Doxycycline improves clinical outcomes during cystic fibrosis exacerbations

Abstract

Matrix metalloprotease-9 (MMP-9) plays a role in progression of cystic fibrosis, and doxycycline can reduce MMP-9 Here, we explore the effect of doxycycline during cystic fibrosis exacerbation treatment on MMP-9 related readouts and clinical end-points.This randomised, double-blind, placebo-controlled study enrolled hospitalised patients with cystic fibrosis undergoing exacerbation. In total, 20 participants were given doxycycline and 19 participants were given placebo over an 8-day period during hospitalisation. Biospecimens were collected at the beginning and the end of the study period. Primary end-points were total MMP-9 levels in the sputum and safety/tolerability. Secondary end-points included change in lung function, time to next exacerbation, and markers of MMP-9-related protease activity (active MMP-9 and TIMP-1). Nonparametric testing was used for within-group and between-group analyses.Doxycycline was well tolerated, with no treatment discontinuations or serious adverse events. Doxycycline reduced total sputum MMP-9 levels by 63.2% (p<0.05), and was also associated with a 56.5% reduction in active MMP-9 levels (p<0.05), a 1.6-fold increase in sputum TIMP-1 (p<0.05), improvement in forced expiratory volume in 1 s (p<0.05), and an increase in time to next exacerbation (p<0.01).Adjunctive use of doxycycline improved dysregulated MMP-9 levels in sputum, along with biomarkers consistent with a reduced proteolytic pulmonary environment. Improvement in clinical outcome measures suggests an important therapeutic benefit of doxycycline for individuals with cystic fibrosis.

Doxycycline Attenuates Atrial Remodeling by Interfering with MicroRNA-21 and Downstream Phosphatase and Tensin Homolog (PTEN)/Phosphoinositide 3-Kinase (PI3K) Signaling Pathway

“…Doxycycline, as an antibiotic, has been applied in clinical practice for many years. Bhattacharyya et al [ 18 ] showed that doxycycline merited an appropriate clinical trial in the management of idiopathic pulmonary fibrosis and related studies suggested that doxycycline can improve the clinical outcomes of patients with cystic fibrosis exacerbations or lymphangioleiomyomatosis [ 19 , 20 ]. In addition, Hori et al [ 21 ] showed that doxycycline attenuates isoproterenol-induced myocardial fibrosis in rats.…”

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

“…However, there were no observable differences in sputum NE activity, lung function, respiratory symptoms, quality of life, or use of reliever medication between both treatment arms [99]. Lastly, 2-O, 3-O-desulfated heparin (ODSH), doxycycline and N-Arylacyl O-sulfonated aminoglycosides were shown to exhibit antiprotease properties [100][101][102][103]. A summary of the findings from these various therapeutic antiprotease studies is outlined in Table 1.…”

Recent advances in the understanding and management of cystic fibrosis pulmonary exacerbations

“…Another recent study examined doxycycline as an adjunct therapy for CF PEx, acting as a small-molecule inhibitor of matrix metalloproteinase-9 (MMP-9), which has been implicated in CF airway pathophysiology, particularly during PEx 50 , 51 . This single-center RCT randomly assigned 39 CF patients with PEx requiring inpatient care to either doxycycline 100 mg orally twice daily or placebo for 8 days in addition to standard patient care (IV antibiotics and increased airway clearance) 52 . Compared with the placebo group, the doxycycline group had a significant decrease in total and active sputum MMP-9 levels, improved protease-antiprotease imbalance in the airways, greater improvement in FEV 1 % predicted from admission, and longer time to next PEx 52 .…”

“…This single-center RCT randomly assigned 39 CF patients with PEx requiring inpatient care to either doxycycline 100 mg orally twice daily or placebo for 8 days in addition to standard patient care (IV antibiotics and increased airway clearance) 52 . Compared with the placebo group, the doxycycline group had a significant decrease in total and active sputum MMP-9 levels, improved protease-antiprotease imbalance in the airways, greater improvement in FEV 1 % predicted from admission, and longer time to next PEx 52 . Whether doxycycline has direct effects on dysregulated protease activity versus indirect effects due to changes in the microbiome remains unclear, but this single-center study has set the stage for a larger multi-center placebo-controlled RCT 52 .…”