Efficacy and Safety of Short-term Administration of Aerosolized Recombinant Human Deoxyribonuclease in Patients with Cystic Fibrosis

Abstract

Chronic endobronchial bacterial infection evokes purulent airway secretions in patients with CF. The viscoelastic properties of these secretions is primarily due to the presence of polymerized DNA from degenerating leukocytes. Recombinant human DNase I (rhDNase) reduces the viscosity of CF sputum in vitro. To test the hypothesis that rhDNase would improve pulmonary function in children and adults with CF, we compared the efficacy and safety of 10-day administration of three doses of aerosolized rhDNase (0.6, 2.5, or 10.0 mg twice daily) in 181 outpatients using a randomized, placebo-controlled parallel design. Forced vital capacity (FVC) improved 10 to 12% (p < 0.05 to 0.001), and forced expiratory volume in one second (FEV1) improved 10 to 15% (p < 0.001) across all doses of rhDNase compared with placebo. The magnitude of effect was dose dependent for both FVC and FEV1 through study Day 21 (p < 0.001). rhDNase was associated with a decreased perception of dyspnea and an improved perception of well-being. No patients developed detectable anti-rhDNase antibodies or bronchial reactivity to rhDNase. Some patients experienced mild upper airway irritation, but no major adverse events were reported. Administration for 10 days of aerosolized rhDNase to pediatric and adult outpatients with CF improves lung function and is well tolerated. Although all three doses were efficacious, the greatest improvement in FEV1 and FEV1/FVC ratio was demonstrated in the 2.5 and 10.0 mg rhDNase treatment groups.

Inhaled heparin in cystic fibrosis

“…The current study aimed to assess the medium-term safety and tolerability of moderately high dose inhaled unfractionated heparin in CF adults and to explore possible in vivo mucolytic (assessed by lung function, symptom scores and quality of life) and anti-inflammatory outcomes. The study was powered to detect a 10% improvement in forced expiratory volume in one second (FEV1) as a result of enhanced sputum clearance, consistent with the short-term effect demonstrated in early studies of DNase [25].…”

No positive effect of rhdnase on the pulmonary colonization in children with cystic fibrosis

“…RhDNAse treatment in CF has been shown to be effective, improving lung function and decreasing the number of respiratory exacerbations [11][12][13][14][15][16][17][18][19]. The exact reason for this positive effect remains unclear.…”

“…RhDNAse breaks down extra cellular DNA, thereby decreasing the viscosity of sputum. Several long term clinical trials showed that rhDNAse treatment is effective, especially in mild to moderate CF, shown by an increase in lung function and a decrease of respiratory exacerbations [10][11][12][13][14][15][16][17][18][19]. A study preformed in Denmark hypothesized that this clinical improvement in lung function might be due to a decrease in bacterial airway colonization [11].…”

Toll-like receptors as therapeutic targets in cystic fibrosis

“…Improvements in lung function have also been documented [157,158] . Viscosity is decrease d by enzymatic degradation of host and bacterial DNA, with the added advantage that TLR9-mediated signalling in response to uCpG DNA is likely to be abrogated also.…”