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  • br Methods br Discussion and conclusions There were no stati


    Discussion and conclusions There were no statistically significant differences in pulmonary function outcomes (FEV1 and FVC) between the placebo and BAY 85-8501 treatment groups. The decline in mean FEV1 from baseline to EOT in the placebo group was attributed statistically to a few patients with marked decreases in FEV1. Overall, there was no improvement in FEV1 over time in the BAY 85-8501 treatment group. While no conclusions can be drawn from this observation, it is likely that the duration of BAY 85-8501 treatment was insufficient to show improvements in lung function, even though a previous study of another HNE inhibitor, AZD9668, in patients with idiopathic or post-infective BE showed a significant improvement in FEV1 versus placebo after 4 weeks of treatment [18]. Possible explanations for this discrepancy include slightly better lung function at baseline in the AZD9668 study than in the current BAY 85-8501 study, suggesting that the degree of irreversible lung destruction due to BE may have differed in the two studies. In addition, in the AZD9668 study, there appeared to be differences in lung function and proportions of patients taking long-acting muscarinic antagonists, inhaled corticosteroid/long-acting β-agonist combinations and azithromycin in the two treatment groups. The lack of any significant changes in health-related quality of life assessed by the SGRQ in the current BAY 85-8501 study was consistent with the absence of improvements in either pulmonary function or sputum weight. There were no significant differences in sputum or urine biomarker levels between the BAY 85-8501 and placebo groups, with the exception of IL-8 in sputum, which showed a small increase in the BAY 85-8501 group. This is unexpected and difficult to interpret because NE activity is known to induce IL-8 expression upregulation in bronchial epithelial LY 2389575 hydrochloride [29]. Additionally, it is notable that NE activity in sputum did not show the expected decrease over time in the BAY 85-8501 treatment group compared with placebo, in contrast to the findings in whole blood. Effective pharmacological treatment of non-CF BE is challenging owing to the established self-enhancing cycle of inflammation and bacterial infection, the irreversible tissue destruction that is pathognomonic for the condition, and the need for topical or systemically delivered drugs to reach and be pharmacodynamically active in the lumen of affected bronchi. This is reflected in the mixed success of investigative therapies to date, which include long-term macrolide treatment as an immunomodulatory strategy. For example, in the EMBRACE study, azithromycin 500 mg three times weekly for 6 months reduced the number of pulmonary exacerbations compared with placebo in patients with non-CF BE, but there was no significant change in FEV1 or in the SGRQ total score [30]. Similarly, administration of azithromycin 250 mg daily for 12 months in the BAT trial [31] and 400 mg erythromycin ethylsuccinate twice daily for 12 months in the BLESS trial [32] reduced exacerbation rates compared with placebo. However, changes in pulmonary function were small: an improvement in FEV1 of 1.03% per 3 months in BAT [31] and an attenuation of the predicted decline of FEV1% (absolute difference from placebo of 2.2%) in BLESS [32]. In the context of these clinical trial results for other immunomodulatory therapies in non-CF BE, it is reasonable to postulate that the lack of clinical effect of BAY 85-8501 in this study could be due to short treatment duration.
    Serpins: inhibitors of proteases SERPINB1, also called Leukocyte Elastase Inhibitor (LEI) is a member of the clade B of the serpin (serine protease inhibitors) superfamily of proteins [1]. Serpins are the largest and most broadly distributed superfamily of protease inhibitors. All multicellular eukaryotes have serpins: humans, Caenorhabditis elegans, Drosophila, Arabidopsis thaliana. They count about 36, 9, 13 and 29, serpin genes, respectively [2]. In contrast, most prokaryotes have only a single gene. The serpin superfamily has been divided in higher animals into 9 clades (A-I). All the clades contain extracellular proteins, except for clade B, which contains predominantly intracellular proteins [3].