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 ::  Abstract
 ::  Introduction
 ::  Materials and Me...
 ::  Results
 ::  Discussion
 ::  Conclusion
 ::  Acknowledgement
 ::  References
 ::  Article Tables

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ORIGINAL ARTICLE
Year : 2010  |  Volume : 56  |  Issue : 4  |  Page : 270-274

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


1 Department of Pharmacology, Government Medical College, Bhavnagar-364001, Gujarat, India
2 Department of Tuberculosis and Respiratory diseases, Sir Takhtsinghji hospital and Government Medical College, Bhavnagar-364001, Gujarat, India

Date of Submission03-Mar-2010
Date of Decision01-May-2010
Date of Acceptance28-Jun-2010
Date of Web Publication7-Oct-2010

Correspondence Address:
C B Tripathi
Department of Pharmacology, Government Medical College, Bhavnagar-364001, Gujarat
India
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Source of Support: Gift samples received from Ranbaxy Laboratories and German Remedies, Conflict of Interest: None


DOI: 10.4103/0022-3859.70937

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 :: 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 (FEV 1 ). Results : All the participants of the three groups had significant improvement in FEV 1 (P < 0.001) and asthma symptoms at the end of 10 weeks. The mean increase in FEV 1 (% 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.


Keywords: Asthma, inhaled corticosteroid, long-acting beta2 agonist, montelukast sodium, doxophylline, add on therapy


How to cite this article:
Patel Y A, Patel P, Bavadia H, Dave J, Tripathi C B. 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. J Postgrad Med 2010;56:270-4

How to cite this URL:
Patel Y A, Patel P, Bavadia H, Dave J, Tripathi C B. 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. J Postgrad Med [serial online] 2010 [cited 2019 Sep 23];56:270-4. Available from: http://www.jpgmonline.com/text.asp?2010/56/4/270/70937



 :: Introduction Top


The 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 corticosteroids. [2],[3] A combination of a long-acting β2 agonist with inhaled corticosteroid is the preferred treatment, when 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 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 Top


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; FEV 1 value of 50% or more of the predicted; and improvement in FEV 1 was 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, 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 FEV 1 . 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 FEV 1 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 FEV 1 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 Top


FEV 1 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 of all groups, during the past six months is shown in [Table 1]. After adjusting for age, sex, and baseline characteristics all the groups had shown significant improvement in FEV 1 at 10 weeks (P < 0.001) [Table 2], but the difference in the extent of improvement among the three groups was not significant (P = 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 of improvement among the three groups was not significant ([Table 2]; P = 0.341). When adjusted for the two-week results (addition of controller medication) improvement in FEV 1 and PEFR at 10 weeks was significant in every group (group A - P = 0.002 for FEV 1 and 0.027 for PEFR; group B - P < 0.001 for FEV 1 and P = 0.001 for PEFR; group C - P < 0.001 for FEV 1 and PEFR; [Table 2]). The difference in the median values of the episodes of poor asthma control rates (EPACs) among the three treatment groups was not significant (P = 0.889; [Table 3]). When adjusted for baseline there was significant improvement in the asthma control questionnaire score in all three groups (P < 0.001), but among the three groups, the difference in the improvement was not significant (P = 0.652; [Table 4]). No major adverse drug reaction was noted in any of the three groups [Table 5]. Furthermore, there was no major alteration in blood counts, liver function tests or kidney function tests in any of the participants at the end of 10 weeks.
Table 1 :Baseline characteristics at the time of recruitment


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Table 2 :Change in pulmonary function tests from baseline by treatment (n=15 in each group)


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Table 3 :EPACs in each group during the study period (n=15 in each group)


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Table 4 :Change in ACQ score in each group by treatment assignment (n=15 in each group)


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Table 5 :Number of participants with ADR in each treatment group


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 :: Discussion Top


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],[18],[19],[20],[21],[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 β2 agonist. 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 on a fixed combination therapy, with inhaled corticosteroid and long-acting β2 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 β2 agonist (formoterol 12 mcg/day) combination helps in a significant improvement in FEV 1 and PEFR. No statistically significant difference was observed among the three groups in the extent of improvement in FEV 1 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 Top


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 FEV 1, 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.


 :: Acknowledgement Top


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 Top

1.Global Initiative for Asthma. Global strategy for asthma management and prevention. Bethesda: National Institutes of Health, 2003. NIH Publication No. 02-3659.  Back to cited text no. 1      
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.  Back to cited text no. 2      
3.Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, Lemanske RF Jr, Sorkness CA, et al. Long-acting b2 -agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001;285:2583-93.  Back to cited text no. 3      
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.  Back to cited text no. 4      
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.   Back to cited text no. 5      
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.  Back to cited text no. 6      
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.  Back to cited text no. 7      
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.  Back to cited text no. 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.   Back to cited text no. 9      
10.Barnes PJ. Theophylline: New Perspectives for an Old Drug. Am J Respir Crit Care Med 2003;167:813-8.  Back to cited text no. 10      
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.  Back to cited text no. 11      
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.  Back to cited text no. 12      
13.Tripathi KD. Drugs for Cough and Asthma. In: Tripathi M, editors. Essentials of Medical Pharmacology, 6 th ed. New Delhi: Jaypee Brothers medical Publishers; 2008. p. 221.  Back to cited text no. 13      
14.Juniper E, O'Byrne P, Guyatt G, Ferrie P, King D. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902-7.  Back to cited text no. 14      
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.  Back to cited text no. 15      
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.  Back to cited text no. 16      
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.  Back to cited text no. 17      
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.  Back to cited text no. 18      
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.  Back to cited text no. 19      
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.  Back to cited text no. 20      
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.  Back to cited text no. 21      
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.  Back to cited text no. 22      
23.Virchow JC, Mehta A, Ljungblad Li, Mitfessel H. Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: The MONtelukast In Chronic Asthma (MONICA) study. Respir Med 2010;104:644-51.  Back to cited text no. 23      
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 b-2-agonists in the management of patients diagnosed with asthma and concurrent allergic rhinitis (The RADAR Trial). Can Respir J 2009;16:17-24.  Back to cited text no. 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.  Back to cited text no. 25      
26.O'Byrne PM, Naya IP, Kallen A, Postma DS, Barnes PJ. Increasing Doses of Inhaled Corticosteroids Compared to Adding Long-Acting Inhaled b2 -Agonists in Achieving Asthma Control. Chest 2008;134;1192-9.  Back to cited text no. 26      
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.  Back to cited text no. 27      
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 b2 -agonists: addition of montelukast in an open-label pilot study. Curr Med Res Opin 2005;21:863-9.   Back to cited text no. 28      
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.  Back to cited text no. 29      



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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