The protective effect of fruit and vegetables against cancer has been related to their high antioxidant content. However, results from intervention trials have not been conclusive on the protective effect of antioxidant supplementation. In a randomized placebo-controlled trial we investigated the effect of dietary supplementation with antioxidants on a biomarker of oxidative DNA damage with mechanistic relation to carcinogenesis. One hundred forty-two smoking men aged 35-65 y were randomly assigned to one of the following seven treatments for 2 mo: 100 mg D-alpha-tocopheryl acetate plus 250 mg slow-release ascorbic acid twice a day (n = 20), 100 mg D-alpha-tocopheryl acetate twice a day (n = 20), 250 mg ascorbic acid twice a day (n = 21), 250 mg slow-release ascorbic acid twice a day (n = 21), 30 mg coenzyme Q10 in oil three times a day (n = 20), 30 mg coenzyme Q10 as granulate three times a day (n = 20), or placebo twice a day (n = 20). The trial outcome was the urinary excretion rate of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG)-a repair product of oxidative DNA damage. Two months of supplementation did not result in significant changes in the urinary excretion rate of 8-oxodG in any group. The lack of effect of antioxidant supplementation on the excretion rate of 8-oxodG, despite substantial increases in plasma antioxidant concentrations, agrees with the results from recent large intervention studies with cancer as an endpoint. The cancer-protective effect of fruit and vegetables seems to rely not on the effect of single antioxidants but rather on other anticarcinogenic compounds or on a concerted action of several micronutrients present in these foods.
Oxidative DNA modification has been implicated in development of certain cancers and 8-oxodG, the most abundant and mutagenic DNA modification, has for some time been considered a biomarker of this activity. Urinary excretion of 8-oxodG over 24h has been used to estimate the rate of damage to DNA, and animal studies have supported this rationale. Reported determinants include tobacco smoking, heavy exercise, environmental pollution and individual oxygen consumption. Samples from three published studies were used to determine the association of urinary 8-oxodG excretion with age, plasma antioxidants, the glutathione-S-transferase phenotype and the activity of the xenobiotic metabolising enzyme CYP1A2. In the age range 35-65 years, age was not related to urinary 8-oxodG excretion, and there were no relations to either the glutathione-S-transferase phenotype or to the plasma antioxidants: vitamin C, alpha-tocopherol, beta-carotene, lycopene or coenzyme Q10. The activity of CYP1A2 showed a significant correlation in two of the three studies, as well as a significant correlation of 0.26 (p < 0.05) in the pooled data set. Regression analysis of CYP1A2 activity on 8-oxodG indicated that 33% increase in CYP1A2 activity would correspond to a doubling of 8-oxodG excretion. This finding needs to be confirmed in independent experiments. Spot morning urine samples can under certain circumstances be used to estimate 8-oxodG excretion rate provided that creatinine excretion is unchanged (in paired experiments) or comparable (in un-paired experiments), as evaluated from the correlation between 8-oxodG excretion in 24 h urine samples and in morning spot urine samples corrected for creatinine excretion (r = 0.50, p < 0.05). We conclude that 8-oxodG excretion is determined by factors like oxygen consumption and CYP1A2 activity rather than by factors like plasma antioxidant concentrations.
Smoking cessation significantly reduces the urinary excretion rate of 8-oxodG, giving direct and controlled evidence that cigarette smoking causes an increased rate of oxidative DNA modification. This could represent a mechanism by which tobacco smoke is carcinogenic.
Numerous studies have shown that cigarette smokers have a lower plasma concentration of ascorbic acid than non-smokers, but only a few have considered the antioxidant status of ex-smokers.' We report the first controlled study monitoring the early effect of smoking cessation on the concentration of ascorbic acid in plasma. Subjects, methods, and resultsThe study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the local ethics committee. Two hundred volunteers were recruited through local advertisement and gave signed informed consent. Eligible subjects of both sexes (aged 35 to 65 years) had smoked at least 15 cigarettes a day for one year and declared motivation to stop. Exclusion criteria were known presence of disease; daily intake of drugs, including hormonal contraceptives; antioxidant supplements within the last month; and pregnancy or breastfeeding.Subjects (n = 182) were assigned by a computer generated random number list either to stop smoking immediately (quitters group, n = 100) or to continue smoking for four weeks (smokers group, n = 82). After four weeks, those in the smokers group left the study and were offered a smoking cessation programme. During the 26 weeks of the study, subjects in the quitters group visited the clinic seven times. Smoking cessation was aided by nicotine patches releasing 15 mg nicotine daily (16 hours; Nicorette, Pharmacia AB, Helsingborg, Sweden).2 After 12 weeks, dosage was reduced during a four week period. None of the subjects used nicotine patches after 26 weeks. After four weeks, the quitters group consisted of 62 subjects and the smokers of 72. The remaining 48 subjects did not succeed in stopping smoking, suffered from acute illness, used intercurrent antioxidant supplements, or withdrew their consent. After 26 weeks, 41 subjects in the quitters group were still not smoking; 28 of these fulfilled the remaining criteria.At the entry and four week visits, fasting blood samples were collected from both groups. The quitter status of the subjects was confirmed at each visit by measurements of end-expiratory carbon monoxide and plasma cotinine.Total ascorbic acid was measured using high performance liquid chromatography with coulometric detection as previously described.3 T tests were used to analyse differences within groups; analysis of covariance with baseline adjustment was used for differences between groups; and intention to treat analysis was used for confirmation.Four weeks after the start of the study, the plasma concentration of ascorbic acid had increased by an average of 23.3% (P<0.001) in the quitters group and 9.8% (P<0.05) in the smokers group (difference 13.5%, P<0.05). Intention to treat analysis showed similar results for the quitters group (21.2%, P<0.001; n = 90) and the smokers group (10.2%, P<0.05; n = 77) (difference 10%, P = 0.06).After 26 weeks, the ascorbic acid concentration had increased by 21.2 % (P<0.005) from baseline in the quitters group as compared with baseline. There was no significant diff...
BackgroundCombining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having in vitro antiviral properties. This may improve outcomes in patients hospitalised for COVID-19.MethodsPlacebo-controlled double-blind randomised multicentre trial. Patients ≥18 years, admitted to hospital for≤48 h (not intensive care) with a positive SARS-CoV-2 RT-PCR test, were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14).ResultsAfter randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on February 1, 2021. A total of 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median of 9.0 DAOH14 (IQR, 3–11) versus. 9.0 DAOH14 (IQR, 7–10) in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for 1 patient in the intervention group versus. 2 patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for 9 patients in the intervention group versus. 6 patients receiving placebo (p=0.57).ConclusionsThe combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.
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