Long term effects of denufosol tetrasodium in patients with cystic fibrosis

Ratjen, Félix; Durham, Todd A.; Navrátil, Tomáš; Schaberg, A.; Accurso, Frank J.; Wainwright, Claire; Barnes, Matthew J.; Moss, Richard B.

doi:10.1016/j.jcf.2012.05.003

Cited by 89 publications

(51 citation statements)

References 27 publications

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“…This concept is supported by studies which showed that nucleotide-mediated activation of CaCC via purinergic (P2Y 2 receptormediated) signalling improves ASL height and mucus transport in primary CF airway epithelia [108]. However, efforts to activate CaCC indirectly using the long-acting P2Y 2 receptor agonist denufosol failed to improve lung function or reduce exacerbations in CF patients in recent trials [109]. Furthermore, the development of drugs that activate CaCC directly has been hampered by the fact that its molecular identity remained elusive for many years.…”

Section: Alternative CL -Channelsmentioning

confidence: 98%

CFTR: cystic fibrosis and beyond

2014

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Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation DF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging. @ERSpublications CFTR dysfunction causes CF and may be implicated in more common chronic obstructive lung diseases, such as COPD

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Section: Alternative CL -Channelsmentioning

confidence: 98%

CFTR: cystic fibrosis and beyond

2014

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“…Alternative pathways exist to hydrate the airway surface via calcium-activated chloride channels. However, attempts to stimulate these channels and maintain ASL volume in CF have clinically failed (7). There are several possible explanations for this outcome, including the short duration of action of the agonist used.…”

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confidence: 99%

Airway Surface Dehydration by Transforming Growth Factor β (TGF-β) in Cystic Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel and Can Be Rescued by the Drug Pirfenidone

Manzanares

Krick

Baumlin

et al. 2015

Journal of Biological Chemistry

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Background: TGF-␤ is associated with worse outcome in cystic fibrosis (CF). Results: TGF-␤ causes mucociliary dysfunction by reducing airway surface liquid (ASL) due to decreased apical BK channel activity and down-regulation of its ␥ subunit LRRC26. Conclusion:The TGF-␤ inhibitor pirfenidone reverses ASL loss via BK and LRRC26 rescue. Significance: Clinical trials could test the usefulness of pirfenidone in CF.

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“…Clinical trials of Denufosol used high doses (concentrations) delivered to the lungs for short time periods via a jet nebulizer and did not produce positive results in phase-3 trials due to suspected P2Y 2 receptor desensitization (4,30,32). Our model predicts that transnasal delivery of a low dose of Denufosol over prolonged intervals to CF subjects can activate the P2Y 2 receptors at a concentration sufficient to increase ASL height but not produce P2Y 2 receptor desensitization (31).…”

Section: Discussionmentioning

confidence: 95%

Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis

Sandefur

Boucher

Elston

2017

Proc. Natl. Acad. Sci. U.S.A.

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Mucociliary clearance is composed of three components (i.e., mucin secretion, airway surface hydration, and ciliary-activity) which function coordinately to clear inhaled microbes and other foreign particles from airway surfaces. Airway surface hydration is maintained by water fluxes driven predominantly by active chloride and sodium ion transport. The ion channels that mediate electrogenic ion transport are regulated by extracellular purinergic signals that signal through G protein-coupled receptors. These purinoreceptors and the signaling pathways they activate have been identified as possible therapeutic targets for treating lung disease. A systems-level description of airway surface liquid (ASL) homeostasis could accelerate development of such therapies. Accordingly, we developed a mathematical model to describe the dynamic coupling of ion and water transport to extracellular purinergic signaling. We trained our model from steady-state and time-dependent experimental measurements made using normal and cystic fibrosis (CF) cultured human airway epithelium. To reproduce CF conditions, reduced chloride secretion, increased potassium secretion, and increased sodium absorption were required. The model accurately predicted ASL height under basal normal and CF conditions and the collapse of surface hydration due to the accelerated nucleotide metabolism associated with CF exacerbations. Finally, the model predicted a therapeutic strategy to deliver nucleotide receptor agonists to effectively rehydrate the ASL of CF airways.airway surface liquid | cystic fibrosis | mathematical modeling | purinergic signaling

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Long term effects of denufosol tetrasodium in patients with cystic fibrosis

Abstract: In patients with CF treatment with denufosol for 48 weeks did not improve pulmonary function or reduce the incidence of pulmonary exacerbations.

Cited by 89 publications

References 27 publications

CFTR: cystic fibrosis and beyond

CFTR: cystic fibrosis and beyond

Airway Surface Dehydration by Transforming Growth Factor β (TGF-β) in Cystic Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel and Can Be Rescued by the Drug Pirfenidone

Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis

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