DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres

Cobos, N.; Danés, Imma; Gartner, Sílvia; González, M.; Liñan, S.; Arnau, J. M.

doi:10.1007/s004310050046

Cited by 19 publications

(11 citation statements)

References 12 publications

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“…[18][19][20] Our data show that sputum obtained from such clinical non-responders could also not be degraded in vitro with rhDNase-I, while sputum from clinical responders was extensively degraded by rhDNase-I. More importantly, biochemical analysis revealed that clinical responders produced sputum that contained significantly higher concentrations of potassium (and especially magnesium) than sputum from clinical non-responders.…”

Section: Discussionmentioning

confidence: 71%

“…[15][16][17] Indeed, different studies have shown a wide variation in the clinical response to rhDNase-I with about 30% of patients-the so-called non-responders-not benefiting from it. [18][19][20] The reason for the failure of rhDNase-I in these patients is not understood. This study was therefore undertaken to elucidate the reason for the failure of rhDNase-I in certain CF patients and to evaluate strategies to overcome this.…”

mentioning

confidence: 99%

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Role of magnesium in the failure of rhDNase therapy in patients with cystic fibrosis

Sanders

Franckx²,

Boeck³

et al. 2006

Thorax

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Background: In the management of cystic fibrosis (CF), rhDNase-I inhalation is widely used to facilitate the removal of the highly viscous and elastic mucus (often called sputum) from the lungs. However, an important group of CF patients does not benefit from rhDNase-I treatment. A study was undertaken to elucidate the reason for the failure of rhDNase-I in these patients and to evaluate strategies to overcome this. Methods: The biochemical properties, physical properties, and degradation by rhDNase-I of sputum obtained from clinical responders and non-responders to rhDNase-I were compared, and the ability of magnesium to reactivate rhDNase-I in DNA solutions and in sputum was investigated. The effect of oral magnesium supplements on magnesium levels in the sputum of patients with CF was also examined. Results: Sputum from clinical responders was extensively degraded in vitro on incubation with rhDNase-I, while sputum from clinical non-responders was not degraded: the median decrease in sputum elasticity in the two groups was 32% and 5%, respectively. Sputum from clinical responders contained significantly higher concentrations of magnesium than sputum from non-responders (2.0 mM v 1.3 mM; p = 0.020). Sputum that could not be degraded by rhDNase-I became degradable after preincubation with magnesium. The effect of magnesium on rhDNase-I activity was mediated through actin. Oral intake of magnesium enhanced the magnesium concentration in the sputum of CF patients. Conclusion: Increasing the magnesium concentration in sputum by, for example, oral magnesium supplements may be a promising new strategy to overcome the failure of rhDNase-I in patients with CF.

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

Role of magnesium in the failure of rhDNase therapy in patients with cystic fibrosis

Sanders

Franckx²,

Boeck³

et al. 2006

Thorax

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“…However, dornase alfa does not improve lung function in all patients (14,16), and there is a need to develop novel mucolytic therapies with the goal of improving lung function and delivery of inhaled drugs, including gene therapy vectors, to the bronchial epithelium (30). Alternative approaches include the use of inhaled osmotic agents such as hypertonic saline and mannitol (17) as mucomodulators that, by setting up osmotic gradients, improve periciliary fluid hydration and mucus clearance.…”

mentioning

confidence: 97%

Unfractionated heparin reduces the elasticity of sputum from patients with cystic fibrosis

Broughton-Head

Shur²,

Carroll³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Mucus obstruction of the airway in patients with cystic fibrosis (CF) reduces lung function, invites infection, and limits delivery of inhaled drugs including gene therapy vectors to target cells. Not all patients respond to presently available mucolytics, and new approaches are needed. Our objectives were to investigate the in vitro effects of unfractionated heparin (UFH) on the morphology and rheology of sputum and the effect of UFH on diffusion of 200-nm nanospheres through sputum from adult CF patients. Confocal laser scanning microscopy was used to image fluorescently stained actin and DNA components of CF sputum, and atomic force microscopy was used to image isolated DNA networks. The viscoelasticity of CF sputum was measured using dynamic oscillatory rheometry. Nanosphere diffusion was measured through CF sputum using a Boyden chamber-based assay. Actin-DNA bundles in CF sputum were disaggregated by UFH at concentrations of 0.1-10 mg/ml, and UFH enhanced the endonuclease activity in sputum from patients on dornase alfa therapy. UFH significantly reduced the elasticity and yield stress, but not the viscosity, of CF sputum from patients not receiving dornase alfa therapy. Heparin dose-dependently significantly increased the diffusion of nanospheres through CF sputum from patients not on dornase alfa therapy from 10.5 +/- 2.5% at baseline to 36.9 +/- 4.4% at 10 mg/ml but was more potent, with maximal effect at 0.1 mg/ml, in patients who were on dornase alfa therapy. Thus the mucoactive properties of UFH indicate its potential as a new therapeutic approach in patients with cystic fibrosis.

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“…Sixty-five out of 184 (35%) patients experienced 106 episodes of airway reactivity in response to nebulized rhDNase [45]. However, most studies did not demonstrate significantly more BHR, dyspnea, cough, wheeze and/or increased pulmonary obstruction in CF patients compared to controls (Supplementary Tables 1) [42,[46][47][48][49][50][51][52][53][54].…”

Section: Rhdnasementioning

confidence: 99%

Bronchial Hyperreactivity Related to Inhalation Therapy in Cystic Fibrosis Patients

Eyns¹

2014

J Pulm Respir Med

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It is presumed that bronchial hyperreactivity (BHR) can occur with any inhaled agent and may be a reason for discontinuation of inhalation therapy in cystic fibrosis (CF) patients. On the other hand, inhalation of antibiotics is being increasingly used to eradicate or treat infections.This review focuses on identifying the mechanisms of BHR for a better understanding of its impact on inhalation treatment. BHR in CF is suggested to be secondary to underlying airway disease (associated to poor pulmonary function, chronic inflammation and aerosol distribution) or to be a separate condition occurring more in CF. Furthermore, certain characteristics of the aerosol solution itself, such as the active molecule, chemical additives and particle size, can cause BHR.Recombinant human DNase (rhDNase), hypertonic saline (HS) and the antibiotics tobramycin, colistin and aztreonam lysine for inhalation (AZLI) are frequently used inhalation drugs in the treatment of CF. Prevalence of BHR related to both short and long-term inhalation of these drugs as reported in the literature was investigated. Acute BHR is documented in up to two thirds of CF patients. Despite the widespread use of rhDNase, HS, tobramycin, colistin and AZLI, only one long-term trial looked for, but did not demonstrate, BHR at the end of the trial period.

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DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres

Cited by 19 publications

References 12 publications

Role of magnesium in the failure of rhDNase therapy in patients with cystic fibrosis

Role of magnesium in the failure of rhDNase therapy in patients with cystic fibrosis

Unfractionated heparin reduces the elasticity of sputum from patients with cystic fibrosis

Bronchial Hyperreactivity Related to Inhalation Therapy in Cystic Fibrosis Patients

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