Leukotriene receptor antagonists in children with cystic fibrosis lung disease : anti-inflammatory and clinical effects.
Cystic fibrosis (CF) lung disease is characterized by chronic endobronchial infection resulting in progressive pulmonary destruction; this is a major cause of mortality and morbidity. Neutrophils are the primary effector cells responsible for the progressive deterioration of lung function. Peptido-leukotriene B4 antagonists, new anti-inflammatory agents that block the neutrophil-dominated inflammation, could have had the potential for long-term use. A trial on the pharmacokinetics of amelubant administered orally as a single dose of up to 75 mg in pediatric patients with CF and 300 mg in adults, and as a repeated dose of 75 mg and 150 mg, respectively, once daily for 15 days provided evidence that amelubant metabolism in adult and pediatric patients with CF is similar to that in healthy adults. In another study using the same dosage regimen, amelubant appeared to be safe and well tolerated. Safety measures included physical examination, vital signs, spirometry, oximetry, ECG, and clinical laboratory testing. However, a randomized, double-blind, placebo-controlled, multinational, phase II trial (Boehringer Ingelheim 543.45) was conducted to investigate the clinical efficacy of 24 weeks of treatment with amelubant in patients with CF with mild-to-moderate lung disease. Two doses of amelubant (75 and 150 mg) were tested in adult patients (> or = 18 years) and one dose of amelubant (75mg) was tested in pediatric (6-17 years) patients. The trial was terminated early due to a statistically significant increase in the risk of pulmonary-related, serious adverse events in adults receiving amelubant. Cysteinyl leukotrienes, eosinophilic inflammation, and viral infections also contribute to progressive pulmonary destruction in CF. Cysteinyl leukotrienes are potential targets for cysteinyl leukotriene receptor antagonist use. A study on the pharmacokinetics of montelukast in children with CF provided evidence that the dose of montelukast and the administration interval does not need to be modified if the goal is to mimic the serum concentrations used to treat asthma. In a randomized, double-blind, crossover, placebo-controlled study, 16 children with mild CF (median age 9.5 years; vital capacity [VC] >70%) were treated with montelukast (5 to < or =14 years; 5 mg; >14 years; 10 mg) or placebo as a once-daily tablet for 21 days. There was a significant (p < or = 0.02) reduction in serum eosinophil cationic protein levels and eosinophils (p < or = 0.027) with montelukast. However, neither lung function tests (VC, forced expiratory volume in 1 second [FEV1], maximum expiratory flow at 25% of forced VC), nor clinical symptom scores changed significantly. In another study, 26 patients aged 6-18 years with moderate CF (VC between 40% and 69% predicted) received montelukast or placebo for 8 weeks in a 20-week, randomized, double-blind, crossover, placebo-controlled trial. After treatment with montelukast there was a significant improvement in FEV1, peak expiratory flow, and forced expiratory flow between 25% and 75%, and a significant decrease in cough and wheezing scale scores (p < 0.001 for all). Montelukast treatment decreased serum and sputum levels of eosinophil cationic protein and interleukin-8 (IL-8), decreased sputum levels of myeloperoxidase, and increased serum and sputum levels of IL-10 (p < 0.001 for all) compared with placebo. To date, clinical experience and research data on the anti-inflammatory effects of leukotriene receptor antagonists in CF are limited. Multicenter trials with longer observation periods and greater patient numbers are needed to prove the hypothesis that leukotriene receptor antagonists have the potential to ameliorate CF lung disease with long term use.
Schmitt-Grohé
Sabina
S
Department of Pediatrics, University of Bonn, Bonn, Germany. s.schmitt.grohe@uni-bonn.de
Zielen
Stefan
S
D000293:Adolescent; D000578:Amidines / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000150:complications; D016535:Bronchial Hyperreactivity / Q000150:complications; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D003550:Cystic Fibrosis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018836:Inflammation Mediators / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D009504:Neutrophils / Q000276:immunology; D012141:Respiratory Tract Infections / Q000150:complications / Q000188:drug therapy; D014777:Virus Diseases / Q000150:complications / Q000188:drug therapy
D000578:Amidines; D002219:Carbamates; D018836:Inflammation Mediators; D020024:Leukotriene Antagonists; C424425:amelubant