Nacystelyn, a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro

Gillissen, Adrian; Jaworska, Małgorzata; Orth, M.; Coffiner, M.; Mäes, Pierrette; App, Ernst M.; Cantin, André M.; Schultze‐Werninghaus, G.

doi:10.1016/s0954-6111(97)90052-4

Cited by 114 publications

(78 citation statements)

References 36 publications

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“…The mucolytic effect of NAL is about the same as that of Pulmozyme and the effects are synergistic, as determined by an in vitro test of CF mucus transport [95]. In addition, NAL may have the potential to decrease oxidantinduced IL-8 production [93], decrease the oxidative burst from neutrophils, and increase intracellular GSH levels [91].…”

Section: Nacystelynmentioning

confidence: 99%

See 1 more Smart Citation

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Cantin

White

Cross

et al. 2007

Free Radical Biology and Medicine

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Although great strides are being made in the care of individuals with cystic fibrosis (CF), this condition remains the most common fatal hereditary disease in North America. Numerous links exist between progression of CF lung disease and oxidative stress. The defect in CF is the loss of function of the transmembrane conductance regulator (CFTR) protein; recent evidence that CFTR expression and function are modulated by oxidative stress suggests that the loss may result in a poor adaptive response to oxidants. Pancreatic insufficiency in CF also increases susceptibility to deficiencies in lipophilic antioxidants. Finally the airway infection and inflammatory processes in the CF lung are potential sources of oxidants that can affect normal airway physiology and contribute to the mechanisms causing characteristic changes associated with bronchiectasis and loss of lung function. These multiple abnormalities in the oxidant/antioxidant balance raise several possibilities for therapeutic interventions that must be carefully assessed. IntroductionCystic fibrosis (CF) is the most common fatal disease caused by a single gene defect in Europe and North America [1,2]. The defective gene was identified in 1989 [3][4][5] and shown to encode the cystic fibrosis trans-membrane conductance regulator protein (CFTR). CFTR is a cyclic AMP-regulated anion channel with greatest selectivity for chloride, and bicarbonate [6][7][8]. Furthermore, CFTR regulates sodium transport across epithelial membranes through interactions with the epithelial sodium channel ENaC [9], and facilitates the trans-membrane export of the small organic anionic peptide glutathione [10]. The expression of CFTR is located in the apical membrane of epithelial cells that line mucous membranes and submucosal glands ☆ A list of participants may be found in the Acknowledgments.

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Section: Nacystelynmentioning

confidence: 99%

“…Trials are also being conducted using cysteine-rich Nacystelyn (NAL), a mucolytic with antioxidant and anti-inflammatory activity [91][92][93][94]. NAL differs from N-acetylcysteine (Mucomyst), which has a long history of use in CF, by the addition of lysine, raising the pH from 2.2 to 6.0 and increasing the water solubility.…”

Section: Nacystelynmentioning

confidence: 99%

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Cantin

White

Cross

et al. 2007

Free Radical Biology and Medicine

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show abstract

“…The advantage of NAL over NAC is that it has a neutral pH in solution, whereas NAC is acidic. NAL can be aerosolized into the lung without causing significant side-effects [248]. GILLISSEN et al [248] compared the effects of NAL and NAC and found that both drugs enhanced intracellular glutathione levels in alveolar epithelial cells and inhibited H 2 O 2 and O 2 .…”

Section: Immune Effector Responsementioning

confidence: 99%

“…NAL can be aerosolized into the lung without causing significant side-effects [248]. GILLISSEN et al [248] compared the effects of NAL and NAC and found that both drugs enhanced intracellular glutathione levels in alveolar epithelial cells and inhibited H 2 O 2 and O 2 . ± release from human blood-derived polymorphonuclear neutrophils (PMNs) from smokers with COPD.…”

Section: Immune Effector Responsementioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

811

555

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Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox‐sensitive transcription factors such as nuclear factor‐κB, and activator protein‐1 (AP‐1), which regulate the genes for pro‐inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra‐ and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro‐inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate‐limiting enzyme in GSH synthesis is γ‐glutamylcysteine synthetase (γ‐GCS). The human γ‐GCS heavy and light subunits are regulated by AP‐1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti‐inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant γ‐GCS and pro‐inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro‐ and anti‐inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor‐κB and activator protein‐1 in the regulation of cellular glutathione and γ‐glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant‐mediated susceptibility/tolerance, γ‐glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

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“…Nacystelyn (NAL) is a derivative of N-acetyl-cysteine with an added L-lysine residue, and has been used for treatment of impaired mucociliary clearance and chronic mucus retention in CF patients. 4,5 NAL has been shown to possess antioxidant, 6 mucolytic and anti-inflammatory properties, thus indicating that it may be beneficial for CF patients. 7,8 Clinical trials conducted with NAL in CF patients have demonstrated an improvement in symptoms, with a dose-dependent decrease in sputum viscoelasticity along with a decrease in sputum solids content, and an increase in chloride and sodium concentrations, thus indicating improved mucus clearance.…”

mentioning

confidence: 99%

Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

2007

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Adenoviral vector-mediated gene delivery has been vastly investigated for cystic fibrosis (CF) gene therapy; however, one of its drawbacks is the low efficiency of gene transfer, which is due to basolateral colocalization of viral receptors, immune responses to viral vectors and the presence of a thick mucus layer in the airways of CF patients. Therefore, enhancement of gene transfer can lead to reduction in the viral dosage, which could further reduce the acute toxicity associated with the use of adenoviral vectors. Nacystelyn (NAL) is a mucolytic agent with anti-inflammatory and antioxidant properties, and has been used clinically in CF patients to reduce mucus viscosity in the airways. In this study, we show that pretreatment of the airways with NAL followed by administration of adenoviral vectors in complex with DEAE-Dextran can significantly enhance gene delivery to the airways of mice without any harmful effects. Moreover, NAL pretreatment can reduce the airway inflammation, which is normally observed after delivery of adenoviral particles. Taken together, these results indicate that NAL pretreatment followed by adenoviral vector-mediated gene delivery can be beneficial to CF patients by increasing the efficiency of gene transfer to the airways, and reducing the acute toxicity associated with the administration of adenoviral vectors.

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Nacystelyn, a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro

Cited by 114 publications

References 36 publications

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Oxidative stress and regulation of glutathione in lung inflammation

Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

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