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Anyone can do an internet search and find out about an amino acid nutrient called N-Acetyl Cysteine (NAC), which breaks up mucus and makes your body produce more glutathione. But not every one does; so that's why we've put together this page to start your education on studies that have already been done.

This is what our founder did, because he was not willing to believe that nothing could be done to help his lung condition and weakened immune system. His research, and subsequent quest for the best quality NAC has improved his health so much, that he felt compelled to share his find and pay it forward!

NAC (N-Acetyl Cysteine) is an amino acid derivative and a precursor to the very powerful antioxidant glutathione. It acts as a mucolytic (breaks up mucus) and increases the elimination of free radicals by increasing glutathione levels. It acts as a chelator for heavy metals like lead, aluminum, cadmium (from cigarettes), mercury, and arsenic. It is the standard treatment in ERs for acetaminophen overdose, protecting the liver and kidneys from the toxins. It strengthens the immune system with higher glutathione levels. There is a consistency in studies we read that a standard dose is 250 mg. to 1200 mg. But since NAC degrades and destabilizes in the presence of air, (Stanford study) most over the counter capsules and tablets have very little active NAC left after sitting for who knows how long on a shelf. Effervescent wafers are individually sealed in foil, so 600 mg. is really 600 mg. Make sure you get the good stuff!

NAC increases glutathione levels, which maximizes your immune system, so why not just take glutathione? Oral glutathione is largely broken down in the digestive system into dipeptides and free amino acids. Although some glutathione is absorbed intact, it still must cross the cell walls to serve many body needs. NAC, on the other hand, is well absorbed, readily passes through cellular membranes.

If you read everything you can on the subject, you will find that 1200 mg. daily seems to be the accepted dose for an average sized person, with no reported toxic side effects, and for nearly 40 years, has had enough clinical testing to warrant a try. Especially when it's so affordable. A petite person may want to try only 600 mg. daily to start, to see if that's enough, for economy reasons. You will also see research that recommends a multiple vitamin containing trace minerals, including selenium and zinc (which most do), since NAC seems to increase excretion of those two minerals. The reason for that is because your body sends its zinc and selenium to bind to the heavy metal toxins in an effort to shield you, and then the NAC removes those toxins, taking the zinc and selenium with it. It also enhances the effectiveness of certain drugs and vitamins, so it would be wise to consult your doctor, especially if you're taking a prescription drug or have a serious condition. Generally, the only specific drug that NAC may react with is nitroglycerin, and may cause a headache. There are a few people who shouldn't take NAC. You should always seek the advice of a qualified healthcare professional. We are not doctors; we're a family business that was born from the persistance of one man who had to take charge of his own health when the best doctors offered no treatment. For him it paid off. Read our founder's story.

Bottom Line: NAC studies are readily available online, done by medical professionals and legitimate scientists. You'll notice that a majority of these studies were done in Europe, where they likely would have used an NAC product made in Europe, according to the GMP, which carries a higher standard than American nutraceutical regulations require. NAC may not help everyone all the time, but if you do your homework like our founder did, you'll decide it's worth a try.


Public Research Reports



COPD, Emphysema, Chronic Bronchitis

Cystic Fibrosis

Chronic Fatigue Syndrome


IPF (Idiopathic Pulmonary Fibrosis)

Liver Toxicity

Multiple Sclerosis

Rheumatoid Arthritis

Smoker's Cough

Cysteine is an amino acid that can be found in many proteins throughout the body. N-acetyl-L-cysteine (NAC), a modified form of cysteine, helps break down mucus and detoxify harmful substances in the body. Both cysteine and NAC have been shown to increase levels of the antioxidant glutathione.
Antioxidants are substances that scavenge free radicals, damaging compounds in the body that alter cell membranes, tamper with DNA, and even cause cell death. Free radicals occur naturally in the body, but environmental toxins (including ultraviolet light, radiation, cigarette smoking, and air pollution) can also increase the number of these damaging particles. Free radicals are believed to contribute to the aging process as well as the development of a number of health problems including heart disease and cancer. Antioxidants such as glutathione can neutralize free radicals and may reduce or even help prevent some of the damage they cause.
Respiratory Illness
A review of scientific studies also found that NAC may help dissolve mucus and improve symptoms associated with chronic bronchitis, asthma, cystic fibrosis and emphysema. Chronic smokers also may benefit from NAC supplementation. Studies on large groups of people have found that NAC appears to have cancer prevention properties in people who are at risk for lung cancer. [Back to Top]

COPD, (Emphysema, Chronic Bronchitis, Asthma)

[N-acetyl cysteine in the therapy of chronic bronchitis]
[Article in German]
Pneumologie, Departement Innere Medizin, Universitätskliniken Basel, Schweiz, Germany.
Chronic bronchitis (CB) shows an increasing global morbidity and mortality with major impact on socioeconomics. N-Acetylcysteine (NAC), previously used as a mucolytic compound in CB, has also antioxidative effects. Furthermore it influences intrabronchial bacterial colonisation. In a randomised pilot study of 24 patients (16-male, 8 female, mean age 66 +/- 10 years) with acute exacerbation of CB and positive bacterial culture in the sputum, the addition of twice daily 600 mg NAC to standard antibiotic therapy lead to a significantly higher bacterial eradication rate (70 % versus 36 %, p < 0.03). Clinical studies suggest that treatment with NAC has different effects in CB including a reduction of the number and duration of acute exacerbation episodes and possibly influences lung function. The improvement of symptoms and quality of life also has an impact on socio-economic costs. The use of NAC in CB as an antioxidative rather than a mucolytic compound should be considered. However, further placebo controlled studies are undergoing to definitively establish the role of NAC for the treatment of CB and COPD.

[Multicenter, double-blind study of oral acetylcysteine vs. placebo]
[Article in French]
The mucolytic activity of acetylcysteine (NAC) was evaluated in a double-blind, placebo controlled, clinical trial performed in three pneumology centres and involving a total of 215 patients with the following diagnoses: 84 acute bronchitis, 95 superinfections of chronic bronchitis, 36 complicated bronchitis in patients with severe chronic respiratory insufficiency. Treatment consisted of 1 sachet of 200 mg NAC t.i.d. for 10 days. Standard antibiotic therapy (amoxycillin 1.5 g/day) was concurrently administered for 7 days. Statistical analysis comparing sputum volume and viscosity, sedation of cough and improvement of PEFR in 108 NAC and in 107 placebo treated patients, showed that NAC was very significantly more effective than placebo. The effect of NAC was negligible in the 36 patients with complicated bronchitis, whereas it was evident and remarkable in patients with acute and chronic bronchitis.

Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis.
Dept. of Lung Medicine, General Hospital, Malmö, Sweden.
The clinical effect of N-acetylcysteine (NAC) controlled-release tablets, 300 mg b.i.d., and placebo, in chronic bronchitis was investigated. The study was performed as a double-blind six month comparison between active drug and placebo in two parallel groups, with statistical evaluation after four and six months. The patients were chosen from nine centres. One hundred and sixteen out-patients were included and ninety one of them completed the six month study. The acetylcysteine-treated group had a significantly reduced number of sick-leave days caused by exacerbations of chronic bronchitis after the four winter months December-March compared with the control group (NAC 173, placebo 456). The number of exacerbation days was also very much reduced, however, not significantly (NAC 204, placebo 399). At the end of the six month trial, including also two spring months, the absolute numbers of sick-leave days and exacerbation days were still fewer in the acetylcysteine-treated group, (NAC 260, placebo 739) and (NAC 378, placebo 557) respectively. This study demonstrates a significant reduction in sick-leave days after four months of NAC-treatment. A constant tendency to reduction in the number of exacerbations and exacerbation days was also registered after four and six months. The differences in these parameters were, however, not statistically significant. This was probably due to the small number of patients participating.
Twenty-four atopic children with allergic rhinitis, asthma and maxillary sinusitis were treated with a combination of cefuroxime 50-80 mg/kg/day and N-acetyl-cysteine 15-25 mg/kg/day administered intramuscularly for 10 days. The efficacy of the treatment was judged on the basis of radiological and clinical evolution. The treatment was effective in 95.8% of the children, and 37.5% of them were able to reduce their treatment for asthma. None of the patients suffered severe side effects. The data obtained confirm that appropriate treatment of the sinusitis frequently results in a significant improvement of the asthmatic condition.

Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease
P.N.R. Dekhuijzen
CORRESPONDENCE: P.N.R. Dekhuijzen, Dept of Pulmonary Diseases, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. Fax: 31 243610324. E-mail:
Keywords: N-Acetylcysteine, chronic obstructive pulmonary disease, inflammation, oxidative stress, pathogenesis
Received: October 29, 2003
Accepted November 11, 2003
Oxidative stress has been implicated in the pathogenesis and progression of chronic obstructive pulmonary disease.
Both reactive oxidant species from inhaled cigarette smoke and those endogenously formed by inflammatory cells constitute an increased intrapulmonary oxidant burden. Structural changes to essential components of the lung are caused by oxidative stress, contributing to irreversible damage of both parenchyma and airway walls. In addition, oxidative stress results in alterations in the local immune response, increasing the risk of infections and exacerbations, which, in turn, may accelerate lung function decline.
The antioxidant N-acetylcysteine, a glutathione precursor, has been applied in these patients in order to reduce symptoms, exacerbations and the accelerated lung function decline. This article reviews the presently available experimental and clinical data on the antioxidative effects of N-acetylcysteine in chronic obstructive pulmonary disease.

High Dose N--Acetylcysteine in Patients With Exacerbations of Chronic Obstructive Pulmonary Disease (this link now requires membership to view)
R. Zuin; A. Palamidese; R. Negrin; L. Catozzo; A. Scarda; M. Balbinot
Author Information
Objective: To investigate the efficacy and tolerability of high-dose N-acetylcysteine (NAC) in the treatment of patients with exacerbations of chronic obstructive pulmonary disease (COPD).
Design and Patients: Randomised, double-blind, double-dummy, placebo-controlled study in 123 patients experiencing an acute exacerbation of COPD.
Interventions: NAC 1200 mg/day, 600 mg/day or placebo administered once daily for 10 days.
Main Outcome Measures: The primary objective was to assess the proportion of patients with normalised C-reactive protein (CRP) levels. Also assessed were effects on interleukin (IL)-8 levels, lung function and symptoms.
Results: Both NAC 600 and 1200 mg/day were associated with a significantly higher proportion of patients achieving normalised CRP levels compared with placebo (52% and 90% vs 19% of patients; p = 0.01); however, NAC 1200 mg/day was superior to NAC 600 mg/day (p = 0.002). Furthermore, treatment with NAC 1200 mg/day was more efficacious than NAC 600 mg/day in reducing IL-8 levels and difficulty of expectoration, while the two active regimens had similar beneficial effects on lung function and other clinical outcomes (cough intensity and frequency, and lung auscultation). Treatments were well tolerated with one adverse event reported in NAC 1200 mg/day recipients and two reported in placebo recipients.
Conclusion: Treatment with NAC 1200 mg/day improved biological markers and clinical outcomes in patients with COPD exacerbations. It is speculated that the effect of NAC on inflammatory markers may be due to both mucolytic and antioxidant properties.
Chronic obstructive pulmonary disease (COPD) is characterised by irreversible or only partially reversible airway obstruction with episodes of symptom exacerbation that are believed to contribute to the progression of the disease and progressive loss of lung function.[1,2] Bacterial or viral infections appear to be responsible for exacerbations by causing an influx of inflammatory cells, such as activated neutrophils and macrophages responsible for the release of elastase and myeloperoxidase,[3] in the bronchial mucosa.[4] Release of elastase and mye- loperoxidase may lead to production of oxygen free radicals,[3] which have pro-inflammatory properties[5] and inhibit a-1 antitrypsin, the most important inhibitor of elastase.[6] A role for oxygen free radicals in the pathogenesis of COPD has been confirmed in a recent study showing a large increase in exhaled hydrogen peroxide during exacerbations.[5] Thus, it seems reasonable to assume that treatment of exacerbations of COPD with drugs possessing antioxidant properties may lead to reductions in markers of airway inflammation and improve clinical outcomes.
Data suggest that N-acetylcysteine (NAC) at dosages of 400-1200 mg/day may reduce symptoms, exacerbation rates and lung function decline in COPD patients, although not all studies have yielded consistent results.[7-9] These effects were originally attributed to the ability of NAC to reduce mucus viscosity and facilitate expectoration. However, other studies have shown that NAC has anti-inflammatory and antioxidant properties.[10-13] In vitro, NAC inhibits neutrophil chemotaxis, interleukin (IL)-8 secretion, and other pro-inflammatory mediators such as the transcription nuclear factor (NF)-?B, which is directly correlated with the production of the systemic inflammatory marker C-reactive protein (CRP).[14]
CRP levels are elevated during exacerbations of COPD and significantly reduced with treatment; thus, they can be used to monitor clinical improvement.[15,16] IL-8 has also been shown to be significantly elevated during exacerbations of COPD.[17]
The aim of this study was to evaluate the efficacy of high-dose NAC (1200 mg/day) in patients with an acute exacerbation of COPD. Since the degree of anti-inflammatory effect of NAC is associated directly with CRP and IL-8 secretion, the anti-inflammatory effect of NAC was inferred from changes in CRP and IL-8, while clinical efficacy was assessed by changes in lung function, symptoms and physical examination. Tolerability was also evaluated by standard clinical and laboratory tests.
[Back to Top]

Idiopathic Pulmonary Fibrosis

High-dose acetylcysteine in idiopathic pulmonary fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive disorder with a poor prognosis. METHODS: We conducted a double-blind, randomized, placebo-controlled multicenter study that assessed the effectiveness over one year of a high oral dose of acetylcysteine (600 mg three times daily) added to standard therapy with prednisone plus azathioprine. The primary end points were changes between baseline and month 12 in vital capacity and in single-breath carbon monoxide diffusing capacity (DL(CO)). RESULTS: A total of 182 patients were randomly assigned to treatment (92 to acetylcysteine and 90 to placebo). Of these patients, 155 (80 assigned to acetylcysteine and 75 to placebo) had usual interstitial pneumonia, as confirmed by high-resolution computed tomography and histologic findings reviewed by expert committees, and did not withdraw consent before the start of treatment. Fifty-seven of the 80 patients taking acetylcysteine (71 percent) and 51 of the 75 patients taking placebo (68 percent) completed one year of treatment. Acetylcysteine slowed the deterioration of vital capacity and DL(CO): at 12 months, the absolute differences in the change from baseline between patients taking acetylcysteine and those taking placebo were 0.18 liter (95 percent confidence interval, 0.03 to 0.32), or a relative difference of 9 percent, for vital capacity (P=0.02), and 0.75 mmol per minute per kilopascal (95 percent confidence interval, 0.27 to 1.23), or 24 percent, for DL(CO) (P=0.003). Mortality during the study was 9 percent among patients taking acetylcysteine and 11 percent among those taking placebo (P=0.69). There were no significant differences in the type or severity of adverse events between patients taking acetylcysteine and those taking placebo, except for a significantly lower rate of myelotoxic effects in the group taking acetylcysteine (P=0.03). CONCLUSIONS: Therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and DL(CO) in patients with idiopathic pulmonary fibrosis better than does standard therapy alone. Copyright 2005 Massachusetts Medical Society.

Antioxidative and Clinical Effects of High-dose N-Acetylcysteine in Fibrosing Alveolitis
Adjunctive Therapy to Maintenance Immunosuppression


Abteilung für Pneumologie, Medizinische Klinik I, and Institut für Chirurgische Forschung, Klinikum Grosshadern der Ludwig-Maximilians-Universität München, München; and Institut für Inhalationsbiologie, GSF Forschungszentrum für Umwelt und Gesundheit, Neuherberg, Germany

In fibrosing alveolitis (FA), activated phagocytes cause excessive oxidative stress in the lower respiratory tract. Additionally, levels of glutathione, a major antioxidant of the human lung, are markedly reduced. Since N-acetylcysteine (NAC) is a known precursor for glutathione synthesis, we investigated the effect of NAC on redox balance and lung function in FA. Eighteen patients with an established diagnosis of FA were treated with 600 mg NAC three times daily for 12 wk in addition to their latest immunosuppressive therapy. Before and after NAC therapy, pulmonary function tests (PFTs) and bronchoalveolar lavage (BAL) were performed. BAL fluid was analyzed with regard to cell differential, glutathione status, and methionine sulfoxide content of BAL proteins (Met(O)), as an indicator of oxidative stress at the alveolar surface. There was an increase of total glutathione (GSHt = GSH + 2 × GSSG: 3.43 ± 0.30 µM versus 4.20 ± 0.66 µM, p < 0.05) and of reduced glutathione (GSH: 2.58 ± 0.24 µM versus 3.42 ± 0.54 µM, p < 0.005) in native BAL fluid and in the epithelial lining fluid (GSHt: 267.3 ± 26.0 µM versus 367.1 ± 36.0 µM, p < 0.005; GSH: 204.5 ± 20.7 µM versus 302.9 ± 32.2 µM, p < 0.005). The increase of GSH was accompanied by a decrease of Met(O) (6.83 ± 0.71% versus 4.60 ± 0.40%, p < 0.005). PFTs significantly improved during NAC treatment. We conclude that high-dose NAC significantly improved the antioxidant screen of the lungs by elevating GSH levels. Moreover, the decrease of Met(O) levels indicated an antioxidant effect at the alveolar surface. These biochemical changes were accompanied by an improvement of PFTs in patients under maintenance immunosuppression. NAC supplementation should, therefore, be considered as an adjunct therapy for FA.

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Cystic Fibrosis

Orally, N-acetyl cysteine is used as an antidote for acetaminophen and carbon monoxide poisoning. It is also used for unstable angina, common bile duct obstruction in infants, lysosomal storage disorders, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Alzheimer's disease, phenytoin-induced hypersensitivity, and keratoconjunctivitis. It is also used for reducing lipoprotein (a) levels, reducing homocysteine levels, reducing risk of cardiovascular events in patients with end-stage renal disease, chronic bronchitis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, fibrosing alveolitis, head and neck cancer, and lung cancer. N-acetyl cysteine is also used orally for myoclonus epilepsy; otitis media; hemodialysis-related pseudoporphyria; chronic fatigue syndrome (CFS); Sjogren's syndrome; preventing sports injury complications; radiation therapy; increasing immunity to flu; and for detoxifying heavy metals such as mercury, lead, and cadmium. It is also used orally for preventing alcoholic liver damage; for protecting against environmental pollutants including carbon monoxide, chloroform, urethanes and certain herbicides; for reducing toxicity of ifosfamide and doxorubicin; as a hangover remedy; for preventing nonionic low-osmolality contrast agent-induced reduction of renal function in patients with renal insufficiency; and for human immunodeficiency virus (HIV).
Topically, N-acetyl cysteine is used for reducing dental plaque.
Intravenously, N-acetyl cysteine is used for acetaminophen overdose, acrylonitrile poisoning, for hepatorenal syndrome, for decreasing mortality rate due to multisystem organ failure, for unstable angina in combination with nitroglycerin, and for acute myocardial infarction with nitroglycerin and streptokinase.
Rectally, N-acetyl cysteine is used for meconium ileus and meconium ileus equivalent.
By inhalation or intratracheal installation, N-acetyl cysteine is used as a mucolytic agent in acute and chronic lung disorders such as pneumonia, bronchitis, emphysema, cystic fibrosis, and others.

Most laypersons only understand the first and last sentence of this next study, but your doctor may be interested…

N-Acetyl-L-cysteine (NAC) is a widely used mucolytic drug in patients with a variety of respiratory disorders including cystic fibrosis (CF). The beneficial effects of NAC are empirical and the exact mechanism of action in the airways remains obscure. In the present study we examined the effects on whole-cell (wc) conductance (Gm) and voltage (Vm) of NAC and the congeners S-carboxymethyl-L-cysteine (CMC) and S-carbamyl-L-cysteine (CAC) and L-cysteine in normal and CF airway epithelial cells. L-Cysteine (1 mmol/l) had no detectable effect. The increase in Gm ((Gm) by the other compounds was concentration dependent and was (all substances at 1 mmol/l) 3.8 - 1.4rnS (NAC; n = 11), 4.2 - 1.0rnS (CMC; n = 16) and 3.8 - 1.6rnS (CAC; n = 18), respectively. The changes in Gm were paralleled by an increased depolarization ((Vm) when extracellular Clm concentration was reduced to 34 mmol/l: under control conditions = m4.1 - 2.1 versus 10.2 - 2.1 mV in the presence of NAC, CMC, CAC (n = 36). In the presence of NAC, CMC and CAC, the reduction in Clm concentration was paralleled by a reduction of Gm by 2.1 - 0.4rnS (n = 35), indicating that all substances acted by increasing the Clm conductance. Analysis of intracellular pH did not reveal any changes by any of the compounds (1 mmol/l). A Clm conductance was also activated in HT29 colonic carcinoma and CF tracheal epithelial (CFDE) cells but not in CFPAC-1 cells, which do not express detectable levels of (F508-CFTR, suggesting that the presence of CFTR may be a prerequisite for the induction of Clm currents. Next we examined the ion currents in Xenopus oocytes microinjected with CFTR-cRNA. Water-injected oocytes did not respond to activation by forskolin and 3-isobutyl-1-methylxanthine (IBMX) ((Gm = 0.08 - 0.04r7S; n = 10) and no current was activated when these oocytes were exposed to NAC or CMC. In contrast, in CFTR-cRNA-injected oocytes Gm was enhanced when intracellular adenosine 3',5'-cyclic monophosphate (cAMP) was increased by forskolin and IBMX (Gm = 4.5 - 1.3r7S; n = 8). Gm was significantly increased by 0.74 - 0.2r7S (n = 11) and 0.46 - 0.1 7S (n = 10) when oocytes were exposed to NAC and CMC, respectively (both 1 mmol/l). In conclusion, NAC and its congeners activate Clm conductances in normal and CF airway epithelial cells and hence induce electrolyte secretion which may be beneficial in CF patients. CFTR appears to be required for this response in an as yet unknown fashion.
[Back to Top]

Chronic Fatigue Syndrome

Epstein-Barr Virus Binding to CD21 Activates the Initial Viral Promoter via NF- B Induction
By Naoyuki Sugano, Weiping Chen, M. Luisa Roberts, and Neil R. Cooper
From the Scripps Research Institute, Department of Immunology, La Jolla, California 92037
J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/08/731/07 $2.00
Volume 186, Number 5, August 29, 1997 731-737
Epstein-Barr virus (EBV), an oncogenic human herpesvirus, binds to and infects normal human B lymphocytes via CD21, the CR2 complement receptor. Studies of the mechanisms that enable EBV to infect nonactivated, noncycling B cells provide compelling evidence for a sequence of events in which EBV binding to CD21 on purified resting human B cells rapidly activates the NF- B transcription factor, which, in turn, binds to and mediates transcriptional activation of Wp, the initial viral latent gene promoter. Thus, EBV binding to its cellular receptor on resting B cells triggers an NF- B-dependent intracellular signaling pathway which is required for infection.
Excerpt from Materials and Methods:
Another NF- B inhibitor, N-acetylcysteine (20 mM), also completely blocked NF- B activation 30 min after EBV addition, and thymidine incorporation 14 d after infection (not shown); this agent inhibits NF- B activation via its antioxidative properties (26), which is likely a different mechanism than aspirin.
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Rheumatoid Arthritis
Evidence for the role of an altered redox state in hyporesponsiveness of synovial T cells in rheumatoid arthritis
MM Maurice, H Nakamura, EA van der Voort, AI van Vliet, FJ Staal, PP Tak, FC Breedveld and CL Verweij
Department of Rheumatology, Leiden University Hospital, The Netherlands.
In rheumatoid arthritis (RA), T cells isolated from the synovial fluid (SF) show impaired responses to mitogenic stimulation compared with T cells from the peripheral blood (PB). Here it is reported that hyporesponsiveness of SF T cells correlated with a significant decrease in the levels of the intracellular redox-regulating agent glutathione (GSH). GSH was decreased in both CD4+ (p = 0.0022) and CD8+ (p = 0.0010) SF T cell subsets compared with PB CD4+ and CD8+ T cells in RA patients. Levels of thioredoxin (TRX), another key redox mediator, previously found to be secreted under conditions of oxidative stress, were found to be significantly increased in SF compared with plasma samples of RA patients (p = 0.005). Increased levels of TRX in the SF of inflamed joints was found to be associated with RA when compared with other arthritides (p = 0.007). Restoration of GSH levels in SF T cells with N-acetyl-L-cysteine (NAC), enhanced mitogenic induced proliferative responses and IL-2 production. Collectively, these data impute an important role to an altered redox state in the hyporesponsiveness of joint T cells in patients with RA.
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Smoker's Cough

Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease

P.N.R. Dekhuijzen
CORRESPONDENCE: P.N.R. Dekhuijzen, Dept of Pulmonary Diseases, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. Fax: 31 243610324. E-mail:
Keywords: N-Acetylcysteine, chronic obstructive pulmonary disease, inflammation, oxidative stress, pathogenesis
Received: October 29, 2003
Accepted November 11, 2003
(Excerpt from full report)
Antioxidant and anti-inflammatory effects
The efficacy of NAC as a precursor in GSH synthesis has been studied in isolated mouse lungs. Cigarette smoke administered directly to the lung through the trachea caused a dose-dependent reduction in total pulmonary GSH. Administering NAC together with cigarette smoke prevented the loss of pulmonary GSH and abolished the effects of cigarette smoke. NAC reduced H2O2-induced damage to epithelial cells in vitro and NF- B activation in some cells. In addition, NAC treatment reduced cigarette smoke-induced abnormalities in polymorphonuclear neutrophils (PMNs) , alveolar macrophages, fibroblasts and epithelial cells in vitro. Treatment with NAC also attenuated rat secretory cell hyperplasia induced by tobacco smoke and prevented hypochlorous acid-mediated inactivation of 1-PI in vitro. In a rat model of cigarette smoke-induced alterations in small airways, NAC prevented thickening of the airway wall and improved distribution of ventilation.
In addition to its effects on PMNs, NAC also influences the morphology and markers of oxidative stress in red blood cells (RBCs). An increased percentage of RBCs in COPD patients is morphologically damaged, with high concentrations of H2O2 and lowered levels of thiols. Such alterations are correlated with reduced oxygen exchange. Treatment of COPD patients with 1.2 or 1.8 mg·day-1 NAC for 2 months improved RBC shape, reduced H2O2 concentrations by 38-54% and increased thiol levels by 50-68%.
Treatment with NAC may alter lung oxidant/antioxidant imbalance. NAC (600 mg·day-1) given orally increased lung lavage GSH levels, reduced O2·- production by alveolar macrophages and decreased BALF PMN chemiluminescence in vitro. In addition, 600 mg·day-1 NAC in COPD patients reduced sputum eosinophil cationic protein concentrations and the adhesion of PMNs. In vitro, NAC reduced adhesion of Haemophilus influenzae and Streptococcus pneumoniae to oropharyngeal epithelial cells.
Effects on cigarette smoke-induced changes
Three studies have investigated the effects of 600 mg·day-1 NAC given orally on parameters of inflammation in the BALF of "healthy" smokers. NAC resulted in a tendency towards normalisation of the cell composition, with an increase in lymphocyte concentration (p<0.05). In addition, improvements were observed in the phagocytic activity of alveolar macrophages, and an increase in secretion of leukotriene B4 (p<0.05), which shows a chemotactic activity that represents an important defence mechanism against aggressive agents. In addition, NAC reduced the stimulated production of O2·- (from p<0.01 to p<0.05, depending on the type of stimulus). Finally, a reduction in the levels of various markers of inflammatory activity, such as eosinophil cationic protein, lactoferrin and antichymotrypsin (p<0.05), was found after administration of NAC.
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A role of free radicals in the progression of ALS recently received support with the discovery of linkage of familial ALS (FALS) with mutations in the gene encoding CuZn SOD (SOD1)21. Levels of SOD1 are decreased in patients with FALS but are often norrnal in sporadic ALS. In a patient with FALS, FRESA analysis indicated an SOD1 activity of approximately 50% of the lower end of the normal range. The remaining FRESA profile was normal. NAC treatment has so far been unsuccessful in altering the progressive course of this patient's disease. In two patients with sporadic ALS, SOD1 activity was normal, but GSHpx and glutathione reductase activities were markedly decreased. In these patients NAC treatment may have modified the course of the disease as one patient (duration of treatment 12 months) has remained stable with an increase in grip strength. A second patient has only marginally progressed during 17 months of treatment with NAC. Recently, Louwerse et al.22 reported on a double-blind trial of NAC in 111 patients with ALS. Patients with limb onset but not bulbar onset of ALS had a 50% decrease in the one year mortality rate with NAC treatment.

N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis.;jsessionid=LpZPnTyZ467tmr1vz1W360gcq1Tk2vGNy2dT28XW1LG1DtSvgQjQ!1902130097!181195629!8091!-1
Neuroreport. 11(11):2491-2493, August 3, 2000.
Andreassen, Ole A. 1; Dedeoglu, Alpaslan 1; Klivenyi, Peter 1; Beal, M Flint 1,2; Bush, Ashley I. 3,4
Increasing evidence implicates oxidative damage as a major mechanism in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the effect of preventative treatment with N-acetyl-L-cysteine (NAC), an agent that reduces free radical damage, in transgenic mice with a superoxide dismutase (SOD1) mutation (G93A), used as an animal model of familial ALS. NAC was administered at 1% concentration in the drinking water from 4-5 weeks of age. The treatment caused a significantly prolonged survival and delayed onset of motor impairment in G93A mice treated with NAC compared to control mice. These results provide further evidence for the involvement of free radical damage in the G93A mice, and support the possibility that NAC, an over-the-counter antioxidant, could be explored in clinical trials for ALS.

Amyotrophic Lateral Sclerosis(ALS): the Mercury Connection
Bernie Windham (Ed.)

...................Lengthy document, but well worth the read. Click here for the whole report.

N-Acetyl-l-cysteine protects SHSY5Y neuroblastoma cells from oxidative stress and cell cytotoxicity: effects on ?-amyloid secretion and tau phosphorylation

Redox changes within neurones are increasingly being implicated as an important causative agent in brain ageing and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). Cells have developed a number of defensive mechanisms to maintain intracellular redox homeostasis, including the glutathione (GSH) system and antioxidant enzymes. Here we examine the effects of N-acetyl-l-cysteine (NAC) on ?-amyloid (A?) secretion and tau phosphorylation in SHSY5Y neuroblastoma cells after exposure to oxidative stress inducing/cytotoxic compounds (H2O2, UV light and toxic A? peptides). A? and tau protein are hallmark molecules in the pathology of AD while the stress factors are implicated in the aetiology of AD. The results show that H2O2, UV light, A?1-42 and toxic A?25-35, but not the inactive A?35-25, produce a significant induction of oxidative stress and cell cytotoxicity. The effects are reversed when cells are pre-treated with 30?mmNAC. Cells exposed to H2O2, UV light and A?25-35, but not A?35-25, secrete significantly higher amounts of A?1-40 and A?1-42 into the culture medium. NAC pre-treatment increased the release of A?1-40 compared with controls and potentiated the release of both A?1-40 and A?1-42 in A?25-35-treated cells. Tau phosphorylation was markedly reduced by H2O2 and UV light but increased by A?25-35. NAC strongly lowered phospho-tau levels in the presence or absence of stress treatment.

Mercury exerts a variety of toxic effects in the body. Lipid peroxidation, DNA damage and depletion of reduced glutathione by Hg(II) suggest an oxidative stress-like mechanism for Hg(II) toxicity. Melatonin, the main secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. N-Acetylcysteine, a precursor of reduced glutathione and an antioxidant, is used in the therapy of acute heavy metal poisoning. In this study the protective effects of melatonin in comparison to that of N-acetylcysteine against Hg-induced oxidative damage in the kidney, liver, lung and brain tissues were investigated. Wistar albino rats of either sex (200-250 g) were divided into six groups, each consisting of 8 animals. Rats were intraperitoneally injected with 1) 0.9% NaCl, control (C) group; 2) a single dose of 5 mg/kg mercuric chloride (HgCl2), Hg group; 3) melatonin in a dose of 10 mg/kg, 1 hr after HgCl2 injection, Hg-melatonin group; 4) melatonin in a dose of 10 mg/kg one day before and 1 hr after HgCl2 injection, melatonin-Hg-melatonin group; 5) N-acetylcysteine in a dose of 150 mg/kg, 1 hr after HgCl2 injection, Hg-N-acetylcysteine group, and 6) N-acetylcysteine in a dose of 150 mg/kg one day before and 1 hr after HgCl2 injection, N-acetylcysteine-Hg-N-acetylcysteine group. Animals were killed by decapitation 24 hr after the injection of HgCl2. Tissue samples were taken for determination of malondialdehyde, an end-product of lipid peroxidation; glutathione (GSH), a key antioxidant, and myeloperoxidase activity, an index of neutrophil infiltration. The results revealed that HgCl2 induced oxidative tissue damage, as evidenced by increases in malondialdehyde levels. Myeloperoxidase activity was also increased, and GSH levels were decreased in the liver, kidney and the lungs. All of these effects were reversed by melatonin or N-acetylcysteine treatment. Since melatonin or N-acetylcysteine administration reversed these responses, it seems likely that melatonin or N-acetylcysteine can protect all these tissues against HgCl2-induced oxidative damage.
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Liver Toxicity

Improvements in Hepatic Serological Biomarkers are Associated with Clinical Benefit of Intravenous N-Acetylcysteine in Early Stage Non-Acetaminophen Acute Liver Failure
Sundeep Singh, M.D., Linda S. Hynan, Ph.D., William M. Lee, M.D., and the Acute Liver Failure Study Group

Abstract Background
N-acetylcysteine (NAC) improves transplant-free survival in early coma grade (I-II) patients with non-acetaminophen induced acute liver failure (ALF). We determined whether the clinical benefit was associated with improvements in hepatic function.
In a prospective, double blind trial, 173 ALF patients without evidence of acetaminophen overdose were stratified by coma grade (I-II vs. III-IV) and randomly assigned to receive either intravenous NAC or dextrose (placebo) for 72 hours, resulting in 4 patient groups. INR, ALT, bilirubin, creatinine, and AST obtained on admission (day 1) and subsequent days (days 2-4) were used for secondary analysis performed by fitting longitudinal logistic regression models to predict death or transplantation or transplantation alone.
Treatment group and day of study in models including bilirubin or ALT were predictors of transplantation or death (maximum p<0.03). Those patients with early coma grade who were treated with NAC showed significant improvement in bilirubin and ALT levels when compared to the other 3 groups (maximum p <0.02 for NAC 1-2 versus the 3 other treatments) when predicting death or transplantation. Treatment group, day of study, and bilirubin were predictors of transplantation (maximum p<0.03) in ALF patients.
The decreased risk of transplantation or death or of transplantation alone with intravenous NAC in early coma grade patients with non-acetaminophen induced ALF was reflected in improvement in parameters related to hepatocyte necrosis and bile excretion: ALT and bilirubin, but not in INR, creatinine, or AST. Hepatic recovery appears hastened by NAC as measured by several important lab values.
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Multiple Sclerosis

N-acetyl-L-cysteine ameliorates the inflammatory disease process in experimental autoimmune encephalomyelitis in Lewis rats
Romesh Stanislaus,1 Anne G Gilg,2 Avtar K Singh,2 and Inderjit Singh 2
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This article has been cited by other articles in PMC.

We report that N-acetyl-L-cysteine (NAC) treatment blocked induction of TNF-?, IL-1?, IFN-? and iNOS in the CNS and attenuated clinical disease in the myelin basic protein induced model of experimental allergic encephalomyelitis (EAE) in Lewis rats. Infiltration of mononuclear cells into the CNS and induction of inflammatory cytokines and iNOS in multiple sclerosis (MS) and EAE have been implicated in subsequent disease progression and pathogenesis. To understand the mechanism of efficacy of NAC against EAE, we examined its effect on the production of cytokines and the infiltration of inflammatory cells into the CNS. NAC treatment attenuated the transmigration of mononuclear cells thereby lessening the neuroinflammatory disease. Splenocytes from NAC-treated EAE animals showed reduced IFN-? production, a Th1 cytokine and increased IL-10 production, an anti-inflammatory cytokine. Further, splenocytes from NAC-treated EAE animals also showed decreased nitrite production when stimulated in vitro by LPS. These observations indicate that NAC treatment may be of therapeutic value in MS against the inflammatory disease process associated with the infiltration of activated mononuclear cells into the CNS.
Keywords: EAE, Macrophages, infiltration N-acetyl-L-cysteine, CNS
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1. Introduction
Multiple sclerosis (MS) is a chronic demyelinating disease marked by focal destruction of myelin, resulting in the loss of oligodendrocytes and axons accompanied by an inflammatory disease process [1-3]. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS. Both MS and EAE are initiated by a T-cell mediated autoimmune response (CD4+ and CD8+) against myelin components followed by induction of inflammatory mediators (chemokines and cytokines) that in turn define the pattern of perivascular migration of activated T-cells and mononuclear cells into the CNS [1-4].
The sequence of events associated with loss of oligodendrocytes and myelin in MS and EAE are not precisely understood. A complex interaction between the mediators released by infiltrating cells and brain endogenous activated glial cells (astrocytes and microglia) are believed to contribute towards the inflammatory disease process and tissue damage [1-3,5-7]. Numerous studies have documented the expression of proinflammatory cytokines (TNF-?, IL-1?, and IFN-?) in EAE and MS tissue and increased levels of IFN-? and TNF-? levels in CNS or plasma appear to predict relapse in MS [1-3,8]. On the other hand, enhanced expression of anti-inflammatory cytokines (IL-4, IL-10 and TGF-?) appears to mediate disease remission [1-3,9]. In MS brain, expression of iNOS by activated astrocytes, microglia and macrophages is associated with the demyelinating regions [10-13]. The NO derived from iNOS as ONOO- (a reaction product of NO and O2-) is thought to play a role in the pathobiology of MS and EAE. Peroxynitrite (ONOO-) is able to modify proteins, lipids and DNA resulting in damage to oligodendrocytes and myelin [1-3].
In spite of extensive research to develop pharmacotherapeutic agents to ameliorate or reduce the number of exacerbations and subsequent progression of neurological disability in MS, only a few therapies are available. Presently, IFN-? [14] and glatiramer acetate [15] are used in treatment of MS but the therapeutic efficacy of these compounds is limited by significant side effects. Recent studies from our laboratory [16,17] and others [18] report the potential of HMG-CoA reductase inhibitors (statins) in attenuating the disease process in EAE. The efficacy derives from a shift from an inflammatory Th1 response towards an anti-inflammatory Th2-biased response [16,18,19], blocked infiltration of mononuclear cells into CNS [20] and attenuation of the induction of proinflammatory cytokines (TNF-?, IFN-?) and iNOS in the CNS of EAE animals [17,20].
Reactive oxygen species (ROS) and reactive nitrogen species (RNS), generated as a result of the inflammatory process, are believed to play a role in the pathobiology of EAE and MS [10,12,13]. Cell culture studies showed that NAC, a potent antioxidant, inhibited induction of TNF-? and iNOS and NO production in peritoneal macrophages, C6 glial cells and primary astrocytes, and blocked the activation of NF?B in peritoneal macrophages [21]. Accordingly, oral administration of the oxidant scavenger NAC was found to attenuate EAE clinical disease [22]. The present studies were designed to elucidate the mechanism of observed therapeutic efficacy of NAC against EAE. These studies document that NAC treatment inhibited the clinical disease by attenuating multiple events in EAE disease such as shifting the immune response from a Th1 bias, increasing IL-10 cytokine production by splenocytes, attenuating transmigration of mononuclear cells, and inhibiting induction of proinflammatory cytokines (TNF-?, IL-1?, IFN-?) and iNOS in the CNS. Taken together these results suggest NAC may be of therapeutic value for cell-mediated autoimmune diseases such as multiple sclerosis.
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