Chemistry:Intravenous ascorbic acid

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Short description: Nonmedical procedure
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-PCSZ51.81
ICD-9-CM267
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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]

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)

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]

Black and white photo of Nobel Prize winner, Linus Pauling.
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

References

  1. ↑ 1.0 1.1 "The Vitamin C Foundation – 514071 – 04/17/2017" (in en). 2019-04-23. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/vitamin-c-foundation-514071-04172017. 
  2. ↑ "Vitamin C in the critically ill – indications and controversies". World Journal of Critical Care Medicine 7 (5): 52–61. October 2018. doi:10.5492/wjccm.v7.i5.52. PMID 30370227. 
  3. ↑ "Vitamin C function and status in chronic disease". Nutrition in Clinical Care 5 (2): 66–74. March 2002. 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) (in en). Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. doi:10.17226/9810. ISBN 9780309069359. 
  5. ↑ "High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer". Anticancer Research 29 (3): 809–815. March 2009. PMID 19414313. http://ar.iiarjournals.org/content/29/3/809. 
  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. 
  7. ↑ "The Marik Protocol: Have We Found a "Cure" for Severe Sepsis and Septic Shock?". 2017-04-07. https://rebelem.com/the-marik-protocol-have-we-found-a-cure-for-severe-sepsis-and-septic-shock/. 
  8. ↑ "Vitamin C Drug Cocktail for Sepsis" (in en). July 9, 2019. https://healthmanagement.org/c/icu/news/vitamin-c-drug-cocktail-for-sepsis. 
  9. ↑ 9.0 9.1 "Wide Interest in a Vitamin C Drug Cocktail for Sepsis Despite Lagging Evidence". JAMA 322 (4): 291–293. July 2019. doi:10.1001/jama.2019.7936. PMID 31268477. 
  10. ↑ ""Ethically and morally unacceptable": Reaction to vitamin C for sepsis trial". 2020-01-28. https://www.nutraingredients.com/Article/2020/01/28/Ethically-and-morally-unacceptable-Reaction-to-vitamin-C-for-sepsis-trial. 
  11. ↑ "Benefits of combination therapy of hydrocortisone, ascorbic acid and thiamine in sepsis and septic shock: A systematic review". Nutr Health 28 (1): 77–93. May 2021. doi:10.1177/02601060211018371. PMID 34039089. 
  12. ↑ "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. December 2018. doi:10.1017/S0954422418000124. PMID 29984680. 
  13. ↑ "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. March 2023. doi:10.1186/s13054-023-04392-y. PMID 36915173. 
  14. ↑ "Vitamin C supplementation in the critically ill patient". Curr Opin Clin Nutr Metab Care 18 (2): 193–201. March 2015. doi:10.1097/MCO.0000000000000148. PMID 25635594. 
  15. ↑ "Association of Oral or Intravenous Vitamin C Supplementation with Mortality: A Systematic Review and Meta-Analysis". Nutrients 15 (8): 1848. April 2023. doi:10.3390/nu15081848. PMID 37111066. 
  16. ↑ 16.0 16.1 "Intravenous Vitamin C for Cancer Therapy – Identifying the Current Gaps in Our Knowledge". Frontiers in Physiology 9: 1182. 2018-08-23. doi:10.3389/fphys.2018.01182. PMID 30190680. 
  17. ↑ 17.0 17.1 "Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence". Frontiers in Physiology 9: 809. 2018-07-03. doi:10.3389/fphys.2018.00809. PMID 30018566. 
  18. ↑ 18.0 18.1 "The controversial place of vitamin C in cancer treatment". Biochemical Pharmacology 76 (12): 1644–1652. December 2008. doi:10.1016/j.bcp.2008.09.024. PMID 18938145. 
  19. ↑ 19.0 19.1 19.2 "Intravenous Vitamin C and Cancer: A Systematic Review". Integrative Cancer Therapies 13 (4): 280–300. July 2014. doi:10.1177/1534735414534463. PMID 24867961. 
  20. ↑ "The discovery of vitamin C". Annals of Nutrition & Metabolism 61 (3): 259–264. 2012. doi:10.1159/000343121. PMID 23183299. 
  21. ↑ 21.0 21.1 "Intravenous Vitamin C: The Historical Progression" (in en). 2017-10-18. https://paulingblog.wordpress.com/2017/10/18/intravenous-vitamin-c-the-historical-progression/. 
  22. ↑ "The Treatment of Poliomyelitis and Other Virus Diseases with Vitamin C". https://www.seanet.com/~alexs/ascorbate/194x/klenner-fr-southern_med_surg-1949-v111-n7-p209.htm. 
  23. ↑ "Clinical Guide to the Use of Vitamin C". https://www.seanet.com/~alexs/ascorbate/198x/smith-lh-clinical_guide_1988.htm. 
  24. ↑ 24.0 24.1 24.2 24.3 "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. October 1976. doi:10.1073/pnas.73.10.3685. PMID 1068480. Bibcode: 1976PNAS...73.3685C. 
  25. ↑ 25.0 25.1 "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. August 2013. doi:10.1186/1479-5876-11-191. PMID 23947403. 
  26. ↑ "Ascorbic acid and the common cold". Scottish Medical Journal 18 (1): 1–2. January 1973. doi:10.1177/003693307301800101. PMID 4577802. 
  27. ↑ "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. September 1990. doi:10.1073/pnas.87.18.7245. PMID 1698293. Bibcode: 1990PNAS...87.7245H. 
  28. ↑ "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. August 1990. doi:10.1073/pnas.87.16.6204. PMID 2143582. Bibcode: 1990PNAS...87.6204R. 
  29. ↑ 29.0 29.1 "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. September 1979. doi:10.1056/NEJM197909273011303. PMID 384241. 
  30. ↑ 30.0 30.1 "A community-based study of vitamin C (ascorbic acid) in patients with advanced cancer". Proceedings of the American Society of Clinical Oncology 2: 92. 1983. 
  31. ↑ 31.0 31.1 31.2 "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. January 1985. doi:10.1056/NEJM198501173120301. PMID 3880867. 
  32. ↑ "Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach". Current Oncology 25 (2): 139–148. April 2018. doi:10.3747/co.25.3790. PMID 29719430. 
  33. ↑ "Vitamin C and cancer: what can we conclude – 1,609 patients and 33 years later?". Puerto Rico Health Sciences Journal 29 (3): 215–217. September 2010. PMID 20799507. 
  34. ↑ "Parenteral ascorbate as a cancer therapeutic: a reassessment based on pharmacokinetics". Antioxidants & Redox Signaling 19 (17): 2141–2156. December 2013. doi:10.1089/ars.2013.5372. PMID 23621620. PMC 3869468. https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=23621620. 
  35. ↑ "Intravenous Vitamin C and Cancer: A Systematic Review". Integrative Cancer Therapies 13 (4): 280–300. July 2014. doi:10.1177/1534735414534463. PMID 24867961. https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=24867961. 
  36. ↑ "Mitomycin C and menadione for the treatment of lung cancer: a phase II trial". Investigational New Drugs 13 (2): 157–162. 1995. doi:10.1007/BF00872865. PMID 8617579. 
  37. ↑ "Phase I study of mitomycin C and menadione in advanced solid tumors". Cancer Chemotherapy and Pharmacology 36 (4): 293–298. 1995. doi:10.1007/BF00689046. PMID 7628048. 
  38. ↑ "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. December 2008. doi:10.1073/pnas.0809328105. PMID 19033231. Bibcode: 2008PNAS..105E..95B. 



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