Review of recent results of montelukast use as a monotherapy in children with mild asthma

Clinical Therapeutics/Volume 30, Theme Issue, 2008

Review of Recent Results of Montelukast Use as a Monotherapy in Children with Mild Asthma Ulrich Wahn, MD1; and S. Balachandra Dass, PhD2 1Charité

Universitätsmedizin, Department for Pediatric Pneumology and Immunology, Berlin, Germany; and 2Merck Research Laboratories, Rahway, New Jersey

ABSTRACT Background: Asthma is a chronic disease with a heterogeneous phenotype that is often associated with allergic sensitization in childhood. The earliest definable form of asthma is mild (intermittent or persistent), a severity level that may be characteristic of a majority of children with asthma. Several asthma controllers are indicated for use in children. International guidelines recommend the use of inhaled corticosteroids as the preferred controller therapy in mild persistent asthma. Objective: This article reviewed recent results from randomized, double-blind studies of children with mild asthma treated with montelukast, a leukotriene receptor antagonist that is approved for the treatment of asthma and allergic rhinitis in children and adults. Methods: A literature search of MEDLINE was conducted to gather relevant, English-language articles using search terms such as randomized controlled studies, double-blind studies, montelukast, leukotriene receptor antagonist, pediatric asthma, mild asthma, exerciseinduced asthma, and bronchoconstriction. Recent articles (since 1998) that described the use of montelukast as a monotherapy were chosen for this review. Results: Relevant studies included a 48-week, placebo-controlled study of 2- to 5-year-old mild intermittent asthmatics (N = 549); a 12-week, placebocontrolled study of 2- to 5-year-old mild persistent asthmatics (N = 689); an analysis of a mild persistent asthmatic cohort (N = 138) from an 8-week, placebocontrolled study of 6- to 14-year-old asthmatics; a 12-month study comparing montelukast with fluticasone in 6- to 14-year-old mild persistent asthmatics (N = 949); and 3 placebo-controlled studies in children with exercise-induced asthma (N = 123). The results from these studies, encompassing end points measuring lung function and symptoms, found that montelukast provided effective and beneficial asthma control to children aged 2 to 14 years with mild asthma. 1026

Conclusion: The evidence suggests that montelukast is an effective monotherapy controller in children with mild asthma. (Clin Ther. 2008;30[Theme Issue]: 1026–1035) © 2008 Excerpta Medica Inc. Key words: therapeutic options in asthma, pediatric asthma, montelukast, mild asthma, leukotriene receptor antagonist.

INTRODUCTION Asthma is a common chronic disease in children. In the European Union, it is estimated that 7% of children and adolescents have self-reported asthma (currently) and 12% have wheezing (currently/ever).1 In a US National Health Interview Survey, 12% of children reported being diagnosed with asthma2; in other studies, >20% of school-aged children reported wheezing.3 Furthermore, asthma prevalence rates are disproportionately high in socioeconomically disadvantaged groups (as high as 37%) and continue to rise.4 The US asthma guidelines also indicate that the prevalence of childhood asthma has increased in several countries.5 The origins of asthma are in childhood, most likely in infancy.6 It is believed that the disease is heterogeneous, with several age-dependent phenotypes that may be associated with multiple pathways of disease activity.6 Recurrent symptomatic periods of wheezing, cough, and breathlessness in infants may be characteristic of the natural history of the disease, serving as early indicators of developing asthma.7 Such wheezing in very young children is believed to be reflective of airway inflammation that underpins the pathologic condition of asthma.8 Data from a prospective birth cohort study suggest that early allergic sensitization, Accepted for publication March 27, 2008. doi:10.1016/j.clinthera.2008.05.018 0149-2918/$32.00 © 2008 Excerpta Medica Inc. All rights reserved.

Volume 30 Theme Issue

U. Wahn and S.B. Dass together with allergen exposure, has to be considered a predictor for asthma persisting into adolescence.9 Children with the atopic wheezing phenotype were less likely to have a remission of symptoms after 5 years of age, compared with children with nonatopic wheezing (Figure 1).9 Diagnosis of asthma becomes practical in older children, where, in addition to such symptoms, reversible and variable airflow limitation may be demonstrated by measurement of lung function. The choice of a long-term asthma controller in children should be based on several factors, including drug efficacy, safety profile, ease of use, and compliance.10 Inhaled corticosteroids (ICSs) are effective controller agents for asthma in children and adults, and current guidelines recommend their use as the preferred therapy in persistent asthma.5,11,12 The guidelines also enumerate other therapies that may be used as alternative treatments or as add-on options to ICS therapy, depending on the severity of asthma and the age of the patient. These include oral corticosteroids, short- and long-acting β-agonists, mast-cell stabilizers, anticholinergics, methylxanthines, and leukotriene modifiers. A review of 5 studies comparing

montelukast and inhaled fluticasone in asthmatic, school-aged children reported that ICSs were significantly better than montelukast in several measures of asthma control, including forced expiratory volume in the first second of expiration (FEV1) and asthma control days.10 Recently, however, several lines of evidence have necessitated a re-evaluation of these recommendations for ICSs, as discussed here. This article reviewed recent results from randomized, doubleblind studies of children with mild asthma treated with montelukast, a leukotriene receptor antagonist that is approved for the treatment of asthma and allergic rhinitis in children and adults.

MATERIALS AND METHODS A literature search of MEDLINE was conducted to gather relevant, English-language articles using search terms such as randomized controlled studies, doubleblind studies, montelukast, leukotriene receptor antagonist, pediatric asthma, mild asthma, exerciseinduced asthma, and bronchoconstriction. Recent articles (since 1998) that described the use of montelukast as a monotherapy were chosen for this review.

Prevalence of Current Wheezing (%)

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Age (y) Figure 1. Prevalence of current wheezing in children with any wheezing episode at school age (5–7 years), stratified according to atopy status at school-age. Patients were followed up from birth to 13 years of age. Data from Illi et al.9

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RESULTS Reappraising the Scope of Inhaled Corticosteroids in Pediatric Asthma Therapy Airway remodeling resulting from chronic inflammation may occur during the course of the disease,13 and early introduction of ICSs to prevent or slow the progressive loss of lung function associated with such structural changes has been recommended.14 However, a study found that intermittent ICS (budesonide) therapy in 294 wheezing infants had no subsequent effect on the progression from episodic to persistent wheezing.15 Inhaled fluticasone for 2 years in 285 preschool children at high risk for asthma showed efficacy (as measured by episode-free days, exacerbations, and supplementary use of controller medication) but did not change the development of asthma symptoms or improve lung function during a third, treatment-free year.16 These results lead to the conclusion that ICS therapy is unlikely to alter the course of asthma in children17 and thus may not have an advantage over other therapies in this regard. Although some reports point to dose-related inhibition of growth with ICSs, these effects appear to be small16,18,19 and may possibly be transient.20 Nevertheless, a survey of primary care physicians treating asthmatic children found that 47% of the physicians expressed concern about ≥1 adverse effect, most commonly (22%) growth delay.21 It has been proposed that the varying effects on growth over time may reflect a gradual decrease in compliance.22 Long-term nonadherence to controller therapy is common among asthmatic children, with less than half of all prescribed doses taken.23 In a 27-month clinical trial of 122 school-aged children with mild asthma, adherence to BID inhaled budesonide dropped steadily from 77% at 3 months to 49% at 27 months.24 Poor adherence to inhalation therapy has been shown to be an important cause of treatment failure: in a study of 24 asthmatic children, the median compliance with ICSs was 14% for those who experienced exacerbations and 68% for those who did not.25 Difficulty with inhaler devices and cumbersome dosing schedules may be critical factors in nonadherence,5 and it has been observed that inappropriate selection or incorrect use of an inhaler is the most common reason for the failure of inhaled drugs in children,26 thus highlighting an important issue in pediatric therapy. 1028

Persistence of Uncontrolled Symptoms A survey of 572 Swiss-German asthmatic children found that the goals of asthma treatment guidelines were not universally met, with excellent or satisfactory control seen only in a minority of the youngest children (44% of 7- to 9-year-olds and 38% of 4- to 6-year-olds).27 A national survey of >60,000 asthmatic patients in the United States found that 48% of children had ≥3 symptoms, consistent with lack of asthma control.28 Halterman et al29 reported that in a US study of children with moderate to severe asthma (N = 1025), 26% had taken a maintenance medication the previous month; children ≤5 years old were more likely than older children to receive inadequate therapy. Among asthmatic children prescribed a daily controller, 63% of children with mild persistent asthma and 66% of children with moderate or severe persistent asthma used them every day.30 A Latin American survey showed that 57% of children with physician-diagnosed asthma had experienced uncontrolled symptoms the previous month.31 These and other results32 are reflective of the need for continuing improvements in national and international guidelines, health care and physician outreach, physician practices, and patient/caregiver education.

Prevalence and Treatment Options in Mild Intermittent and Mild Persistent Asthma The earliest definable form of asthma is mild asthma (intermittent or persistent), a severity classification based on the presence and frequency of symptoms and the level and variability of airflow obstruction.5,11,12 The prevalence of mild asthma in asthmatic adults and children is high, estimated at 40% to 70% worldwide.33 In a US study of the general population, children reporting physician-diagnosed asthma and who were aged >5 years were more likely to have mild asthma, while younger children were more likely to have moderate to severe asthma.29 In another US study of 826 children (81% Hispanic) who had not been treated (controller naive), children aged ≤5 years were more likely to have mild asthma (intermittent, 41%; persistent, 10%), while older children were more likely to have moderate or severe asthma.34 Reflective of these results, several surveys—although confounded by limitations in design—reported that a majority of children with asthma have symptoms that would be classified as mild asthma (38% had daytime symptoms ≥1 time per week according to the Asthma Volume 30 Theme Issue

U. Wahn and S.B. Dass Insights and Reality in Europe [AIRE] survey, and >40% missed school because of their asthma according to the AIRE survey and the Allergies in America survey).35 Hence, it is not surprising that these authors35 posit that the understanding of mild persistent asthma may likely be an important challenge in childhood asthma research. Mild persistent asthma is characterized by less frequent but persistent symptoms12; it is nevertheless associated with morbidity that may lead to exacerbations33,35 and hence requires monitoring and control. ICSs are the recommended first-line daily controller agents in mild persistent asthma.36 In children with mild asthma who are aged ≥5 years, depending on the treatment step and what is considered necessary and appropriate, US guidelines allow the substitution of ICSs with leukotriene receptor antagonists, chromones, or theophylline, or the addition of leukotriene receptor antagonists, theophylline, or long-acting β2agonists to ICS therapy; ICSs are recommended for children aged <5 years.5,12,37 When necessary and as appropriate, the UK guidelines allow the substitution of ICSs with theophylline, leukotriene receptor antagonists, or chromones in patients using short-acting β2-agonists alone and the addition of leukotriene receptor antagonists, theophylline, or long-acting β2agonists to ICS therapy in children aged ≥5 years.11 As noted earlier, this review highlights several studies whose results support the case for expanding the therapeutic options available for children with mild intermittent and mild persistent asthma. Our focus was on recent data from controlled studies of the leukotriene receptor antagonist montelukast. This medicine is currently approved for the prophylaxis and chronic treatment of asthma in adults and children aged ≥12 months (United States)38 and, in some countries, infants as young as 6 months of age.39 In the European Union, montelukast is indicated for the treatment of asthma as add-on therapy in children (6 months to 14 years of age) with mild to moderate persistent asthma whose disease is inadequately controlled on ICSs and in whom “as-needed” short-acting β-agonists provide inadequate clinical control of asthma.39,40 It is also indicated as an alternative treatment option to ICSs in those children (2–14 years old) with mild persistent asthma who do not have a recent history of serious asthma attacks that required oral corticosteroid use and who had shown that they were unable to use an ICS.39,40 Montelukast is generally 2008

well tolerated in children and adults, with a tolerability profile generally similar to that of placebo.41 Furthermore, recent short-term (3-week knemometry) and long-term (1-year linear growth) studies reported that montelukast did not affect growth rates in children with mild asthma.42,43

Efficacy Studies of Montelukast in 2- to 5-Year-Old Mild Asthmatic Children The Prevention of Virus-Induced Asthma (PREVIA) study was a multinational, randomized, double-blind, 2‑period, parallel-group trial of 2- to 5-year-old children with mild intermittent asthma symptoms (mean baseline daytime asthma symptoms, 1.7 days/week; short-acting β‑agonist use, 0.6 day/week) associated with the common cold and with minimal symptoms between episodes.44 During the 48-week treatment period, 549 children received either montelukast 4 mg/d or placebo; patients were allowed the use of an as-needed short-acting β-agonist. The primary end point was the number of asthma episodes, defined as any 3 consecutive days with a minimal level of daytime symptoms and β-agonist use ≥2 times per day, use of rescue oral corticosteroids/ICSs, or hospitalization for asthma. The results of the PREVIA study showed a 31.9% reduction in yearly exacerbation rate in the montelukast group compared with placebo (relative rate, 0.68; 95% CI, 0.56–0.83; P < 0.001).44 The time to the first asthma exacerbation episode was significantly longer (P = 0.024) in children receiving montelukast (median time, 206 days) compared with placebo (147 days). There appeared to be a seasonal pattern to asthma exacerbations, with significantly greater risk (P < 0.05) during the fall season and a significantly lower risk (P < 0.05) during the summer season for both treatment groups. However, when adjusted for season effect, the montelukast group still had significantly reduced exacerbation episodes compared with the placebo group (P = 0.017). The effect of montelukast on each individual component of the asthma exacerbation episode was consistent with the results of the primary end point.44 Other secondary end points (days without asthma, use of corticosteroids [inhaled or oral]) were consistent with improved asthma control with montelukast. Montelukast significantly decreased the rate of ICS use by 39.8% (P = 0.027), while oral corticosteroid use was not significantly different between montelu1029

Clinical Therapeutics kast and placebo. Montelukast also decreased the peripheral blood eosinophil count (a marker of inflammation) compared with placebo. A post hoc analysis found that ~33% of the patients met the criteria for mild persistent asthma based on Global Initiative for Asthma guidelines5; in this subgroup, the main efficacy end point results were consistent with those of the entire study population (data on file, Department of Biostatistics and Research Decision Sciences, Merck Research Laboratories, Rahway, New Jersey, 2005). Knorr et al45 described a multicenter, double-blind, randomized study of 689 patients aged 2 to 5 years who received either montelukast 4 mg/d or placebo for 12 weeks. The patient population was characterized as mild persistent asthmatics who used shortacting β-agonists a mean of 5.6 days per week and had asthma symptoms a mean of 6.1 days per week during the 2-week baseline period. The results showed significant improvements (P < 0.05) in multiple parameters of asthma control, including daytime asthma symptoms (cough, wheezing, trouble breathing, and activity limitation), overnight asthma symptoms (cough), the percentage of days with asthma symptoms, the percentage of days without asthma symptoms, the need for rescue β-agonist or oral corticosteroids, physician global evaluations, and peripheral blood eosinophil counts.45 The percentage of days on which β-agonists were used and the percentage of patients requiring oral corticosteroid use were significantly lower in the montelukast group (P < 0.01). The percentage of patients experiencing ≥1 asthma attack decreased in the montelukast group, although the difference was not significant. The effects of montelukast were consistent across the 2- to 5-year range and did not differ between those patients on allowed concomitant medication (40% were on inhaled/nebulized corticosteroids or cromolyn) and those who were not.

Efficacy Studies of Montelukast in 6- to 14-Year-Old Mild Asthmatic Children A multicenter, randomized, double-blind study examined the effect of montelukast (5 mg/d) versus placebo in 336 children aged 6 to 14 years with mild to moderate asthma (mean FEV1, 72% of predicted).46 During 8 weeks of treatment, morning FEV1 (the primary end point) increased significantly (P < 0.001) with montelukast; the mean difference between the 2 groups was 4.7% (95% CI, 1.9–7.4). Subsequently, data from a cohort with a baseline FEV1 >75% of 1030

predicted were analyzed in a post hoc, secondary study.47 This cohort of 138 children had a mean FEV1 81% of predicted and a mean rescue β-agonist use ≤6 days per week at baseline. The difference between montelukast and placebo in mean percent change from baseline in FEV1 was 4.9% (95% CI, 1.5–8.3) in favor of montelukast (P = 0.005). Of these 138 children, 68% were not on ICSs throughout the study; treatment difference in FEV1 in this subgroup was 5.6% (95% CI, 1.7–9.4).47 The Montelukast Study of Asthma in Children (MOSAIC) was a multicenter, randomized, doubleblind, 2‑period, parallel-group, noninferiority trial comparing oral montelukast 5 mg/d with inhaled fluticasone 200 µg/d for 12 months in children aged 6 to 14 years (N = 949).48 The patient population had mild persistent asthma, with a mean FEV1 89% of predicted and a short-acting β‑agonist use ≥1 time per week but less than daily. The predefined primary end point was asthma rescue-free days; this referred to any day where there was no utilization of asthma rescue medication (including short-acting β‑agonists and systemic corticosteroids) and asthma-related health care resource (unscheduled visit to physician, urgent/ emergent care visit, or hospitalization). The noninferiority margin for the MOSAIC study was based on data from the Childhood Asthma Management Program (CAMP) study,49 and it was chosen such that montelukast was to be considered noninferior to fluticasone if the upper bound of the 95% CI for the difference (montelukast minus fluticasone) in mean percentage of asthma rescue-free days was <7% (corresponding to ~2 days/month). The results of the study revealed an increase from baseline in asthma rescue-free days by 22.4% in the montelukast group and by 25.2% in the fluticasone group over 12 months of treatment.48 The mean percentage of asthma rescue-free days was 84.0% on montelukast compared with 86.7% on fluticasone. The difference between treatments was –2.8% (95% CI, – 4.7 to – 0.9) in favor of fluticasone but within the prespecified noninferiority limit. The estimated mean difference was equivalent to <1 asthma rescue-free day per month (a difference that may not be meaningful to patients, as has been commented on by others50). In a post hoc, nonparametric analysis of the primary end point, there was a large degree of overlap (84.3%; 95% CI, 77.0 to 91.6) in the response of patients treated with either active therapy (Figure 2). Volume 30 Theme Issue

U. Wahn and S.B. Dass Such a high degree of overlap in the distribution of response to montelukast and ICSs has been found in previous studies with adults and children.51–54 The increase in FEV1 percent predicted (a secondary end point) in the fluticasone group was higher than in the montelukast group (difference, –2.2%; 95% CI, –3.6 to – 0.7).48 Because the assessment of FEV1 percent predicted may depend in part on height, it is possible that this difference may be the result of the decreased growth rate of children in the ICS group (difference between treatment groups in mean growth rate, 0.41 cm/y [95% CI, 0.07 to 0.75], in favor of montelukast). A similar association of height with the change in FEV1 as a percentage of the predicted value was seen in the CAMP study.53 No significant difference between the treatment groups was seen in absolute FEV1: the difference was –0.02 L (95% CI, – 0.06 to 0.02). Overall, for the other secondary end points, the MOSAIC study found that children who received inhaled fluticasone generally had a significantly better mean treatment effect compared with those who received montelukast.48 However, these differences were generally similar to the treatment effect difference

seen with the primary end point. The small difference in means of – 0.13 (95% CI, – 0.25 to – 0.01) in favor of fluticasone in the asthma quality-of-life score was not considered clinically important because the minimal clinically important difference for this questionnaire was a change in score of 0.42.55 Significant treatment effects in favor of fluticasone in the percentage of patients with additional rescue medication use and the percentage of patients with asthma attacks were mainly driven by the difference in the percentage of patients with systemic corticosteroid use (~85% of patients did not have systemic corticosteroid use during the 12-month study). Of those patients with systemic corticosteroid use, most patients (~10%) receiving montelukast needed only the use of 1 corticosteroid rescue medication during the study. Of those patients with no prior corticosteroid use, the proportion of patients with ≥1 asthma attack was similar between montelukast (78/334 [23%]) and fluticasone (75/348 [22%]) (difference, 1.05% [95% CI, 0.8 to 1.4]).

Montelukast in Exercise-Induced Asthma Exercise-induced bronchoconstriction or exerciseinduced asthma (EIA) is a common clinical manifesta-

Montelukast Fluticasone

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>10–20

>20–30

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>40–50

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Percentage of Asthma Rescue-Free Days Figure 2. O  verlap of distribution of response in the percentage of asthma rescue-free days. From the Montelukast Study of Asthma in Children.48

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Clinical Therapeutics tion of asthma; it is estimated to occur in a majority of asthmatic patients.56 Bisgaard and Szefler35 suggest that in some children the symptoms of EIA might constitute a burden consistent with that of mild persistent asthma. They also point out that the disease burden of this condition in children often remains unrecognized and its prevalence underreported. A multicenter, double-blind, placebo-controlled, 2-period crossover study examined the effect of montelukast on 6- to 14-year-old asthmatic children (N = 27) with a fall in FEV1 of ≥20% after 2 prerandomization exercise challenges.57 Children were administered montelukast 5 mg/d or placebo for 2 days, followed by exercise challenge 20 to 24 hours after the last dose in each period. The results found that montelukast significantly attenuated EIA at the end of the dosing interval. Thus, montelukast reduced postexercise percent-fall in FEV1 over 60 minutes measured as the area above the curve (265% × min vs 590% × min for montelukast vs placebo; P < 0.05) and the postexercise maximum percent-fall in FEV1 (18% vs 26%; P < 0.05). In a placebo-controlled study, children (N = 64) with mild asthma had significant improvements in asthma symptom score (25.2 vs 18.3; P < 0.01), maximum percent-fall in FEV1 after exercise (36.8% vs 27.6%; P < 0.01), and time to recovery (43.0 vs 26.1 minutes; P < 0.01) after receiving montelukast 5 mg/d for 8 weeks; no significant improvements were seen in the placebo group.58 In another randomized, double-blind, placebo-controlled study, montelukast 5 mg/d provided significant protection against EIA in 32 asthmatic children 6 to 12 years old over a 4-week period, suggesting an absence of tolerance to its bronchoprotective effect.59 The mean percent drops in FEV1 for montelukast versus placebo were 13.6% versus 22.4% (after 3 days), 12.0% versus 21.8% (after 7 days), and 11.6% versus 21.0% (after 28 days) (P < 0.05 at each interval).

contribute to more consistent drug delivery and asthma control. In montelukast/cromolyn and montelukast/ beclomethasone preference studies, the oral therapy (montelukast) had significantly higher adherence, satisfaction, and preference when compared with an inhaled therapy (cromolyn or beclomethasone).60,61 The impact of compliance may partly be reflected in “realworld” outcome studies in 2- to 5-year-olds and in 6- to 15-year-olds: there were no significant differences in asthma-related outcomes when treated with montelukast or ICSs.62,63 The response to asthma therapy appears to be variable: asthmatic children who do not respond to ICSs may respond to other therapies, such as montelukast, and vice versa.51,64 It was shown that if response was defined as an improvement in FEV1 of ≥7.5%, ~40% of children responded to fluticasone and 22% to montelukast and 55% to none (17% responded to both montelukast and fluticasone, 5% to montelukast alone, and 23% to fluticasone alone).51 These reports further highlight the importance of expanded choice in the therapeutic options available to physicians who treat children with asthma.

CONCLUSIONS Several treatment options must be considered when seeking the right therapeutic balance of efficacy, tolerability, adherence, and ease of use for the control and management of asthma in children. ICS therapy is the mainstay of asthma treatment. However, montelukast may serve as an appropriate monotherapy controller medication for many children with mild asthma and in particular for those who have difficulty with inhalation therapies, have concerns about the systemic effects of treatment, exhibit poor compliance, or have EIA as a dominant component of their asthma.

ACKNOWLEDGMENTS DISCUSSION Although it is important to recognize that the use of ICSs is currently the recommended first-line, primary long-term treatment for children with asthma, the studies discussed here suggest that montelukast provides effective disease control to many children with mild asthma. Furthermore, an oral, age-appropriate, once-daily medication may have advantages for younger children in terms of ease of use. This, in turn, may be associated with better compliance and may 1032

Dr. Wahn has received honoraria for lectures and consultancies from GlaxoSmithKline (Munich, Germany), AstraZeneca Pharmaceuticals LP (Wilmington, Delaware), Merck & Co., Inc. (Whitehouse Station, New Jersey), Novartis International AG (Basel, Switzerland), Schering-Plough Corporation (Kenilworth, New Jersey), Allergopharma (Reinbek, Germany), Stallergenes (Antony, France), Phadia AB (Uppsala, Sweden), and Hitachi, Ltd. (Tokyo, Japan). Dr. Dass owns stock and options in Merck & Co., Inc. Volume 30 Theme Issue

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U. Wahn and S.B. Dass 58. Kim JH, Lee SY, Kim HB, et al. Prolonged effect of montelukast in asthmatic children with exerciseinduced bronchoconstriction. Pediatr Pulmonol. 2005;39:162–166. 59. de Benedictis FM, del Giudice MM, Forenza N, et al. Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children. Eur Respir J. 2006;28:291–295. 60. Bukstein DA, Bratton DL, Firriolo KM, et al. Evaluation of parental preference for the treatment of asthmatic children aged 6 to 11 years with oral montelukast or inhaled cromolyn: A randomized, open-label, crossover study. J Asthma. 2003;40: 475–485. 61. Maspero JF, Dueñas-Meza E, Volovitz B, et al. Oral montelukast versus inhaled beclomethasone in 6to 11-year-old children with asthma: Results of an open-label extension study evaluating long-term safety, satisfaction, and adherence with therapy. Curr Med Res Opin. 2001; 17:96–104. 62. Davies GM, Dasbach EJ, Santanello NC, et al. The effect of montelukast versus usual care on health care resource utilization in children aged 2 to 5 years with asthma. Clin Ther. 2004;26:1895–1904. 63. Bukstein DA, Luskin AT, Bernstein A. “Real-world” effectiveness of daily controller medicine in children with mild persistent asthma [published correction appears in Ann Allergy Asthma Immunol. 2003;91:308]. Ann Allergy Asthma Immunol. 2003;90: 543–549. 64. Zeiger RS, Szefler SJ, Phillips BR, et al, for the Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute. Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol. 2006;117:45–52.

2008

Address correspondence to: Ulrich Wahn, MD, Charité Universitätmedizin, Department for Pediatric Pneumology and Immunology, Augustenburger Platz 1, DE-13353 Berlin, Germany. E-mail: [email protected] 1035