Discussion:
Pharmaceutical grade NAC matters
(too old to reply)
Arbor B
2009-08-18 07:47:57 UTC
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In all clinical studies except where NAC is administered as an
antidote, the effervescent tablets (e-NAC) have been used. e-NAC is
the most sold form of pharmaceutical grade NAC that is sold (and
manufactured) outside of the USA.
The question why, has been in the back of my mind for a while.
However, because this form of NAC isn't available in the US, and
because clinical studies (few in more advanced clinical trial stages)
are fairly recent, I have not taken the time to search for answers
until now.

The answer is YES, it does matter that e- NAC was used in this study
as well as other studies because:
1) Lack of pharmacological standards in manufacturing and storing of
NAC supplement.
2) e-NAC is rapidly absorbed which, matters wrt the purpose of the
study that I posted several days ago PMID19636205 (see thread:
http://tinyurl.com/klozhv)

These 2 issues are reviewed in the paper below.

In preparation for the fall and winter seasons, I ordered some e-NAC
from this site:
http://goldpharma.com/.
Arbor

[Includes the relevant parts of the review]
N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency.
Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA.
Curr Opin Pharmacol. 2007 Aug;7(4):355-9. Epub 2007 Jun 29. Review.
PMID: 17602868
Glutathione (GSH) deficiency is associated with numerous pathological
conditions. Administration of N-acetylcysteine (NAC), a cysteine
prodrug, replenishes intracellular GSH levels. NAC, best known for its
ability to counter acetaminophen toxicity, is a safe, well-tolerated
antidote for cysteine/GSH deficiency. NAC has been used successfully
to treat GSH deficiency in a wide range of infections, genetic defects
and metabolic disorders, including HIV infection and COPD. Over two-
thirds of 46 placebo-controlled clinical trials with orally
administered NAC have indicated beneficial effects of NAC measured
either as trial endpoints or as general measures of improvement in
quality of life and well-being of the patients.
Loss of balance between the antioxidant defence and oxidant production
in the cells, which commonly occurs as a secondary feature in many
human diseases, is loosely termed as ‘oxidative stress’. This balance
is important because the intracellular redox environment must be more
reducing than being oxidative to maintain optimal cell function. Four
major inter-dependent redox couples — GSH/GSSG, NADPH/NADP+, NADH/NAD+
and thioredoxin [Trx(SH)2/TrxS-S] — interact to regulate this redox
environment [1]. The loss of antioxidant capacity in an oxidatively
stressed cell is, however, mainly due to a decrease in GSH and/or an
increase in GSSG, because glutathione (GSH) is the most abundant
intracellular free thiol. Thus, oxidative stress in vivo mainly
translates to deficiency of GSH and/or its precursor, cysteine.

Antioxidant supplementation has been studied extensively as a method
to counter disease-associated oxidative stress. Several antioxidants
have been used with varying degrees of success. Although the commonly
used antioxidants, which include vitamin C, vitamin K and lipoic acid
can directly neutralize free radicals, they cannot, however, replenish
the cysteine required for GSH synthesis and replenishment [2]. Thus,
not surprisingly, the cysteine prodrug N-acetylcysteine, which
supplies the cysteine necessary for GSH synthesis, has proven to be
more effective in treating disease-associated oxidative stress. NAC
has been used in the clinic to treat a variety of conditions including
drug toxicity (acetaminophen toxicity) [3•], human immunodeficiency
virus/AIDS [[4] and [5]], cystic fibrosis (CF) [[6] and [7••]],
chronic obstructive pulmonary disease (COPD) [8], diabetes [9], etc.

In this review, we summarize the biochemical and pharmacological
aspects of NAC that make it a ‘wise choice’ to treat cysteine/GSH
deficiencies. We then focus on the various NAC formulations that are
currently available. Comprehensive reviews of placebo-controlled
trials with NAC have been published previously [[10••], [11], [12],
[13] and [14]]. Here, we briefly comment on the various clinical
trials with NAC with special reference to acetaminophen toxicity, HIV
and CF, in which our laboratory has a special interest.
Biochemistry and function

In vitro and in vivo studies have shown that NAC acts as a cysteine
prodrug and a GSH precursor [15]. It can also reduce disulphide bonds
in proteins [[16] and [17]], scavenge free radicals [18] and bind
metals to form complexes [19]. However, its principal use
pharmacologically is to replenish the cysteine and GSH that are lost
due to acetaminophen toxicity.

Chemically NAC is similar to cysteine. The presence of the acetyl
moiety, however, reduces the reactivity of the thiol as compared with
that of cysteine. Thus as compared with the cysteine, NAC is less
toxic, less susceptible to oxidation (and dimerization) and is more
soluble in water, making it a better source of cysteine than the
parenteral administration of cysteine itself [20].

Although NAC (and GSH) can directly scavenge free radicals, the rate
constants for their reaction with reactive oxygen species (ROS) are
several orders of magnitude lower than those of antioxidant enzymes
such as superoxide dismutase (SOD), catalase and glutathione
peroxidase [21]. Thus, the direct free radical scavenging activity of
NAC is not likely to be of great importance for its antioxidant
activity in vivo.

The direct antioxidant activity of NAC has been proposed primarily
based on data from in vitro studies, where NAC has been shown to
reduce oxidant-induced cell damage and cell death by apoptosis [15].
Recent studies from our laboratory, however, indicate that the
observed beneficial effects of NAC on cells in culture is due, at
least in part, to replenishment of the intracellular GSH that is lost
in cells maintained under typical cell culture conditions. This GSH
loss, as we have shown, is substantially greater in cells maintained
at the atmospheric oxygen levels (i.e. 20% oxygen) typically used in
CO2 incubators than in cells maintained at more physiological oxygen
levels (5% oxygen). It can be prevented by adding NAC to the cultures,
though NAC does not completely prevent the adverse effects of
culturing cells at atmospheric oxygen (Atkuri et al., 2007, PNAS in
press).
In vivo metabolism

NAC's primary function in vivo is to supply cysteine necessary for GSH
synthesis and replenishment. Consistent with this, pharmacokinetics
studies have shown that NAC undergoes extensive first pass metabolism
in the liver and kidneys resulting in very low concentrations of
‘free’ NAC in the plasma [[22] and [23]] and virtually undectable
levels of NAC in other body fluids such as broncho-alveolar lavage
[24].

Orally delivered NAC is readily taken up in the stomach (low pH in the
stomach makes the neutral species of NAC the predominant form and
hence easily penetrable) and gut [25] and is sent to the liver via the
portal route where it is almost entirely converted to cysteine [23].
The liver incorporates most of the cysteine into GSH, which is then
largely secreted into circulation [26].

NAC has most widely been used for countering acetaminophen (or
paracetamol) toxicity and associated liver injury. Acetaminophen
mediated liver toxicity is due to the generation of its metabolite N-
acetyl-p-benzoquinoneimine by the hepatic cytochrome P450 enzymes.
Detoxification of this metabolite requires high concentrations of GSH.
Thus excessive GSH depletion during acetaminophen overdose can cause
permanent liver damage. NAC administration supplies the cysteine
required for the de novo synthesis of hepatic GSH.
NAC administration and toxicity

NAC has been administered orally, intravenously and topically (e.g. as
aerosol). Topical delivery of NAC has not been shown to increase
systemic NAC, cysteine or GSH levels. Further, aerosol delivery can
result in NAC oxidation, which may have negative consequences [27].
Intravenous administration of NAC transiently increases plasma NAC to
very high levels (during administration) and is known to cause adverse
effects. Although clinical situations sometimes dictate the need for
intravenous administration of NAC [3], most needs for NAC therapy can
be met by oral NAC administration. In the interests of brevity, we
therefore largely restrict this review to consider settings in which
NAC has been administered orally.

Oral administration of NAC at doses up to 8000 mg/day is not known to
cause clinically significant adverse reactions [5]. A small fraction
of individuals to whom oral NAC was administered reported experiencing
nausea, vomiting and heartburn. In a placebo-controlled trial testing
NAC at an average dose of 6900 mg/day, for example, 14/60 subjects
reported gastric distress. On analysis, however, 7 of the 14 subjects
reporting such adverse events were in the placebo arm [5], suggesting
that the distress that was encountered was related to the ingestion of
the excipient (which was later recognized as containing lactose).
Consistent with this interpretation, no adverse effects were reported
in a recent phase II clinical trial for CF in which NAC (or placebo)
was administered orally as lactose-free flavoured effervescent tablets
(BioAdvantex Pharma Inc., Mississauga, Ontario) (Tirouvanziam et al.,
unpublished). Similarly, a review of over 46 placebo-controlled trials
where NAC was administered orally to a total of 4000 subjects did not
reveal significant adverse effects from NAC treatment.

In contrast, severe and in some instances life-threatening
anaphylactoid reactions, which include urticuria, hypotension and
vomiting, have been reported after intravenous administration of NAC
[3•]. These reactions subside rapidly when NAC administration is
discontinued or the rate of intravenous administration of NAC is
decreased. NAC is not known to interact with other drugs although
extensive studies in these aspects have not been performed.

Overall, the data available from NAC trials suggest that when cysteine
is delivered orally in a non-toxic form (e.g. as NAC rather than as
cysteine itself), toxicity associated with high cysteine intake is
negligible. Thus, since cysteine is known to spare methione, addition
of NAC (a source of cysteine) to parenteral nutrition formations may
be useful [28••].
NAC formulations

The best known NAC formulation in the US is Mucomyst™ (or the generic
version thereof). Although it is commonly administered orally for the
treatment of acetaminophen overdose, it has a strong, disagreeable
flavour and therefore is usually mixed with a fruit juice or a soft
drink before consumption. In contrast, NAC is produced and packaged in
Europe in pill and capsule formulations, as well as in a variety of
effervescent formulations (‘fizzy tabs’) that can be dissolved in
water, juice or carbonated drinks to create a pleasant tasting,
readily tolerated beverage containing soluble NAC that can be rapidly
absorbed. A Canadian company (BioAdvantex Pharma, Inc., Mississauga,
Ontario) also offers pleasant-tasting effervescent NAC tablets that
are manufactured according to European Good Manufacturing Practice
(GMP) standards [7••].

The manufacture of NAC requires minimization of NAC oxidation to its
dimeric form (‘di-NAC’), which is pharmacologically active at very low
concentrations with immunologic effects opposite to those of NAC [27].
In an experimental model with rodents, di-NAC was found to be 100–1000
times more effective in enhancing contact sensitivity to oxazolone
than NAC. In general, di-NAC constitutes less than 0.1% of NAC
produced according to European GMP standards [29].

Several US nutriceutical dealers manufacture and sell NAC alone or in
combination with other daily supplements such as vitamins and
antioxidants. However, since the FDA does not regulate the production
and packaging of nutriceutical products in the US, neither the content
nor the purity of the NAC formulations currently produced and marketed
in the US can be reliably judged. It is important to note that
manufacturing methods for these NAC preparations may not include
measures to prevent oxidation of NAC to its dimeric form either during
manufacture or while the product is stored.

We have recently suggested [30] that NAC be co-administered, and
perhaps co-formulated, with acetaminophen to decrease its potential
toxicity. Animal studies suggest that administration of roughly
equimolar amounts of NAC and acetaminophen may be sufficient to
accomplish this goal [31]. Co-administration of acetaminophen with NAC
could minimize acetaminophen toxicity in setting where GSH deficiency
is present or is transiently induced by alcohol or other drug
ingestion. In addition, co-administration with NAC may safely allow
administration of higher doses of acetaminophen when clinically
warranted.

Conclusions/future directions
Oral administration of NAC, a safe, well-tolerated drug with no
clinically significant adverse effects, has been shown to be
beneficial in settings where GSH deficiency occurs, for example, HIV
infection, CF and diabetes. Although many trials have been conducted,
more are needed to further ascertain the effect of NAC in diseases
associated with GSH deficiency.

In individual patients, the extent of GSH deficiency that develops may
vary depending on the disease severity, patient diet and other drug
use (including alcohol). This caveat is quite important and may be at
the heart of controversies where NAC has been shown to work in some
trials but not in others (e.g. contrast nephropathy). Resolution of
this issue would, however, require trials to routinely include whole
blood (rather than plasma) GSH/GSSG measurements, which can be done
now by mass spectrometry that are neither easy nor amenable to
widespread clinical use. Improvement in the accessibility of these
assays would considerably facilitate all studies in which GSH levels
are at issue and would as well improve the ability of physicians to
judge whether NAC supplementation is advisable for individual patients
with diseases in which NAC has been shown to be beneficial.
David
2009-08-18 22:35:57 UTC
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Post by Arbor B
In preparation for the fall and winter seasons, I ordered some e-NAC
from this site:http://goldpharma.com/.
Arbor
I wonder why all the European brands over 200 mg are effervescent-
only? Maybe to help reduce the risk of cysteine renal stones.

Arbor, which brand did you order, if you don't mind my asking?
Arbor B
2009-08-19 02:35:27 UTC
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Post by David
Post by Arbor B
In preparation for the fall and winter seasons, I ordered some e-NAC
from this site:http://goldpharma.com/.
Arbor
I wonder why all the European brands over 200 mg are effervescent-
only?  Maybe to help reduce the risk of cysteine renal stones.
Arbor, which brand did you order, if you don't mind my asking?
I ordered Sandoz - the only company that I recognized there and given
that all products of the same amount X dose, are sold for the same
price. But I was ready to order the Canadian PharmaNAC because it was
the only brand name that came up in my extensive search as if it was
still sold by the US site (mentioned above) that I thought to be
reliable.
However, there is another small US site ( http://www.healthierlungs.com/checkout.htm)
that sells e-NAC (only), made by the German company Hexal (only) in
one size (only)- a box of 20 tablets of 600 mg each for $11.00 (a
great price vs. Goldpharma) and in addition it offers a discount for
larger orders.
I ended up not ordering from this site because I preferred to deal
with a big site especially that it will be the 1st time that I try e-
NAC, and want to observe its effect. If by any chance you live
somewhere near the Canadian border, it worth a trip to buy the
PharmaNAC that is sold in a box of 20 tabs of 900mg each for $18.5

What I don't understand is why a product that is sold OTC even in the
EU (that often has more restricting rules) is not in the US.

Arbor
David
2009-08-19 03:24:08 UTC
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Post by Arbor B
Post by David
Post by Arbor B
In preparation for the fall and winter seasons, I ordered some e-NAC
from this site:http://goldpharma.com/.
Arbor
I wonder why all the European brands over 200 mg are effervescent-
only?  Maybe to help reduce the risk of cysteine renal stones.
Arbor, which brand did you order, if you don't mind my asking?
I ordered Sandoz - the only company that I recognized there and given
that all products of the same amount X dose, are sold for the same
price. But I was ready to order the Canadian PharmaNAC because it was
the only brand name that came up in my extensive search as if it was
still sold by the US site (mentioned above) that I thought to be
reliable.
However, there is another small US site (http://www.healthierlungs.com/checkout.htm)
that sells e-NAC (only), made by the German company Hexal (only) in
one size (only)- a box of 20 tablets of 600 mg each for $11.00 (a
great price vs. Goldpharma) and in addition it offers a discount for
larger orders.
I ended up not ordering from this site because I preferred to deal
with a big site especially that it will be the 1st time that I try e-
NAC, and want to observe its effect.  If by any chance you live
somewhere near the Canadian border, it worth a trip to buy the
PharmaNAC that is sold in a box of 20 tabs of 900mg each for $18.5
What I don't understand is why a product that is sold OTC even in the
EU (that often has more restricting rules) is not in the US.
Arbor
Thanks for the info, Arbor.....I went ahead and ordered a few boxes
from the small U.S. site you mentioned.

I understand your frustration -- I can only assume that since the
demand isn't (yet) that high for NAC in the U.S. nutritional
supplement market, and since the importance of processing/packaging
isn't (yet) widely known, there's no driving force for U.S.
manufacturers to spend more money to change their methods to make a
superior and yet higher-priced NAC supplement that may not sell as
well as cheaper brands.

What is also frustrating to me is that even though I have prescribing
privileges, all I can get through that route is nasty-tasting generic
Mucomyst!

-David
Arbor B
2009-08-19 15:47:17 UTC
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Post by David
What is also frustrating to me is that even though I have prescribing
privileges, all I can get through that route is nasty-tasting generic
Mucomyst!
-David
Have you tried Mucoyst? This is an alternative that I consider trying
later. One way to make Mucomyst bearable is to mix it with juice. My
understanding is that adding fruit flavor and sweetness is how the
taste of NAC is modified in the e-NAC tablets.

Please let us know of your experience with healthierlungs.com.

Arbor
David
2009-08-21 12:06:55 UTC
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Have you tried Mucoyst?  This is an alternative that I consider trying
later.  One way to make Mucomyst bearable is to mix it with juice.  My
understanding is that adding fruit flavor and sweetness is how the
taste of NAC is modified in the e-NAC tablets.
Please let us know of your experience with healthierlungs.com.
Arbor
No I haven't tried Mucomyst because I never realized (before your post
above) that NAC manufacturing processes were so potentially important.

Interestingly enough, I had stopped taking Source Naturals NAC because
it actually seemed to paradoxically *cause* chest congestion after
taking it for a couple of days, an effect which I never expected and
therefore doubt would be any kind of placebo effect (I was taking it
just as an antioxidant, not for any specific medical issues).

That actually might make sense if the quality of the supplement is
poor, with lots of di-NAC. I'll definitely let you know my
experiences with the European NAC when it gets here (should arrive
today).

-David
Ted
2009-08-21 13:47:36 UTC
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Raw Message
Post by David
Have you tried Mucoyst?  This is an alternative that I consider trying
later.  One way to make Mucomyst bearable is to mix it with juice.  My
understanding is that adding fruit flavor and sweetness is how the
taste of NAC is modified in the e-NAC tablets.
Please let us know of your experience with healthierlungs.com.
Arbor
No I haven't tried Mucomyst because I never realized (before your post
above) that NAC manufacturing processes were so potentially important.
Interestingly enough, I had stopped taking Source Naturals NAC because
it actually seemed to paradoxically *cause* chest congestion after
taking it for a couple of days, an effect which I never expected and
therefore doubt would be any kind of placebo effect (I was taking it
just as an antioxidant, not for any specific medical issues).
That actually might make sense if the quality of the supplement is
poor, with lots of di-NAC.  I'll definitely let you know my
experiences with the European NAC when it gets here (should arrive
today).
-David
Would LEF's be a good choice?

http://www.lef.org/Vitamins-Supplements/Item00215/N-acetyl-Cysteine.html
Arbor B
2009-08-21 15:30:38 UTC
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Post by David
Interestingly enough, I had stopped taking Source Naturals NAC because
it actually seemed to paradoxically *cause* chest congestion after
taking it for a couple of days, an effect which I never expected and
therefore doubt would be any kind of placebo effect (I was taking it
just as an antioxidant, not for any specific medical issues).
That actually might make sense if the quality of the supplement is
poor, with lots of di-NAC.  I'll definitely let you know my
experiences with the European NAC when it gets here (should arrive
today).
-David
Wow, what a coincidence, I also have been taking Source Natural NAC
(600 mg) tablets every now and then. I started taking NAC prior to
starting CR in a hope that it would solve frequent mucus problem I had
(dxed by ENT as idiopathic retinitis (IR]). It didn't help at all;
Fortunately CR did - completely.
While trying it for IR, I noticed that it quells hunger pangs and
continued taking it on irregular as-needed basis.

Arbor
David
2009-08-25 02:36:03 UTC
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Raw Message
Post by Arbor B
Post by David
Interestingly enough, I had stopped taking Source Naturals NAC because
it actually seemed to paradoxically *cause* chest congestion after
taking it for a couple of days, an effect which I never expected and
therefore doubt would be any kind of placebo effect (I was taking it
just as an antioxidant, not for any specific medical issues).
That actually might make sense if the quality of the supplement is
poor, with lots of di-NAC.  I'll definitely let you know my
experiences with the European NAC when it gets here (should arrive
today).
-David
Wow, what a coincidence, I also have been taking Source Natural NAC
(600 mg) tablets every now and then. I started taking NAC prior to
starting CR in a hope that it would solve frequent mucus problem I had
(dxed by ENT as idiopathic retinitis (IR]).  It didn't help at all;
Fortunately CR did - completely.
While trying it for IR, I noticed that it quells hunger pangs and
continued taking it on irregular as-needed basis.
Arbor
Well, calling the German (Hexal brand) Fizzy NAC "pleasant-tasting" is
a bit of a stretch. Ok, a huge stretch. Unless you like the
aftertaste of sulfur, that is.
Arbor B
2009-08-25 07:19:29 UTC
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Raw Message
Post by David
Well, calling the German (Hexal brand) Fizzy NAC "pleasant-tasting" is
a bit of a stretch.  Ok, a huge stretch.  Unless you like the
aftertaste of sulfur, that is.
David, the text says "pleasant" when a juice or carbonated drink is
added:

"In contrast, NAC is produced and packaged in
Europe in pill and capsule formulations, as well as in a variety of
effervescent formulations (‘fizzy tabs’) that can be dissolved in
water, juice or carbonated drinks to create a pleasant tasting,
readily tolerated beverage containing soluble NAC that can be rapidly
absorbed."
Arbor
David
2009-08-26 13:07:48 UTC
Permalink
Raw Message
Post by Arbor B
Post by David
Well, calling the German (Hexal brand) Fizzy NAC "pleasant-tasting" is
a bit of a stretch.  Ok, a huge stretch.  Unless you like the
aftertaste of sulfur, that is.
David, the text says "pleasant" when a juice or carbonated drink is
Arbor
True, but it's already berry-flavored and sweetened, and the
directions say dissolve in water. I don't see how adding more sugar
and fruit flavor would get rid of the sulfury aftereffect, but we'll
see.
Arbor B
2009-08-26 15:50:09 UTC
Permalink
Raw Message
Post by David
True, but it's already berry-flavored and sweetened, and the
directions say dissolve in water.  I don't see how adding more sugar
and fruit flavor would get rid of the sulfury aftereffect, but we'll
see.
My Sandoz e-NAC tabs will be here in few days (come from Europe) so
the following is just a thought.
You may try to break the tablets to pieces small enough fit 1-2 empty
capsules and wash them down with a lot of water on empty stomach (as
is recommended anyway) .
Even if the taste of the Sandoz tabs is OK, their price, like the
prices of all the e-NAC brands that this site carries, is too high-
not a long-term solution anyway. So the next to try is Mucomyst - at
least you can "flavor" it yourself. Mucomyst comes as oral solution
(small bottle). Depends on how concentrated it is, it might be
possible to drip it into a capsule and wash it down with water
immediately before it dissolves the capsule. Will see.

Arbor
m***@gmail.com
2017-08-15 19:57:00 UTC
Permalink
Raw Message
Post by Arbor B
Post by David
Interestingly enough, I had stopped taking Source Naturals NAC because
it actually seemed to paradoxically *cause* chest congestion after
taking it for a couple of days, an effect which I never expected and
therefore doubt would be any kind of placebo effect (I was taking it
just as an antioxidant, not for any specific medical issues).
That actually might make sense if the quality of the supplement is
poor, with lots of di-NAC.  I'll definitely let you know my
experiences with the European NAC when it gets here (should arrive
today).
-David
Wow, what a coincidence, I also have been taking Source Natural NAC
(600 mg) tablets every now and then. I started taking NAC prior to
starting CR in a hope that it would solve frequent mucus problem I had
(dxed by ENT as idiopathic retinitis (IR]). It didn't help at all;
Fortunately CR did - completely.
While trying it for IR, I noticed that it quells hunger pangs and
continued taking it on irregular as-needed basis.
Arbor
Hey sorry for my ignorance but what do you mean by CR here?
Winston
2017-08-16 12:05:31 UTC
Permalink
Raw Message
Post by m***@gmail.com
... I started taking NAC prior to starting CR in a hope that it
would solve frequent mucus problem I had (dxed by ENT as idiopathic
retinitis (IR]). It didn't help at all; Fortunately CR did -
completely.
Hey sorry for my ignorance but what do you mean by CR here?
In this newsgroup, it usually means Calorie Restriction.
-WBE

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