Subject: AIDS Treatment News #139 Date: Nov 22 1991 (786 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Copyright 1991 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue #139, November 22, 1991 phone 800/TREAT-12, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Azithromycin and Clarithromycin Approved Soluble Melanins: Potential HIV Treatment? "L-Drug" Resistance Problem; Merck Stops Single-Agent Trial Pneumocystis: 566C80 Treatment IND Anal Cancer Study in San Francisco ddC: NDA Filed Therapeutic Marijuana Initiative Approved by San Francisco Voters ***** Azithromycin and Clarithromycin Approved by Denny Smith Two drugs which promise to become important weapons against some AIDS-related illnesses have won approval for use in certain infections not specific to AIDS. On November 1, Abbott Laboratories announced that the Food and Drug Administration (FDA) had approved clarithromycin, an oral antibiotic which Abbott will market under the trade name "Biaxin." Three days later, Pfizer Inc announced FDA approval of a related antibiotic, azithromycin. Pfizer's drug will be marketed as "Zithromax," and will also be administered orally. Each drug is approved to treat skin and respiratory infections, and azithromycin is also indicated for uncomplicated chlamydial infections. Both drugs were developed from the macrolide class of antibiotics, which includes the commonly used erythromycin. Because of azithromycin's exceptional tissue- penetration properties, Pfizer considers it the prototype of a new class called azalides. Neither drug was approved specifically to treat AIDS-related infections, though one or both have shown activity in lab studies or clinical trials against toxoplasmosis, Mycobacterium avium complex (MAC), and possibly cryptosporidiosis. For background information, see AIDS TREATMENT NEWS #113. The approvals are of course good news, because they allow physicians to prescribe the drugs at their discretion, for any diagnosis. But since the indications which won FDA clearance do not cover infections specific to AIDS, insurance companies may balk at paying for such use. Another uncertainty concerns the optimal dosing for treating AIDS infections, assuming one or both of the drugs is indeed effective. Looking for the current consensus, we contacted three physicians known to be experienced with the research or clinical use of these drugs in treating opportunistic infections. Jack Remington, M. D., a Professor of Medicine at Stanford University, is widely known as a prominent authority on Toxoplasma infections, and was among the first to call for studies of azithromycin. When we spoke by phone, he cautioned that not only are these drugs not officially approved to treat toxoplasmosis, but they are not yet medically proven -- they lack solid data demonstrating efficacy against this infection in humans. But he acknowledged that people with AIDS and their physicians will likely begin using one or both of the drugs anyway. In that light, Dr. Remington expects neither drug would be sufficient by itself against toxoplasmosisPthat either will have to be combined with pyrimethamine. He added that azithromycin was more active against Toxoplasma in mice studies. Even with those qualifications, the drugs may represent a critical option in many situations when the standard combinations -- pyrimethamine with sulfadiazine, or pyrimethamine with clindamycin -- either cannot be tolerated or fail to control the infection. Lowell Young, M. D., is Director of the Kuzell Institute of Arthritis and Infectious Diseases in San Francisco. For some time Dr. Young has been investigating the drugs' value against MAC infections, and recent results of his work appear in last week's issue of the Lancet. He told us that when used alone, 500 mg of azithromycin daily obtained a good response in 75% of MAC patients. In animal studies, azithromycin worked even better when combined with ethambutol and clofazimine. Dr. Young suggested that a possible approach for newly diagnosed patients would be to start them on all three drugs, discontinue the clofazimine after one month, and continue the remaining two indefinitely. The most common side effect to watch for with azithromycin is loose stools. He noted that clarithromycin may be just as effective for treating MAC, but that four times as much drug is needed. In other words, two grams of clarithromycin would be needed to approximate the value of 500 mg of azithromycin. Robert Thomas, M. D., maintains a large HIV practice in Washington, D. C., and has had clinical experience with at least one of the drugs for treating three different infections. He said that azithromycin alone worked very effectively on three of his patients who were failing the standard drugs for toxoplasmosis. The dose was 1.2 grams daily until the infection was reversed, followed by maintenance at 600 mg daily. He is convinced that this is a viable option for treating this infection. Some of Dr. Thomas' patients with MAC had a fairly good initial response to 2 grams of clarithromycin daily, but symptoms tended to return. Because of this, he doubts that the drug will be used alone, except maybe as a prophylactic agent for people at risk for active MAC. Cryptosporidiosis largely failed to respond to either azithromycin or clarithromycin. This seems in line with most anecdotal reports our readers have shared with AIDS TREATMENT NEWS. Dr. Thomas has seen much better control of cryptosporidial diarrhea with paromomycin and Sandostatin. We are grateful to these physicians for sharing information and experience which necessarily depend on some anecdote and guesswork. Abbott and Pfizer are expected to continue investigating their products in AIDS-related protocols. ***** Soluble Melanins -- Potential HIV Treatment? by John S. James In a June 1990 poster presentation at the Sixth International Conference on AIDS, researchers at Vanderbilt University Medical School reported that when a soluble melanin synthesized from L-dopa was fed to mice in their drinking water, their urine showed anti-HIV activity even when diluted up to 200 times. (Note: the animal results were presented only on the poster itself; the published abstract(1) reports laboratory work in which the melanins blocked infection by three different HIV strains in three different cell lines, apparently by preventing viral gp120 from binding with the CD4 receptor on the cell surface. The animal work has not been published, except in AIDS TREATMENT NEWS #107, July 20, 1990, which reported on the Sixth International Conference presentation.) There was no evidence of toxicity to the mice. In addition to the conference presentation, two major papers on anti-HIV activity of melanins in laboratory tests have been published(2,3), both by the same Vanderbilt team led by David C. Montefiori, Ph.D., a well-known researcher who has co-authored dozens of papers and conference presentations on HIV. The melanin work has attracted little attention, however, because of widespread reluctance to believe that these common chemicals, widely found in nature and already present in the body in other forms, could possibly work as an antiviral. Then about six weeks ago a chemist who had synthesized one of the soluble melanins in a home laboratory began taking a large dose, over 200 mg once per day, for his own HIV treatment. He is enthusiastic about the result and provided the melanin to friends with HIV or AIDS. Today over six people are taking it. They are reporting good results, but almost no objective data is yet available. Because of the power of the placebo effect, and the hopes and excitement of trying something new, many drugs go through a similar "honeymoon" period of early enthusiasm. Most of them later prove not to be useful. (There is even an old medical saying, "Make haste to use a new remedy, while it still has power to heal.") In view of the many disappointments in the history of AIDS drug development, there is much concern over the risk of a false alarm about something which may not work, and which could be harmful since it has not been through the standard toxicity tests in animals. Because of this danger, we had mixed feelings about publishing this article now, instead of waiting until more is known. We decided to go ahead, since waiting will gain little; there will never be a "right" time. The peculiar nature of both melanin itself and of the prevailing attitudes toward it almost guarantees that this treatment lead will not be developed rapidly by the research mainstream, if it is developed at all. Therefore the AIDS community itself must take the lead in determining whether the early reports of good human results will be sustained. It is important that more people be involved in this effort. Yet it is also important to realize that it is much too early to recommend melanins as an HIV treatment. Background on Melanins Melanins are pigments responsible for the color of skin, hair, and eyes; they are also found in other organs, including the brain. In the body they are insoluble, however, and do not have an antiviral effect. There are many different kinds of melanins. But while these chemicals have been familiar for decades (almost 5,000 published papers mentioning melanins since 1966 are listed in the Medline file of the U. S. National Library of Medicine), their chemical structure is still not entirely known. While melanins are generally considered relatively harmless, no medical use for them has ever been found. Therefore, while there are many papers studying the metabolism of melanins, especially in regard to melanoma (which is a cancer of melanin-producing cells), there are few if any published reports about administering these chemicals either to humans or to animals. The form of melanin of most current interest as a possible HIV treatment is called l-dopa melanin. (Other melanins worked about as well in laboratory tests, but as far as we know, only this one has been tried in humans as an anti-HIV treatment.) In the laboratory, l-dopa melanin is easily synthesized from l-dopa, an amino acid which is found in certain edible beans and is best known as an important treatment for Parkinson's disease; the chemist who first tried taking the melanin used a synthesis procedure based on the one published by Dr. Montefiori(2,3); a similar procedure was published in 1938.(4) Melanins and HIV Since there was little or no reason to suspect that any kind of melanin would have anti-HIV activity, we asked Dr. Montefiori why he first thought to try it. He explained that the discovery was in part accidental. He was studying a pigmented compound which showed anti-HIV activity in laboratory tests. Because he was familiar with melanins (having worked with them as a graduate student), because there was a theoretical possibility that they might account for the effect found, and because Dr. Montefiori had excellent facilities for economically screening substances for anti-HIV activity, he tried melanin to see if it might be causing the antiviral effect. It later turned out that the original substance being investigated did not contain melanin, but by then the antiviral activity of the chemical had already been noted. The first of the two papers published so far on HIV and melanins appeared in April 1990 in Biochemical and Biophysical Research Communications, a journal which specializes in rapid publication of current research. In laboratory tests, melanin synthesized from three starting substances -- dopamine, norepinephrine, and serotonin -- prevented infection of cells at very low concentrations, with 50 percent protection with concentrations as low as 0.09 ug/ml (micrograms per milliliter). [Note: the unreacted starting substances used in this experiment (dopamine, norepinephrine, and serotonin) can be toxic to humans. The starting substances which were used in the later research, described below (L-tyrosine and L-dopa) are safer.] In another experiment, higher concentrations were required to prevent the formation of syncytia, abnormal giant cells formed when HIV-infected cells merge with each other and with normal cells; concentrations of 5 ug/ml were needed for best results. But if infected cells were pre-incubated with melanin before being mixed with the uninfected cells, syncytia were inhibited at 0.625 ug/ml. By contrast, pre-incubation of the uninfected cells did not help. This difference suggests that melanins work by interacting directly with viral proteins, not by protecting normal cells; a beneficial consequence is that their action is not specific to any particular kind of cell. The starting substances themselves were tested and found to have no antiviral effect -- even though a small amount of melanin formed spontaneously (by oxidation) while the viral tests were being run. Results of confirmatory and followup studies(3) were published in January 1991 in Antiviral Research. Melanin synthesized from L-dopa provided 100 percent protection against two HIV strains, at 0.31 and 0.62 ug /ml respectively. It was also tested against HIV-2, a different AIDS virus found mostly in parts of Africa, and was found to be less effective; a 3 ug/ml concentration provided 50 percent protection. Other research reported in the same paper explored the possible mechanisms of the antiviral activity of melanins. These substances seem to work early in the viral replication cycle; they need to be present with the virus (or viral proteins), since treating uninfected cells and then washing the melanin off does not protect the cells. Another test showed that melanin inhibits binding of the viral protein gp120 to the CD4 receptor on T-cells -- the mechanism by which virus attaches to uninfected cells and enters them. Free gp120 or gp160, which bind to the CD4 receptor, were added to cell cultures; later, the unbound portion was washed away, and that which remained on the cells was measured. Melanin blocked this binding process; complete blockage of gp160 binding was achieved at 10 ug/ml, although gp120 binding was only partly blocked. Another experiment, with monoclonal antibodies, suggested that melanins specifically blocked the binding of HIV proteins to the CD4 receptor, not binding to receptors in general. Melanins were also found to have no effect on the enzyme reverse transcriptase. Therefore their antiviral effect is due to a different mechanism of action than that of AZT or other reverse-transcriptase inhibitors. It also appears that soluble melanins do not get inside the cells, which is consistent with the theory that they work by direct interaction with free virus, or with viral gp120 on the cell surface or elsewhere. We asked Dr. Montefiori why the mouse-urine result presented at the Sixth International Conference on AIDS was not included in the published article. He told us that there was nothing wrong with the work, but that all the animal results had been deleted by the reviewer assigned by the journal, due to the preliminary nature of the experiments. There was also a prevailing skepticism in the scientific community about melanins as an antiviral. (In fact, three other journals had rejected the paper, before it was accepted by Antiviral Research.) The animal work is important, because it shows that melanin given orally (or some antiviral component or product of it) could be absorbed by mice and appear in their urine, which then inhibited HIV even when diluted many times. Unfortunately this evidence that soluble melanins may be orally bioavailable has not yet been published in the scientific literature. Additional pharmacological studies are urgently needed. One reason for the skepticism about melanins is that no one knows their mechanism of action as an antiviral. Montefiori and Zhou(3) suggest that certain chemical sites in melanin might bind to gp120 or another substance needed for viral entry into cells. Melanins "have been shown to contain substituted hydroxyindoles, indolequinones, pyrroles, free carboxylic acid groups, phenolic hydroxyls, carbon-based free radicals, and uncyclized aliphatic chains" (page 22). Another possibility suggested in the same paper is that part of the melanin molecule might resemble a peptide sequence in gp120 and bind specifically to it. Insoluble melanin in the body is "known to bind certain chloroquine and phenothiazine antibiotics" (Montefiori and Zhou, page 22). Whether soluble melanins would affect these antibiotics is unknown. Biosource Genetics Corporation in Vacaville, California is developing melanins as an absorber of ultraviolet light in sunscreens, and also for possible medicinal uses. Bob Erwin, president of Biosource Genetics, told AIDS TREATMENT NEWS that the company's animal tests had found little or no toxicity, whether the chemicals were given orally or by injection -- and that another potential advantage is that melanins can be produced at low cost. Biosource Genetics specializes in developing methods to manufacture high-purity melanins and related indole chemicals economically; its scientists recently published an article on using genetically engineered bacteria to produce new kinds of melanins.5 Dr. Erwin also noted that melanins occur in many foods. Anecdotal Reports The chemist who first tried the L-dopa melanin has been taking 200 mg per day for two months now. A total of eight people people are now using it, with the same dose. Four of them have taken it for several weeks and reported back about their experience. (The chemist himself has tried a larger dose, up to 200 mg four times a day for a week, to look for any toxicity. He did not find any problem, but also did not find any additional benefit over the dose of 200 mg once per day.) The most uniform result reported is that people felt much better, with energy, motivation, and appetite coming back, starting very quickly, usually the day after the first dose. (The only exception is one person who was already feeling well, who did not notice any change). The chemist said that he felt better after starting the drug than he had since becoming ill. His myopathy is gone, neuropathy which he has had for two years has improved, and he has gained 10 pounds after losing weight during his illness. After three days his wife, who also has symptomatic HIV disease, started taking the melanin, also with good results. Both have taken it continuously for two months. A third person who had fevers was feeling good and back at work a day after starting the melanin. He once ran out of the drug for about a week and fevers returned; they went away after he restarted the treatment. The fourth person had been hospitalized before starting melanin, and was in such poor condition that his physician, a leading AIDS clinician, discontinued the patient's conventional drug treatments, believing that he had less than one week to live. He had starting taking melanin four days before the other treatments were discontinued. Recovery began several days after he started the melanin, and at his family's request, the regular medications were restarted. According to what we have heard both from the chemist and from a friend of ours who knows the patient well, this person greatly improved after starting melanin, becoming ambulatory and lucid; serious neuropathy had entirely disappeared by the sixth day (and has not returned since), and his skin was described as looking much better. The patient was discharged from the hospital one week after he had been expected to die, and a week later he was able drive his car. He is still seriously ill with MAC, despite treatment with clarithromycin. The only bloodwork now available from anyone who has used melanin is from the chemist himself. His T-helper count had been declining very rapidly, losing about 30 percent a month for several months. The last count before starting the melanin was 100; the only count since, with blood drawn about three weeks after the treatment began, was 111. The increase of 11 is well within the range of error of the test. It is possible that the melanin treatment stopped or reversed the ongoing decline -- but it is also possible that the apparent reversal was coincidence. The melanin dose has usually been taken in the evening, usually with an antacid. The antacid might or might not be useful. Melanin is stable in acid, but it precipitates out of solution. It would likely dissolve again in the intestines, but this is not known. The antacid may help to keep it from coming out of solution in the stomach. Speculation: Mechanism of Action What is surprising about these reports is how rapidly a substantial improvement has been seen -- usually within one day of starting treatment. It seems unlikely that so rapid a change would result from reducing viral replication. The two theories which seem most consistent with the available information are (1) a placebo effect, and (2) that the drug may block harmful effects of gp120, a toxic protein produced by HIV which may be responsible for immune dysregulation and other pathogenic effects of HIV infection. Melanin did block the binding of gp120 to the CD4 receptor of cells (which is probably how gp120 causes harm) in the laboratory tests cited above. If melanin does work by blocking gp120 (in addition to any effect it may or may not have on viral replication), then it might be especially useful late in the course of illness, when the gp120 levels are presumably high. It would not be the whole answer, however, as it apparently does not get into cells, so the virus in infected cells would still remain active. If melanin does work this way, then theory suggests that viral resistance to it may be slow to develop. For if a drug blocks the harmful effect of gp120 on the body, without directly inhibiting the virus, then there would be no selective pressure on the virus to develop resistance. If the drug also works as an antiviral, then there would be such pressure. But the binding of gp120 to the CD4 receptor may be critical, and if so, viruses which changed the binding region would be unlikely to be able to infect cells. Comment It is too early to know for sure if the melanin is helpful, or if the reports from the human experience so far result from placebo effect and lucky coincidence. But clearly this potential treatment deserves serious attention immediately. The above reports of patients' experiences came to us from three different people; all three are well known to this writer, very knowledgeable about HIV, and skeptical of new-drug claims. All three learned what they told us from personal observation, not by hearing it from others. A research organization could begin by sending a medical team follow up the information available from the people who have used the treatment so far, interviewing and examining them and checking their medical records; this could be done without the ethical or legal complications (and resulting delays) of giving someone an untested drug. Also, it would take advantage of the two months of human experience already available. Perhaps the next step would be for other patients to start take L-dopa melanin under the supervision of a research physician, who would make sure that the appropriate baseline and other research tests were done. A formal trial should begin as soon as possible; but at this time, no such trial is being planned. For More Information DATA (Direct Action for Treatment Access), a new research and advocacy organization (see AIDS TREATMENT NEWS #137, October 18, 1991), is collecting information on treatment uses of melanins. For the latest available information, send a self- addressed stamped envelope with a note requesting melanin information to: DATA, P. O. Box 60391, Palo Alto, CA 94306, or phone 415/323-6051. References 1. Candia AF, Modliszewski M, Shaff DI, and Montefiori DC. Inhibition of HIV replication and cytopathicity in vitro by synthetic soluble melanins. Sixth International Conference on AIDS, San Francisco, June 20-24, 1991 [abstract number Th.A. 228]. 2. Montefiori DC, Modliszewski A, Shaff DI, and Zhou J. Inhibition of human immunodeficiency virus type 1 replication and cytopathicity by synthetic soluble catecholamine melanins in vitro. Biochemical and Biophysical Research Communications. April 16, 1990; volume 168, number 1, pages 200-205. 3. Montefiori DC and Zhou J. Selective antiviral activity of synthetic soluble L-tyrosine and L-dopa melanins against human immunodeficiency virus in vitro. Antiviral Research. January 1991; volume 15, pages 11-25. 4. Arnow LE. The preparation of dopa-melanin. Science. Volume 87, page 308. 5. Della-Cioppa G, Garger SJ, Sverlow GG, Turpen TH, and Grill LK. Melanin production in Escherichia coli from a cloned tyrosinase gene. Biotechnology. July 1990; volume 8, pages 634-638. ***** "L-Drug" Resistance Problem; Merck Stops Single-Agent Trial by John S. James After data from human trials showed very rapid development of viral resistance to Merck's experimental anti-HIV drug L-661, the company decided to stop the trial of L-661 alone, which had been ongoing at the U. S. National Institutes of Health, at the University of Alabama in Birmingham, and at centers in Brussels and Amsterdam. A combination trial of L-661 and AZT will continue in Frankfurt. In the laboratory, viral resistance is caused by a single mutation that results in a change at position number 181 in the reverse transcriptase enzyme. It makes the virus ten to one hundred fold less sensitive to L-661, making the drug an ineffective inhibitor against the resistant strain. This same mutation also makes the virus resistant to most other drugs of the same class (non-nucleoside reverse transcriptase inhibitors, such as BI-RG-587 and the TIBO derivatives), even though it has never been exposed to them. Resistant virus has been found at the seventh week of treatment in all seven volunteers so far analyzed. The new data does show that L-661 has biological activity against HIV in humans; p24 antigen levels fall quickly in some patients after treatment begins. But these levels come up again as the viral resistance develops. L-661 will still be tested in combination with AZT, because it is hoped that combination treatments can help delay the emergence of drug resistance. (To avoid resistance entirely, a drug combination must completely shut down all variants of the organism, either by killing them or by otherwise preventing them from multiplying.) The resistant virus to L-661 is still susceptible to AZT. A new Merck drug, L-229, is closely related to L-661 but can reach higher blood levels in humans, because it binds less to plasma proteins. Therefore it may be able to shut down the virus more quickly and minimize the emergence of resistance, especially if used in combination with AZT or other anti-HIV drugs. According to spokesman John Doorley, Merck hopes that L-229 will eventually supercede L-661. But first there must be more preliminary testing of L-229, especially to show that it has biologic activity against HIV in humans (as L-661 is known to have). Because L-661 is further along in its development, it is important to continue to test the combination of L-661 with AZT to provide data on the combination, to help the design of the trials with L-229, to determine if L-661 resistance still occurs in the presence of AZT, and to gain additional data on the effectiveness of these compounds as single agents. Resistance to Class of Drugs Several new antivirals -- Boehringer Ingelheim's BI-RG-587, Janssen's TIBO derivative R82150, and the new Upjohn BHAP drugs -- have the same mechanism of action as L-661 and L-229. All of them inhibit the enzyme reverse transcriptase, which is required by HIV but not used by the human body. But unlike AZT, ddC, and ddI, which also inhibit reverse transcriptase, the new drugs are not nucleoside analogs; they do not act as false building blocks of the virus. For this reason, the new class of drugs (Merck's L-661 and L-229, and the related compounds being developed by other companies) are called non-nucleoside reverse transcriptase inhibitors. It is hoped that they will be less toxic than AZT and other nucleoside drugs, and therefore can be used in larger doses. But viral resistance seems to be a big problem with this class of drugs. And it is known that if HIV becomes resistant to BI-RG-587, or TIBO derivative R82150, it will be resistant to L- 661 also. (The new BHAP drugs are chemically similar and are likely to share this cross resistance.) If a virus becomes resistant after treatment with a drug, will it revert to a sensitive strain if the drug is removed? No one knows at this time; Merck will test volunteers who stop taking L-661 to see if their virus becomes sensitive. (In many cases, viruses or other organisms which become resistant to a drug do become susceptible again if the drug is stopped, because the resistant strains are less able than the non-resistant ones to survive in the body when the drug is not present. This is not surprising, since if the resistant organisms were more able to survive, they would already have become the predominant strains and the drug would never have worked in the first place.) In laboratory cultures, however, virus which has become resistant to L-661 does not spontaneously become susceptible. Volunteers in trials of non-nucleoside reverse transcriptase inhibitors should realize that there is a risk that they could develop resistant viral strains which might later prevent them from benefiting from other drugs in the same class. This would only be a problem if (1) more effective non-nucleoside reverse transcriptase inhibitors are developed, and (2) the virus does not revert to drug-sensitive strains after the drug is stopped or replaced with AZT. Merck's researchers have not found any virus which is resistant to both L-661 and also to AZT -- a fact which supports trying the treatments in combination. ***** Pneumocystis: 566C80 Treatment IND by John S. James On November 12, after several months of effective cooperation between Burroughs Wellcome Corporation and AIDS organizations, the experimental drug 566C80 was made available without charge through a "treatment IND" to patients with pneumocystis who cannot tolerate or fail to respond to conventional treatment with trimethoprim/sulfamethoxazole (Septra, or Bactrim), or who have a history of intolerance to sulfa drugs. Burroughs Wellcome plans to make the drug available within 24 hours. Physicians who want to enroll a patient can call 800/755-2020, 24 hours a day, seven days a week. The data now available suggests Septra may be the more effective pneumocystis treatment, but it is also more toxic. (About 25 percent of patients had to discontinue Septra because of side effects, compared to less than 10 percent who had to discontinue 566C80 for this reason, in a phase II/III trial.) 566C80 may have another important advantage in that, in animal tests, it can kill the cysts of pneumocystis, potentially eradicating the disease; however, it is not known if it will do so in humans. Burroughs Wellcome will run two 566C80 programs through the same phone number given above. One, the treatment IND, will provide the drug for those with mild to moderate pneumocystis. The other, an open-label protocol, is for those with severe disease. The reason for the difference is that the drug has only been in trials for mild to moderate illness; those more severely ill who need to use 566C80 because they have no other options will get it through a study designed to learn whether the drug can be effective in that case. 566C80 is given orally. (An intravenous form is now being developed; it might be useful for more severe illness.) The current oral formulation should be taken with food when possible. According to David Peck of ACT UP/Boston, who led the activist efforts for access to 566C80, the drug is easy to obtain and the paperwork is not a problem. The FDA requires local IRB approval when possible; exceptions include unavailability of an IRB, or an immediately life-threatening event. In exceptional circumstances, the drug might be released for toxoplasmosis on an individual basis. However, there is no formal program for toxoplasmosis at this time. Studies for this infection are ongoing. 566C80 is also being studied for cryptosporidiosis. Note: ACT UP/Boston, ACT UP/New York, and Project Inform have been most closely involved in working with Burroughs Wellcome to develop this 566C80 distribution program. Last July over 50 organizations formed a national coalition seeking access to this drug. ***** Anal Cancer Study in San Francisco by Denny Smith Because immunosuppressed men may be at higher risk for anal cancer than those with intact immune systems, The University of California San Francisco and the San Francisco Men's Health Study are initiating a study of anal neoplasia (also called dysplasia or precancerous formations) in men with HIV infection. Pap smears will be taken periodically to observe any precancerous changes in anal tissues. The removal of those cells can halt progression to cancer. The study is now recruiting, and interested persons may call Joel Palefsky, M. D., at 415/476-1574. Men who are seronegative will also be recruited, as a control group. Dr. Palefsky told us that Pap smears are abnormal in about 40% of HIV+ men, and a high proportion of those may go on to develop cancer if not treated. This study is a good opportunity to be monitored for this potential problem. A related concern in women with HIV is the increased incidence of neoplasia of the cervix. For that reason, many clinicians recommend six-month, instead of yearly, Pap smears for HIV+ women. Dr. Palefsky noted that women may also want to ask for an anal Pap smear when they get their regular cervical Pap smears. For both men and women with HIV, regular Pap smears are important for timely diagnosis and treatment of anal or cervical neoplasia. ***** ddC: NDA Filed On October 31, Hoffmann-La Roche announced that it had completed its filing of a New Drug Application (NDA) with the FDA, seeking approval to market ddC (also called zalcitabine, trade name HIVID). The application consists of 550 volumes of data and reports, a total of 165,000 pages. The NDA is seeking approval (1) for ddC alone as treatment for persons who have failed AZT, or developed an intolerance, and (2) for ddC and AZT in combination as a first-line therapy. According to Hoffmann-La Roche, there are 23 completed or ongoing clinical studies of ddC. Over 8,000 people are currently receiving this drug in the clinical trials and expanded-access program. ***** Therapeutic Marijuana Initiative Approved by San Francisco Voters by Denny Smith San Francisco has become the first city in the U. S. to publicly support the medical use of marijuana. On November 6, San Franciscans voted almost four to one to approve a city proposition urging the state of California to add marijuana to its list of available medications. Marijuana is useful for countering glaucoma, as well as the nausea and loss of appetite experienced by people with AIDS or cancer (see AIDS TREATMENT NEWS #131, July 27, 1991). For about thirteen years, the Food and Drug Administration (FDA) has reluctantly made marijuana available on a compassionate-use basis, although the Drug Enforcement Administration (DEA) continues to classify the plant as a narcotic with no therapeutic value. Technically the San Francisco vote cannot overrule the DEA classification; but the measure of public sentiment may discourage successful prosecution of people who make medical use of marijuana. On a cautionary note, several published articles have alerted physicians to the risk of acquiring the fungal infection aspergillosis by ingesting marijuana. One recent letter appeared in the October 1 issue of the Annals of Internal Medicine (volume 115, number 7, pages 578-579). The authors of the letter said that "most illegally obtained" marijuana plants harbor two different species of Aspergillus, the spores of which can travel on marijuana smoke into the lungs. In people with compromised immunity, this exposure may lead to pulmonary aspergillosis. A possible solution was offered. The authors described an experiment in which parsley, oregano and tea were inoculated with three species of Aspergillus, and then baked at varying times and temperatures. Cultures for survivors indicated that the fungi were consistently killed after five minutes of dry heat at 275 degrees Fahrenheit/135 Centigrade. To compensate for variations in non-laboratory situations, marijuana users could bolster the conditions to 300 degrees Fahrenheit/150 Centigrade for 15 minutes, without degrading THC, the active ingredient in marijuana. The letter cautions that even after this sterilization, Aspergillus antigens could provoke bronchospasms in sensitized individuals. In other respects, the proposed solution may greatly reduce the hazards of using marijuana therapeutically. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display