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===Heart disease===
===Heart disease===
Vitamin C is the main component of the three ingredients in [[Linus Pauling]]'s patented but unvalidated preventive cure for [[lipoprotein(a)]]-related heart disease <ref>Rath MW, Pauling LC. {{US patent|5278189}} Prevention and treatment of occlusive cardiovascular disease with ascorbate and substances that inhibit the binding of lipoprotein(A). USPTO. 11 Jan 1994.</ref>, the other two being the amino acid [[lysine]] and [[niacin]] (a form of Vitamin B<sub>3</sub>). Lp(a) as an atherosclerotic, evolutionary substitute for ascorbate<ref>
Vitamin C is the main component of the three ingredients in [[Linus Pauling]]'s patented but unvalidated preventive cure for [[lipoprotein(a)]]-related heart disease <ref>Rath MW, Pauling LC. {{US patent|5278189}} Prevention and treatment of occlusive cardiovascular disease with ascorbate and substances that inhibit the binding of lipoprotein(A). USPTO. 11 Jan 1994.</ref>, the other two being the amino acid [[lysine]] and [[niacin]] (a form of Vitamin B<sub>3</sub>). Lp(a), as an atherosclerotic, evolutionary substitute for ascorbate<ref>
Rath M, Linus P. [http://www.pnas.org/cgi/reprint/87/16/6204 Hypothesis: Lipoprotein (a) is a surrogate for ascorbate]. Proc Natl Acad Sci USA. Vol 87, 6204–6207, Aug 1990.</ref> is still discussed as a hypothesis by mainstream medical science<ref>Kniffin CL, McKusick VA, Brennan P. [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=152200 APOLIPOPROTEIN(a); LPA]. OMIMTM - Online Mendelian Inheritance in Man, Johns Hopkins University. 1986–2006</ref> and the [[Matthias Rath|Rath]]-Pauling related protocols<ref>{{cite web |url=http://www.vrp.com/art/798.asp?c=1162763143031&k=/det/2100.asp&m=/includes/vrp.css&o=0&p=no&s=0 |title=Vitamin C & Heart Health - Linus Pauling's Collagen Connection |accessdate=2007-02-19 |author=Jim English and Hyla Cass |publisher=Vitamin Research Products }}</ref> have not been rigorously tested, nor have they been evaluated by the FDA (because no one has submitted a drug approval application).{{Citation needed|date=June 2009}}
Rath M, Linus P. [http://www.pnas.org/cgi/reprint/87/16/6204 Hypothesis: Lipoprotein (a) is a surrogate for ascorbate]. Proc Natl Acad Sci USA. Vol 87, 6204–6207, Aug 1990.</ref>, is still being discussed as a hypothesis by mainstream medical science.<ref>Kniffin CL, McKusick VA, Brennan P. [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=152200 APOLIPOPROTEIN(a); LPA]. OMIMTM - Online Mendelian Inheritance in Man, Johns Hopkins University. 1986–2006</ref> The [[Matthias Rath|Rath]]-Pauling related protocols<ref>{{cite web |url=http://www.vrp.com/art/798.asp?c=1162763143031&k=/det/2100.asp&m=/includes/vrp.css&o=0&p=no&s=0 |title=Vitamin C & Heart Health - Linus Pauling's Collagen Connection |accessdate=2007-02-19 |author=Jim English and Hyla Cass |publisher=Vitamin Research Products }}</ref> have not been rigorously tested, nor have they been evaluated by the FDA (because no one has submitted a drug approval application).{{Citation needed|date=June 2009}}


=== Cancer ===
=== Cancer ===

Revision as of 21:58, 25 November 2010

Chemical structure of vitamin C
Chemical structure of vitamin C

Vitamin C megadosage is the consumption of vitamin C (ascorbate) in doses well beyond the current Dietary Reference Intake. This dose is similar to the consumption of ascorbate in other primates which, like humans, cannot synthesize their own vitamin C.[1] Nearly all other animals synthesize vitamin C internally. As such, their cellular vitamin C concentrations are considerably higher than those achieved with the Reference Daily Intake set for humans.[2]

Vitamin C is a recognized antioxidant, which has led to its endorsement by some researchers as a complementary therapy for improving quality of life.[3] 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, although vitamin C is generally regarded as a beneficial antioxidant. There is a strong advocacy movement for such doses of vitamin C, despite a prolonged lack of conclusive medical evidence or large scale, formal trials in the 10 to 200+ grams per day range.

Background

Vitamin C is needed in the diet to prevent scurvy; however, since the 1930s, when it first became available in pure form, some physicians have experimented with vitamin C as a treatment for diseases other than scurvy.[4] Orthomolecular-based megadose recommendations for vitamin C are based mainly on theoretical speculation and observational studies. The speculation arises from the fact that most animals synthesize vitamin C and achieve much higher cellular concentrations than humans. Irwin Stone coined the term hypoascorbia to describe what he thought was a genetic defect in humans leading to a lower level of vitamin C than other primates. Observational studies began with work by McCormick and Klenner, who used intravenous (IV) vitamin C to treat a wide range of illnesses. The highest dose treatments, published clinical results of specific orthomolecular therapy regimens pioneered by Drs. Klenner (repeated IV treatments, 400–700+ (mg/kg)/day[5][6]) and Cathcart (oral use until the onset of diarrhea,[7] up to ~150 grams ascorbate per day for flu), have remained experimentally unaddressed by conventional medical authorities for decades.

A comprehensive systematic review of vitamin C and the cold found a minor effect (8% for adults, 14% for children) of reducing the cold's duration, but vitamin C failed to reduce the cold's occurrence in general cases, excluding extreme environments; a substantial reduction of the cold's occurrence (50%) was noticed, however, in "marathon runners, skiers, and soldiers exposed to significant cold and/or physical stress." [8] The minimum dose rate in the studies examined (0.2g) was much lower than the dose advocated by megavitamin proponents. Its effect on cancer has been controversial, beginning with a heavily criticized[9] 1976 study which alleged to find significantly increased survival among cancer patients treated with intravenous and oral vitamin C.[10] Three subsequent studies using oral ascorbate failed to replicate these findings,[11][12][13] the original series was criticized for failing to randomize and control the treatment versus placebo groups,[14] and vitamin C's use as a cancer treatment was dismissed by mainstream medicine.[15][9] Recently, research has found that high dose i.v. vitamin C, which was found to kill in vitro cancer cells through the generation of hydrogen peroxide,[16] and tests of intravenous vitamin C on cancer patients, are not toxic, though they were also found to be ineffective at killing cancer cells or shrinking tumours.[17]

Conditions

Common cold

See also: Vitamin C and the common cold

The results of three meta-analyses show vitamin C in doses ranging from 200 mg to 2 grams per day reduces the duration, but not the incidence, of the common cold by 8% for adults and 14% for children. Incidence appears to be reduced by 50% in stressed adults, such as soldiers or athletes, in extreme cold environments. The clinical significance of these effects is uncertain, but the biological effect appears genuine.[8][18]

A 2010 Cochrane Review concluded:[19]


The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine prophylaxis is not justified. Vitamin C could be useful for people exposed to brief periods of severe physical exercise. While the prophylaxis trials have consistently shown that vitamin C reduces the duration and alleviates the symptoms of colds, this was not replicated in the few therapeutic trials that have been carried out. Further therapeutic RCTs are warranted.

Heart disease

Vitamin C is the main component of the three ingredients in Linus Pauling's patented but unvalidated preventive cure for lipoprotein(a)-related heart disease [20], the other two being the amino acid lysine and niacin (a form of Vitamin B3). Lp(a), as an atherosclerotic, evolutionary substitute for ascorbate[21], is still being discussed as a hypothesis by mainstream medical science.[22] The Rath-Pauling related protocols[23] have not been rigorously tested, nor have they been evaluated by the FDA (because no one has submitted a drug approval application).[citation needed]

Cancer

In 1976 Pauling and Ewan Cameron published a trial of 100 patients which suggested that treatment with intravenous vitamin C significantly increased lifespans.[10] Three large, placebo-controlled trials of only oral (not intravenous asorbic acid, as with Paulings' study) vitamin C in 1979, 1983 and 1985[13][11][12] did not find a positive effect of vitamin C in cancer patients and a re-analysis of Pauling and Cameron's initial data found that the comparison groups were not adequately controlled or randomized, with the vitamin C group being less sick than controls when entering the study.[14][15] More recent Phase I clinical trial studies, which were limited in scope to a "dose-finding phase" have confirmed that while vitamin C is not necessarily toxic to cancer patients,[24] it is not useful as a treatment for cancer in humans when doses do not exceed 1.5 grams ascorbic acid/kg body weight [17] and in vitro tests on cell lines which used dehydroascorbic acid (not asorbic acid) indicate that it may interfere with the effectiveness of chemotherapy.[25] Though there have been some recent research projects on vitamin C as a chemotherapeutic agent, no treatment protocols have been developed based on the substance.[26]

Treatment of phencyclidine psychosis

Large dosages of vitamin C can be used in the acute treatment of phencyclidine (PCP) psychosis, It operates as a secondary rather than primary treatment. Usually, 1000–2000 mg. of vitamin C are given intravenously over the course of 5–10 minutes. It is given in combination with a DA-2 antagonist such as haloperidol or risperidone. The antagonist is given intramuscularly and not combined with vitamin C. The vitamin acts synergistically with phencyclidine or its metabolites.[27]

Gout

In 2008 researchers established that higher vitamin C intake reduces serum uric acid levels, and is associated with lower incidence of gout. The effect is more pronounced as intake increases into the megavitamin range.[28]

Lifespan

A study published in 1992 suggested that men who took 800 mg of vitamin C daily lived approximately six years longer than men who took only 60 mg of vitamin C daily[29] though there were substantial differences between the groups aside from vitamin intake; because correlation does not imply causation it is impossible to determine if the extended lifespan was due to increased vitamin intake, or if other factors (e.g. greater concern regarding health and disease or greater disposable income to spend on vitamin supplements) caused both the extended lifespan and an increased vitamin intake.[30]

Possible adverse effects

While being harmless in most typical quantities, as with all substances to which the human body is exposed, vitamin C can still cause harm under certain conditions. In the medical community, these are known as contraindications.

  • A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD), can cause sufferers to develop hemolytic anemia after ingesting specific oxidizing substances (favism), such as very large dosages of vitamin C. There are common, inexpensive tests for G6PD deficiency.
  • There is a longstanding belief among the mainstream medical community that vitamin C causes kidney stones, which seems based little on science.[31] Although some individual recent studies have found a relationship[32] there is no clear relationship between excess ascorbic acid intake and kidney stone formation.[33]

Side effects

Although vitamin C can be well tolerated at doses well above the RDA recommendations, megadosing may cause side effects such as stomach upset and laxative effects such as diarrhea. The dose at which these effects may occur varies with the individual and health condition.

  • Relatively large doses of vitamin C may cause indigestion, particularly when taken on an empty stomach. This generally occurs at doses larger than 10,000 mg / day, but may occur at much higher doses if the patient is ill.[34]
  • When taken in large doses, vitamin C causes diarrhea. The minimum dose that brings about this laxation effect varies on the individual. The amount of vitamin C that is just short of the dose which produces diarrhea has been called the "bowel tolerance" dose. It is said to range from 4 to 15 grams per day in healthy individuals, and up to 200 grams per day or more during illness. Robert Cathcart M.D. reported that the sicker a patient is, the more ascorbic acid he can tolerate by mouth before diarrhea is produced.[35]
  • It has been suggested that large doses of acidic vitamin C solution (ascorbic acid) swished around the mouth, rather than swallowed directly without a neutral rinse, may erode dentition.[36]
  • A 31-year-old Australian woman who had received a kidney transplant died soon afterward as a result of calcium oxalate deposits that destroyed her new kidney function. Her doctors concluded that high-dose vitamin C therapy should be avoided in patients with kidney failure.[37]
  • It has been speculated that high dosage vitamin C ingestion may cause early onset of puberty in females. The source of the vitamin is said to be independent of the effect.[38] [verification needed]

Chance of overdose

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.[39] This is equivalent to a 150-pound human ingesting 1.8 pounds of Vitamin C.

Conflicts with prescription drugs

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%, 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.[40]

Potential harmful effects

  • Some test-tube experiments have interpreted that Vitamin C may have possible adverse effects on decomposition of lipid peroxides[41] in nonviable in vivo quantities and conditions[42] and inhibit caspase-8 dependent apoptosis.[43] In April 1998 the journal Nature reported pro-oxidant effects of excessive doses of vitamin C / ascorbic acid.[44] The effects were noted in test tube experiments and on only two of the 20 markers of free radical damage to DNA. They have not been supported by further evidence from living organisms.[42]
  • A speculated increased risk of kidney stones may be a side effect of taking vitamin C in larger than normal amounts (more than 1 gram). The potential mechanism of action is through the metabolism of vitamin C to dehydroascorbic acid, which is then metabolized to oxalic acid,[45] a known constituent of kidney stones. However, this oxalate issue is still controversial, with evidence being presented for[46] and against[47] the possibility of this side effect.
  • "Rebound scurvy" is a theoretical, never observed, condition that could occur when daily intake of vitamin C is rapidly reduced from a very large amount to a relatively low amount. Advocates suggest this is an exaggeration of the rebound effect which occurs because ascorbate-dependent enzyme reactions continue for 24–48 hours after intake is lowered, and use up vitamin C which is not being replenished.
  • Some writers[48] have identified a risk of poor copper absorption from high doses of vitamin C. Ceruloplasmin levels seem specifically lowered by high vitamin C intake. In one study, 600 milligrams of vitamin C daily led to lower ceruloplasmin levels similar to those caused by copper deficiency.[49] In another, ceruloplasmin levels were significantly reduced.[50]
  • Some alternative medicine proponents suggest that doses of around 6-10 grams per day of vitamin C can induce an abortion in women under 4 weeks of pregnancy.[51] This is based on evidence that high-dose vitamin C increases estrogen levels that may contribute to abortion in early-stage pregnancy, and that these properties have been demonstrated in laboratory animals.[52] This theory however is in direct opposition to Dr. Klenner's claim that there were no miscarries in over 300 consecutive pregnant patients who received 3g to 6g per day of Vitamin C,[53] whereby Dr. Klenner concluded that failure to use this agent in sufficient amounts in pregnancy borders on malpractice.

Genetic deficiency and broad spectrum hypotheses

Since its discovery vitamin C has been considered almost a universal panacea[citation needed] by some, although this led to suspicions of it being overhyped by others.[54]

Humans and higher primates, as well as guinea pigs and small number of other animal species, carry a mutated and ineffective form of the enzyme L-gulonolactone oxidase, the fourth and last step in the ascorbate-producing machinery. This mutation likely occurred 40 to 25 million years ago (in the anthropoids lineage). The three surviving enzymes continue to produce the precursors to vitamin C but the process is incomplete and the body then disassembles them.

It is agreed by most researchers, proponents and critics alike, that the amounts of vitamin C consumed by our common anthropoid ancestor in its normal habitat (African rainforests) was amply sufficient to prevent death from scurvy and did not limit its ability to reproduce: i.e., it was an evolutionarily feasible change. Bourne[55] (quoted in Stone[56]), Pauling[1] and, recently, Milton,[57] showed that these amounts were likely 10 to 20 times higher than what modern humans consume when eating cultivated species, as opposed to the less palatable vitamin-C-rich plant species growing in rainforests.

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.

In the 1960s, the Nobel-Prize-winning chemist Linus Pauling, after contact 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 10,000 milligrams 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 as much as 100,000 mg daily when faced with life-threatening disease, trauma, or stress.[58] Pauling's book sold widely and many advocates today see its influence as the reason there was a marked downward trend in US heart disease from the early 1980s onwards.[citation needed]

Stone's work also informed the practise of Dr. Robert Cathcart, in the 1970s and 1980s. Cathcart developed the concept of bowel tolerance, the use until the onset of diarrhea, followed by tapering of dose. He found that, unlike healthy people, seriously ill persons could tolerate levels of hundreds of grams per day before their bowel tolerance limit is reached.

Matthias Rath is a controversial German physician who once worked with Pauling and published in the Proceedings of the National Academy of Sciences.[59][60] He is an active proponent and publicist for high dose vitamin C. Pauling's and Rath's extended theory [61] 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 (higher primates and guinea pigs). Pauling and Rath theorised that, although eventually harmful, lipoprotein deposition on artery walls was beneficial to the human species and a "surrogate for ascorbate" in that it kept individuals alive until access to vitamin C allowed arterial damage to be repaired. Atherosclerosis is thus a vitamin-C-deficiency disease.

Based on another study by Pauling and colleagues[62] and other studies,[63][64][65] Rath argued publicly that high doses of vitamin C can be effectively used against viral epidemics such as HIV,[66] SARS and bird flu.[67][68]

It has been suggested by some advocates that vitamin C is really a food group in its own right, like carbohydrates or protein, and should not be seen as a pharmaceutical or vitamin at all. {Irwin Stone: "The Healing Factor"}

Genetic rationales for high doses

Four gene products are necessary to manufacture vitamin C from glucose. The loss of activity of the gene for the last step, Pseudogene ΨGULO (GLO) the terminal enzyme responsible for manufacture of vitamin C, has occurred separately in the history of several species. The loss of this enzyme activity is responsible for the inability of guinea pigs to synthesize vitamin C enzymatically, but this event happened independently of the loss in the haplorrhini suborder of primates, including humans. The remains of this non-functional gene with many mutations are, however, still present in the genome of the guinea pigs and in primates, including humans.[69][70] GLO activity has also been lost in all major families of bats, regardless of diet.[71] In addition, the function of GLO appears to have been lost several times, and possibly reacquired, in several lines of passerine birds, where ability to make vitamin C varies from species to species.[72]

Loss of GLO activity in the primate order supposedly occurred about 63 million years ago, at about the time it split into the suborders haplorrhini (which lost the enzyme activity) and the more primitive strepsirrhini (which retained it). The haplorrhini ("simple nosed") primates, which cannot make vitamin C enzymatically, include the tarsiers and the simians (apes, monkeys and humans). The suborder strepsirrhini (bent or wet-nosed prosimians), which are still able to make vitamin C enzymatically, include lorises, galagos, pottos, and to some extent, lemurs.[73]

Stone[74] and Pauling[75] calculated, based on the diet of our primate cousins[76] (similar to what our common ancestors are likely to have consumed when the gene mutated), that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human requiring 2,500 kcal a day.

The established RDA has been criticized by Pauling to be one that will prevent acute scurvy, and is not necessarily the dosage for optimal health.[77]

Regulation of vitamin C

Regulation

There are regulations in most countries which limit the claims on the treatment of disease that can be placed on food, drug, and nutrient product labels. Regulations include:

  • Claims of therapeutic effect with respect to the treatment of any medical condition or disease are prohibited by the Food and Drug Administration (in the USA, and by the corresponding regulatory agencies in other countries) unless the substance has gone through a well established clinical trial with neutral oversight.
  • In the United States, the following notice is mandatory on food, drug, and nutrient product labels which make 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.[78]

Advocacy arguments

Vitamin C advocates argue that there is a large body of scientific evidence that the vitamin has a wide range of health and therapeutic benefits but which they claim have been ignored. They claim the following factors affect the marketing and distribution of vitamin C, and the dissemination of information concerning the nutrient:[79]

  • There is some evidence of the applications and efficacy of vitamin C, but governmental agency dose and frequency of intake recommendations have remained relatively fixed. This has led some researchers to challenge the recommendations. In 2003 Steve Hickey and Hilary Roberts of the Manchester Metropolitan University published a fundamental criticism of the approach taken to fix the nutritional requirement of vitamin C. They again argued in 2004 that the RDA which is based on blood plasma and white blood cell saturation data from the National Institutes of Health (NIH) was based on flawed data.[80] According to these authors, the doses required to achieve blood, tissue and body "saturation" are much larger than previously believed. They allege that the Institute of Medicine (IoM) and the NIH have failed to respond to an open letter from a number of scientists and medical researchers, notably Doctors Steve Hickey, Hilary Roberts, Ian Brighthope, Robert Cathcart, Abram Hoffer, Archie Kalokerinos, Tom Levy, Richard Passwater, Hugh Riordan, Andrew Saul and Patrick Holford, which called for revision of the RDI (Reference Daily Intake).

See also

References

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  20. ^ Rath MW, Pauling LC. U.S. patent 5,278,189 Prevention and treatment of occlusive cardiovascular disease with ascorbate and substances that inhibit the binding of lipoprotein(A). USPTO. 11 Jan 1994.
  21. ^ Rath M, Linus P. Hypothesis: Lipoprotein (a) is a surrogate for ascorbate. Proc Natl Acad Sci USA. Vol 87, 6204–6207, Aug 1990.
  22. ^ Kniffin CL, McKusick VA, Brennan P. APOLIPOPROTEIN(a); LPA. OMIMTM - Online Mendelian Inheritance in Man, Johns Hopkins University. 1986–2006
  23. ^ Jim English and Hyla Cass. "Vitamin C & Heart Health - Linus Pauling's Collagen Connection". Vitamin Research Products. Retrieved 2007-02-19.
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  34. ^ "Bowel Titration>".
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  41. ^ [1] Vitamin C produces gene-damaging compounds Accessed July 2007
  42. ^ a b Balz Frei, Ph.D. (November, 2001). "Vitamin C Doesn't Cause Cancer!". Oregon State University. Retrieved 2007-02-21. {{cite web}}: Check date values in: |date= (help)
  43. ^ Perez-Cruz I, Cárcamo JM, Golde DW (2007). "Caspase-8 dependent TRAIL-induced apoptosis in cancer cell lines is inhibited by vitamin C and catalase". Apoptosis. 12 (1): 225–34. doi:10.1007/s10495-006-0475-0. PMID 17031493. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  44. ^ Ian D. Podmore, Helen R. Griffiths, Karl E. Herbert, Nalini Mistry, Pratibha Mistry and Joseph Lunec (9 April 1998). "Vitamin C exhibits pro-oxidant properties". Nature. 392 (6676): 559. doi:10.1038/33308. PMID 9560150.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  45. ^ Hokama S, Toma C, Jahana M; et al. (2000). "Ascorbate conversion to oxalate in alkaline milieu and Proteus mirabilis culture". Mol Urol. 4 (4): 321–8. PMID 11156698. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
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  47. ^ Stephen Lawson (November 1999). "What About Vitamin C and Kidney Stones?". The Linus Pauling Institute. Retrieved 2007-02-21.
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  51. ^ Vitamin C A Home Abortion Remedy?
  52. ^ E.P. Samborskaia, "The Mechanism of Artificial Abortion by Use of Ascorbic Acid", Biulleten Eksperimental’noi Biologii i Meditsiny, Vol 62, 1966, pp96-98. Cited in Irwin Stone, The Healing Factor: Vitamin C Against Disease (New York; Grossent & Dunlap, 1977)
  53. ^ [2] Klenner's "primary and lasting benefits in pregnancy"
  54. ^ Harri Hemilä (2006). "Do vitamins C and E affect respiratory infections?" (PDF). University of Helsinki. Retrieved 2007-02-21. {{cite web}}: Unknown parameter |month= ignored (help)
  55. ^ Bourne GH (1949). "Vitamin C and immunity". Brit J Nutrit. 2 (4): 341–7. doi:10.1079/BJN19480063. PMID 18145790.
  56. ^ Stone I (1966). "On the genetic etiology of scurvy". Acta geneticae medicae et gemellologiae. 15 (4): 345–50. PMID 5971711. {{cite journal}}: |access-date= requires |url= (help)
  57. ^ Milton K (1999). "Nutritional characteristics of wild primate foods: do the diets of our closest living relatives have lessons for us?". Nutrition (Burbank, Los Angeles County, California). 15 (6): 488–98. PMID 10378206. {{cite journal}}: |access-date= requires |url= (help)
  58. ^ Stone, Irwin (July 16, 1978). "Eight Decades of Scurvy. The Case History of a Misleading Dietary Hypothesis". Retrieved 2007-04-06. Biochemical research in the 1950's showed that the lesion in scurvy is the absence of the enzyme, L-Gulonolactone oxidase (GLO) in the human liver (Burns, 1959). This enzyme is the last enzyme in a series of four, which converts blood sugar (glucose) into ascorbate in the mammalian liver. This liver metabolite, ascorbate, is produced in an unstressed goat, for instance, at the rate of about 13,000 mg per day per 150 pounds body weight (Chatterjee, 1973). A mammalian feedback mechanism increases this daily ascorbate production many fold under stress (Subramanian et al., 1973) {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  59. ^ 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): 9388–90. doi:10.1073/pnas.87.23.9388. PMC 55170. PMID 2147514.
  60. ^ Rath M, Pauling L (1990). "Hypothesis: lipoprotein(a) is a surrogate for ascorbate". Proc Natl Acad Sci USA. 87 (16): 6204–7. doi:10.1073/pnas.87.16.6204. PMC 54501. PMID 2143582.
  61. ^ 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.
  62. ^ Harakeh S, Jariwalla RJ, Pauling L (1990). "Suppression of human immunodeficiency virus replication by ascorbate in chronically and acutely infected cells". Proc Natl Acad Sci USA. 87 (18): 7245–9. doi:10.1073/pnas.87.18.7245. PMC 54720. PMID 1698293.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  64. ^ Harakeh S, Jariwalla R (1997). "NF-kappa B-independent suppression of HIV expression by ascorbic acid". AIDS Res Hum Retroviruses. 13 (3): 235–9. doi:10.1089/aid.1997.13.235. PMID 9115810.
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  66. ^ "Nigeria: Vitamin C Can Suppress HIV/Aids Virus". All Africa.com. 22 May 2006. Retrieved 2006-06-16.
  67. ^ Sarah Boseley (May 14, 2005). "Discredited doctor's 'cure' for Aids ignites life-and-death struggle in South Africa". The Guardian. Retrieved 2007-02-21.
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  69. ^ Nishikimi M, Kawai T, Yagi K (25 October 1992). "Guinea pigs possess a highly mutated gene for L-gulono-gamma-lactone oxidase, the key enzyme for L-ascorbic acid biosynthesis missing in this species". J Biol Chem. 267 (30): 21967–72. PMID 1400507.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  70. ^ Ohta Y, Nishikimi M (1999). "Random nucleotide substitutions in primate nonfunctional gene for L-gulono-gamma-lactone oxidase, the missing enzyme in L-ascorbic acid biosynthesis". Biochim Biophys Acta. 1472 (1–2): 408–11. PMID 10572964. {{cite journal}}: Unknown parameter |month= ignored (help)
  71. ^ A trace of GLO was detected in only 1 of 34 bat species tested, across the range of 6 families of bats tested: See Jenness R, Birney E, Ayaz K (1980). "Variation of L-gulonolactone oxidase activity in placental mammals". Comparative Biochemistry and Physiology. 67B: 195–204.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    Earlier reports of only fruit bats being deficient were based on smaller samples.
  72. ^ Carlos Martinez del Rio (1997). "Can passerines synthesize vitamin C?". The Auk. {{cite journal}}: Unknown parameter |month= ignored (help)
  73. ^ Pollock JI, Mullin RJ (1987). "Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius". Am J Phys Anthropol. 73 (1): 65–70. doi:10.1002/ajpa.1330730106. PMID 3113259. {{cite journal}}: Unknown parameter |month= ignored (help)
  74. ^ Stone, Irwin (1972). The Healing Factor: Vitamin C Against Disease. Grosset and Dunlap. ISBN 0-448-11693-6. OCLC 3967737.
  75. ^ Pauling, Linus (1970). "Evolution and the need for ascorbic acid". Proc Natl Acad Sci USA. 67 (4): 1643–8. doi:10.1073/pnas.67.4.1643. PMC 283405. PMID 5275366.
  76. ^ Milton K (2003). "Micronutrient intakes of wild primates: are humans different?" (PDF). Comp Biochem Physiol a Mol Integr Physiol. 136 (1): 47–59. doi:10.1016/S1095-6433(03)00084-9. PMID 14527629.
  77. ^ Pauling, Linus (1986). How to Live Longer and Feel Better. W. H. Freeman and Company. ISBN 0-380-70289-4. OCLC 154663991 15690499. {{cite book}}: Check |oclc= value (help)
  78. ^ "Dietary Supplement Health and Education Act of 1994".
  79. ^ Richards E (1988). "The Politics of Therapeutic Evaluation: The Vitamin C and Cancer Controversy". Social Studies of Science. 18 (4): 653–701. doi:10.1177/030631288018004004. {{cite journal}}: Unknown parameter |month= ignored (help)
  80. ^ Hickey S, Roberts H (2005). "Misleading information on the properties of vitamin C". PLoS Med. 2 (9): e307, author reply e309. doi:10.1371/journal.pmed.0020307. PMC 1236801. PMID 16173838. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)

External links

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