**3. Conclusion**

defend the intestinal system against reactive oxygen species, and keeping inflammation in

In a recent placebo-controlled, randomized, double-blinded, clinical trial in 44 paediatric CF patients aged between 18 months and 10 years [32], treatment with oral glutathione (65 mg/kg/day) increased weight and BMI z score and improved measures of gut inflammation (faecal calprotectin) over the course of six months, without adverse side effects. The authors therefore concluded that Oral GSH might primarily be beneficial in those children with more severe inflammation of the gut, and suggested that early intervention with oral glutathione in young CF children with growth failure could forestall decline in pulmonary function in later

Several studies have investigated the potential therapeutic role of inhaled GSH in patients with CF. Three short-term clinical trials, including a placebo-controlled one, have shown the tolerability and efficacy of inhaled GSH on pulmonary function in these subjects [33-34]. A recent 12-month randomized single-blind placebo-controlled trial demonstrated the efficacy of inhaled GSH (600 mg twice daily) on lung function in CF adults [35]. Three months of therapy with inhaled GSH resulted in a statistically significant improvement in percentagepredicted FEV1, measured as a pre-post difference from baseline values, when compared to the placebo, which persisted at six and nine but not at 12 months. A reduced compliance with therapy in adult patients could explain the decrease in FEV1 values registered in the last visit. The best improvements in functional parameters were registered in the subgroup of patients with moderate lung disease (FEV1 below 81%). These results are in concordance with those reported by Griese et al. [36], who showed a significant increase of FEV1 absolute values (but not when expressed as percentage-predicted) from the baseline after three months of GSH

N-acetylcysteine (NAC), a well-known cysteine donor for the synthesis of glutathione, has been used in different diseases to treat GSH deficiency [37]. High-dose oral NAC has been shown to increase neutrophil GSH levels, decrease airway neutrophil recruitment and reduce neutrophilic release of airway elastase in CF patients [38]. Skov et al. demonstrated that highdose oral NAC (1200 mg x 2/day for 30 days) in CF patients with chronic *P. Aeruginosa* infection

Indications of a positive effect of NAC treatment on the lung function of a subgroup of CF patients have previously been published [40]. Recently, a placebo-controlled randomized clinical trial (70 CF patients) was conducted in the USA to study the effect of oral NAC on lung inflammation (ClinicalTrials.gov Identifier: NCT00809094). Oral NAC was administered in a dose of 1800 mg/day divided into two dosages over a period of 24 weeks and the effects on the sputum levels of human neutrophil elastase (HNE) were assessed as a primary end-point. While no statistical significant difference was found between the two groups with regard to the primary end-point, an improvement in the predicted FEV1% was observed in the NAC-

A recent Cochrane review on the use of thiol derivatives, such as NAC, did not find sufficient evidence to recommend the use of these compounds in the management of CF lung disease,

check under normal circumstances [31].

78 Cystic Fibrosis in the Light of New Research

decreased the level of oxidized vitamin C [39].

but concluded that further studies were warranted [41].

years.

therapy.

treated group.

In conclusion, there appears to be conflicting evidence regarding the clinical effectiveness of antioxidant supplementation in CF patients. Based on the available evidence, glutathione (administered either orally or by inhalation) and high doses of β-carotene appear to improve lung function in some cases and decrease oxidative stress. Further studies, especially in very young patients, examining clinically relevant outcomes, dose levels and other promising therapies like CFTR modulation, are necessary before a firm conclusion can be made regarding the effects on oxidative stress in these patients.
