Health Cures

Nutriment – Vitamin C 1-3

### VITAMIN C, Ascorbate : page 1/3

Following is a reproduction of articles about benefits of vitamin C, for full details on the best dosages to take, please refer to the advises of :

Dr. PAULING, Dr. RATH, Dr. FONORROW, Dr. NIEPER and Dr. KLENNER; see links above, in the menu

## The Many Faces of Vitamin C, HEALTH E-BYTES, Issue No. 9, June, 2005, http://tomlevymd.com/archiveissue9.htm

A question that has been presented to me numerous times since the publication of my book, Curing the Incurable: Vitamin C, Infectious Diseases, and Toxins, is:

“What kind of vitamin C should I take, and why?” It is a very good question, indeed, as the variable effects on both short-term and long-term clinical outcomes can be dramatic.

It should first be emphasized that all of the forms of vitamin C share the characteristic of having a positively-charged cation and a negatively-charged anion in the dissolved form.

Ascorbic acid is the hydrogen ion with the ascorbate anion; sodium ascorbate is the sodium ion with the ascorbate anion; calcium ascorbate is the calcium ion with the ascorbate anion; and so on. It is now readily apparent that all forms of vitamin C share the characteristic of having the ascorbate anion. In fact, it is the ascorbate anion that is the electron-donating, clinically active portion of all vitamin C preparations. However, the companion cations can have significant biological impacts as well, and this needs to be considered when choosing the best forms of supplementation for both short-term and long-term needs.

Mineral Ascorbates

The lion’s share of all forms of vitamin C come as mineral ascorbates. The most common mineral ascorbates used in vitamin C supplementation include the following:

# Sodium ascorbate
# Calcium ascorbate
# Magnesium ascorbate
# Potassium ascorbate
# Manganese ascorbate
# Zinc ascorbate
# Molybdenum ascorbate
# Chromium ascorbate

# Sodium ascorbate is probably the best and certainly the least expensive of the mineral ascorbates for regular supplementation at relatively high doses (six grams or more daily). Many doctors and patients fear the regular dosing of sodium, however, due to the long-standing medical admonition to minimize sodium intake, especially for hypertension and cardiac failure patients. Indeed, sodium chloride (table salt) has long been known to facilitate fluid retention (increased plasma volume), a state that directly aggravates hypertension and heart failure. However, it appears that only sodium really results in significant fluid retention when administered with the chloride anion. Sodium when given with the anions citrate, ascorbate, or bicarbonate does not appear to adversely affect hypertension or to increase blood volume. Because of these findings, it has been directly suggested that the concept of “sodium-dependent” hypertension should be changed to “sodium chloride-dependent” hypertension (Kurtz and Morris, 1983; Kurtz et al., 1987).

Anecdotally, I have never found multi-gram doses of sodium ascorbate to adversely affect blood pressure or blood volume status. However, since there always appear to be exceptions to every rule in biology, anyone who notices elevated blood pressures or ankle edema after high doses of sodium ascorbate would probably be well-advised to supplement with a different form of vitamin C.

# Calcium ascorbate is currently a very popular form of vitamin C supplementation. In addition to being directly labeled as calcium ascorbate, this form of vitamin C is also marketed as an “ester” form of vitamin C or a “buffered” form of vitamin C. Much of the popularity of this form of vitamin C comes from the fact that many people are looking for extra sources of calcium on a daily basis in addition to taking their vitamin C. With some minor variability, these products typically deliver approximately 100 mg of calcium for every 800 to 900 mg of ascorbate given. Also, the 100 mg or so of calcium with each gram of product usually has a very high degree of absorption when compared to other common forms of calcium supplementation, such as calcium chloride or calcium bicarbonate (Tsugawa et al., 1999).

However, the calcium-delivering properties of calcium ascorbate are precisely the best reasons for avoiding this product. Although it appears from the early work of Weston A. Price, D.D.S. that acutely raising the ionic calcium levels in the blood can greatly improve the acute phases of healing in damaged tissues, this does not address what the long-term consequences of calcium administration may entail. In fact, it appears that the bulk of the scientific data supports the concept that the vast majority of the older population is massively overdosed on calcium and legitimately suffering from calcium toxicity. We continue to be stressed with warnings of increased risk of osteoporosis while the data clearly shows that most deaths in patients with osteoporosis relate to the vascular system and not the bones (Kruger and Horrobin, 1997). Furthermore, excess calcium in the coronary arteries, one marker of long-term calcium overdosage, is also directly correlated to increased risk of heart attack (Raggi et al., 2003), increased incidence of chronic degenerative disease (Arad et al., 2001; Christian et al., 2003; Kiryu et al., 2003; Wong et al., 2003), and increased degree of overall “all-cause mortality” (Shaw et al., 2003).

So, if you are a older chronic calcium supplement taker, just be aware that there are negatives to this practice. The chance of dying from an osteoporotic fracture doesn’t remotely approach the chances of dying from a heart attack, cancer, or another chronic degenerative disease. Furthermore, it is far from clear that the traditional treatment approach to osteoporosis significantly affects the likelihood of a subsequent fracture. The scientific evidence, however, is very clear that supplemental calcium often fuels the progression of atherosclerosis, with the expected increased chance of heart attack.

If the above does not convince you that supplemental calcium, with very rare exceptions, should be completely avoided, at least start tracking your calcium accumulations. The coronary artery CAT scan should show no calcium. Check it. Your heart should not be calcifying. Check your ECHOcardiogram. Hair analysis should not show excess calcium. Check it. If any or all of these tests are positive for calcium, you should be especially concerned about dumping still more supplemental calcium into your blood and body on a daily basis.

# Magnesium ascorbate is another significant mineral ascorbate. Unlike the other mineral ascorbates (except for sodium ascorbate) it is very difficult to overdose on this form of ascorbate. This is because the magnesium cation is very bioavailable and very effective in reversing the damage done by excess calcium, a condition shared by most older individuals. Bioavailable magnesium (as ascorbate or as magnesium-amino acid chelates; NOT the commonly taken magnesium oxide form) is very effective in mobilizing abnormally deposited calcium throughout the body. As such, it is one of the most effective (and still least utilized) treatments available for osteoporosis.

While there is nothing wrong with taking large amounts of magnesium ascorbate, it is more economical to take large doses of bioavailable magnesium and sodium ascorbate separately to obtain the optimal effects of both these supplements.

# Potassium, manganese, zinc, molybdenum, and chromium ascorbates are additional mineral ascorbates. All of the cations are desirable as supplements, but they can be easily be overdosed if they are used to deliver multi-gram doses of ascorbate.

# Ascorbyl Palmitate

Ascorbyl palmitate is another form of vitamin C that is somewhat unique in that it has both water-soluble and fat-soluble qualities. It is touted by some as a superior delivery form of vitamin C as ascorbate into the body. This has not really been clearly proven, and even if it were, ascorbyl palmitate would be a very expensive way to provide daily multi-gram doses of ascorbate. The fat-soluble qualities of ascorbyl palmitate do make it a good form of vitamin C to include in various skin creams and other dermatological preparations.

# Liposome-encapsulated Ascorbate

Liposomes were first proposed as a unique drug delivery system approximately 35 years ago (Bangham, 1995; Gregoriadis, 1995). One of the primary reasons for utilizing a liposome-encapsulation delivery system is to assure a near complete absorption of the encapsulated nutrient or drug into the bloodstream. The physical qualities of the liposome also eliminate the need for digestive activity before absorption.

Anecdotally speaking, I have taken a liposome-encapsulated form of ascorbate and found that it is virtually impossible to induce the “C-flush” effect that can be seen with large enough doses of the mineral ascorbates, most commonly sodium ascorbate and calcium ascorbate. Furthermore, it appears that the enhanced absorption along with the phospholipid dose absorbed at the same time has uniquely positive clinical benefits.

My Current Recommendations

For the reasons mentioned above, I never recommend the regular ingestion of vitamin C as calcium ascorbate. The remaining mineral ascorbates are acceptable forms of vitamin C supplementation, but one can risk overdosing the cations if multi-gram doses of these forms of vitamin C are taken, with the exceptions of the sodium and magnesium ascorbates.

For regular daily supplementation, sodium ascorbate is an economical, well-tolerated form of vitamin C. While many wish to avoid the “C-flush” effect, it appears to be a very good way to keep the gut relatively detoxified and clean. For those wishing to have a near-complete absorption of their vitamin C dose, the liposome-encapsulated form of vitamin C is optimal.

For acute infectious and toxic states, I still recommend getting intravenous sodium ascorbate, usually at doses of 50 grams or more over several hours for most individuals. However, I would also recommend adding the liposome-encapsulated form of vitamin C orally at the same time. If the intravenous sodium ascorbate is not available, I recommend taking sodium ascorbate to bowel tolerance, and then taking the liposome-encapsulated form of vitamin C, several grams hourly, guided by symptoms and clinical response to determine subsequent dosing.

Resources for Liposomal Vitamin C

More information about liposomal vitamin C can be found at http://www.livonlabs.com/ . If you are a health professional and express an interest in acquiring liposomal vitamin C for resale to your patients, you can get a free information packet, including free product samples by going to http://www.LivOnLabs.com/health_professional or calling LivOn Labs at (702) 897-1065 or sending an email to lnachman@livonlabs.com.

Bibliography

– Arad, Y., D. Newstein, F. Cadet, M. Roth, and A. Guerci (2001) Association of multiple risk factors and insulin resistance with increased prevalence of asymptomatic coronary artery disease by an electron-beam computed tomographic study. Arteriosclerosis, Thrombosis, and Vascular Biology 21(12):2051-2058.
– Bangham, A. (1995) Surrogate cells or Trojan horses. The discovery of liposomes. Bioessays 17(12):1081-1088.
– Christian, R., D. Dumesic, T. Behrenbeck, A. Oberg, P. Sheedy, and L. Fitzpatrick (2003) Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism 88(6):2562-2568.
– Gregoriadis, G. (1995) Engineering liposomes for drug delivery: progress and problems. Trends in Biotechnology 13(12):527-537.
– Kiryu, S., V. Raptopoulos, J. Baptista, and H. Hatabu (2003) Increased prevalence of coronary artery calcification in patients with suspected pulmonary embolism. Academic Radiology 10(8):840-845.
– Kruger, M. and D. Horrobin (1997) Calcium metabolism, osteoporosis and essential fatty acids: a review. Progress in Lipid Research 36(2-3):131-151.
– Kurtz, T. and R. Morris, Jr. (1983) Dietary chloride as a determinant of “sodium-dependent” hypertension. Science 222(4628):1139-1141.
– Kurtz, T., H. Al-Bander, and R. Morris, Jr. (1987) “Salt-sensitive” essential hypertension in men. Is the sodium ion alone important? The New England Journal of Medicine 317(17):1043-1048.
– Raggi, P., B. Cooil, L. Shaw, J. Aboulhson, J. Takasu, M. Budoff, and T. Callister (2003) Progression of coronary calcium on serial electron beam tomographic scanning is greater in patients with future myocardial infarction. The American Journal of Cardiology 92(7):827-829.
– Shaw, L., P. Raggi, E. Schisterman, D. Berman, and T. Callister (2003) Prognostic value of cardiac risk factors and coronary artery calcium screening for all-cause mortality. Radiology 228(3):826-833.
– Tsugawa, N., T. Yamabe, A. Takeuchi, M. Kamao, K. Nakagawa, K. Nishijima, and T. Okano (1999) Intestinal absorption of calcium from calcium ascorbate in rats. Journal of Bone and Mineral Metabolism 17(1):30-36.
– Wong, N., M. Sciammarella, D. Polk, A. Gallagher, L. Miranda-Peats, B. Whitcomb, R. Hachamovitch, J. Friedman, S. Hayes, and D. Berman (2003) The metabolic syndrome, diabetes, and subclinical atherosclerosis assessed by coronary calcium. Journal of the American College of Cardiology 41(9):1547-1553.

Copyright 2005 by Thomas E. Levy, MD, JD
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## Pregnancy risk reduction: http://www.nutraingredients.com/news/news-ng.asp?n=59359-vitamin-c-reduces

Vitamin C reduces risk of pregnancy complication, conclude researchers

13/04/2005 – Researchers at Mexico’s National Institute of Perinatology have found that women taking 100mg of vitamin C supplement a day from the 20th week of pregnancy may reduce the risk of their waters breaking too early.

The relatively common condition known as premature rupture of the chorioamniotic membranes (PROM) may result in premature delivery and infection.

Earlier studies have found that vitamin C plays an important role in maintaining the collagen in the membrane throughout gestation but it is not stored well by the body, which excretes whatever it does not need on a daily basis.

The researchers, led by Esther Casanueva, set out to determine the effectiveness of a daily 100mg dose in preventing PROM.

In the controlled double-blind trial, 120 women in their 20th week of pregnancy were randomly assigned to two groups; one group received 100mg of vitamin C each day and the other received a placebo.

The women’s plasma and leukocyte vitamin C concentrations were measured every fourth week and the results published in the April issue of the American Journal of Clinical Nutrition (81, 4: 859-863).

They showed that mean plasma vitamin C concentrations decreased as pregnancy progressed in all of the 109 women who completed the study, irrespective of whether they were taking the vitamin C or the placebo. This decrease is typically seen in normal pregnancies.

However the mean leukocyte vitamin C concentrations decreased in the placebo group between weeks 20 and 36 from 17.5 to 15.23 µg/108 cells, compared to an increase from 17.26 to 22.17 µg/108 cells in the vitamin C group.

When it came to the birth, 14 of the 57 women in the placebo group experienced PROM, compared with just four of the 52 women in the vitamin C group.

The Institute of Medicine recommends that women consume 75mg of vitamin C a day, increasing to 80-85mg during pregnancy and 115-120 mg during lactation.

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## Vitamin C deficiency common in people with severe asthma, http://www.nutraingredients.com/news/news-ng.asp?n=61634-severe-asthma-linked

29/07/2005 – Increasing vitamin C intake could help people with severe asthma, report researchers today, who call for further investigation of the vitamin’s role in protecting against the disease, writes Dominique Patton.

Previous population studies have found an association between with decreased intakes of antioxidants such as vitamin C and incidence of asthma although follow-up studies looking particularly at vitamin C have produced conflicting results.

The new study, published in the August issue of the European Respiratory Journal (vol 26, no2), investigated the possibility that decreased levels of antioxidants may also contribute to the development of severe asthma.

Neil Misso from the Asthma & Allergy Research Institute in Australia and his colleagues compared the dietary intakes and blood concentrations of antioxidants, including vitamin C, in 28 patients with severe asthma compared with 53 mild asthmatic patients and 43 subjects without asthma.

Among all subjects the dietary intakes of vitamin C and carotene, which are mainly derived from fruit and vegetables, were lower in males than in females.

Men with severe asthma had a particularly low intake of these antioxidants.

The blood concentrations of vitamin C were markedly lower in patients with severe asthma compared to subjects with mild asthma or those without asthma, and this difference was observed in both males and females, said the researchers.

The study also identified patients with severe asthma as being more overweight, with a higher intake of fat and a higher blood cholesterol concentration compared with the other subjects.

In addition, lung function was better in subjects with high blood vitamin C and low blood cholesterol concentrations.

The study suggests that patients, and particularly males, with severe asthma may benefit from making sure they have an adequate intake of antioxidants such as vitamin C in their diet.

The researchers noted that in a recent trial, children with mild asthma found no benefit from taking vitamin C.

But they write that “the results of the present study, together with recent evidence that the beneficial effects of antioxidants may be influenced by polymorphisms in the glutathione S-transferase gene, indicate that there is a need for further trials of vitamin C supplementation in patients with more severe asthma”.

If confirmed in future trials, taking supplements or vitamin-rich foods could be a relatively easy strategy to help decrease the morbidity and socioeconomic burden associated with severe asthma, said the researchers.

In the UK, one in eight children has asthma and this figure has increased six-fold in the last 25 years, according to Asthma UK.

## Vitamin C Transforms Mouse Stem Cells Into Heart Muscle Cells, http://www.sciencedaily.com/releases/2003/04/030401073122.htm

Source: American Heart Association
Posted: April 1, 2003

DALLAS, April 1 — Vitamin C helped convert mouse embryonic stem cells growing in the laboratory to heart muscle cells, researchers report today’s rapid track publication of Circulation: Journal of the American Heart Association.

Rapid track articles are released online early because they have major clinical impact or represent important basic science discoveries. This basic-research discovery could lead to future research on ways to treat people suffering from damaged heart muscle.

“Although the findings of this study are very preliminary with respect to their impact on human lives, this line of research has enormous implications for the future care of thousands of patients who develop heart failure each year,” says Robert O. Bonow, M.D., president of the American Heart Association.

“Identifying mechanisms to transform stem cells into differentiated heart muscle cells is an important step toward clinical reality.”

Richard T. Lee, M.D., senior author of the study, says: “We have been taught for decades that when your heart cells are dead, they are dead and there is nothing we can do about it. We are excited about anything suggesting that we can grow more heart cells.”

Lee and his colleagues tested 880 bioactive substances — including drugs and vitamins — approved by the U.S. Food and Drug Administration (FDA) to see if they stimulated the mouse stem cells to become heart muscle cells. The cells were genetically altered to give off a fluorescent bright green color when viewed under a microscrope if they had become heart muscle cells.

“We only got 1 out of the 880 to light up, and that was from ascorbic acid, the chemical commonly known as vitamin C,” says Lee, an associate professor of medicine at Harvard Medical School in Brigham and Women’s Hospital in Boston, and a lecturer in biological engineering at the Massachusetts Institute of Technology in Cambridge, Mass.

He stresses, however, that the finding is preliminary and it should not encourage people to take vitamin C hoping to strengthen or protect their hearts. “There is no clinical evidence that it would help,” he says. The ability to grow or implant new heart muscle could save or improve the quality of life of countless people suffering from heart failure — the inability of a weakened heart to pump enough blood to supply the body. About 550,000 new cases and more than 51,500 heart-failure deaths occur each year in the United States as the result of a damaging heart attack, genetic disease, or other causes.

Embryonic stem cells are derived from the very early stages of fetal development and can become any type of cell in the body through a process called differentiation. Efforts to stimulate the differentiation of stem cells to specific types of cells have drawn growing research attention in recent years.

Working with a well-established line of mouse embryonic cells grown by first author Tomosaburo Takahashi, M.D., Ph.D., they placed about 2,000 stem cells each in tiny “wells” and treated each well with a different one of the FDA-approved compounds. The stem cells had a gene inserted that would fluoresce bright green if the cell converted into the heart-muscle cell.

Beyond finding the green glow of the vitamin C-treated cells, the researchers detected several other important pieces of evidence that the stem cells had converted to heart muscle.

For example, they found that both cardiac myosin and actin (proteins involved in relaxing and contracting muscle) were present in the cells. They also detected three other heart-muscle genes that activated in proper sequence. The differentiated cells also beat spontaneously and rhythmically.

Vitamin C’s beneficial activity has been attributed to its ability to neutralize oxidants, which are damaging substances produced naturally by the body. However, other antioxidant compounds tested, including vitamin E, did not trigger the development of heart cells.

“This suggests that the effect of vitamin C on cardiac differentiation is independent of its antioxidant effect,” Lee says.

He and his colleagues repeated their experiment many times, always with the same results. “The real significance of the study is that it indicates that we will be able to find other ways to generate heart cells from stem cells more efficiently,” Lee says. “It also raises interesting questions about the role of vitamin C in the development of the embryo’s heart.

The team is investigating other so-called “chemical libraries” that contain far larger numbers of compounds than the group initially tested.

“A really big issue is going to be whether we can encourage the heart to fix itself, or whether we will need to implant cells of some sort,” Lee says. “That is an important and unresolved question for this century, given the prevalence of heart failure.”

Co-authors are P. Christian Schulze, M.D.; Bernadette Lord, B.S.; Ryan M. Fryer, Ph.D.; Satinder S. Sarang, Ph.D.; and Steven R. Gullans, Ph.D.

This research was partly funded by the National Heart, Lung, and Blood Institute.

## Misleading information on the properties of vitamin C, from PLoS Medicine

# Dr. Steve Hickey, Manchester Metropolitan University
Additional Authors: Dr Hilary Roberts
Published: 05 July 2005

Douglas and Hemila’s review[1] covers 60 years of research into vitamin C and the common cold. However, the review omits pharmacokinetic data which invalidates the conclusion that vitamin C is ineffective. This conclusion is not derivable from the data presented.

The dual-phase pharmacokinetics of vitamin C are described by the dynamic flow model.[2,3] Low intakes of ascorbate, leading to blood plasma levels below 70 microM/L, have a half-life of 8-40 days. Higher gram-level intakes have a plasma half-life of 30 minutes.[2] A large oral dose raises blood levels briefly, reaching a peak after 2-3 hours, before decaying back to baseline. Frequent repeated doses allow sustained high plasma levels of about 250 microM/L.[3,4]

Douglas and Hemila reviewed intakes that transiently raise plasma ascorbate above 70 microM/L. A single dose does not raise the median level.[5,6] Daily supplements would thus not increase disease resistance to any great degree.[2,3] Single or twice daily doses will not increase background plasma levels, regardless of the magnitude of the dose.[5,6] Since plasma ascorbate is at background level for the majority of the day, effects will be minimal.

There is widespread confusion of nutritional and pharmacological levels of supplementation.[2] Linus Pauling typically described nutritional gram-level doses to provide a degree of disease prevention.[7] By contrast, pharmacological doses used for treatment are, at minimum, an order of magnitude larger and involve frequent doses. The doses should be at intervals of three hours or less.[2] Treatment doses are described by Cathcart’s paper on titration to bowel tolerance.[8]

To treat the onset of a cold, the therapy is perhaps a minimum of 10 grams of oral ascorbic acid, followed by at least two grams each hour.[2,3]

Douglas and Hemila give a misleading impression, by not making it clear that the doses they consider are not pharmacological. They claim that the results of one study, giving an 8 gram dose at the start of symptoms, are ‘tantalising and deserve further assessment’. However, once this single dose has been excreted, the protective effects will be lost. During illness, ascorbate is depleted rapidly and higher oral intakes are tolerated – up to 200g per day.[8] It would be surprising if this eight gram dose had a large effect.

Studies on ascorbate require appropriate doses. Douglas and Hemila have only confirmed that 60 years of vitamin C research has largely been wasted, because of confusion between nutritional and pharmacological intakes, and a misunderstanding of the pharmacokinetics. It is essential that high dose studies take into account ascorbate’s dual-phase pharmacokinetics. The dosing regime should allow sustained, high plasma levels to be achieved. The claim that vitamin C cannot prevent or cure the common cold is both premature and unwarranted.

1. Douglas R.M. Hemila H. (2005) Vitamin C for Preventing and Treating the Common Cold, PLoS Med., 2(6), e168, Jun 28.
2. Hickey S. Roberts H.J. (2004) Ascorbate: The Science of Vitamin C, Lulu press.
3. Hickey S. Roberts H.J. Cathcart R.F (2005) Dynamic flow: a new model for ascorbate, J. Orthomolecular Med, in press.
4. Padayatty S.J. Sun H. Wang Y. et al (2004) Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use, Ann Intern Med, 140, 533-7.
5. Levine M, Conry-Cantilena C, Wang Y. et al (1996) Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance, Proc. Natl. Acad. Sci. USA, 93, 3704???9.
6. Levine M. Wang Y. Padayatty S.J. et al (2001) A new recommended dietary allowance of vitamin C for healthy young women Proc. Natl. Acad. Sci. USA, 14, 98 (17), 9842-6.
7. Pauling L. (1970) Vitamin C and the Common Cold, W. H. Freeman, New York.
8. Cathcart R.F. (1981) Vitamin C, titrating to bowel tolerance, anascoremia, and acute induced scurvy, Medical Hypotheses 7, 1359-76

# Narrow scope of vitamin C review, William Sardi, Published: 05 July 2005

Sixty years of flawed research, without a mention of it in a review paper, should negate any conclusion. There was no mention of the revealing paper published last year [1} which shows three times greater blood concentration can be achieved with oral dose vitamin C than previously thought possible. Since viruses increase the demand for ascorbic acid, the oral doses used in the reviewed studies appear trivial and would not be expected to produce any positive effect. Compare human oral dose studies to what animals synthesize throughout the day. It is obvious that a single dose of a water soluble vitamin, regardless of the number of milligrams consumed, will not elevate blood levels significantly to produce a preventive or therapeutic effect.

[1] Padayatty SJ, Sun H, Wang Y, et al, Vitamin C pharmacokinetics: implications for oral and intravenous use.
Ann Intern Med. 2004 Apr 6;140(7):533-7.

# Response to the two earlier comments, Harri Hemila, MD, PhD, Department of Public Health, University of Helsinki, Helsinki, Finland

Published: 29 July 2005

The two responses to our article by Hickey and Roberts, and by Sardi, make the same point, namely that a recent pharmacokinetic study reported that frequent oral intakes of vitamin C would be necessary to elevate plasma ascorbic acid levels to the point where they believe it would have a pharmacological impact. Both authors suggest that the conclusions of our Cochrane review are flawed because all of the placebo-controlled trials that have been carried out so far have used, for both prophylaxis and therapy, one to three times per day of vitamin C ranging from 200 mg daily to as much as 8 grams in a single daily dose.

We have not, as our critics imply, concluded that vitamin C in the doses used in trials reported in the literature has no effect on the common cold. On the contrary, our evidence indicated that in marathon runners and those exposed to high physical and/or cold stress, a substantial prophylactic effect was observed, and that in the general population using regular vitamin C prophylaxis, cold duration was consistently shortened, but the level of shortening was relatively trivial.

We do not consider the vitamin C and the common cold story closed. Nor are we persuaded by the arguments of these three critics that frequent large doses would necessarily result in substantially greater benefits than earlier trials have demonstrated.

We consider that it may be useful to distinguish between

a) prophylactic supplementation of people who are in good health and
b) therapeutic supplementation of people who have an infection. The kidneys reabsorb essentially all vitamin C when the dietary intake is below 60-100 mg/day and vitamin C level in leukocytes is saturated by approximately 100 mg/day [1], and in this respect we doubt that prophylactic supplementation of healthy people, using doses higher than those in the published trials, might be expected to benefit the general healthy population. On the other hand, there is evidence indicating that common cold infection decreases vitamin C level in leukocytes suggesting changes in vitamin C metabolism [2], and in this respect there seems to be rationale to study the effects of supplementation on people infected with the common cold using even higher doses.

To this point, the claim that these two letters make has not been reported in properly conducted randomized controlled trials of either therapy or prophylaxis. We look forward to incorporating such trials when they have been carried out, in future versions of the Cochrane review. Meanwhile we stand firmly by the conclusions reported in our article.

References

1. Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, et al. (1996) Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A 93: 3704-3709.
2. Hume R, Weyers E (1973) Changes in leucocyte ascorbic acid during the common cold. Scott Med J 18: 3-7.

PLoS Medicine is an open-access journal published by the nonprofit organization Public Library of Science.
All journal content, except where otherwise noted, is licensed under a Creative Commons Attribution License.

## Vitamin C Supplementation and Respiratory Infections: a Systematic Review, http://www.findarticles.com/p/articles/mi_qa3912/is_200411/ai_n9469932

Military Medicine http://www.findarticles.com/p/articles/mi_qa3912 , by Hemilä, Harri

In this review, the vitamin C trials with military personnel and with other subjects living under conditions comparable to those of military recruits are analyzed to find out whether vitamin C supplementation affects respiratory infections. For this systematic review, we identified seven trials with military personnel, three trials with students in crowded lodgings, and two trials with marathon runners. Eight of these trials were double blind and placebo controlled and seven were randomized. Five small trials found a statistically significant 45 to 91% reduction in common cold incidence in the vitamin C group. These trials were short and the participants were under heavy exertion during the trial. Furthermore, three other trials found a statistically significant 80 to 100% reduction in the incidence of pneumonia in the vitamin C group. The large number of positive findings seems to warrant further consideration of the role of vitamin C in respiratory infections, particularly in military recruits.

# Introduction

A high incidence of pneumonia and other respiratory infections is a common problem among military recruits, possibly caused by the crowding together of young adults from widely dispersed geographic areas.1-4 Navy and Marine recruits were at 30 times higher risk of hospital admission for pneumonia than were nonrecruits,1 and Navy and Marine personnel with less than 1 year of service were at five times higher risk of pneumonia than their peers with 4 or more years of service.4 Consequently, factors affecting susceptibility to respiratory infections in military recruits are of considerable practical importance.

The notion that vitamin C affects susceptibility to various infections-and respiratory infections in particular-is an old one,5,6 but the topic came to wider popularity only in the 1970s, when Pauling, 7,8 suggested that vitamin C supplementation would reduce the incidence and severity of colds. Trials carried out since then have consistently found that vitamin C alleviates common cold symptoms, but yields only modest benefit.9-12 Vitamin C had no effect on the incidence of the common cold in the largest trials,6,12,13 but trials with British men, 13 and with subjects under heavy, acute physical stress, 14 found reduction in common cold incidence, suggesting that vitamin C affects susceptibility to respiratory infections in restricted groups of people. Although Pauling was considerably overoptimistic about the potential benefits of vitamin C, 7,8,11-13 another problem in this area of interest has been the negative bias against vitamin C. Three influential reviews concluded that vitamin C is ineffective against colds; however, the reviews presented data inconsistent with the original reports, overlooked several highly relevant findings, and analyzed data inappropriately.9,10

The purpose of the present review was to analyze the findings of vitamin C trials with military personnel and of trials with participants under conditions similar to those of military recruits to find out whether vitamin C affects the incidence or severity of respiratory infections.

# Methods, Selection of the Trials

I previously searched the literature on vitamin C and respiratory infections using various MEDLINE, EMBASE, and SCISEARCH database searches, and I inspected the reference lists of reviews and original reports.6,11,13 One other author independently searched for trials on vitamin C and the common cold and published the identified bibliography. 15. For this systematic review, further MEDLINE searches covering the years 1999-2002 were carried out.

The present review covers only controlled trials in which vitamin C was administered to one study group; the control group may or may not have received a placebo. This analysis focused on trials reporting respiratory tract infection outcomes. Two groups of trials were selected on the basis of subjects used in the trials: military personnel (seven trials; Table I) and students accommodated in crowded lodgings and marathon runners (five trials; Table II). Except for one trial,18 the trials in the tables are prophylactic such that participants were healthy at the trial’s outset and supplementation continued over the occurring respiratory infection episodes. Although one trial examined patients hospitalized for influenza A, it was nevertheless prophylactic with respect to the occurrence of pneumonia after the initiation of vitamin C supplementation. 18

# Statistical Methods

Tables I and II show the p values calculated by the current author for the differences in the outcome values between the two groups. For dichotomous data, the mid-p modification, 28, of the Fisher’s exact test, 29, was used to calculate p. For continuous variables, the exact p value was calculated using the t test, 29, when mean and SD were reported in the original articles. The ‘sup 2’ test, 29, was used to test whether the distribution of participants with correct and incorrect answers in the Pitt and Costrini tria, l16, is explained by random variation. Assuming pure guessing, the expected number of correct and wrong answers is equal; both are one-half of all of the answers. Consequently, with 316 answers in the Pitt and Costrini trial, the expected number of correct and wrong answers is 158.

The one-tailed p values are used In the tables and text because the explicit question in the present analysis is whether vitamin C supplementation decreases the incidence and severity of respiratory infections. There is no experimental or theoretical reason to expect that vitamin C supplementation would increase morbidity from respiratory infections. Confidence intervals are not calculated because the primary purpose of this review was to test the hypothesis that vitamin C affects respiratory infections. Trial settings and outcome definitions vary substantially, which limits the possibility to generalize the point estimates; therefore, no pooled estimates were calculated.

# Trials with Military Personnel

Seven trials examined the effect of vitamin C supplementation on respiratory infections in military personnel. Table I shows the number of participants, the duration of the trial, the dosage of vitamin C, and the outcome values. There is substantial variation in the common cold incidence in the control groups. Pitt and Costrini, 113, observed 11 colds per person-year, whereas Dahlberg et al., 17, observed only 0.4 colds per person-year, although both of these large trials examined military recruits.

Pitt and Costrini, 16, carried out a large-scale, randomized, double-blind, placebo-controlled trial with Marine recruits in a training camp in South Carolina in the wintertime. The participants were vaccinated against adenovirus and influenza, and they received penicillin or erythromycin as streptococcal prophylaxis. The study groups showed no difference in common cold incidence. Vitamin C caused a statistically significant, although clinically minor, reduction in common cold severity. Of the eight pneumonia cases observed, five were caused by pneumococcus but two of them had a coinfection with parainfluenza virus. The incidence of pneumonia was significantly lower in the vitamin C group.

Interestingly, Pitt and Costrini, 16, also found that a considerable proportion of their participants correctly inferred their treatment from subjective observations (for a comparable case, see Ref. 10). When asked which pill they thought they were taking, 53% (358) of all participants (674) stated they did not know. Of those who replied vitamin C or placebo (316), 27% (89) and 26% (89) answered correctly, whereas 20% (66) and 21% (72) answered incorrectly in the vitamin C and placebo groups, respectively. Consequently, in all, 178 participants answered correctly and 138 incorrectly. Assuming pure guessing, the expected number of correct and incorrect answers is 158, which allows the calculation of observed and expected difference to yield ?^sup 2^(1 df] = 5.0 and p[one-tail] = 0.013. Consequently, 40 participants (178 – 138) correctly inferred their treatment in this double-blind trial. Formulated from citric acid, the placebo tablets were indistinguishable in appearance and taste from the ascorbic acid tablets. Therefore, it is worth noting that 6% (40 of 674) of all participants inferred their treatment by subjective perception alone.

Dahlberg et al., 17, performed a large-scale, double-blind, placebo-controlled trial with infantry recruits in Northern Sweden in the wintertime. Allocation to the study groups was by odd and even identity numbers. Low doses of vitamin C had no effect on the number of participants who caught the common cold. However, the number of participants in the vitamin C group with more severe respiratory infections was only one-half that of the placebo group level, although the difference was not statistically significant.

1 – http://www.findarticles.com/p/articles/mi_qa3912/is_200411/ai_n9469932/pg_2

## PROOF IS PROVIDED THAT VITAMIN C CAN POTENTIALLY ERADICATE CORONARY ARTERY DISEASE, BUT A MAJOR MEDICAL JOURNAL DECLINES TO PUBLISH IT ,

By Bill Sardi, 8/3/2005

So, the New England Journal of Medicine (report below) publishes a report showing elevated levels of oxidized LDL and Lipoprotein(a) cholesterol particles circulating in the blood increase the risk for coronary artery disease by 14 times (that’s 1400%!). The report drew widespread attention in the news media (see news report below). It’s significant because a recent report published in the Journal of the American Medical Association dismissed the value of dietary supplements to promote health and stated that:

“In 2003, after reviewing the data, a joint committee of the American College of Cardiology and American Heart Association (AHA) concluded that “… there is currently no basis for recommending that patients take vitamin C or E supplements or other antioxidants for the express purpose of preventing or treating coronary artery disease.” In 2004, the AHA Nutrition Committee similarly concluded that “At this time, the scientific data do not justify the use of antioxidant vitamin supplements for cardiovascular disease risk reduction.” [Journal American Medical Association Volume 294, 20 July 2005, p 351-358]

So I wrote a letter to the New England Journal of Medicine as follows:

Letter submitted to editor: New England Journal of Medicine

Corresponding Author:
Mr. Bill Sardi,Knowledge of Health, Inc., 457 West Allen Avenue Suite 117, San Dimas, CA 91773
Issue Date: 7/7/2005

Article Referenced: Original Article – Oxidized Phospholipids, Lp(a) Lipoprotein, and Coronary Artery Disease

To the Editor:

The report concerning oxidized phospholipids and lipoprotein(a) as a risk factor for coronary artery disease (CAD)once again raises the prospect of oral antioxidants for CAD prevention. Vitamin C concentrations in LDL cholesterol ~250-280 uM are capable of inhibiting oxidation of LDL cholesterol by about 75%. [1] A recent study conducted by NIH researchers dispels the common notion that ascorbate concentrations cannot exceed 70-85 uM and indicates serum concentrations > ~250 uM can be achieved through oral dosing. [2] The primary reason why oral dose vitamin C has failed to exhibit effectiveness for coronary artery disease is its pharmacokinetics have been misunderstood. Repeated oral dosing through the day is required to maintain blood concentrations for this water-soluble antioxidant. Most animals continually synthesize ascorbate and escape CAD. [3] University of North Carolina researchers have shown that chronic vitamin C deficiency “does not influence the initiation or progression of atherosclerotic plaques but severely compromises collagen deposition and induces a type of plaque morphology that is potentially vulnerable to rupture.” [4] Plaque rupture is involved in sudden cardiac death.

Bill Sardi, bsardi@aol.com

References:

1. [1] Chu YF, Liu RH,Novel Low-Density Lipoprotein (LDL) Oxidation Model: Antioxidant Capacity for the Inhibition of LDL Oxidation. J Agric Food Chem 2004, 52: 6818-6823
2. [2] Padayatty SJ, Sun H, Wang Y, et al, Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 2004, 140:533-7.
3. [3] Rath M, Pauling L, Hypothesis: lipoprotein(a) is a surrogate for ascorbate. Proc Natl Acad Sci 87: 6204-07, 1990.
4. [4] Nakata Y, Maeda N, Vulnerable atherosclerotic plaque morphology in apolipoprotein E-deficient mice unable to make ascorbic Acid. Circulation 2002, 105: 1485-90.

Figure or Table:
…picture not available…

Figures Brief Legend:
The above chart conclusively reveals that vitamins C, E and quercetin (naturally found in red onions) can inhibit the oxidation (hardening) of LDL cholesterol by 75%. The blood concentrations of vitamin C required to accomplish this are achievable through oral dosing (500-1000 mg 3-5 times a day) [Journal Agriculture Food Chemistry 2004, 52: 6818-6823]

Here is the response received from the editor of The New England Journal of Medicine

RE: NEJM Correspondence #: 05-2110
8/2/2005 7:44:32 AM Pacific Standard Time

Dear Mr. Sardi,

I am sorry that we will not be able to print your recent letter to the editor regarding the Tsimikas article of July 7. The space available for correspondence is very limited, and we must use our judgment to present a representative selection of the material received. Many worthwhile communications must be declined simply for lack of space.

Sincerely yours,
Gregory D. Curfman, M.D., Executive Editor, New England Journal of Medicine

Copyright 2005 Bill Sardi, Knowledge of Health, Inc.

# Original article: New England Journal Medicine. 2005 Jul 7; 353(1):46-57.

Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease.

Tsimikas S, Brilakis ES, Miller ER, McConnell JP, Lennon RJ, Kornman KS, Witztum JL, Berger PB.

Division of Cardiovascular Diseases, University of California, San Diego, La Jolla, CA 92093-0682, USA. stsimikas@ucsd.edu

BACKGROUND: Lipoprotein(a) lipoprotein binds proinflammatory oxidized phospholipids. We investigated whether levels of oxidized low-density lipoprotein (LDL) measured with use of monoclonal antibody E06 reflect the presence and extent of obstructive coronary artery disease, defined as a stenosis of more than 50 percent of the luminal diameter. METHODS: Levels of oxidized LDL and Lp(a) lipoprotein were measured in a total of 504 patients immediately before coronary angiography. Levels of oxidized LDL are reported as the oxidized phospholipid content per particle of apolipoprotein B-100 (oxidized phospholipid:apo B-100 ratio).

RESULTS: Measurements of the oxidized phospholipid:apo B-100 ratio and Lp(a) lipoprotein levels were skewed toward lower values, and the values for the oxidized phospholipid:apo B-100 ratio correlated strongly with those for Lp(a) lipoprotein (r=0.83, P
CONCLUSIONS: Circulating levels of oxidized LDL are strongly associated with angiographically documented coronary artery disease, particularly in patients 60 years of age or younger. These data suggest that the atherogenicity of Lp(a) lipoprotein may be mediated in part by associated proinflammatory oxidized phospholipids. Copyright 2005 Massachusetts Medical Society.

Oxidized lipids, predictors of coronary artery disease

By measuring specific oxidized phospholipid molecules in the blood, researchers led by University of California, San Diego ( UCSD ) School of Medicine found that the levels of this toxic molecule circulating in the bloodstream strongly reflect how much blockage is present in the coronary arteries. This measurement could help doctors better determine the risk of a myocardial infarction.

The study, published in the New England Journal of Medicine, presents two key findings:

• A test to detect oxidized phospholipids in the bloodstream strongly predicts the presence of coronary blockages, especially in patients younger than 60 years old who also have elevated cholesterol levels.

• The oxidized phospholipid particles are strongly attached to another cholesterol-containing lipoprotein that circulates in the bloodstream called Lp(a), which might explain why Lp(a) may be atherogenic.

Lp(a), discovered in the 1960s, has received little attention by researchers for the last decade due to the lack of understanding of its role in atherosclerosis.

This study suggests that Lp(a), which has a strong affinity for binding to the blood vessel wall, may play a key role in developing atherosclerosis as a “partner in crime” with oxidized phospholipids. Both are known to be highly pro-inflammatory.

The risk attributable to Lp(a) may in fact be due to its ability to bind and travel with oxidized phospholipids, attaching these toxic particles to the vessel walls, where they then may induce inflammation that can lead to blocked arteries.

“We’ve known about other lipid risk factors for years, such as elevated Low Density Liposprotein ( LDL ) cholesterol, low levels of High Density Lipoprotein ( HDL ) cholesterol, and elevated triglycerides,” said Tsimikas. “Lp(a) appears to be another risk predictor, particularly in patients with abnormal cholesterol levels, but it has not been determined how it actually causes arterial blockages.

“This study provides a potential explanation, and shows that high levels of oxidized phospholipids and Lp(a) are tightly associated with coronary heart disease, indicating that they could be useful tests to determine risk in patients,” he said. “It also demonstrates that these molecules could be promising targets for pharmaceutical research, particularly in developing new drugs to reduce their levels in the bloodstream and in the vessel wall.”

The team analyzed blood samples from 500 patients being treated for heart problems at the Mayo Clinic in Rochester, including the clinical and laboratory risk factors associated with atherosclerosis and heart disease in patients who were referred for coronary angiography, a procedure to determine blockage in the coronary arteries. They found that levels of oxidized phospholipids could predict the presence of coronary blockages even after taking into account all other known risk factors such as abnormal cholesterol levels, high blood pressure, smoking and gender.

Interestingly, said Tsimikas, the risk attributable to oxidized phospholipids was nearly identical to the risk attributable to Lp(a) in the overall group, but in patients under 60 years old, the oxidized phospholipid measure was a strong indicator, independent of Lp(a). This suggests that oxidized phospholipids may be more powerful determinants of risk for coronary artery disease in patients younger than 60 years old compared to those older than 60 years old.

“These results suggest that Lp(a) and oxidized phospholipid levels are very tightly linked and each helps the other contribute toward atherosclerosis when found at high levels in the blood,” Tsimikas said. “These two molecules may be working differently in younger patients, so that oxidized phospholipids may generate additional risk above and beyond Lp(a). As this is the first study to show this, further confirmation will be required in other studies.”

He noted that while elevated LDL cholesterol levels alone were very strong predictors of coronary artery disease, the combination of oxidized phospholipids with elevated cholesterol levels was the highest predictor for determining the presence of coronary blockages, showing a 16-fold higher risk for coronary blockages in those with the highest levels of both compared to the lowest levels of both. This suggests that these biomarkers may provide improved diagnostic accuracy in patients, above and beyond knowing the cholesterol levels.

Levels of Lp(a) in the blood are genetically determined, said Tsimikas, which means that patients with elevated levels have them starting at birth. This may explain why these biomarkers are more predictive in younger patients. Elevated Lp(a) levels are found in approximately 25% of the population. This also implies that in patients found to have high Lp(a) levels, one of the parents had the gene for developing high Lp(a) levels, and approximately half of the siblings will also have it. Thus, it is important to review the family history to determine additional family members that may be at risk.

Levels can also increase when an acute stress occurs, such as a heart attack, but generally return to their baseline over months. Clinical tests are available that can measure Lp(a) levels in a clinic, providing physicians with a tool to determine which patients may be at the highest risk of heart disease. The test to measure oxidized phospholipid levels is not yet available for clinical use, and more studies such as this one will be required to prove its clinical utility and whether it provides independent information in addition to knowing Lp(a) levels.

“The finding that Lp(a) binds to oxidized phospholipids also allows us to hypothesize that it may have a potential beneficial function in clearing these toxic particles from the circulating blood. However, as too much of a good thing can be detrimental, it is possible that low levels of Lp(a) may be beneficial, but high levels are associated with higher rates of heart disease, suggesting that testing for Lp(a) levels could help determine a patient’s risk for the presence of current or future heart disease,” said Tsimikas.

“For this reason I think it is important for physicians to consider measuring Lp(a) in patients with coronary risk factors, particularly a strong family history of heart disease, or those patients that suffer from heart problems at a relatively young age,” Tsimikas suggested.

Source: University of California, San Diego, 2005