&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1986 by John S. James; permission granted for non-commercial use. AL 721: Experimental AIDS Treatment by John S. James Published in AIDS Treatment News, April 11, 1986 Update January 1987 [The following article was published nine months ago in DAIR Update, the newsletter of the Documentation of AIDS Issues and Research Foundation, San Francisco. Since then, new information has become available.] A pharmaceutical industry newsletter (F-D-C Reports, November 17, 1986) published some results released by Praxis Pharmaceuticals from a trial of AL 721 on eight ARC patients at St. Luke's-Roosevelt Hospital Center in New York. Six of the seven patients tested showed a reduction in reverse transcriptase levels; reductions averaged over 80 percent. No signs of toxicity were found in any patient. New trials with 50 to 80 patients will study AL 721 for later stages of AIDS. Also see AIDS Treatment News #21, January 2, 1987, for the description of a case of a person who was near death from AIDS in early 1986, but is now healthy after AL 721 treatment in Israel. AL 721 is recommended for patients with opportunistic infections, including pneumocystis, but probably not for those with KS or other cancers. Several issues of AIDS Treatment News have expressed concern about how AL 721 is being handled. In November 1985, a letter by Sarin, Gallo and others in the New England Journal of Medicine published laboratory results which suggested its possible use for AIDS. The substance was known at that time to be safe, easy to make and use, and not expensive; there is no rational reason for its unavailability. Yet fourteen monthslater, only a handful of patients have been able to obtain AL 721, through clinical trials or otherwise; and according to F-T-C Reports, cited above, the new trial with 50-80 patients may take up to a year. These delays illustrate a major failure of public policy in the AIDS epidemic -- lack of commitment to modify business as usual when necessary to save lives. What is needed is either government distribution, or emergency licensing to allow any competent company to make and sell AL 721 without medical claims. Then those who want to use it could do so. There are no significant risks, and if benefits are even nearly as dramatic as all available evidence suggests, that fact would quickly become known. Meanwhile it might be possible to obtain AL 721 treatment in Israel. For information about doing so, call Michael at(201) 887-5060. My article below, on the scientific background of AL 721, first appeared in April 1986, but is still relevant and is reproduced here essentially unchanged. ***** AL 721 is an unusual lipid mixture which acts differently from other drugs being tested against AIDS. It removes cholesterol from the outer membranes of cells and perhaps of viruses, increasing the fluidity of the membranes and apparently making it harder for viruses to attach to receptor sites, part of the process by which they infect the cell. Unlike most of the other drugs being tested, AL 721 appears to be entirely safe. In human trials on elderly subjects, AL 721 restored immune functioning (lymphocyte proliferative capacity) which had been lost due to the normal aging process (Shinitzky and colleagues, cited by Sarin and colleagues, 1985). In recent laboratory tests at the U. S. National Cancer Institute and elsewhere, AL 721 greatly reduced infection of human cells by the AIDS virus (Sarin and colleagues, 1985). Apparently it can cross the blood-brain barrier: "Mixture 721 ('active lipid') was previously shown to be of practical use for membrane fluidization of brain tissue both in vitro and in vivo (Lyte and Shinitzky, 1985). However, AL 721 has not yet been given to persons with AIDS or any related condition, to our knowledge. Due to the history of disappointing drugs which looked good in the laboratory, we should avoid raising hopes prematurely, before a treatment has passed the key test of improving the condition of patients. Background AL 721 was developed several years ago at the Weizmann Institute of Science in Rehovot, Israel, by Meir Shinitzky and others. It is composed of three lipids, mixed in a ratio which has much more effect on cell membranes than other ratios tested. "AL" stands for "active lipid"; "721" is the ratio, 7: 2: 1, of the ingredients. Lyte and Shinitzky, 1985, tested the effects of different ratios on human lymphocyte and erythrocyte cells in the laboratory. The three lipids are (1) various neutral lipids, prepared by a published procedure 70%; (2) phosphatidylcholine (purified lecithin), 20%; and (3) phosphatidylethanolamine, 10%. All three components were extracted from egg yolks. They were thoroughly mixed, using ultrasound. The procedure for making AL 721 has been published (Lyte and Shinitzky, 1985). AL 721 can be given either orally or by injection; in at least one animal study, injection was difficult but more effective (Heron and colleagues, 1982). Researchers suspect that the "aqueous dispersion of this mixture consists of chylomicron-like assemblies where the neutral lipids provide the hydrophobic core on the surface of which phospholipids are spread as a monolayer" (Lyte and Shinitzky, 1985). Lecithin is the active ingredient, and the other components cause it to be applied effectively. Clinical studies in France are testing AL 721 against cystic fibrosis in children (Research newsletter of the Weizmann Institute of Science, Rehovot, Israel, cited in UPI news story September 2, 1985). Laboratory and animal studies have suggested that AL 721 might also be useful against certain other viruses such as herpes (see AP News stories November 13 and 14, 1985), and other conditions including opiate and alcohol addiction (Heron and colleagues, 1982), and faulty neurotransmitter activity in the aging brain (Research newsletter). These different possibilities rest on the same mechanism: removing cholesterol, which normally increases with age, to restore fluidity (mobility of proteins) to the membranes. Researchers hope that this "membrane engineering" could eventually provide a whole new method of treatment for many conditions. Safety AL 721 appears to be safe. All three ingredients are contained in food. AL 721 has even been proposed as a dietary supplement for the elderly (Research newsletter). In the trials on normal elderly patients mentioned above, each person took 10-15 grams of AL 721 orally per day for six weeks, with no adverse effects (Shinitzky, references above). One possible concern for some patients is the hypothesis that decreasing, not increasing, membrane fluidity may be useful in treating some cancers. "Rigidification of membrane lipids may be of great potential for exposure of tumor-associated antigens, which may render tumor cells with specific immunogenicity. This approach can elicit antitumor immune reactivity both in vivo and in vitro." (Shinitzky, 1984, vol. 1 page 38). Could Diet Help? Could special diets provide some of the effect of AL 721? Shinitzky discusses treatment possibilities in the "Towards Membrane Engineering" section of Physiology of Membrane Fluidity, Volume 1. "The obvious candidate for membrane fluidization both in vitro and in vivo is lecithin from natural sources (e.g. egg yolk)." But the efficacy depends on how the lecithin is presented to the membranes. The AL 721 mixture forms physical structures which transport the lecithin to the membranes effectively. Heron and colleagues (1982) found that lecithin alone had some effect in increasing fluidity in mouse brain membranes, though much less than AL 721. Crude egg lecithin had a slightly greater effect than pure egg lecithin -- possibly because the impurities included the other ingredients -- although this difference was not statistically significant. (All three ingredients of AL 721 are contained in egg yolk.) The same paper also mentioned a report published over fifty years ago that lecithin relieved morphine withdrawal symptoms in mice (Wen-Chao Ma, 1931) -- an effect which would be expected from increased membrane fluidity. Discussion in the same paper also suggests the possibility that AL 721 may do much better what lecithin has done all along. "Diets with a high lecithin content have been frequently recommended for a variety of disorders on the basis that they replen ish choline (Zeisel et al., 1980). However (data presented in the article) indicate that the previously proposed rationale for lecithin treatment covers only a minor aspect of this approach, and that treatment of deteriorated functions with AL could be much more effective in alleviating symptoms associated with lipid imbalances and in restoring the normal membrane lipid fluidity." Other mysteries remain. In all the membrane fluidity work we have seen, the lecithin used was extracted from eggs; how would lecithin from other sources compare? We have not seen any study on whether egg yolk in diet could affect membrane fluidity. Also, we don't know of any work on how AL 721 passes through the digestive system; it would probably be digested into its components, suggesting that the special mixing of the ingredients might not be necessary. In short, it might or might not be possible to produce some of the effect of AL 721 by diet, if AL 721 itself is not available. No one knows at this time. Clinical Testing and Availability As of mid January 1986, clinical tests of AL 721 against AIDS are being planned, but have not received final approvals. The first human trials will use only a handful of patients. We have heard that the earliest possible date that results of very limited clinical tests could be available is late spring. Clinical trials are also being planned or carried out in Europe. We don't know if these are against AIDS. AL 721 is licensed to Praxis Pharmaceuticals in Beverly Hills, CA, and is manufactured by its subsidiary, Matrix Research Laboratories in New York. According to a report in a business publication dated September, 1985, Praxis believed that it would be at least four years before the FDA allows any commercial sale (Scrip, 1985). Naturally we expect that it would not take so long if AL 721 does show usefulness against AIDS. We should continue to watch AL 721, along with the other proposed new treatments for AIDS. It is important that testing and availability not be blocked by bureaucratic inertia and red tape, especially when, as in this case, safety concerns are minimal. Drugs must be proven effective as well as safe before being released for general use; but here it seems that no one outside of a single company is in a position to take initiative to bring about formal testing, or even to find out whether timely and adequate studies are planned. Research and treatment for life-threatening illnesses must not be held up to suit the schedule of a handful of researchers or companies. Physicians must be able to participate in studies which place the welfare of their patients first. For More Information Shinitzky's 2-volume Physiology of Membrane Fluidity (reference below) gives extensive background information on the science behind AL 721. However, neither volume mentions AIDS. The only published information we could find concerning AL 721 and AIDS is the letter to the New England Journal of Medicine by Sarin, Gallo and others (see below); wire-service reports which interviewed some of its authors (AP and UPI, November 13 and 14); a UPI report September 2 on the Weizmann Institute's newsletter Research; and a business report on Praxis Pharmaceuticals (Scrip, reference below). The most recent scientific background on AL 721 is the article by Lyte and Shinitzky, 1985. Acknowledgements The author wishes to thank Dennis McShane, M. D., for reading and commenting on a draft of this article. All statements are of course the author's responsibility. References Associated Press. AIDS. Boston, November 13 and 14, 1985. Heron D, Shinitzky M, Samuel D. Alleviation of drug withdrawal symptoms by treatment with a potent mixture of natural lipids. European Journal of Pharmacology 1982; 83: 253-61. Lyte M, Shinitzky M. A special lipid mixture for membrane fluidization. Biochimica et Biophysica Acta 1985; 812: 133-8. Ma, Wen-Chao. A Cytopathological Study of Acute and Chronic Morphinism in the Albino Rat. Chinese Journal of Physiology 1931; 5: 251-274. Sarin PS, Gallo RC, Scheer DI, Crews F, Lippa AS. Effects of a novel compound (AL 721) on HTLV-III infectivity in vitro. New England Journal of Medicine 1985; 313: 1289-90 (November 14). Scrip (ISSN 0143-7690). Praxis' Offering Yields $3.7 M. Scrip Issue 1032 (paragraph) 9/9/85, page 8. Shinitzky M. (ed) Physiology of Membrane Fluidity, Vols. 1 and 2, CRC Press, Boca Raton, FL 184. Shinitzky M, Samuel D, Antonian L, Lippa AS. AL 721, a novel membrane fluidizer. Drug Development Research (in press). United Press International. Aids drug. Boston, November 14, 1985. United Press International. Eggs. London, September 2, 1985. ***** [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display - - - - - - - - - - - - AIDS Info BBS, 415-626-1246 (free) 8-N-1 From: Ben Gardiner Return address: ben@maggadu.Queernet.ORG