Gay Men's Health Crisis Treatment Issues, Vol. 5, No. 7 - October, 1991
Dave Roche

PRE-CLINICAL TRIALS

In September, 1989, two Stanford University microbiologists, Drs. Leonard and Leonore Herzenberg, announced at a conference in Switzerland that NAC inhibits HIV activity in test tube studies. NAC, currently prescribed to treat bronchitis and Tylenol overdoses, works by raising blood levels of a substance called glutathione. This substance has been found in levels well below the average in many HIV-infected individuals.[1] It is thought that glutathione is necessary to moderate the effects of tumor necrosis factor (TNF), a naturally-occurring protein which may trigger HIV activity in the body. TNF has been found in elevated levels in people with AIDS.[2]

The Herzenbergs published other findings in June, 1990, showing that TNF stimulation of HIV activity can be inhibited by adding NAC to HIV-infected cells. These results were later confirmed in another study.[3] In fact, low levels of glutathione appear to correlate with over-sensitivity to TNF, implying that keeping glutathione at a normal level may prevent HIV activation.[4] In February, 1991, work by NIAID scientists, including Dr. Anthony Fauci, who has conducted much research with TNF and HIV, revealed that NAC suppresses TNG-triggered HIV activity.

Additional test tube work published in June, 1991, indicates that NAC works in both recently-infected and chronically-infected T-cells and monocyte cells.[5] This is a potentially important finding, considering the immune function of T-cells and the fact that monocytes are reservoirs for HIV in the body.

CLINICAL TRIALS

The first of a total of twelve HIV-infected participants have enrolled in a NIAID study of NAC in Bethesda, Maryland in May, 1991. This phase I study is designed to last approximately one year and will test the safety and pharmacokinetics of the drug. Patients with T4 cells under 500 will be divided into three four-person groups. Both oral NAC (administered at home) and intravenous (IV) NAC (administered three times weekly at a clinic) will be given for a period of six weeks. Oral doses are 150 mg, 300 mg or 600 mg every 6 hours in the form of an effervescent tablet dissolved in water. The first of the three groups is now being completed, and so far no changes in surrogate markers (T4 cells, etc.) have been noted.[6] Patient recruitment is currently in progress for the second group but cost constraints limit it to people living within a 100-mile radius of Bethesda. Recruitment is still open, and more information can be obtained by contacting Chris Boenning, RN at 1-800-772-5464 ext. 401.

ANECDOTAL INFORMATION

Additional results of NAC are, for the most part, anecdotal and can lead to widely divergent conclusions. One patient featured in a December 10, 1989 New York Newsday article who had been taking NAC since January, 1989, died recently of lymphoma. However, another long-term NAC recipient, taking the drug for almost three years, has seen T4 cells increase from 300 to 450 and p24 levels drop sharply to near zero.[7] NAC is available through various buyers' groups that import different brands from Europe.

One common brand, Fluimucil, is available in a 600 mg tablet. In general, Fluimucil is taken two or three times daily by many PWAs experimenting with the drug. Treatment Issues has also heard that some people are taking doses as low as 90 mg per day. It is unclear whether this dosing will result in levels comparable to those which were necessary to inhibit HIV in the test tube. The number of people taking NAC remains fairly high. The PWA Health Group in New York indicates that the drug is their second-highest seller (after ddC), with about 150 customers monthly. The approximate cost of taking NAC three times daily is approximately $2.25-$3.50 per day. To buy the drug or get more information, call the PWA Health Group at (212) 532-0280.

Side effects and toxicity of NAC appear to be low but may involve infrequent allergic reactions, nausea, vomiting and fevers. There have been reports that NAC is also available through certain health food companies. However, it is likely that drugs produced under supervision at a pharmaceutical company may result in better quality control. It is believed NAC must be wrapped in foil (as Fluimucil is) to prevent potentially damaging exposure to air.

ADDITIONAL THOUGHTS

NAC has a relatively brief half-life of 5-6 hours in the body, implying frequent dosing to maintain appropriate levels of drug in the blood. Twenty to 25% of oral and intravenous NAC is eliminated unchanged in urine, raising questions about the degree to which the drug is absorbed in the body.

Trials of another TNF-inhibiting drug, pentoxifylline, are in development at the NIH. A recent report has emerged that the FDA has granted the go-ahead to Clintec Nutrition Co. for a phase I trial of a glutathione-raising substance called Procysteine. Clintec reports that this trial will begin immediately.

REFERENCES

1. Eck, HP et al. Low concentrations of acid soluble thiol (cysteine) in the blood plasma of HIV-1 infected patients. Biol Chem Hoppe-Seyler 370:101-108, Feb 1989.

2. Lahdevirta J et al. Am J Med 85:289-291, 1988.

3. Roederer M et al. Cytokine-stimulated human innumodeficiency virus is inhibited by N-acetyl-L-cysteine. Proc of Nat Acad of Sciences 87 (12):4884-8, 1990; and Staal et al. Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human innumodeficiency virus. Proc Nat Acad of Sciences 87(24):9943-7, 1991.

4. Kalebic et al. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc of Nat Acad of Sciences 88(3):986-990, 1991.

5. Roederer at al. N-acetylcysteine inhibits latent HIV expression in chronically infected cells. AIDS Research and Human Retroviruses 7(6):563-567, 1991.

6. Personal communication, Dr. R. Walker.

7. Personal communication, Dr. Leonore Herzenberg.

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