Report of the Pilot Study Done for the Proposed Investigation on the Possible Synergic Effect between High-Dose Ascorbic Acid Application and Oncothermia Treatment

According to recent investigations, the parenteral application of ascorbic acid (vitamin C) at high doses has significant antitumor activity in in vitro assays. The goal of our experiment was to determine the possible potentiating effect of application of high dose pH-neutralized ascorbic acid to the normal oncothermia treatment method. The NMRI mice were inoculated with C26 murine colon carcinoma cell line subcutaneously at both of their femoral regions and were kept till the tumors reached symmetrically 10 mm in diameter. We created four experimental groups, containing 5 male and 5 female animals in each. Both vitamin-C and oncothermia treatments were applied once; ascorbic acid was applied intra-peritoneally. Oncothermia treatment was applied only to the right limb tumor; the other side will be used as internal control. After the treatment, the animals were sacrificed, and all tumors were removed and analyzed histopathologically. Our main question centers on the comparison of the cell destruction ratio of the various applied treatment regimes, and studies the possible synergy or additive cross-potentiating of the methods. The results of this experiment turned out to be controversial, since the ascorbic acid did not change the remission rate of the allografts and showed no synergy with oncothermia.

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Unintended Consequence of High-Dose Vitamin C Therapy for an Oncology Patient: Evaluation of Ascorbic Acid Interference With Three Hospital-Use Glucose Meters

Journal of Diabetes Science and Technology ◽

10.1177/1932296820932186 ◽

2020 ◽

pp. 193229682093218

Author(s):

Brooke M. Katzman ◽

Brandon R. Kelley ◽

Gayle R. Deobald ◽

Nikki K. Myhre ◽

Sean A. Agger ◽

...

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

High Dose ◽

Oncology Patient ◽

Glucose Meter ◽

High Doses ◽

The Impact ◽

Very High ◽

High Dose Vitamin ◽

Hospital Use

The use of high-dose vitamin C in cancer care has offered promising results for some patients. However, the intravenous (IV) doses used for these patients can reach concentrations that interfere with some strip-based glucose meters. We characterized the impact of vitamin C interference, from standard to the very high doses used for some cancer protocols, using three different hospital-use glucose meters. For two of the three devices tested, increasing concentrations of ascorbic acid caused false elevations in the glucose measurements. The third glucose meter did not provide inaccurate results, regardless of the vitamin C concentration present. Rather, above a certain threshold, the device generated error messages and no results could be obtained.

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Decreased expression of the vitamin C transporter SVCT1 by ascorbic acid in a human intestinal epithelial cell line

British Journal Of Nutrition ◽

10.1079/bjn2001492 ◽

2002 ◽

Vol 87 (2) ◽

pp. 97-100 ◽

Cited By ~ 68

Author(s):

Lauren MacDonald ◽

Alfred E. Thumser ◽

Paul Sharp

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Cell Model ◽

Human Kidney ◽

The Body ◽

Epithelial Cell Line ◽

High Dose ◽

Acid Uptake ◽

Cellular Processes ◽

High Doses

Vitamin C (ascorbic acid) is an essential nutrient that is involved in a number of cellular processes. However, unlike most mammals, man is unable to synthesize vitamin C and it must therefore be acquired from the diet. Absorption of vitamin C is achieved by two transporters, SVCT1 and SVCT2, recently cloned from rat and human kidney. SVCT1 is thought to be the predominant transporter in the intestine. Vitamin C supplements are increasingly common, thus contributing to an increased dietary load, and therefore the aim of the present study was to investigate the effect of high doses of ascorbic acid on SVCT1 expression. Using the Caco-2 TC7 cell model of small intestinal enterocytes, we measured the effects of ascorbic acid (4·5 mg/ml culture medium) on L-[14C]ascorbic acid uptake and SVCT1 expression (determined by reverse transcription-polymerase chain reaction). Ascorbic acid uptake was decreased significantly in Caco-2 TC7 cells exposed to ascorbate for 24 h (-50 %, P<0·0005). Expression of SVCT1 was also significantly reduced by exposure to elevated levels of ascorbate for 24 h (-77 %, P<0·005). Taken together these results suggest that high-dose supplements might not be the most efficient way of increasing the body pool of vitamin C.

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Intravenous ascorbic acid protocol for cancer patients: scientific rationale, pharmacology, and clinical experience

Functional Foods in Health and Disease ◽

10.31989/ffhd.v3i8.43 ◽

2013 ◽

Vol 3 (8) ◽

pp. 344 ◽

Cited By ~ 5

Author(s):

N. A. Mikirova ◽

J. J. Casciari ◽

R. E. Hunninghake ◽

N. H. Riordan

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Cancer Patients ◽

Clinical Experience ◽

Animal Studies ◽

Biological Response ◽

High Dose ◽

Pharmacokinetic Data ◽

Intravenous Vitamin

Background: Ascorbic acid (vitamin C, ascorbate) has been shown to protect cells against various types of oxidant injury at physiologically relevant concentrations. Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels. This article reviews the scientific rational for intravenous vitamin C as a potential treatment for cancer. Many mechanisms of action for ascorbate efficacy against cancer have been proposed over the years. Cancer patients are often deficient in vitamin C, and require large doses to replenish depleted stores. It has been demonstrated in vitro and in animal studies that vitamin C is preferentially toxic to tumor cells at millimolar concentrations; moreover, pharmacokinetic data suggest that these concentrations are clinically achievable when ascorbate is administered intravenously. Data suggests that ascorbate may serve as a biological response modifier, affecting inflammation and angiogenesis as well as improving immune function parameters. While Phase II clinical trials using ascorbate in cancer therapy are under way, vitamin C is not subject to the regulations that synthetic drugs are and therefore has been used clinically for decades to treat cancer patients. This clinical experience suggests the therapy is safe, and may be effective in some instances. Attached to this article is the Riordan IVC Protocol, which details an intravenous vitamin C protocol that can be safely administered to cancer patients.Keywords: Cancer, inflammation, C-reactive protein, inflammatory cytokines, high-dose vitamin C

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Vitamin C—Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination

Nutrients ◽

10.3390/nu13020615 ◽

2021 ◽

Vol 13 (2) ◽

pp. 615

Author(s):

Martin Doseděl ◽

Eduard Jirkovský ◽

Kateřina Macáková ◽

Lenka Krčmová ◽

Lenka Javorská ◽

...

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Iron Absorption ◽

Plasma Concentrations ◽

Physiological Role ◽

Renal Stones ◽

Anti Oxidant ◽

High Doses ◽

Epigenetic Processes

Vitamin C (L-ascorbic acid) has been known as an antioxidant for most people. However, its physiological role is much larger and encompasses very different processes ranging from facilitation of iron absorption through involvement in hormones and carnitine synthesis for important roles in epigenetic processes. Contrarily, high doses act as a pro-oxidant than an anti-oxidant. This may also be the reason why plasma levels are meticulously regulated on the level of absorption and excretion in the kidney. Interestingly, most cells contain vitamin C in millimolar concentrations, which is much higher than its plasma concentrations, and compared to other vitamins. The role of vitamin C is well demonstrated by miscellaneous symptoms of its absence—scurvy. The only clinically well-documented indication for vitamin C is scurvy. The effects of vitamin C administration on cancer, cardiovascular diseases, and infections are rather minor or even debatable in the general population. Vitamin C is relatively safe, but caution should be given to the administration of high doses, which can cause overt side effects in some susceptible patients (e.g., oxalate renal stones). Lastly, analytical methods for its determination with advantages and pitfalls are also discussed in this review.

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Decreased Platelet Vitamin C in Diabetes Mellitus; Possible Role in Peraggregatoon

10.1055/s-0039-1687640 ◽

1979 ◽

Author(s):

K.E. Sarji ◽

J. Gonzalez ◽

H. Hempling ◽

J.A. Colwell

Keyword(s):

Ascorbic Acid ◽

Arachidonic Acid ◽

Platelet Aggregation ◽

Vitamin C ◽

Platelet Rich Plasma ◽

Solution Ph ◽

Dose Dependent Fashion ◽

Insulin Dependent Diabetic ◽

Induced Aggregation

To determine whether Vitamin C might relate to the increased platelet sensitivity in the diabetic, we have measured levels of platelet Vitamin C and studied the effects of Vitamin C on platelet aggregation. Ascorbic acid levels in washed platelets from diabetics were significantly lower than from normals (4s.2±3 μg/1010 platelets vs. 2s.s±2 μg/1010 platelets, p<.001). The effects of ascorbic acid on platelet aggregation in vitro were studied by adding ascorbic acid in buffered solution (pH 7.35) prior to-aggregating agents. Ascorbic acid in platelet-rich plasma consistently inhibited platelet aggregation with threshold concentrations of ADP, epinephrine, and collagen. With washed platelets, ascorbic acid inhibited arachidonic, acid-induced aggregation. When platelets were incubated at 37°C for 10 minutes with varying concentrations of ascorbic acid, rewashed, and aggregation with arachidonic acid tested, aggregation was inhibited in a linear dose-dependent fashion. Oral ingestion of ascorbic acid (2 gm/day) for seven days by normal non-smoking males produced a marked inhibition of aggregation. In a similar study, platelets from an insulin-dependent diabetic showed no change in aggregation. These results suggest that platelet levels of ascorbic acid may relate to the hyperaggregat ion of platelets from diabetics.

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Ascorbic acid attenuates activation and cytokine production in sepsis-like monocytes

10.1101/2021.04.15.21255504 ◽

2021 ◽

Author(s):

Tobias Schmidt ◽

Robin Kahn ◽

Fredrik Kahn

Keyword(s):

Flow Cytometry ◽

Ascorbic Acid ◽

Cytokine Production ◽

In Vitro Study ◽

Surface Expression ◽

High Dose ◽

Functional Assay ◽

Dependent Manner ◽

Dose Dependent

Objective To investigate the effects of high dose ascorbic acid (AA) on monocyte polarization and cytokine production in vitro Design Experimental in vitro study of cells from healthy subjects and patients with sepsis Setting University research laboratory and academic hospital Subjects Six healthy controls and three patients with sepsis Interventions Monocytes were isolated from whole blood of healthy donors (n=6) and polarized in vitro for 48hrs using LPS or LTA. Polarization was confirmed by surface marker expression using flow cytometry. As a comparison, monocytes were also isolated from septic patients (n=3) and analyzed for polarization markers. The effect of AA on monocyte polarization was evaluated. As a functional assay, AA-treated monocytes were analyzed for cytokine production of TNF and IL-8 by intracellular staining and flow cytometry following activation with LPS or LTA. Measurements and Main Results Both LPS and LTA induced polarization in healthy monocytes in vitro, with increased expression of both pro- (CD40 and PDL1, p<0.05) and anti-inflammatory (CD16 and CD163, p<0.05) polarization markers, with non-significant effects on CD86 and CD206. This pattern resembled, at least partly, that of monocytes from septic patients. Treatment with AA significantly inhibited the upregulation of surface expression of CD16 and CD163 (p<0.05) in a dose dependent manner, but not CD40 or PDL-1. Finally, AA attenuated LPS or LTA-induced cytokine production of IL-8 and TNF in a dose-dependent manner (both p<0.05). Conclusions AA inhibits upregulation of anti-, but not pro-inflammatory related markers in LPS or LTA polarized monocytes. Additionally, AA attenuates cytokine production from in vitro polarized monocytes, displaying functional involvement. This study provides important insight into the immunological effects of high dose AA on monocytes, and potential implications in sepsis.

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Toll-Like Receptor Signaling in Airborne Burkholderia thailandensis Infection

Infection and Immunity ◽

10.1128/iai.00618-09 ◽

2009 ◽

Vol 77 (12) ◽

pp. 5612-5622 ◽

Cited By ~ 17

Author(s):

T. Eoin West ◽

Thomas R. Hawn ◽

Shawn J. Skerrett

Keyword(s):

Low Dose ◽

Inflammatory Responses ◽

High Dose ◽

Tlr Signaling ◽

Necrosis Factor Alpha ◽

Airborne Infection ◽

Essential Components ◽

High Doses

ABSTRACT Melioidosis is a tropical disease endemic in southeast Asia and northern Australia caused by the gram-negative soil saprophyte Burkholderia pseudomallei. Although infection is often systemic, the lung is frequently involved. B. thailandensis is a closely related organism that at high doses causes lethal pneumonia in mice. We examined the role of Toll-like receptors (TLRs), essential components of innate immunity, in vitro and in vivo during murine B. thailandensis pneumonia. TLR2, TLR4, and TLR5 mediate NF-κB activation by B. thailandensis in transfected HEK293 or CHO cells. In macrophages, TLR4 and the adaptor molecule MyD88, but not TLR2 or TLR5, are required for tumor necrosis factor alpha production induced by B. thailandensis. In low-dose airborne infection, TLR4 is needed for early, but not late, bacterial containment, and MyD88 is essential for control of infection and host survival. TLR2 and TLR5 are not necessary to contain low-dose infection. In high-dose airborne infection, TLR2 deficiency confers a slight survival advantage. Lung and systemic inflammatory responses are induced by low-dose inhaled B. thailandensis independently of individual TLRs or MyD88. These findings suggest that redundancy in TLR signaling or other MyD88-dependent pathways may be important in pneumonic B. thailandensis infection but that MyD88-independent mechanisms of inflammation are also activated. TLR signaling in B. thailandensis infection is substantially comparable to signaling induced by virulent B. pseudomallei. These studies provide additional insights into the host-pathogen interaction in pneumonic Burkholderia infection.

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High-dose vitamin C enhances cancer immunotherapy

Science Translational Medicine ◽

10.1126/scitranslmed.aay8707 ◽

2020 ◽

Vol 12 (532) ◽

pp. eaay8707 ◽

Cited By ~ 17

Author(s):

Alessandro Magrì ◽

Giovanni Germano ◽

Annalisa Lorenzato ◽

Simona Lamba ◽

Rosaria Chilà ◽

...

Keyword(s):

Immune System ◽

Vitamin C ◽

Clinical Evidence ◽

High Dose ◽

Dependent Manner ◽

Cancer Cell Growth ◽

Mutational Burden ◽

Cancer Types ◽

High Doses ◽

High Dose Vitamin

Vitamin C (VitC) is known to directly impair cancer cell growth in preclinical models, but there is little clinical evidence on its antitumoral efficacy. In addition, whether and how VitC modulates anticancer immune responses is mostly unknown. Here, we show that a fully competent immune system is required to maximize the antiproliferative effect of VitC in breast, colorectal, melanoma, and pancreatic murine tumors. High-dose VitC modulates infiltration of the tumor microenvironment by cells of the immune system and delays cancer growth in a T cell–dependent manner. VitC not only enhances the cytotoxic activity of adoptively transferred CD8 T cells but also cooperates with immune checkpoint therapy (ICT) in several cancer types. Combination of VitC and ICT can be curative in models of mismatch repair–deficient tumors with high mutational burden. This work provides a rationale for clinical trials combining ICT with high doses of VitC.

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Fluconazole plus Cyclosporine: a Fungicidal Combination Effective against Experimental Endocarditis Due to Candida albicans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.11.2932-2938.2000 ◽

2000 ◽

Vol 44 (11) ◽

pp. 2932-2938 ◽

Cited By ~ 78

Author(s):

O. Marchetti ◽

J. M. Entenza ◽

D. Sanglard ◽

J. Bille ◽

M. P. Glauser ◽

...

Keyword(s):

Candida Albicans ◽

Amphotericin B ◽

Cyclosporine A ◽

Test Organism ◽

The Other ◽

High Dose ◽

Therapeutic Results ◽

Fluconazole Therapy ◽

High Doses

ABSTRACT Recent observations demonstrated that fluconazole plus cyclosporine (Cy) synergistically killed Candida albicans in vitro. This combination was tested in rats with C. albicansexperimental endocarditis. The MICs of fluconazole and Cy for the test organism were 0.25 and >10 mg/liter, respectively. Rats were treated for 5 days with either Cy, amphotericin B, fluconazole, or fluconazole-Cy. Although used at high doses, the peak concentrations of fluconazole in the serum of rats (up to 4.5 mg/liter) were compatible with high-dose fluconazole therapy in humans. On the other hand, Cy concentrations in serum (up to 4.5 mg/liter) were greater than recommended therapeutic levels. Untreated rats demonstrated massive pseudohyphal growth in both the vegetations and the kidneys. However, only the kidneys displayed concomitant polymorphonuclear infiltration. The therapeutic results reflected this dissociation. In the vegetations, only the fungicidal fluconazole-Cy combination significantly decreased fungal densities compared to all groups, including amphotericin B (P < 0.0001). In the kidneys, all regimens except the Cy regimen were effective, but fluconazole-Cy remained superior to amphotericin B and fluconazole alone in sterilizing the organs (P < 0.0001). While the mechanism responsible for the fluconazole-Cy interaction is hypothetical, this observation opens new perspectives for fungicidal combinations between azoles and other drugs.

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Dietary regulation of intestinal ascorbate uptake in guinea pigs

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1991.260.1.g108 ◽

1991 ◽

Vol 260 (1) ◽

pp. G108-G118 ◽

Cited By ~ 3

Author(s):

W. H. Karasov ◽

B. W. Darken ◽

M. C. Bottum

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Brush Border ◽

Guinea Pigs ◽

Dietary Regulation ◽

Intestinal Brush Border ◽

Pregnancy And Lactation ◽

Human Adults ◽

Ascorbate Uptake

We measured ascorbic acid (AA) uptake across the intestinal brush border in vitro in intact tissue from guinea pigs fed maintenance AA (200 mg/kg diet) or made hypervitaminotic (5,000 mg/kg diet) or hypovitaminotic (chronically and acutely). Total uptake per centimeter ileum was 25-50% lower in hypervitaminotic juvenile, adult male, and lactating guinea pigs compared with their respective controls, whereas carrier-mediated D-glucose uptake and Na(+)-independent AA uptake were similar. High dietary ascorbate specifically reduced the Vmax for carrier-mediated AA uptake. Hypovitaminosis had no significant effect on uptake of AA or other solutes. We performed diet-switching experiments (high-AA diet to maintenance diet) with young and adult guinea pigs to determine the reversibility of the downregulation. In adult guinea pigs, the downregulation of AA uptake was reversible within 7 days. In the young of mothers fed high AA during pregnancy and lactation, and which fed on high AA for 14 days after weaning, the downregulation was reversible within 14 days. Thus regulation of AA uptake is reversible and therefore probably does not play a significant role in the development of vitamin C dependency in human adults, or their young, after ingestion of megadoses of ascorbic acid.

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