Sodium channel blockers for cystic fibrosis

Burrows, E.; Southern, Kevin W; Noone, Peadar G.

doi:10.1002/14651858.cd005087.pub2

Cited by 9 publications

(6 citation statements)

References 24 publications

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“…Nebulization with HTS can regulate sodium transport across airway lining [93]. Inhalation of HTS improve cilliary function of epithelial cell in which can be useful in these patients [94].…”

Section: Methodsmentioning

confidence: 99%

Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

et al. 2012

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ObjectiveSulfur mustard (SM) is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980–1988). It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries.MethodThis review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment.ResultsMustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung.ConclusionComplementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments.

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Section: Methodsmentioning

confidence: 99%

Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

et al. 2012

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“…Early studies in this vein explored the use of amiloride and similar small molecule ENaC blockers. Unfortunately, given the low potency and easily reversible nature of these compounds, no evidence was found supporting their application in the treatment of CF respiratory conditions (8,16,17). These early studies also raised concerns over renal side effects, since amiloride and other related compounds are often readily absorbed across epithelial barriers allowing them to enter systemic circulation where they antagonize ENaC in the kidney, eliciting renal Na ϩ loss and K ϩ retention (2,54).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a SPLUNC1-derived peptide for the treatment of cystic fibrosis lung disease

Terryah

Fellner

Ahmad

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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In cystic fibrosis (CF) lungs, epithelial Na channel (ENaC) hyperactivity causes a reduction in airway surface liquid volume, leading to decreased mucocilliary clearance, chronic bacterial infection, and lung damage. Inhibition of ENaC is an attractive therapeutic option. However, ENaC antagonists have failed clinically because of off-target effects in the kidney. The S18 peptide is a naturally occurring short palate lung and nasal epithelial clone 1 (SPLUNC1)-derived ENaC antagonist that restores airway surface liquid height for up to 24 h in CF human bronchial epithelial cultures. However, its efficacy and safety in vivo are unknown. To interrogate the potential clinical efficacy of S18, we assessed its safety and efficacy using human airway cultures and animal models. S18-mucus interactions were tested using superresolution microscopy, quartz crystal microbalance with dissipation, and confocal microscopy. Human and murine airway cultures were used to measure airway surface liquid height. Off-target effects were assessed in conscious mice and anesthetized rats. Morbidity and mortality were assessed in the β-ENaC-transgenic (Tg) mouse model. Restoration of normal mucus clearance was measured in cystic fibrosis transmembrane conductance regulator inhibitor 172 [CFTR(inh)-172]-challenged sheep. We found that S18 does not interact with mucus and rapidly penetrated dehydrated CF mucus. Compared with amiloride, an early generation ENaC antagonist, S18 displayed a superior ability to slow airway surface liquid absorption, reverse CFTR(inh)-172-induced reduction of mucus transport, and reduce morbidity and mortality in the β-ENaC-Tg mouse, all without inducing any detectable signs of renal toxicity. These data suggest that S18 is the first naturally occurring ENaC antagonist to show improved preclinical efficacy in animal models of CF with no signs of renal toxicity.

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“…The respiratory tract represents a primary target of CF treatments due to the high mortality and morbidity stemming from pulmonary complications [2,3]. Therapeutics topically administered to the lungs, either on the market or under clinical development, include: mucolytics [4], antibiotics [5], the cystic fibrosis transmembrane conductance regulator (CFTR) gene [6], CFTR modulators [7], and other ion transport agents [8,9]. To improve therapeutic efficacy, a promising and increasingly tested strategy is to encapsulate drugs and genes within polymeric or liposomal nanoparticles.…”

Section: Introductionmentioning

confidence: 99%

The penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by non-adhesive polymer nanoparticles

et al. 2009

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Highly viscoelastic and adhesive sputum has precluded efficient nanoparticle-based drug and gene delivery to the lungs of patients with cystic fibrosis (CF). We sought to determine whether nanoparticles coated with non-mucoadhesive polymers could penetrate CF sputum, and to use these "muco-inert particles" (MIPs) as non-destructive nanoprobes to characterize the sputum microstructure. Particles as large as 200 nm in diameter that were densely coated with low MW polyethylene glycol (PEG) moved through undiluted CF sputum with average speeds up to 90-fold faster than similarly-sized uncoated particles. On the other hand, the transport of both coated and uncoated 500 nm particles was strongly hindered. The local viscosity of sputum, encountered by the fastest 10% of 200 nm MIPs, was only 5-fold higher than that of water, whereas the bulk viscosity was 10,000-fold higher at low shear rates. Using measured transport rates of various sized MIPs combined with an obstruction-scaling model, we determined that the average 3D mesh spacing of CF sputum is ~140 ± 50 nm (range: 60-300 nm). Taken together, these results demonstrate that nanoparticles up to 200 nm in diameter that do not adhere to CF sputum can move rapidly through this critical barrier by accessing pores that are filled with a low viscosity fluid. The results also offer hope that desperately needed sputum-penetrating drug-and gene-carrier nanoparticles can be developed for CF.

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Sodium channel blockers for cystic fibrosis

Cited by 9 publications

References 24 publications

Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

Evaluation of a SPLUNC1-derived peptide for the treatment of cystic fibrosis lung disease

The penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by non-adhesive polymer nanoparticles

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