Passwater: You mentioned that vitamin E didn’t provide the protection against the UV-B, were other antioxidants studied as well, and, if so, how did they compare to the protective effects of Pycnogenol?


Arstila: No. We were trying to test nutrients that had a good chance of working. Vitamin E had shown promise from in vitro studies, but it had failed human studies. We wanted to look at both vitamin E and Pycnogenol. Pycnogenol was protective whereas vitamin E was not.

Passwater: What distinguishes Pycnogenol from other antioxidants?

Arstila: Each antioxidant has a unique antioxidant profile. There are many types of free radicals and other reactive oxygen species that harm the body, and antioxidants vary in their ability to quench these various reactive oxygen species. In addition, some antioxidants are water-soluble and others are fat-soluble. Their solubility determines where they can travel and what they will be able to protect. Pycnogenol is very water-soluble and is more protective against some reactive oxygen species such as measured by the TBARS test than either vitamin C or vitamin E, and is more protective against at least one stable free radical than vitamin E and more protective against superoxide than vitamin C. There are other reactive oxygen species in which vitamins C and E are more protective than Pycnogenol. The best approach is to utilize many different antioxidants — vitamins C and E, selenium, carotenoids, and Pycnogenol as they tend to be synergistic.

What is of particular interest about the nutrients of Pycnogenol is their affinity for the skin proteins such as collagen and elastin. This is why we chose Pycnogenol for our UV-B study.

Passwater: What distinguishes Pycnogenol from other bioflavonoids?

Arstila: Pycnogenol is a water-extracted mixture of monomers, dimers, and oligomers, plus other polyphenols and organic acid “building-blocks.” Therefore all of the nutrients so extracted are water soluble, whereas the bioflavonoid rutin is not very water- soluble. In addition, the nutrients in Pycnogenol are very bioavailable, whereas rutin is not very bioavailable. The oligomers present in Pycnogenol are unique and have unique antioxidant profiles.

Passwater: You have written books on Toxicology, what can you tell us about the safety of Pycnogenol?

Arstila: Yes, I have written many research papers on toxicology and there is no question that Pycnogenol is a non-toxic natural product. Pycnogenol was well tested before it was introduced in Europe originally as “Pycnoforton,” and it has been well tested throughout the years to keep up with the increased sophistication of toxicological tests. As an example, Pycnogenol has been subjected to tests for mutagenicity, carcinogenicity, teratogenic (birth defects), and acute and gross toxicities in several species of animals. Many clinical studies have been made and no adverse effects have been reported. Pycnogenol has received extensive toxicity testing in comparison to food supplements such as vitamins because of its widespread use by physicians in Europe.

Passwater: Where are your current research interests?


Arstila: I am now concentrating on the free-radical damage of our genetic material DNA. It may be that DNA damage by free radicals is by far more important than other forms of free radical damage. The DNA damage may be important factors in cancer and aging.

Passwater: Thank you Professor Arstila.

All rights, including electronic and print media, to this article are copyrighted to � Richard A. Passwater, Ph.D. and Whole Foods magazine (WFC Inc.).

Bendich: Niacinamide is the molecule commonly used in multivitamin supplements and is safe. Niacinamide does not lower cholesterol levels. Nicotinic acid has been shown to be a very effective agent in lowering cholesterol when given at high doses. Nicotinic acid, as is true for all cholesterol-lowering agents, increases liver enzyme levels and can cause liver toxicity. High doses of nicotinic acid should be taken only under a physician’s supervision, which should include the monitoring of liver enzymes. There have been reports that the use of time-release nicotinic acid has resulted in liver damage severe enough to require liver transplant.

Passwater: Yes, there is such a big difference in nicotinic acid and niacinamide, some may wonder how such two different compounds can be the same vitamin. They both prevent pellagra (the “black tongue” disease that produces skin eruptions, gastric disturbances and nervous disorders including insanity), and they both can form nicotinamide nucleotide coenzymes (NAD+, NADP+ and NADH). One — nicotinic acid — can cause a temporary skin “flushing” and lower blood cholesterol levels, while the other — niacinamide — does neither.

Since the mid-1980’s, there has been increasing concern over possible adverse effects of vitamin B-6. Do any of the pyridoxine vitamers cause nerve damage?
Bendich: Vitamin B-6 has been used in pharmacologic doses to treat conditions such as premenstrual syndrome, carpal tunnel syndrome, homocystinuria, galactorrhea and kidney stones. These treatments have generally not been associated with severe adverse effects. However, since 1983, reports have appeared in the literature suggesting that high-dose, long-term administration of pyridoxine produces sensory neuropathy (symptoms such as tingling sensation, loss of feeling, or weakness due to damage or disease of a nerve) in some patients.

Dr. Marvin Cohen and I evaluated the published scientific literature and reported our results in Toxicology Letters in 1986. That study found that the human data on the safety of pyridoxine suggest that oral administration of doses greater than 500 milligrams per day for a prolonged period of time can result in the development of sensory neuropathy. Doses less than 500 milligrams per day appear to be safe on the basis of reports where pyridoxine was administered for periods ranging from six months to six years.

The survey did not reveal any consistent trends for any other adverse effects.

In 1990, we updated our review and examined closely the dose-duration relationship. [12] We concluded that vitamin B-6 intakes of less than 500 milligrams per day for up to two years were safe. However, daily doses above one gram (1,000 milligrams) or total lifetime intakes above 1,000 grams (1,000,000 milligrams) were consistently associated with neuropathy.

As a precaution, I would not recommend the use of vitamin B-6 supplements at levels greater than 200 milligrams per day. Higher doses, if needed, should be used under the supervision of a physician who monitors neurological function.

Passwater: You mentioned that folic acid (folate or folacin) reduces the risk of neural tube birth defects. Yet some hesitate to recommend folate supplements because of a fear of masking B-12 deficiency. Would a supplement containing vitamin B-12 in addition to the folic acid, eliminate this worry? Isn’t the risk of birth defects greater in young women than the risk of a hidden vitamin B-12 deficiency?

Bendich: The U.S. Public Health Service recommendation is that all women of child bearing potential consume 400 micrograms a day of folic acid for the purpose of preventing neural tube defects. There are no data that indicate that this level of folic acid provided through multivitamin supplementation increases the risk of masking vitamin B-12 deficiency. In fact, a recent report showed that elderly who routinely took a multivitamin, which usually contained both folic acid (400 micrograms) and vitamin B-12 ( at 6 micrograms) had a significantly reduced risk of low vitamin B-12 status. Moreover, vitamin B-12 deficiency is rare in women of child bearing potential and the level of vitamin B-12 in the multivitamin would probably help ensure against vitamin B-12 deficiency in young women as well as other age groups.

I continue to recommend folic acid-containing multivitamin supplements as the most practical, inexpensive, and safe source of folic acid for all women of child bearing potential. Another important source is fully fortified breakfast cereals containing 100 percent of the daily value (DV) of folic acid and other essential vitamins and minerals..

I do not recommend that women choose a single supplement of folic acid alone because of three major reasons: first, the research showed added benefits with the multivitamin supplement, such as reduction in the risk of other birth defects in addition to neural tube defects. Second, many young women have numerous marginal deficiencies, including iron, vitamin E, and vitamin B-6 to name a few. The multivitamin can help to eliminate these deficiencies. Third, if a woman is going to change her daily habits and begin to take a “pill” every day, then wouldn’t it be best that the “pill” include all the essential vitamins and minerals?

My answer is Yes!

Passwater: Does vitamin C cause kidney stones?

Bendich: Several studies have found no evidence that vitamin C increases the risk of kidney stone formation. 13-17] Most kidney stones are composed largely of calcium oxalate, and urinary oxalate levels are used as a marker for kidney stone risk. Recently, Dr. Theodore Wandzilak and his team at the University of California at Davis investigated the claim that vitamin C increases urinary oxalate levels. Previous studies suggesting that vitamin C may increase urinary oxalate levels have been flawed because vitamin C interferes with most of the previous methods used to measure urinary oxalate levels. Dr. Wandzilak’s group used a new ion chromatography procedure in which vitamin C does not interfere. Their data show that the ingestion of increasingly large quantities of vitamin C did not cause an increase in the urinary excretion of oxalate. They concluded, “Therefore, the safety concerns raised about increased urinary oxalate level and, as a consequence, an increase in kidney stone formation in healthy subjects are not supported by our findings.” [18]

Passwater: That information, plus the new evidence that calcium does not increase kidney stone formation, shows that the conventional wisdom is not always correct, and that tests must be conducted before valid conclusions can be made. Does vitamin C destroy vitamin B-12?

Bendich: In 1980, Dr. M. Marcus showed that an earlier report suggesting this possibility was due to an artifact of the analytical procedure. [19]

Passwater: Do people have rebound scurvy when they skip or stop taking vitamin C?

Bendich: There is an indication that there is some degree of “conditioning” in white blood cell levels of vitamin C, but this effect is temporary and blood levels of vitamin C do not indicate that vitamin C deficiency develops.

Passwater: Does vitamin C increase iron overload disease incidence?

Bendich: The overall scientific data do not support the premise that vitamin C causes iron overload in normal persons. However, persons with the genetic disorders of hemochromatosis or thalassemia major may find that vitamin C increases the iron toxicity that they are suffering from by mobilizing more of their stored iron. Persons with genetic iron disorders should consult their physicians about the use of vitamin C supplements.

The effect of vitamin C on iron absorption is still an area of active interest. Vitamin C appears to enhance the absorption of non-heme iron consumed in the same meal. However, this effect does not appear to continue to increase with increasing intake of vitamin C. Dr. Marvin Cohen and I reviewed 24 studies which included 1,412 subjects eating meals designed to measure the iron absorption at different levels of vitamin C. We found that vitamin C doses above the RDI level do not increase susceptibility to iron overload in normal individuals.

Passwater Is vitamin C an in vivo pro-oxidant or mutagenic?

Bendich: Harvard researchers have found evidence that vitamin C acts only as an antioxidant in vivo. [20] Even in the presence of transition metal ions, the researchers found that vitamin C acted as an antioxidant rather than a pro-oxidant.

Stich and others have shown that old suggestions that vitamin C might be mutagenic was due to a problem with the testing method. [21] Vitamin C has not been shown to be mutagenic. In fact, many published studies show that vitamin C has anti-mutagenic properties because it is an important antioxidant.

Passwater: Does vitamin C impair copper utilization?

Bendich: This has not been shown in controlled studies. Two groups have investigated this question without finding such a relationship. [22-23]

Passwater: When we were chatting at a scientific meeting a few years ago, you were trying to trace the report that vitamin E could raise blood pressure in some individuals. I remember that the Drs. Shute used to say that this could happen in some diabetics or those who had rheumatic fever. Were you ever able to find evidence to verify these reports? Does vitamin E increase blood pressure in some individuals?

Bendich: No. There are no published reports of increases in blood pressure in any of the placebo-controlled, double-blind studies with dosages up to 2,000 IU per day.

Passwater: Does vitamin E cause tiredness?

Bendich: There are no peer-reviewed, placebo-controlled studies to support this. There have been several studies to examine the safety of vitamin E even at very large doses, and none have reported this as an observation. Usually, the anecdotal reports often suggest increased energy levels.

Passwater: In 1974, I conducted a study of vitamin E usage and health effects [24]. Drs. Linus Pauling and James Enstrom used data from the California subjects in my study and they conducted a follow-up study that showed health benefits in taking supplements. [25] The data on vitamin E showed benefit at all intakes of vitamin E as shown in Table 1. Although, the data showed greater freedom from disease and longevity at the 300 to 499 IU per day levels than the levels above 1,000 IU per day, there was better longevity at all intakes of vitamin E than among those not taking vitamin E.

Some have incorrectly used these data to imply that the higher level represented a toxic effect. What it was actually reflecting was the fact that some very ill persons began taking a large amount of vitamin E to help fight their diseases. Typically, persons in apparent good health usually decide to take about 400 IU of vitamin E daily if they wish its protection against free radicals. If people have a need for extra action from vitamin E, such as to prevent hot flashes during menopause or to relieve intermittent claudication, they often take about 600-800 IU daily. If they are recovering from a heart attack or have been diagnosed with cancer, they often start with 1,000- 1,200 IU daily. Thus, those who are taking more than 1,000 IU of vitamin E daily are often those already suffering from life-shortening diseases.

Still, the 1,000 IU per day level produced greater health and longevity than found in the control group not taking vitamin E supplements. The proportion that died among those taking more than 1,000 IU daily was 0.37, compared to the higher portion of 0.43 among those taking no vitamin E supplements.

]]> 23573 https://healthy.net/2019/08/26/bioflavonoids-vitamin-p-and-inflammation/?utm_source=rss&utm_medium=rss&utm_campaign=bioflavonoids-vitamin-p-and-inflammation Mon, 26 Aug 2019 21:02:31 +0000 https://healthy.net/2019/08/26/bioflavonoids-vitamin-p-and-inflammation/ In October, I was privileged to meet Professor Miklos Gabor of the Albert
Szent-Gyorgyi Medical University of Szeged, Hungary. Dr. Gabor has published
more than 200 research reports and five books on flavonoids. He has also
served as the scientific editor of other books on bioflavonoids. In 1990,
Dr. Gabor received the Jancso Medal and Award for his outstanding results
and scientific work of high quality, and in 1993, he received the Novicardin
Prize awarded by the Hungarian Academy of Sciences.



Professor Gabor and I had a common interest besides Pycnogenol(R) research.
We had a common friend, the late Nobel Laureate, Dr. Albert Szent-Gyorgyi
(1893-1986). Professor Gabor was now carrying on bioflavonoid research at
the University named in honor of Dr. Szent-Gyorgyi (Americanized pronunciation
is Saint Jor’-jee).



Before I share what I learned about bioflavonoids from Dr. Gabor with you,
let me tell you a little about Dr. Szent-Gyorgyi, who discovered the biological
importance of bioflavonoids. Dr. Szent-Gyorgyi was born in Budapest, but
was claimed by the U. S. and Hungary alike, and he conducted his research
while spending time in Cambridge, England; the Mayo Clinic, Minnesota; Woods Hole, Massachusetts and Hungary.



Dr. Szent-Gyorgyi was more than a pioneer of biochemistry — he was a “father” of biochemistry. He was awarded the Nobel Prize in Medicine in 1937 for
his discovery of the biological oxidation process with special regard to
vitamin C and fumaric acid catalysis. In 1928 he isolated what he at first
called “hexuronic acid,” but is now called “ascorbic acid”
or vitamin C. He also “discovered” the muscle protein actin, actomyosin
and their relationship to ATP. He discovered the C4 dicarboxylic acid catalysis
that forms the basis of the Krebs cycle which was pioneering research on
how food is converted into energy. His keen mind and bright ideas opened
the doors to many areas of biochemical research. He taught us so much, yet
he was often labeled a “maverick” because of his new ideas.



Dr. Szent-Gyorgyi always professed that his discovery of the biological
function of bioflavonoids was serendipitous. He found something he did not
seek. While he was trying to isolate vitamin C, his colleague Professor
I. (St.) Rusznyak had a patient with subcutaneous capillary bleedings. They
thought that vitamin C might help, so they gave the patient an impure preparation
that contained vitamin C plus other compounds. They achieved a rapid success.
Later, a similar patient was treated with a pure solution of vitamin C expecting
quicker success, but instead, the pure solution had no effect. So they went
back to the impure solution. Dr Szent-Gyorgyi suspected that a flavone might
be the key factor.



In 1935, Dr. Szent-Gyorgyi and his associate Dr. I. (St.) Rusznyak, isolated
a “factor” from lemon juice that decreased the permeability and
increased the resistance of the capillary wall. At first, chemical analysis
indicated that this factor was a single flavonoid compound and it was named
“citrin.” Because of the effect on capillary health, Dr. Szent-Gyorgyi
also called this factor “vitamin P.” [Nature 138:798;1936, Nature
137:27;1936]



He chose “a letter on the far unoccupied side of the ABC” letters
already being used to designate vitamins in case that bioflavonoids were
not found to be true vitamins “correction could be made without confusion.”
The letter “P” was convenient because it could stand for “permeability,”
“purpura” or “petechiae.” The “vitamin P”
normalized the low capillary resistance of vascular purpura patients. In
1936, Dr. Szent-Gyorgyi and his associate, Dr. V. Bruckner found that citrin
was actually a mixture of the flavone hesperidin and eriodictiol glycoside,
a flavonol glucoside. [Nature 138:1057;1936]



By 1936, studies by Dr. Szent-Gyorgyi and associates with guinea pigs indicated
bioflavonoids and vitamin C were synergistic and interdependent. In 1936,
Dr. Janey reported the favorable effects of flavonoids on intact and poisoned
frog hearts. In 1937, Dr. Huszak reported on the biochemistry of parenterally
administered “citrin.” Other researchers such as Zemplen, Bognar,
and Farkas actively researched the biochemistry of flavonoids. However,
in 1938, Dr. Szent-Gyorgyi reported that he could not substantiate that
bioflavonoids were truly essential nutrients.



It was the discovery in Szeged that called attention to the biological actions
of flavonoids, and from 1940 onwards, researchers from many countries began
studying the biochemical effects of flavonoids such as catechins, proanthocyanidins,
rutin, etc. Hungarian researchers had started the research on the biochemistry
of flavonoids, and today remain leaders in the field.



I had the pleasure of discussing vitamin C and the role of electron transport
and the electronic desaturation of protein molecules in the cancer process
with Dr. Szent-Gyorgyi many times during 1972 through 1979, as well as lecturing
together. Dr. Szent-Gyorgyi would discuss my joint research with Dr. Keith
Brewer on energy transfer in cell membranes via double bond excitation.
This research was published in American Laboratory in a five-part series
from 1974 through 1976.



In a March 19, 1973 letter to me, Dr. Szent-Gyorgyi remarked, “I have
not published anything on cancer in a long time, though I have been working
very hard. I arrived at a new concept, but my ideas are not in disagreement
with yours, they are complementary.”



We were both working on our “electronic theory for cancer,” or
as Dr. Szent-Gyorgyi liked to call it, the “electronic dimension of
life and cancer.” Dr. Szent-Gyorgyi called our approaches complementary
because we were both examining the participation of cellular structures
— not just the liquid-state compounds. Also, I was publishing on the free-radical
initiation of cancer and he was investigating the electron transfer system
within structural proteins that allowed them to become semiconductors by
oscillating between two states — one of which was a free radical state.



He had observed that structural proteins in cells are the color of “a
good Swiss chocolate.” The color is due to the presence of an electron
transfer system in structural proteins which transforms them into free radicals.
However, the structural proteins in cancer cells are colorless, indicating
that their electron acceptors are missing or have been damaged.



Dr. Szent-Gyorgyi also found that dicarbonyls produced by the electron transfer
process were capable of stopping cell division. He reasoned that the defective
electron transfer system in cellular proteins allowed the cells to engage
in uncontrolled cell division, thus become cancer cells.



Cancer cells have lost their ability to be semiconductors. Their structural
proteins can no longer accept the single electrons of free radicals, and
thus in turn temporarily become free radicals themselves, and then cause
the formation of cell-regulating by-products such as dicarbonyls.



Dr. Szent-Gyorgyi was a fascinating man with many brilliant concepts, and
provided much encouragement for my research. He often shared his views on
true discovery and how it must by nature seem radical and wrong to everyone
— or it wouldn’t be a true discovery. Occasionally, Dr. Szent-Gyorgyi and
I would discuss the role of bioflavonoids as nutrients, and that Dr. Szent-Gyorgyi
still thought that some good modern research would clarify the “essential
or nearly essential” importance of bioflavonoids. You can see that
my meeting Dr. Gabor has brought back many fond memories of Dr. Szent-Gyorgyi
and that Dr. Gabor and I had some long chats about our mutual friend.



In the foreword to one of Professor Miklos Gabor’s books, Dr. Szent-Gyorgyi
remarked in 1972, “American science did not take in a friendly spirit
to vitamin P and the name “vitamin” was dropped. More than that,
discussions have been going on to strike the flavones altogether from the
lists of (nutrients and) drugs, since no therapeutic action has been found.
I think the contradiction is due to the fact that in the USA, citrus fruits
belong to people’s regular daily diet. They are rich in flavones, so a (total)
lack in flavones is very rare, and if there is no deficiency, a vitamin
has no action. In contrast to this, in countries where citrus fruits are
expensive, the lack of flavones may cause trouble and their medication may
show favorable effects. While these discussions were going on, important
experimental material was collected in Hungary which, in my mind, leaves
no doubt about the vitamin nature and the biological activity of flavones. ”




However, others do not share this conclusion. In Dr. Gabor’s 1986 book,
Dr. Middleton writes in the foreword, “There seems to be a resurgence
of interest in flavonoid research in recent years after the vitamin P
era had come to its proper conclusion. ” Dr. Middleton also remarks,
“For many years one worker and his colleagues in the “flavonoid
fields” persistently has kept our attention focused on the relevance
of flavonoid research. This individual, Professor Miklos Gabor, deserves
great credit for his insight and perseverance.”



In October 1993, I had the chance to chat with Dr Gabor who is the world’s
leading expert on the role of bioflavonoids and capillary health and also
to compare stories about Dr. Szent-Gyorgyi. I will try to share some of
his knowledge of bioflavonoids and capillary health with you.



Passwater: Dr. Gabor, did you have the opportunity to do research
with Dr. Szent-Gyorgyi?



Gabor: No, during the stay of Dr. Szent-Gyorgyi at Szeged, I was
a student. However, I did attend his lectures and have the opportunity to
know him then, and of course, we had a continuing scientific dialog through
the years.



Passwater: You are the world’s leading authority on bioflavonoids
and capillary health. You have published many research reports and have
written several books on bioflavonoids, capillary permeability edema and
inflammation. What originally aroused your interest in this field, and what
continues to hold your interest?



Gabor: During the period from 1950 to 1954 in the Department of Pharmacology
of the Szeged University Medical School, I began my research with some naturally
occurring compounds — haematoxylin, haematein, brasilin and brasilein —
which can be broadly considered as members of the bioflavonoid family. Our
research group demonstrated that these natural dyestuffs can decrease the
increased vascular permeability in guinea pig eyes and skin capillaries
of rats.



After we demonstrated the permeability-decreasing action of haematoxylin
compounds, we examined their ability to normalize lowered capillary resistance.
The permeability of capillaries is quite important to health, and the effect
of various nutrients on capillary permeability fascinates me. My first book
deals with the pharmacology of capillary resistance, including the effects
of bioflavonoids. This book “Die Pharmakologische Beeinflussung der
Kapillarresistenz und Ihrer Regulationsmechahanismen” was published
by the Hungarian Academy of Sciences (Akademiai Kiado, Budapest) in 1960.



In 1965, the Hungarian Academy of Sciences founded a Committee for Flavonoid
research. In 1965 and 1967, I was privileged to organize the first and second
international symposia on bioflavonoids. Since then, these symposia have
been held every four-to-five years. The next international bioflavonoid
symposium entitled the “Ninth Hungarian Bioflavonoid Symposium”
will be held in Wien (Austria) in 1995. However, I have to emphasize that
a conference more limited in scope was the conference on “Bioflavonoids
and the Capillary,” which was organized by the New York Academy of
Sciences and held on February 11, 1955.



In 1972, Dr. Szent-Gyorgyi wrote the foreword for my English-language book,
“The Anti-inflammatory Action of Flavonoids.” The foreword to
my 1986 English-language book, “The Pharmacology of Benzopyrone Derivatives
(Flavonoids) and Related Compounds” was written by Professor Elliott
Middleton, Jr. of the State University of New York at Buffalo. So you can
see that my interest in bioflavonoids is very strong.



Passwater: Yes, and so is the interest of Professor Middleton. I
have co-authored a book on Pycnogenol(R) [Keats Publ., 1993] with a colleague
of Professor Middleton at Buffalo, Dr. Chithan Kandaswami. We discuss Drs.
Middleton’s and Kandaswami’s research on cancer and bioflavonoids in this
new book and in upcoming Health Connection columns continuing the interview
series with Dr. Kandaswami.



I also note that Dr. Hans Selye wrote a foreword to your 1974 book, “Pathophysiology
and Pharmacology of Capillary Resistance.”



Evidence is lacking that bioflavonoids are essential nutrients. Is that
because they are not essential or is it merely because that no diets have
been developed that are totally free of bioflavonoids? I note that in the
scientific literature you have studied the blood brain barrier and aorta
structural abnormalities produced by what you call “P avitaminosis”
(a deficiency of “vitamin P”) produced by flavonoid-free diets.
Would you please elaborate a little for us on “P avitaminosis? Do humans
and other animals get enough bioflavonoids in their experimental or normal
diets to prevent a recognized bioflavonoid deficiency from being observed?



Gabor: Many experimental “fragilizing” diets have now been
developed that are totally free of bioflavonoids. Humans and other animals
get enough bioflavonoids in their normal or experimental diets to prevent
a frank bioflavonoid deficiency.



I should like to mention here that the estimated daily dietary intake of
flavonoids in the United States is about one gram. This originates from
cereals, potatoes, bulbs, roots, peanuts, nuts, vegetables, herbs, fruits,
fruit juices, cocoa, cola, coffee, beer and wine. Flavonoids may be present
in amounts up to a hundred milligrams per kilogram of fresh weight in soft
fruits and their juices. Anthocyanin may be present in rich amounts in some
foods such as raspberry, which can contain hundreds of milligrams per hundred
grams of fresh weight. Notable sources of anthocyanins are red cabbage,
onion, beans, radishes, and rhubarb sticks.



The concentration of catechins in ripe fruits is about five -to-twenty milligrams
per hundred grams of fresh weight. Dimeric proanthocyanidins occur in unripe
berries and the leaves of soft fruit plants in amounts ranging between fifty
and five hundred milligrams per hundred grams of fresh weight. Some proanthocyanidins
are present in apples and grapes. Flavonoids are in tea, cocoa, wine and
beer.



Perhaps, Dr. Szent-Gyorgyi was technically correct in saying that certain
bioflavonoids, as a group, should have vitamin status. However, frank bioflavonoid
deficiency is not a major problem. Today we don’t seem to eat enough bioflavonoids
for optimal health, but we do seem to get enough to prevent “P
avitaminosis.” Keep in mind that bioflavonoids are important to blood
vessel health and even protection from heart disease, and there is a definite
benefit to be obtained by optimizing dietary bioflavonoid intake. We should
do more research on the benefits of bioflavonoids and not be distracted
by the question of whether or not bioflavonoids should have vitamin status.



Keep in mind that Dr. Szent-Gyorgyi’s experiments indicated that at least
a trace of vitamin C must be present to observe the vitamin-like effect
of the bioflavonoids. In his experiments, guinea pigs were kept on the scorbutic
Sherman – La Mer – Campbell deficiency diet. One group, the untreated controls,
died in an average of 28.5 days. The group given one milligram of citrin
daily for six weeks lived an average of 44 days. All of the animals in both
groups showed the typical symptoms of scurvy. Dr. Szent-Gyorgyi and his
colleagues concluded, “these results suggest that experimental scurvy,
as commonly known, is a deficiency disease caused by the combined lack of
vitamins C and P.”



Dr. Szent-Gyorgyi asked other scientists to repeat his studies. The results
were partly corroborative and partly negative. In 1937, Drs. Szent-Gyorgyi
and Bentsath stated, “vitamin P requires for its activity the presence
of ascorbic acid. A scurvy diet frequently contains traces which in themselves
have no influence on the development of scurvy, but enable vitamin P to
act. In the total absence of ascorbic acid, vitamin P is inactive.”
[Nature 140:426;1937]



Passwater: There certainly is a synergism between vitamin C and the
bioflavonoids. They protect each other against oxidation and have other
interactions. Let’s move on to the importance of bioflavonoids to health.
Capillaries are important because they carry nutrients to cells and carry
away waste. Capillaries must be permeable enough to allow fluids to seep
out of the capillaries, mix with the fluid that surrounds all of the cells,
and then reenter the capillaries. If the capillaries are too permeable,
too much fluid and protein seep out resulting in edema, and even red blood
cells may also seep out causing bruising and red spots. You have even designed
a simple portable petechiometer to measure the degree of petechiae (small
hemorrhages appearing as red spots) formation permitted by weak capillaries.
If capillaries are too permeable, they are no longer a barrier to infection.
Dr. Gabor, what has your research shown regarding Pycnogenol(R) and capillary
permeability.?



Gabor: I have studied the effect of water-soluble flavone derivatives
including proanthocyanidins and hesperidin-methylchalcone on the vascular
wall resistance in rats with spontaneous hypertension (high blood pressure).
My investigation revealed that the pathologically low capillary resistance
in rats with spontaneous hypertension was normalized by treatment with oligomeric
proanthocyanidin. This research will be published this year in Scripta
Phlebologica.



Thus, Pycnogenol(R) increases pathologically low capillary resistance, decreases
undesirably high capillary permeability and improves circulation. As I explain
in my upcoming Scripta Phlebologica report, the anti-inflammatory
action of proanthocyanidins may be based on increasing the capillary resistance,
but additional factors should be considered. The antioxidant action of Pycnogenol(R)
has been reported; it can scavenge superoxide radicals, it reduces UV-B
radiation-induced cytotoxicity of fibroblasts and inhibits lipid peroxidation.



Free radicals and other reactive oxygen species are formed at the sites
of inflammation and contribute to tissue damage. The scavenging effect of
Pycnogenol(R) for radicals correlates with its anti-inflammatory activity.
Pycnogenol(R) may also act by inhibiting lipoxygenase and cyclooxygenase.



Passwater: Aha! Most people assume that it’s the high blood pressure
alone that bursts the blood vessels, but it is the decreased capillary resistance
and increased permeability that cause the blood vessel to bleed and weaken
enough to burst.



So, if low capillary resistance is common in people with high blood pressure,
and this is a major factor that leads to stroke and retinal hemorrhage,
your study is of major importance to the millions of people with high
blood pressure. Your findings could drastically reduce the incidence of
strokes. Please elaborate on your study.



Gabor: It has long been known that the capillary resistance is pathologically
decreased in a considerable proportion of hypertensive persons [Griffith
and Lindauer, 1944; Kuchmeister and Scharfe, 1950; Gough, 1962; Davis and
Landau, 1970; etc.]



Special mention should be made of the observation that, if hypertension
is associated with a low capillary resistance, the incidence of cerebral
insults (apoplexy, stroke) and retinal hemorrhage is essentially higher
[Griffith and Lindauer, 1944]. It was established by Paterson in 1940 that
capillary rupture accompanied by intimal bleeding plays a role in the mechanism
of cerebral arterial thrombosis. He assumed that, at the intracapillary
pressure resulting from the high blood pressure, the capillary fragility
(which is enhanced for various reasons) is responsible for the intimal rupture
of the cerebral arterial capillaries.



These data stimulated us to carry out capillary resistance determinations
in spontaneous hypertension rats. As the results reveal, pathologically
low values were observed in the large majority of the experimental animals.



In connection with the flavonoids used, it may be mentioned that oligomeric
proanthocyanidin, isolated from Pinus maritima, was selected because its
indications are to increase pathologically low capillary resistance, to
decrease an enhanced capillary permeability, and to improve the circulation.



My study revealed that the pathologically low vascular wall resistance of
spontaneous hypertension rats can be elevated by treatment with oligomeric
proanthocyanidin.



Passwater: Does your research indicate that Pycnogenol(R) would be
of help to people having fragile capillaries that might result in problems
such as bleeding gums, floaters caused by bleeding into the retina, glaucoma,
bleeding kidneys, and stroke? Also, I have seen European studies that show
that Pycnogenol(R) is a nutritional adjunct that helps against varicose
veins, heavy menstrual bleeding, hemorrhoids and the complications of diabetes.




Gabor: I have not personally conducted clinical trials on these conditions
per se, however, capillary health is compromised in all of these conditions,
and Pycnogenol(R) acts to improve capillary health by improving their bioflavonoid
nourishment.



Passwater: For many years you have been studying the effects of flavonoids
on the capillary resistance of psoriatic patients. A friend of mine in Manchester,
England, Dennis Gore, has reported anecdotal data to me that proanthocyanidins
seem to be effective against psoriasis itself. Have you noticed this in
your studies?



Gabor: Proanthocyanidins are used successfully against diseases characterized
by capillary bleeding associated with increased capillary fragility. The
capillary resistance of psoriatic patients is significantly lower than that
of healthy persons. Pycnogenol(R) tends to restore normal capillary resistance
in these psoriatic patients. However, I have not conducted a clinical trial
of the effect of Pycnogenol(R) on psoriasis as a disease state. I have studied
what may be the causative component of the disease and I have shown that
bioflavonoids can correct this factor.



Passwater: How do the bioflavonoids help capillaries maintain their
proper resistance and permeability?



Gabor: As you know, I have been studying the actions of the flavonoids
in elevating capillary resistance since the early 1950’s and in 1974 I published
a detailed survey of the results of all of the relevant research up to that
date. However, just as with inflammation, we still have a lot to learn about
the “how” part. Even though we need to learn more about the mechanism
involved, we do know that the effects are real. I have observed that Pycnogenol(R)
improves the capillary resistance within two hours and maintains it longer
than eight hours.



Passwater: What has your research shown about bioflavonoids and inflammation?



Gabor: I earlier reported that proanthocyanidin significantly decreased
the inflammation and edema induced by serotonin, prostaglandin or carrageenin.
The decrease is dose-dependent and statistically significant. [Gabor &
Razga, Acta Physiol. Hung. 77:197-207 (1991)] Pycnogenol(R), sophoricoside
and fisetin are the most effective flavonoids against inflammation that
I have tested, and Pycnogenol(R) has the advantage of being very water soluble
and bioavailable.



The mechanisms at play involve the inhibition of several chemical mediators
including histamine, prostaglandins, 5-hydroxytryptamine and kinins. Also,
these flavonoids can block undesirable actions of lipoxygenase and cyclooxygenase.




The actions of Pycnogenol(R) against inflammation are different than those
of rutin, hesperidin and the citroflavonoids.



Passwater: What are your interests for future research?



Gabor: Sixty years after the pioneering research by Rusznyak and
Szent-Gyorgyi, the question naturally arises as to the explanation of the
renaissance in flavonoid research. The answer is clear: chemists have synthesized
new flavonoid derivatives with previously unknown biological effects; phytochemists
have isolated numerous new flavonoids from many plants; biochemists have
demonstrated the most varied effects on different enzymes; and an ever increasing
number of pharmacologic effects have become known through variations of
the chemical structures of the flavonoids and related compounds. This research
has led to the discovery of many new drugs that can be applied for therapeutic
purposes. In these words you can find the future of the research of bioflavonoids.
Personally, I am working now with experimentally induced edema and with
the effects of various drugs on this phenomenon.



Thank you, Dr. Gabor.



All rights, including electronic and print media, to this article are copyrighted
to © Richard A. Passwater, Ph.D. and Whole Foods magazine (WFC Inc.).

Membership dues to the American Aging Association are $35 per year; members
receive AGE NEWS four times per year. Subscription to the journal is $35
per year for non-members and $25 per year for members.



Passwater: The American Aging Association has done a great job so
far, and if you receive the funds, I know you will do more. Have you accomplished
what you set out to do in 1970?



Harman: I was a member of a small group that started the American
Aging Association. The organizers started the American Aging Association
because they felt that more effort should be devoted to basic biomedical
aging. I can’t emphasize enough the need to do basic aging research and
the benefits that it will bring. The American Aging Association has promoted
this area of research and has continued to grow until now it is the largest
group involved in this research area.



Our annual meeting serves to bring together scientists involved in biomedical
aging research and provides an opportunity for the media, and in turn, the
general public, to be informed of progress in this area. Several awards
are presented at the meeting. These include the Distinguished Achievement
Award, the Research Award, and the Excellence in Journalism Award.



The American Aging Association sponsored formation of the American College
of Clinical Gerontology in 1986 in order to more effectively apply the growing
knowledge of aging to the problem of increasing the functional life span.



Formation of the International Association of Biomedical Gerontology was
sponsored in 1985 to help bring together scientists around the world involved
in basic biomedical research. The Sixth Congress of the International Association
of Biomedical Gerontology will be held in August 1995 in Tokyo.



Passwater: There is no point in doing research if you can’t bring
the findings to the public and the physicians who need to incorporate these
findings into the care of their patients.



You were to be the father of this theory, you nourished it, brought it to
people’s attention, beat people over the head with it to get them to expand
the research, you help form the American Aging Association, and now you
are raising funds to support more research. I hope people appreciate all
of your efforts.



Harman: I hope they continue to support increased funding for basic
biomedical aging research. I have testified before Congressional committees
in support of more money for this research field. It is very difficult
to get individuals to understand that cancer or a heart attack is caused
by the aging process and that if we slow this process the disorders that
kill us will be put off in time so that we will have longer functional life
spans. Funding is increasing slowly — it is now about 25 million dollars
per year, very little in comparison to the billions spent on the obvious
secondary disorders.



Passwater: In 1970 or 1971 you estimated that based on your research
and what was happening that antioxidants might add as much 15 years to the
typical lifespan. Today would you still say proper antioxidant nurture could
add 15 years to the typical lifespan?



Harman: I am not sure because the average life expectancy has improved
during that time. In the early 1970s, we were working with mice and it seemed
reasonable that it might be possible to increase the average life expectancy
of man by around 15 years with the antioxidants. Average life expectancy
in the United States has now reached about 75 years. Since the maximum value
for the average life expectancy at birth is about 85 years, it is now likely
that antioxidants may increase life expectancy an additional five to seven
years.



It would also help to increase life expectancy if people would decrease
their caloric intake somewhat.



Passwater: Well, 50 million Americans are taking antioxidant supplements
and that’s largely why our average life span is increasing. Many people
have already put research into practice. The heart disease death rate has
also decreased — there are many factors involved, but an important factor
is that so many Americans have started taking antioxidant supplements over
the last thirty years.



Your point is well taken that the average life span has increased. But,
still, 30 years ago when you made that statement there was a shorter average
lifespan so you might have been correct saying 10 to 15 years.



Harman: Yes, at that time it might have been true. Today, though,
it is more likely to be around five to seven years. I am very hopeful that
the increase will be a great deal greater. The field of biomedical aging
research is expanding rapidly, particularly since the discovery of superoxide
dismutase by Drs. McCord and Fridovich in 1969, and may lead to practical
measures to slow the biological clock



Passwater: Well now we are zeroing in on getting antioxidants more
efficiently into the mitochondria to control free-radical reactions in what
appears to be a prime factor in our biological clocks. We can also reduce
the amount of free radicals generated in the mitochondria by reducing the
oxygen consumption needed to metabolize all the extra calories of food that
we eat. The problem is to get people to eat fewer calories. That is a big
problem!



Harman: That is education. People need to realize that there are
foods which provide adequate nutrients but with fewer calories. The food
industry is actively involved in this area. For example, they are making
fat substitutes.



Passwater: Also, we can reduce the formation of AGEs by reducing
food consumption and being optimally nourished with chromium. The on-going
research is leading us to new and better antioxidants, as well as new basic
discoveries. If people support the American Aging Association, we will speed
the discovery process and better the lives of more people.



Dr. Harman, what supplements do you take?



Harman: I take 200 milligrams of vitamin E per day; ten milligrams
of coenzyme Q-10 with each meal; one yeast tablet containing 50 micrograms
of selenium twice a day, and I also take one multivitamin tablet.



There are other things involved in living a long life. These include keeping
your weight down at a level compatible with a sense of well-being, getting
a moderate amount of exercise, little or no smoking, and minimal alcohol.
There is nothing new about these suggestions; they have come down to us
from our ancestors.



Passwater: A lot of times, mother was right. Dr. Harman, your research
has taken us for quite a journey into understanding our own biochemistry.
You must feel good when you look back on it.



Harman: I am delighted to see the rapid progress being made in our
understanding of the role of free-radical reactions in biological systems.
From this research are coming measures that will increase our span of healthy
productive life. I appreciate your efforts to keep the general public informed
of these studies.



Passwater: Dr. Harman, thanks again for sharing your journey along
your fascinating research that has already helped millions of people.



All rights, including electronic and print media, to this article are copyrighted
to © Richard A. Passwater, Ph.D. and Whole Foods magazine (WFC Inc.).

1. High stored iron levels are associated with excess risk ofmyocardial
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2. Trace elements, hair analysis and nutrition.Passwater, Richard A. and
Cranton, Elmer M.Keats Publishing, New Canaan, CT (1983)

3. Bothwell, T. H. and Charlton, R. W.Annu. Rev. Med. 21:145-6 (1970)

4. Forth, W. and Rummel, W.Physiol. Rev. 53:724-92 (1973)

5. Linder, M. C. and Munro, H. N. J. Proc. Fed. Amer. Soc. Exp.Biol. 36:2017-23
(1977)

6. Role of free radicals and catalytic metal ions in humandisease: An overview.Halliwell,
B. and Gutteridge, JMCin: Packer, Lester and Glazer, A. N. (eds)Methods
in Enzymology, vol. 186, pp 1-85, Academic Press,San Diego, (1990)

7. The iron paradigm of ischemic heart disease.Sullivan, Jerome Amer. Heart
J. 17:1177-88 (1989)

8. Iron and the risk of cancer.Stevens, R. G.Med. Oncol. Tumor Pharmacother.
7(2-3):177-81 (1990)

9. Iron: Health-enhancing or cancer promoting?Somer, ElizabethNutr. Rept.
42 (June 1992)

1) Several new studies show that antioxidant vitamins prevent heart disease.





2) We now know how HDL removes cholesterol from the interior of a
cell, even though the HDL receptor is attached to the cell membrane.





3) Lipoprotein(a) [Lp(a)] is one of the best markers of heart disease risk,
and it in turn is controlled by vitamin C.





4) We have identified a molecular “grappling hook,” a peptide,
that LDL sinks into the free-radical damaged artery linings.

1. The New Supernutrition Passwater, Richard A.Pocket Books, NY (May 1991)

2. McGrady, Patrick Ladies Home Journal

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4. Supernutrition For Healthy Hearts Passwater, Richard A. Dial Press, NY
(1977)

5. Dietary Cholesterol Passwater, Richard A., Amer. Lab. 5(6): 10-22 (June
1973)

6. Oh, Suk Y. and Miller, Lorraine T. Amer. J. Clin. Nutr. 42(3) 421-31
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7. Flaim, Evelyn, et al., Amer. J. Clin. Nutr. 34:1103-8 (June 1981)

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10. Kannell, William B. and Gordon, Tavia USDHEW Report 24 (1970)

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13. Drawber, Thomas R., et al., Amer. J. Clin. Nutr. 36:617-25 (Oct. 1982)

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15. Slater, G., et al., Nutr. Rept. Internat. 14:249-52 (1976)

16. Kummerow, Fred A., et al., Amer. J. Clin. Nutr. 30:664-73 (1977)

17. Flynn, M. A., et al., Amer. J. Clin. Nutr. 32:1051-7 (1979)

18. Hirshowitz, B., et al., Brit. J. Plastic Surg. 23:529 (1976)

19. Heart Study of 50- 59 Year Olds. Passwater, Richard A., Prevention
28 (5) 111- 115 (May 1976)

20. Heart Study of 60- 69 Year Olds. Passwater, Richard A. Prevention 28
(4) 107- 113 (Apr. 1976)

21. Heart Study of 70- 79 Year Olds. Passwater, Richard A., Prevention 28
(2) 61- 68 (Feb. 1976)

22. Hermann, W., Ann. NY Acad. Sci. 462 (1982)

23. Cloarec, M. J., et al., Israel J. Med. Sci. 23(8) 869-72 (Aug. 1987)

24. Bazzarre, T., Nutr. Rep. Internat. 33:711-20 91986)

25. Selenium and Cardiovascular disease. Oster, O. and Prellwitz, W., Biol.
Trace Elements Res.
24:91-103 (1990)

26. …. Lancet II 175 (1982)

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28. Inhibition of cyclooxygenase-independent platelet aggregation by low
vitamin E concentration. Violi, F., et al., Atherosclerosis 82:247-52 (1990)

29. Fackelmann, K. A., Science News 23 (Jan. 12, 1991)

30. Gaziano, J. Michael, American Heart Association’s 63rd Scientific Sessions,
Dallas (November 1990)

31. Hypothesis: Lipoprotein(a) is a surrogate for ascorbate. Rath, M. and
Pauling, L., Proc. Natl. Acad. Sci. 87:6204-7 (1990)

32. Correlation of plasma ascorbic acid with cardiovascular risk factors.
Esk, C. et al., Clin. Res. 38:A747 (1990)

33. Free radical-mediated chain oxidation of low density lipoprotein and
its synergistic inhibition by vitamin E and vitamin C. Sato, K., et al.,
Arch. Biochem. Biophys. 279:402-5 (1990)

34. Hennig, B., Internat. J. Vit. Nutr. Res. 59:273-9 (1989)

35. Del Boccio, G., et al., Atherosclerosis 81:127-35 (1990)

36. Bankhead, Charles D., Medical World News 12-3 (Jan. 1991)


All rights, including electronic and print media, to this article are copyrighted
to Ricahard A. Passwater, Ph.D. and Whole Foods magazine (WFC Inc.)

1. Human Aging ResearchPasswater, Richard A. and Welker, Paul A.Amer. Lab.
3(5):21-6 (May 1971)

2. Pharmokinetics of oral acetylcysteine.Rodenstein, D., DeCoster, A. and
Gazzaniga, A.Clin. Pharmacokin. 3:247-54 (1978)

3. Toxicological, pharmacokinetics and metabolic studies onacetylcysteine.Bonanomi,
L. and Gazzaniga, A.Eur. J. Respir. Dis. 61(Sup):45-51 (1980)

4. Clinical pharmacokinetics of N-acetylcysteine.Borgstrom, L., Kagedal,
B. and Paulsen, O.Eur. J. Clin. Pharmacol. 31:217-22 (1986)

5. Pharmokinetics and bioavailability of reduced and oxidizedN-acetylcysteine.Olsson,
B., et al.Eur. J. Clin. Pharmocol. 34:77-82 (1988)

6. Acetylcysteine: A drug that is much more than a mucokinetic.Ziment, I.Biomed.
Pharmacother. 42:513-20 (1988)

7. Pharmacokinetics and bioavailability of oral acetylcysteinein healthy
volunteers.De Caro, L., et al.Arzneim.-Forsch/Drug Res., 39:382 (1989)

8. Suppression of Cytokine-induced Human Immunodeficiency Virus(HIV) expression
by N-acetylcysteine (NAC), glutathione(GSH) and Glutathione monoester (GSE)Kinter,
Audrey L., et al.75th Annual Meeting of the Federation of American Societiesfor
Experimental Biology, Atlanta, Georgia (April 21-5, 1991)J. FASEB 5(5) A1265
(1991)

9. Suppression of human immunodeficiency virus expression inchronically
infected monocytic cells by glutathione,glutathione ester, and N-acetylcysteine.
Kalebic, Thea, et al.Proc. Natl. Acad. Sci. 88(3):986-90 (1991)

10. Thiol-based compounds may limit AIDS progression.CDC AIDS Weekly p3
(Feb. 25, 1991)

11. Cytokine-stimulated human immunodeficiency virus replicationis inhibited
by N-acetylcysteine.Roederer, M., et al.Proc. Natl. Acad. Sci. 87:4884-8
(1990)

12. Reducing agents and AIDS – Why are we waiting?Turner, V. F.Med. J. Aust.
153/8, 502 (1990)

13. Mercaptoethanol and N-acetylcysteine enhance T-cell colonyformation
in AIDS and ARC. Wu, J., et al.Clin. Exp. Immunol. 77/1, 7-10 (1989)

14. AIDS – Drug therapy; Acetylcysteine research.Cooper, MikeCDC AIDS Weekly
p4 (Oct. 2, 1989)

15. Glutathione deficiency and radiosensitivity in AIDSpatients.Vallis,
K. A.The Lancet 337:918-9 (April 13, 1991)

16. Lipoprotein(a) reduction by N-acetylcysteine.Gavish, Dov and Breslow,
Jan L.The Lancet 337:203-4 (Jan. 26, 1991)

17. N-acetylcysteine and lipoprotein.Stalenhoef, A. F. H., et al.The Lancet
337:491 (1991)

18. AcetylcysteineEditorialThe Lancet 337(8749):1069-70 (May 4, 1991)

19. N-Acetylcysteine and immunoreactivity of lipoprotein(a).Scanu, Angelo
M.The Lancet 337:1159 (May 4, 1991)

20. Metabolic disorder as early consequence of SimianImmunodeficiency Virus
infection in Rhesus macaques.Eck, Hans-Peter, et al.Lancet 338:346-7 (Aug.
10, 1991)

21. Mercaptoethanol and N-acetylcysteine enhance T-cell colonyformation
in AIDS and ARC.Wu, J., Levy, E. M. and Black, P. H.Clin. Exp. Immunol.
77:7-10 (1989)

22. Clinical application for heavy metal-complexing potential ofN-acetylcysteine.Lorber,
A., et al.J. Clin. Pharmacol. 13:332-6 (1973)

23. Treatment of acute methylmercury ingestion byhemodialysis with N-acetylcysteine.Lund,
M. E., Clarkson, T. W. and Berlin, M.J. Toxicol. Clin. Toxicol. 22:31-49
(1984)

24. N-acetylcysteine therapy of acute heavy metal poisoning inmice.Henderson,
P., et al.Vet. Hum. Toxicol. 27:522-5 (1985)

25. Experimental chelation therapy in chromium, lead and boronintoxification
with N-acetylcysteine.Tong, T. G.Toxicol. Appl. Pharmacol. 83:142-7 (1986)

26. Mechanism of action of N-acetylcysteine in the protectionagainst hepatotoxicity
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Mitchell, J. R.J. Clin. Invest. 71:980-991 (1983)

27. Role of glutathione in prevention of acetaminophen-inducedhepatotoxicity
by N-acetyl-L-cysteine in vivo.Corcoran, G. B. and Wong, B. K.J. Pharmacol.
Exp. Ther. 238:54-61 (1986)

28. Effect of N-acetylcysteine on plasma cysteine andglutathione following
paracetamol administration.Burgunder, J. M., Varriale, A. and Lauterberg,
B. H.Eur. J. Clin. Pharmacol. 36:127-31 (1989)

29. Improvement by acetylcysteine of hemodynamics and oxygentransport in
fulminant hepatic failure.Harrison, Phillip M., et al.N. Engl. J. Med. 324(26):1852-7
(June 27, 1991)

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(1963)

All rights, including electronic and print media, to this article are copyrighted
by Richard A. Passwater, Ph.D. and Whole Foods magazine (WFC Inc.)

Sulfur-containing nutrients play several critical roles in the body including
detoxification and protecting cells and cellular components against oxidative
stress. My interest in glutathione and cysteine began in the 1960’s when
they were found to be protective against nuclear radiation. I reasoned that
the same mechanism of action would make them excellent free-radical scavengers
as well. They did, and twenty-one years ago I reported that, “sulfhydryl
compounds that are excellent radiation protectors are also free-radical
scavengers, peroxide decomposers, catalysts of sulfhydryl-disulfide exchange,
and possibly can implement repair of damaged sites. Sulfhydryl compounds
and vitamin E also increase the body’s tolerance to selenium.” [2]



Today, NAC is of greater interest than glutathione itself. NAC is produced
in living organisms from the amino acid cysteine. Thus, NAC is a natural
sulfur-containing amino acid derivative found naturally in foods and is
a powerful antioxidant. [3,4] These dual properties help repair oxidative
damage in the body.



Both NAC and glutathione are well absorbed. [5-8] NAC is rapidly metabolized,
and only about ten percent of the amount consumed stays in the blood for
an appreciable time. [9] Much of the NAC is very rapidly consumed in producing
intracellular glutathione. However, even the thiol metabolites of NAC are
good antioxidants.



NAC readily crosses cell membranes, even in HIV-infected cells, whereas
glutathione does not enter into HIV-infected cells in adequate amounts.
[10-12] Even so, NAC does not seem to raise tissue or blood levels of glutathione
above the desired ranges. [9] Thus, the nutrient role of NAC is to help
maintain healthy levels of intracellular glutathione , especially
whenever a condition has limited glutathione production. This nutrient role
of maintaining optimal levels of essential body compounds is different from
“drug roles” in which body compounds are just elevated without
homeostasis or normal body regulation.



Exercise

Since NAC is a powerful antioxidant nutrient, it has been of special interest
to athletes for some time as heavy exercise increases oxidative damage in
the body. [13-15] But the latest research interests are in AIDS and heart
disease.



Heart Disease

A growing area of interest is that research has pinpointed a specific lipoprotein
called Lp(a) as one of the two most reliable indicators of heart disease
risk. [16-20] The other reliable indicator is the level of vitamin E in
the blood. [21] Lp(a) is a much more reliable indicator than blood cholesterol
level, low density lipoprotein, high-density lipoprotein or their ratios
to each other.



Diets and drugs designed to lower blood cholesterol levels do not lower
Lp(a) levels. Now recent research has found that NAC is the most effective
nutrient known to lower Lp(a) levels. NAC reduces Lp(a) by almost 70%. [22-25]
Lp(a) consists of a LDL particle attached to the large glycoprotein apo(a)
by one or more disulfide bonds. NAC breaks up the disulfide bonds by converting
each disulfide group into two sulfhydryl groups now in two separate compounds.



NAC also inhibits heart damage by preventing LDL from being oxidized and
by destroying free radicals produced after an infarction. [26-29]



Immunity and AIDS

NAC affects immunity via its role in intracellular glutathione production.
This role becomes critical when normal glutathione production pathways are
impaired, as for example, by the Human Immunodeficiency Virus (HIV). Eck
has shown that reduced intracellular glutathione is the “direct and
early consequence of retroviral infection.” [12]



Intracellular glutathione has a powerful influence on how well T- and B-lymphocyte
cells function . [12,30] In addition, intracellular glutathione
availability affects the production of phagocytes (macrophages,
monocytes and neutrophils). T-cells and B-cells are lymphocytes (white cells
that are the principal cells of lymph). B-cells produce antibodies and are
responsible for humoral response, while T-cells help produce antibodies,
secrete interferon and other lymphokines, and are responsible for cell-mediated
response. The phagocytes have the function of killing viruses, bacteria
and fungi.



Free radicals can impair the immune system and NAC can protect against free
radicals and enhance the immune system. [31-33]



As discussed in detail in the previous issue, NAC has been shown to block
the AIDS virus (HIV) production in vitro, apparently by increasing glutathione
levels in HIV-infected cells. [34-46] In the previous article, I also discussed
the synergism of NAC and vitamin C. Beside vitamin C reducing oxidized glutathione
back to free reduced (active) glutathione, vitamin C and NAC had complementary
actions to slow the replication of the AIDS virus.



I reported last month that in addition to NAC and vitamin C (especially
Ester-C ™), AIDS Related Complex (ARC) and AIDS patients should be sure
that they are well-nourished with cysteine, selenium, garlic, vitamin B-12,
folic acid, zinc and Dimethylglycine (DMG). Add Coenzyme Q-10 to this list.
Dr. Karl Folkers and colleagues at the Institute for Biomedical Research
at the University of Texas have expanded on their recent study of ARC patients
who have now lived for over four years with ARC without developing “full-blown”
AIDS by taking 200 milligrams of Coenzyme Q-10 daily. Their first small-scale
study was published in Biochemical and Biophysical Research, and their expanded
study will be published in the Journal of Applied Nutrition. [47]Detoxification



These sulfur-containing nutrients are also gaining new interest because
they protect against toxins. NAC is particularly effective and NAC detoxifies
several toxic agents including the heavy metals such as mercury, lead and
cadmium [48-54], drugs including acetaminophen (e. g. Tylenol ™) [9,55-61],
herbicides such as paraquat [62], environmental pollutants such as carbon
tetrachloride and urethane [63-67], and microorganism including aflatoxin
and Escherichia coli [68-70].



NAC, cysteine and glutathione contain sulfur in the form of sulfhydryl groups.
Sulfhydryl groups directly react with many poisons, especially heavy metals
such as lead, mercury and cadmium. These sulfur-containing nutrients are
the bodies first line of defense against many poisons as they tie-up the
poisons right in the gut. They also offer second-line and third-line defenses
in the liver and various individual cells. Sulfhydryl groups also help remove
toxins indirectly via an enzyme system called the P-450 System.



NAC also has a secondary role in detoxification since it helps produce optimal
amounts of glutathione which also conjugates with most “foreign”
compounds and excess oxidizers that enter cells. The harmful compounds that
have been conjugated with glutathione then pass harmlessly out of the body
through the biliary system. [54]



Although NAC is a food component and a nutrient accessory factor, it is
also marketed as a drug with approved medical claims. Other nutrients also
have dual classifications, but just because a nutrient is also approved
for “drug” usage, its role as a nutrient is not affected unless
drug claims are made. If the nutrient is used to nourish the body, it remains
a nutrient. If the nutrient is used to treat a non-deficiency disease, then
this use changes its legal classification to a drug.



NAC is approved as a drug for use to prevent liver damage from acetaminophen
overdose. Either NAC tablets or solutions may be used to protect against
acetaminophen overdose. Normally, the 20 percent solution is mixed with
a cola drink.



The Lancet reports that NAC is also effective in reducing the toxic
effects of carbon tetrachloride, chloroform and carbon monoxide. [9] NAC
can also reduce the side effects of drugs such as doxorubicin, ifosphamide,
valproic acid and alcohol. [9,60,61]



Cancer

NAC protects against cancer by both of its roles as antioxidant and detoxifier.
[4,70-76]



NAC also reduces the toxic effects of some chemotherapy agents such as cisplatin
and oxazophosporine-based agents. [77,78]



Mucolytic

NAC has been used for about thirty years to break up mucus in persons having
bronchopulmonary diseases including chronic bronchitis, cystic fibrosis,
asthma, sinusitis and pneumonia. [79] NAC helps reduce the viscosity of
mucus so that it may be more easily coughed up. [80] NAC accomplishes this
by converting the disulfide bonds of the mucoproteins into sulfhydryl bonds
and cleaving the mucoproteins into smaller molecules.



Several companies provide a 10 or 20 percent NAC solution as a nebulizer
spray (such as Bristol Laboratories’ Mucomyst TM), while others such as
Italy’s Zambon group provides NAC in tablet form. When a nutrient is topically
applied or sprayed into the lungs, it can then be classified also as a drug
because it does not then enter into metabolism to nourish the body when
it is administered in this way. (However, this is different from having
a nutrient absorbed into the body by sublingual or nasal membrane
application which allows the nutrient to nourish the body.)



Optimal Intake Ranges

There are a few toxicological studies of NAC available and the following
observations can be made. NAC in normal food supplementation ranges is without
known toxicity and has been administered by physicians under supervision
in doses of 500 milligrams to four grams daily. Daily levels of 1,000 milligrams
of NAC per kilogram in rats for several months did not produce adverse effects
in behavior, weight gain, hematology, liver function and kidney function.
[81] (That’s the equivalent of 60 grams of NAC per day for a 132 pound person,
80 grams per day for a 176 pound person, or 100 grams per day for a 220
pound person.)



When administered via nebulizer, adverse effects can include stomatitis,
nausea and nasal irritation. [42] Intravenous administration could also
produce edema and a rapid heart beat. [9]



Larger quantities used for treating acetaminophen overdoses have produced
adverse reactions such as nausea, vomiting, and other gastrointestinal symptoms.
[42] Rash, with or without mild fever, has been reported on rare occasions
with very large quantities. intravenous administration of
more than 150 milligrams of NAC per kilogram of body weight within a fifteen
minute period may produce toxic or other undesirable effects. [9]



The mouse LD50 of oral NAC is reported to be about 8,000 milligrams of NAC
per kilogram in the mouse, and 5050 milligrams per kilogram in the rat.
[81,82] For more details on NAC safety, please refer to references 83 through
88.

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