NAC replenishes glutathione in HIV

Glutathione (GSH) deficiency in HIV-infected individuals

Glutathione (GSH) is a cysteine-containing tripeptide that plays a wide variety of physiological roles, including regulation of signal transduction, intracellular defense against oxidative stress, and systemic defense

against drug toxicity [5,6]. (!!!!!)

http://aliveandwellsf.org/articles/derosa_NAC_GSH_2000.pdf N-acetylcysteine replenishes glutathione in HIV infection

The clinical significance of this HIV-associated GSH deficiency is reflected by the strong association demonstrated recently between decreased survival in HIV disease and both low thiol levels in serum [42] and low GSB levels in CD4 T cells [46]. Clinical methods for replenishing GSH are well established [47]. N-acetylcysteine (NAC), a prodrug that supplies bioavailable cysteine necessary for the replenishment, is routinely administered to overcome pharmacologically induced GSH deficiency [5,6,48—51], for example due to acetaminophen or cyclophosphamide overdose. Thus, Droge [12,32,52], ourselves [45,53] and other studies [54—56] have suggested that NAC be evaluated as an effective means for preventing or reversing the GSH deficiency in HIV infection.

Drug dosage

NAC and placebo were supplied as indistinguishable effervescent tablets to be dissolved in water, juice or soda before ingestion.

Subjects were given 10 tablets (8000 mg of NAC) per day in distributed doses day.

NAC treatment is safe for HIV-infected subjects

We found no evidence of toxicity associated with NAC administration, either during the 8-week placebo controlled trial segment or the 6-month open-label segment.

NAC administration and survival In previous studies, we have shown that low GSB levels are associated with decreased survival in an overall study group that included subjects from this trial.

Consistent with these findings,

we find a significant association between NAC ingestion and improved 2—3 years survival

in a Cox Proportional Hazards analysis comparing the survival (adjusted for baseline CD4 T-cell count and b2-microglobulin) of trial subjects who took NAC during the placebo-controlled and/or the open label segment of the trial with those who never took NAC.

Since NAC effectively replenishes GSH in HIV-infected people, it may also prove to be a useful therapeutic adjunct for replenishing GSH in other clinical situations.

GSH deficiency induced by alcohol and certain drugs

is well-known.

In addition,

recent studies have implicated GSH deficiency in acute respiratory distress syndrome (ARDS)

and septic shock [31,87—89], hepatitis [29], liver cirrhosis [18,90], hepatorenal failure [31], preeclampsia of pregnancy [91], cardiac failure [92], rheumatoid arthritis [93], neurodegenerative disorders [25,94], aging [27,95], pancreatitis [96], age-related macular degeneration [97] and diabetes [98,99].

Exploration of NAC therapy has already begun in some of these diseases [31].

Although NAC is clearly not a panacea, the success in treating hepatorenal failure with NAC [31] provides good reason to suspect that NAC treatment may support recovery or slow disease progression in a variety of settings when administered as part of a specific therapeutic regime.

Finally, the potential association we have found between NAC treatment (and hence GSH replenishment) and improved survival in HIV infection argues strongly for a definitive trial designed specifically to test this association. Conduct of such a trial is virtually impossible in this protease inhibitor era. However, there are good reasons to test NAC as an adjunct to these therapies, since NAC has many sites of potential action that could improve health and drug tolerance. Furthermore, because NAC is inexpensive and safe enough to be administered with minimal medical supervision, it could prove useful in developing countries or other situations where protease inhibitors are unavailable or inadvisable. Thus, having shown that NAC effectively replenishes GSH in HIV disease, our data argue both for NAC treatment in suspected cases of GSH depletion due to any cause and for further testing to determine whether other potential benefits of NAC treatment can be identified in HIV disease.