What is an active dose of glutathione

New insights into a proven active ingredient

Indirect antioxidant effect


In humans, NAC is mainly deacetylated in the liver after oral ingestion. The cysteine ​​released is available for the cellular production of the body's most important antioxidant, glutathione. NAC thus indirectly contributes to increasing the antioxidant protection. This increased protective function due to NAC was impressively demonstrated in in-vitro tests. If one adds granulocytic or mononuclear cells cultivated with NAC in increasing concentrations and activated with PMA (12-myristate-13-acetate), the H.2O2 significantly reductively intercept (12). These results are due to the additional "glutathione prodrug effect" in the cells (13). Likewise, bronchoepithelial cells of the airways are able to produce the required glutathione from NAC. This effect can best be demonstrated in cells that have been cultivated in a cysteine ​​/ cystine-free lean medium (14, 15).


NAC for paracetamol intoxication


When taking large amounts of paracetamol (> 6 g), the cellular glutathione stores in the liver are quickly depleted and cannot be replenished quickly enough. The result is hepatogenic damage caused by paracetamol, including the formation of liver cell necrosis, as a result of which the patient can die. 5 to 10 percent of the ingested paracetamol is metabolized in the liver to form N-acetylbenzochionimine. This metabolite reacts with thiols like glutathione, is thereby bound and can then be excreted via the biliary tract. For this reason, NAC is also approved as a »glutathione prodrug« for the treatment of paracetamol intoxication, as it replenishes the cellular glutathione stores and thus helps prevent liver cell necrosis (15). Dosage recommendation according to Prescott, 1989 (16):


150 mg / kg body weight in 200 ml 5 percent glucose solution / 15 minutes

then 50 mg / kg body weight in 500 ml 5 percent glucose solution / 4 hours

followed by 100 mg / kg body weight in 1000 ml 5 percent glucose solution / 16 hours


In the past three decades, NAC has been extensively investigated in clinical studies for its anti-inflammatory effects, with a particular focus on its antioxidant potential in various diseases.


Protective effects of NAC


In animal experiments, NAC reduces the extent of arteriosclerotic changes (17). On the one hand, this effect is based on antioxidant and secondary anti-inflammatory effects at the endothelial cell level (e.g. lowering of cytokines), on the other hand, NAC reduces lipid peroxidation and thus indirectly arteriosclerosis (18, 19, 20). Various clinical studies with vitamins C or E, but also with NAC, were carried out with the aim of proving the effectiveness of such an antioxidant-protective treatment approach (21, 22). Despite encouraging results in vitro and in animal experiments, these have not yet been transferred to humans.


NAC for nephro protection


NAC has been studied to protect against radiocontrast agent-induced nephropathy and meta-analyzes have also been published on the subject. The results are partially positive, but not yet consistent overall (23, 24). In most studies, 600 mg of NAC were administered twice. Ultimately, however, it remains to be seen at this point in time what an optimized therapy regimen with NAC would have to look like in these patients in order to achieve significant prevention and justify routine use (25).


NAC for the protection of ischemia-related damage


The protective role of NAC in reperfusion ischemia has been known since 1990. Animal experiments and ex vivo studies show that the administration of NAC before or at the time of artificially generated ischemia leads to a significantly lower infarct and necrosis zone than placebo, faster reperfusion, a reduction in the ROS load and a likewise significant reduction in the ventricular Arrhythmias resulted. So far, only a few clinical studies have been carried out on humans in which the effect of fibrinolysis with or without NAC was investigated (26). Since the number of patients in the individual groups so far only comprised around 20 patients and the studies were not blinded, but also because of the inconsistent study results, NAC is not yet a regularly used substance in cardiology and cardiac surgery (27).


NAC in long-term therapy for COPD


Based primarily on studies from the 1980s, NAC was seen as a useful therapeutic addition to the therapy of COPD (28, 29, 30, 31). This assessment was justified by the positive effects found in the studies, such as lowering the exacerbation rate and improving lung function, which were viewed as direct effects of the secretolytic and antioxidant effects of this substance. According to the BRONCUS study (Bronchitis, Randomized on NAC, Cost-Utility Study) published in 2005, this positive assessment had to be put into perspective with regard to the long-term effect (32): a moderate NAC dose of 600 resulted over a period of three years mg / day in COPD patients (GOLD stage II and III) compared to placebo neither for a significant reduction in the annual FEV1 drop (volume per second = tidal volume that can be exhaled in one second after maximum inspiration) nor for a corresponding reduction in the exacerbation rate or the Improvement of the diffusion capacity. However, a clear clinical advantage in lowering the frequency of exacerbations under NAC therapy compared to placebo (130 versus 187) was found in the subgroup that did not receive inhaled steroids (p = 0.04). A distortion of the study results due to a possible lack of quality of the spirometric measurement results could be ruled out (33).


Critical evaluation of the BRONCUS study


Two factors are likely to have contributed significantly to the ultimately disappointing result of the BRONCUS study:


The dosage of 1 x 600 mg is probably too low for a disease that already responds badly to pharmaceuticals, such as COPD. A comparison of 1200 mg / day NAC versus 600 mg / day versus placebo showed a significant clinical superiority in the 1200 mg group versus placebo and the lower NAC dose (34).

It is possible that one of the primary target parameters - FEV1 - is not suitable for adequately depicting the expected NAC effect, especially since COPD is a disease that by definition does not respond adequately to pharmacotherapy on the part of FEV1. In the BRONCUS study, other important target and outcome parameters, such as pulmonary hyperinflation, patient-centered parameters or exercise parameters, were not taken into account. In contrast, Stav et al., 2009 (35) found in a placebo-controlled, double-blind, cross-over study that even a six-week therapy with 1200 mg NAC reduced the inspiratory capacity (IC) and the forced vital capacity (FVC), especially after exercise, significantly improved compared to placebo. A placebo-controlled study at the Kwong Wah Hospital in China (FDA study number: NCT01136239) is currently investigating whether stable COPD patients are given 600 mg / day NAC twice per day, which is given as an additional medication to the standard therapy for a period of one year , Air trapping parameters, airway resistance, exacerbation rate, quality of life and exercise capacity can be improved.


Current status of NAC in the COPD guideline


There is a major discrepancy with regard to the evaluation of the clinical use of mucoactive substances in COPD: Basically positive study data from the 1980s and the meta-analyzes that are also positive from this contrast with studies with less clear or negative results from the past ten years or so. The comparatively stricter rules for conducting such studies today, as well as the placebo-controlled and double-blind study design necessary for evaluating pharmaceuticals as a conditio sine qua non, may be at least a partial cause of these differences in effectiveness. The recommendation in the COPD therapy guideline is accordingly cautious: »The indication for the use of mucopharmaceuticals for better secretion elimination should be viewed critically and based on the subjective success of the therapy. N-acetylcysteine, ambroxol, myrthol and cineol can be helpful in some patients with viscous secretions (evidence level D). According to several controlled studies and meta-analyzes, prophylactic administration of acetylcysteine ​​in daily doses of 400-1200 mg has shown a reduction (20 to 25 percent) of acute exacerbations during the winter months "(42).


NAC for the therapy of idiopathic pulmonary fibrosis


In IPF, there is a glutathione deficit in the airways. At the same time, there is an accumulation of activated alveolar macrophages and neutrophils, which produce active oxygen radicals (36).


Both orally and intravenously administered NAC (oral: 1.8 g / d; intravenous: 1.8 g / d and 4.8 g / d) shows a significant increase in the initially decreased glutathione concentration in the bronchoalveolar fluid ( ELF) of these patients up to values ​​that correspond to those of the healthy controls (37, 38). However, the collectives examined were still small until then (oral therapy n = 10 or 17; i.v. therapy n = 8) and the duration of therapy was short with a treatment time of one week.


Subsequently, Behr et al. Patients over twelve weeks with histologically proven fibrosing alveolitis (1.8 g / d NAC) and were able to increase the glutathione level in the ELF from initially 2.7 ± 0.3 * 10-4 mol / l to 3.7 ± Raise 0.4 * 10-4 and reduce oxidative stress (lowering of oxidized methionine). In addition, surprisingly, even with simultaneous immunosuppressive therapy with cyclophosphamide or azathioprine, there was an additional improvement in the transfer factor for carbon monoxide (DLCO) in the diffusion capacity measurement (30).


In the IFIGENIA study, using three times 600 mg NAC in addition to the standard treatment, which consisted of systemic corticosteroid and azathioprine therapy, the following improvements were achieved after a therapy period of twelve months compared to immunosuppression alone (40):


Increase in vital capacity (∆VC): 180 ml = 9 percent (p = 0.02)

Increase in diffusion capacity (∆DLCO): 0.75 mmol / minute / kilopascal = 24 percent (p = 0.003)

Reduction in mortality: NAC group = 9 percent, placebo group = 11 percent (p = 0.69)


There is currently no other substance with which such a therapeutic effect has been proven in addition to immunosuppressive therapy (41). It now remains to be seen to what extent the findings will also be reflected in the upcoming therapy guidelines.




In addition to its mucolytic effects, NAC has a direct and an indirect (glutathione prodrug) antioxidant effect. It increases the body's own cysteine ​​and glutathione levels and thus strengthens the body's own antioxidant protection.

Its antioxidant effectiveness in preventing liver cell necrosis after paracetamol and paraquat intoxication is clinically proven and approved as an application area

The benefit of NAC as an adjuvant protective agent for arteriosclerotic changes is experimentally good, but not yet clinically proven

The use of NAC to protect against nephropathy caused by radio contrast media is already being discussed for use in routine clinical practice

Good experimental results and initial clinical results on the use of NAC to protect against reperfusion ischemia could foreseeably make NAC a regularly used substance in cardiology and cardiac surgery


NAC is recognized worldwide as a proven mucolytic for the treatment of acute and chronic bronchitis. Its use is also recommended temporarily in COPD guidelines and is known to be perceived by patients as subjectively pleasant and helpful.


In a long-term study (BRONCUS), a significant reduction in the COPD exacerbation rate or an improvement in lung function could not be proven. A dose that was perhaps too low and the selection of non-representative outcome parameters may have contributed to this result.

If the higher dosage with twice 600 mg NAC was used for COPD (2009), the result was a significant reduction in pulmonary overinflation and an increase in physical resilience.

Another placebo-controlled COPD study is currently examining the clinical effectiveness of NAC dosing in a higher daily dose.

In patients with IPF, NAC therapy (three times 600 mg / day) carried out in addition to prednisolone / azathioprine led to a significant reduction in mortality and a significant increase in vital and diffusion capacity. So far, such a therapeutic effect in addition to immunosuppressive therapy has not been proven for any other substance.

The oral tolerance of NAC is very good, the side effect profile is negligible and the price is low. /