AIDS TREATMENT NEWS No. 092 - December 1, 1989
John S. James

This article reviews a major academic study, published December 2; the study did not directly involve NAC, but it confirmed the existence (in symptom-free persons with HIV) of the serious biochemical defect which this drug has been found to treat. In addition, we interviewed an activist in Florida who has followed 24 people who are using NAC; he told us that all of them seemed to benefit.

Background

Use of NAC for HIV infection was first suggested by a German immunologist, Dr. Wulf Droge. Dr. Droge knew that levels of a chemical called glutathione were abnormally low in persons with AIDS; these levels fell further as the disease progressed. He also knew that NAC increased glutathione levels to normal or almost normal values (within a few hours in the two HIV-positive people who tried the drug), and that proper glutathione levels are important for immune functions and for other reasons.

In October 1988, Dr. Droge sent a cover letter and unpublished manuscript to colleagues in various countries, urging that they give appropriate attention to this information, which "may be life-saving or life-prolonging for many AIDS patients." The manuscript had been submitted to Nature; it was later published, but in a journal not well known to U. S. AIDS researchers or physicians (Eck and others, 1989). The cover letter had pointed out that pharmaceutical companies were unlikely to pursue NAC aggressively, because it was already widely available and would be difficult to protect by patent.

NAC first came to public attention in October, 1989, after news reports that two professors of genetics at Stanford University (Dr. Leonard Herzenberg and Dr. Leonore Herzenberg) told a scientific conference in Geneva of laboratory results suggesting that the drug might inhibit the AIDS virus. At that time we also reported that at least ten people were using NAC as an HIV treatment, apparently with good results.

In the United States, NAC has been available only in an aerosol form, which is not suitable for oral use for treating HIV. Buyers clubs are now beginning to obtain oral forms of the drug.

(For more background information, see "NAC: Bronchitis Drug May Slow AIDS Virus," AIDS TREATMENT NEWS #88, October 6, 1989.)

New Scientific Study: Glutathione Deficiency Confirmed

A study by seven researchers at the National Heart, Lung, and Blood Institute of the U. S. National Institutes of Health, and an eighth at Universitaire Sherbrooke, Quebec, was published in The Lancet, December 2, 1989 (Buhl and others, 1989). The researchers reported that glutathione levels in blood plasma of symptom-free HIV-positive subjects were found to be only 30 percent of those of uninfected controls. (The 14 HIV-positive subjects, all symptom-free, had an average T-helper count of 346; four were taking AZT and the other ten were untreated.) Fluid from the lungs, obtained by bronchoalveolar lavage, was also tested for glutathione, and persons with HIV were found to have 60 percent of normal levels.

The paper listed many important functions of glutathione. It is believed to protect cells from oxidation injury, aid in synthesis of proteins and DNA precursors, and serve as a cofactor for certain enzymes. It also has direct effects on the immune system:

"Glutathione is also believed to be important in the initiation and progression of lymphocyte activation, and thus essential for host defense. Furthermore, depletion of intracellular glutathione inhibits lymphocyte activation by mitogens, and glutathione is critical for the function of natural killer cells and for lymphocyte-mediated cytotoxicity."

In short, this paper confirms and extends the pioneering work of Droge, two of whose papers are cited in its references.

On December 1, The New York Times published an article on this work ("New Research Suggests Underlying Factor in AIDS"), and interviewed one of the researchers, Dr. Ronald G. Crystal. According to the Times article, the researchers have developed an aerosolized glutathione (not NAC) to spray directly into the lungs to see if it will correct the deficiency there. Several months will be required just to find the right dose of this chemical.

Question

Why develop a new drug to restore glutathione levels only in the lungs, when NAC has already been found to do so systemically? We could not reach the researchers by press time to answer this question. Another scientist familiar with the subject pointed out that this research team consists of pulmonary specialists and experts in aerosol medication; their interest is studies of the lungs. The paper seems to go out of its way to avoid mentioning NAC, especially in the short section at the end where less promising methods of raising glutathione levels are discussed.

The Florida Study

The Fight for Life Committee, an AIDS activist organization in North Lauderdale, FL, is collecting information from 24 people who are using NAC as an HIV treatment. (The Fight for Life Committee is described by chairman Lenny Kaplan as a "Southern-style ACT UP"--one which works through court challenges and the media more than through demonstrations. For example, the organization has successfully gone to court to obtain AZT for prisoners with AIDS. It is also working through the state legislature and otherwise to reduce the cost of aerosol pentamidine treatment in local hospitals.)

When we interviewed Mr. Kaplan on December 3, the 24 people had used NAC for between 10 and 45 days. All of them are keeping diaries. All of them have ARC or AIDS. Interpretation of results is complicated by the fact that 12 of the 24 are also using Compound Q; but those involved attribute the following benefits and side effects to NAC. (Mr. Kaplan told us that the NAC seemed to work better and sooner for those who had also used compound Q; he felt there should definitely be a clinical trial to test the combination.)

Everybody reported increased energy, often greatly increased; persons who once needed naps during the day have become able to work full time without them. Only a few have blood work results available after using NAC; their T-helper counts were up by an average of about 75.

The two who showed the most benefit both had wasting syndrome. One gained 12 pounds, and his physician found no new growth of KS. The other gained 10 pounds.

Some people had headache or dizziness during the first week. The dose had to be reduced to 1000 mg per day (500 mg after breakfast and 500 mg after dinner) after three of the first five had stomach upset on a higher dose. These side effects may have been due to the formulation of the drug (see below).

For more information about the NAC study or about The Fight for Life Committee, call Lenny Kaplan, 305/566-6753. Donations are needed. Fight for Life is planning a conference on AIDS treatments in Ft. Lauderdale on February 2 and 3; for information, call the number above.

Drug Formulation Issues

Many brands of NAC are sold in different countries in Europe for oral use. As far as is known, any of these brands would be satisfactory; however, most contain large amounts of sugar or other sweeteners to cover the bad taste of the NAC; some patients might not want the sweeteners. Prices vary as much as 3-fold between expensive countries (such as Germany or England) and inexpensive countries (such as Spain). Persons with HIV are using somewhat more of the medication than persons with bronchitis; as a result, NAC costs about $2. per day even from the less expensive countries, with doses of 1600 mg per day (400 four times per day) or 1800 mg per day (600 three times).

Meanwhile, the chemical NAC has been pressed into tablets and sold at prices much less than the European brands. Because these tablets are not regulated as drugs, there is widespread concern that they might not be safe. Some of the concerns we have heard are:

* Customers can only trust that the manufacturer used a grade of the chemical intended for human use;

* According to one chemist, the European products are packed in foil because they oxidize rapidly when exposed to air. The other tablets are just put into bottles. They may have a short shelf life, especially after the bottles have been opened. The shelf life needs to be checked.

* All or almost all of the European brands are intended to be dissolved in water outside the body before being taken. Usually the drug is provided as a single-dose packet of powder. These packets are not as convenient as pills, especially since NAC has an unpleasant taste; presumably the packets are provided for a reason, possibly to reduce stomach irritation.

To avoid such problems, the PWA Health Group in New York is planning to obtain one of the European NAC preparations. For more information, call them at 212/532-0280. The PWA Health Group is also planning to do its own chemical testing and other research on the suitability of the various formulations.

It may be possible to create a very inexpensive product which is satisfactory--perhaps by putting pharmaceutical-grade NAC into capsules to be opened before use, and dissolved in water. Some research--for example, checking with pharmacologists in Europe--would be necessary.

There are efforts to organize a formal clinical trial of NAC as an HIV treatment. These efforts are moving slowly, and it will probably be years before the drug is officially approved. NAC is not a high priority for any organization. Meanwhile the AIDS community must organize itself to obtain proper supplies, and to collect the best information possible about this potential treatment and its uses.

References

Buhl, R. and others. Systemic glutathione Deficiency in Symptom-Free HIV-Seropositive Individuals. The Lancet, pages 1294-1297, December 2, 1989.

Droge, W and others. Glutathione augments the activation of cytotoxic T lymphocytes in vivo. Immunobiology, volume 172 number 1-2, pages 151-156, August 1986.

Eck, HP and others. Low concentrations of acid-soluble thiol (cysteine) in the blood plasma of HIV-1 infected patients. Biol Chem Hoppe Seyler, volume 370 number 2, pages 101-108, February 1989.

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