2009-08-18 07:47:57 UTC
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
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
2) e-NAC is rapidly absorbed which, matters wrt the purpose of the
study that I posted several days ago PMID19636205 (see thread:
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:
[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.
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 . 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 . 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 [ and ], cystic fibrosis (CF) [ and [7••]],
chronic obstructive pulmonary disease (COPD) , diabetes , 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••], , ,
 and ]. 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 . It can also reduce disulphide bonds
in proteins [ and ], scavenge free radicals  and bind
metals to form complexes . 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 .
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 . 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 .
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
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 [ and ] and virtually undectable
levels of NAC in other body fluids such as broncho-alveolar lavage
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  and is sent to the liver via the
portal route where it is almost entirely converted to cysteine .
The liver incorporates most of the cysteine into GSH, which is then
largely secreted into circulation .
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 .
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 , 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 . 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 , 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••].
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 .
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 .
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  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 . 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
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.