Reduction in viscoelasticity in cystic fibrosis sputum in vitro using combined treatment with Nacystelyn and rhDNase

Dasgupta, Bonnie; King, M.

doi:10.1002/(sici)1099-0496(199609)22:3<161::aid-ppul4>3.0.co;2-s

Cited by 40 publications

(21 citation statements)

References 17 publications

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“…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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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%

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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“…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. 9 At the same time, no adverse effects were observed in CF patients, even at a high dose of 24 mg given via inhaler. 10 Presently, multiple phase I and phase II clinical trials are being undertaken in Europe and USA to assess the efficacy of NAL treatment in CF patients.…”

mentioning

confidence: 93%

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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“…A large phase III study 3 and other clinical trials [4][5][6] revealed the beneficial effects of dornase alfa on the rheological properties of sputum and the improvement of pulmonary function in patients with CF. Dornase alfa acts by cleaving extracellular DNA released by degenerating leukocytes, [7][8][9][10] and was recently also applied in the management of other acute and chronic lung conditions, such as bronchiectasis, 11,12 atelectasis, [13][14][15] Kartagener's syndrome, 16 asthma, 17 and chronic bronchitis. 18 To date, only a few groups have published reports about the successful use of dornase alfa in the treatment of mechanically ventilated children.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Human Deoxyribonuclease Shortens Ventilation Time in Young, Mechanically Ventilated Children

Riethmueller

Borth-Bruhns

Kumpf

et al. 2005

Pediatric Pulmonology

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Summary. Recombinant human deoxyribonuclease I (dornase alfa) is currently used as an inhaled mucoactive agent in the treatment of cystic fibrosis. In a randomized, placebo-controlled, double-blind clinical study in 100 infants, we investigated whether the therapeutic use of dornase alfa can be extended to ventilated, fluid-restricted children to reduce reintubation rate, ventilation duration, pediatric intensive care unit (PICU) stay, and ventilation complications. While reintubation rates were similar for dornase alfa 7% vs. placebo 9% (odds ratio, 0.77; confidence interval, 0.11-4.9), the incidence of atelectasis (6 vs. 17, respectively; P-value 0.051), median ventilation time (2.2 vs. 3.4 days, respectively; P-value 0.043), median length of PICU stay (7 vs. 8 days, respectively; P-value 0.051), and mean costs (s4,830 vs. s6,320, respectively) were lower in the dornase alfa group. No adverse effects were observed, even in critically ill patients. We found that dornase alfa was beneficial and safe. Our findings also indicate that dornase alfa is possibly of value from the first day of mechanical ventilation onward, particularly when longer ventilation (>3 days) is expected in fluid-restricted children after cardiac surgery.

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Reduction in viscoelasticity in cystic fibrosis sputum in vitro using combined treatment with Nacystelyn and rhDNase

Cited by 40 publications

References 17 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

Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

Recombinant Human Deoxyribonuclease Shortens Ventilation Time in Young, Mechanically Ventilated Children

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