Dr. Weeks’ Comment:   When the editors feel the need to make the extra effort to explicitly warn readers, supposedly intelligent readers, to take the scientific findings of the published article with a grain of salt, one has to wonder about their motivation.   Here is an article  which powerfully underscores the therapeutic role of high dose vitamin C  and yet the Editors are telling the readers to be cautions in applying this date in clinical settings.  What is so scary about using high dose vitamin C ?   Since Pauling and Cameron published their exciting results in 1978,  conventional oncologists have been doing back flips and other contortions to tell the readers  “there’s nothing here to see folks… just keep moving along….”   But patients see high dose vitamin C as safe and effective.  They want it, but the FDA and Big Pharma are presently trying to terminate the availability of  IV  high dose vitamin C  in USA. ( see https://weeksmd.com/?p=4967 )

Here is the Editor’s caution

Cautions

• Although this study provides better understanding of the pharmacokinetic issues involved in research on vitamin C, it provides no evidence that vitamin C has any effect on cancer cells and cannot be used to support its clinical use for therapeutic purposes.

-The Editors

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and here is the article which causes such  consternation!

`

Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use

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1. Sebastian J. Padayatty, MRCP, PhD;
2. He Sun, PhD, CBS;
3. Yaohui Wang, MD;
4. Hugh D. Riordan, MD;
5. Stephen M. Hewitt, MD, PhD;
6. Arie Katz, MD;
7. Robert A. Wesley, PhD; and
8. Mark Levine, MD

+ Author Affiliations

1.       From the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, and the Clinical Center, National Institutes of Health, Bethesda, Maryland; the Food and Drug Administration, Rockville, Maryland; and Bio-Communications Research Institute, Wichita, Kansas.

Abstract

Background: Vitamin C at high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration.

Objective: To determine whether plasma vitamin C concentrations vary substantially with the route of administration.

Design: Dose concentration studies and pharmacokinetic modeling.

Setting: Academic medical center.

Participants: 17 healthy hospitalized volunteers.

Measurements: Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g.

Results: Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose. Vitamin C at a dose of 1.25 g administered orally produced mean (±sd) peak plasma concentrations of 134.8 ± 20.6 µmol/L compared with 885 ± 201.2 µmol/L for intravenous administration. For the maximum tolerated oral dose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 µmol/L and 13 400 µmol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses.

Limitations: Patient data are not available to confirm pharmacokinetic modeling at high doses and in patients with cancer.

Conclusions: Oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated.

Editors’ Notes

Context

• Clinical studies of vitamin C as a potential anticancer agent have produced inconsistent results despite in vitro evidence that high concentrations kill cancer cells.
• Pharmacokinetic studies in healthy persons, using a depletion-repletion design, show that intravenous administration can achieve 70-fold higher blood levels of vitamin C than the highest tolerated oral dose.
• Although this study provides better understanding of the pharmacokinetic issues involved in research on vitamin C, it provides no evidence that vitamin C has any effect on cancer cells and cannot be used to support its clinical use for therapeutic purposes.

Cautions

• Although this study provides better understanding of the pharmacokinetic issues involved in research on vitamin C, it provides no evidence that vitamin C has any effect on cancer cells and cannot be used to support its clinical use for therapeutic purposes.

-The Editors

`

`

Vitamin C in gram doses is taken orally by many people and administered intravenously by complementary and alternative medicine practitioners to treat patients with advanced cancer (1, 2). After oral intake, vitamin C plasma concentrations are tightly controlled at 70 to 85 µmol/L for amounts (as much as 300 mg daily) that can be obtained from food (3, 4). However, concentrations achieved by higher pharmacologic doses are uncertain. Despite poor rationale, vitamin C in gram doses was proposed as an anticancer agent decades ago (5). Unblinded studies with retrospective or nonrandom controls reported clinical benefit from oral and intravenous vitamin C administered to patients with terminal cancer at a dosage of 10 g daily (1, 6, 7). Placebo-controlled trials in patients with cancer reported no benefit from oral vitamin C at a dosage of 10 g daily (8, 9), and vitamin C treatment was judged ineffective (10). However, in vitro evidence showed that vitamin C killed cancer cells at extracellular concentrations higher than 1000 µmol/L (11, 12), and its clinical use by some practitioners continues.

We recognized that oral or intravenous routes could produce substantially different vitamin C concentrations (13). We report here that intravenous doses can produce plasma concentrations 30- to 70-fold higher than the maximum tolerated oral doses. These data suggest that the role of vitamin C in cancer treatment should be reexamined, and insights from vitamin C pharmacokinetics can guide its clinical use.

Methods

Pharmacokinetic Studies in Healthy Persons

The study was approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. After we obtained written informed consent, 17 healthy volunteers (7 men, 10 women; age, 19 to 27 years) were studied as inpatients by using a depletion-repletion study design (3, 4). Participants were hospitalized for 3 to 6 months and consumed a vitamin C-deficient diet containing less than 0.005 g of vitamin C per day. At plasma vitamin C concentrations less than 8 µmol/L, persons were depleted without signs of scurvy. Vitamin C, 0.015 g twice daily, was then administered orally until participants achieved a steady state for this dose (0.03 g daily). Participants received successive oral daily vitamin C doses of 0.03 g, 0.06 g, 0.1 g, 0.2 g, 0.4 g, 1.0 g, and 2.5 g until a steady state was achieved for each dose. Bioavailability sampling was conducted at a steady state for vitamin C doses of 0.015 g, 0.03 g, 0.05 g, 0.1 g, 0.2 g, 0.5 g, and 1.25 g. For each bioavailability sampling, vitamin C was administered in the fasting state. After oral administration, blood samples were collected at 0, 15, and 30 minutes and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 19, 22, and 24 hours (3, 4). After intravenous administration at 250 mg/min, blood samples were collected at 0, 2.5, 5, 10, 15, and 30 minutes and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, and 10 hours. Data obtained from bioavailability samplings were used to determine peak plasma and urine vitamin C concentrations.

Pharmacokinetic Modeling

We used data from 7 men to construct a unique 3-compartment vitamin C pharmacokinetic model with parameters describing saturable absorption, tissue distribution, and renal excretion and reabsorption (14). This model was used to predict peak plasma and urine vitamin C concentrations attained when pharmacologic doses of the vitamin are administered. For intravenous administration, it was assumed that vitamin C was infused at a rate of 1 g/min, and urine output was 100 mL/h.

Vitamin C Assay

Vitamin C was measured by using high-performance liquid chromatography with coulometric electrochemical detection (3, 4, 15).

Statistical Analysis

We compared plasma vitamin C concentration curves (against either dose or time) by repeated-measures analyses of variance (ANOVA). In addition to the repeating factor (dose or time), other factors considered were sex and route of administration. In the comparison of routes of administration at multiple doses, in which sex not only was an important factor itself but also had an important interaction with route, separate ANOVA were determined for men and women to assess the importance of route of administration. Analyses were performed by using DataDesk, version 5 (1995) (Data Description, Inc., Ithaca, New York).

Role of the Funding Source

The funding source had no role in the design, conduct, and reporting of the study or in the decision to submit the manuscript for publication.

Results

When 1.25 g of vitamin C was given intravenously, plasma concentrations were significantly higher than when the vitamin was given orally (P < 0.001 by repeated-measures ANOVA) (Figure 1). In addition, plasma concentrations were significantly higher over all doses (P < 0.001 by repeated-measures ANOVA) with intravenous compared with oral administration (Figure 1, inset). At the highest dose of 1.25 g, mean peak values from intravenous administration were 6.6-fold higher than mean peak values from oral administration. When all doses were considered, peak plasma vitamin C concentrations increased with increasing intravenous doses, whereas peak plasma vitamin C concentrations seemed to plateau with increasing oral doses. Urine vitamin C concentrations were higher for the same dose given intravenously compared with that administered by the oral route. At the highest dose of 1.25 g, peak urine concentrations from intravenous administration were approximately 3.5 times higher than from oral administration (data not shown).

Figure 1. Plasma vitamin C concentrations are shown as a function of time after the 1.25-g oral or intravenous dose administered at steady state for that dose in 12 persons (3 men, 9 women). Peak plasma vitamin C concentrations as a function of dose after oral or intravenous administration of vitamin C. Seventeen persons (7 men, 10 women) received doses from 0.015 to 0.1 g, 16 persons (6 men, 10 women) received the 0.2-g dose, 14 persons (6 men, 8 women) received the 0.5-g dose, and 12 persons (3 men, 9 women) received the 1.25-g dose. Persons received each dose while at steady state for that dose. Plasma vitamin C concentrations in healthy volunteers after intravenous or oral administration of vitamin C.Inset:

The 3-compartment vitamin C pharmacokinetic model that we developed predicted that a single oral dose of 3 g, the maximum tolerated single dose, produced a peak plasma concentration of 206 µmol/L (Figure 2, top). Peak predicted concentration after a single 1.25-g oral dose was slightly lower at 187 µmol/L. For 200 mg, an amount obtained from vitamin C-rich foods, peak predicted concentration was approximately 90 µmol/L. Plasma concentrations for all of these amounts returned to steady-state values, approximately 70 to 85 µmol/L, after 24 hours. With 3 g given orally every 4 hours, the maximum tolerable (6), peak predicted plasma concentration was approximately 220 µmol/L (Figure 2, top). By contrast, after intravenous administration, predicted peak plasma vitamin C concentrations were approximately 1760 µmol/L for 3 g, 2870 µmol/L for 5 g, 5580 µmol/L for 10 g, 13 350 µmol/L for 50 g, and 15 380 µmol/L for 100 g (Figure 2, bottom). Doses of 60 g given intravenously are used for cancer treatment by complementary and alternative medicine practitioners (2). Predicted peak urine vitamin C concentrations were as much as 140-fold higher after intravenous administration compared with oral administration (data not shown).

Discussion

Our data show that vitamin C plasma concentrations are tightly controlled when the vitamin is taken orally, even at the highest tolerated amounts. By contrast, intravenous administration bypasses tight control and results in concentrations as much as 70-fold higher than those achieved by maximum oral consumption. Both findings have clinical relevance.

Vitamin C oral supplements are among the most popular sold, and gram doses are promoted for preventing and treating the common cold, managing stress, and enhancing well-being (1). Our data show that single supplement gram doses produce transient peak plasma concentrations that at most are 2- to 3-fold higher than those from vitamin C-rich foods (200 to 300 mg daily). In either case, plasma values return to similar steady-state concentrations in 24 hours. Because differences in plasma concentrations from supplements and from food intake are not large, supplements would be expected to confer little additional benefit, a finding supported by available evidence (16, 17).

However, consumption of fruits and vegetables, which contain vitamin C, is beneficial for unknown reasons (16, 17). On the basis of current knowledge and the pharmacokinetics presented here, physicians should advise their patients to consume fruits and vegetables, not vitamin C supplements, to obtain potential benefits.

Just as important, our data show that intravenous administration of vitamin C produces substantially higher plasma concentrations than can be achieved with oral administration of vitamin C. This difference was previously unrecognized and may have treatment implications. Case series published by Cameron, Campbell, and Pauling (l, 6, 7) have been controversial. In these series, several hundred patients with terminal cancer treated with 10 g of vitamin C intravenously for 10 days and then 10 g orally indefinitely were compared with more than 1000 retrospective and prospective controls. Patients treated with vitamin C survived 150 to 300 days longer than controls (1, 6, 7). Other researchers reported benefit consisting of increased survival, improved well-being, and reduced pain (1). All of these studies were uncontrolled, and factors unrelated to intervention may have affected outcome. Two randomized, double-blind, placebo-controlled studies from the Mayo Clinic found no benefit (8, 9). These studies included 200 patients who were treated with 10 g of vitamin C daily. The Mayo Clinic studies were considered to be definitive (10). However, in these studies, vitamin C was given orally, which is in contrast to the intravenous and oral use in other studies. On the basis of our pharmacokinetic data, we conclude that the Mayo Clinic studies, which used oral administration of vitamin C, are not comparable to studies with intravenous administration. The Mayo Clinic studies neither support nor refute possible effects of intravenously administered vitamin C on cancer.

Intravenous vitamin C may have a role in the treatment of cancer as a result of the plasma concentrations that can be achieved only by this route. With consumption of 5 to 9 servings of fruits and vegetables daily, steady-state plasma concentrations are 80 µmol/L or less, and peak values do not exceed 220 µmol/L, even after maximum oral administration of 3 g 6 times daily. By contrast, intravenous vitamin C may produce plasma concentrations as high as 15 000 µmol/L. At extracellular concentrations greater than 1000 µmol/L, vitamin C is toxic to cancer cells, although mechanisms and interpretation are controversial (11, 12, 18). The vitamin C free radical species, ascorbyl radical, is detectable in animals only when they receive intravenous vitamin C equivalent to a 10-g dose in humans (19). We propose that detectable ascorbyl radical forms only when human plasma concentrations are greater than 1000 µmol/L and that either the radical itself or its unpaired electron induces oxidative damage that can be repaired by normal but not cancer cells. Understanding mechanisms of cytotoxicity may further the investigational use of vitamin C in patients with cancer, used alone or with other agents that potentiate such actions (20). Although minimal data are available, intravenous vitamin C is expected to have little toxicity compared with conventional chemotherapeutic agents (3). In this context and in light of our new pharmacokinetic data, a role for intravenous vitamin C in cancer treatment should be reevaluated.

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Related Article

• Summaries for Patients: How Vitamin C Is Administered Affects How Much Reaches the Bloodstream and May Affect the Results of Studies of Its Potential Effect on Cancer Ann Intern Med April 6, 2004 140:I-61

Criteria and Recommendations for Vitamin C Intake

Mark Levine, MD; Steven C. Rumsey, PhD; Rushad Daruwala, PhD; Jae B. Park, PhD; Yaohui Wang, MD

JAMA. 1999;281:1415-1423.

Recommendations for vitamin C intake are under revision by the Food and Nutrition Board of the National Academy of Sciences. Since 1989 when the last recommended dietary allowance (RDA) of 60 mg was published, extensive biochemical, molecular, epidemiologic, and clinical data have become available. New recommendations can be based on the following 9 criteria: dietary availability, steady-state concentrations in plasma in relationship to dose, steady-state concentrations in tissues in relationship to dose, bioavailability, urine excretion, adverse effects, biochemical and molecular function in relationship to vitamin concentration, direct beneficial effects and epidemiologic observations in relationship to dose, and prevention of deficiency. We applied these criteria to the Food and Nutrition Board’s new guidelines, the Dietary Reference Intakes, which include 4 reference values. The estimated average requirement (EAR) is the amount of nutrient estimated to meet the requirement of half the healthy individuals in a life-stage and gender group. Based on an EAR of 100 mg/d of vitamin C, the RDA is proposed to be 120 mg/d. If the EAR cannot be determined, an adequate intake (AI) amount is recommended instead of an RDA. The AI was estimated to be either 200 mg/d from 5 servings of fruits and vegetables or 100 mg/d of vitamin C to prevent deficiency with a margin of safety. The final classification, the tolerable upper intake level, is the highest daily level of nutrient intake that does not pose risk or adverse health effects to almost all individuals in the population. This amount is proposed to be less than 1 g of vitamin C daily. Physicians can tell patients that 5 servings of fruits and vegetables per day may be beneficial in preventing cancer and providing sufficient vitamin C intake for healthy people, and that 1 g or more of vitamin C may have adverse consequences in some people.
Author Affiliations: Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md (Drs Levine, Rumsey, Daruwala, and Wang); Phytonutrients Laboratory, Beltsville Human Nutrition Research Center, US Department of Agriculture, Beltsville, Md (Dr Park).

Journal of the American College of Nutrition, Vol. 22, No. 1, 18-35 (2003)
Published by the American College of Nutrition

= Review Article

Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention

Sebastian J. Padayatty, MRCP, PhD, Arie Katz, MD, Yaohui Wang, MD, Peter Eck, PhD, Oran Kwon, PhD, Je-Hyuk Lee, PhD, Shenglin Chen, PhD, Christopher Corpe, PhD, Anand Dutta, BS, Sudhir K Dutta, MD, FACN and Mark Levine, MD, FACN

Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (S.J.P., A.K., Y.W., P.E., O.K., J.-H.L., S.C., C.C., M.L.), Maryland
Division of Gastroenterology, Sinai Hospital of Baltimore, University of Maryland School of Medicine, Baltimore (A.D., S.K.D.), Maryland

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.

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For more info on high dose vitamin C   see  https://weeksmd.com/?p=1786 and

Here is Linus Pauling’s  1978  article (abstract)

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Supplemental ascorbate in the supportive treatment of cancer: Reevaluation of prolongation of survival times in terminal human cancer ^*

Abstract

A study has been made of the survival times of 100 terminal cancer patients who were given supplemental ascorbate, usually 10 g/day, as part of their routine management and 1000 matched controls, similar patients who had received the same treatment except for the ascorbate. The two sets of patients were in part the same as those used in our earlier study [Cameron, E. & Pauling, L. (1976) Proc. Natl. Acad. Sci. USA 73, 3685-3689]. Tests confirm that the ascorbate-treated patients and the matched controls are representative subpopulations of the same population of “untreatable” patients. Survival times were measured not only from the date of “untreatability” but also from the precisely known date of first hospital attendance for the cancer that eventually reached the terminal stage. The ascorbate-treated patients were found to have a mean survival time about 300 days greater than that of the controls. Survival times greater than 1 yr after the date of untreatability were observed for 22% of the ascorbate-treated patients and for 0.4% of the controls. The mean survival time of these 22 ascorbate-treated patients is 2.4 yr after reaching the apparently terminal stage; 8 of the ascorbate-treated patients are still alive, with a mean survival time after untreatability of 3.5 yr.

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Moertel and Creagan  published a hachet job in 1979 ( Creagan, E. T., Moertel, C. G., O’Fallon, J. R., Schutt, A. J., O’Connell, M. J., Rubin, J. & Frytak, S. (1979) N. Engl. J. Med. 301 , 687-690.pmid:384241 )  which refuted Pauling and Cameron’s work but they did NOT honestly replicate the Pauling study  since they used ONLY oral vitamin C  -despite Pauling and Cameron publishing in their methodology that they gave patients both ORAL and IV  vitamin C.

Dr. Levin, 40 years later called them on their unethical scientific fraud, in a politically gracious manner:  “The originally reported observational studies used i.v. and oral ascorbate, but the subsequent double-blind placebo-controlled studies used only oral ascorbate. It was not recognized that the route of ascorbate administration might produce large differences in plasma concentrations.” (see https://weeksmd.com/?p=1786)

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