Pilot application of lipoxin A(4) analog and lipoxin A(4) receptor agonist in asthmatic children with acute episodes

摘要

Previous studies have demonstrated that lipoxin A4 (LXA(4)) analogs blocked both airway hyper-responsiveness and pulmonary inflammation in a murine model of asthma. The present pilot study investigated the initial efficacy and safety of inhaled 5(S),6(R)-LXA(4) methyl ester and BML-111, a LXA(4) agonist, in the treatment of asthmatic children with acute episodes. A total of 50 asthmatic children diagnosed with acute moderate asthma were randomly assigned into groups and subjected to an inhalation challenge with pulmicort (n=10), ventolin (n=10), 5(S),6(R)-LXA(4) methyl ester (n=10), BML-111 (n=10) or normal saline as a placebo (n=10). Pulmonary function was assessed prior to and following the challenge. Acute toxicity and safety of the inhaled 5(S),6(R)-LXA(4) methyl ester and BML-111 in normal BALB/c mice were investigated prior to the current pilot study conducted in patients. Following the inhalation challenge, pulmonary function parameters in all groups with the exception of the normal saline-treated group indicated an improvement. The efficacies of 5(S),6(R)-LXA(4) methyl ester and BML-111 were superior to the efficacy of pulmicort but reduced when compared to the efficacy of ventolin with regard to the improvement of pulmonary function following the inhalation challenge. No clinical adverse events were observed in the enrolled patients. All safety parameters in the full blood counts, routine urine and feces examination, electrocardiogram and liver and kidney function tests at baseline and the end of the current study were within normal limits for all patients. No significant differences in kidney or liver function tests were observed in mice treated with 5(S),6(R)-LXA(4) methyl ester and BML-111. Light and electron microscopy demonstrated no airway epithelium or alveolar epithelial cell damage in the treated mice. The present preliminary study of a small sample demonstrates the initial efficacy and safety of inhaled 5(S),6(R)-LXA(4) methyl ester and BML-111 in the treatment of asthmatic children with acute moderate episodes, and suggests that an inhaled LXA(4) analog and LXA(4) receptor agonist may exhibit potential as a novel therapeutic strategy for asthma.