Intravenous ascorbic acid

Last updated
Intravenous ascorbic acid
Infuuszakjes.jpg
Intravenous bag and drip chamber on a pole, used to administer ascorbic acid solution through peripheral IV line
Other namesVitamin C, Ascorbate, L-ascorbic acid
ICD-10-PCS Z51.81
ICD-9-CM 267

Intravenous Ascorbic Acid (also known as vitamin C or L-ascorbic acid), is a process that delivers soluble ascorbic acid directly into the bloodstream. It is not approved for use to treat any medical condition. [1]

Contents

The use of intravenous ascorbic acid as a proposed cancer treatment or co-treatment has been a controversial topic since the emergence of misleading data in the 1970s. [2]

Contraindications

High doses of ascorbic acid administered by intravenous infusion have been shown to increase the absorption of iron. [3] In individuals with hemochromatosis (a genetic disorder where the body takes up and stores too much iron), intravenous ascorbic acid is contraindicated as high dosages of ascorbic acid may result in iron overloading and therefore, lead to life-threatening complications such as heart disease, diabetes, or tissue damage. [4]

High dosages of ascorbic acid (such as those used in intravenous therapy) have been reported to cause some intestinal discomfort, diarrhoea, as well as increased gas and urination. [5]

Alternative medicine and unproven applications

Sepsis

The "Marik protocol", or "HAT" protocol, as devised by Paul E. Marik, proposed a combination of intravenous vitamin C, hydrocortisone, and thiamine as a treatment for preventing sepsis for people in intensive care. Marik's own initial research, published in 2017, [6] showed a dramatic evidence of benefit, leading to the protocol becoming popular among intensive care physicians, [7] especially after the protocol received attention on social media and National Public Radio, drawing criticism of science by press conference from the wider medical community. [8] [9] Subsequent independent research failed to replicate Marik's positive results, indicating the possibility that they had been compromised by bias. [9] [10] A systematic review of trials in 2021 found that the claimed benefits of the protocol could not be confirmed. [11]

People in sepsis may have micronutrient deficiencies, including low levels of vitamin C. [12] Reviews mention that an intake of 3.0 g/day via intravenous administration may needed to maintain normal plasma concentrations. [13] [14] Sepsis mortality is reduced with administration of intravenous vitamin C. [15]

Pharmacology

Chemical structure of ascorbic acid (reduced form) Ascorbic acid structure.svg
Chemical structure of ascorbic acid (reduced form)

Mechanism of action

Ascorbic acid operates as an anti-oxidant and essential enzyme cofactor in the human body. In in vitro studies, the primary mechanism of high dosage intravenous ascorbic acid can be related to ascorbic acid's pro-oxidant activity, whereby hydrogen peroxide is formed. [16] [17] [18] In the extracellular fluid of cells, ascorbic acid dissociates into an ascorbate radical upon the reduction of transition metal ions, such as ferric or cupric cations. [16] These transition metal ions will then reduce dissolved oxygen into a superoxide radical – this will then react with hydrogen to form hydrogen peroxide. [17]

Furthermore, according to Fenton chemistry, these transition metal ions can be further oxidised by hydrogen peroxide to generate a highly reactive hydroxyl radical. [19] The formation of hydrogen peroxide and hydroxyl radicals is believed to induce cytotoxicity and apoptosis of cancer cells. [19] Although many in vitro studies have studied hydrogen peroxide generation by ascorbic acid, the pharmacological mechanism of intravenous ascorbic acid in vivo is still unclear. [19]

History

Pioneering research

Although the pharmacology of ascorbic acid had been studied since its discovery in the 1930s, [20] the method of administration and its medicinal potential to human patients was not investigated until the 1940s. [21] In 1949, American physician, Frederick Klenner, published his scientific report, “The Treatment of Poliomyelitis and Other Virus Diseases with ascorbic acid”, [22] which detailed the use of intravenous ascorbic acid to treat polio in children. [21] Klenner's research pioneered future studies investigating the medicinal role of intravenous ascorbic acid. Klenner's work was recognised by Linus Pauling in the foreword to the Clinical Guide: "Dr. Fred Klenner's early research reports provide much information on the use of high-dose ascorbic acid for the prevention and cure of many diseases, and these reports are still important." [23]

Nobel Prize winner, Linus Pauling, is recognised as one of the early pioneers of ascorbic acid research Linus Pauling.jpg
Nobel Prize winner, Linus Pauling, is recognised as one of the early pioneers of ascorbic acid research

Linus Pauling

Nobel Prize winner and biochemist, Linus Pauling, was pivotal in the re-emergence of intravenous ascorbic acid research. Over the course of the 1970s, Pauling would begin a long-term collaboration with fellow physician, Ewan Cameron, on the medical potential of intravenous ascorbate acid as cancer therapy in terminally ill patients. In 1976, Pauling and Cameron co-authored a study whereby a group of 100 terminal cancer patients underwent supplementary ascorbic acid therapy (10g/day by intravenous infusion and oral thereafter) and the control group of 1,000 patients did not. [24] Their findings reported that the survival rate of the terminal cancer patients increased by four-fold, compared to the control group, stating that: "the treatment of ascorbate in amounts of 10g/day or more is of real value in extending the life of patients with advanced cancer." [24]

Subsequent studies by Pauling and Cameron hypothesised that ascorbic acid's role in enhanced collagen production would lead to the encapsulation of tumours and thus, protect normal tissue from metastasis. [25] Following these findings, Pauling became a strong advocate for vitamin megadosing and continued to investigate the medicinal potential of intravenous ascorbic acid across a range of illnesses, including: HIV transmission, the common cold, atherosclerosis, and angina pectoris. [26] [27] [28]

Medical controversy

The efficacy of intravenous ascorbic acid therapy came under scrutiny of the medical and science community, following the numerous high-profile studies authored by Linus Pauling in the 1970s. [18] The experimental design of Pauling and Cameron's 1976 publication, "Supplemental ascorbate in the supportive treatment of cancer", [24] had garnered considerable criticism as it was neither randomised nor placebo controlled. To test the validity of Pauling and Cameron's findings, the Mayo Clinic conducted three independent experiments in 1979, 1983 and 1985, whereby terminal cancer patients were given doses of oral ascorbic acid under randomised, double bind and placebo-controlled conditions. [29] [30] [31] All studies concluded that high doses of oral ascorbic acid were not effective against cancer.

The use of intravenous ascorbic acid in the treatment of cancer has been a contentious issue. There is no evidence to indicate that intravenous ascorbic acid therapy can cure cancer. [32] [31] According to the U.S. Food and Drug Administration (FDA), high-dose vitamin C (such as intravenous ascorbic acid therapy) has not been approved as a treatment for cancer or any other medical condition. [1]

There many been multiple studies devoted to investigating the medicinal properties of ascorbic acid. The use of high-dosage intravenous ascorbic acid as a cancer treatment was first promoted by Linus Pauling and Ewan Cameron in the 1970s; [24] [25] however, these findings were not reproduced using oral administration by subsequent Mayo Clinic studies in the 1980s. [29] [30] [31] In 2010, an academic review which detailed 33 years of ascorbic acid and cancer research stated: "we still do not know whether Vitamin C has any clinically significant anti-tumor activity. Nor do we know which histological types of cancers, if any, are susceptible to this agent. Finally, we don't know what the recommended dose of Vitamin C is, if there is indeed such a dose, that can produce an anti-tumor response". [33]

Research

The turn of the 21st century saw a renewed interest in the medical potential of intravenous ascorbic acid therapy. In the early 2010s, in vitro preclinical and clinical trials were undertaken to investigate the pharmacological mechanism of action of intravenous ascorbic acid therapy. [34] [35] These findings demonstrated ascorbic acid's pro-oxidant capabilities to produce hydrogen peroxide and thus, proposed a possible pharmacological mechanism of action against cancer cells. Nonetheless, ascorbic acid's potential as an anti-tumour therapy is still dubious, as other pro-oxidant substances (such as menadione [36] [37] ) have been unsuccessful in the treatment of cancer patients. [38]

See also

Related Research Articles

<span class="mw-page-title-main">Chemistry of ascorbic acid</span> Chemical compound

Ascorbic acid is an organic compound with formula C
6H
8O
6, originally called hexuronic acid. It is a white solid, but impure samples can appear yellowish. It dissolves freely in water to give mildly acidic solutions. It is a mild reducing agent.

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Foods are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Vitamin C</span> Essential nutrient found in citrus fruits and other foods

Vitamin C is a water-soluble vitamin found in citrus and other fruits, berries and vegetables, also sold as a dietary supplement and as a topical "serum" ingredient to treat melasma and wrinkles on the face. It is used to prevent and treat scurvy. Vitamin C is an essential nutrient involved in the repair of tissue, the formation of collagen, and the enzymatic production of certain neurotransmitters. It is required for the functioning of several enzymes and is important for immune system function. It also functions as an antioxidant. Most animals are able to synthesize their own vitamin C. However, apes and monkeys, most bats, most fish, some rodents, and certain other animals must acquire it from dietary sources because a gene for a synthesis enzyme has mutations.

<span class="mw-page-title-main">Linus Pauling</span> American scientist, peace activist, and Nobel Laureate (1901–1994)

Linus Carl Pauling was an American chemist, biochemist, chemical engineer, peace activist, author, and educator. He published more than 1,200 papers and books, of which about 850 dealt with scientific topics. New Scientist called him one of the 20 greatest scientists of all time. For his scientific work, Pauling was awarded the Nobel Prize in Chemistry in 1954. For his peace activism, he was awarded the Nobel Peace Prize in 1962. He is one of five people to have won more than one Nobel Prize. Of these, he is the only person to have been awarded two unshared Nobel Prizes, and one of two people to be awarded Nobel Prizes in different fields, the other being Marie Curie.

<span class="mw-page-title-main">Sepsis</span> Life-threatening organ dysfunction triggered by infection

Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs.

Orthomolecular medicine is a form of alternative medicine that aims to maintain human health through nutritional supplementation. The concept builds on the idea of an optimal nutritional environment in the body and suggests that diseases reflect deficiencies in this environment. Treatment for disease, according to this view, involves attempts to correct "imbalances or deficiencies based on individual biochemistry" by use of substances such as vitamins, minerals, amino acids, trace elements and fatty acids. The notions behind orthomolecular medicine are not supported by sound medical evidence, and the therapy is not effective for chronic disease prevention; even the validity of calling the orthomolecular approach a form of medicine has been questioned since the 1970s.

<span class="mw-page-title-main">Alendronic acid</span> Chemical compound

Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementation, and lifestyle changes.

<span class="mw-page-title-main">Folinic acid</span> Derivative of folic acid used in cancer treatment

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.

<span class="mw-page-title-main">Rasburicase</span> Pharmaceutical drug

Rasburicase is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The complementary DNA (cDNA) coding for rasburicase was cloned from a strain of Aspergillus flavus.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2− (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

Dehydroascorbic acid (DHA) is an oxidized form of ascorbic acid. It is actively imported into the endoplasmic reticulum of cells via glucose transporters. It is trapped therein by reduction back to ascorbate by glutathione and other thiols. The (free) chemical radical semidehydroascorbic acid (SDA) also belongs to the group of oxidized ascorbic acids.

<small>L</small>-gulonolactone oxidase Enzyme involved in the synthesis of vitamin C

L-Gulonolactone oxidase is an enzyme that produces vitamin C, but is non-functional in Haplorrhini, in some bats, and in guinea pigs. It catalyzes the reaction of L-gulono-1,4-lactone with oxygen to form L-xylo-hex-3-gulonolactone (2-keto-gulono-γ-lactone) and hydrogen peroxide. It uses FAD as a cofactor. The L-xylo-hex-3-gulonolactone then converts to ascorbic acid spontaneously, without enzymatic action.

Megavitamin therapy is the use of large doses of vitamins, often many times greater than the recommended dietary allowance (RDA) in the attempt to prevent or treat diseases. Megavitamin therapy is typically used in alternative medicine by practitioners who call their approach orthomolecular medicine. Vitamins are useful in preventing and treating illnesses specifically associated with dietary vitamin shortfalls, but the conclusions of medical research are that the broad claims of disease treatment by advocates of megavitamin therapy are unsubstantiated by the available evidence. It is generally accepted that doses of any vitamin greatly in excess of nutritional requirements will result either in toxicity or in the excess simply being metabolised; thus evidence in favour of vitamin supplementation supports only doses in the normal range. Critics have described some aspects of orthomolecular medicine as food faddism or even quackery. Research on nutrient supplementation in general suggests that some nutritional supplements might be beneficial, and that others might be harmful; several specific nutritional therapies are associated with an increased likelihood of the condition they are meant to prevent.

<span class="mw-page-title-main">Sodium ascorbate</span> Chemical compound

Sodium ascorbate is one of a number of mineral salts of ascorbic acid (vitamin C). The molecular formula of this chemical compound is C6H7NaO6. As the sodium salt of ascorbic acid, it is known as a mineral ascorbate. It has not been demonstrated to be more bioavailable than any other form of vitamin C supplement.

<span class="mw-page-title-main">Potassium ascorbate</span> Chemical compound

Potassium ascorbate is a compound with formula KC6H7O6. It is the potassium salt of ascorbic acid (vitamin C) and a mineral ascorbate. As a food additive, it has E number E303, INS number 303. Although it is not a permitted food additive in the UK, USA and the EU, it is approved for use in Australia and New Zealand. According to some studies, it has shown a strong antioxidant activity and antitumoral properties.

<span class="mw-page-title-main">Dichlorophenolindophenol</span> Chemical compound

2,6-Dichlorophenolindophenol is a chemical compound used as a redox dye. When oxidized, DCPIP is blue with a maximal absorption at 600 nm; when reduced, DCPIP is colorless.

A banana bag is a bag of IV fluids containing vitamins and minerals. The bags typically contain thiamine, folic acid, and magnesium sulfate, and are usually used to correct nutritional deficiencies or chemical imbalances in the human body. The solution has a yellow color, hence the term "banana bag".

<span class="mw-page-title-main">Vitamin C megadosage</span> Consumption or injection of very large doses of vitamin C

Vitamin C megadosage is a term describing the consumption or injection of vitamin C in doses well beyond the current United States Recommended Dietary Allowance of 90 milligrams per day, and often well beyond the tolerable upper intake level of 2,000 milligrams per day. There is no scientific evidence that vitamin C megadosage helps to cure or prevent cancer, the common cold, or some other medical conditions.

Critical illness–related corticosteroid insufficiency is a form of adrenal insufficiency in critically ill patients who have blood corticosteroid levels which are inadequate for the severe stress response they experience. Combined with decreased glucocorticoid receptor sensitivity and tissue response to corticosteroids, this adrenal insufficiency constitutes a negative prognostic factor for intensive care patients.

Paul Ellis Marik is a medical doctor and former professor of medicine who until his resignation in January 2022 served as chair of the Division of Pulmonary and Critical Care Medicine at Eastern Virginia Medical School in Norfolk, Virginia, and was also a critical care doctor at Sentara Norfolk General Hospital. His research interests include sepsis and tissue oxygenation. In August 2023 the American Board of Internal Medicine informed Marik his certification was to be revoked for spreading misinformation.

References

  1. 1 2 "The Vitamin C Foundation – 514071 – 04/17/2017". U.S. Food and Drug Administration. 2019-04-23. Retrieved 2019-06-07.
  2. ↑ Nabzdyk CS, Bittner EA (October 2018). "Vitamin C in the critically ill – indications and controversies". World Journal of Critical Care Medicine. 7 (5): 52–61. doi: 10.5492/wjccm.v7.i5.52 . PMC   6201324 . PMID   30370227.
  3. ↑ Jacob RA, Sotoudeh G (March 2002). "Vitamin C function and status in chronic disease". Nutrition in Clinical Care. 5 (2): 66–74. doi:10.1046/j.1523-5408.2002.00005.x. PMID   12134712.
  4. ↑ Institute of Medicine (US) Panel on Dietary Antioxidants Related Compounds (2000-04-11). Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. doi:10.17226/9810. ISBN   9780309069359. PMID   25077263.
  5. ↑ Ohno S, Ohno Y, Suzuki N, Soma G, Inoue M (March 2009). "High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer". Anticancer Research. 29 (3): 809–815. PMID   19414313.
  6. ↑ Marik, Paul E.; Khangoora, Vikramjit; Rivera, Racquel; Hooper, Michael H.; Catravas, John (2017). "Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock". Chest. Elsevier BV. 151 (6): 1229–1238. doi:10.1016/j.Chest.2016.11.036. ISSN   0012-3692. PMID   27940189. S2CID   3509326.
  7. ↑ "The Marik Protocol: Have We Found a "Cure" for Severe Sepsis and Septic Shock?". Rebel EM – Emergency Medicine Blog. 2017-04-07. Retrieved 2021-07-22.
  8. ↑ "Vitamin C Drug Cocktail for Sepsis". HealthManagement. July 9, 2019. Retrieved 2021-09-24.
  9. 1 2 Rubin R (July 2019). "Wide Interest in a Vitamin C Drug Cocktail for Sepsis Despite Lagging Evidence". JAMA. 322 (4): 291–293. doi:10.1001/jama.2019.7936. PMID   31268477. S2CID   195788169.
  10. ↑ ""Ethically and morally unacceptable": Reaction to vitamin C for sepsis trial". Dietary supplements, Nutraceuticals, Functional foods, Health ingredients, Herbals. 2020-01-28. Retrieved 2021-07-22.
  11. ↑ Lee YR, Vo K, Varughese JT (May 2021). "Benefits of combination therapy of hydrocortisone, ascorbic acid and thiamine in sepsis and septic shock: A systematic review". Nutr Health. 28 (1): 77–93. doi:10.1177/02601060211018371. PMID   34039089. S2CID   235215735.
  12. ↑ Belsky JB, Wira CR, Jacob V, Sather JE, Lee PJ (December 2018). "A review of micronutrients in sepsis: the role of thiamine, L-carnitine, vitamin C, selenium and vitamin D". Nutrition Research Reviews. 31 (2): 281–90. doi:10.1017/S0954422418000124. PMID   29984680. S2CID   51599526.
  13. ↑ Liang B, Su J, Shao H, Chen H, Xie B (March 2023). "The outcome of IV vitamin C therapy in patients with sepsis or septic shock: a meta-analysis of randomized controlled trials". Crit Care. 27 (1): 109. doi: 10.1186/s13054-023-04392-y . PMC   10012592 . PMID   36915173.
  14. ↑ Berger MM, Oudemans-van Straaten HM (March 2015). "Vitamin C supplementation in the critically ill patient". Curr Opin Clin Nutr Metab Care. 18 (2): 193–201. doi:10.1097/MCO.0000000000000148. PMID   25635594. S2CID   37895257.
  15. ↑ Xu C, Yi T, Tan S, Xu H, Hu Y, Ma J, Xu J (April 2023). "Association of Oral or Intravenous Vitamin C Supplementation with Mortality: A Systematic Review and Meta-Analysis". Nutrients. 15 (8): 1848. doi: 10.3390/nu15081848 . PMC   10146309 . PMID   37111066.
  16. 1 2 Carr AC, Cook J (2018-08-23). "Intravenous Vitamin C for Cancer Therapy – Identifying the Current Gaps in Our Knowledge". Frontiers in Physiology. 9: 1182. doi: 10.3389/fphys.2018.01182 . PMC   6115501 . PMID   30190680.
  17. 1 2 Vissers MC, Das AB (2018-07-03). "Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence". Frontiers in Physiology. 9: 809. doi: 10.3389/fphys.2018.00809 . PMC   6037948 . PMID   30018566.
  18. 1 2 Verrax J, Calderon PB (December 2008). "The controversial place of vitamin C in cancer treatment". Biochemical Pharmacology. 76 (12): 1644–1652. doi:10.1016/j.bcp.2008.09.024. PMID   18938145.
  19. 1 2 3 Fritz H, Flower G, Weeks L, Cooley K, Callachan M, McGowan J, et al. (July 2014). "Intravenous Vitamin C and Cancer: A Systematic Review". Integrative Cancer Therapies. 13 (4): 280–300. doi: 10.1177/1534735414534463 . PMID   24867961.
  20. ↑ Carpenter KJ (2012). "The discovery of vitamin C". Annals of Nutrition & Metabolism. 61 (3): 259–264. doi:10.1159/000343121. PMID   23183299. S2CID   37436503.
  21. 1 2 "Intravenous Vitamin C: The Historical Progression". PaulingBlog. 2017-10-18. Retrieved 2019-05-20.
  22. ↑ "The Treatment of Poliomyelitis and Other Virus Diseases with Vitamin C". www.seanet.com. Retrieved 2019-05-20.
  23. ↑ "Clinical Guide to the Use of Vitamin C". www.seanet.com. Retrieved 2019-05-20.
  24. 1 2 3 4 Cameron E, Pauling L (October 1976). "Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer". Proceedings of the National Academy of Sciences of the United States of America. 73 (10): 3685–3689. Bibcode:1976PNAS...73.3685C. doi: 10.1073/pnas.73.10.3685 . PMC   431183 . PMID   1068480.
  25. 1 2 Mikirova N, Casciari J, Riordan N, Hunninghake R (August 2013). "Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients". Journal of Translational Medicine. 11: 191. doi: 10.1186/1479-5876-11-191 . PMC   3751545 . PMID   23947403.
  26. ↑ Pauling L (January 1973). "Ascorbic acid and the common cold". Scottish Medical Journal. 18 (1): 1–2. doi:10.1177/003693307301800101. PMID   4577802. S2CID   28875346.
  27. ↑ Harakeh S, Jariwalla RJ, Pauling L (September 1990). "Suppression of human immunodeficiency virus replication by ascorbate in chronically and acutely infected cells". Proceedings of the National Academy of Sciences of the United States of America. 87 (18): 7245–7249. Bibcode:1990PNAS...87.7245H. doi: 10.1073/pnas.87.18.7245 . PMC   54720 . PMID   1698293.
  28. ↑ Rath M, Pauling L (August 1990). "Hypothesis: lipoprotein(a) is a surrogate for ascorbate". Proceedings of the National Academy of Sciences of the United States of America. 87 (16): 6204–6207. Bibcode:1990PNAS...87.6204R. doi: 10.1073/pnas.87.16.6204 . PMC   54501 . PMID   2143582.
  29. 1 2 Creagan ET, Moertel CG, O'Fallon JR, Schutt AJ, O'Connell MJ, Rubin J, Frytak S (September 1979). "Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial". The New England Journal of Medicine. 301 (13): 687–690. doi:10.1056/NEJM197909273011303. PMID   384241.
  30. 1 2 Tschetter L, Creagan E, O'Fallon J (1983). "A community-based study of vitamin C (ascorbic acid) in patients with advanced cancer". Proceedings of the American Society of Clinical Oncology. 2: 92.
  31. 1 2 3 Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, Ames MM (January 1985). "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". The New England Journal of Medicine. 312 (3): 137–141. doi:10.1056/NEJM198501173120301. PMID   3880867.
  32. ↑ Klimant E, Wright H, Rubin D, Seely D, Markman M (April 2018). "Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach". Current Oncology. 25 (2): 139–148. doi:10.3747/co.25.3790. PMC   5927785 . PMID   29719430.
  33. ↑ Cabanillas F (September 2010). "Vitamin C and cancer: what can we conclude – 1,609 patients and 33 years later?". Puerto Rico Health Sciences Journal. 29 (3): 215–217. PMID   20799507.
  34. ↑ Parrow NL, Leshin JA, Levine M (December 2013). "Parenteral ascorbate as a cancer therapeutic: a reassessment based on pharmacokinetics". Antioxidants & Redox Signaling. 19 (17): 2141–2156. doi:10.1089/ars.2013.5372. PMC   3869468 . PMID   23621620.
  35. ↑ Fritz H, Flower G, Weeks L, Cooley K, Callachan M, McGowan J, et al. (July 2014). "Intravenous Vitamin C and Cancer: A Systematic Review". Integrative Cancer Therapies. 13 (4): 280–300. doi: 10.1177/1534735414534463 . PMID   24867961.
  36. ↑ Tetef M, Margolin K, Ahn C, Akman S, Chow W, Leong L, et al. (1995). "Mitomycin C and menadione for the treatment of lung cancer: a phase II trial". Investigational New Drugs. 13 (2): 157–162. doi:10.1007/BF00872865. PMID   8617579. S2CID   10086469.
  37. ↑ Margolin KA, Akman SA, Leong LA, Morgan RJ, Somlo G, Raschko JW, et al. (1995). "Phase I study of mitomycin C and menadione in advanced solid tumors". Cancer Chemotherapy and Pharmacology. 36 (4): 293–298. doi:10.1007/BF00689046. PMID   7628048. S2CID   7283959.
  38. ↑ Borst P (December 2008). "Mega-dose vitamin C as therapy for human cancer?". Proceedings of the National Academy of Sciences of the United States of America. 105 (48): E95, author reply E96. Bibcode:2008PNAS..105E..95B. doi: 10.1073/pnas.0809328105 . PMC   2596258 . PMID   19033231.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.