Subject: AIDS Treatment News #146 Date: Mar 06 1992 (602 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Copyright 1992 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue #146, March 6, 1992 CONTENTS: [items are separated by "*****" for this display] Hypericin, February 1992 AIDS Research Budget Threatened Announcements: Herpes Zoster (Shingles) Trial in Cities Across U. S. IGF-1: Stanford University Weight-Loss Treatment Study New York: Managing HIV Disease Seminar, March 18 Canada: Phone Number for Clinical Trials Information ACT UP Presidential Project ***** Hypericin, February 1992 by John S. James Hypericin is an antiviral found in small amounts in a plant (St. John's wort, a medicinal herb) and also synthesized chemically. It has shown activity against HIV in laboratory tests, and against other retroviruses in animal tests; in addition, laboratory tests and some human anecdotal reports have suggested broad-spectrum activity against a number of other disease-causing viruses. But hypericin also has an important side effect -- large doses cause phototoxicity, or abnormal sensitivity to sunlight and other strong light, especially in people with light skin. The key medical question at this time is whether it will be possible to administer large enough doses of hypericin to be useful for treating HIV and/or other viruses. There are also concerns about whether enough resources are available to quickly determine the best uses and ultimate value of this potentially important treatment. AIDS TREATMENT NEWS has covered hypericin for over three years, starting with issue #63, August 26, 1988; for technical background and references, see AIDS TREATMENT NEWS #125, April 19, 1991. Last November we reported the beginning of the first clinical trial of pure hypericin, in three cities (issue #138, November 1, 1991). The Current Clinical Trial This trial, at New York University in New York City, Beth Israel Hospital in Boston, and the University of Minnesota in Minneapolis, has been stopped temporarily after significant phototoxicity developed at the second dose being tested. This study had set out to enter eight patients at each of four different doses, adjusted by body weight; the doses were 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg, taken twice per week. (Even the lowest dose is much higher than that from the St. John's wort extracts which have previously been available in buyers' clubs and health-food stores, which have contained little hypericin, usually providing a fraction of a milligram per dose.) And the hypericin in the trial was given intravenously, even though the drug is expected to be used orally in practice; intravenous administration is preferred in early trials in order to obtain better scientific data. At the 0.5 mg dose, most if not all of the study volunteers with white skin had phototoxicity which was severe enough that they had to drop out of the trial. They had skin rashes and irritation, and some were unable to go outdoors. But according to Fred Valentine, M. D., principal investigator of the study at New York University, there was no sign of any systemic toxicity -- and all the problems which did occur were temporary, going away after the drug was stopped. And one volunteer, who is Black, had less severe problems; apparently the pigment in his skin protected him against some of the phototoxicity by preventing light from reaching deeper layers of the skin. No information is yet available about whether the lowest dose tested, which could be tolerated by most patients, showed any signs of efficacy. This early trial also collected information about hypericin's pharmacokinetics (how long the drug lasted in the body). The half- life of hypericin in the blood was found to be about 25 hours, which was less than had been expected from studies in monkeys. Therefore it may be necessary to give the drug more often than twice a week to maintain blood levels. Also, more frequent but lower doses may reduce toxicity by reducing peak blood levels. At this time, the researchers have applied to the U. S. Food and Drug Administration for permission to change the dosing of the drug, to give lower amounts three times per week; they also want to recruit volunteers with very dark skin, since they may be much less affected by the phototoxicity. Also, the National Institute of Allergy and Infectious Diseases (NIAID), which is supporting the current trial, has contracted with the University of Iowa to produce an oral formulation of the drug, perhaps a time-release version to avoid peak concentrations and reduce possible toxicity. The current status of hypericin, then, is that the drug could be successful if any one or more of the following are true: (1) The drug might be useful even in the 0.25 mg/kg dose (which can usually be tolerated) -- either alone or in combination; (2) If not, then it may be possible to administer higher doses by reformulating the drug, changing the schedule of administration, or providing better protection against sunlight; (3) Even if hypericin turns out not to be useful for everybody, it might still be effective for persons with dark skin; and (4) In addition, hypericin may be effective against other viruses, possibly in lower doses than would be required for treatment of HIV. Other Viruses At this time there is scientific and community interest in the possible usefulness of hypericin for treating at least four other viruses, listed below. But little information is available at this time, so these possible applications of the drug must be considered speculative. (1) Hepatitis B. This possible use was noticed by accident during an earlier hypericin trial, by the Community Research Initiative in New York using low doses of the drug from a widely-available St. John's wort plant extract. Because of an earlier report that hypericin might have liver toxicity -- now believed to have been a false alarm -- liver function tests were being watched very carefully. When apparent improvements were seen in persons who had hepatitis, others who heard about the result tried treating themselves for that condition. At this time there seem to be about ten reports of apparent improvement. We are checking further into this possibility. (2) Cytomegalovirus (CMV). Laboratory tests have found antiviral activity against murine CMV, which is related to but not identical to human CMV. Now that hypericin is becoming available in larger doses than before, it should be tested as a CMV treatment. (3) Influenza. Both laboratory and anecdotal reports suggest the possibility that hypericin might be useful in treating this infection. (4) Human papillomavirus. One person in the current hypericin trial had an unexpected improvement in warts caused by this virus. We want to emphasize that these possibilities are leads for future research, and based on very little information at this time. On the other hand, this list is not complete; over the years laboratory tests have shown activity of hypericin against a number of viruses. The chemical may have other uses which have not yet been considered or tested. Future Development There is widespread concern that the development of hypericin, which has been seriously delayed in the past, may wait again -- this time until the chemically synthesized drug is reformulated and tested for oral use. The developer, VIMRx Pharmaceuticals Inc. of Stamford, Connecticut, is a small company with limited resources; fortunately the AIDS Clinical Trials Group (ACTG) of the U. S. National Institute of Allergy and Infectious Diseases has been willing to help, but this agency has little experience in most aspects of drug development, which has usually been left to private corporations. Meanwhile, more concentrated hypericin extracts from the St. John's wort plant are becoming available. The plant extracts are not pure hypericin, however; they also contain other chemicals from St. John's wort, which might cause allergic reactions or other adverse effects. Therefore, large doses should be approached cautiously. An oral dose of 10 mg of hypericin, taken three times a week, would approximate the total amount at which phototoxicity began to be seen in the recent clinical trial with synthetic hypericin. But a number of people (probably several dozen) have been using 10 mg per day or more of hypericins extracted from the St. John's wort plant -- taken orally -- with very few adverse reports. According to Pacific BioLogic in Oakland, California, which produces the concentrated extract, there has been one case of severe sunburn, after half an hour exposure to the sun without protection, and a few cases of diarrhea. It is possible that these larger oral doses were tolerated because the hypericin is only partly absorbed from the digestive system; in the clinical trial, by contrast, the hypericin was given intravenously, so all of it reached the bloodstream immediately. Keep in mind that anyone using concentrated hypericin, no matter how it is taken, should avoid sunlight, by using good sunscreen and a hat and other protective clothing, or by staying indoors, until at least several days after the last dose is used. Comment Instead of just waiting indefinitely for results of future trials, the AIDS community is experimenting with more concentrated hypericin extracts, to see what can be learned from practical experience with the treatment. It is clear that scientific trials produce the most reliable information; but the modern approach of controlled trials is a recent innovation, which largely developed in the last three or four decades. Until then, all drugs throughout history were developed through clinical experience. When the mainstream drug-development system fails (for whatever reason) to meet the needs of the current emergency, we should not abandon clinical experience as a first step in drug development. Modern viral-burden tests, data collection and analysis techniques, and other scientific methods can work together with clinical experience to make possible smaller, cleaner, faster, and more focused treatment trials than we have usually seen in the past. Recent Technical References Our last major hypericin article, "Hypericin Update," in AIDS TREATMENT NEWS #125, April 19, 1991, listed 18 technical references for background on antiviral uses of hypericin. The following 1991 and 1992 references were not included in that list: Anderson DO, Weber ND, Wood SG, Hughes BG, Murray BK, and North JA. In vitro virucidal activity of selected anthraquinones and anthraquinone derivatives. ANTIVIRAL RESEARCH 1991: volume 16, number 2, pages 185-196. Barnard DL, Huffman JH, Morris JLB, Wood SG, Hughes BG, and Sidwell RW. Evaluation of the antiviral activity of anthraquinones, anthrones and anthraquinone derivatives against human cytomegalovirus. ANTIVIRAL RESEARCH 1992: volume 17, number 1, pages 63-77. Davis C. HIV-specific treatment. DERMATOL. CLIN. (USA) 1991: volume 9 number 3, pages 585-596. Dressler S. Alternative therapies in the treatment of HIV infections [translation of German title]. THERAPIEWOCHE 1992: volume 42, number 1-2, pages 34-37. Dresser S. Antiretroviral therapy for AIDS infection [translation of German title]. Zeitschrift fuer Klinische MEDIZINE 1991: volume 46, number 20, pages 1405-1415. Hudson JB, Lopez-Bazzocchi I, and Towers GHN. Antiviral activities of hypericin. ANTIVIRAL RESEARCH 1991: volume 15, number 2, pages 101-112. Liebes L, Mazur Y, Freeman D and others. A method for the quantitation of hypericin, an antiviral agent, in biological fluids by high-performance liquid chromatography. ANALYTICAL BIOCHEMISTRY 1991: volume 195, number 1, pages 77-85. Meier B. The extraction strength of ethanol/water mixtures commonly used for the processing of herbal drugs. PLANTA MEDICA 1991: volume 57, supplement 2, pages A26-A27. Mitsuya H, Yarchoan R, Kageyama S, and Broder S. Targeted therapy of human immunodeficiency virus-related disease. FASEB JOURNAL 1991: volume 5, number 10, pages 2369-2381. Stock S. and Holzl J. Pharmacokinetic test of (14C)-labelled hypericin and pseudohypericin from Hypericum perforatum and serum kinetics of hypericin in man. PLANTA MEDICA 1991: volume 57, supplement 2, pages A61-A62. Vlietinck AJ and Vanden Berghe DA. Can ethnopharmacology contribute to the development of antiviral drugs? JOURNAL OF ETHNOPHARMACOLOGY 1991: volume 32, number 1-3, pages 141- 153. Weiser D. Pharmacokinetics of hypericin after oral administration of St. John's extract. [English translation of German title.] NERVENHEILKUNDE 1991: volume 10, number 7, pages A17-18. ***** AIDS Research Budget Threatened By Laura Thomas Funds for AIDS research are in danger of being reduced to levels that would seriously impede progress towards effective treatments. President Bush recently released his proposed budget for 1993, including figures for AIDS research. The President requested $873 million dollars for AIDS Research Programs at the National Institutes of Health (NIH). This is a 3.5% increase over last year's $841 million dollars. However, the current rate of inflation for biomedical research is 5%, the cost of treating people with HIV is increasing by about 20% annually, and the number of people with HIV will go up by an estimated 30% in the next year. Given those figures, the President is grossly underfunding research on AIDS treatments. Prevention and care are also being threatened with cuts and underfunding. Funding for the NIH pays for all government funded clinical trials of HIV treatments, including both the AIDS Clinical Trials Group (ACTG) and the Community Programs for Clinical Research on AIDS (CPCRA) trial systems at the National Institute for Allergies and Infectious Disease (NIAID). It also funds basic laboratory research, some natural history and epidemiological studies, and grants to encourage researchers to work on HIV. The budget for the NIH, unlike the budget for other Federal agencies, is not earmarked for specific funding areas. Thus, advocates have difficulty knowing exactly how much the NIH is planning to spend on AIDS. It is particularly difficult to find out how much will go into specific areas, such as the ACTG system, natural history studies in women, or AIDS-related cancer research. We can look back at previous years' spending to have a rough idea of where the money will go if priorities stay the same, but there is little that advocates can do to know whether or not particular projects will be adequately funded. One solution to this problem, which has been raised by several people, is to create a Federal AIDS Institute, along the lines of the National Cancer Institute. This would centralize HIV-related research into one place, enabling advocates and people with HIV to push for adequate funding for it and to have more oversight on the priorities for those funds. It might also encourage researchers from different fields to collaborate. A weakness of this plan is that the institute would be vulnerable to politically-motivated cuts. Another problem is that since the manifestations of HIV disease are so complex it may make more sense to encourage each of the components of the NIH to do research in their HIV-related area of expertise, with the National Cancer Institute investigating HIV-related cancers, for example,and the National Eye Institute researching CMV retinitis and other eye infections. Money within the NIH is traditionally not earmarked, so that scientists rather than politicians can decide what the "scientifically justified" priorities are. However, the funds are still very vulnerable to political pressure. For example, last year funds were dramatically shifted away from adult clinical trials into pediatric trials, even in regions where there are very few pediatric cases. In New Orleans, the adult AIDS Clinical Trials Unit at Tulane was defunded under recompetition, and the funds were moved to Tulane's pediatric research branch. There is no question that, along with all other AIDS research, pediatric HIV research was desperately underfunded and that more money is needed. But however much "innocent" children with AIDS are a safer political choice than adults, it is robbing Peter to pay Paul to give money for research on children while taking it away from research that could help their mothers. Dr. Thomas Merigan from Stanford University's clinical trials unit testified to Congress last week that AIDS researchers are worried and frustrated by the cuts in their budgets for adult research to fund pediatric research. He said "The funding for pediatric AIDS...is nearly equivalent to that for the adult ACTGs. It is important to recognize...the needs in pediatrics are very important. However, there are 20 times more infected adults than children....the funding of adult units should be increased to at least two if not three times that of the pediatric units in order to allow an adequate effort to be made nationally." Congress is currently having preliminary discussions on the AIDS budget. Rep. Henry Waxman (Democrat, California) held hearings on the AIDS research budget before the House Health and the Environment Subcommittee on February 24, 1992 in Washington, DC. Speakers included Dr. Anthony Fauci, NIH Associate Director for AIDS Research, and Martin Delaney of Project Inform, as well as Dr. Merigan. Fauci estimated that his agency would need an additional $100-200 million more to fund all the scientifically justified basic and clinical research. He said projects that would have to be cut under the proposed budget include vaccine research, clinical trials networks, natural history studies and training new researchers. Martin Delaney testified that according to figures from the NIAID budget office "the actual amount spent on clinical AIDS research through NIAID is less than $130 million annually." This includes funds spent on the ACTG and CPCRA systems, NIAID's intramural research, and pediatric AIDS research, and is a far cry from the $4 billion that President Bush has claimed is being spent on HIV-related research. Delaney listed several areas of HIV research that have been particularly neglected, including immune-based therapies, surrogate markers of disease progression, combined treatments for opportunistic infections, and studies in special population groups. What You Can Do Congress needs to continue to hear from people who are concerned about the US AIDS research budget. Other sections of the AIDS budget, including prevention and education programs and the Ryan White/CARE bill, which provides emergency assistance to the states and to the cities hardest hit by AIDS, are also in danger of being cut or underfunded. All of these services are essential to winning the fight against AIDS, and we cannot afford to let Congress fund any of them at the expense of another. The AIDS budget must be increased across the board if there is going to be any substantial progress towards ending the epidemic. Readers who are concerned about the amount of money being allocated to AIDS can write or call their Representative and their Senators. Some of the most influential people to reach are those serving on the Sub-committee on Labor, Health and Human Services, Education and Related Agencies of the Appropriations Committees in both houses, listed below. Individuals who do not live in their districts are also encouraged to write these committee members concerning the NIH budget, as well as their own Representative and Senators. Letters to House members should be addressed: The Honorable...., House of Representatives, Washington, DC, 20515. Letters to Senators should be addressed: The Honorable..., US Senate, Washington, DC, 20510. The House will be deciding on the budget in March or early April, and the Senate in April or early May. For more information on lobbying, readers may want to contact the Human Rights Campaign Fund, 1012 14th Street, NW, Suite 607, Washington, D. C., 20005, phone 202/628-4160. They are in the process of putting together an information packet on the NIH 1993 AIDS budget -- including a list of other important members of Congress not included below. House of Representatives, Committee on Appropriations, Subcommittee on Labor, Health and Human Services, Education and Related Agencies: Joseph D. Early, D., Worcester, MA Steny H. Hoyer, D., Prince George's Co., MD Robert Mrazek, D., Huntington, NY William H. Natcher, D., Bowling Green, KY David Obey, D., Wausau, WI John Edward Porter, R., Deerfield, IL Carl Pursell, R., Ann Arbor, MI Edward Roybal (D., Los Angeles, CA Neal Smith, D., Des Moines, IA Louis Stokes, D., Cleveland, OH Vin Weber, R., Willmar, MN C. W. Bill Young, R., St. Petersburg, FL Senate, Committee on Appropriations, Subcommittee on Labor, Health and Human Services, Education and Related Agencies: Brock Adams, D., Washington Dale Bumpers, D., Arkansas Quentin Burdick, D., North Dakota Robert C. Byrd, D., West Virginia Thad Cochran, R., Mississippi Slade Gorton, R., Washington Phil Gramm, R., Texas Tom Harkin, D., Iowa Mark Hatfield, R., Oregon Ernest Hollings, D., South Carolina Daniel Inouye, D., Hawaii Harry Reid, D., Nevada Warren Rudman, R., New Hampshire Arlen Specter, R., Pennsylvania Ted Stevens, R., Alaska ***** Announcements ** Herpes Zoster (Shingles) Treatment Trial in Cities Across U. S. A multicenter trial will test the Bristol-Myers drug BV- ara-U (other names: Brovavir; SQ 32,756) as a treatment for herpes zoster. In laboratory tests, this drug is effective against zoster in concentrations up to one thousand times less than the concentrations of acyclovir (Zovirax) required. The drug has already been in several human trials; doses greater than or equal to those used in this study have been given to several hundred people. Volunteers will be randomized to receive either 40 mg of BV-ara-U once per day, or 800 mg of acyclovir five times per day. The treatment lasts for 10 days. All volunteers will be seen daily for the first ten days, then once per week for three weeks. Later, there will be monthly telephone interviews for 11 months to check for development of any zoster complications or recurrences. Volunteers must be entered in this study within 72 hours of development of their lesions. Also, the zoster must be localized, and not involve the trigeminal nerve. Exclusion criteria include: any systemic anti-herpes therapy within two weeks before study entry; concomitant use of cimetidine, heparin, interferon, probenecid, or high-dose corticosteroids; and certain abnormal blood counts or blood-chemistry values. The trial is now recruiting or expected to begin soon in the following cities (note -- this list could change): Albuquerque, Augusta, Baltimore, Bethesda, Birmingham, Boston (4 sites), Charlotte, Charlottesville, Chicago, Columbus, Dallas, Dayton, Denver, Galveston (2 sites), Honolulu, Houston, Los Angeles, Martinez, New York (4 sites), Oakland, Portland, Rochester, Salem (VA), San Diego, San Francisco, Seattle (2 sites), St. Louis, Stony Brook, Syracuse, Toledo, Washington (2 sites), Wauwatosa, and Worcester. For more information, or to locate the site nearest you, call the AIDS Clinical Trials Information Service, 800/TRIALS-A. [San Francisco note: To enroll in San Francisco, call Jay Lalezari, M. D., 476-6356. Dr. Lalezari will also answer questions about this study from people elsewhere.] ** IGF-1: Stanford University Weight-Loss Treatment Study A study of IGF-I (Insulin-like growth factor-I), a naturally-occurring hormone, is now enrolling volunteers with AIDS at the Palo Alto Veterans Administration Hospital. According to the researchers, animal studies have suggested that IGF-I may prevent or reverse protein and muscle loss in severe illness, and may improve the functioning of the immune system. This study requires six visits, including a two-week stay in the Study Unit at the Palo Alto VA Hospital, and use of a special diet, which will be provided. The study will pay $500 to those who complete it. To be eligible, volunteers must have AIDS, have lost 5 percent to 30 percent of their normal body weight, be using AZT, ddI, or ddC, have no untreated infections, and not have any type of cancer. For more information, call Steven Lieberman, M. D., 415/493-5000 ext. 4148. ** New York: Managing HIV Disease Seminar, March 18 A one-evening seminar, "Managing HIV Disease: Clinical Observations and Research Protocols" will take place March 18, 6:00 p.m. to 10:00 p.m. at the New York University Medical Center auditorium. Attendance is limited to 250, and advance registration by March 16 is required. The registration fee is $25. Topics include vaccines; combination antiviral therapy; hypericin; 566C80; nursing in HIV care and in clinical research; clinical study protocols; gynecological manifestations in women; and people of color and HIV disease. The event is sponsored by The National League for Nursing, The AIDS Treatment and Data Network, Burroughs- Wellcome Company, and American Preferred Prescription. Continuing education credit is available. For more information, or to register by phone or fax, contact either: Marck Fedor, The National League for Nursing, 800/669-1656, ext. 123; or Kenneth Fornataro, The AIDS Treatment and Data Network, 212/268-4196, or 212/643-0870 (Spanish), or 212/268-4199 (fax). ** Canada: Phone Number for Clinical Trials Information The Canadian HIV Trials Network, a service of the Canadian government, maintains a computerized registry of AIDS/HIV clinical trials in Canada. Canadians can call 604/631-5327, collect if necessary, or fax requests to 604/631-5210. Information can be given over the phone, or mailed if requested, in French or English. This registry includes a brief description of each trial, centers running the trial, brief inclusion/exclusion criteria, and where to phone (locally) for more information. The office is open weekdays between 8:00 a.m. and 4:00 p.m. Pacific time. ** ACT UP Presidential Project The ACT UP Presidential Project is following the Presidential campaign trail, raising AIDS issues (and gay/lesbian/bisexual issues) along the way. Their goal is to make all the major candidates address these issues, and so far all of the main Democratic candidates have issued position papers on AIDS. The Presidential Project recently helped to form ACT UP/South Dakota and confronted Presidential candidates there, while raising AIDS awareness at the same time with a condom distribution. The Presidential Project is working on a very low budget and would appreciate support. According to their press release, "Your money will go directly toward getting our issues off the lips of the candidates, into the news and onto the minds of Americans everywhere." They need volunteers, donations, frequent flier miles, in kind help, or housing, and can be reached at: ACT UP Presidential Project, P. O. Box 34673, Martin Luther King Station, Washington, DC, 20043-4673. Phone: 202/328-AIDS. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display