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Recognizing the Legitimacy of the Non-Mainstream

Posted By Thomas E. Levy, MD, JD, Thursday, November 19, 2015

To my friends and colleagues,

Attached is a rebuttal argument I put together to help a physician in responding to an action taken against him by his state medical board. After an hour or so meeting with the board, no fault was found with his therapy for the patient in question, nor with the use of vitamin C and glutathione in that patient's treatment. In accordance with this finding, no fines were levied, and no restriction was placed on his license. Some additional CME (continuing medical education) was about the only tangible recommendation that resulted.

It should be noted that this physician not only rendered excellent medical care, he had never had an action initiated against him in roughly 40 years. Furthermore, he put together a massive and, I believe, excellent written scientific defense of his course of medical care for this patient. Nevertheless, the last communication before the hearing took place seemed to focus on the vitamin C and glutathione aspect of the patient's care, as the board expert continued to press with his or her lack of awareness of "any significant uses for vitamin C and glutathione in the treatment of sepsis." 

While it is doubtful it will ever be known exactly what the board's reasoning was, it would appear that some truly objective scientific minds were part (or all?) of the committee ruling on this case. While I will not mention what state board this was, I will say that this was one state that has historically been absolutely brutal in dealing with any physicians who did not tow the mainstream party line. Maybe the hard-liners are finally disappearing, who knows. 

So, are the times a-changing? This is only one case, but it tells me that the mainstream is finally beginning to recognize the legitimacy of the non-mainstream (aka alternative, complementary, integrative). Progress by microincrementalism goes slow, but it does proceed. 

Feel free to use the reasonings and concepts in this letter for any similar cases in the future that you might encounter.
READ COMPLETE REBUTTAL

 

Best regards,

Thomas E. Levy, MD, JD

Tags:  glutathione  patient treatment  SME  vitamin c 

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Motion Sickness Medicine

Posted By Murray Susser, MD, Thursday, March 19, 2015
Motion sickness occurs in certain people when they travel, especially in a cars, trains, airplanes and boats. It’s symptoms include queasy and/or dizzy feelings and cold sweats. It also can lead to nausea and vomiting.

Motion sickness is different from Vertigo, which is often caused by an inner ear problem. Vertigo is a sensation of spinning, as if the room you are in is moving around you.  Motion Sickness, unlike Vertigo, is dependent on the person traveling, as in a car. READ MORE

Tags:  arthritis  Calcium  inner ear  magnesium  medicine  motion sickness  vertigo  Vitamin C 

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Vitamin C and Cancer Revisited

Posted By Administration, Friday, August 27, 2010
Updated: Friday, April 18, 2014

3237070041_a872337c89_oIn the issue of Proceedings of the National Academy of Sciences of the United States of America (PNAS), Chen et al. (1) it shows that i.p. injection of “pharmacologic doses” of vitamin C decreases the growth and weight of human, rat, and murine tumor xenografts in athymic, nude mice. This work follows a number of articles by the same group, led by Mark Levine at the National Institute of Diabetes and Digestive and Kidney Diseases, showing that millimolar concentrations of extracellular vitamin C kill cancer cells but not normal cells in a hydrogen peroxide (H2O2)-dependent manner (1–3). Such millimolar concentrations of vitamin C can be achieved in humans by i.v. infusion but not by diet or supplements (4). Hence, vitamin C is postulated to exert local pro-oxidant effects in the interstitial fluid surrounding tumor cells, killing them or inhibiting their growth, while leaving normal cells intact (1–3). 

It is well known that vitamin C, or ascorbic acid, is an effective biologic antioxidant and does not act as a pro-oxidant under normal conditions (5) because it does not readily autoxidize, i.e., react with oxygen (O2) to produce reactive oxygen species, such as superoxide radicals (O2•−) or H2O2. However, ascorbate readily donates an electron to redox-active transition metal ions, such as cupric (Cu2+) or ferric (Fe3+) ions, reducing them to cuprous (Cu+) and ferrous (Fe2+) ions, respectively (Reaction 1). In fact, reduction of copper or iron in the catalytic site of certain enzymes underlies ascorbate's well known biologic function as a co-substrate in procollagen, carnitine, and catecholamine biosynthesis (6). Reduced transition metal ions, in contrast to ascorbic acid, readily react with O2, reducing it to superoxide radicals (Reaction 2), which in turn dismutate to form H2O2 and O2 (Reaction 3): 

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The H2O2 produced this way (Reactions 1–3) seems to be key to ascorbate's antitumor effect because H2O2 causes cancer cells to undergo apoptosis, pyknosis, and necrosis (2). In contrast, normal cells are considerably less vulnerable to H2O2. The reason for the increased sensitivity of tumor cells to H2O2 is not clear but may be due to lower antioxidant defenses (7). In fact, a lower capacity to destroy H2O2—e.g., by catalase, peroxiredoxins, and GSH peroxidases—may cause tumor cells to grow and proliferate more rapidly than normal cells in response to low concentrations of H2O2. It is well known that H2O2 exerts dose-dependent effects on cell function, from growth stimulation at very low concentrations to growth arrest, apoptosis, and eventually necrosis as H2O2 concentrations increase (8). This dose-dependency may be shifted to the left in tumor cells, making them more sensitive to both the growth stimulatory and cytotoxic effects of H2O2. Whatever the exact mechanism, the increased sensitivity of tumor cells to killing by H2O2 may provide the specificity and “therapeutic window” for the antitumor effect of extracellular ascorbate (1, 2). 

 


Millimolar concentrations of extracellular vitamin C kill cancer cells but not normal cells. 

The chemical reactions linking ascorbate to H2O2, as explained above (Reactions 1–3), require a redox-active transition metal—without it, ascorbate cannot exert pro-oxidant effects. Chen et al. (2) speculate that there is an extracellular “metalloprotein catalyst” of between 10 and 30 kDa in size that interacts with ascorbate. Identification of this metal-containing protein will be critical because it seems to be the cause for millimolar concentrations of ascorbate to act as a pro-oxidant in interstitial fluid. In contrast, the protein must be absent or inactive in blood, otherwise ascorbate would become oxidized to the ascorbyl radical or be unstable, which is not observed (1). If this putative metalloprotein can be identified and characterized, it may serve as an additional target for anticancer therapy. For example, other naturally occurring reducing agents, such as certain flavonoids or thiol compounds, may be particularly effective in reducing the protein's metal center, or drugs may be developed specifically targeting this center. 

Although Chen et al. (1) provide no direct evidence for the existence of the metalloprotein or the formation of reduced transition metal ions by extracellular ascorbate, they measure the other reaction product formed between ascorbate and the putative metal center, i.e., the ascorbyl radical (Reaction 1). They show formation of this radical in a time-dependent and ascorbate-dose-dependent manner in interstitial fluid of tissues, including tumor xenografts, but not in blood (1, 3). They also show that the concentration of the ascorbyl radical correlates with the concentration of H2O2 in interstitial fluid, whereas no H2O2 can be detected in blood or plasma (3, 9). These observations, combined with the inhibitory effect on xenograft growth, provide the proof of concept that millimolar concentrations of extracellular ascorbate, achievable by i.p. injection or i.v. infusion in experimental animals and humans, respectively, exert pro-oxidant, antitumor effects in vivo

PERSPECTIVE 

Why is it important to understand how vitamin C can produce H2O2 and kill cancer cells but not normal cells? Because without this detailed knowledge, we do not have a scientific rationale to revisit the question of whether i.v. infusion of vitamin C may have value in treating cancer patients. The potential cancer-therapeutic activity of vitamin C has a long and controversial history. In 1973, Linus Pauling and Ewan Cameron (10) postulated that vitamin C inhibits tumor growth by enhancing immune response and stabilizing glycosaminoglycans of the extracellular matrix by inhibiting hyaluronidase. Cameron and Campbell (11) reported on the response of 50 consecutive patients with advanced cancer to continuous i.v. infusions (5–45 g/d) and/or oral doses (5–20 g/d) of vitamin C. No or minimal response was observed in 27 patients; 19 patients exhibited tumor retardation, cytostasis, or regression; and 4 patients experienced tumor hemorrhage and necrosis. The first clinical study by Cameron and Pauling (12) compared survival times between 100 patients with terminal cancer treated with i.v. and oral vitamin C, usually 10 g/d, and 1,000 comparable patients not given vitamin C. Patients treated with vitamin C survived approximately four times longer than controls, with a high degree of statistical significance (P < 0.0001). A follow-up study reported that patients given vitamin C had a mean survival time almost 1 year longer than matched controls (13). Overall, 22% of vitamin C-treated patients but only 0.4% of controls survived for more than 1 year. 

The National Cancer Institute sponsored two randomized, placebo-controlled, double-blind trials of vitamin C and advanced cancer at the Mayo Clinic (14, 15). In both trials, patients were given 10 g/d vitamin C or placebo. Survival rates were essentially the same for all groups. Plasma concentrations of vitamin C were not measured in either study, and vitamin C was given only orally. In retrospect, the Mayo Clinic trials may have failed to properly evaluate the clinical efficacy of vitamin C in cancer because of insufficient plasma concentrations of vitamin C attained with oral supplementation (4). 

Pauling and colleagues (16) emphasized host resistance to cancer but recognized the anticancer role of redox chemistry, especially reactive oxygen species formed from the reaction of vitamin C with copper. When mice were inoculated with Ehrlich tumor cells and injected i.p. with the copper-containing tripeptide copper:glycylglycylhistidine (Cu:GGH) and vitamin C, 40% survived 60 days, whereas no controls survived for longer than 30 days. The combination of Cu:GGH and vitamin C was also toxic to Ehrlich tumor cells in vitro, but the cytotoxicity was abrogated by catalase, suggesting that H2O2 was the cytotoxic species. The work of Chen et al. (1–3) also strongly suggests that H2O2 is responsible for the anticancer activity of vitamin C. 

Interestingly, Chen et al. (1) noted that metastases were present in ≈30% of athymic mice grafted with glioblastoma tumors, whereas no metastases were detected in similar mice injected i.p. with ascorbate. This observation warrants further investigation because metastases account for a substantial percentage of cancer mortality.   

RECENT CLINICAL STUDIES 

Two Phase 1 clinical trials of cancer and vitamin C have recently been published that demonstrated remarkable tolerance and safety for high-dose (up to 1.5 g/kg) i.v. vitamin C in patients screened to eliminate hyperoxaluria, glucose-6-phosphate dehydrogenase deficiency, and other medical conditions (17, 18). Additionally, a series of case reports indicated that high-dose i.v. vitamin C was associated with long-term tumor regression in three patients with advanced renal cell carcinoma, bladder carcinoma, or B-cell lymphoma (19). Clinical plausibility has been repeatedly suggested, and Chen et al. (1–3) now have convincingly demonstrated biologic plausibility and are poised to explore the potential value of “pharmacologic ascorbate in cancer treatment” in humans. 

FOOTNOTES 

The authors declare no conflict of interest. See companion article on page 11105. 

REFERENCES 

1. Chen Q, et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci USA. 2008;105:11105–11109. [PMC free article] [PubMed] 

2. Chen Q, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci USA. 2005;102:13604–13609. [PMC free article] [PubMed] 

3. Chen Q, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci USA. 2007;104:8749–8754. [PMC free article] [PubMed] 

4. Padayatty SJ, et al. Vitamin C pharmacokinetics: Implications for oral and intravenous use. Ann Intern Med. 2004;140:533–537. [PubMed] 

5. Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 1999;13:1007–1024. [PubMed] 

6. Englard S, Seifter S. The biochemical functions of ascorbic acid. Annu Rev Nutr. 1986;6:365–406. [PubMed] 

7. Oberley TD, Oberley LW. Antioxidant enzyme levels in cancer. Histol Histopathol. 1997;12:525–535. [PubMed] 

8. Davies KJ. The broad spectrum of responses to oxidants in proliferating cells: A new paradigm for oxidative stress. IUBMB Life. 1999;48:41–47. [PubMed] 

9. Frei B, Yamamoto Y, Niclas D, Ames BN. Evaluation of an isoluminol chemiluminescence assay for the detection of hydroperoxides in human blood plasma. Anal Biochem. 1988;175:120–130. [PubMed] 

10. Cameron E, Pauling L. Ascorbic acid and the glycosaminoglycans. Oncology. 1973;27:181–192. [PubMed] 

11. Cameron E, Campbell A. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem-Biol Interact. 1974;9:285–315. [PubMed] 

12. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA. 1976;73:3685–3689. [PMC free article] [PubMed] 

13. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA. 1978;75:4538–4542. [PMC free article] [PubMed] 

14. Creagan ET, et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med. 1979;301:687–690. [PubMed] 

15. Moertel CG, et al. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy: A randomized double-blind comparison. N Engl J Med. 1985;312:137–141. [PubMed] 

16. Kimoto E, Tanaka H, Gyotoku J, Morishige F, Pauling L. Enhancement of antitumor activity of ascorbate against Ehrlich ascites tumor cells by the copper:glycylglycylhistidine complex. Cancer Res. 1983;43:824–828. [PubMed] 

17. Riordan HD, et al. A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. PR Health Sci J. 2005;24:269–276. 

18. Hoffer LJ, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. 2008 doi: 10.1093/annonc/mdn 377. [Cross Ref] 

19. Padayatty SJ, et al. Intravenously administered vitamin C as cancer therapy: Three cases. Can Med Assoc J. 2006;174:937–942. [PMC free article] [PubMed]

Source: Frei, Balz. Lawson, Stephen. Linus Pauling Institute, Oregon State University, Corvallis, OR 97331. Proc Natl Acad Sci U S A. 2008 August 12; 105(32): 11037–11038. Published online 2008 August 5. doi: 10.1073/pnas.0806433105. 

Tags:  cancer  vitamin C 

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Vitamin C: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects

Posted By Administration, Monday, July 12, 2010
Updated: Friday, April 18, 2014

Abstract 

Background: Anecdotal information and case reports suggest that intravenously administered vitamin C is used by Complementary and Alternate Medicine (CAM) practitioners. The scale of such use in the U.S. and associated side effects are unknown. 

Methods and Findings: We surveyed attendees at annual CAM Conferences in 2006 and 2008, and determined sales of intravenous vitamin C by major U.S. manufacturers/distributors. We also queried practitioners for side effects, compiled published cases, and analyzed FDA’s Adverse Events Database. Of 199 survey respondents (out of 550), 172 practitioners administered IV vitamin C to 11,233 patients in 2006 and 8876 patients in 2008. Average dose was 28 grams every 4 days, with 22 total treatments per patient. Estimated yearly doses used (as 25g/50ml vials) were 318,539 in 2006 and 354,647 in 2008. Manufacturers’ yearly sales were 750,000 and 855,000 vials, respectively. Common reasons for treatment included infection, cancer, and fatigue. Of 9,328 patients for whom data is available, 101 had side effects, mostly minor, including lethargy/fatigue in 59 patients, change in mental status in 21 patients and vein irritation/phlebitis in 6 patients. Publications documented serious adverse events, including 2 deaths in patients known to be at risk for IV vitamin C. Due to confounding causes, the FDA Adverse Events Database was uninformative. Total numbers of patients treated in the US with high dose vitamin C cannot be accurately estimated from this study. 

Conclusions: High dose IV vitamin C is in unexpectedly wide use by CAM practitioners. Other than the known complications of IV vitamin C in those with renal impairment or glucose 6 phosphate dehydrogenase deficiency, high dose intravenous vitamin C appears to be remarkably safe. Physicians should inquire about IV vitamin C use in patients with cancer, chronic, untreatable, or intractable conditions and be observant of unexpected harm, drug interactions,orbenefit.

 

Introduction 

Among the most enduring of alternative medical treatments, vitamin C (ascorbic acid, ascorbate) is also one of the most popular. In 2007, it was the most widely sold single vitamin, with sales of 884 million dollars in the US1 [1]. Independent of its use to treat the deficiency disease scurvy, vitamin C has been used by non- mainstream physicians orally and parenterally for more than 60 years as a therapeutic agent [2–7]. Oral vitamin C is widely used by the public to prevent or treat infections, especially the common cold [8]. In one of its more controversial applications, gram doses of vitamin C were promoted by the two-time Nobel Laureate Linus Pauling as a cancer treatment agent [9,10]. Anecdotal evidence led us to posit that intravenous (IV) vitamin C is still used by Complementary and Alternative Medicine (CAM) practitioners to treat diverse conditions including infections, autoimmune diseases, cancer and illnesses of uncertain origin [11–13]. 

Despite its purported popularity, the extent of use of IV vitamin C is unknown. Its use in CAM has not been well publicized by practitioners and their patients, and is likely to be unrecognized by mainstream physicians. Benefits if any and especially side effects of such use may be unreported or under-reported. It is useful to know if high dose IV vitamin C therapy is widely used, and if so how and for what, so that conventional physicians can improve patient care by identifying any ill effects or drug interactions, and reporting benefit if any. 

New knowledge has elucidated possible mechanisms of action of IV vitamin C and for the first time made therapeutic effects biologically plausible [14]. It is now known that IV but not oral administration of vitamin C produces pharmacologic plasma concentrations of the vitamin [15,16]. Past studies used oral and/ or IV routes inconsistently, making such studies, in retrospect, flawed and difficult to interpret [17]. Recent in vitro experiments indicated that vitamin C only in pharmacologic concentrations killed cancer cells but not normal cells, and that the mechanism was via hydrogen peroxide formation [18]. In vivo animal data indicated that hydrogen peroxide was produced selectively in extracellular fluid around normal and tumor tissues by pharma- cologic vitamin C concentrations [19,20]. At these concentrations, vitamin C slowed tumor growth [20,21]. Pharmacologic vitamin C concentrations produced in animals by parenteral administration were reproduced in patients in a recent phase I clinical trial [16]. 

Because of the new interest in IV vitamin C, coupled to need to characterize use and uncover side effects, we surveyed CAM practitioners anonymously. We also searched for side effects of IV vitamin C administration in the published medical literature and in the Food and Drug Administration (FDA) adverse events database, and estimated sales volumes of IV vitamin C preparations. 

Our study obtained quantitative information that substantiated previous anecdotal reports. Despite unexpected wide use, we found side effects of vitamin C were surprisingly few when patients were properly screened. The findings in this paper will alert conventional practitioners about unrecognized wide use of IV vitamin C, will remind them to query patients about such use, and may help to uncover either unexpected adverse events or benefit and spur further research in this area. 

 


Methods 

Survey Methods 

The study was reviewed by the Human Subjects Committee/ Institutional Review Board at the University of Kansas Medical Center. The survey was categorized as an exempt study. It contained no personal identifiers; therefore informed consent was not necessary under exempt status and was not obtained. Survey forms were distributed to practitioners attending a conference on CAM in 2006 and 2008. Participants were requested to return completed survey forms before the end of each conference. Participants were asked whether they used high dose IV vitamin C during the preceding 12 months, and if so, to detail its use by answering specific questions in the survey form (see Survey S1 for the survey form used). It was not possible to identify the respondent from the survey form or survey data. The same form was used in both years, with an additional line on the 2008 form inquiring whether the respondent had also responded in 2006 (See Survey S1). 

Vitamin C doses sold 

The major manufacturers/importers in the US of vitamin C preparations that can be administered IV were contacted by telephone. Data on annual sales of vitamin C in the US were obtained with the understanding that the names and sales figures of individual companies would not be linked nor made public. 

Side effects of high dose IV vitamin C

We searched the Adverse Events Reporting System, a database of drug side effects maintained by the Food and Drug Administration (FDA). Data from 20 consecutive quarters available from 2004–2008 were queried. We also searched for side effects in publications on therapeutic use of high dose IV vitamin C. We searched Medline, Web of Science (ISI Thompson) and Scopus databases for papers in English that reported IV vitamin C administration in humans. Several different search terms and possible variants of each search term were used to capture the maximum number of papers. Papers reporting oral vitamin C treatment only, or those using IV doses of 1g or less, were excluded. Because vitamin C is sometimes administered IV in patients undergoing hemodialysis, there are many published studies in this area. A separate search was conducted for papers reporting these to ensure that these were excluded from our analysis. IV administered vitamin C is also used to study the acute effects of antioxidants or of vitamin C itself on metabolism and physiology, particularly on cardiovascular and endothelial reac- tivity. This does not constitute a therapeutic use of vitamin C. Hence publications reporting these were identified and removed from the search results. Separately, we searched the same databases for specific reports of side effects of IV administered vitamin C and followed up references and cited papers. From papers so collected, we manually eliminated duplicate citations and those that did not meet the above criteria. From the remaining reports, adverse reactions attributable to IV adminis- tered vitamin C were noted. 

Results 

Survey response 

We distributed 300 survey forms in 2006 to attendees at their annual CAM conference. 106 forms were returned, a response rate of 35%. In 2008, 250 survey forms were distributed and 93 completed forms were returned, a response rate of 37%. Of the 2008 respondents, 22 (24%) had previously responded in 2006. An unknown number of conference attendees were not practitioners but spouses, researchers or industry representatives who did not return survey forms, reducing response rates. 

Vitamin C usage 

Of 199 total respondents for 2006 and 2008: 172 practitioners administered vitamin C; 27 did not use IV Vitamin C; 48 practitioners treated more than 100 patients each per year; and 5 treated more than 1000 patients each per year (Figure 1A, B). 11,233 patients received IV vitamin C in 2006 and 8876 in 2008 (figure 1A, B). On average, each patient received 22 treatments (Table 1). Treatments occurred at a mean of once every 4 days, each at a mean dose of 28 grams (Table 1). Doses used were as low as 1gram or as high as 200grams, with a similar wide range for each of the parameters queried. Based on dosing vials of 25g/ 50ml, estimated total yearly dosing vials administered were 318,539 in 2006 and 354,647 in 2008. Estimated total number of dosing vials sold was independently obtained from the major manufacturers of vitamin C in the U.S. Total dosing vials of IV vitamin C sold in the United States were approximately 750,000 in 2006 and 855,000 in 2008 (Table 1). 

Seventy seven percent of respondents reported the numbers of patients treated for broad indications, labeled as infection (44%), cancer (19%) or other conditions (37%) (Table 2). Numbers of practitioners who listed specific indications for treatment are shown in figure 2. Practitioners listed fatigue as the most common specific single indication for treatment in 2006, and breast cancer in 2008. There were a large number of indications for which less than four practitioners used high dose IV vitamin C (Table S1). 

Adverse effects 

Adverse events reported by survey respondents were minor (Table 3). No side effects were reported for 9227 patients while 59 were reported to have lethargy or fatigue. A single practitioner listed change in mental status in 10% of his patients (20 patients) but provided no details. One patient with pre existing renal impairment and cancer metastases to kidneys was reported to have developed unconfirmed renal failure. Some practitioners reported side effects without reporting patient numbers. The most common of these side effects were lethargy or fatigue (reported by 27 practitioners), vein irritation (by 9 practitioners), and nausea and vomiting (by 9 practitioners). Other reported side effects are listed in table 3. Less commonly reported adverse effects are listed in Table S2. 

Data obtained from the FDA Adverse Events Reporting System database for 20 consecutive quarters indicated that 77 patients treated with 0.2–1.0 gram doses of IV vitamin C had reported adverse events (Table 4). However, all patients either had serious or life-threatening systemic illnesses, and/or were receiving many potentially toxic drugs (i.e. cancer therapeutics) in addition to IV vitamin C (for details, see Table S3). Some individual patients appear to have been reported multiple times (see Table S3). In comparison to CAM practitioners, the dose of vitamin C administered was very low (1 gram or less). In no case could we exclude multiple confounding factors as the cause of the reported adverse effects (Table 4). Whether vitamin C caused or contributed to these side effects cannot be determined from the available data. 

Through searching published literature (see methods for details), 187 papers were found on the use of high dose IV vitamin C, including papers that reported side effects. There were three cases of renal failure, all in patients with pre existing renal impairment [22,23], [24]. Two patients with glucose 6 phosphate dehydroge- nase deficiency developed hemolysis [25,26] (Table 5). 

Practitioner Demographics 

86% of practitioners were physicians (Table 6) and most patients were treated at for-profit centers. Some practitioners did not provide requested demographics data. Therefore, the numbers given in this table do not tally with the total number of survey respondents. (For detailed demographic information, see Table S4).

Table 1. Details of high dose IV vitamin C use by survey respondents for the years 2006 and 2008. 

2006

 

                                                                                                                      Mean Median Range

Dose (g/treatment)                                                                 28    31       1-200

Number of treatments per patient                                                19    16       1-80

Number treated by one practitioner                                              121    40       1-1150

Duration of treatments (min)                                                      105    90       2-1440

Frequency of treatments (once every so many days)                           4     3.5       1-7

Lowest dose (g/treatment)                                                         12    9       1-60

Highest dose (g/treatment)                                                         79    75       5-200

Infusion rate (g/min)                                                                0.89    0.5     0.03-25

Total number of vials of vitamin C used (25g/50ml) (Calculated from survey data)       318,539

Total number of vials of vitamin C sold by companies in the US (25g/50 ml)               750,000

2008

                                                                                                                         Mean Median Range

 

Dose (g/treatment)                                                                                          28    50       1-200

Number of treatments per patient                                       24    16       1-80                

Number treated by one practitioner                                                               112    40       1-3000

Duration of treatments (min)                                                                         81    90       1-900

Frequency of treatments (once every so many days)                                      4      2       1-7

Lowest dose (g/treatment)                                                                             17    15       1-75

 

Highest dose (g/treatment)                                                                            87    95       20-200

Infusion rate (g/min)                                                                                      0.525  0.5    0.028-2.5        

Total number of vials of vitamin C used (25g/50ml) (Calculated from survey data)     354,647 

Total number of vials of vitamin C sold by companies in the US (25g/50 ml)          855,000 

Vitamin C is supplied in 50 ml bottles containing 25 grams. Estimated total number of doses (bottles) used each year was calculated as the cumulative sum of each practitioners’ number of patients that practitioners’ average dose in bottles that practitioner’s average number of doses per patient. doi:10.1371/journal.pone.0011414.t001

 

 

Table 2.Indications for treatment with high dose IV vitamin C. 

 

 

 

 

Year                                                                                                        2006     2008

Total number of patients treated                                                          11233    8876

 

Number of patients with data available                             9481      5928

Number of patients with          Infection                                  4587      2264

                              Cancer                              1379     1509

                              Other Conditions                   3515     2155

 

 

 

 

 

Some respondents did not list the number of patients treated for each of the 

 

 

 

conditions for which they used intravenous vitamin C treatment. Therefore, the 

 

 

 

data do not provide indications for treatment for all patients who received IV 

 

 

 

vitamin C. 

 

 

 

doi:10.1371/journal.pone.0011414.t002

 

 

Discussion 

The data here show that 11,233 and 8876 patients received IV vitamin C over two periods of one year each, with a mean number of infusions per patient of 19–24 and a mean dose of approximately 28 grams per patient. We estimate that survey respondents used approximately 318,539 and 354,647 dosing units of vitamin C each year. These numbers account for less than half of the doses of vitamin C doses sold within the United States for the matching year. Considered together, these data indicate that use of IV vitamin C was both substantial and probably underestimated. This is one of the first papers to document previously unrecognized and widespread use of a CAM agent administered IV. To our knowledge, only two other CAM therapies are used IV. The first, chelation therapy, is also used in standard medical practice [27]. The second, an IV vitamin and mineral mixture termed the Myer’s cocktail, has variable components, has had little formal investigation, and contains less than 5 grams of vitamin C [28,29]. Further, there have been few surveys of CAM practitioners, as opposed to surveys of patients. There were minimal adverse effects reported, which was also the case in the published literature. Exceptions were for patients with pre-existing renal insufficiency/failure or glucose 6-phosphate dehydrogenase (G6PD) deficiency, both known to predispose to vitamin C toxicity [30]. Adverse events reported to the FDA could not be interpreted due to confounding factors. 

Table 3. Adverse events reported with IV vitamin C use in the survey for the years 2006 and 2008.

                                                                                                              # of Patients

 

Complication                                                                                         2006   2008 

None Described                                                   5349   3878 

Lethargy/Fatigue                                                 10       49 

Local Vein Irritation                                                3        - 

Phlebitis                                                           3        - 

Kidney Stone (oxalate)                                             -         1 

Kidney Stone (urate)                                               -         1 

Kidney Stone (unspecified)                                         2         - 

Hemolysis                                                         2         - 

Elevated Blood Glucose                                            2         - 

Muscle Cramps                                                                 1         - 

Headache                                                         1        - 

Change in Mental Status                                           1       20 

Nausea/Vomiting                                                  1       - 

Flu Like Syndrome                                                 1        - 

Renal Failure                                                                   -         1* 

Syncope                                                                         -         1 

Pain at Tumor                                                     -         1 

No Data                                                                        5857      4924 

Data included in the table represent only those practitioners who reported exact patient numbers. *Described as ‘‘not confirmed (possible). Patient had partial renal failure and cancer metastases to kidneys.’’ Data on practitioners who reported adverse events but did not report the number of patients affected are detailed below as: side effect (with the number of practitioners who reported each side effect in parenthesis). For the year 2006: lethargy/fatigue (9), local vein irritation (3), nausea/vomiting (2), hypoglycemia (2), allergy (2), phlebitis (1), cellulitis (1), hematuria (1), dry mouth (1), Herxheimer reaction (1), localized thrombosis (1), and syncope (1). For the year 2008: lethargy/fatigue (9), nausea/vomiting (6), local vein irritation (4), headache (3), phlebitis (3), heartburn (1), dizziness (1), venosclerosis (1), mild palpitation (1), and cold (1), dizziness (1), ‘‘initiation of mem occasionally’’ (1), and other (1). doi:10.1371/journal.pone.0011414.t003

Soon after its discovery and synthesis in 1932, parenteral vitamin C was shown to significantly decrease polio virus infections in primates [31,32]. Although these findings were not repeatable [33,34], one practitioner treated thousands of patients with parenteral vitamin C, primarily for infections, and popular- ized its use [2,3,5]. Such reports probably were a basis for continued use of parenteral vitamin C by other CAM practitioners [6,7,35]. Independently, others postulated that vitamin C could be useful in cancer treatment by enhancing or strengthening collagen and intercellular matrix synthesis and thereby decreasing metas- tases [36,37]. Ewan Cameron, joined by Nobelist Linus Pauling, reported in retrospective case series that oral and IV vitamin C might benefit patients with advanced cancers [9,10]. Placebo- controlled double blinded clinical trials at the Mayo Clinic showed no efficacy [38–40] but CAM practitioners continued to use IV vitamin C [11,13,35], consistent with our survey results. Pharmacokinetics evidence [15,41,42] now reveals that the exclusively oral vitamin C doses used in the Mayo studies would have produced peak plasma concentrations of approximately 0.2 mM, while the same dose given IV would produce peak plasma concentrations approximately 25 fold higher [15].  

Table 4.Adverse effects reported to the Food and Drug Administration (FDA) in patients treated with IV vitamin C. 

 

Year      Number of Cases reported        Dose Range(g/day)        Can confounders be eliminated? 

2004       15                                              0.5–1                               No 

2005       7                                                0.25–1                             No 

2006      11                                               0.2–1                               No 

2007      11                                              Not Given                         No 

2008      33                                               0.5–1                               No 

 

When the vitamin C dose was provided as ml, the dose was converted to mg on the basis that vitamin C is supplied as 0.5gram/ml solution. Some practitioners did not mention the dose of vitamin C used. The format of the FDA adverse events database did not permit identification of specific patients, so that the same patient may have been reported multiple times in the same quarter or in several quarters, inflating the number of patients with adverse events. doi:10.1371/journal.pone.0011414.t004 

 

 

Pharmacologic doses of vitamin C given IV may produce drug effects in many body tissues, mediated by hydrogen peroxide formation in extracellular fluid but not blood [18–20]. Emerging clinical data are consistent with plausibility [43] and safety [16], but whether there is benefit or harm in humans can only be addressed by rigorous clinical trials. 

IV vitamin C administered in gram doses can cause serious side effects in some patients. A metabolic end-product of vitamin C metabolism is oxalate, and oxalate nephropathy has been reported in patients with renal impairment given gram doses of IV vitamin C [22–24]. Prolonged treatment with vitamin C increases plasma oxalate concentrations in patients with renal failure [44] and results in increased urinary oxalate in patients receiving total parenteral nutrition [45], although in these patient groups the consequences of hyperoxalemia are unknown. Patients with glucose 6-phosphate dehydrogenase deficiency can develop intravascular hemolysis when gram doses of vitamin C are given IV [25,26]. Vitamin C, even with oral dosing, might induce hemolysis in patients with Paroxysmal Nocturnal Hemoglobinuria [46,47]. A recent phase one study of high dose IV vitamin C in patients with advanced cancer did not find any serious side effects [16]. Exclusion criteria for the phase I study included renal failure and glucose-6-phosphate dehydrogenase deficiency. Recently, a study in mice reported decreased efficacy of cancer chemother- apeutic agents with parenteral dehydroascorbic acid, a metabolite of vitamin C [48]. Dehydroascorbic acid cannot be detected in human blood or tissues, is not commercially available for parenteral use nor used by CAM practitioners, is toxic at high concentrations [49,50], and should not be administered parenterally in humans. 

No definitive serious adverse events were reported by survey respondents. Despite the anonymity of the survey, practitioners may have been reluctant to describe adverse events. Whether IV vitamin C is safe for general use remains to be determined. Because of the possibility of unrecognized side effects or of drug interactions, practitioners should enquire whether their patients, especially those with chronic, intractable or difficult to treat conditions, are receiving high dose IV vitamin C treatment elsewhere. Physicians should be alert to potential interactions of high dose vitamin C not only with conventional medicines but also with CAM treatments. An example is the case of exacerbated, severe cyanide poisoning in a patient on concurrent treatment with high dose oral vitamin C and Amygdalin (laetrile, a metabolic product of which is cyanide) [51]. 

Our study has limitations that, when considered together, may underestimate use of IV vitamin C. Because our survey was distributed to participants in a CAM conference, the survey excluded the vast majority of CAM practitioners. Respondents who filled in the survey form did so from memory without access to records, so that the information obtained can only be considered approximate. The format of the survey questions may have inadvertently resulted in underestimating vitamin C use, because the survey questions used ranges, for simplicity. For example, the highest value listed for numbers of patients treated in a calendar year was ‘‘>40’’. If practitioners did not specify precise numbers as requested in subsequent questions, 40 was used as the number of patients treated, although the true number may have been higher. That there was only 24% overlap between survey respondents in 2006 and 2008 provides additional evidence that community use of IV vitamin C was underestimated. Data concerning industry sales of IV ascorbate only give approxima- tions of use. On one hand, because not all units sold would have been used, use may be overestimated. Conversely, other smaller companies and compounding pharmacies may supply parenteral vitamin C but were not included in the survey. Therefore, the total number of vials sold may also be underestimated. The exact number of doses of parenteral vitamin C used in the US per year remains unknown. The survey response rate of approx 35% suggests we underestimated use, and perhaps adverse events. A reduced response rate may have occurred because some conference attendees were not practitioners and therefore did not return survey forms. Because of these uncertainties, the number of US patients treated with IV vitamin C cannot be accurately estimated from survey data. Since a primary aim of the survey was to determine if IV administered vitamin C is in use, and not a census of patients treated, the response rate does not detract from the value of the data. 

Data obtained on adverse effects from PUBMED and the FDA also have limitations. Physicians may have not reported compli- cations because they were not recognized, or were delayed, or were not attributed to vitamin C. Most practitioners do not report or publish adverse events. There may be as yet unknown adverse effects or interactions of IV ascorbate with other drugs. Side effects reported to FDA are difficult to interpret because of confounding factors. All reported patients received other potentially toxic drugs and/or had other diagnoses that may have been responsible for the reported adverse effects (see Table S3). Because of the FDA adverse events format, the same patient was likely to have been reported multiple times. Because of the low doses of IV vitamin C in the FDA dataset, it is highly unlikely that any of the reported adverse effects were due to the vitamin. Despite this, and because the information available in the FDA database is limited, it is not possible to accurately determine whether vitamin C caused or contributed to the reported side effects. 

IV vitamin C is already in wide use, and physicians should know that their patients may seek IV vitamin C treatment in addition to conventional therapies. Beneficial effects of intravenous vitamin C on the disease conditions for which it is used are unproven, but side effects appear to be minor. Physicians should be cognizant of potential adverse or other unexpected effects, and of unrecognized interactions with drugs used in conventional and alternative medicine. CAM practitioners have an obligation to screen patients and should not administer high dose IV vitamin C to patients with pre existing renal disease, renal insufficiency or renal failure; glucose 6-phosphate dehydrogenase deficiency; a history of oxalate nephrolithiasis; or paroxysmal nocturnal hemoglobinuria. Based on emerging evidence, vitamin C in pharmacologic concentrations appears to be a pro-drug for delivery of hydrogen peroxide to the extravascular space. High dose IV vitamin C appears to have a positive safety profile, favorable pharmacology, evidence for mechanism of action, some anti-cancer effects in vitro and in animals, and widespread use outside conventional medicine with minimal harm, but without any proven clinical benefit. 

Supporting Information 

Table S1 

Found at: doi:10.1371/journal.pone.0011414.s001 (0.18 MB DOC) 

Table S2 

Found at: doi:10.1371/journal.pone.0011414.s002 (0.05 MB DOC) 

Table S3 

Found at: doi:10.1371/journal.pone.0011414.s003 (0.17 MB DOC) 

Table S4 

Found at: doi:10.1371/journal.pone.0011414.s004 (0.04 MB DOC) 

Survey S1 Survey Form 

Found at: doi:10.1371/journal.pone.0011414.s005 (0.05 MB DOC) 

Acknowledgments 

We thank CAM practitioners for their cooperation in completing the surveys, and Dr. Jill Norris, University of Colorado Health Sciences Center, for advice on preparing the survey. 

Author Contributions 

Conceived and designed the experiments: SJP AYS QC MGE JD ML. Performed the experiments: SJP AYS QC MGE JD ML. Analyzed the data: SJP AYS QC MGE JD ML. Contributed reagents/materials/analysis tools: SJP AYS QC MGE JD ML. Wrote the paper: SJP AYS QC MGE JD ML.

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Source: Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, et al. (2010) Vitamin C: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects. PLoS ONE 5(7): e11414. doi:10.1371/journal.pone.0011414. Editor:Joel Joseph Gagnier, University of Michigan, Canada. ReceivedFebruary 23, 2010;AcceptedMay 30, 2010;PublishedJuly 7, 2010. 

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