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From the Townsend Letter
December 2011

Open Letter to Integrative Medicine Friends and Colleagues: Prediction of Adverse Effects when Combining Intravenous Vitamin C with Intravenous Glutathione on the Same Day in Cancer Patients
by Jeanne A. Drisko, MD; Garrett G. Sullivan, MD; Qi Chen, PhD*
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Thank you to all who participated in our intravenous (IV) vitamin C/ascorbic acid (AA) surveys in 2006, 2008, and 2011. Your voice has helped advance IV AA research.

By way of background, Levine and colleagues found that when IV AA is given, it bypasses tight-control and pharmacologic plasma levels are attained in millimolar ranges.1 This is in contrast to oral vitamin C, wherein plasma levels are tightly controlled and plasma AA levels reach only micromolar concentrations. No amount or particular form of oral vitamin C preparation will increase the plasma AA levels beyond micromolar levels like IV AA, and at these concentrations, oral vitamin C is an antioxidant. Our team has also shown that IV AA is a prooxidative therapy and does not act as an antioxidant when administered intravenously.2-4

Chen and colleagues have demonstrated that IV AA is a pro-drug for hydrogen peroxide and the conversion occurs in the extracellular space through oxidative reactions.2-4 Hydrogen peroxide promotes neoplastic cell death but leaves normal cells unharmed. These findings have been validated by independent labs.5-9 Because of these findings and other information from our collaborating labs at the NIH and the University of Kansas Medical Center, we became quite interested in how IV AA was being used by you, our integrative colleagues.

Our surveys were distributed at the American College for the Advancement in Medicine (ACAM) meetings first in 2006 and again in 2008. These data were very informative and the results were published in 2010.10 Because of the rich and varied experiences of our survey respondents, we learned how often IV AA was given to how many patients, on average what dose of IV AA was given per infusion, and for what conditions practitioners gave the infusions. What was remarkable from these data was the finding that IV AA administered at high doses was remarkably safe.10

Around this time we became concerned that the prooxidative therapy, IV AA, was being given concurrently with IV glutathione (GSH) or even mixed in the same bag of fluid. But we didn't have any evidence from the scientific literature to guide us or even evidence that this practice was occurring. So we designed another survey focusing on IV GSH use, or lack of, with IV AA.

GSH is a tripeptide of glutamate, cysteine, and glycine that actively scavenges reactive oxygen species such as superoxide, hydroxyl radical, and notably hydrogen peroxide.11-15 GSH is known to act synergistically with oral AA to quench reactive oxygen species (ROS). However, at pharmacologic concentrations where IV AA acts as a prooxidant creating hydrogen peroxide, the synergism should not hold true. In fact, if GSH's role is to clear hydrogen peroxide, the therapeutic effect of IV AA should be canceled when they are combined on the same day.

We surveyed attendees at the 2011 iMOSAIC meeting, a joint conference of ACAM, American Academy of Environmental Medicine (AAEM), International College of Integrative Medicine (ICIM), and American Holistic Medical Association (AHMA). Surveys were distributed and collected on 3 successive days. Ninety-four participants completed surveys (169 surveys distributed), and we found that 45% use IV AA and IV GSH in the same patient, 38.5% infused IV AA and IV GSH on the same day, and 8% mixed IV AA and IV GSH in the same IV bag. Further details of the survey are available.16 Because there was no scientific literature to advise us about the concurrent use of IV AA and IV GSH, we devised experiments to evaluate the effects of combining AA with GSH in cell tissue cultures and in accepted animal cancer models. Our data reconfirmed the prooxidative and antineoplastic effects of high-dose AA using equivalent doses commonly administered to patients. When we added GSH concurrently with AA, we found that AA-induced cancer cell death was significantly reduced. There is now scientific evidence to advise that IV AA and IV GSH have competing effects, and we are recommending that they not be coadministered on the same day until further research is done.

IV GSH should be an important tool in clinic practice because of its role in drug and xenobiotic metabolism, antioxidant defense, nutrient metabolism, and regulation of cellular events.11-13 There are obvious benefits of GSH use in reducing oxidant damage to normal cells such as the nervous tissue. IV GSH is important for clinical practice in settings where protection from highly oxidative processes is needed. However, in clinical settings where treatments depend on ROS and free radicals, IV GSH effects are counterproductive. When IV AA produces hydrogen peroxide needed for ROS, GSH has potential for decreasing oxidative signals that trigger neoplastic cell death. At this juncture, it does not appear as if high-dose IV GSH acts as a prooxidative therapy in the same way as high-dose IV AA does, although more research is needed. Based on these findings, we advise that IV AA and IV GSH not be administered on the same day to cancer patients. Simply stated, IV AA is a prooxidant and IV GSH is an antioxidant and when used concurrently the effects can be canceled.

The research was supported by a grant from the Hilton Family Foundation. The Hilton Family Foundation had no input in trial design, evaluation of data, or writing of the report. The authors have no conflicts of interest to report.

1.   Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140:533–537.
2.   Chen Q, Espey MG, Krishna MC, 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.
3.   Chen Q, Espey MG, Sun AY, 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.
4.   Chen Q, Espey MG, Sun AY, 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.
5.   Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med. 2009;47:32–40.
6.   Pollard HB, Levine MA, Eidelman O, Pollard M. Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In Vivo. 2010;24:249–255.
7.   Takemura Y, Satoh M, Satoh K, Hamada H, Sekido Y, Kubota S. High dose of ascorbic acid induces cell death in mesothelioma cells. Biochem Biophys Res Commun. 2010;394:249–253.
8.   Ullah MF, Khan HY, Zubair H, Shamim U, Hadi SM. The antioxidant ascorbic acid mobilizes nuclear copper leading to a prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer. Cancer Chemother Pharmacol. 2010.
9.   Du J, Martin SM, Levine M, et al. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res. 2010;16:509–520.
10. Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One. 2010;5:e11414.
11. Winterbourn CC, Metodiewa D: Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide. Free Radic Biol Med. 1999;27:322–328.
12. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134:489–492.
13. Winkler BS, Orselli SM, Rex TS. The redox couple between glutathione and ascorbic acid: a chemical and physiological perspective. Free Radic Biol Med. 1994;17:333–349.
14. Cascinu S, Cordella L, Del Ferro E, Fronzoni M, Catalano G. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. J Clin Oncol. 1995;13:26–32.
15. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Ann Oncol. 1997;8:569–573.
16. Chen P, Stone J, Sullivan G, Drisko J, Chen Q. Supplementary glutathione counteracts with pharmacologic ascorbate in pre-clinical cancer models. Free Radic Biol Med. 1 August 2011;51 (3):681–687;doi:10.1016/j.freeradbiomed.2011.05.031.

Corresponding author:
Jeanne Drisko, MD
University of Kansas Medical Center
3901 Rainbow Blvd., MS1017
Kansas City, Kansas 66160
Office: 913-588-6208
Fax: 913-588-0012



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