A Randomized Controlled Trial on the Effect of Montelukast on Sputum Eosinophil Cationic Protein in Children with Corticosteroid-Dependent Asthma

Abstract

Previous adult studies demonstrated the clinical efficacy of an additional treatment with leukotriene receptor antagonists on steroid-dependent asthma, but there is little knowledge about anti-inflammatory add-on effects within the lung. In this study, we hypothesized that steroid-treated children exhibit a decrease in bronchial inflammation in induced sputum under additional treatment with montelukast. Twenty-five asthmatic children aged 6 to 14 y, who had been taking inhaled corticosteroids (400 -800 g/d budesonide) regularly for at least 12 wk, were randomized to receive additional treatment with either montelukast (5 mg orally, once daily) or placebo over a 4-wk period. As primary efficacy variable, eosinophil cationic protein (ECP) in induced sputum as direct measurement of bronchial inflammation was assessed before and after treatment. To assure a baseline level of inflammation, an ECP concentration above 100 g/L was required. Sputum eosinophil count, concentration of exhaled nitric oxide, urinary excretion of eosinophil protein X, and quality-oflife items were considered as secondary outcome variables. After treatment with montelukast, ECP in sputum was significantly reduced (montelukast: median Ϫ975 g/L [5 to 95% confidence interval: Ϫ4295 to 583 g/L]; placebo: 561 g/L [Ϫ1335 to 3320 g/L]; p Ͻ 0.01) and the quality-of-life score had significantly improved (p Ͻ 0.05) compared with placebo. Partly explained by low baseline levels, no statistically significant change in concentration of exhaled nitric oxide (p Ͼ 0.05), urinary excretion of eosinophil protein X (p Ͼ 0.05), or eosinophil count (p Ͼ 0.05) was found. In conclusion, add-on treatment with montelukast can suppress sputum ECP in children with steroid-dependent asthma, while at the same time an improvement in quality of life items occurs. Asthma is the most common chronic disease in children and results in a considerable burden in the child's daily life (1). Inhaled glucocorticosteroids are the most potent antiinflammatory drugs currently available and are the first-line therapy in patients with chronic asthma (2). However, longterm side effects of inhaled corticosteroids in young children cannot be fully excluded (3). Moreover, several studies have shown a persistent inflammation in steroid-treated asthmatics (4 -7), and it has been postulated that inadequate treatment of airway inflammation may lead to irreversible changes in airway function (8). LTRA such as zafirlukast, pranlukast, and montelukast are able to reduce effects of Cys-LT (leukotriene C4, D4, and E4) and are increasingly used as additional anti-inflammatory drugs. The local pulmonary efficacy of zafirlukast was demonstrated in bronchoscopy-based studies (9, 10). Recently, it has been shown that pranlukast is able to reduce bronchial inflammation assessed by sputum markers in asthmatic adults (11).Montelukast, although frequently used for children, has been evaluated on the basis of indirect measurements (e.g. eosinophils in serum, FeNO) (12-15) but not on the basis of direct measurem...

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…These data support early reports demonstrating the inhibitory action of CysLT 1 R antagonists on eosinophil activation and migration (Virchow et al, 2001;Fregonese et al, 2002;Suzuki et al, 2003;Ueda et al, 2003;Saito et al, 2004;Nagata et al, 2005), as well as on adhesion (Fregonese et al, 2002;Nagata et al, 2002;Kushiya et al, 2006;Meliton et al, 2007;Profita et al, 2008). There is considerable information available to demonstrate the ability of CysLTR antagonists to reduce airway eosinophilia and eosinophil cationic protein (ECP) in animals (Underwood et al, 1996;Ihaku et al, 1999) and in humans (Pizzichini et al, 1999;Obase et al, 2002;Steinke et al, 2003;Strauch et al, 2003;Laitinen et al, 2005;Kopriva et al, 2006). CysLT 1 Rs are also found to be expressed in B lymphocytes and CD34 ϩ hematopoietic progenitor cells .…”

The effect of montelukast on lung function and exhaled nitric oxide in infants with early childhood asthma

“…As a cys-LT1 receptor antagonist, montelukast is known to have an anti-inflammatory effect, which has been demonstrated in several studies. Montelukast has been found to cause a significant decrease in the levels of sputum eosinophil cationic protein [23], soluble interleukin-2 receptor, interleukin-4 and soluble intercellular adhesion molecule-1 and eosinophil blood counts [18]. While studies in adults [20,25,30] and school-aged children [9,31] treated with montelukast have shown a fall in FeNO, the data from the present study illustrate that this effect of montelukast on FeNO is also present in infants and very young children aged ,2 yrs suffering from early childhood asthma.…”

“…Although some studies have demonstrated a positive effect on markers of airway inflammation [9,18,20,23,24], namely FeNO and levels of sputum eosinophils and eosinophil cationic protein, others have not [25]. Montelukast is orally administered once daily and is therefore easy to apply.…”

Novel montelukast sodium-loaded clear oral solution prepared with hydroxypropyl-β-cyclodextrin as a solubilizer and stabilizer: enhanced stability and bioequivalence to commercial granules in rats

“…Asthma is a problematic disease that is prevalent worldwide, and about 200 million asthma patients are estimated to be present. Half of childhood asthma cases persist until adulthood and continue as adult asthma [4]. Therapeutic agents of asthma are mainly divided into disease-controlling agents and symptom-alleviating agents [5,6].…”