This study was conducted to evaluate whether vitamin C (VC) was associated with total antioxidant status (TAS) in human plasma and to determine the usefulness of VC on TAS in the treatment of patients with paraquat poisoning. VC and TAS were measured in 56 healthy subjects. Then, various concentrations (1-100 mg/dl) of VC in pooled plasma from 10 volunteers were constructed in vitro and TAS was measured. The VC and TAS were measured in vivo at 0.5, 1, 2, 3, 5, 7, 9, and 11 h after injection of VC (50 mg/kg) in seven volunteers and pharmacokinetic data were calculated. Finally, various amounts of VC (100, 500, 1000, 3000 mg/day, and 3000 mg/8 h) were given to 10 paraquat-poisoned patients for 5 consecutive days, and blood was taken for TAS 1 h after each injection. The means (SD) of VC and TAS in healthy subjects were 2.22 (0.16) mmol/l and 0.48 (0.10) mg/dl, respectively. Positive correlation between VC and TAS was observed in both in vitro and in healthy volunteers. The pharmacokinetic results in vivo were as follows: means (SD) of distribution volume, area under curve, plasma clearance, half life, C(max), and T(max) were 32.0 (4.4) l, 36.4 (11.3) mg h/dl, 2.13 (1.36) l/h, 10.2 (7.8) h, 17.1 (7.1) mg/dl, and 0.64 (0.24) h, respectively. Estimated loading and maintenance doses of VC were 2278 mg and 146 mg/h, respectively. The means of TAS were increased over 5 consecutive days as 2.26, 2.76, 2.81, 3.18, and 3.58 mmol/l in paraquat patients. All patients were recovered within mean (SD) 21.2 (5.4) admission days. Our data suggested that VC was a significant antioxidant as TAS in human plasma and that increased TAS by high doses of VC could be useful as a free radical scavenger for paraquat poisoned patients.

The faith that an oxidizing of LDL is necessary for he foam cell formation is basically for the so called oxidative hypothesis of atherosclerosis. The role of LDL-oxidation for the atherosclerotic plaque formation, as well as its association with inflammatory processes in the vascular wall, are well established. The important conclusion of this hypothesis is the possible role of the antioxidants attenuating atherosclerotic mechanisms. The advances in studying the principal antioxidant vitamins E, C and beta-carotene effects, revealed a great part of their molecular mechanisms, which are not necessarily antioxidative. The important aspects of the cooperative antioxidant action are revealed too, including the so called tocopherol-mediated peroxidation, suggesting the need for the co-antioxidants for effective antioxidant defense. In the recent years many vitamin antioxidant supplementations are used. The epidemiological results of such supplementation do not always reveal the same beneficial effects as expected theoretically or based on the observations made with a diet rich in fruits and vegetables. The present paper generalizes the thought concerning the impact of oxidized LDL in atherosclerosis, as well as mechanisms of action and pharmacokinetiks of the most widely used antioxidant vitamins--E, C and beta-carotene, and the perspectives of their usage in cardiovascular prophylaxy bazed upon the recent experience in antioxidant vitamin supplementation.

This study was designed to examine the effect of 500 to 5,000 mg of ascorbic acid on DNA adducts, natural killer (NK) cell activity, programmed cell death, and cell cycle analysis of human peripheral blood leukocytes. According to our hypothesis, if ascorbic acid is a pro-oxidant, doses between 500 and 5,000 mg should enhance DNA adduct formation, decrease immune function, change the cell cycle progression, and increase the rate of apoptosis. Twenty healthy volunteers were divided into four groups and given either placebo or daily doses of 500, 1,000 or 5,000 mg of ascorbic acid for a period of 2 weeks. On days 0, 1, 7, 15, and 21, blood was drawn from them, and the leukocytes were separated and examined for intracellular levels of ascorbic acid, the level of 8-hydroxyguanosine, NK cell activity, cell cycle progression, and apoptosis. Depending on the subjects, between a 0% and a 40% increase in cellular absorption of ascorbic acid was observed when daily doses of 500 mg were used. At doses greater than 500 mg, this cellular absorption was not increased further, and all doses produced equivalent increases in ascorbic acid on days 1 to 15. This increase in cellular concentration of ascorbic acid resulted in no statistically meaningful changes in the level of 8-hydroxyguanosine, increased NK cytotoxic activity, a reduced percentage of cells undergoing apoptosis, and switched cell cycle phases from S and G2/M to G0/G1. After a period of 1 week, with no placebo or vitamin washout, ascorbic acid levels along with functional assays returned to the baseline and became equivalent to placebos. In comparison with baseline values, no change (not more than daily assays variation) was seen in ascorbate concentrations or other assays during oral placebo treatment. We concluded that ascorbic acid is an antioxidant and that doses up to 5,000 mg neither induce mutagenic lesions nor have negative effects on NK cell activity, apoptosis, or cell cycle.

Am J Clin Nutr. 1999 Jun;69(6):1086-107.
Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans.
Carr AC, Frei B.
Linus Pauling Institute, Oregon State University, Corvallis 97331, USA.

The current recommended dietary allowance (RDA) for vitamin C for adult nonsmoking men and women is 60 mg/d, which is based on a mean requirement of 46 mg/d to prevent the deficiency disease scurvy. However, recent scientific evidence indicates that an increased intake of vitamin C is associated with a reduced risk of chronic diseases such as cancer, cardiovascular disease, and cataract, probably through antioxidant mechanisms. It is likely that the amount of vitamin C required to prevent scurvy is not sufficient to optimally protect against these diseases. Because the RDA is defined as "the average daily dietary intake level that is sufficient to meet the nutrient requirement of nearly all healthy individuals in a group," it is appropriate to reevaluate the RDA for vitamin C. Therefore, we reviewed the biochemical, clinical, and epidemiologic evidence to date for a role of vitamin C in chronic disease prevention. The totality of the reviewed data suggests that an intake of 90-100 mg vitamin C/d is required for optimum reduction of chronic disease risk in nonsmoking men and women. This amount is about twice the amount on which the current RDA for vitamin C is based, suggesting a new RDA of 120 mg vitamin C/d.

The concentrations of antioxidant vitamins, particularly vitamin C, are often low in the plasma of institutionalized elderly subjects, and could explain their susceptibility to oxidative stress. However, as such low levels were not always found in home-living healthy elderly persons, the antioxidant vitamin depletion in the formers could result from environmental conditions better than aging itself. The objective of this study was therefore to verify the antioxidant vitamin status in institutionalized elderly persons and to evaluate if a low vit C supplement could be sufficient to improve the plasma vit C concentration in those subjects. This study confirms that plasma vitamin C levels are in the scurvy range in 20 elderly institutionalized subjects and significantly lower than in healthy home-living elderly persons. Beta-carotene concentrations were found marginally low but alpha-tocopherol levels were in the normal range. All three vitamins were correlated. Fifteen days on a physiological vitamin C (150 mg/day) supplementation was sufficient to restore normal vit C levels (50 mumol/l). A further pharmacological vit C administration (750 mg/day) during 30 days only allowed a marginal increase in the plasma vit C concentrations.

The amount of oral ascorbic acid that a patient can tolerate without diarrhea, increases somewhat proportionately to the "toxicity" of his disease. Clinically, in a disease ameliorated by ascorbate, there is a suppression of symptoms only with very high doses and approximately to that extent which a nonrate-limited, antioxidant free radical scavenger, might be expected to affect that disease process if all harmful free radicals and highly reactive oxidizing substances were quenched. In most pathologic processes, the rate at which free radicals and highly reactive oxidants are produced, exceeds the rate at which the ordinary rate-limited antioxidant free radical scavenging mechanisms can quench those free radicals and oxidants. When ascorbate acts as a scavenger, dehydroascorbate is formed; but if the ascorbate/dehydroascorbate (AA/DHA) ratio is kept high (the redox potential kept reducing) until the unstable dehydroascorbate undergoes hydrolysis or can be reduced back to ascorbate, the dehydroascorbate will do no harm. Since even at very high doses, ascorbate is virtually nontoxic, it may be given in the enormous doses necessary to quench almost all unwanted free radicals and oxidants. The wide spectrum of infectious diseases ameliorated by massive doses of ascorbate indicates some common pathologic processes in these diseases.

My previous experience with the utilization of ascorbic acid in the treatment of viral diseases led me to hypothesize that ascorbate would be of value in the treatment of AIDS (acquired immune deficiency syndrome). Preliminary clinical evidence is that massive doses of ascorbate (50-200 grams per 24 hours) can suppress the symptoms of the disease and can markedly reduce the tendency for secondary infections. In combination with usual treatments for the secondary infections, large doses of ascorbate will often produce a clinical remission which shows every evidence of being prolonged if treatment is continued. This clinical remission is achieved despite continuing laboratory evidence of helper T-cell suppression. There may be a complete or partial destruction of the helper T-cells during an initial infection that does not necessitate a continuing toxicity from some source to maintain a permanent or prolonged helper T-cell suppression. However, it is possible ascorbate may prevent that destruction if used adequately during that prodrome period. Emphasis is put upon the recognition and treatment of the frequent intestinal parasites. Food and chemical sensitivities occur frequently in the AID syndrome and may aggravate symptoms considered to be part of the AID syndrome. A topical C-paste has been found very effective in the treatment of herpes simplex and, to a lesser extent, in the treatment of some Kaposi's lesions. Increasingly, clinical research on other methods of treating AIDS is being "contaminated" by patients taking ascorbate.

Previous studies of cultured skin cells and murine skin in vivo have indicated that UVR-induced damage involves the generation of reactive oxygen species and depletion of endogenous antioxidant systems. In order to explore the relevance of this to UVR-induced damage to human skin, we have undertaken a detailed examination of the time-course of changes in markers of oxidative stress in human skin following exposure to physiological amounts of UVR in vivo. In addition, we have examined the skin bioavailability of a common nutritional antioxidant, vitamin C, and have assessed the effects of supplementation on markers of oxidative stress. Our hypothesis was that acute exposure of human skin to UVR in vivo would lead to oxidation of cellular biomolecules that could be prevented by prior vitamin C treatment. A UVR-challenge of 120 mJ/cm2 of broadband UVB (peak 310 nm, range 270-400 nm) was applied to buttock skin of 8 healthy volunteers. This caused a rapid and significant rise in activity of skin catalase at 1 h and an increase in the oxidized/total glutathione ratio at 6 h post-UVR. AP-1 DNA binding also peaked at 1-6 h post-UVR, then declined rapidly to baseline levels. No significant changes were seen in skin malonaldehyde content. Oral vitamin C supplements (500 mg/day) were taken by 12 volunteers for 8 weeks resulting in significant rises in plasma and skin vitamin C content. Supplementation had no effect on the UVR-induced erythemal response. The skin malonaldehyde content was reduced by vitamin C supplementation, but surprisingly, reductions in the skin content of total glutathione and protein thiols were also seen. We speculate that this apparently paradoxical effect could be due to regulation of total reductant capacity by skin cells, such that vitamin C may have been replacing other reductants in these cells. No evidence was obtained for an effect of the supplementary vitamin C on the mild oxidative stress seen in human skin following UVR exposure.

The aim of this study was to investigate whether post-exercise vitamin C supplementation influences recovery from an unaccustomed bout of exercise. Sixteen male subjects were allocated to either a placebo (P; n=8) or vitamin C (VC) group ( n=8). Subjects performed a prolonged (90-min) intermittent shuttle-running test, and supplementation began after the cessation of exercise. Immediately after exercise the VC group consumed 200 mg of VC dissolved in a 500 ml drink, whereas the subjects in the P group consumed the drink alone. Later on the same day and then in the morning and evening of the following 2 days, subjects consumed additional identical drinks. Plasma VC concentrations in the VC group increased above those in the P group 1 h after exercise and remained above P values for the 3 days after exercise. Nevertheless, post-exercise VC supplementation was not associated with improved recovery. Post-exercise serum creatine kinase activities and myoglobin concentrations were unaffected by supplementation. Muscle soreness and the recovery of muscle function in the leg flexors and extensors were not different in VC and P groups. Furthermore, although plasma concentrations of interleukin-6 and malondialdehyde increased following exercise, there was no difference between VC and P groups. These results suggest that either free radicals are not involved in delaying the recovery process following a bout of unaccustomed exercise, or that the consumption of VC wholly after exercise is unable to deliver this antioxidant to the appropriate sites with sufficient expediency to improve recovery.

BACKGROUND: Vitamin C is one of the key antioxidant vitamins which is abundant in the extracellular fluid lining the lung and low vitamin C intake has been associated with pulmonary dysfunction. OBJECTIVES: To evaluate the evidence for the effectiveness of vitamin C in the treatment of asthma. SEARCH STRATEGY: The Cochrane Airways Review Group asthma register was searched and bibliographies of studies identified were also checked for further trials. SELECTION CRITERIA: Only randomised controlled trials were eligible for inclusion. Studies were considered for inclusion if they dealt with the treatment of asthma using vitamin C supplementation. Two independent reviewers identified potentially relevant studies using pre-defined criteria and selected studies for inclusion. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers. Information on patients, methods, interventions, outcomes and results was extracted using standard forms. MAIN RESULTS: A total of 65 abstracts and titles were identified. Ten studies were selected for potential inclusion, six met the inclusion criteria. All included studies were placebo-controlled and randomised. Only three provided data in a form that permitted further analysis and none could be aggregated in a meta analysis. The individual studies produced no significant effect on any asthma outcome. REVIEWER'S CONCLUSIONS: At present, evidence from randomised-controlled trials is insufficient to recommend a specific role for vitamin C in the treatment of asthma. A methodologically strong and large-scale randomised controlled trial is warranted in order to address the question of the effectiveness of vitamin C in patients with asthma.

We have investigated vitamin C supplementation effects on immunoglobulin oxidation (carbonyls) and total plasma protein sulfhydryls in healthy human volunteers. After receiving placebo, plasma ascorbate and oxidation markers were unchanged. Following 5 weeks supplementation with vitamin C (400 mg/day), plasma ascorbate increased but no significant effect on protein oxidation was observed. At 10 and 15 weeks supplementation, carbonyl levels were significantly reduced (P < 0.01) in subjects with low baseline ascorbate (29.51 +/- 5.3 microM) but not in those with normal baseline ascorbate (51.81 +/- 2.3 microM). To eliminate any effect from seasonal variation in dietary antioxidant intake, a second phase was undertaken. Subjects on vitamin C for 15 weeks were randomly assigned to receive either placebo or vitamin C. No difference in plasma sulfhydryl content was observed. Subjects withdrawn from supplementation showed an increase in immunoglobulin carbonyl content (P < 0.01). This demonstrates that dietary vitamin C supplementation can reduce certain types of oxidative protein damage in subjects with low basal antioxidant.

Atherosclerosis is associated with stiffening of conduit arteries and increased platelet activation, partly as a result of reduced bioavailability of nitric oxide (NO), a mediator that normally has a variety of protective effects on blood vessels and platelets. Increased levels of oxygen free radicals are a feature of atherosclerosis that contributes to reduced NO bioavailability and might lead to increased arterial stiffness and platelet activation. Vitamin C is a dietary antioxidant that inactivates oxygen free radicals. This placebo-controlled, double-blind, randomized study was designed to establish whether acute oral administration of vitamin C (2 g), would reduce arterial stiffness and in vitro platelet aggregation in healthy male volunteers. Plasma vitamin C concentrations increased from 42+/-8 to 104+/-8 microM at 6 h after oral administration, and were associated with a significant reduction in augmentation index, a measure of arterial stiffness (by 9.6+/-3.0%; p = 0.016), and ADP-induced platelet aggregation (by 35+/-13%; p = 0.046). There was no change in these parameters after placebo. Vitamin C, therefore, appears to have beneficial effects, even in healthy subjects. The mechanism responsible is likely to involve protection of NO from inactivation by oxygen free radicals, but this requires confirmation. If similar effects are observed in patients with atherosclerosis or risk factors, vitamin C supplementation might prove an effective therapy in cardiovascular disease.

Although the role of vitamin C in common cold incidence had been studied extensively, the level of vitamin C intake has not been unequivocally shown to affect the incidence of colds. In the present study the six largest vitamin C supplementation (> or = 1 g/d) studies, including over 5000 episodes in all, have been analysed, and it is shown that common cold incidence is not reduced in the vitamin C-supplemented groups compared with the placebo groups (pooled rate ratio (RR) 0.99; 95% CI 0.93, 1.04). Consequently these six major studies give no evidence that high-dose vitamin C supplementation decreases common cold incidence in ordinary people. Nevertheless, the analysis was continued with the hypothesis that vitamin C intake may affect common cold susceptibility in specific groups of people. It was assumed that the potential effect of supplementation might be most conspicuous in subjects with low dietary vitamin C intake. The average vitamin C intake has been rather low in the UK and plasma vitamin C concentrations are in general lower in males than in females. In four studies with British females vitamin C supplementation had no marked effect on common cold incidence (pooled RR 0.95; 95% CI 0.86, 1.04). However, in four studies with British male schoolchildren and students a statistically highly significant reduction in common cold incidence was found in groups supplemented with vitamin C (pooled RR 0.70; 95% CI 0.60, 0.81). Thus, these studies with British males indicate that vitamin C intake has physiological effects on susceptibility to common cold infections, although the effect seems quantitatively meaningful only in limited groups of people and is not very large.

A human volunteer study was conducted to test the effect of vitamin C supplementation on biomarkers of oxygen radical-mediated damage in individuals with a range of serum cholesterol levels. A group of 48 non-smokers, 24 men and 24 women, was selected from a panel of over 100 volunteers to give as wide a range of serum cholesterol levels as possible. None of the volunteers was taking medication to control cholesterol levels and they maintained their normal dietary habits so as not to compromise their cholesterol status. Volunteers were allocated to three groups of 16, each consisting of four males with low cholesterol levels (< 6 mmol/L) matched for age and build with four males with high cholesterol levels (> 6 mmol/L) and eight females matched in the same way. A three-treatment, three-treatment period, cross-over design was adopted to take account of any temporal differences in response. The three treatments given were placebo, 60 mg vitamin C/day (the recommended daily allowance) and 6 g vitamin C/day. Each treatment was given for 14 days with 6 weeks between the treatment periods. All procedures were performed to the standards of Good Clinical Practice. Blood samples were taken at the end of each treatment period. Serum was assayed for cholesterol whilst vitamin C, total antioxidant capacity, lipid peroxidation breakdown products and ras p21 protein levels were measured in plasma. Lymphocytes were examined for DNA damage using the Comet assay and chromosome aberration test. The Comet assay was conducted with and without challenge with hydrogen peroxide and the chromosome aberration test with and without challenge with bleomycin. Vitamin C supplementation caused a statistically significant increase in plasma vitamin C concentrations and total antioxidant capacity but did not affect cholesterol levels or ras p21 protein levels. There was a non-significant dose-related decrease in lipid peroxidation breakdown products with vitamin C supplementation. No effect on DNA damage was observed in the Comet assay, either with or without hydrogen peroxide challenge, or in the chromosome aberration test without bleomycin. However, a statistically significant increase in bleomycin-induced aberrations was found after vitamin C supplementation. This may be due to effects of vitamin C on iron status. Comparison of male and female subjects showed statistically significant differences in plasma vitamin C levels, the antioxidant capacity of the plasma and the number of chromosome aberrations induced by bleomycin challenge of lymphocytes in vitro. The results were the same for both low and high cholesterol subjects. This study provides no evidence of a beneficial effect on any of the biomarkers studied of vitamin C supplementation over a short-term supplementation period of 2 weeks in a population of healthy, non-smoking individuals eating a nutritionally adequate diet.

Vitamin C in humans must be ingested for survival. Vitamin C is an electron donor, and this property accounts for all its known functions. As an electron donor, vitamin C is a potent water-soluble antioxidant in humans. Antioxidant effects of vitamin C have been demonstrated in many experiments in vitro. Human diseases such as atherosclerosis and cancer might occur in part from oxidant damage to tissues. Oxidation of lipids, proteins and DNA results in specific oxidation products that can be measured in the laboratory. While these biomarkers of oxidation have been measured in humans, such assays have not yet been validated or standardized, and the relationship of oxidant markers to human disease conditions is not clear. Epidemiological studies show that diets high in fruits and vegetables are associated with lower risk of cardiovascular disease, stroke and cancer, and with increased longevity. Whether these protective effects are directly attributable to vitamin C is not known. Intervention studies with vitamin C have shown no change in markers of oxidation or clinical benefit. Dose concentration studies of vitamin C in healthy people showed a sigmoidal relationship between oral dose and plasma and tissue vitamin C concentrations. Hence, optimal dosing is critical to intervention studies using vitamin C. Ideally, future studies of antioxidant actions of vitamin C should target selected patient groups. These groups should be known to have increased oxidative damage as assessed by a reliable biomarker or should have high morbidity and mortality due to diseases thought to be caused or exacerbated by oxidant damage.