Vitamin C megadosage

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Chemical structure of vitamin C
3D molecular model of vitamin C

Vitamin C megadosage is a term describing the consumption or injection of vitamin C (ascorbic acid) in doses comparable to the amounts produced by the livers of most other mammals. Such dosages correspond to amounts well beyond the current Recommended Dietary Allowance of 90 mg/day, and often well beyond the Tolerable upper intake level of 2,000 mg/day.[1] Oral dosages are usually divided and consumed in portions over the day. Injections of hundreds of grams per day are advocated by some physicians for the treatment of certain conditions, poisonings, or recovery from trauma. People who practice vitamin C megadosage may consume many vitamin C pills throughout each day or dissolve pure vitamin C crystals in water or juice and drink it throughout the day.

Historic advocates of vitamin C megadosage include Linus Pauling, who won the Nobel Prize in Chemistry in 1954. Pauling argued that, due to a non-functional form of L-gulonolactone oxidase, an enzyme required to make vitamin C that is functional in most other mammalian relatives, humans have developed a number of adaptations to cope with the relative deficiency. These adaptations, he argued, ultimately shortened lifespan but could be reversed or mitigated by supplementing humans with the hypothetical amount of vitamin C that would have been produced in the body if the enzyme were working.

Vitamin C megadoses are claimed by alternative medicine advocates including Matthias Rath and Patrick Holford to have preventative and curative effects on diseases such as cancer and AIDS,[2][3] but the available scientific evidence does not support these claims.[4] Some trials show some effect in combination with other therapies, but this does not imply vitamin C megadoses in themselves have therapeutic effect.[5]

Background[edit]

The World Health Organization recommends a daily intake of 45 mg/day of vitamin C for healthy adults, and 25–30 mg/day in infants.[6] The Vitamin C article provides examples of recommendations from individual countries. None exceed 110 mg/day. Vitamin C is necessary for production of collagen and other biomolecules, and for the prevention of scurvy.[7] Vitamin C is an antioxidant, which has led to its endorsement by some researchers as a complementary therapy for improving quality of life.[8] Since the 1930s, when it first became available in pure form, some physicians have experimented with higher than recommended vitamin C consumption or injection.[9] Certain animal species, including haplorhine primates (which includes humans),[10][11] members of the Caviidae family of rodents (including guinea pigs and capybaras),[12] most species of bats,[13] many passerine birds,[14] and about 96% of fish (the teleosts),[14] do not synthesize vitamin C internally.

Since its discovery, vitamin C has been considered almost a panacea by some,[15] although this led to suspicions of it being overhyped by others.[16] Vitamin C has been promoted in alternative medicine as a treatment for the common cold, cancer, polio and various other illnesses. The evidence for these claims is mixed. Orthomolecular-based megadose recommendations for vitamin C are based mainly on theoretical speculation and observational studies, such as those published by Fred R. Klenner from the 1940s through the 1970s. There is a strong advocacy movement for such doses of vitamin C, and there is an absence of large scale, formal trials in the 10 to 200+ grams per day range.

The single repeatable side effect of oral megadose vitamin C is a mild laxative effect if the practitioner attempts to consume too much too quickly. In the United States and Canada, a tolerable upper intake level (UL) was set at 2000 mg/day, referencing this mild laxative effect as the reason for establishing the UL.[1] However, the European Food Safety Authority (EFSA) reviewed the safety question in 2006 and reached the conclusion that there was not sufficient evidence to set a UL for vitamin C.[17] The Japan National Institute of Health and Nutrition reviewed the same question in 2010 and also reached the conclusion that there was not sufficient evidence to set a UL.[18]

About 70-90% of vitamin C is adsorbed by the body when taken orally at normal levels (30–180 mg daily). Adsorption is only about 50% for daily doses of 1 g. Oral administration, even of mega doses, cannot raise blood concentration above 0.22 mM.[19]

Relative deficiency hypothesis[edit]

Linus Pauling's popular and influential book How to Live Longer and Feel Better, first published in 1986, advocated very high doses of vitamin C.

Humans and other species that do not synthesize vitamin C carry a mutated and ineffective form of the enzyme L-gulonolactone oxidase, the fourth and last step in the ascorbate-producing machinery. In the anthropoids lineage, this mutation likely occurred 40 to 25 million years ago. The three surviving enzymes continue to produce the precursors to vitamin C, but the process is incomplete and the body then disassembles them.

In the 1960s, the Nobel-Prize-winning chemist Linus Pauling, after contact[20] with Irwin Stone, began actively promoting vitamin C as a means to greatly improve human health and resistance to disease. His book How to Live Longer and Feel Better was a bestseller and advocated taking more than 10 grams per day orally, thus approaching the amounts released by the liver directly into the circulation in other mammals: an adult goat, a typical example of a vitamin-C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and much more when stressed.[21][unreliable medical source?]

Matthias Rath is a controversial German physician who worked with and published two articles discussing the possible relationship between lipoprotein and vitamin C with Pauling.[22][23] He is an active proponent and publicist for high-dose vitamin C. Pauling's and Rath's extended theory states that deaths from scurvy in humans during the ice age, when vitamin C was scarce, selected for individuals who could repair arteries with a layer of cholesterol provided by lipoprotein(a), a lipoprotein found in vitamin C-deficient species.[24]

Stone[25] and Pauling[10] believed that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human requiring 2,500 kcal a day.

Pauling criticized the established US Recommended Daily Allowance, pointing out that it is based on the known quantities that will prevent acute scurvy but is not necessarily the dosage for optimal health.[26]

Adverse effects[edit]

Although sometimes considered free of toxicity, there are known side effects from vitamin C intake, and it has been suggested that intravenous injections should require "a medical environment and trained professionals."[27]

Blood levels of vitamin C remain steady at approximately 200 mg per day.[clarification needed] Although vitamin C can be well tolerated at doses well above what government organizations recommend, adverse effects can occur at doses above 3 grams per day. The common 'threshold' side effect of megadoses is diarrhea. Other possible adverse effects include increased oxalate excretion and kidney stones, increased uric-acid excretion, systemic conditioning ("rebound scurvy"), preoxidant effects, iron overload, reduced absorption of vitamin B12 and copper, increased oxygen demand, and acid erosion of the teeth with chewing ascorbic-acid tablets.[1] In addition, one case has been noted of a woman who had received a kidney transplant followed by high-dose vitamin C and died soon afterwards as a result of calcium oxalate deposits that destroyed her new kidney. Her doctors concluded that high-dose vitamin C therapy should be avoided in patients with renal failure.[29]

Overdose[edit]

As discussed previously, vitamin C generally exhibits low toxicity. The LD50 (the dose that will kill 50% of a population) is generally accepted to be 11900 milligrams [11.9 grams] per kilogram in rat populations.[30]

It is interesting to note, however, that the American Association of Poison Control Centers has reported zero(0) deaths from vitamin C. Annual reports are available at the AAPCC website[31]. From the years 1999 to 2016, the years for which the reports are currently available, a study of them for vitamin C deaths show no reported fatalities as a result of vitamin C. There are no pharmaceutical medications for which this can be stated with authority, again, according to the AAPCC annual reports.

Interactions[edit]

Pharmaceuticals designed to reduce stomach acid, such as the proton-pump inhibitors (PPIs), are among the most widely sold drugs in the world. One PPI, omeprazole (Prilosec), has been found to lower the bioavailability of vitamin C by 12% after 28 days of treatment, independent of dietary intake. The probable mechanism of vitamin C reduction, intragastric pH elevated into alkalinity, would apply to all other PPI drugs, though not necessarily to doses of PPIs low enough to keep the stomach slightly acidic.[32] In another study, 40 mg/day of omeprazole lowered the fasting gastric vitamin C levels from 3.8 to 0.7 µg/mL.[33]

Aspirin may also inhibit the absorption of vitamin C.[34][35][36]

Regulation[edit]

There are regulations in most countries that limit the claims on the treatment of disease that can be placed on food and dietary supplement product labels. For example: Claims of therapeutic effect with respect to the treatment of any medical condition or disease are prohibited by the United States Food and Drug Administration even if substance has gone through well conducted clinical trials with positive outcomes. Claims are limited to Structure:Function phrasing ("Helps maintain a healthy immune system") and the following notice is mandatory on food and dietary supplement product labels that make these types of health claims: These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.[37]

Research[edit]

Cancer[edit]

The use of vitamin C in high doses as a treatment for cancer was promoted by Linus Pauling, based on a 1976 study published with Ewan Cameron which reported intravenous vitamin C significantly increased lifespans of patients with advanced cancer.[38][39] This trial was criticized by the National Cancer Institute for being designed poorly, and three subsequent trials conducted at the Mayo Clinic could not replicate these results.[39][40] However, the trials at the Mayo Clinic were conducted with oral doses of ascorbate, not IV ascorbate as was done in the original trial. This massive difference in dosage is the most likely reason for the failure of the Mayo Clinic trials to replicate the original trial results.[41]

More recently, in vivo findings from animal models have furnished evidence that high-dose intravenous ascorbic acid at may hold some promise in the treatment of cancer; however, this has not been supported in more rigorous clinical trials in humans. Preliminary clinical trials in humans have shown that it is unlikely to be a "miracle pill" for cancer and more research is necessary before any definitive conclusions about efficacy can be reached.[27] A 2010 review of 33 years of research on vitamin C to treat cancer stated "we have to conclude that we still do not know whether Vitamin C has any clinically significant antitumor 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."[40]

The American Cancer Society has stated, "Although high doses of vitamin C have been suggested as a cancer treatment, the available evidence from clinical trials has not shown any benefit."[39]

Burns[edit]

One study performed in 2000 used high intravenous doses of vitamin C (66 mg/kg/hour over 24 hours, for a total dose of around 110 grams) after severe burn injury,[42] but despite being described as promising, it has not been replicated by independent institutions and thus is not a widely accepted treatment.[43] Based on that study, the American Burn Association (ABA) considers high-dose ascorbic acid an option to be considered for adjuvant therapy in addition to the more accepted standard treatments.[44] However, one medical review article noted vitamin C at the doses studied can be toxic, and recommended further validation by future studies before this therapy is clinically used.[42]

Cardiac effects[edit]

Atrial fibrillation (AF) is a common cardiac rhythm disturbance and it is associated with oxidative stress. Four meta-analyses have concluded that there is strong evidence that 1-2 g/day of vitamin C before and after cardiac operations can decrease the risk of post-operative AF.[45][46][47][48] However, five randomized studies did not find benefit in the USA, so that the benefit was restricted to less wealthy countries.[48][49]

A meta-analysis of 29 trials calculated that vitamin C, with a median dose of 0.5 g/day and a median duration of 8 weeks, decreased systolic blood pressure on average by 3.8 mmHg and diastolic blood pressure by 2.4 mmHg.[50]

Exercise-induced bronchoconstriction[edit]

Exercise-induced bronchoconstriction (EIB) indicates acute narrowing of the airways as a result of vigorous exercise. EIB seems to be caused by the loss of water caused by increased ventilation, which may lead to the release of mediators such as histamine, prostaglandins and leukotrienes, all of which cause bronchoconstriction. Vitamin C participates in the metabolism of these mediators and might thereby influence EIB.[51] A meta-analysis of three randomized trials calculated that 0.5 to 2 g/day of vitamin C before exercise decreased EIB by half.[52]

The common cold[edit]

A meta-analysis calculated that large doses of vitamin C do not prevent the common cold in the general community, although 0.25 to 1 g/day of vitamin C halved the incidence of colds in people under heavy short-term physical stress.[53] Another meta-analysis calculated that in children 1-2 g/day vitamin C shortened the duration of colds by 18%, and in adults 1-4 g/day vitamin C shortened the duration of colds by 8%.[53] Furthermore, there is evidence of linear dose-dependency in the effect of vitamin C on common cold duration up to 6-8 g/day.[54]

Contrast-induced acute kidney injury[edit]

A meta-analysis of 9 trials with 1536 patients undergoing coronary angiography calculated that vitamin C decreased the risk of contrast-induced acute kidney injury by 33%.[55]

Endothelial function[edit]

A meta-analysis of 44 trials showed a significant positive effect of vitamin C on endothelial function. Benefit was found of vitamin C in doses in the range from 0.5 to 4 g/day, whereas lower doses from 0.09 to 0.5 g/day were not effective.[56]

See also[edit]

References[edit]

  1. ^ a b c Institute of Medicine (2000). "Vitamin C". Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: The National Academies Press. pp. 95–185. ISBN 0-309-06935-1. Retrieved 2017-09-01. 
  2. ^ Bad Science, Ben Goldacre
  3. ^ Trick Or Treatment, Simon Singh & Edzard Ernst
  4. ^ The Dark Side Of Linus Pauling's Legacy, Quackwatch
  5. ^ David Gorski, Science Based Medicine, 18 Aug 2008
  6. ^ Vitamin and mineral requirements in human nutrition (PDF) (2nd ed.). World Health Organization. 2004. p. 138. ISBN 9241546123. Retrieved 31 December 2014. 
  7. ^ Gropper SS, Smith JL, Grodd JL (2004). Advanced Nutrition and Human Metabolism (4th ed.). Belmont, CA. US: Thomson Wadsworth. pp. 260–275. 
  8. ^ Yeom CH, Jung GC, Song KJ (2007). "Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration". J. Korean Med. Sci. 22 (1): 7–11. doi:10.3346/jkms.2007.22.1.7. PMC 2693571Freely accessible. PMID 17297243. 
  9. ^ "Vitamin C (Ascorbic Acid)". University of Maryland Medical Center. April 2002. Retrieved 2007-02-19. 
  10. ^ a b Pauling L (1970). "Evolution and the need for ascorbic acid". Proc. Natl. Acad. Sci. USA. 67 (4): 1643–1648. Bibcode:1970PNAS...67.1643P. doi:10.1073/pnas.67.4.1643. PMC 283405Freely accessible. PMID 5275366. 
  11. ^ Pollock, J. I.; Mullin, R. J. (1987). "Vitamin C biosynthesis in prosimians: Evidence for the anthropoid affinity of Tarsius". American Journal of Physical Anthropology. 73 (1): 65–70. doi:10.1002/ajpa.1330730106. PMID 3113259. 
  12. ^ R. Eric Miller; Murray E. Fowler (2014-07-31). Fowler's Zoo and Wild Animal Medicine, Volume 8. p. 389. ISBN 9781455773992. Retrieved 2016-06-02. 
  13. ^ Jenness R, Birney E, Ayaz K (1980). "Variation of l-gulonolactone oxidase activity in placental mammals". Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology. 67 (2): 195–204. doi:10.1016/0305-0491(80)90131-5. 
  14. ^ a b Martinez del Rio C (July 1997). "Can passerines synthesize vitamin C?". The Auk. 114 (3): 513–16. doi:10.2307/4089257. JSTOR 4089257. 
  15. ^ Levy, Thomas (2011). Primal Panacea. MedFox Publishing. p. 352. ISBN 0983772800. 
  16. ^ Harri Hemilä (January 2006). "Do vitamins C and E affect respiratory infections?" (PDF). University of Helsinki. Retrieved 2007-02-21. 
  17. ^ "Tolerable Upper Intake Levels For Vitamins And Minerals" (PDF). European Food Safety Authority. 2006. Archived (PDF) from the original on March 16, 2016. 
  18. ^ Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins Journal of Nutritional Science and Vitaminology 2013(59):S67-S82.
  19. ^ "Office of Dietary Supplements - Vitamin C". ods.od.nih.gov. Retrieved 2016-02-26. 
  20. ^ "My Love Affair with Vitamin C" (PDF). 
  21. ^ Stone, I. (1979). "Homo sapiens ascorbicus, a biochemically corrected robust human mutant". Medical Hypotheses. 5 (6): 711–721. doi:10.1016/0306-9877(79)90093-8. PMID 491997. 
  22. ^ Rath M, Pauling L (1990). "Immunological evidence for the accumulation of lipoprotein(a) in the atherosclerotic lesion of the hypoascorbemic guinea pig". Proc Natl Acad Sci USA. 87 (23): 9388–9390. Bibcode:1990PNAS...87.9388R. doi:10.1073/pnas.87.23.9388. PMC 55170Freely accessible. PMID 2147514. 
  23. ^ Rath M, Pauling L (1990). "Hypothesis: lipoprotein(a) is a surrogate for ascorbate". Proc. Natl. Acad. Sci. USA. 87 (16): 6204–6207. Bibcode:1990PNAS...87.6204R. doi:10.1073/pnas.87.16.6204. PMC 54501Freely accessible. PMID 2143582. 
  24. ^ Rath M, Pauling L (1992). "A unified theory of human cardiovascular disease leading the way to the abolition of this disease as a cause for human mortality" (PDF). Journal of Orthomolecular Medicine. 7 (1): 5–15. 
  25. ^ Stone, Irwin (1972). The Healing Factor: Vitamin C Against Disease. Grosset and Dunlap. ISBN 0-448-11693-6. OCLC 3967737. 
  26. ^ Pauling, Linus (1986). How to Live Longer and Feel Better. W. H. Freeman and Company. ISBN 0-380-70289-4. OCLC 154663991. 
  27. ^ a b c d Verrax J, Calderon PB (December 2008). "The controversial place of vitamin C in cancer treatment". Biochem. Pharmacol. 76 (12): 1644–52. doi:10.1016/j.bcp.2008.09.024. PMID 18938145. 
  28. ^ Rees; Kelsey, Richards (March 1993). "Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency" (PDF). British Medical Journal. 306 (6881): 841–2. doi:10.1136/bmj.306.6881.841. PMC 1677333Freely accessible. PMID 8490379. 
  29. ^ Nankivell, BJ; Murali KM (2008). "Renal failure from vitamin C after transplantation" (PDF). The New England Journal of Medicine. 358 (4): e4. doi:10.1056/NEJMicm070984. PMID 18216350. 
  30. ^ "Safety (MSDS) data for ascorbic acid". Oxford University. October 9, 2005. Retrieved 2007-02-21. 
  31. ^ http://www.aapcc.org/annual-reports/
  32. ^ E. B. Henry, A. Carswell, A. Wirz, V. Fyffe & K. E. L. Mccoll (September 2005). "Proton pump inhibitors reduce the bioavailability of dietary vitamin C". Alimentary Pharmacology and Therapeutics. Alimentary Pharmacology & Therapeutics. 22 (6): 539–45. doi:10.1111/j.1365-2036.2005.02568.x. PMID 16167970. Retrieved 2007-02-21. 
  33. ^ C. Mowat; A. Carswell; A. Wirz; K.E. McColl (April 1999). "Omeprazole and dietary nitrate independently affect levels of vitamin C and nitrite in gastric juice". Gastroenterology. Alimentary Pharmacology & Therapeutics. 116 (4): 813–22. doi:10.1016/s0016-5085(99)70064-8. PMID 10092303. 
  34. ^ Loh HS, Watters K & Wilson CW (1 November 1973). "The Effects of Aspirin on the Metabolic Availability of Ascorbic Acid in Human Beings". J Clin Pharmacol. 13 (11): 480–486. doi:10.1002/j.1552-4604.1973.tb00203.x. PMID 4490672. Archived from the original on 16 March 2007. Retrieved 31 July 2007. 
  35. ^ Basu TK (1982). "Vitamin C-aspirin interactions". Int J Vitam Nutr Res Suppl. 23: 83–90. PMID 6811490. 
  36. ^ Ioannides C, Stone AN, Breacker PJ & Basu TK (1982). "Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs". Biochem Pharmacol. 31 (24): 4035–4038. doi:10.1016/0006-2952(82)90652-9. PMID 6818974. 
  37. ^ "Dietary Supplement Health and Education Act of 1994". 
  38. ^ Cameron E, Pauling L (October 1976). "Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer". Proc. Natl. Acad. Sci. USA. 73 (10): 3685–3689. Bibcode:1976PNAS...73.3685C. doi:10.1073/pnas.73.10.3685. PMC 431183Freely accessible. PMID 1068480. 
  39. ^ a b c "Vitamin C". American Cancer Society. 
  40. ^ a b Cabanillas, F (2010). "Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later?". Puerto Rico Health Sciences Journal. 29 (3): 215–7. PMID 20799507. 
  41. ^ The Riordan IVC Protocol for Adjunctive Cancer Care Intravenous Ascorbate as a Chemotherapeutic and Biological Response Modifying Agent
  42. ^ a b Berger MM (October 2006). "Antioxidant micronutrients in major trauma and burns: evidence and practice". Nutr Clin Pract. 21 (5): 438–49. doi:10.1177/0115426506021005438. PMID 16998143. 
  43. ^ Greenhalgh DG (2007). "Burn resuscitation". J Burn Care Res. 28 (4): 555–65. doi:10.1097/bcr.0b013e318093df01. PMID 17665515. 
  44. ^ Pham TN, Cancio LC, Gibran NS (2008). "American Burn Association practice guidelines burn shock resuscitation". J Burn Care Res. 29 (1): 257–66. doi:10.1097/BCR.0b013e31815f3876. PMID 18182930. 
  45. ^ Baker, W. L; Coleman, C. I (2016). "Meta-analysis of ascorbic acid for prevention of postoperative atrial fibrillation after cardiac surgery". American Journal of Health-System Pharmacy. 73 (24): 2056. doi:10.2146/ajhp160066. PMID 27806938. 
  46. ^ Polymeropoulos, Evangelos; Bagos, Pantelis; Papadimitriou, Maria; Rizos, Ioannis; Patsouris, Efstratios; Toumpoulis, Ioannis (2016). "Vitamin C for the Prevention of Postoperative Atrial Fibrillation after Cardiac Surgery: A Meta-Analysis". Advanced Pharmaceutical Bulletin. 6 (2): 243. doi:10.15171/apb.2016.033. PMID 27478787. 
  47. ^ Hu, Xiaolan; Yuan, Linhui; Wang, Hongtao; Li, Chang; Cai, Junying; Hu, Yanhui; Ma, Changhua (2017). "Efficacy and safety of vitamin C for atrial fibrillation after cardiac surgery: A meta-analysis with trial sequential analysis of randomized controlled trials". International Journal of Surgery. 37: 58–64. doi:10.1016/j.ijsu.2016.12.009. PMID 27956113. 
  48. ^ a b Hemilä, Harri; Suonsyrjä, Timo (2017). "Vitamin C for preventing atrial fibrillation in high risk patients: A systematic review and meta-analysis". BMC Cardiovascular Disorders. 17. doi:10.1186/s12872-017-0478-5. 
  49. ^ Hemilä, Harri (2017). "Publication bias in meta-analysis of ascorbic acid for postoperative atrial fibrillation". American Journal of Health-System Pharmacy. 74 (6): 372–373. doi:10.2146/ajhp160999. PMID 28274978. 
  50. ^ Juraschek, Stephen P; Guallar, Eliseo; Appel, Lawrence J; Miller, Edgar R (2012). "Effects of vitamin C supplementation on blood pressure: A meta-analysis of randomized controlled trials". The American Journal of Clinical Nutrition. 95 (5): 1079. doi:10.3945/ajcn.111.027995. PMC 3325833Freely accessible. PMID 22492364. 
  51. ^ Hemilä, Harri (2014). "The effect of vitamin C on bronchoconstriction and respiratory symptoms caused by exercise: A review and statistical analysis". Allergy, Asthma & Clinical Immunology. 10: 58. doi:10.1186/1710-1492-10-58. 
  52. ^ Hemilä, Harri (2013). "Vitamin C may alleviate exercise-induced bronchoconstriction: A meta-analysis". BMJ Open. 3 (6): e002416. doi:10.1136/bmjopen-2012-002416. PMC 3686214Freely accessible. PMID 23794586. 
  53. ^ a b Hemilä, Harri; Chalker, Elizabeth (2013). "Vitamin C for preventing and treating the common cold". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD000980.pub4. 
  54. ^ Hemilä, Harri (2017). "Vitamin C and Infections". Nutrients. 9 (4): 339. doi:10.3390/nu9040339. 
  55. ^ Sadat, Umar; Usman, Ammara; Gillard, Jonathan H; Boyle, Jonathan R (2013). "Does Ascorbic Acid Protect Against Contrast-Induced Acute Kidney Injury in Patients Undergoing Coronary Angiography". Journal of the American College of Cardiology. 62 (23): 2167. doi:10.1016/j.jacc.2013.07.065. PMID 23994417. 
  56. ^ Ashor, Ammar W; Lara, Jose; Mathers, John C; Siervo, Mario (2014). "Effect of vitamin C on endothelial function in health and disease: A systematic review and meta-analysis of randomised controlled trials". Atherosclerosis. 235 (1): 9–20. doi:10.1016/j.atherosclerosis.2014.04.004. PMID 24792921. 

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