High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers

Mühlhöfer, A; Mrosek, S; Schlegel, Beate; Trommer, Wolfgang E.; Rozario, Fabian; Böhles, H.; Schremmer, D.; Wg, Zoller; Biesalski, H. K.

doi:10.1038/sj.ejcn.1601943

Cited by 46 publications

(29 citation statements)

References 31 publications

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“…Repeated i.v. injection of 750-7500 mg/day of vitamin C for 6 days in healthy volunteers does not induce a pro-oxidant change in plasma markers (38). Further, i.v.…”

Section: Vitamin C Dosage and Safetymentioning

confidence: 99%

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Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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Significance: Evidence is emerging that parenteral administration of high-dose vitamin C may warrant development as an adjuvant therapy for patients with sepsis. Recent Advances: Sepsis increases risk of death and disability, but its treatment consists only of supportive therapies because no specific therapy is available. The characteristics of severe sepsis include ascorbate (reduced vitamin C) depletion, excessive protein nitration in microvascular endothelial cells, and microvascular dysfunction composed of refractive vasodilation, endothelial barrier dysfunction, and disseminated intravascular coagulation. Parenteral administration of ascorbate prevents or even reverses these pathological changes and thereby decreases hypotension, edema, multiorgan failure, and death in animal models of sepsis. Critical Issues: Dehydroascorbic acid appears to be as effective as ascorbate for protection against microvascular dysfunction, organ failure, and death when injected in sepsis models, but information about pharmacodynamics and safety in human subjects is only available for ascorbate. Although the plasma ascorbate concentration in critically ill and septic patients is normalized by repletion protocols that use high doses of parenteral ascorbate, and such doses are tolerated well by most healthy subjects, whether such large amounts of the vitamin trigger adverse effects in patients is uncertain. Future Directions: Further study of sepsis models may determine if high concentrations of ascorbate in interstitial fluid have pro-oxidant and bacteriostatic actions that also modify disease progression. However, the ascorbate depletion observed in septic patients receiving standard care and the therapeutic mechanisms established in models are sufficient evidence to support clinical trials of parenteral ascorbate as an adjuvant therapy for sepsis.

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“…Repeated i.v. injection of 750-7500 mg/day of vitamin C for 6 days in healthy volunteers does not induce a pro-oxidant change in plasma markers (38). Further, i.v.…”

Section: Vitamin C Dosage and Safetymentioning

confidence: 99%

“…However, concerns have been raised that highdose ascorbate may induce pro-oxidant effects in patients (38). One basis for this concern is that ascorbate reduces the valence of free transition metals, such as iron (e.g., ascorbate reduces FeIII to FeII), which then catalyze the formation of hydrogen peroxide.…”

Section: Vitamin C Dosage and Safetymentioning

confidence: 99%

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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“…The volunteers were instructed by a nutritionist to exclude from their diets foods rich in AA and iron (such as vegetables, legumes, fruit, juice, coffee, tea, egg and all types of meat) as well as foods containing phytates, tannins and calcium, among others, on the day before and during the blood sampling period. The time points were selected based on literature absorption curves for AA and iron [16,20,26,27] . The 24-hour time point was chosen with the intention of searching for a possible delayed prooxidative effect of vitamin C and Iron.…”

Section: Subjectsmentioning

confidence: 99%

“…AA is a powerful water-soluble antioxidant which can prevent peroxidation in plasma after exposure to a variety of prooxidative situations [14][15][16] . In line with this, AA deficiency is always associated with an increase in oxidative stress and tissue injury [17] .…”

Section: Introductionmentioning

confidence: 99%

A Single High Dose of Ascorbic Acid and Iron Is Not Correlated with Oxidative Stress in Healthy Volunteers

Colpo

de²,

Pieniz³

et al. 2008

Ann Nutr Metab

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Fe (II) is a potential prooxidant in vivo and can induce cellular oxidative stress. Ascorbic acid (AA) is a powerful physiological antioxidant and, in the presence of free Fe (II), can exhibit prooxidant effects in vitro. However, in vivo prooxidant effects of Fe (II) and AA have not yet been indisputably demonstrated. Here we evaluate the potential toxic effect of supplementation of Fe (II) associated with AA. Nine healthy, nonsmoking male volunteers (20–31 years old) participated in the crossover study design. The volunteers were supplemented with either a dose of 2 g of AA, 150 mg of iron carbonyl or 2 g of AA plus 150 mg of iron carbonyl with a washout period of 15 days between each treatment. AA, iron, ferritin, thiobarbituric acid-reactive substances, catalase, δ-aminolevulinic dehydratase and SH thiol groups were measured in the blood of the volunteers. Plasma AA levels were increased at 2, 5 and 24 h after AA or AA plus iron ingestion. Plasma Fe levels were increased at 2 and 5 h in the AA plus iron group. Erythrocyte malondialdehyde levels decreased at 5 and 24 h after AA and 5 h after AA plus iron ingestion. Catalase activity from erythrocytes was increased 5 h after supplementation with AA plus iron. There was no significant difference between groups in the other biochemical parameters evaluated. Thus, the present study does not support the hypothesis that the combination of high plasma concentrations of AA and iron, or iron alone, could cause in vivo oxidative damage after a single supplementation dose.

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“…Based on the simulation of the mathematical model, the increase of intracellular H2O2 due to IVA in humans should be limited and unlikely to induce cell death. Muhlhofer et al's study might provide some evidence for this, which showed that there was no increase in the plasma concentrations of α-tocopherol and thiobarbituric acid-reactive substances, a well-established parameter for lipid peroxidation, in six healthy males who received daily infusions of up to 7.5 grams ascorbate for six consecutive days [127], though the dose used was only around 1/10 of that was usually used in a IVA treatment for cancer [36].…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of ascorbate to cancer cells: mathematical modelling, mechanisms and clinical implications

Chen¹

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Studies over the last few decades provided supportive evidence for further research on the use of intravenous administration of high-dose ascorbate (0.5 -1.5 grams per kilogram of body weight) in cancer treatment. Although intravenous ascorbate showed limited anticancer activity in the recent clinical trials, its potential beneficial effects were noted, such as improvement in quality of life, reduction of chemotherapy-associated toxicity, reduction of inflammation and stabilization of cancer progression. These observations were in agreement with the outcomes of three cancer patients who declined chemotherapy and received intravenous ascorbate as an alternative in a preliminary clinical case study (Chapter 4). It was commonly accepted that the cytotoxicity of ascorbate was mediated by hydrogen peroxide (H2O2). However, our analysis and interpretation of the published results were not consistent with this being the sole mechanism of cytotoxicity, and an additional dehydroascorbate-mediated mechanism was proposed in this thesis (Chapter 1).In order to have a holistic understanding of the differential effects of ascorbate treatment in in vitro, animal and human studies, the treatment-induced changes in the intracellular H2O2 concentrations of the targeted cells should be compared. However, precise measurement of intracellular H2O2concentrations in vivo is difficult. In Chapter 2, a mathematical model was established for estimating the extracellular and intracellular H2O2 concentrations in a biological system that was challenged with H2O2 and/or an agent that could induce H2O2 production (such as ascorbate). Simulation of the mathematical model was carried out with the values of variables estimated from the published scientific literature and the experimental data obtained from this study. Several predictions were made and validated with the experimental results. One simulation predicted a limited increase of intracellular H2O2 concentration in a typical intravenous ascorbate treatment, which should be insufficient to induce cell death in tumours. The mathematical model also provided methods for estimating intrinsic intracellular H2O2 production rate and intracellular H2O2 concentration based on extracellular H2O2 concentration and other cell-dependent parameters, which were easier to be obtained with the current experimental methods.In Chapter 3, it was demonstrated in vitro that the cytotoxicity of ascorbate was mediated by both H2O2 and dehydroascorbate (DHA). The associations between the responses of cells to ascorbate (0 -30 mM) and some extracellular, cellular and molecular variables, such as cell culture medium, serum, glucose, pyruvate, cell cycle, cell volume and the expression and activities of H2O2 ii decomposing enzymes catalase and glutathione peroxidase, were investigated. Pyruvate but not glucose showed protective effect on cells in DHA treatment. Increased oxygen reactive species (ROS) levels in the DHA-treated cells was observed. These results supported our hypothesis that DHA might be able t...

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High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers

Cited by 46 publications

References 31 publications

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

A Single High Dose of Ascorbic Acid and Iron Is Not Correlated with Oxidative Stress in Healthy Volunteers

Cytotoxicity of ascorbate to cancer cells: mathematical modelling, mechanisms and clinical implications

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