Special Issue "Vitamin C: Current Concepts in Human Physiology"

A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: closed (31 January 2018)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Guest Editor
Prof. Dr. Ramesh Natarajan

Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
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Interests: sepsis; acute lung injury; hemorrhagic shock and trauma; transplantation medicine; hemostasis and thrombosis; ischemia-reperfusion; inflammation; wound healing; coagulation; gene regulation; nitric oxide; molecular biology; cell biology
Guest Editor
Dr. Anitra C. Carr

Department of Pathology, University of Otago, Christchurch Street: 2 Riccarton Ave, Christchurch 8011, New Zealand
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Interests: vitamin C bioavailability and health effects; role of vitamin C in mood and quality of life; role of vitamin C in cancer and infection; human intervention studies; vitamin C recommended dietary intakes

Special Issue Information

Dear Colleagues,

Vitamin C is synthesized by almost all animals. However, for humans, it is a vitamin that needs constant replenishment in the diet. While its role as an anti-oxidant and for preventing scurvy have been known for a long time, novel functions and unrecognized associations continue to be identified for this enigmatic molecule. In the past decade, new details have emerged regarding differences in its uptake by oral and intravenous modes. While vitamin C deficiency remains largely unknown and poorly addressed in many segments of the population, novel pharmacological roles for high dose intravenous vitamin C in many disease states have now been postulated and investigated. This has shifted its role in health and disease from the long perceived notion as merely an anti-oxidant, to a pleiotropic molecule with a broad anti-inflammatory, epigenetic and anti-cancer profile.

This Special Issue will publish original research papers and reviews on vitamin C metabolism and function that relate to the following topics: Unrecognized nutritional deficiency in disease; understanding its role in the modulation of inflammation and immunity; therapeutic applications of pharmacological ascorbate in disease; epigenetic modulation of disease by vitamin C; and the emerging role of vitamin C as a pleiotropic modulator of critical care illness and cancer.

Prof. Dr. Ramesh Natarajan
Dr. Anitra Carr
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 550 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Bioavailability
  • Gene regulation
  • Inflammation
  • Critical care illness
  • Cardiovascular diseases
  • Epigenetics
  • Metabolism
  • Cancer
  • Cognition
  • Quality of life

Published Papers (12 papers)

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Research

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Open AccessArticle High Vitamin C Status Is Associated with Elevated Mood in Male Tertiary Students
Antioxidants 2018, 7(7), 91; https://doi.org/10.3390/antiox7070091
Received: 13 June 2018 / Revised: 10 July 2018 / Accepted: 12 July 2018 / Published: 16 July 2018
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Abstract
Micronutrient status is thought to impact on psychological mood due to the role of nutrients in brain structure and function. The aim of the current study was to investigate the association of vitamin C status with mood state in a sample of male
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Micronutrient status is thought to impact on psychological mood due to the role of nutrients in brain structure and function. The aim of the current study was to investigate the association of vitamin C status with mood state in a sample of male tertiary students. We measured fasting plasma vitamin C levels as an indicator of vitamin C status, and subjective mood was determined using the Profile of Mood States (POMS) questionnaire. One hundred and thirty-nine male students aged 18 to 35 years were recruited from local tertiary institutes in Christchurch, New Zealand. The average plasma vitamin C concentration was 58.2 ± 18.6 (SD) µmol/L and the average total mood disturbance score was 25.5 ± 26.6 (possible score −32 to 200 measuring low to high mood disturbance, respectively). Plasma vitamin C concentration was inversely correlated with total mood disturbance as assessed by POMS (r = −0.181, p < 0.05). Examination of the individual POMS subscales also showed inverse associations of vitamin C status with depression, confusion, and anger. These findings suggest that high vitamin C status may be associated with improved overall mood in young adult males. Full article
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Open AccessArticle Spatial Memory Dysfunction Induced by Vitamin C Deficiency Is Associated with Changes in Monoaminergic Neurotransmitters and Aberrant Synapse Formation
Antioxidants 2018, 7(7), 82; https://doi.org/10.3390/antiox7070082
Received: 18 May 2018 / Revised: 21 June 2018 / Accepted: 27 June 2018 / Published: 29 June 2018
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Abstract
Vitamin C (vitC) is important in the developing brain, acting both as an essential antioxidant and as co-factor in the synthesis and metabolism of monoaminergic neurotransmitters. In guinea pigs, vitC deficiency results in increased oxidative stress, reduced hippocampal volume and neuronal numbers, and
[...] Read more.
Vitamin C (vitC) is important in the developing brain, acting both as an essential antioxidant and as co-factor in the synthesis and metabolism of monoaminergic neurotransmitters. In guinea pigs, vitC deficiency results in increased oxidative stress, reduced hippocampal volume and neuronal numbers, and deficits in spatial memory. This study investigated the effects of 8 weeks of either sufficient (923 mg vitC/kg feed) or deficient (100 mg vitC/kg feed) levels of dietary vitC on hippocampal monoaminergic neurotransmitters and markers of synapse formation in young guinea pigs with spatial memory deficits. Western blotting and high performance liquid chromatography (HPLC) were used to quantify the selected markers. VitC deficiency resulted in significantly reduced protein levels of synaptophysin (p = 0.016) and a decrease in 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio (p = 0.0093). Protein expression of the N-methyl-d-aspartate receptor subunit 1 and monoamine oxidase A were reduced, albeit not reaching statistical significance (p = 0.0898 and p = 0.067, respectively). Our findings suggest that vitC deficiency induced spatial memory deficits might be mediated by impairments in neurotransmission and synaptic development. Full article
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Open AccessArticle No Reported Renal Stones with Intravenous Vitamin C Administration: A Prospective Case Series Study
Antioxidants 2018, 7(5), 68; https://doi.org/10.3390/antiox7050068
Received: 3 April 2018 / Revised: 11 May 2018 / Accepted: 19 May 2018 / Published: 21 May 2018
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Abstract
A few cases associating high dose intravenous vitamin C (IVC) administration with renal stone formation have been reported in the literature, however, no long-term studies investigating IVC administration and reported renal stones have been carried out. Our aim was to measure the frequency
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A few cases associating high dose intravenous vitamin C (IVC) administration with renal stone formation have been reported in the literature, however, no long-term studies investigating IVC administration and reported renal stones have been carried out. Our aim was to measure the frequency of reported renal stones in patients receiving IVC therapy. We carried out a prospective case series study of 157 adult patients who commenced IVC therapy at Integrated Health Options clinic between 1 September 2011 and 31 August 2012, with follow-up for 12 months. Inquiries into the occurrence of renal stones were conducted at enrolment, 6 and 12 months, and renal function blood tests were conducted at enrolment, 4 weeks and every 12 weeks thereafter in a subgroup of patients. No renal stones were reported by any patients in the study, despite 8% of the patients having a history of renal stones. In addition, the majority of patients investigated had stable renal function during the study period as evidenced by little change in serum creatinine levels and estimated glomerular filtration rate (eGFR) following IVC. In conclusion, IVC therapy was not associated with patient-reported renal stones. Although not the primary focus of this study, it was also observed that there was no significant change in mean serum creatinine or eGFR for those who had follow-up renal function blood tests. Full article
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Open AccessArticle Appropriate Handling, Processing and Analysis of Blood Samples Is Essential to Avoid Oxidation of Vitamin C to Dehydroascorbic Acid
Antioxidants 2018, 7(2), 29; https://doi.org/10.3390/antiox7020029
Received: 21 December 2017 / Revised: 8 February 2018 / Accepted: 9 February 2018 / Published: 11 February 2018
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Abstract
Vitamin C (ascorbate) is the major water-soluble antioxidant in plasma and its oxidation to dehydroascorbic acid (DHA) has been proposed as a marker of oxidative stress in vivo. However, controversy exists in the literature around the amount of DHA detected in blood samples
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Vitamin C (ascorbate) is the major water-soluble antioxidant in plasma and its oxidation to dehydroascorbic acid (DHA) has been proposed as a marker of oxidative stress in vivo. However, controversy exists in the literature around the amount of DHA detected in blood samples collected from various patient cohorts. In this study, we report on DHA concentrations in a selection of different clinical cohorts (diabetes, pneumonia, cancer, and critically ill). All clinical samples were collected into EDTA anticoagulant tubes and processed at 4 °C prior to storage at −80 °C for subsequent analysis by HPLC with electrochemical detection. We also investigated the effects of different handling and processing conditions on short-term and long-term ascorbate and DHA stability in vitro and in whole blood and plasma samples. These conditions included metal chelation, anticoagulants (EDTA and heparin), and processing temperatures (ice, 4 °C and room temperature). Analysis of our clinical cohorts indicated very low to negligible DHA concentrations. Samples exhibiting haemolysis contained significantly higher concentrations of DHA. Metal chelation inhibited oxidation of vitamin C in vitro, confirming the involvement of contaminating metal ions. Although EDTA is an effective metal chelator, complexes with transition metal ions are still redox active, thus its use as an anticoagulant can facilitate metal ion-dependent oxidation of vitamin C in whole blood and plasma. Handling and processing blood samples on ice (or at 4 °C) delayed oxidation of vitamin C by a number of hours. A review of the literature regarding DHA concentrations in clinical cohorts highlighted the fact that studies using colourimetric or fluorometric assays reported significantly higher concentrations of DHA compared to those using HPLC with electrochemical detection. In conclusion, careful handling and processing of samples, combined with appropriate analysis, is crucial for accurate determination of ascorbate and DHA in clinical samples. Full article
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Open AccessArticle High Dose Ascorbate Causes Both Genotoxic and Metabolic Stress in Glioma Cells
Antioxidants 2017, 6(3), 58; https://doi.org/10.3390/antiox6030058
Received: 10 May 2017 / Revised: 30 June 2017 / Accepted: 19 July 2017 / Published: 22 July 2017
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Abstract
We have previously shown that exposure to high dose ascorbate causes double stranded breaks (DSBs) and a build-up in S-phase in glioblastoma (GBM) cell lines. Here we investigated whether or not this was due to genotoxic stress as well as metabolic stress generated
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We have previously shown that exposure to high dose ascorbate causes double stranded breaks (DSBs) and a build-up in S-phase in glioblastoma (GBM) cell lines. Here we investigated whether or not this was due to genotoxic stress as well as metabolic stress generated by exposure to high dose ascorbate, radiation, ascorbate plus radiation and H2O2 in established and primary GBM cell lines. Genotoxic stress was measured as phosphorylation of the variant histone protein, H2AX, 8-oxo-7,8-dihydroguanine (8OH-dG) positive cells and cells with comet tails. Metabolic stress was measured as a decrease in NADH flux, mitochondrial membrane potential (by CMXRos), ATP levels (by ATP luminescence) and mitochondrial superoxide production (by mitoSOX). High dose ascorbate, ascorbate plus radiation, and H2O2 treatments induced both genotoxic and metabolic stress. Exposure to high dose ascorbate blocked DNA synthesis in both DNA damaged and undamaged cell of ascorbate sensitive GBM cell lines. H2O2 treatment blocked DNA synthesis in all cell lines with and without DNA damage. DNA synthesis arrest in cells with damaged DNA is likely due to both genotoxic and metabolic stress. However, arrest in DNA synthesis in cells with undamaged DNA is likely due to oxidative damage to components of the mitochondrial energy metabolism pathway. Full article
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Open AccessArticle Attenuation of Red Blood Cell Storage Lesions with Vitamin C
Antioxidants 2017, 6(3), 55; https://doi.org/10.3390/antiox6030055
Received: 6 June 2017 / Revised: 6 July 2017 / Accepted: 8 July 2017 / Published: 12 July 2017
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Abstract
Stored red blood cells (RBCs) undergo oxidative stress that induces deleterious metabolic, structural, biochemical, and molecular changes collectively referred to as “storage lesions”. We hypothesized that vitamin C (VitC, reduced or oxidized) would reduce red cell storage lesions, thus prolonging their storage duration.
[...] Read more.
Stored red blood cells (RBCs) undergo oxidative stress that induces deleterious metabolic, structural, biochemical, and molecular changes collectively referred to as “storage lesions”. We hypothesized that vitamin C (VitC, reduced or oxidized) would reduce red cell storage lesions, thus prolonging their storage duration. Whole-blood-derived, leuko-reduced, SAGM (saline-adenine-glucose-mannitol)-preserved RBC concentrates were equally divided into four pediatric storage bags and the following additions made: (1) saline (saline); (2) 0.3 mmol/L reduced VitC (Lo VitC); (3) 3 mmol/L reduced VitC (Hi VitC); or (4) 0.3 mmol/L oxidized VitC (dehydroascorbic acid, DHA) as final concentrations. Biochemical and rheological parameters were serially assessed at baseline (prior to supplementation) and Days 7, 21, 42, and 56 for RBC VitC concentration, pH, osmotic fragility by mechanical fragility index, and percent hemolysis, LDH release, glutathione depletion, RBC membrane integrity by scanning electron microscopy, and Western blot for β-spectrin. VitC exposure (reduced and oxidized) significantly increased RBC antioxidant status with varying dynamics and produced trends in reduction in osmotic fragility and increases in membrane integrity. Conclusion: VitC partially protects RBC from oxidative changes during storage. Combining VitC with other antioxidants has the potential to improve long-term storage of RBC. Full article
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Review

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Open AccessReview Systematic Review of Intravenous Ascorbate in Cancer Clinical Trials
Antioxidants 2018, 7(7), 89; https://doi.org/10.3390/antiox7070089
Received: 10 May 2018 / Revised: 3 July 2018 / Accepted: 6 July 2018 / Published: 12 July 2018
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Abstract
Background: Ascorbate (vitamin C) has been evaluated as a potential treatment for cancer as an independent agent and in combination with standard chemotherapies. This review assesses the evidence for safety and clinical effectiveness of intravenous (IV) ascorbate in treating various types of cancer.
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Background: Ascorbate (vitamin C) has been evaluated as a potential treatment for cancer as an independent agent and in combination with standard chemotherapies. This review assesses the evidence for safety and clinical effectiveness of intravenous (IV) ascorbate in treating various types of cancer. Methods: Single arm and randomized Phase I/II trials were included in this review. The PubMed, MEDLINE, and Cochrane databases were searched. Results were screened by three of the authors (GN, RP, and CJP) to determine if they met inclusion criteria, and then summarized using a narrative approach. Results: A total of 23 trials involving 385 patients met the inclusion criteria. Only one trial, in ovarian cancer, randomized patients to receive vitamin C or standard of care (chemotherapy). That trial reported an 8.75 month increase in progression-free survival (PFS) and an improved trend in overall survival (OS) in the vitamin C treated arm. Conclusion: Overall, vitamin C has been shown to be safe in nearly all patient populations, alone and in combination with chemotherapies. The promising results support the need for randomized placebo-controlled trials such as the ongoing placebo-controlled trials of vitamin C and chemotherapy in prostate cancer. Full article
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Open AccessReview Influence of Vitamin C on Lymphocytes: An Overview
Antioxidants 2018, 7(3), 41; https://doi.org/10.3390/antiox7030041
Received: 8 February 2018 / Revised: 6 March 2018 / Accepted: 8 March 2018 / Published: 10 March 2018
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Abstract
Vitamin C or ascorbic acid (AA) is implicated in many biological processes and has been proposed as a supplement for various conditions, including cancer. In this review, we discuss the effects of AA on the development and function of lymphocytes. This is important
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Vitamin C or ascorbic acid (AA) is implicated in many biological processes and has been proposed as a supplement for various conditions, including cancer. In this review, we discuss the effects of AA on the development and function of lymphocytes. This is important in the light of cancer treatment, as the immune system needs to regenerate following chemotherapy or stem cell transplantation, while cancer patients are often AA-deficient. We focus on lymphocytes, as these white blood cells are the slowest to restore, rendering patients susceptible to often lethal infections. T lymphocytes mediate cellular immunity and have been most extensively studied in the context of AA biology. In vitro studies demonstrate that T cell development requires AA, while AA also enhances T cell proliferation and may influence T cell function. There are limited and opposing data on the effects of AA on B lymphocytes that mediate humoral immunity. However, AA enhances the proliferation of NK cells, a group of cytotoxic innate lymphocytes. The influence of AA on natural killer (NK) cell function is less clear. In summary, an increasing body of evidence indicates that AA positively influences lymphocyte development and function. Since AA is a safe and cheap nutritional supplement, it is worthwhile to further explore its potential benefits for immune reconstitution of cancer patients treated with immunotoxic drugs. Full article
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Open AccessReview Vitamin C and Microvascular Dysfunction in Systemic Inflammation
Antioxidants 2017, 6(3), 49; https://doi.org/10.3390/antiox6030049
Received: 6 June 2017 / Revised: 26 June 2017 / Accepted: 27 June 2017 / Published: 29 June 2017
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Abstract
Sepsis, life-threatening organ dysfunction caused by a dysfunctional host response to infection, is associated with high mortality. A promising strategy to improve the outcome is to inject patients intravenously with ascorbate (vitamin C). In animal models of sepsis, this injection improves survival and,
[...] Read more.
Sepsis, life-threatening organ dysfunction caused by a dysfunctional host response to infection, is associated with high mortality. A promising strategy to improve the outcome is to inject patients intravenously with ascorbate (vitamin C). In animal models of sepsis, this injection improves survival and, among others, the microvascular function. This review examines our recent work addressing ascorbate’s ability to inhibit arteriolar dysfunction and capillary plugging in sepsis. Arteriolar dysfunction includes impaired vasoconstriction/dilation (previously reviewed) and impaired conduction of vasoconstriction/dilation along the arteriole. We showed that ascorbate injected into septic mice prevents impaired conducted vasoconstriction by inhibiting neuronal nitric oxide synthase-derived NO, leading to restored inter-endothelial electrical coupling through connexin 37-containing gap junctions. Hypoxia/reoxygenation (confounding factor in sepsis) also impairs electrical coupling by protein kinase A (PKA)-dependent connexin 40 dephosphorylation; ascorbate restores PKA activation required for this coupling. Both effects of ascorbate could explain its ability to protect against hypotension in sepsis. Capillary plugging in sepsis involves P-selectin mediated platelet-endothelial adhesion and microthrombi formation. Early injection of ascorbate prevents capillary plugging by inhibiting platelet-endothelial adhesion and endothelial surface P-selectin expression. Ascorbate also prevents thrombin-induced platelet aggregation and platelet surface P-selectin expression, thus preventing microthrombi formation. Delayed ascorbate injection reverses capillary plugging and platelet-endothelial adhesion; it also attenuates sepsis-induced drop in platelet count in systemic blood. Thrombin-induced release of plasminogen-activator-inhibitor-1 from platelets (anti-fibrinolytic event in sepsis) is inhibited by ascorbate pH-dependently. Thus, under acidotic conditions in sepsis, ascorbate promotes dissolving of microthrombi in capillaries. We propose that protected/restored arteriolar conduction and capillary bed perfusion by ascorbate contributes to reduced organ injury and improved survival in sepsis. Full article

Other

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Open AccessCase Report The Use of Intravenous Vitamin C as a Supportive Therapy for a Patient with Glioblastoma Multiforme
Antioxidants 2018, 7(9), 115; https://doi.org/10.3390/antiox7090115
Received: 6 August 2018 / Revised: 21 August 2018 / Accepted: 28 August 2018 / Published: 30 August 2018
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Abstract
Glioblastoma multiforme is a high grade malignant brain tumour with a poor prognosis. Here we report the case of a woman with glioblastoma who lived for over four years from diagnosis (median survival 12 months and 2% survival for three years), experiencing good
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Glioblastoma multiforme is a high grade malignant brain tumour with a poor prognosis. Here we report the case of a woman with glioblastoma who lived for over four years from diagnosis (median survival 12 months and 2% survival for three years), experiencing good quality of life for most of that time. She underwent initial debulking craniotomy, radiotherapy and chemotherapy, as well as having intravenous vitamin C infusions 2–3 times weekly over the four years from diagnosis. Her progress was monitored by blood tests, regular computerised tomography (CT) and magnetic resonance imaging (MRI) scans, clinical reviews and European Organization for the Research and Treatment of Cancer quality of life questionnaires (EORTC QLQ C30). Our case report highlights the benefits of intravenous vitamin C as a supportive therapy for patients with glioblastoma. Full article
Open AccessCase Report Intravenous Vitamin C Administration Improved Blood Cell Counts and Health-Related Quality of Life of Patient with History of Relapsed Acute Myeloid Leukaemia
Antioxidants 2018, 7(7), 92; https://doi.org/10.3390/antiox7070092
Received: 8 June 2018 / Revised: 10 July 2018 / Accepted: 12 July 2018 / Published: 16 July 2018
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Abstract
A 52-year-old female presented to Integrated Health Options Clinic in October 2014 with a history of relapsed acute myeloid leukaemia (AML, diagnosed in 2009 and relapsed in 2014). Intravenous(IV) vitamin C therapy was initiated (in 2014) following completion of chemotherapy as an alternative
[...] Read more.
A 52-year-old female presented to Integrated Health Options Clinic in October 2014 with a history of relapsed acute myeloid leukaemia (AML, diagnosed in 2009 and relapsed in 2014). Intravenous(IV) vitamin C therapy was initiated (in 2014) following completion of chemotherapy as an alternative to haematopoietic stem cell transplantation. IV vitamin C was administered twice weekly at a dose of 70 g/infusion. Within 4 weeks of initiation of IV vitamin C therapy, there was a dramatic improvement in the patient’s blood indices with platelet cell counts increasing from 25 × 109/L to 196 × 109/L and white blood cell counts increasing from 0.29 × 109/L to 4.0 × 109/L, with further improvements observed over the next 18 months. Furthermore, there was a clear and sustained improvement in the patient’s health-related quality of life scores assessed using a validated questionnaire. She has remained healthy and in complete remission until the present day. This case study highlights the benefits of IV vitamin C as a supportive therapy for previously relapsed AML. Full article
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Open AccessMeeting Report Symposium on Vitamin C, 15th September 2017; Part of the Linus Pauling Institute’s 9th International Conference on Diet and Optimum Health
Antioxidants 2017, 6(4), 94; https://doi.org/10.3390/antiox6040094
Received: 12 November 2017 / Revised: 17 November 2017 / Accepted: 18 November 2017 / Published: 21 November 2017
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Abstract
The Linus Pauling Institute’s 9th International Conference on Diet and Optimum Health took place on 13–15 September 2017 in Corvallis, OR, USA, on the beautiful Oregon State University campus [...]
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