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AIDS TREATMENT INFORMATION
Article: NAC, Glutamine, and Alpha Lipoic Acid--reprinted with
permission of AIDS.org.
Date: 04/04/97
Issue: 268
Author: Lark Lands
[Note, by John S. James: Lark Lands, Ph.D., a well-known health
educator and consultant, is the author of POSITIVELY WELL: LIVING
WITH HIV AS A CHRONIC, MANAGEABLE SURVIVABLE DISEASE, an 800-page
book which will be published later this year. AIDS TREATMENT NEWS
published her article "Neuropathy: Nutrient Therapies,"
in issue #250, July 5, 1996.
[Two issues ago, AIDS TREATMENT NEWS described the results of a
clinical trial of n-acetylcysteine "Stanford NAC Study:
Glutathione Level Predicts Survival," issue #266, March 7,
1997). Dr. Lands believes that NAC may work better if combined
with other supplements, especially glutamine, alpha lipoic acid,
and vitamin C, within a healthy overall diet. We did not mention
these supplements in our earlier article, as they were not used in
the study we were reporting. Instead we interviewed Dr. Lands, who
gave us permission to reprint material from her book (below).
Note that all of these supplements -- including NAC -- are
unlikely to be suggested by mainstream physicians. The reason is
that there is nowhere near the evidence supporting them as there
is supporting FDA-approved drugs (such as the new protease
inhibitors). There is no good evidence against most supplements,
either. But there can be risks for persons with certain medical
conditions; therefore it is important that anyone receiving
medical care let their physician know about any treatments they
are using or considering.
The problem is that research is needed, but there is little money
for research on treatments which are inexpensive and generally
available. While mainstream drugs are approved based on trials
with hundreds of volunteers, what trials there may be for a
nutritional supplement treatment may include only a handful of
volunteers. And sometimes there are only laboratory and animal
studies, and informed guesses based on possible mechanisms of
action. That is why such treatments are "alternative" in
the first place. (We prefer the term "complementary" to
"alternative," meaning nutritional and other treatment
approaches which may be used with -- not instead of -- standard
medical care.)
What people do with complementary treatments usually depends on
their personal philosophies; some have nothing to do with them,
others build their medical care around them. We suggest
considering a middle course. People with HIV respond very
differently to different treatments, mainstream and otherwise. We
suspect that complementary treatments which are well thought out
might significantly benefit some people, but not others. One
approach, then, is to view proposed complementary treatments --
when they are reasonably safe and have some plausibility -- as
suggestions for strategies one could try to see if they seem to be
helping.
Aside from the book excerpts published below, we asked Dr. Lands
the following questions:
AIDS TREATMENT NEWS: How many people do you know who have combined
NAC with glutamine and other supplements you suggest? In other
words, to what extent are your recommendations based on peoples'
experiences, and to what extent are they based on the published
literature (which is limited here, since many important studies
have not been done)?
Lark Lands: I personally know and have worked with many hundreds
of people who have combined multiple antioxidants to help combat
the oxidative stress of this disease. In order to maintain optimal
glutathione levels, this has usually included NAC, vitamin C,
L-glutamine, and alpha-lipoic acid. In addition, at almost every
one of the 40-50 conferences where I speak each year people will
come up to tell me that they have been including such nutrients as
parts of their programs for years. Both they and my own clients
make it clear that they believe strongly that using supplements in
this way is a very important part of their long-term programs for
living long and well with HIV. Many have reported what appears to
be significant disease stabilization and even, in some cases,
significant increases in CD4s after beginning comprehensive
supplementation programs, as well as very significant symptom
reduction. And the research to date certainly seems to support
this, with multiple studies showing slower disease progression
with higher levels of nutrients, in general, and, of course, the
Herzenberg study suggesting the much higher level of survival in
those with higher glutathione levels.
ATN: If someone tries combining NAC with the other supplements you
suggest, what could they look for as an indicator of how well it
may be working for them?
LL: It would depend on the particular supplement and on the prior
existence of symptoms that might be related to nutrient
deficiencies. In other words, if someone has a symptom that
obviously improves when a nutrient or combination of nutrients is
tried, then it may be obvious that there had previously been one
or more nutrient deficiencies which, when corrected, resulted in
symptomatic improvement. For example, if you have neuropathy and
find that the numbness or pain is lessened or eliminated when you
use alpha-lipoic acid, then you can reasonably assume that the
lipoic acid is helping you. If you have lost muscle tissue and
find that taking L-glutamine seems to help restore the muscles, or
you have diarrhea and find that using L-glutamine seems to improve
it, then you can reasonably assume that your glutamine levels were
too low for all your body's needs and that supplementation with it
is helping you.
Unfortunately, there are no such obvious signs of improvement when
you're simply taking multiple nutrients in order to try to
maintain optimal antioxidant status in the body and, thus, slow
disease progression. There is, however, a theoretical support for
this, based on the work of many different researchers, including
the Herzenbergs. I feel very strongly that long-term use of such
supplements is important for those who wish to (1) protect their
bodies from the oxidative stress known to be caused by HIV disease
and the internal body damage and inflammation that can result from
that, and (2) maintain the higher levels of antioxidant compounds
in their bodies that seem to be tied to slower disease
progression.
ATN: What could you say about the importance of a balanced diet
overall?
LL: It is essential to have a healthful, whole-foods diet as the
base that underlies any supplementation program. Such a diet
should be the foundation upon which you place additional
supplements. Pills alone simply cannot suffice. For anyone, the
basic rule here is simple: get all the nutrients you can with a
fork and spoon. In that way, you will be getting at least some of
the whole broad spectrum of nutrients that are important to human
health, along with their cofactors. And this will include the
nutrients we have not yet discovered; you cannot get those in a
pill. Unfortunately, because of the extraordinary demands for
nutrients created by this disease, I do not believe that it is
possible to get an optimal level of all the nutrients needed for
living long and well with HIV from food alone. Several studies
support this view, including one from the University of California
at Berkeley which found that only the higher levels of nutrients
that could only be achieved by supplementation were linked to a
reduced hazard of AIDS and increased CD4 levels. They did not find
an association between the level of nutrients that was obtained
from food alone and any reduced risk of AIDS. This does not mean
that eating well and obtaining nutrients from food is not
important. It only means that it is apparently insufficient to
obtain the level of nutrients needed to support immune function
and protect the body in someone living with HIV. The demand for
certain nutrients, including L-glutamine and multiple
antioxidants, is just too great. However, if purchasing
supplements is out of the question, then at least careful food
choices can optimize your intake from your daily diet.
***
The following is from Dr. Lands' forthcoming book, POSITIVELY
WELL: LIVING WITH HIV AS A CHRONIC, MANAGEABLE SURVIVABLE DISEASE.
Glutamine
Glutamine is an amino acid which is normally found in greater
abundance in the body than any other free amino acid. It is
crucial for many aspects of healthy body function, including
maintenance of optimal antioxidant status, building and
maintenance of muscle tissue, maintenance of optimal immune
function, and repair and maintenance of intestinal tissue. Because
it has long been classified as "non-essential" --
meaning that the body can normally synthesize what it needs --
little attention has been paid to its importance in HIV disease.
Luckily, the work of Judy Shabert, M.D., M.P.H., is changing that.
She has shown that glutamine deficiency may cause many serious
problems, including inadequate antioxidant status in the body,
wasting, and loss of both intestinal and immune function. Dr.
Shabert points to the research showing that during the stress of
infection or injury, the demand for glutamine is very high. The
muscles respond to this demand by releasing their stored
glutamine. In fact, the rate of release of glutamine from the
muscles is dramatically increased, to levels 3-4 times normal.
According to Dr. Shabert, the body does this in order to provide
glutamine to the intestinal tract, liver, kidneys, and immune
system cells.
With the short-term metabolic stress that is created by acute
infections, the body can soon return to normal rates of glutamine
use. The muscle glutamine levels are quickly restored and the
muscles are not damaged. Unfortunately, with the continuous
metabolic stress that results from the chronic infection of HIV
disease, the demand for glutamine continues and the concentration
of this amino acid in the muscles falls rather rapidly. This
results in a decline in the synthesis of muscle tissue and,
eventually, a wasting away of the muscles. Since the muscles can
no longer provide sufficient glutamine, blood levels will also
stay chronically low. Only when glutamine levels are restored to
normal will muscle synthesis be able to work normally in order to
restore the muscle tissue. Thus, supplementation of this amino
acid at levels sufficient to restore normal status in the body is
vitally important. Muscle loss may be restored or, better yet,
muscle wasting may be prevented in the first place. This, of
course, makes glutamine crucial for the prevention of internal
decline and wasting.
In addition, glutamine is very important for the maintenance of
immune function. It is the primary fuel source for lymphocytes and
macrophages. These cells consume glutamine at high rates even when
there are no special demands for immune system response to an
infection. During an immune response when the immune cells have to
increase in number and do their work of destroying pathogens, the
rate at which glutamine is used increases dramatically. When the
body's supply of glutamine runs short, immune function is
compromised. Dr. Shabert notes that both the speed at which T
cells mature and the proliferative responses of T cells have been
shown to be positively affected by supplementation with
L-glutamine. Glutamine also increases the activity of natural
killer cells and improves the function of neutrophils. In
addition, glutamine is critical for the immune function of the
respiratory tract, the genitourinary tract, and the intestinal
tract. The linings of these tracts produce secretory
immunoglobulin A (sIg-A), a type of antibody which works in and on
the linings to provide immune defense. Glutamine is a required
nutrient for sIg-A-producing cells. This antibody provides the
primary immunological defense of the intestinal tract. Thus,
supplementation with L-glutamine may help restore sIg-A production
in a way that will improve the immune defense of the gut lining
and help prevent infections... It may also help to restore the
immune function of the respiratory tract... For all these reasons,
giving the body sufficient L-glutamine to help restore adequate
amounts of sIg-A to the linings of the body might significantly
boost immune defenses.
Glutamine is also critical for maintaining the health of the
intestinal tract since it is required for the constant rebuilding
of intestinal cells. The cells lining the intestine function to
absorb nutrients and to block the uptake of pathogens. These cells
are regenerated every 3-4 days. The energy which allows this
process to occur comes from glutamine. If glutamine concentrations
are low, the result is intestinal tissue atrophy and decreased
absorption, with resulting lack of uptake of nutrients vital to
the body's function. Glutamine is also necessary to maintain the
barrier function of the intestines, the body's ability to block
the uptake of pathogens, improperly digested food particles, and
so on. As is readily apparent, glutamine's ability to help repair
the intestines is among its most important benefits for people
living with HIV.
For those on intravenous nutrition (total parenteral nutrition/TPN),
it may be important to add glutamine to the IV solution. In an
extensive review article on the role of glutamine in critically
ill hospitalized patients, it is suggested that supplemental
glutamine in either enteral or parenteral feedings may greatly
improve nutrition management and increase the speed of recovery,
thus shortening hospital stays. In part, this is almost certainly
due to its capacity to heal the intestines or prevent their
atrophy. Dr. Shabert points out that the usual failure to replete
lean tissue that is seen when standard TPN or most oral
nutritional formulas are used in an attempt to address wasting is
due to the fact that most such formulas fail to provide the
rate-limiting amino acid for muscle tissue building, L- glutamine.
Restoring glutamine sufficiently to achieve optimal blood levels
can also be critically important for maintaining the antioxidant
status in the body. Glutathione is one of the body's best
antioxidant defenses against the oxidative damage of HIV disease.
The reason that L-glutamine is important to maintain glutathione
levels is somewhat complicated but the simple version is this. The
amino acid cysteine is generally the rate-limiting factor in the
production of glutathione in the body. In other words, the amount
of glutathione that you can produce will be dependent on the
amount of cysteine that is available for that process. That's why
N-acetylcysteine (NAC), discussed below, is important for
glutathione synthesis. However, once you've provided all the
cysteine that's necessary, glutamine becomes the rate-limiting
factor in the production of glutathione. Thus, in a body depleted
of glutamine, glutathione production will never be optimal.
Supplementing with both NAC and L-glutamine can greatly improve
the chances for full glutathione replenishment, with all the
benefits that come from that. It will also help to ensure that
your body remains capable of properly breaking down all the drugs
you may be taking. The liver uses glutathione for the
detoxification of drugs. When levels of glutathione in the liver
are too low, its ability to properly break drugs down may be
compromised.
Dr. Shabert believes that the combination of all these needs for
glutamine results in a demand for it that is well beyond what the
body can possibly provide for itself. Thus, supplementation with
sufficient amounts of L-glutamine to provide the body what it
needs for all these important functions is very crucial. The
L-glutamine can be given either orally or intravenously to
accomplish this. Glutamine normally makes up 5-8% of dietary
protein so the average person eating approximately 100 grams of
protein per day is getting around 5-8 grams daily. However, this
level appears to be inadequate even for maintenance of glutamine
levels in someone living with HIV who is asymptomatic. For someone
in more advanced disease stages or in need of intestinal repair or
muscle rebuilding, it is hopelessly insufficient. It appears that
even those in early, asymptomatic disease stages may need
approximately 10 grams per day to protect their bodies. As the
disease progresses, moving toward 15 grams per day is probably
appropriate. When there are already existing problems, increasing
to even higher doses may be necessary.
Charlie Smigelski, R.D., a registered dietitian and researcher at
Harvard University, has suggested that doses of 40 grams per day
may be useful for those who need to repair the intestines or gain
weight and muscle tissue. Based on his work and that of other
researchers, it appears that doses of 30-40 grams per day (30,000-
40,000 mg), spread out over five doses of 6-8 grams each
(6,000-8,000 mg), continued for at least 7-10 days may be helpful.
Lengthier periods on this higher dosage may be necessary for some,
especially if the need for intestinal repair coincides with the
need to restore wasted muscles. Substantial amounts of L-glutamine
are necessary for both of these so when these two problems
coincide, it may be necessary to continue higher dosage levels
until both the intestines and the muscles are well restored. It is
only when all the extraordinary demands for glutamine needed to
effect intestinal and muscle repair are met that the body will be
able to return to meeting day-to-day needs for maintenance of
those tissues and of proper antioxidant status in the body with
lower levels of L-glutamine.
There is a blood test available that can measure glutamine levels
as part of an assay of amino acids in plasma. Unfortunately, blood
levels can be somewhat misleading because the body will attempt to
keep blood levels normal even when the level in the muscles is
low...
Glutamine is available in both capsules (usually 500 mg each) and
powdered form. However, in general, the powdered form is
preferable since far too many capsules would be required to meet
the dosage levels necessary for the best results. For those in
need of higher dosages, the powdered form is a must. It will be
much easier to take and is considerably less expensive than the
encapsulated forms. In addition, you'd never want to take 80
gelatin capsules per day of anything. The gelatin in the capsules
could cause diarrhea. With most products, each teaspoon of
L-glutamine powder contains approximately 4 grams. If you're doing
the higher dose of 40 g per day, this would mean taking
approximately 2 teaspoons, five times per day. After the intensive
therapy period, the dosage can be reduced to 3/4 to one teaspoon
(3-4 grams), 3-4 times per day. The powder can be mixed in a half
a cup of water or juice or, if you prefer, in a warm liquid such
as soup or tea. Do not, however, add it to hot liquids.
Individuals who are on protein-restricted diets because of
advanced liver or kidney disease should not take glutamine without
their physician's approval since it would have to be considered
part of the limited amount of protein allowed.
Lipoic Acid (Thioctic Acid)
Alpha-lipoic acid (also known as thioctic acid) is an important
antioxidant which quenches many different reactive oxygen species,
including hydroxyl radicals, hypochlorous acid, and singlet
oxygen. It readily crosses cell membranes and works as an
antioxidant in both lipid and aqueous parts of the body. In other
words, it can counter many different forms of oxidative stress and
prevent the cellular damage they might cause. It both directly
reduces oxidative stress in the body and indirectly spares or
recycles or regenerates the other major antioxidants, raising
their levels in the bloodstream. It can recycle vitamin E from its
oxidized form back to its reduced form (in which it again becomes
an antioxidant), thus helping to protect cell membranes. Vitamin C
can also be regenerated through reaction with alpha-lipoic acid,
as can glutathione. In fact, alpha-lipoic acid has been shown to
protect against the symptoms of vitamin E or vitamin C deficiency
in animals fed diets deficient in those nutrients. One small study
(10 HIV+'s in CDC Stage 4) showed a combination of effects from
supplementation with alpha-lipoic acid including increases in
blood levels of vitamin C and glutathione, increases in CD4 cells,
and decreases in the body compounds that result from oxidative
stress. The latter shows that it was indeed working well as an
antioxidant. Although most of the HIV community has focused in the
past on NAC as a way to raise glutathione, research carried out by
Dr. Lester Packer at the University of California at Berkeley has
shown that alpha-lipoic acid may be the best way to raise
glutathione levels in people living with HIV.
Alpha-lipoic acid is very important to the liver cell metabolic
pathways and can be rapidly depleted when the liver is under
stress. In Europe, it has long been used in the treatment of
hepatic disorders because of its liver-sparing effects which can
help the liver repair. Although later research has shown that it
is not specifically helpful for mushroom poisoning or alcoholic
liver degeneration (two things for which it had been used in the
past), there are other causes of liver damage for which it may be
quite useful. Its effectiveness in raising cellular glutathione
levels is probably very important for liver repair with a disease
like HIV that induces glutathione deficiency. Especially when used
in combination with silymarin, I have seen it work quite well to
reduce elevated liver enzymes, even in some people in whom the
levels had been elevated for quite some time. Some of my clients,
in fact, have successfully used this combination to lower enzymes
sufficiently to get into clinical trials of various drugs, where
too-high liver enzymes would have otherwise excluded them. Its
combined usefulness in repairing the liver and working as an
antioxidant has led to its extensive use in Europe for radiation
sickness, drug poisonings, and chemical overdoses. It may provide
some protection against the damage induced by radiation therapy
during cancer treatment.
In addition, both in vivo and in vitro research has shown
potential for alpha-lipoic acid to serve as an antiretroviral
agent. It has been shown to inhibit replication of HIV in both
acutely and chronically infected cells by a mode of action
different than that of nucleoside analogues. In vitro, alpha-lipoic
acid has been shown to have synergistic effects when combined with
AZT, with the combination of the two showing stronger inhibition
of HIV replication than either had when used alone. In vitro
research done at Kumamoto University in Japan has shown that
alpha-lipoic acid significantly depresses both HIV tat gene
activity and HIV infectivity, and is active in both acute and
chronically infected cells. Other in vitro research done in the
Department of Molecular and Cell Biology at the University of
California, Berkeley, has shown that alpha-lipoic acid inhibits
NF-kappa B activity. German in vitro research has also shown that
alpha-lipoic acid inhibits the infectivity of virus particles and
suppresses viral replication, and follow-up in vivo studies by the
same researchers showed that it does have antiviral effects in
HIV+'s, reducing viral titers just as had been predicted by the in
vitro research. Since NF-kappa B is, in essence, an on-off switch
for the activation of HIV, and tat inhibition is considered a
promising antiviral approach, and anything non-toxic that
effectively suppresses viral replication and reduces infectivity
is immensely desirable, alpha lipoic acid may be a very important
part of a comprehensive antiviral approach. So why haven't other
researchers been rushing to pursue its antiviral possibilities?
Gee, it couldn't be because it's unpatentable and, thus, unlikely
to be profitable, do you think?
Alpha-lipoic acid has long been used in Europe for the treatment
of peripheral neuropathy in diabetics. A number of controlled
clinical trials have shown its usefulness for reducing both the
pain and numbness suffered by those with diabetic neuropathy, and
its use for this condition is approved in Germany. Its antioxidant
properties may help protect the nerves from the inflammation and
oxidative damage that HIV induces, as has been shown to be true
with diabetic neuropathy. Alpha- lipoic acid is also a true oral
chelating agent that has been widely used in Europe in the
treatment of heavy metal toxicity caused by chemicals such as
arsenobenzoles, mercuric chloride, and carbon tetrachloride. Thus,
it is possible that it might be removing something that is toxic
to nerves. Because of its liver protective and antioxidant
benefits, it has been included as a component of the programs of
many of my clients for several years now. It may have contributed
to the success of the multi-nutrient neuropathy elimination
programs some of them have used.
Alpha-lipoic acid may also be useful for cognitive dysfunction in
HIV disease. Tissues of the central nervous system are known to be
particularly vulnerable to oxidative stress because of their high
rate of oxygen consumption and high mitochondrial density. The
mitochondria produce lots of free radicals during normal oxidative
metabolism and, especially without sufficient antioxidant
protection, the mitochondrial tissue may be damaged. It is
believed that this sort of oxidative stress damage may be
partially responsible for neurodegenerative diseases. In animal
studies, alpha-lipoic acid has been shown to improve memory,
apparently by reversing the damage that had been induced by
oxidative stress. Although no research has been done to look at
the possible usefulness of alpha-lipoic acid for neurocognitive
degeneration in people living with HIV, it is certainly an
interesting possibility.
Because it not only appears to be non-toxic but also may improve
T-cell function, while helping keep the liver healthy (especially
where there is long-term drug usage that may adversely affect the
liver), serving as a powerful antioxidant, and possibly protecting
the nerves, it seems like an extremely useful part of a total
integrated approach. If it also has an antiviral effect, so much
the better.
Many people take 100-200 mg, three times per day with meals,
sometimes increasing the amounts when liver enzymes are elevated
or neuropathy is present. There is no known toxicity, but one
report shows possibility of thrombocytopenia (decreased platelets)
from higher doses. Because it is an effective mineral chelating
agent, some writers have raised the question of whether alpha
lipoic acid might remove important minerals; although no problems
have been observed at the doses listed here, to err on the side of
safety, its use could be accompanied by the daily intake of a good
multiple vitamin/mineral supplement and an iron supplement, and
blood cell tests (RBC and platelets) could be monitored while it's
being taken.
**Statements contained herein
have not been evaluated by the Food and Drug Administration. These
products are not intended to diagnose, treat and cure or prevent
disease. Always consult with your professional health care provider
before changing any medication.**
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