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.