Kong Xia, Wu Sheng-Hua, Zhang Li, Chen Xiao-Qing
Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Department of Pediatrics, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China.
Exp Ther Med. 2017 Sep;14(3):2284-2290. doi: 10.3892/etm.2017.4787. Epub 2017 Jul 12.
Previous studies have demonstrated that lipoxin A (LXA) 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 methyl ester and BML-111, a LXA 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 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 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 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 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 methyl ester and BML-111 in the treatment of asthmatic children with acute moderate episodes, and suggests that an inhaled LXA analog and LXA receptor agonist may exhibit potential as a novel therapeutic strategy for asthma.
先前的研究表明，脂氧素A（LXA）类似物可在哮喘小鼠模型中同时阻断气道高反应性和肺部炎症。本初步研究调查了吸入5(S),6(R)-LXA甲酯和LXA激动剂BML-111治疗急性发作期哮喘儿童的初步疗效和安全性。共有50名被诊断为急性中度哮喘的儿童被随机分组，分别接受普米克（n=10）、万托林（n=10）、5(S),6(R)-LXA甲酯（n=10）、BML-111（n=10）吸入激发试验，或作为安慰剂的生理盐水（n=10）吸入激发试验。在激发试验前后评估肺功能。在对患者进行当前初步研究之前，先研究了吸入5(S),6(R)-LXA甲酯和BML-111对正常BALB/c小鼠的急性毒性和安全性。吸入激发试验后，除生理盐水治疗组外，所有组的肺功能参数均有所改善。在吸入激发试验后改善肺功能方面，5(S),6(R)-LXA甲酯和BML-111的疗效优于普米克，但与万托林相比有所降低。在入组患者中未观察到临床不良事件。在本研究基线和结束时，所有患者全血细胞计数、尿常规和粪便检查、心电图以及肝肾功能检查的所有安全参数均在正常范围内。在用5(S),6(R)-LXA甲酯和BML-111治疗的小鼠中，未观察到肝肾功能检查有显著差异。光镜和电镜检查显示，治疗后的小鼠气道上皮或肺泡上皮细胞无损伤。本小样本初步研究证明了吸入5(S),6(R)-LXA甲酯和BML-111治疗急性中度发作期哮喘儿童的初步疗效和安全性，并表明吸入LXA类似物和LXA受体激动剂可能具有作为哮喘新型治疗策略的潜力。
