Original Article www.jpgmonline.

com

A randomized, open labeled, comparative study

to assess the efficacy and safety of controller
medications as add on to inhaled corticosteroid
and long-acting β2 agonist in the treatment of
moderate-to-severe persistent asthma
Patel YA, Patel P, Bavadia H1, Dave J1, Tripathi CB

Department of
Pharmacology,
Government Medical
College, 1Department
of Tuberculosis and
Respiratory diseases,
Sir Takhtsinghji hospital
and Government
Medical College,
Bhavnagar-364001
Gujarat, India
Address for correspondence:
Dr. C. B. Tripathi
E-mail: cbrtripathi@yahoo.
co.in
Received : 03-03-10
Review completed : 01-05-10
Accepted : 28-06-10
PubMed ID : ***
DOI: 10.4103/0022-3859.70937
J Postgrad Med 2010;56:270-74
ABSTRACT
Background: The goal of asthma therapy is to achieve clinical control and near normal lung functions. Many
patients with persistent asthma fail to achieve this goal with a single controller medication add on to a inhaled
corticosteroid. We have checked whether another controller medication add on to inhaled corticosteroid and
long-acting β2 agonist helps in achieving the asthma goal or not. Objectives: To identify the effect of controller
medication add on to inhaled corticosteroid and the long-acting β2 agonist on the clinical symptom, lung function,
and compliance in patients with asthma. Materials and Methods: We conducted a randomized, open-labeled,
comparative trial in 50 participants with moderate-to-severe persistent asthma. The study duration was of 10
weeks. During the first two weeks of the run-in period all the participants received a dry powder inhaler drug
delivery of budesonide (400 mcg/day) and formoterol (12 mcg/day) combination. At the end of the run-in period
the participants were randomly allocated into three groups: group A (n = 16) received oral montelukast (10
mg/day); group B (n = 17) received oral doxophylline (400 mg/day), and group C (n = 17) received inhaled
budesonide (400 mcg) as add on to the above-mentioned drugs of the run-in period. The primary outcome
was improvement in forced expiratory volume at 1 second (FEV1). Results: All the participants of the three
groups had significant improvement in FEV1 (P < 0.001) and asthma symptoms at the end of 10 weeks. The
mean increase in FEV1 (% of predicted) from the baseline, in groups A, B, and C was: 24.6; 21.33, and 19.86%,
respectively. Conclusions: All add on controller medications helped, with a significant improvement of lung
functions and asthma symptoms.
KEY WORDS: Asthma, inhaled corticosteroid, long-acting beta2 agonist, montelukast sodium, doxophylline,
add on therapy

Introduction corticosteroids.[2,3] A combination of a long-acting β2 agonist

with inhaled corticosteroid is the preferred treatment, when

T he goal of asthma therapy is to achieve and maintain

asthma control, that is, clinical control and near-normal
lung functions.[1] Controller medications are taken daily on
a long-term basis to keep asthma under control. Among the
controller medications, inhaled corticosteroids (ICS), long-acting
β2 agonist (LABA), leukotrine receptor antagonist (LTRA),
methylxanthines, and anti-cholinergics are the ones mainly used.
Inhaled corticosteroids are the most effective anti-inflammatory
medications in reducing asthma symptoms, improving the lung
function, and reducing the airway inflammation in persistent
asthma.[1] The long acting β2 agonists, like formoterol and
salmeterol, are most effective when combined with inhaled
the inhaled corticosteroid alone fails to achieve control of the
asthma.[1] In spite of the combination of these two medications,
many patients with persistent asthma fail to achieve the desired
goal.[4,5] Therefore, addition of another controller medication is
often required. A combination of inhaled corticosteroid and the
long-acting β2 agonist is more effective than a combination of an
inhaled corticosteroid and a leukotrine receptor antagonist.[6,7]
Monotherapy with montelukast, a leukotrine receptor antagonist
has shown improvement in the lung function in previous studies.[8,9]
Theophylline, a methylxanthine, has additional anti-inflammatory
and immunomodulatory effects at a lower serum concentration (<
10 mg/L) apart from a bronchodilator effect.[10] Daily single dose

 270 Journal of Postgraduate Medicine October 2010 Vol 56 Issue 4


therapy with theophylline as an add on to inhaled corticosteroid
has shown more benefit in persistent asthma than inhaled
corticosteroid alone, in previous studies.[11,12] Doxophylline,
a newer methylxantine claims to have better gastrointestinal
tolerability than theophylline.[13]
From the above information we wanted to identify whether or
not another controller medication in the form of montelukast,
doxophylline or inhaled budesonide as add on to the
combination of inhaled budesonide and formoterol would help
in achieving better control of the symptoms and improving
the lung functions in the case of a moderate-to-severe type of
persistent asthma.
Materials and Methods
Protocol
The study was a randomized, open-labeled, and comparative
clinical trial. The protocol was approved by the institutional
review board of the Government Medical College; Bhavnagar
(Gujarat).The study was conducted according to the ICH GCP
guidelines, 2008 amendment. The participants were recruited
from the Department of Tuberculosis and Respiratory Diseases,
Sir T. General Hospital, Bhavnagar, a tertiary care hospital. The
participants included in the study were aged between 15 and
65 years, either gender; had clinically diagnosed asthma; poor
asthma control, defined by an asthma control questionnaire
score (ACQ) of 1.5 or greater; FEV1 value of 50% or more of the
predicted; and improvement in FEV1was greater than 15% after
bronchodilator inhalation.[14,15] The participants were excluded if
they were smokers; pregnant and lactating woman; had a major
illness other than of the respiratory system; had a major illness of
the respiratory system other than asthma; had taken long-acting
antihistamines within the preceding week of enrollment, or had a
history of hypersensitivity to any of the above-mentioned drugs.
No formal sample size calculation was performed, as this was
a pilot study to compare the effectiveness of three different
treatment strategies with controller medications, in the
management of moderate-to-severe asthma. The total study
period was of 10 weeks, which included a run-in period of two
weeks. The aim of the run-in period (based on previous studies
[16,25]
) was to make all the groups comparable, with regard to
the treatment strategy at the point of randomization.[16,25] At
the time of recruitment: informed consent; a detailed medical
history and physical examination; baseline pulmonary function
tests; and asthma control questionnaire score calculation was
conducted.[14,15] Also the laboratory test including routine
blood counts, liver function tests, and kidney function tests
were conducted at the time of recruitment and at the end of 10
weeks. During the run-in period, all the participants were given
dry powder inhaler drug delivery of budesonide (400 mcg/day)
and formoterol (12 mcg/day) combination, with the help of a
dry powder inhaler (Rotahaler; Cipla Ltd.), in two divided doses.
(Budamate dry powder inhaler drug delivery; Lupin Pharma) The
next follow-up was conducted at the end of two weeks. On this
visit, pulmonary function tests, history of medical illness, and
physical examination were carried out. The participants were
randomly allocated to three groups: A, B, and C with 16, 17,
Journal of Postgraduate Medicine October 2010 Vol 56 Issue 4 271 
Patel, et al.: Controller medications in asthma 
and 17 participants in each group, respectively, with the help of
random allocation software version 1.0.0.
After randomization, participants of groups A, B, and C were
daily given an oral tablet of montelukast 10 mg/day (Romilast;
Ranbaxy Laboratories Ltd.) in the evening, an oral tablet of
doxophylline sustained release 400 mg/day (Doxolin-SR; German
Remedies) in the morning, and inhaled budesonide 400 mcg/day
(Budate dry powder inhaler drug delivery; Lupin Pharma) in two
divided doses, respectively, as add on to the above combination
of budesonide (400 mcg/day) and formoterol (12 mcg/day) dry
powder inhaler drug delivery.
The participants were followed at two, four, and eight weeks
post randomization. During each visit a detailed medical history,
physical examination, pulmonary function tests, asthma control
questionnaire score calculation, and inquiry about any adverse
drug reactions was conducted. During the study period all the
participants were allowed to use metered dose inhaler of a short
acting β2 agonist as a rescue medication.
Outcomes
The primary outcome was a percentage of improvement
in FEV1. The secondary outcomes included a percentage
of improvement in the peak expiratory flow rate (PEFR),
improvement in the asthma control questionnaire scores, rates
of adverse drug reactions, and episodes of poor asthma control
(EPACs) defined by any of the following events occurring any
time during the follow-up period: a decrease in PEFR more
than 30% over baseline; increased use of metered dose inhaler
of the short acting β2 agonist by more than four metered doses
a day; use of oral corticosteroid; or any unscheduled asthma
healthcare visit.
Statistical analysis
The statistical analysis was done using Sigma Stat version 3.5.
Wilcoxon signed ranked test was used to compare the 10-week
values of FEV1 and PEFR with the baseline and the two-week
values, and to compare the 10-week values of the asthma control
questionnaire score with the baseline value. Kruskal-Wallis One
Way Analysis of Variance on Ranks was used to compare the 10-
week values of FEV1 and PEFR among the three groups, when
adjusted for the baseline, age, and sex; to compare the episodes
of poor asthma control rates (EPACs) among the three groups;
and the group difference of asthma control questionnaire score
at 10 weeks. A P value of < 0.05 was considered significant. Per
protocol analysis has performed.
Results
FEV1 and PEFR
A total of 50 participants were randomized. Forty-five
participants had completed all the follow-up visits, with 15
participants in each group. Five participants were excluded
from the final analysis because they were lost to follow up (n =
4) before the first follow-up visit, and withdrawal of consent (n
= 1), at the first follow-up visit, 15 days after randomization.
Baseline characteristics of the participants were matched and
are shown in Table 1. The daily treatment history of participants
 Patel, et al.: Controller medications in asthma

of all groups, during the past six months is shown in Table 1. weeks (P < 0.001) [Table 2], but the difference in the extent of
After adjusting for age, sex, and baseline characteristics all improvement among the three groups was not significant (P =
the groups had shown significant improvement in FEV1 at 10 0.807). Similarly in the case of PEFR all the groups had shown
significant improvement at 10 weeks (P = 0.004 for Group A; P
< 0.001 for Groups B and C), but the difference in the extent
Table 1: Baseline characteristics at the time of recruitment of improvement among the three groups was not significant
Group A (ICS Group B (ICS Group C (Table 2; P = 0.341). When adjusted for the two-week results
+LABA+ +LABA + (double ICS (addition of controller medication) improvement in FEV1 and
montelukast) doxophylline) +LABA)
PEFR at 10 weeks was significant in every group (group A — P
Age 39.33±8.78 41.33±12.15 37.13±12.92 = 0.002 for FEV1 and 0.027 for PEFR; group B — P < 0.001
Male 09 06 10 for FEV1 and P = 0.001 for PEFR; group C — P < 0.001 for
Female 07 11 07 FEV1 and PEFR; Table 2). The difference in the median values
Age at asthma onset (yr) 31.40±9.59 32.33±11.80 30.00±11.11 of the episodes of poor asthma control rates (EPACs) among the
Daily treatment history three treatment groups was not significant (P = 0.889; Table 3).
of past six months When adjusted for baseline there was significant improvement
(number of participants) in the asthma control questionnaire score in all three groups
Inhaled long acting β2 05 06 05 (P < 0.001), but among the three groups, the difference in
agonist the improvement was not significant (P = 0.652; Table 4).
Leukotrine receptor 02 03 01 No major adverse drug reaction was noted in any of the three
antagonist
groups [Table 5]. Furthermore, there was no major alteration
Oral steroid 00 00 00 in blood counts, liver function tests or kidney function tests in
Inhaled anticholinergic 04 05 07 any of the participants at the end of 10 weeks.
Inhaled short acting β2 10 08 10
agonist
Combination drugs 07 07 08 Table 3:EPACs in each group during the study period
Oral methylxanyhine 11 07 08 (n=15 in each group)
Age (in years) is expressed as Mean ± SD, Male and female are Group A (ICS +LABA Group B (ICS +LABA Group C (ICS +LABA)
absolute number in each groups (n=16, 17 and 17 in group A, B and C + montelukast) + doxophylline)
respectively)
0.00 0.00 1.00
0.00, 1.75 0.00, 2.75 0.00, 1.00
Table 2: Change in pulmonary function tests from baseline Kruskal-Wallis one way analysis of variance on ranks. (P=0.889), Data
by treatment (n=15 in each group) expressed as median and Interquartile range

Change from Group A (ICS Group B (ICS Group C (double

baseline +LABA + +LABA + ICS +LABA) Table 4: Change in ACQ score in each group by treatment
montelukast) doxophylline) assignment (n=15 in each group)
FEV1
Group A Group B Group C
Baseline 66.00 66.00 60.00 (ICS +LABA + (ICS +LABA (double ICS
34.25, 73.50 34.25, 73.50 45.25, 71.00 montelukast) + doxophylline) +LABA)
2 weeks 68.00† 74.00† 57.00 Baseline 2.10 2.10 1.90
65.25, 80.75 50.75, 83.25 50.25, 76.75 1.70, 2.37 1.70, 2.92 1.80, 2.42

6 weeks 83.00†‡ 74.00* 72.00†‡ 10 Weeks 1.30† 1.30† 1.40†

1.02, 1.47 1.02, 1.92 1.30,1.50
73.75, 86.75 52.75, 84.00 63.50, 88.25 †
P value < 0.001 compared with baseline, P value is derived by
10 weeks 86.000†‡ 83.000†§ 82.000†§ Wilcoxon signed ranked test, Data expressed as median and Interquartile
76.25, 91.25 54.75, 92.50 67.25, 88.50 range
PEFR
Baseline 31.00 31.00 39.00
Table 5: Number of participants with ADR in each
25.25, 41.75 23.50,45.75 29.25, 48.50 treatment group
2 weeks 38.00 38.00* 44.000
Number of participants
29.00, 48.50 30.75, 58.25 32.75, 50.00
ADR Group A Group B Group C
6 weeks 41.00* 47.00* 49.000*‡ (ICS +LABA (ICS +LABA (double ICS
33.00,55.00 42.00, 60.00 38.00, 53.25 + montelukast) + doxophylline) +LABA)
10 weeks 44.000*‡ 54.00†§ 50.00†§ Anorexia 1 0 2
37.50,54.75 36.50,61.00 43.00, 62.25 Nausea/ Vomiting 0 2 1
FEV1: Forced Expiratory Volume at 1 second, PEFR: Peak Expiratory Abdominal pain 4 1 0
Flow rate (Wilcoxon signed ranked test) * P value < 0.05- Compared with Headache 1 3 0
baseline value, † P value < 0.001- Compared with baseline value, ‡ P value
< 0.05- Compared with 2 weeks value, § P value < 0.001- Compared with Anxiety 2 1 2
2 weeks value, Data expressed as median and Interquartile range Number shown above are absolute number in each groups

 272 Journal of Postgraduate Medicine October 2010 Vol 56 Issue 4


Discussion
The main aim of the study was to identify the effect of another
controller medication added on, to the inhaled corticosteroid
and long-acting β2 agonist, on the clinical symptoms, lung
functions, and compliance in patients of moderate-to-
severe persistent asthma. Among the controller medications
inhaled corticosteroids were the mainstay, because of their
potent anti-inflammatory action in the respiratory tract, but
corticosteroids did not have any effect on the leukotrine
production or its receptor, therefore, addition of a leukotrine
receptor antagonist would have additional benefit than
doubling the dose of the inhaled steroid. Theophylline,
a Methylxanthine had additional anti-inflammatory and
immunomodulatory actions at low concentration. These
included: inhibition of neutrophil migration, inhibition of
neutrophil, lymphocyte, and monocyte activation, production
of the anti-inflammatory cytokine IL-10, and inhibition of
inflammatory mediators and the pro-inflammatory gene
regulator NF-Kappa B.[10,17-22]
Additionally, it is well-recognized that not all patients achieve
well-controlled asthma despite an appropriately high dose
of inhaled corticosteroid or inhaled corticosteroid + long-
acting β2 agonist combination therapy.[4,5] In such patients,
there is a need for additional add on therapy. Findings of the
MONICA and RADAR trial have shown the effectiveness of
montelukast add on to the inhaled corticosteroid alone or to
a combination of inhaled corticosteroid and long-acting β2
agonist, in improving the asthma control and quality of life
without affecting the tolerability of the patients much.[23,24]
Theophylline, a methylxanthine was quite effective in
improving the lung function when used as an add on to
inhaled corticosteroid in patients with persistent asthma.[25]
Also, in the presence of a long-acting β2 agonist, a higher
dose of inhaled corticosteroid has shown more improvement
in asthma control compared to a higher dose of inhaled
corticosteroid alone or a combination of long-acting β2 agonist
with a low dose of inhaled corticosteroid.[26] On the basis
of the findings in these studies, we decided montelukast,
doxophylline(claimed to have better tolerability), and
inhaled corticosteroid as add on controller medications to
the combination of inhaled corticosteroid and long-acting
β 2agonist. As, our primary focus was on the maximum
improvement in the lung function and asthma symptoms and
on the fact that many patients failed to improve significantly
with the adequate dose of inhaled corticosteroid alone
or combination of inhaled corticosteroid and long-acting
β2 agonist; we added these controller medications to the
combination of inhaled corticosteroid and the long-acting
β2 agonist.
In a six-week study of symptomatic patients on high-dose
inhaled corticosteroid (≥ 1200 mcg of budesonide) and
short-acting β2-agonists, the addition of a leukotrine receptor
antagonist (zafirlukast) significantly improved the lung
function and reduced exacerbations. [27] In an open-label
study of 313 patients with insufficiently controlled patients
Journal of Postgraduate Medicine October 2010 Vol 56 Issue 4 273 
Patel, et al.: Controller medications in asthma 
on a fixed combination therapy, with inhaled corticosteroid
and long-acting β 2 agonists, Dupont et al. observed an
improvement in asthma symptoms and pulmonary function
with add-on leukotrine receptor antagonist therapy, after
two months of therapy.[28] In addition, few more studies have
shown the effectiveness of controller medications as add on, in
improving asthma symptoms and lung functions, when used
for a relatively short period of eight weeks.[24,25,29] Based on the
above findings, a 10-week study duration was considered to
be sufficient to identify the effectiveness of these controller
medications. However, this may be the potential limitation of
our study, as the study period is relatively short and long-term
asthma control, especially asthma exacerbations could not be
reliably measured. Another probable weakness of the study
is the open-labeled design. However, this was necessary for
closer emulation of the real life setting and routine clinical
practice in which blinding of the treatment is not applicable.
Our study shows that addition of the second controller
medication in the form of montelukast (10 mg/day),
doxophylline sustained release (400 mg/day) or inhaled
corticosteroid (budesonide 400 mcg/day) to the inhaled
budesonide (400 mcg/day) and long-acting β 2 agonist
(formoterol 12 mcg/day) combination helps in a significant
improvement in FEV1 and PEFR. No statistically significant
difference was observed among the three groups in the extent
of improvement in FEV1 and PEFR. Episodes of poor asthma
control among the three groups did not show any significant
difference, suggesting that all the above-mentioned controller
medications were equally effective in controlling the asthma
symptoms, improving the lung functions, and reducing the
unscheduled asthma healthcare visit. Also, a significant
improvement in asthma control questionnaire score at 10
weeks, in all the three groups, further suggested that addition
of second controller medication helps in decreasing the
nocturnal symptoms and early morning awakening, increasing
the work capacity and decreasing the use of short acting β2
agonist. Again, the difference in improvement in asthma
control questionnaire score among the three groups is not
significant, suggesting that all the controller medications are
equally effective in controlling asthma symptoms.
Among the three groups, no any major adverse drug reaction
was noted. This suggests that these controller medications are
well-tolerated when added as a second controller to inhaled
corticosteroids, with the primary add on controller being a
long-acting β2 agonist.
Conclusion
Controller medications in the form of montelukast, doxophylline
or inhaled budesonide as an add on to inhaled corticosteroid and
long-acting β2 agonist are effective in the improvement of FEV1,
PEFR, and asthma symptoms, without adversely affecting the
tolerability of the participants of a moderate-to-severe type of
persistent asthma. However, considering the small sample size,
a short study duration, and open-label design, more studies with
larger sample size, longer duration, and blinding techniques are
necessary to substantiate our observations.
 Patel, et al.: Controller medications in asthma
Acknowledgement
The authors are thankful to Ranbaxy Laboratories ltd. India for
providing tablet Romilast -10 mg (montelukast) as a gift sample
and German Remedies for providing tablet Doxolin SR-400 mg
(doxophylline sustained release) as a gift sample.
References
1. Global Initiative for Asthma. Global strategy for asthma management
and prevention. Bethesda: National Institutes of Health, 2003. NIH
Publication No. 02-3659.
2. Lemanske RF Jr, Sorkness CA, Mauger EA, Lazarus SC, Boushey
HA, Fahy JV, et al. Inhaled corticosteroid reduction and elimination in
patients with persistent asthma receiving salmeterol: a randomized
controlled trial. JAMA 2001;285:2594-603.
3. Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, Lemanske
RF Jr, Sorkness CA, et al. Long-acting β2-agonist monotherapy
vs continued therapy with inhaled corticosteroids in patients
with persistent asthma: a randomized controlled trial. JAMA
2001;285:2583-93.
4. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ,
Pauwels R, et al. Can guideline-defined asthma control be achieved?
The Gaining Optimal Asthma ControL Study. Am J Respir Crit Care
Med 2004;170:836-44.
5. Rabe KF,  Adachi M,  Lai CK,  Soriano JB,  Vermeire PA,  Weiss KB,
et al. Worldwide severity and control of asthma in children and
adults: the global asthma insights and reality surveys. J  Allergy
Clin Immunol 2004;114:40-7.  montelukast in inadequately controlled asthma patients in a
6. Nelson HS, Busse WW, Kerwin E, Church N, Emmett A, Rickard K,
et al. Fluticasone propionate/salmeterol combination provides more
effective asthma control than low-dose inhaled corticosteroid plus
montelukast. J Allergy Clin Immunol 2001;107:614.
7. Ringdal N, Eliraz A, Pruzinec R, Weber HH, Mulder PG, Akveld M,
et al. The salmeterol/fluticasone combination is more effective
than fluticasone plus oral montelukast in asthma. Respir Med
2003;97:234-41.
8. Kanniess F, Richter K, Bohme S, Jorres R A, Magnussen H.
Montelukast versus fluticasone: effects on lung function, airway
responsiveness and inflammation in moderate asthma. Eur Respir
J 2002;20:853-8.
9. The American Lung Association Asthma Clinical Research
Centers. Clinical Trial of Low dose Theophylline and Montelukast
in Patients with Poorly Controlled Asthma. Am J Respir Crit Care
Med 2007;175:235-42.
10. Barnes PJ. Theophylline: New Perspectives for an Old Drug. Am
J Respir Crit Care Med 2003;167:813-8.
11. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O’Connor BJ, Barnes
PJ. A comparison of low-dose inhaled budesonide plus theophylline
and high dose inhaled budesonide for moderate asthma. N Engl
J Med 1997;337:1412-8.
12. Ukena D, Harnest U, Sakalaukas R, Magyar P, Vetter N, Steffen H,
et al. Comparison of addition of theophylline to inhaled steroid
with doubling of the dose of inhaled steroid in asthma. Eur Respir
J 1997;10:2754-60.
13. Tripathi KD. Drugs for Cough and Asthma. In: Tripathi M, editors.
Essentials of Medical Pharmacology, 6th ed. New Delhi: Jaypee
Brothers medical Publishers; 2008. p. 221.
14. Juniper E, O'Byrne P, Guyatt G, Ferrie P, King D. Development and
validation of a questionnaire to measure asthma control. Eur Respir
 274 Journal of Postgraduate Medicine October 2010 Vol 56 Issue 4
J 1999;14:902-7.
15. Juniper EF, Bousquet J, Abetz L, Bateman ED. The GOAL
Committee. Identifying ‘well controlled' and 'not well-controlled'
asthma using the Asthma Control Questionnaire. Respir Med
2006;100:616-21.
16. Vaquerizo MJ, Casan P, Castillo J, Perpina M, Sanchis J, Sobradillo V,
et al. Effect of montelukast added to inhaled budesonide on control
of mild to moderate asthma. Thorax 2003;58:204-10.
17. Mascali JJ, Cvietusa P, Negri J, Borish L. Anti-inflammatory effects
of theophylline: modulation of cytokine production. Ann Allergy
Asthma Immunol 1996;77:34-8.
18. Tenor H, Hatzelmann A, Church MK, Schudt C, Shute JK. Effects
of theophylline and rolipram on leukotriene C4 (LTC4) synthesis
and chemotaxis of human eosinophils from normal and atopic
subjects. Br J Pharmacol 1996;118:1727-35.
19. Condino-Neto A, Vilela MM, Cambiucci EC, Ribeiro JD, Guglielmi
AA, Magna LA, et al. Theophylline therapy inhibits neutrophil and
mononuclear cell chemotaxis from chronic asthmatic children. Br
J Clin Pharmacol 1991;32:557-61.
20. Umeda M, Ichiyama T, Hasegawa S, Kaneko M, Matsubara T,
Furukawa S. Theophylline inhibits NF-kappaB activation in human
peripheral blood mononuclear cells. Int Arch Allergy Immunol
2002;128:130-5.
21. Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ.
Immunomodulation by theophylline in asthma. Am J Respir Crit
Care Med 1995;151:1907-14.
22. Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J. Anti-
inflammatory effects of low dose oral theophylline in atopic asthma.
Lancet 1994;343:1006-8.
23. Virchow JC, Mehta A, Ljungblad Li, Mitfessel H. Add-on
6-month open-label study: The MONtelukast In Chronic Asthma
(MONICA) study. Respir Med 2010;104:644-51.
24. Keith PK, Koch C, Djandji M, Bouchard J, Psaradellis E, Sampalis JS,
et al. Montelukast as add-on therapy with inhaled corticosteroids
or inhaled corticosteroids and long-acting β-2-agonists in the
management of patients diagnosed with asthma and concurrent
allergic rhinitis (The RADAR Trial). Can Respir J 2009;16:17-24.
25. Shah AR, Sharples LD, Solanki RN, Shah KV. Double-Blind,
Randomised, Controlled Trial Assessing Controller Medications
in Asthma. Respiration 2006;73:449-56.
26. O'Byrne PM, Naya IP, Kallen A, Postma DS, Barnes PJ. Increasing
Doses of Inhaled Corticosteroids Compared to Adding Long-
Acting Inhaled β2-Agonists in Achieving Asthma Control. Chest
2008;134;1192-9.
27. Virchow JC Jr, Prasse A, Naya I, Summerton L, Harris A. Zafirlukast
improves asthma control in patients receiving high-dose inhaled
corticosteroids. Am J Respir Crit Care Med 2000;162:578-85.
28. Dupont L, Potvin E, Korn D, Lachman A, Dramaix M, Gusman J, et
al. Improving asthma control in patients sub optimally controlled
on inhaled steroids and long-acting β 2-agonists: addition of
montelukast in an open-label pilot study. Curr Med Res Opin
2005;21:863-9. 
29. Korn D,  Van den BP,  Potvin E,  Dramaix M,  Herbots E,  Peche R.
Efficacy of add-on montelukast in patients with non-controlled
asthma: a Belgian open-label study. Curr Med Res Opin
2009;25:489-97. 
Source of Support: Gift samples received from Ranbaxy Laboratories and
German Remedies, Conflict of Interest: None declared.