Effect of double-blind cross-over selenium supplementation on lipid peroxidation markers in cystic fibrosis patients. Single- and multiple-dose-response relationships of beta-carotene in cystic fibrosis. Improved antioxidant and fatty acid status of patients with cystic fibrosis after antioxidant supplementation is linked to improved lung function. Effects of beta-carotene supplementation for six months on clinical and laboratory parameters in patients with cystic fibrosis.
Lipid peroxidation was assessed in 27 cystic fibrosis children during a double-blind selenium supplementation study (2.8 micrograms of sodium selenite per kg per day) with a placebo control and inversion of treatment periods. Simultaneously, 17 healthy children living in the same area were also investigated as control subjects. Before any treatment whatsoever and despite a selenium status close to those of control subjects, cystic fibrosis patients showed significant increase in plasma lipid peroxidation markers. Thiobarbituric acid reactants (TBARs) were normalized after the first treatment period of 5 months in both cystic fibrosis groups receiving either selenium supplementation or placebo. In this latter group, TBARs were reduced despite a significant decrease in plasma selenium concentrations as compared with the control group. Organic hydroperoxide concentrations were also simultaneously normalized in both cystic fibrosis groups at the end of the second treatment period. These results showed that improvement of lipid peroxidation markers was not related to the selenium supplementation. Nevertheless, oxidative stress sustained by cystic fibrosis children must be taken into account so that it does not aggravate the prognosis of the disease. Concentrations of carotenoids are low in patients with cystic fibrosis (CF) and are associated with essential fatty acid deficiency and increased markers of inflammation. We conducted single- and multiple-dose studies of beta-carotene supplementation in patients with CF. Dose-proportional increases in beta-carotene concentrations were found, although clearance was independent of dose. Large doses of beta-carotene were necessary to achieve normal plasma levels. Oxidative stress, as measured by 8-iso-prostaglandin F(2)(alpha) (8-iso-PGF(2)(alpha)), and depleted antioxidant defenses were shown in stable cystic fibrosis (CF) patients. The plasma fatty acid status of CF patients was linked to oxidative stress after respiratory exacerbations.
                We examined changes in plasma 8-iso-PGF(2)(alpha), antioxidant defenses, plasma fatty acid status, and clinical markers resulting from short-term antioxidant supplementation.
                Forty-six CF patients were randomly assigned to either group A [low dose of supplement (10 mg vitamin E and 500 micro g vitamin A)] or group B [high dose of supplement (200 mg vitamin E, 300 mg vitamin C, 25 mg beta-carotene, 90 micro g Se, and 500 micro g vitamin A)]. Plasma concentrations of 8-iso-PGF(2)(alpha), vitamins E and C, beta-carotene, zinc, selenium, and copper; plasma fatty acid composition; erythrocyte glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities; lung function; and dietary intake were measured before and after 8 wk of supplementation.
                Antioxidant defenses in group B improved, whereas those in group A did not: in groups B and A, the mean (+/- SEM) changes (Delta) in vitamin E were 10.6 +/- 1.5 and -1.9 +/- 0.9 micro mol/L, respectively (P < 0.001), (Delta)beta-carotene were 0.1 +/- 0.04 and -0.01 +/- 0.02 micro mol/L, respectively (P = 0.007), (Delta)selenium were 0.51 +/- 0.10 and -0.09 +/- 0.04 micro mol/L, respectively (P < 0.001), and (Delta)glutathione peroxidase activity were 1.3 +/- 0.3 and -0.3 +/- 0.6 U/g hemoglobin, respectively (P = 0.016). There were no significant differences between the groups in Delta8-iso-PGF(2)(alpha), (Delta)vitamin C, (Delta)fatty acid composition, (Delta)superoxide dismutase activity, (Delta)lung function, or (Delta)white cell count. Within group B, (Delta)beta-carotene correlated with (Delta)percentage of forced vital capacity (r = 0.586, P = 0.005), (Delta)selenium correlated with (Delta)percentage of forced expiratory volume in 1 s (r = 0.440, P = 0.046), and (Delta)plasma fatty acid concentrations correlated with (Delta)percentage of forced expiratory volume in 1 s (r = 0.583, P = 0.006) and Delta8-iso-PGF(2)(alpha) (r = 0.538, P = 0.010).
                Whereas increased beta-carotene, selenium, and fatty acid concentrations are linked to improved lung function, increased plasma fatty acid concentrations are linked to oxidative stress. If oxidative stress is deemed to be important to the clinical outcome of CF patients, means of reducing oxidative stress while maintaining a high-fat, high-energy diet must be investigated. Patients with cystic fibrosis (CF) have significantly decreased plasma concentrations of nutrient antioxidant vitamins, especially of beta-carotene, which is thought to result from fat malabsorption and chronic pulmonary inflammation. The aim of this double blind, placebo controlled study was to investigate the effect of oral beta-carotene supplementation for six months on clinical parameters.
                Twenty four patients with CF were randomised to receive beta-carotene 1 mg/kg/day (maximum 50 mg/day) for three months (high dose supplementation) and 10 mg/day for a further three months (low dose supplementation) or placebo. At monthly follow up visits the plasma beta-carotene concentration, total antioxidant capacity, malondialdehyde (MDA) as a marker of lipid peroxidation, and clinical parameters (Shwachmann-Kulczycki score, body mass index (BMI), height, and lung function (FEV(1))) were assessed. The number of pulmonary exacerbations requiring antibiotic treatment (in days) three months before and during the study were evaluated.
                The plasma concentration of beta-carotene increased significantly to the normal range during the three months of high dose supplementation (baseline 0.08 (0.04) micromol/l to 0.56 (0.38) micromol/l; p<0.001) but decreased to 0.32 (0.19) micromol/l in the period of low dose supplementation. Initially raised plasma levels of MDA fell to normal levels and the total antioxidant capacity showed a non-significant trend towards improvement during high dose supplementation. Antibiotic treatment decreased significantly in the supplementation group from 14.5 (14.9) days/patient during the three months before the study to 9.8 (10.3) days/patient during high dose supplementation (p=0.0368) and to 10.5 (9.9) days/patient during low dose supplementation, but increased in the placebo group. The Shwachmann-Kulczycki score, lung function, and BMI did not show any changes in either of the treatment groups. No adverse events were observed during the study period.
                Oral beta-carotene supplementation in a dose of 1 mg/kg/day only was effective in normalising the plasma concentration of beta-carotene and resulted in a decrease in pulmonary exacerbations. These data suggest that patients with CF may benefit clinically from supplementation with beta-carotene and further studies are warranted.
There appears to be conflicting evidence regarding the clinical effectiveness of antioxidant supplementation in CF. Based on the evidence, antioxidants appear to decrease quality of life and oxidative stress; however, few trials contributed data towards analysis. Further trials examining clinically important outcomes and elucidation of a clear biological pathway of oxidative stress in CF are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn.