Management of asthma in preschool children with inhaled corticosteroids and leukotriene receptor antagonists

PURPOSE OF REVIEW: The aim of this article is to review the recently published studies addressing various treatment approaches for asthma in preschool children. RECENT FINDINGS: The heterogeneity of wheezing in the preschool years complicates the study of asthma in this age group. Once children at highest risk for persistence of wheezing are identified, various management strategies may be thoroughly studied. Several recent studies have confirmed the efficacy and safety of both inhaled corticosteroids and leukotriene receptor antagonists in the management of early childhood asthma. In addition to examining clinical efficacy, studies investigating the effects of these treatment modalities on the underlying airway inflammation have recently increased in number and quality and confirm the anti-inflammatory actions of these therapeutic strategies in the preschool child with asthma. SUMMARY: Evidence for the preferred treatment strategies for persistent asthma in young children remains incomplete. Based on the current body of evidence, there is rationale for further investigation of these management strategies, including direct comparisons between inhaled corticosteroids and leukotriene receptor antagonists, as well as the role of long-acting beta-agonists, potentially targeting the subpopulations of early childhood with wheezing who are at highest risk for persistence of asthma symptoms.     

Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma

Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipids, are proinflammatory mediators that play an important role in the pathophysiology of asthma. These mediators are among the most potent of bronchoconstrictors and cause vasodilation, increased microvascular permeability, exudation of macromolecules and edema. The cysteinyl leukotrienes also have potent chemoattractant properties for eosinophils, causing an influx of eosinophils into the airway mucosa, which further fuels the inflammatory process. In addition, the cysteinyl leukotrienes are potent secretagogues and reduce ciliary motility, which may hinder mucociliary clearance. Asthmatic patients demonstrate increased production of cysteinyl leukotrienes during naturally occurring asthma and acute asthma attacks as well as after allergen and exercise challenge. The leukotriene receptor antagonists montelukast, zafirlukast and pranlukast inhibit bronchoconstriction in asthmatic patients undergoing allergen, exercise, cold air or aspirin challenge. They attenuate the hallmarks of asthmatic inflammation, including eosinophilia in the airway mucosa and peripheral blood. Moreover, exhaled nitric oxide concentrations, another correlate of airway inflammation, are decreased during montelukast treatment in children. Cysteinyl leukotriene synthesis is not blocked by corticosteroid therapy. This important observation suggests that the leukotriene receptor antagonists represent a novel therapeutic approach, one that may provide benefits that are additive with corticosteroid therapy. This supposition is supported by clinical observations that treatment with leukotriene receptor antagonists significantly improve asthma control when added to inhaled corticosteroid therapy. Moreover, the bronchodilator properties of the leukotriene receptor antagonists are additive with those of β agonists. These data provide strong support for the use of leukotriene receptor antagonists for treating asthma.     

The role of leukotriene receptor antagonists in the treatment of chronic asthma in childhood

A considerable increase in the prevalence of childhood asthma over the last few decades has been mirrored by a dramatic increase in usage of anti-asthma drugs; however, there has been no reduction in the numbers of patients dying of asthma. Concern has been expressed about the development of tolerance with continuous use of inhaled β-agonist bronchodilators and about the potential adverse systemic effects of high-dose inhaled corticosteroids in children. Moreover, patient compliance with inhaled therapy tends to be poor. The leukotriene receptor antagonists, including montelukast, pranlukast and zafirlukast, are orally administered agents with proven benefits in asthma. In a large, placebo-controlled pediatric trial, montelukast significantly ( P <0.02) reduced requirements for rescue β-agonist bronchodilators, improved quality of life, reduced the circulating level of blood eosinophils and produced improvements in lung function. In adult studies, montelukast reduced sputum eosinophils and attenuated early and late phase allergen-induced reactions. Montelukast has also demonstrated protective effects against exercise-induced bronchospasm in both adults and children, and this protection was maintained during the trough period at the end of the once-daily administration interval (namely, 20–24 h post-dose). Several studies have demonstrated that the formation of cysteinyl leukotrienes in the airways of asthmatic patients is not suppressed by corticosteroids; thus, it is not surprising that montelukast demonstrates complementary effects when given with inhaled corticosteroids. Currently, the most compelling evidence from published trials suggests that leukotriene receptor antagonists can be used as add-on therapy to inhaled corticosteroids to allow tapering of corticosteroid dose and reduction in β-agonist use. Recent clinical trial results suggest there may also be a role for these agents as first-line therapy in children with mild asthma.     

Clinical implications of airway inflammation in mild intermittent asthma.

OBJECTIVE: To determine whether inhaled corticosteroids should be prescribed to patients with milder forms of asthma and whether markers of airway inflammation should be considered when making therapy decisions. DATA SOURCES: A PubMed search was performed of the English-language literature published in the preceding 10 years (January 1, 1993, through December 31, 2003) concerning epidemiology, pathophysiology, therapy, and prognosis of mild intermittent asthma, with asthma, mild, and intermittent as indexing terms. STUDY SELECTION: All relevant studies including author's expert opinions were selected. RESULTS: Several studies have addressed the question of a possible benefit of maintenance therapy (ie, inhaled steroids) in patients with mild intermittent asthma. Although a diminishing effect on airway inflammation has been widely demonstrated, even in patients with mild disease, the impact of inhaled steroids on the long-term prognosis is much less clear. For patients with mild disease who are long-term inhaled steroid users, alternative therapy strategies, including low-dose inhaled steroids and leukotriene receptor antagonists, have been advocated. CONCLUSIONS: Mild intermittent asthma is a disease characterized not only by infrequent symptoms and normal lung function but also by chronic airway inflammation, possibly resulting in irreversible airflow limitation if left unattended. Therefore, maintenance therapy, such as (low-dose) inhaled steroids or leukotriene receptor antagonists, should be considered in patients with mild disease. Future studies should give more insight into the impact of prolonged anti-inflammatory therapy on the long-term prognosis of mild intermittent asthma patients. Whether results from these studies will justify a more aggressive treatment for these patients remains to be answered.     

Seven cases of complete and incomplete forms of Churg-Strauss syndrome not related to leukotriene receptor antagonists.

BACKGROUND: Various forms of Churg-Strauss syndrome have been reported in association with the use of leukotriene receptor antagonists in asthmatic patients. OBJECTIVE: Our purpose was to increase awareness that different forms of the Churg-Strauss syndrome occur in patients not receiving leukotriene modifiers. METHODS: We searched for all the cases of Churg-Strauss syndrome that were seen in the University of Rochester Medical Center, New York, in the past 4 years. RESULTS: We identified 7 patients, 6 of whom fulfilled the American College of Rheumatology criteria for the classification of Churg-Strauss syndrome. None of them used leukotriene receptor antagonists. All had asthma and sinus disease. The duration and severity of their asthma varied considerably. In the majority of the patients the features of Churg-Strauss syndrome became obvious as the systemic corticosteroid dose was being tapered or discontinued, although 3 patients had not been receiving maintenance oral corticosteroids at disease onset. Three patients had positive antineutrophil cytoplasmic antibodies test result (perinuclear pattern). There was histologic documentation of vasculitis in 4 patients. Five of 7 patients responded to high-dose corticosteroid treatment. CONCLUSION: Our 7 cases are similar to the various forms of Churg-Strauss syndrome that have been reported in association with the leukotriene receptor antagonists. Complete or incomplete forms of this syndrome can become apparent in asthmatic patients as systemic corticosteroids are being tapered but can also occur in patients with mild asthma of short duration who use only inhaled corticosteroids.     

Clinical activity of leukotriene inhibitors

Data from the emerging clinical trials with compounds such as zileuton, ICI 204,219, Bay X1005, MK571, MK679, and MK591 are demonstrating the importance of the leukotrienes as mediators of asthma and possibly other diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. One of the major questions facing the asthma community is how much improvement in the FEV1 is needed to improve the quality of life of the asthmatic patient. Comparing the various approaches to asthma treatment, there is typically 15–20% improvement in the lung function with inhaled steroids. Leukotriene interventions apparently will improve lung function to similar levels as with inhaled steroids, and thus may offer an alternative to steroids. Like the steroids, zileuton appears to also reduce the inflammatory cell influx into the antigen-challenged site, which may have the long-term effect of reversing some of the tissue alterations that occur as a result of the inflammation seen with asthma. Importantly, the reported experience to date has shown that the leukotriene modulators do not have the same side-effects as the current therapies, and thus offer the hope that both safe and effective treatment may be derived from this approach. The clinical data reported do not yet define a preferred approach to the modulation of leukotriene pathology. As more studies are published in other diseases the broad spectrum use of these inhibitors will become known.     

Diagnosis and management of early asthma in preschool-aged children

Asthma is a common disease in young children and is associated with significant morbidity and an increasing prevalence over time. Early childhood wheezing and asthma are heterogeneous disorders; thus identifying phenotypes of asthma remains a goal to identify high-risk children who might benefit from specific therapies or secondary prevention interventions. The typical pattern of illness in preschool-aged children consists of short but recurrent exacerbations of cough and wheeze usually triggered by viral respiratory tract infections. Documenting reversible airflow obstruction on lung function, allergen sensitization, increased IgE levels, or blood eosinophilia is helpful in establishing a diagnosis of asthma in preschool-aged children, if present; however, the diagnosis is most often based on symptom patterns, presence of risk factors, and therapeutic responses. The preschool-aged asthmatic population tends to be characterized as exacerbation prone with relatively limited impairment, unlike older children and adolescents who have more impairment-dominant disease. However, management of persistent disease is based largely on expert opinion and extrapolation from studies in older children given the relative lack of data in this age group. Strategies used to manage intermittent disease include daily and intermittent controller therapy. Management strategies for persistent asthma include daily inhaled corticosteroids, daily leukotriene receptor antagonists, and combination therapies. Finally, regular monitoring of symptom control and medication side effects is important along with titrating controllers to the minimally effective dose.     

Pharmacotherapy for allergic rhinitis: a critical review of leukotriene receptor antagonists compared with other treatments.

OBJECTIVE: To review the mechanisms and clinical efficacy of leukotriene receptor antagonists, which are investigational therapies for allergic rhinitis, compared with intranasal corticosteroids and nonsedating antihistamines, which are the most commonly prescribed pharmacotherapies for allergic rhinitis. DATA SOURCES: Computer-assisted MEDLINE searches for articles and manual searches of conference proceedings on intranasal corticosteroid, antihistamine, leukotriene receptor antagonist, leukotriene modifier, zafirlukast, montelukast, allergic rhinitis, rhinitis, and asthma. SELECTION: Published articles and pertinent abstracts on the topics identified above were selected. Head-to-head comparator trials as well as data from placebo-controlled trials were selected. RESULTS AND CONCLUSIONS: The studies published to date demonstrate that leukotriene receptor antagonists are sometimes more effective than placebo, are no more effective than nonsedating antihistamines, and are less effective than intranasal corticosteroids in the treatment of allergic rhinitis. The combination of a leukotriene receptor antagonist and an antihistamine has not been proven to be more effective than either agent alone. This review reveals several inconsistencies that require resolution. First, whereas leukotriene receptor antagonists are predicted on the basis of their mechanism of action to improve nasal congestion significantly, clinical studies reveal leukotriene receptor antagonists to be no better than antihistamines at improving congestion. Second, leukotriene receptor antagonists would not be expected on the basis of their putative mechanism of action or nasal challenge data to improve significantly sneezing, nasal itching, or drainage. However, some studies show improvement in these symptoms during treatment with leukotriene receptor antagonists. Considered in aggregate, the data available to date do not clearly support a unique role of leukotriene receptor antagonists in the treatment of allergic rhinitis whether or not it is accompanied by asthma.     

Heterogeneity in response to asthma medications

PURPOSE OF REVIEW: Evidence for the heterogeneity of response to asthma medications including inhaled corticosteroids and leukotriene receptor antagonists is mounting. beta2-Adrenoceptor gene polymorphisms may contribute to asthma responsiveness to short- and long-acting beta2-agonists. This review examines recent articles describing variability in response to inhaled corticosteroids, leukotriene receptor antagonists and short-acting beta2-agonists specifically in pediatric persistent asthmatics. RECENT FINDINGS: In the late 1990's, differences in the response to a leukotriene receptor antagonist and an inhaled corticosteroid in adults with moderate persistent asthma were first described. Subsequently, similar findings have recently been elucidated in children with mild to moderate persistent asthma. The variability in response to these two classes of control medicines now appears to encompass all ages with persistent asthma. In general, despite the variability in response to these medications, both resulted in improved clinical and physiologic control measures. SUMMARY: Childhood asthma is a complex disease with numerous clinical phenotypes that contribute to response variability to asthma medications.     

Body composition and growth in asthmatic children treated with inhaled steroids.

BACKGROUND: Prolonged treatment with inhaled steroids is recommended for long-term control of asthma in children; however, it can interfere with growth and body composition. OBJECTIVE: The aim of this study is to answer the question whether 6 months treatment with inhaled steroids causes body fat accumulation and growth velocity reduction. METHODS: Hospital-based, open study of body composition [by dual-energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA) and skinfolds] and growth of 26 asthmatic children, treated for 6 months with inhaled steroids [budesonide (BUD) 400 microg/day (group 1) or fluticasone proprionate (FP) 200 microg/day (group 2)], sodium cromoglycate and beta2-agonist (salbutamol) compared with a control group of 16 asthmatic children treated only with sodium cromoglycate and beta2-agonist. RESULTS: On average, total and regional fat mass, adjusted for pubertal stage and gender, and growth velocity were similar in all three groups of patients and were not influenced by treatment (% mean change +/- 1 SD of fat mass during treatment in BUD 0.1 +/- 3.0%, FP -1.1 +/- 3%, and control -2.8 +/- 3.5%; ANOVA P > or = .05); however seven patients, two in group 1 (1 preschool child), three in group 2 (2 preschool children) and two in the control group (two prepubertal boys aged 8.5 and 9.5 year), during treatment, showed a growth velocity standard deviation score below the third percentile. CONCLUSION: A 6-month treatment with inhaled BUD and FP does not induce body fat accumulation; however, in a few preschool children the treatment was associated with growth velocity below the third percentile. Our results suggest the need for constant monitoring of growth in all asthmatic children on chronic treatment with inhaled steroids. Further studies devoted to the effects of inhaled steroids use in preschool children are needed.     

Fluticasone propionate and bronchial hyperresponsiveness in childhood asthma.

Bronchial asthma is now agreed as being a chronic inflammatory disease of the airways. Inhaled steroids are widely accepted as a preventive medication in asthmatic patients of all ages and severity. However, the optimal use of inhaled steroids and the important issue of safety and efficacy still remain of concern, particularly in children. Recently, fluticasone propionate (FP) has been developed for use as an inhaled preparation for the treatment of asthma. Because of its high topical potency and increased lipophilicity, it is claimed that FP has an improved risk/benefit compared with other inhaled steroids. In order to evaluate the use of FP in children, we have studied the efficacy of high dose FP (500 microg/day) in asthmatic children. Thirteen children (9 boys and 4 girls), aged 7-17 years (10.8 +/- 2.6), were instructed to use a pressurized metered-dose inhaler connected to a Volumetric spacer. The standard methacholine bronchial challenge test was used as a principal outcome parameter. The PD20, a cumulative dose of methacholine inducing a 20% decrease in FEV1, was measured pre- and post-treatment with inhaled FP. After 4 weeks of FP, PD20 significantly increased from 21.6 +/- 14.3 inhalation unit to 106.6 +/- 78.5 inhalation unit (4.9 fold, p = 0.004) reflecting the improvement of airway reactivity. All subjects improved clinically. These results demonstrate that the anti-inflammatory action of FP 500 microg a day for four weeks can markedly reduce bronchial hyperresponsiveness, the basic physiologic abnormality in bronchial asthma.     

治疗方式对哮喘儿童治疗依从性的影响

目的调查影响儿童哮喘治疗依从性的相关因素,为更好地防治儿童哮喘提供依据。方法对本院2006年4月至2007年10月共收治的118例哮喘儿童,根据是否按全球哮喘防治创议方案系统规范用药情况分为依从性良好（41例）、依从性中等（46例）以及依从性差（31例）三组,采取问卷的方法,对118例哮喘儿童的缓解期治疗方案及主要监护人进行调查和咨询。结果患儿居住环境、主要监护人对哮喘知识的了解、治疗信心、药物安全性认识、学历、制定哮喘治疗书面计划、专人监督用药、定期复诊咨询等与哮喘患儿治疗的依从性具有关联性：在校正了上述影响哮喘患儿治疗依从性的因素后,发现口服顺尔宁治疗患儿的依从性明显好于普米克气雾剂治疗的哮喘患儿的依从性,后者放弃治疗的发生风险是前者的1．39倍。结论影响哮喘儿童治疗依从性的因素是多种的。在其中药物的治疗方式上,口服白三烯受体拮抗剂较吸人糖皮质激素的依从性更好。     

Effect of different monotherapies on serum nitric oxide and pulmonary functions in children with mild persistent asthma

Introduction

Common medications used to treat mild persistent asthma are glucocorticoids, leukotriene receptor antagonists and theophylline. The aim of the study was to evaluate monotherapy with either inhaled steroids, oral leukotriene receptor antagonist or theophylline in Egyptian children with mild persistent asthma by determining their clinical, laboratory and spirometric responses to treatment.

Material and methods

Thirty-nine mild asthmatic children between 8 and 13 years of age were included in the study. Patients were classified according to therapy received into four groups: oral leukotriene receptor antagonist (montelukast), inhaled corticosteroid (fluticasone propionate), sustained-release (SR) theophylline, and no treatment. Pulmonary function testing was performed at the start of therapy and 8 weeks later using spirometry. Eosinophil count and serum nitric oxide were estimated in the blood. Minitab statistical package was used for analysis of data.

Results

Follow-up after 8 weeks revealed significant improvement in FEV1% in groups 1 (p < 0.01) and 3 (p < 0.05), significant improvement in PEFR in groups 1 (p < 0.05) and 2 (p < 0.01), significant decline in serum NO levels in groups 1 (p < 0.05) and 2 (p < 0.05), as well as significant improvement in eosinophil count in groups 1, 2 and 3 (p < 0.01, < 0.001, < 0.01 respectively). There was a statistically significant positive correlation between the decline in serum NO and the decline in blood eosinophil % in group 2 (p < 0.05).

Conclusions

Inhaled corticosteroids and montelukast have a significant role in controlling the pulmonary functions and the inflammatory process in children with mild persistent asthma, although inhaled corticosteroids seem to yield a better response. Children with mild persistent asthma should receive a controller medication, and SR theophylline may be a good cost-benefit alternative for low socio-economic groups of patients.     

Non-Corticosteroid Anti-Inflammatory Drugs in Asthma

Asthma is a chronic inflammatory disease of the airways. As airways inflammation plays a principal role in the pathogenesis of asthma, even in patients with mild disease, current recommendations give anti-inflammatory therapy a central position in the treatment of asthma. Although inhaled corticosteroids are the most widely used anti-inflammatory drugs in the management of patients with asthma, nonsteroidal anti-inflammatory agents may be used as a first step. Sodium cromoglycate (cromolyn sodium) and nedocromil are anti-inflammatory drugs which are effective in many patients with asthma of mild to moderate severity. Both drugs have been demonstrated to be well tolerated. Nedocromil is more potent than sodium cromoglycate, although the number of clinical studies that have compared these two drugs is small. Nedocromil may also be effective as a corticosteroid-sparing agent in the treatment of patients with asthma who require high dosages of inhaled corticosteroids. This may be important, as high dosages of inhaled corticosteroids may cause adverse effects. A novel approach to the treatment of asthma is represented by the leukotriene synthesis inhibitors and leukotriene receptor antagonists, new classes of anti-inflammatory drugs. Although the number of clinical studies with these agents is relatively small, they indicate effectiveness in the treatment of patients with mild to moderate asthma with no systemic adverse effects. Theophylline has only recently been reconsidered as a potential anti-inflammatory drug. Although serious toxicity may occur with this agent, theophylline is effective in reducing symptoms and improving lung function in patients with mild chronic asthma, even in those already treated with inhaled corticosteroids.     

Therapeutic strategies to reduce asthma exacerbations

Asthma exacerbations can occur in patients with all degrees of asthma severity. They generally develop over 5 to 7 days and are most often initiated by an upper respiratory tract infection (usually with human rhinovirus) or by environmental allergen exposure in atopic subjects. Inhaled corticosteroids (ICSs) taken on a regular basis are very effective in reducing the risk of asthma exacerbations, and the combination of ICSs and long-acting inhaled β?-agonists further reduces this risk. In addition, use of the combination of the ICS budesonide and the long-acting inhaled β?-agonist formoterol, both as maintenance asthma treatment and also as rescue treatment (instead of a short-acting inhaled β?-agonist), has a significant further beneficial effect on asthma exacerbation risk. Other therapies that have been demonstrated to reduce severe asthma exacerbations are leukotriene receptor antagonists, which have been demonstrated to be effective most consistently in this regard in children, and anti-IgE mAbs, which are effective in subjects with difficult-to-treat allergic asthma. Approximately 50% of severe asthma exacerbations are eosinophilic in nature, whereas many of the remaining are neutrophilic. Several studies have demonstrated that making asthma treatment decisions based on minimizing airway eosinophil numbers (measured in induced sputum) can reduce the risks of severe exacerbations. In addition, treatment of patients with severe asthma with an anti-IL-5 mAb also reduces the number of severe asthma exacerbations, demonstrating a central role of eosinophils in many exacerbations.     

Management approaches to intermittent wheezing in young children

PURPOSE OF REVIEW: To review the recently published studies addressing various treatment approaches for episodic wheezing in young children. RECENT FINDINGS: A landmark study demonstrated that short courses of oral corticosteroids initiated at the first sign of an upper respiratory tract infection decreased wheezing episode frequency and severity. Since then, alternative treatment strategies have been investigated. Montelukast decreased short-term daytime cough and delayed exacerbations following hospitalization for respiratory syncytial virus bronchiolitis, and led to fewer exacerbations without decreasing oral corticosteroids use among children with intermittent asthma. Preschool children with frequent wheezing at high risk for asthma receiving daily inhaled corticosteroids experienced lower rates of exacerbations requiring oral corticosteroids. Episodic use of inhaled corticosteroids, initiated at the early signs of an upper respiratory infection, led to modest reduction in symptoms, but not oral corticosteroid use. Among young children with 'preasthma', inhaled corticosteroids initiated after 3 days of wheezing did not affect the frequency or severity of wheezing episodes. SUMMARY: Evidence for the preferred treatment strategies for intermittent wheezing in young children remains incomplete. Most of the studies represent heterogeneous populations and lack adequate statistical power to evaluate relevant outcomes. Based on the evidence, there is rationale for further investigation of several management strategies, including corticosteroids and/or leukotriene receptor antagonists administered daily or episodically.     

Leukotriene receptor antagonist, montelukast, can reduce the need for inhaled steroid while maintaining the clinical stability of asthmatic patients

BACKGROUND: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma. OBJECTIVE: To determine whether the addition of montelukast could lead to a reduction in inhaled corticosteroid dose without a significant decrease in peak expiratory flow rate (PEFR). METHODS: After a 4-week run-in period, 191 moderate-to-severe asthmatic patients whose asthma had been well controlled with daily inhaled corticosteroid therapy (beclometasone dipropionate 800 to 1600 micro g/day), were randomly assigned to one of two treatments - placebo (n = 98) or montelukast 10 mg once daily (n = 93) - for a 24-week, multicentre, double-blind, treatment period. At the beginning of the active treatment period, the daily dose of inhaled corticosteroid was halved in all of the patients. In addition, the inhaled corticosteroid dose was subsequently titrated every 8 weeks, based on PEFR, asthma symptoms and beta-agonist use. RESULTS: After 8 weeks of a 50% reduction in inhaled corticosteroid use, morning PEFR increased by 5.3 +/- 32.3 L/min from baseline in patients receiving montelukast and significantly decreased by 6.9 +/- 29.0 L/min in those receiving placebo (P = 0.035). In addition, evening PEFR significantly decreased by 9.8 +/- 28.5 L/min (P = 0.003) in the placebo group, but was maintained in the montelukast group. In spite of a subsequent 50% reduction in the inhaled corticosteroid dose every 8 weeks, morning and evening PEFRs were maintained over the 24-week treatment period in the montelukast group; PEFR significantly decreased in the placebo group. There was a significant difference between the two groups with regard to morning PEFR, therapy score and asthmatic score at weeks 8, 16 and 24, as well as evening PEFR at week 8. However, the symptom scores were not significantly different between the two groups or within each group. CONCLUSION: These data suggest that montelukast reduces the need for inhaled corticosteroids while maintaining asthma control over a 24-week period. Therefore, montelukast may be useful for long-term treatment in patients with asthma who require high doses of inhaled corticosteroids.     

Leukotriene modifiers for asthma treatment

Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB₄, are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor subtypes for CysLTs, CysLT₁ and CysLT₂, have been identified. The activation of the CysLT₁ receptor is responsible for most of the pathophysiological effects of CysLTs in asthma, including increased airway smooth muscle activity, microvascular permeability, and airway mucus secretion. LTB₄ might have a role in severe asthma, asthma exacerbations, and the development of airway hyperresponsiveness. CysLT₁ receptor antagonists can be given orally as monotherapy in patients with mild persistent asthma, but these drugs are generally less effective than inhaled glucocorticoids. Combination of CysLT₁ receptor antagonists and inhaled glucocorticoids in patients with more severe asthma may improve asthma control and enable the dose of inhaled glucocorticoids to be reduced while maintaining similar efficacy. The identification of subgroups of asthmatic patients who respond to CysLT₁ receptor antagonists is relevant for asthma management as the response to these drugs is variable. CysLT₁ receptor antagonists have a potential anti‐remodelling effect that might be important for preventing or reversing airway structural changes in patients with asthma. This review discusses the role of LTs in asthma and the role of LT modifiers in asthma treatment. Cite this as: P. Montuschi and M. L. Peters‐Golden, Clinical & Experimental Allergy, 2010 (40) 1732–1741.     

Oral montelukast treatment of preschool-aged children with acute asthma.

BACKGROUND: Increased amounts of cysteinyl leukotrienes have been demonstrated in urine samples from asthmatic patients, particularly during exacerbations of asthma. Although the use of leukotriene receptor antagonists has been recommended in the treatment of chronic asthma, no guidelines are available regarding their use in the treatment of acute asthma. OBJECTIVE: To investigate the safety and effectiveness of a 4-mg tablet of oral montelukast in addition to short-acting beta2-agonist bronchodilator as the initial treatment in mild to moderate asthma exacerbations in children between 2 and 5 years old. METHODS: Fifty-one patients who were experiencing mild to moderate asthma exacerbation were included in a randomized, double-blind, placebo-controlled, parallel-group study. Each patient received either a 4-mg tablet of montelukast or placebo in addition to inhaled salbutamol and were followed up for 4 hours. The pulmonary index score, respiratory rate, and pulse were determined at baseline and throughout 4 hours after administration. RESULTS: Compared with placebo, the pulmonary index scores and respiratory rates were significantly lower in the montelukast group starting at 90 minutes (P = .01). This difference persisted at 120, 180, and 240 minutes of the study (P = .008, P = .02, and P = .048, respectively). At the end of the first hour of treatment, oral steroid need was 20.8% and 38.5% in patients randomized to the montelukast and placebo groups, respectively (P = .22). Hospitalization rates were not different between the 2 treatment groups. CONCLUSION: A single 4-mg tablet of montelukast had the potential to provide additive clinical benefit in mild to moderate acute asthma in preschool-aged children when administered concomitantly with short-acting beta2-agonist bronchodilators as the initial treatment.     

Effects of pranlukast, a cysteinyl leukotriene receptor 1 antagonist, combined with inhaled beclomethasone in patients with moderate or severe asthma.

BACKGROUND: Although inhaled steroids are used as the first line of therapy in asthmatic patients, symptoms of asthma do not improve completely in some patients. OBJECTIVE: To investigate the effects of pranlukast, a cysteinyl leukotriene receptor 1 antagonist, in patients with moderate/severe asthma, when combined with beclomethasone dipropionate (BDP). METHODS: Protocol 1: After a 2-week observation period, 41 patients with moderate asthma were divided into those receiving BDP at 1,600 microg/day or 800 microg/day + pranlukast (450 mg/day). The effect of treatment was evaluated by measuring AM peak expiratory flow rate, symptom score, frequency of beta2-agonists, and daily variability of peak expiratory flow rate. Protocol 2: 39 patients participated in this study including those with moderate asthma on 800 microg/day BDP (group I), severe asthma on BDP at 1,600 microg/day (group II), and severe asthma on 1,600 microg/day BDP + 5 to 20 mg prednisolone (group III). Patients of all groups were additionally treated with pranlukast. RESULTS: Protocol 1: Both treatment regimens resulted in improvement in each clinical parameter. There were no significant differences in the effects of two treatment regimens. Protocol 2: Pranlukast was effective in group I and II, but not in group III. In groups I and II, pranlukast tended to be more effective when BDP was introduced within the first year of onset of asthma. CONCLUSIONS: Pranlukast is effective for patients with moderate asthma and those patients with severe asthma who are not treated with oral steroids. Pranlukast is more effective in patients treated with BDP early after onset.