and FEV1, the subject inhaled 360 µg
albuterol to avoid possible bronchoconstriction during sputum
induction, and the FEV1 was remeasured. Next, the
subject inhaled 3% sterile saline solution for 20 min from an
ultrasonic nebulizer (Ultraneb 99; DeVilbiss; Jackson, TN),
while actively coughing and expectorating sputum and saliva into
separate sterile specimen containers every 2 min. The collected sputum
was diluted 1:1 with a 0.1% dithiothreitol solution and was
homogenized by gentle vortex mixing and shaking in a water bath at
37°C for 15 min. A 10-µL aliquot of homogenized sputum was used to
determine the total cell count using a standard hemocytometer. WBCs,
columnar epithelial cells, and squamous epithelial cells were counted
under blind conditions, and the results were expressed as
thousands of cells per milliliter of sputum. A 250-µL aliquot was
diluted in saline solution and cytocentrifuged (Cytospin 3; Shandon;
Pittsburgh, PA) onto glass slides, which were air dried and
subsequently stained with May-Grünwald-Giemsa stain (Diff-Quik
Kit; Hamilton Thorne Research; Beverly, MA) for differential
counting. For each subject under each experimental condition, a minimum
of 500 nonsquamous cells were read from three or four slides, each with
> 50% nonsquamous nucleated cells. Monocytes, lymphocytes,
neutrophils, eosinophils, and columnar epithelial cells were counted by
a blinded investigator, and the results were expressed as percentages
of the total of these five cell types.
Data Analysis
Response measurements included SRaw, FEV1,
and symptom scores before, immediately after, 1 h after, and
2 h after exposure, as well as airway inflammation indexes
(ie, total sputum cell counts and differential counts)
2 h after exposure. FEV1 and SRaw were
analyzed in their original units and also as percentages of their
baseline values, which were defined as the means of the two preexposure
measurements with placebo pretreatment (ie, the best
estimates of FEV1 or SRaw in the absence of any
experimental intervention). Statistical conclusions were essentially
the same either way. For SRaw, FEV1, and symptom
score, we analyzed changes from before exposure to immediately after
exposure, when group mean responses were maximal.
FEV1 data were reanalyzed in terms of the
time-integrated deficit as determined from the area under the curve of
FEV1 vs time postexposure, plotted from all six
measurements during the first 2 h after exposure. Statistical
conclusions were essentially the same as in the original analysis. The
principal statistical technique was analysis of variance with repeated
measures on subjects (each subject as his/her own control), employing
commercial statistical software (BMDP Dynamic; SPSS Inc; Chicago, IL).
When necessary to stabilize variance, data were log-transformed before
analysis. All the aforementioned analyses necessarily excluded subject
2, who missed two treatments. The analyses of total cell counts also
excluded subjects 3 and 7, whose data were unsatisfactory on one
occasion. As described in the "Results" section, additional
analyses were performed to compare the two conditions of most interest
(montelukast/SO2 and
placebo/SO2) for which data were available for
all 12 subjects.
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Results
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Table 1
summarizes demographic and physiologic characteristics of the 12
recruited subjects. Eleven subjects underwent all four
pretreatments/expo- sures. Subject 2 withdrew (for personal
reasons unrelated to the study) after completing only the
montelukast/SO2 and
placebo/SO2 parts of the study. Apart from the
expected postexposure bronchoconstriction, no clinically adverse events
were associated with any experimental medications or procedures. The
mean (± SD) ventilation rates measured near the end of exposure
periods were 35 ± 13 L/min; they did not vary significantly between
placebo and montelukast, or between filtered air and
SO2.
Lung Function and Symptom Responses
Tables 2
, 3
and Figures 1
, 2
show the effects of montelukast pretreatment on lung function and
symptom responses to the experimental exposures. With placebo
pretreatment, the subjects showed, on average, mild airways
constriction after filtered air exposure with exercise
(ie, a mild increase in SRaw and a mild decrease in
FEV1 without a net increase in symptoms) and a
more marked bronchoconstriction after 0.75 ppm
SO2 exposure/exercise (ie, much larger
decrements in lung function and increases in lower respiratory
symptoms). These responses were as expected in a group of subjects with
mild-to-moderate asthma who were prescreened for responsiveness to
SO2. With montelukast pretreatment, mean
preexposure lung function and symptom scores improved slightly,
responses to filtered air/exercise were still slight, and responses to
0.75 ppm SO2/exercise were mitigated to a
clinically and statistically significant extent, relative to placebo
pretreatment. Repeated-measures analyses of variance (Table 3)
showed
that the main effect of montelukast pretreatment vs placebo was
significant (p < 0.05) in the favorable direction for SRaw,
FEV1, and total symptom score; one or more
interactions of drug with exposure and time effects were also
significant for each of the three response measures, reflecting the
mitigation of SO2 and/or exercise effects by
montelukast. As Table 2
indicates, the improvement of preexposure
FEV1 or SRaw attributable to montelukast
pretreatment was small; thus, mitigation of
SO2/exercise effects was the more important
effect of montelukast in maintaining airway patency.
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Figure 1.. FEV1 (expressed as a percentage of
baseline value mean ± 95% confidence limit) before and after exposure
to 0.75 ppm SO2 with exercise following placebo or
montelukast (Monte) pretreatment. Pre = pretreatment.
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For the 11 subjects who completed the study, the mean
FEV1 immediately after exposure, relative to
baseline (ie, the mean of placebo preexposure measurements)
was 97% with placebo/filtered air, 101% with montelukast/filtered
air, 85% with placebo/SO2, and 95% with
montelukast/SO2. For all 12 subjects, the means
were 95% with montelukast/SO2 and 82% with
placebo/SO2; this difference was significant
(p < 0.05), as measured by paired t test. The analogous
paired comparisons were also significant for SRaw and total symptom
score. In terms of SO2/exercise effects on
FEV1, the protective index (ie, one
minus the ratio of the percentage loss after montelukast administration
to the percentage loss after placebo administration) was 54%. This
understates the beneficial effect of montelukast, in that mean
FEV1 preexposure/postmontelukast administration
was increased relative to the mean FEV1
preexposure/postplacebo administration, thus yielding a larger
percentage loss for a given level of FEV1
postexposure/postmontelukast administration. Calculated in terms of the
mean 5% loss from baseline FEV1 postmontelukast
administration, relative to the mean 18% loss from baseline
postplacebo administration, the protective index was 72%. With
montelukast pretreatment, 9 of 12 subjects retained at least 90% of
baseline FEV1 after SO2
exposure/exercise, and no subject fell to < 80% of baseline
FEV1. With placebo pretreatment, only five
subjects retained at least 90% of their baseline
FEV1, while five subjects fell to < 80% of
baseline. These differences were significant (p < 0.05 by McNemar’s
test for paired measurements of categorical variables). Even with
placebo pretreatment, unfavorable responses to
SO2/exercise reversed promptly;
FEV1 averaged 95% of baseline after 1 h,
and 98% after 2 h (Fig 1)
.
Inflammatory Cells in Induced Sputum
Table 4
presents results of total cell counts for the nine subjects with
complete data. None of the total cell counts varied significantly
according to pretreatment and/or exposure atmosphere (p > 0.10 for
main effects and interactions), although they tended to be lower after
montelukast pretreatment than after placebo, and higher after
SO2 exposure than after filtered air exposure.
Table 5
presents results from differential counts of sputum cells for the 11
subjects who completed the study. Variations in the percentages of
monocytes, lymphocytes, and columnar epithelial cells were
nonsignificant. Neutrophil percentages were lower with montelukast
pretreatment than with placebo, and the main effect of the drug
approached significance (p = 0.053). Significant variation occurred
with the measurement of sputum eosinophils. In the analysis of
log-transformed data, the main effect of the drug (ie, the
decreased percentage of eosinophils after montelukast pretreatment) was
significant (p = 0.008), as was the main effect of atmosphere
(ie, the increased percentage after
SO2 exposure) (p = 0.039). The interaction was
nonsignificant. A paired t test comparing
montelukast/SO2 with
placebo/SO2 showed a significant (p = 0.03)
difference for all 12 subjects. Individual sputum eosinophil data are
shown in Figure 3
.
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Figure 3.. Individuals’ percentages of eosinophils
among sputum cells induced 2 h after exposure to 0.75 ppm
SO2 or filtered air (FA), after placebo or montelukast
pretreatment. Symbols represent individual subjects, and horizontal
lines represent means. Two subjects showed no eosinophils in any
pretreatment/exposure condition. See Figures 1
, 2
for abbreviations not
used in the text.
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Discussion
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A variety of therapeutic agents, including {beta}-adrenergic
agonists, theophylline, atropine, ipratropium bromide, cromolyn,
nedocromil, and H1-antihistamine, can partially
block SO2-induced bronchoconstriction in
asthmatic subjects.1
15
{beta}-Adrenergic agonists appear to
be the most effective, but none of these drugs completely blocks the
response, suggesting that more than one mechanism is involved. Proposed
mechanisms of SO2-induced bronchoconstriction
include a reflex involving both vagal afferent nerves and cholinergic
efferent nerves to airway smooth muscle, as well as stimulation of mast
cells or sensory receptors. Our finding that montelukast can mitigate
bronchoconstrictive responses to SO2 is
consistent with the previous physiologic findings reported by Lazarus
et al6
concerning another leukotriene receptor antagonist,
zafirlukast. Quantitative comparisons of the
SO2/lekotriene-modifier studies are difficult
because the study designs and SO2 exposures
differed substantially. However, both studies support the concept that
leukotrienes are important mediators of the bronchoconstrictive
response to SO2. Both show only partial blocking
of the response, again suggesting that more than one mechanism is
involved. Nevertheless, our findings indicate that montelukast has
relatively high effectiveness in preventing SO2
response, similar to that of {beta}-agonists. In our previous study of
medication effects on SO2/exercise
response,15
the immediate decrease in
FEV1 averaged about 7% after pretreatment
with inhaled salmeterol. In the present study, with a similar exposure
protocol and subject selection criteria, the immediate
FEV1 decrease averaged about 8%.
We also detected a significant SO2-induced
increase in sputum eosinophilia within several hours after exposure,
indicating that sufficient exposure to SO2 in
asthmatic subjects can acutely elicit allergic (eosinophilic) airways
inflammation. Such a cellular response in the proximal airways has not
been previously reported with exposure to these levels of
SO2, to our knowledge, although inflammatory cell
influx has been observed by BAL after exposure to 8 ppm
SO2.16
The increased airways
responsiveness of atopic/asthmatic individuals to the effects of air
pollutants such as SO2 may result from increased
susceptibility to cell-membrane injury by pollutants and the propensity
of airway epithelial cells to release increased amounts of specific
proinflammatory mediators following interaction with inhaled
irritants.17
The release of interleukin (IL)-5, IL-8, and
cysteinyl leukotrienes, as well as other mediators, may cause
chemoattraction, activation, and recruitment of eosinophils into the
airways.17
18
19
A short course of montelukast pretreatment had a significant
anti-inflammatory effect by reducing the number of sputum eosinophils
with both filtered air and SO2 exposures. The
findings with filtered air are qualitatively consistent with the
previous observation by Pizzichini et al7
of a 3.6
percentage point decrease in sputum eosinophils after 4 weeks of
montelukast treatment in asthmatic subjects. A direct comparison
between their study and ours is problematic, in that we did not recruit
asthmatic subjects with > 5% sputum eosinophils and did not conduct
sputum induction weeks after the montelukast therapy was initiated.
However, Diamant et al10
reported that montelukast
pretreatment did not significantly affect sputum eosinophils or other
markers of airway inflammation in nine asthmatic volunteers who were
challenged with house dust mite extract. However, sputum analysis was
not a main focus of their study, and their subjects’ eosinophil counts
were somewhat unstable and typically higher than those of our subjects,
so no firm conclusions can be drawn from the comparison.
This study was limited by several factors. The number of subjects was
relatively small, but the group still demonstrated both significant
SO2 exposure and drug (montelukast) effects,
including a rapid onset of drug protection. Measurements of drug levels
in blood and of mediators in sputum (eg, IL-5, IL-8, and
eosinophil cationic protein), as well as measurements of response at
more than one concentration of SO2, would have
been helpful for mechanistic reasons but were not feasible in this
study. The cellular profiles in the induced sputum might have been
different if sputum induction had been performed 18 h or 24 h
after exposure, allowing more time for effects of the same or different
mediators to be manifested. If anything, greater or more highly
significant effects of montelukast and SO2 would
be expected 18 to 24 h postexposure.
In summary, in our mildly asthmatic,
SO2-responsive volunteer group, pretreatment with
montelukast (10 mg/d for 3 days) had unequivocally favorable effects on
the following different outcome measures: airways inflammation (as
reflected by sputum eosinophil counts); airway physiology (as reflected
by SRaw and FEV1 levels); and respiratory
symptomatology (as reflected by symptom scores) after exposure to 0.75
ppm SO2 during moderate exercise. Montelukast
both improved airway status preexposure and mitigated responses to
exposure. On average, improvement preexposure was more important with
respect to sputum eosinophil counts, while the mitigation of the
SO2/exercise response was more important with
respect to lung function and symptom measures.
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Figure 2.. Symptom score change under each
pretreatment/exposure condition. Horizontal line indicates the mean
score preexposure, symbols indicate the mean score immediately
postexposure, and the vertical error flags indicate 95% confidence
limits of change preexposure to postexposure. The scoring procedure is
described in Table 2
. Plac = placebo. See Figure 1
for other
abbreviations not used in the text.
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Footnotes
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Abbreviations: IL = interleukin;
SO2 = sulfur dioxide; SRaw = specific airways
resistance
Supported by Merck & Co Medical School Grant Program SING-US-33–97, by
National Institute of Environmental Health Sciences grants
5P30-ES07048–03 and 1P01ES09581–01, and by US Environmental
Protection Agency grant R826708–01-0. One author (H.G.) is a member of
the Merck & Co. Speakers Bureau.
Received for publication May 4, 2000.
Accepted for publication August 3, 2000.
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M. Gaga, N. Papageorgiou, E. Zervas, D. Gioulekas, and S. Konstantopoulos
Control of Asthma Under Specialist Care: Is It Achieved?
Chest,
July 1, 2005;
128(1):
78 - 84.
[Abstract]
[Full Text]
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I.E. Zuhlke, F. Kanniess, K. Richter, D. Nielsen-Gode, S. Bohme, R.A. Jorres, and H. Magnussen
Montelukast attenuates the airway response to hypertonic saline in moderate-to-severe COPD
Eur. Respir. J.,
December 1, 2003;
22(6):
926 - 930.
[Abstract]
[Full Text]
[PDF]
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TOP
Abstract
Introduction
