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Clinical Trial
. 2012 Apr 1;302(7):L688-99.
doi: 10.1152/ajplung.00171.2011. Epub 2012 Jan 20.

Protandim Does Not Influence Alveolar Epithelial Permeability or Intrapulmonary Oxidative Stress in Human Subjects With Alcohol Use Disorders

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Free PMC article
Clinical Trial

Protandim Does Not Influence Alveolar Epithelial Permeability or Intrapulmonary Oxidative Stress in Human Subjects With Alcohol Use Disorders

Ellen L Burnham et al. Am J Physiol Lung Cell Mol Physiol. .
Free PMC article

Abstract

Alcohol use disorders (AUDs), including alcohol abuse and dependence, have been linked to the development of acute lung injury (ALI). Prior clinical investigations suggested an association between AUDs and abnormal alveolar epithelial permeability mediated through pulmonary oxidative stress that may partially explain this relationship. We sought to determine if correcting pulmonary oxidative stress in the setting of AUDs would normalize alveolar epithelial permeability in a double-blinded, randomized, placebo-controlled trial of Protandim, a nutraceutical reported to enhance antioxidant activity. We randomized 30 otherwise healthy AUD subjects to receive directly observed inpatient oral therapy with either Protandim (1,350 mg/day) or placebo. Subjects underwent bronchoalveolar lavage (BAL) and blood sampling before study drug administration and after 7 days of therapy; all AUD subjects completed the study protocol without adverse events. BAL total protein was measured at each timepoint as an indicator of alveolar epithelial permeability. In subjects with AUDs, before study drug initiation, BAL total protein values were not significantly higher than in 11 concurrently enrolled controls (P = 0.07). Over the 7-day study period, AUD subjects did not exhibit a significant change in BAL total protein, regardless of their randomization to Protandim {n = 14, -2% [intraquartile range (IQR), -56-146%]} or to placebo [n = 16, 77% (IQR -20-290%); P = 0.19]. Additionally, among those with AUDs, no significant changes in BAL oxidative stress indexes, epithelial growth factor, fibroblast growth factor, interleukin-1β, or interleukin-10 were observed regardless of drug type received. Plasma thiobarbituric acid reactive substances, a marker of lipid peroxidation, decreased significantly over time among AUD subjects randomized to placebo (P < 0.01). These results suggest that Protandim for 7 days in individuals with AUDs who are newly abstinent does not alter alveolar epithelial permeability. However, our work demonstrates the feasibility of safely conducting clinical trials that include serial bronchoscopies in a vulnerable population at risk for acute lung injury.

Figures

Fig. 1.
Fig. 1.
Bronchoalveolar lavage (BAL) total protein measurements were performed after centrifugation of fluid to remove cellular elements. A: %change in total protein, corrected for urea dilution. Amount of total protein increased in the group of alcohol use disorders (AUDs) subjects randomized to placebo but remained relatively stable among those randomized to Protandim, although this was not statistically significant. B: %change in total protein, uncorrected for dilution. A nonsignificant increase was observed in the total protein concentration among those randomized to placebo. Thick bars represent median values, while black crossbars represent the intraquartile range of the data. Statistical comparisons made with Wilcoxon signed rank test.
Fig. 2.
Fig. 2.
BAL thiol/disulfide glutathione measurements were performed via HPLC. A: reduced glutathione (GSH), corrected for urea dilution. B: oxidized glutathione (GSSG), corrected for urea dilution. C: %GSSG relative to total GSSG plus GSH in BAL was calculated with uM values of GSH and GSSG. D: GSSG redox potential in BAL was calculated using the Nernst equation with GSH and GSSG values corrected for urea dilution. No significant changes over time for any of these parameters were observed for subjects randomized to either placebo or Protandim. Thick bars represent median values, where dark grey is pretreatment (day 1) and light grey is posttreatment (day 8) time points, while black crossbars represent the intraquartile range of the data. Statistical comparisons made with Wilcoxon signed rank test.
Fig. 3.
Fig. 3.
BAL thiol/disulfide cysteine (CyS) and cystine (CySS) measurements were performed via HPLC. A: CyS, corrected for urea dilution. B: CySS, corrected for urea dilution. C: %cystine relative to total cystine plus cysteine in BAL was calculated with the uM values of CyS and CySS. D: CySS redox potential in BAL was calculated using the Nernst equation with CyS and CySS values corrected for urea dilution. No significant differences over time for any measured parameters were observed for subjects randomized to either placebo or Protandim. Thick bars represent median values, where dark grey is pretreatment (day 1) and light grey is posttreatment (day 8) time points, while black crossbars represent the intraquartile range of the data. Statistical comparisons made with Wilcoxon signed rank test.
Fig. 4.
Fig. 4.
Plasma thiol/disulfide glutathione measurements were performed via HPLC. A: GSH. B: GSSG. C: %GSSG present in plasma was calculated with uM values of GSH and GSSG. D: redox potential of oxidized glutathione in plasma was calculated using the Nernst equation with GSH and GSSG values. No significant differences over time were observed subjects randomized to either placebo or Protandim. Thick bars represent median values, where dark grey is pretreatment (day 1) and light grey is posttreatment (day 8) time points, while black crossbars represent the intraquartile range of the data. Statistical comparisons made with Wilcoxon signed rank test.
Fig. 5.
Fig. 5.
Plasma cystine/cysteine measurements were performed via HPLC. A: CyS. B: CySS. C: %CySS present in plasma was calculated with uM values of CyS and CySS. D: CySS redox potential in plasma was calculated using the Nernst equation with CyS and CySS values. A trend for decreased %CySS was observed in the Protandim group; however, no statistically significant differences in parameters over time were observed in either the placebo or Protandim group for any parameter assessed. Thick bars represent median values, where dark grey is pretreatment (day 1) and light grey is posttreatment (day 8) time points, while black crossbars represent the intraquartile range of the data. Statistical comparisons made with Wilcoxon signed rank test.
Fig. 6.
Fig. 6.
Plasma samples were assessed for the change in thiobarbituric acid reactive substances (TBARS; A) over time in association with Protandim or placebo administration, reported as uM malondialdehyde equivalents (MDE) and the change in paroxanase-1 (PON-1; B) activity over time in association with Protandim or placebo administration. Placebo group was observed to have a significant decrease in plasma TBARS over the 7 days of observation, while a trend was observed for decreased TBARS in the Protandim group. Neither the placebo nor Protandim groups' PON-1 activity changed significantly over the duration of the study. Thick bars represent median values, with dark grey is pretreatment (day 1) and light grey is posttreatment (day 8) time points, while black crossbars represent the intraquartile range of the data. Statistical comparisons made with Wilcoxon signed rank test.
Fig. 7.
Fig. 7.
Total protein in BAL measured in subjects with AUDs and controls. A: in our previously published cohort (7), the diagnosis of an AUD was associated with higher BAL total protein when the analysis was performed using BAL total protein values uncorrected for dilution (P < 0.01 for comparison between 18 AUD subjects vs. 18 controls group matched for age, smoking, and gender). NS, nonsmoker. B: in the present cohort, AUDs were associated with small but significantly lower BAL total protein when the analysis was performed without correcting total protein values for dilution (P < 0.05 between 30 AUD and 11 control subjects). However, when BAL total protein values were corrected for dilution (urea techniques; C), subjects with AUDs (n = 27) tended to have increased total protein compared with controls (n = 9; P = 0.07). Compared with the previously published cohort, there were an increased number of smokers in our AUD subjects and fewer smokers among controls in the current cohort.

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