Date: Sun, 18 Sep 1994 14:01:37 -0700 From: "John S. James" Subject: AIDS TREATMENT NEWS #202 /* Written 2:41 PM Jul 10, 1994 by aidsnews in igc:aidstreatment */ /* ---------- "AIDS TREATMENT NEWS #202" ---------- */ AIDS TREATMENT NEWS Issue #202, July 8, 1994 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: Thymomodulin Thymomodulin Bibliography Zerit (d4T) Approved Thymopentin (TP-5) Trial Starting, 24 U.S. Cities ***** Thymomodulin by John S. James and Jeff Getty Thymomodulin, a preparation made from the thymus glands of calves, is an approved drug in Italy, and is used in Europe as an immune treatment. Human trials have shown good results with a number of conditions involving immune deficiency or dysfunction -- for example, in treating hepatitis B,(1) in reducing recurrent respiratory infections in children,(2,3) and in reducing fever and sepsis after surgery in patients who were immune deficient (as shown by lack of response to skin tests of delayed-type hypersensitivity); thymomodulin also helped to restore skin-test responsiveness.(4) Other studies have shown that the drug reduced certain immune deficiencies of aging,(5) helped cancer patients tolerate chemotherapy,(6) and was useful in treating certain allergic conditions, including food allergies in children.(7,8) Many laboratory and animal studies have demonstrated various mechanisms by which thymomodulin might improve certain immune responses (see bibliography sections, below). A small, observational study in persons with HIV, conducted in Europe several years ago, reported striking improvement in clinical condition, as well as improvement in blood work.(9) But this early result was not followed up. The entire area of thymus treatments for HIV has been seriously neglected -- and all but completely neglected in the United States. AIDS TREATMENT NEWS recently reported on another thymus preparation, thymosin a1 (thymosin alpha 1), which recently showed good results in a small trial in Italy (see "Thymosin Alpha 1: Sustained T-helper Count Rise in Three-Drug Combination," AIDS TREATMENT NEWS # 194, March 4, 1994). Thymosin a1 is now tied up in a business dispute, and is unavailable anywhere in the world, except to a few patients in clinical trials. But while researching thymosin a1, we learned that three people we know personally have been using thymomodulin for over two years. All have been able to reverse declining blood counts, especially total lymphocyte and CD8 counts, bringing them from dangerous levels to normal or near normal, where they have remained for the last two years. The one person of the three who has advanced AIDS continued to have a decline in his CD4 (T-helper) count, but had a dramatic improvement in his CD8 count. These people referred us to others, who have used thymomodulin for a shorter time, but have also had good results. Since thymomodulin is the only scientifically studied thymus product which does not need to be injected but can be taken orally -- and one of the few which is available to patients today -- we focused this article on it. Thymomodulin is not approved in the United States, but patients can obtain a personal supply. We are fortunate to have the anecdotal reports, summarized later in this article, because, when combined with the medical literature on thymomodulin, they provide enough rationale to bring this treatment to the attention of the AIDS community. The scientific studies of thymomodulin and HIV infection are small, uncontrolled, and usually several years old; they may not provide a strong enough rationale to get new studies going. But several cases of sustained improvement in blood counts, on top of the scientific work, makes this potential treatment hard to ignore. And since we personally know three people who have used thymomodulin for over two years, we can be confident that they are credible. Human Studies of Thymomodulin to Treat HIV Thymomodulin is one of at least six substances produced by the thymus gland which have been scientifically examined as a possible HIV/AIDS treatment: the others are thymosin a1, THF (thymic humoral factor), TP-5 (thymopentin), thym-uvocal, and thymostimulin. Of the six, thymomodulin, thym-uvocal, and thymostimulin are crude, or "natural," thymic extracts, containing a number of chemically distinct substances; the other three are made synthetically, each consisting of a single molecule. * The largest published study of thymomodulin and HIV was conducted in Italy, and published in 1987. It reported on 15 patients with HIV who were treated with the drug (60 mg per day orally, as a syrup) for more than 50 days. Two of the patients with late-stage AIDS had no change in their condition, and died shortly after the end of the study. The only one with Kaposi's sarcoma who entered the study was reported to have had "an evident clinical and laboratory improvement with remission of the neoplasia."(9) All of the other 12 showed resolution of fever. All of them started the study with chronic lymphadenopathy, which disappeared in six of them. Six started with thrush, which disappeared in all but one case. The CD4/CD8 ratio (a measure no longer considered useful) increased; and the average CD8 count decreased. (This CD8 result is opposite from all of the anecdotal reports we have heard, a discrepancy which is unexplained.) There was also a statistically significant increase in T-helper cells. No side effects of thymomodulin were seen. And there was no increase in neopterin, an indicator of T-cell activation. * A later study, conducted in Argentina and reported at the International Conference on AIDS in Amsterdam, in July 1992, treated 11 patients with HIV -- ten of whom had AIDS -- with a combination of thymomodulin, AZT, and lithium carbonate "which stimulates granulocytic colony forming units." Two of the patients had died by the time the results were reported; the other nine were still on the treatment. "All have a better life-style, weight gaining, less opportunistic infection episodes, and half of them returned to work... Overall, they all improved their CD4 count."(10) Unfortunately this study was only accepted for publication of the abstract; it was not even among the thousands of submissions given space for a poster presentation, and therefore it received little attention at the conference or afterwards. * A paper from Germany, published in 1990, may have reported on an additional study.(11) We could not obtain a copy or abstract by press time, however, so we have only the title -- Immunoprophylaxis and/or Immunotherapy with Thymic Hormones in HIV-Seropositive Asymptomatic Subjects and in AIDS Patients -- and the fact that it was indexed under thymomodulin. Aside from clinical trials, a number of laboratory and animal studies have described effects of thymomodulin on immunological measurements, outlining potential mechanisms of action.(12-18) Anecdotal Reports We have received four anecdotal reports, three from persons well known to us, who have used thymomodulin for about two and a half years. All four are still using the treatment. The three we know (patient #1, patient #2, and patient #3 below) have tried both the oral and the injectable forms of the drug, and find about the same effects with each. Usually they use the injectable, but only because it costs less. Patient #1 believes he is the first person to try thymomodulin as an HIV treatment in the U.S. He has kept careful records of his blood work, and has T-cell subsets measured 28 times since November 1987. His T-helper count started at 630 and then declined, going as low as 380, 344, and 340 (three successive measurements, the last in November, 1990). Then he began high-dose compound Q in November or December 1990, and began thymomodulin in the fall of 1991. In December 1990 his T-helper count rose to about 500 and stabilized there. His CD8 count showed a similar pattern, reaching a low of about 700 to 800, then rising and stabilizing at about 1000 in December 1990 (although there is considerable variation in the numbers). Total lymphocyte count was similar, starting at about 2000, declining to 1400 to 1500, and currently at about 1600. His blood work also includes the percentage of activated T- cells. An abnormally high value is a bad sign, because HIV can reproduce in activated cells, but not in resting cells. Activation increased to about 40 percent in 1990 (on six separate measurements). But then it fell to 8 percent (within the normal range) in February 1991 -- shortly after he began high-dose compound Q -- and remained under 10 percent for at least a year, through February 1992. By July 1992 it was 26 percent, however, a rise he suspects may have been due to starting thymomodulin. Then the activation fell back gradually, to 9 percent in March 1994. Patient #1 is very concerned that people not use thymomodulin or other thymus extract without an antiviral. He strongly believes that compound Q has been helpful for him. (That particular antiviral is not feasible for most people, however, since there few physicians with the training and experience to use it safely.) Patient #2 has also used thymomodulin for two and a half years, mainly to increase his total lymphocyte count. Before starting thymomodulin, his lymphocyte count had declined fairly consistently, from a high of 1900 in August 1988 to 951 in September 1991. After several months of using the thymosin, his total lymphocyte count went up to the 1200 range. His last three counts were 1789, 1248, and 1264. T- helper and CD8 cells have shown similar reversals of decline. Patient #2 is also using compound Q, which he started taking about two years ago. Patient #3 has also used thymomodulin for two and a half years. His T-helper count has continued to decline; it was 150 before he began thymomodulin, and is 35 now. But his CD8 count went up greatly, from about 400 (a seriously low level) to about 1200 after ten months. Now he maintains a level of around 900 -- unusually high for a person with advanced HIV disease. While using thymomodulin he has also used d4T, and other treatments. Patient #4 has used thymomodulin for one year -- one 80 mg capsule every other day. He also takes low-dose aspirin on the alternate days, because of research suggesting that low- dose aspirin can increase production of IL-2 and gamma interferon, and lower the level of prostaglandin E2 -- effects which might be beneficial in HIV disease. His last counts before starting the treatment, in March 1993, were CD4 330, CD8 572, and total lymphocytes 1786. Shortly after starting, in August, his CD4 was 351, CD8 715, and lymphocytes 2040. His last blood draw, in February 1994, was CD4 624, CD8 1508, and lymphocytes 3089. On the negative side, patient #4 has also had signs of possible viral activation -- despite continuing use of ddI (which he had been using for 66 weeks). His beta 2 microglobulin went up, from 2.1 to 3.6. He was able to get a Roche PCR test for HIV RNA, and the result was 186,000 copies per ml, which is high. He has no baseline RNA copies from before starting thymomodulin, however. Besides these four, we have also heard of several other U.S. patients who have used thymomodulin and had CD8 count increases, but we do not have details. The CD8 count may be at least as important as the CD4 (T- helper) count as an indicator of disease progression. It has been known for several years that some CD8 cells produce a substance (as yet unidentified) which inhibits HIV. The CD8 count has also been found to help predict (independently of the T-helper count) the risk of death or certain opportunistic infections in late-stage HIV disease.(19,20) These patients also used a number of other experimental and standard treatments while they were using thymomodulin; we do not have the full information. For this and other reasons, these anecdotal reports are only a guide to further research, not proof of benefit of the treatment. Side Effects and Risks Thymomodulin is widely considered to be nontoxic; we could not find any reference to toxicity in the literature. However, this safety information is from HIV-negative persons, and from animal studies. For persons with HIV, there is a concern that immune stimulation might stimulate growth of the virus. No one knows if this danger is real, because there is so little human experience with the drug in treating persons with HIV. Patient #1 above, who is probably as familiar with thymomodulin as anyone in the U.S., strongly believes that no one with HIV should use thymomodulin unless they are also using anti-HIV treatment. Anecdotal reports have said that the drug often causes an aggravated, unpleasantly stimulated feeling, and that there can also be redness of the skin, and sometimes headache. These effects may mean that one is using too high a dose. Incidentally, patients #1, #2, and #3 reported that thymomodulin causes them to feel warmth in the chest, where the thymus is located, shortly after it is taken. We have not heard from the others about this. How to Obtain Thymomodulin Thymomodulin is not approved in the United States. However, it is possible to obtain a supply for personal use. The Atlanta Buyers' Club (404/874-4845) carries thymomodulin capsules; a prescription is required. It does not carry the injectable form. It may also be possible to get the drug through pharmacies in Italy, England, Switzerland, or some other countries. Again, a prescription is required. The four patients whose use of the drug is described above suggest that the drug be taken on an empty stomach. They started with a loading dose, two 80 mg capsule per day (or one, if the larger dose cannot be tolerated) for two to four weeks. Then they reduced the dose to one capsule every other day, or one capsule three times a week. (The lowest price we have heard is about $4 per 80 mg. capsule.) Comment Clearly more research is needed -- work which could easily be done by a community-based research organization. Some possible studies: * Can consistent improvement in blood work -- especially CD8 count, T-helper count, or total lymphocyte count -- be shown in a prospective trial, for any group of patients? (This effect might be easiest to show in those at a fairly early stage of HIV disease, but who show evidence of impaired thymus function on certain blood tests.) * Does such immune improvement (if found) lead to reduced viral measurements, by helping the immune system to keep the virus under control? * Could thymomodulin help to reduce certain chronic or repeated infections -- as has been reported for both HIV- positive and HIV-negative patients? * Would thymomodulin work better if combined with alpha interferon (as well as with an antiviral). * Could thymomodulin have any role in the treatment of KS -- or was the single case reported so far only a coincidence? Acknowledgment The authors thank Curtis Ponzi for his help with this article. References 1. Seaman K, Dworniak D, Tchorzewski H, Pokoca L, and Majewska E. Effect of thymic extract on allogeneic MLR and mitogen-induced responses in patients with chronic active hepatitis B. Immunological Investigations. 1991; volume 20, number 7, pages 545-555. 2. Schoeller MC, Careddu P, Sandri MT, and Cazzola P. Recurrent respiratory infections in children: Prevention of acute episodes by oral administration of thymomodulin. Current Therapeutic Research, Clinical and Experimental. 1988; volume 44, number 4, pages 503-509. 3. Fiochhi A, Borella E, Riva E, and others. A double-blind clinical trial for the evaluation of the therapeutical effectiveness of a calf thymus derivative (Thymomodulin) in children with recurrent respiratory infections. Thymus. 1986; volume 8, page 331. 4. Terrizzi A, Di Somma C, Dato D, Sandri MT, Cazzola P, and Berti Riboli E. Thymomodulin prevents post-operative immunodepression measured by means of skin tests. International Journal of Immunotherapy. 1988; volume 4, number 3, pages 193-198. 5. Miglietta A, Coniglio D, Gravilli C, Schiraldi O, Sandri MT, and Cazzola P. In vivo effect of oral thymomodulin on some immunological parameters in elderly subjects. Current Therapeutic Research. 1989; volume 45, number 5, pages 838- 843. 6. Bartalucci S, Gemelli MT, Giorgi F, and others. Efficacy of thymomodulinon leukocyte recovery in patients undergoing antiblastic chemotherapy. Current Therapeutic Research, Clinical and Experimental. 1989; volume 46, number 6, pages 1136-1141. 7. Cavagni G, Piscopo E, Rigoli E, Iuliano P, Bertolini P, and Cazzola P. Food allergy in children: an attempt to improve the effects of the elimination diet with an immunomodulating agent (thymomodulin). A double-blind clinical trial. Immunopharmacology and Immunotoxicology. 1989; volume 11, number 1, pages 131-142. 8. Genova R and Guerra A. Thymomodulin in the management of food allergy in children. International Journal of Tissue Reactions. 1986; volume 8, number 3, pages 239-242. 9. Valesini G, Barnaba V, Benvenuto R, Balsano F, Mazzanti P, and Cazzola P. A calf thymus acid lysate improves clinical symptoms and T-cell defects in the early stages of HIV infection: Second report. European Journal of Cancer and Clinical Oncology. 1987; volume 23, number 12, pages 1915- 1919. 10. Bouchovsky G, Popescu B, Corrales JL, Esvivel G, Plama D, and Sorretino C. AZT thymomoduline & lithum carbonate for HIV patients. VIII International Conference on AIDS, Amsterdam, July 19-24, 1992 [abstract #7067]. 11. Pesic MC, Czarnecki J, Kornaszewski W, and others. Immunoprophylaxis and/or immunotherapy with thymic hormones in HIV-seropositive asymptomatic subjects and in AIDS patients. Archives of AIDS Research (current title, Archives of STD - HIV Research).1990; volume 4, issues 3-4, page 218. 12. Paroli M, Balsano C, Valesini G, Biffoni M, Perrone A, and Barnaba V. In vitro effect of alpha-interferon and thymomodulin on natural killer activity in patients with AIDS-related complex. [Italian, with English abstract.] Ann. Ital. Med. Int. 1988; volume 3, number 1, pages 39-42. 13. Balbi B, Valle MT, Oddera S, and others. Thymomodulin increases release of granulocyte-macrophage colony stimulating factor and of tumour necrosis factor in vitro. European Respiratory Journal. October 1992; volume 5, number 9, pages 1097-1103. 14. Di Massimo AM, Gilardini MS, Bardone MR, and others. The combined treatment of human peripheral blood mononuclear cells with thymolymphotropin and interleukin 2 increases PPD- driven T-cell proliferation and IL-2 induced cellular cytotoxicity against HIV-infected cells. International Jounal of Immunopharmacology. 1991; volume 13, number 8, pages 1157- 1165. 15. Colizzi V, Cazzola P, and Mazzanti P.The combined administration of thymomodulin and interleukin 2 reverses T- cell unresponsiveness in mice infected with Mycobacterium bovis-BCG. International Journal of Immunopharmacology. 1988; volume 10, number 3, pages 271-275. 16. Montagna D, Maccario R, Nespoli L, Mazzanti P, and Cazzola P. Thymomodulin enhances in vitro natural killer (NK) activity of human cord blood lymphocytes (CBL). Thymus. 1988; volume 11, number 3, pages 201-205. 17. Kouttab NM, Prada M, and Cazzola P. Thymomodulin: biological properties and clinical applications. Medical Oncology and Tumor Pharmacotherapy. 1989; volume 6, number 1, pages 5-9. 18. Grasso G, Muscettola M, Stecconi R, Muzzioli M, and Fabris N. Restorative effect of thymomodulin and zinc on interferon-gamma production in aged mice. Annals of the New York Academy of Sciences. December 26, 1992; volume 673, pages 256-259. 19. Schlumpberger JM, Wolde-Tsadik G, Yao JFF, and Hara J. CD8+ lymphocyte counts and the risk of death in advanced HIV infection. The Journal of Family Practice. 1994; volume 38, number 1, pages 33-38. 20. Fiala M, Kermani V, and Gornbein J. Role of CD8+ in late opportunistic infections of patients with AIDS. Res. Immunol. 1992; number 143, pages 903-907. ***** Thymomodulin Bibliography The following bibliography includes all the medical-journal articles we can find about thymomodulin -- not only regarding HIV, but research for any use. This bibliography is in two parts. Part I includes 41 articles indexed under "thymomodulin" by the U.S. National Library of Medicine, in the MEDLINE or AIDSLINE databases. These are the articles that U.S. researchers will find when they do a standard computer search. Part II includes 41 different articles, which U.S. researchers will not usually find when doing a computer search, either because they are not indexed under "thymomodulin," or because they are not indexed at all, in the U.S. databases. Hundreds -- probably thousands -- of European medical journals are not indexed in the U.S. computers; when articles are published in those journals, the U.S. medical and scientific community usually does not know of their existence. Much early, leading-edge research about potential treatments for AIDS, cancer, and other conditions remains largely unknown in the U.S. (U.S. researchers could find these in EMBASE [Excerpta Medica database], but that is not the usual procedure.) We prepared this two-part bibliography so that U.S. researchers would know how much work has been done with thymomodulin. The articles in each section are arranged in order by publication year, with the most recent year first. We included the institution at which the work was done, when that was available, to show how many research groups which have worked with this substance. Part I: Thymomodulin Articles Indexed in U.S. Databases Braga PC, Piatti G, Dal Sasso M, Maci S, and Blasi F. Department of Pharmacology, School of Medicine, University of Milan, Italy. Thymomodulin stimulates phagocytosis in vitro by rat macrophages and human polymorphonuclear cells. Chemother. October 1993; volume 5, number 5, pages 313-316. Koudela B and Hermanek J. Institute of Parasitology, Academy of Sciences of Czech Republic, Ceske Budejovice. Nonspecific immunomodulation influences the course and location of Cryptosporidium parvum infection in neonatal BALB/c mice. Ann. Parasitol. Hum. Comp. 1993; volume 68, number 1, pages 3-10. Lantero S, Oddera S, Silvestri M, Ottolini V, Sacco O, and Rossi GA. Division of Pneumology, G. Gaslini Institute, Genoa, Italy. Thymomodulin enhances phagocytic and intracellular killing activities of polymorphonuclear leucocytes without increasing release of chemotactic factors. Monaldi Arch. Chest Dis. 1993; volume 48, number 1, pages 29- 33. Balbi B, Valle MT, Oddera S, Manca F, Rossi GA, and Allegra L. Interuniversitary Center for Lung Diseases of Northern Italy, Milan. Thymomodulin increases HLA-DR expression by macrophages but not T-lymphocyte proliferation in autologous mixed leucocyte reaction. European Respiratory Journal. January 1993; volume 6, number 1, pages 102-109. Bouchovsky G, Popescu B, Corales JL, Esvivel G, Plama D, and Sorretino C. Hospital Escuela, Corrientes, Argentina. AZT thymomoduline & lithum carbonate for HIV patients. VIII International Conference on AIDS, Amsterdam, July 19-24, 1992 [abstract #7067]. Abraham AD, Borsa M, Sandu VD, Puica C, Cicos V, and Uray Z. Biological Research Institute, Cluj-Napoca, Romania. The effects of thymomodulin and thymolymphotropin on the stress response of neuroendocrine system by gamma-irradiated Wistar rat. Rom. J. Morphol. Embryol. July to December 1992, volume 38, numbers 3-4, pages 81-89. Grasso G, Muscettola M, Stecconi R, Muzzioli M, and Fabris N. Institute of Human Anatomy, Siena, Italy. Restorative effect of thymomodulin and zinc on interferon-gamma production in aged mice. Annals of the New York Academy of Sciences. December 26, 1992; volume 673, pages 256-259. Zaczynska E, BLach-Olszewska Z, Feldmane G, and others. Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw. Effect of natural and synthetic immunomodulators on the synthesis of interferon by peritoneal cells of mice. Acta. Virol. March 1992; volume 36, number 2, pages 121-128. Balbi B, Valle MT, Oddera S, and others. Interuniversity Center for Lung Diseases of Northern Italy, Milan. Thymomodulin increases release of granulocyte-macrophage colony stimulating factor and of tumour necrosis factor in vitro. European Respiratory Journal. October 1992; volume 5, number 9, pages 1097-1103. Wysocki J, Wierusz-Wysocka B, Wykretowicz A, and Wysocki H. Institute of Pediatrics, Academy of Medicine, Poznan, Poland. The influence of thymus extracts on the chemotaxis of polymorphonuclear neutrophils (PMN) from patients with insulin-dependent diabetes mellitus (IDD). Thymus. August 1992; volume 20, number 1, pages 63-67. Cocchi D, Bardone MR, Moretti R, and Travaglini P. Department of Pharmaco-Biology, University of Bari. Effect of thymomodulin on luteinizing hormone, prolactin and testosterone in male rats. Thymus. February 1992; volume 19, number 1, pages 53-58. Di Massimo AM, Gilardini MS, Bardone MR, and others. Department of Biology, II University of Rome, Italy. The combined treatment of human peripheral blood mononuclear cells with thymolymphotropin and interleukin 2 increases PPD- driven T-cell proliferation and IL-2 induced cellular cytotoxicity against HIV-infected cells. International Journal of Immunopharmacology 1991; volume 13, number 8, pages 1157-1165. Zeman K, Dworniak D, Tchorzewski H, Pokoca L, and Majewska E. Department of Pathophysiology & Immunology, Military Medical Academy, Lodz, Poland. Effect of thymic extract on allogeneic MLR and mitogen-induced responses in patients with chronic active hepatitis B. Immunol. Invest. December 1991; volume 20, number 7, pages 545-555. Pecora R, Cherubini V, Cardinale G, and Bartolotta E. Divisione di Pediatria, Ospedale Santa Lucia, Recanati (MC), Italia. Circadian variability of IgE in children: effects of a thymic hormone (thymomodulin). [Italian, with English abstract.] Pediatr. Med. Chir. May-June 1991; volume 13, number 3, pages 277-278. Hermanek J. Institute of Parasitology, Czechoslovak Academy of Sciences, Ceske Budejovice. Nonspecific immunomodulation influences resistance of mice to experimental infection with Mesocestoides corti and Ascaris suum. J. Helminthol. June 1991; volume 65, number 2, pages 121-132. Galli L, de Martino M, Azzari C, and others. Centro di Allergologia e di Immunologia Clinica, Clinica Pediatrica III, Universita di Firenze, Italia. Preventive effect of thymomodulin in recurrent respiratory infections in children. [Italian, with English abstract.] Pediatr. Med. Chir. May- June 1990; volume 12, number 3, pages 229-232. Szkaradkiewicz A, and Kiczka W. Clinic of Infectious Diseases, Medical Academy, Poznan, Poland. Reciprocal effects of prostaglandin E2 (PGE2) and of thymic factor (TFX- thymomodulin) on bactericidal activity of human neutrophils. Materia Medica Polona. July-September 1989; volume 21, number 3, pages 231-233. Szkaradkiewicz A, and Kiczka W. Reciprocal effects of prostaglandin E2 (PGE2) and of thymic factor (TFX- thymomodulin) on bactericidal activity of human neutrophils. Materia Medica Polona. April-June 1989; volume 21, number 2, pages 97-99. Maiorano V, Chianese R, Fumarulo R, and others. Department of Physiopathology, University of Bari, Italy. Thymomodulin increases the depressed production of superoxide anion by alveolar macrophages in patients with chronic bronchitis. International Journal of Tissue Reactions. 1989; volume 11, number 1, pages 21-25. Fiorino A, Frigo G, and Cucchetti E. Ellem Research Centre, Milan, Italy. Liquid chromatographic analysis of amino and imino acids in protein hydrolysates by post-column derivatization with o-phthalaldehyde and 3-mercaptopropionic acid. J. Chromatogr. August 4, 1989; issue 476, pages 83-92. Cavagni G, Piscopo E, Rigoli E, Iuliano P, Bertolini P, and Cazzola P. Clinica Pediatrica-Universita degli Studi di Parma, Italy. Food allergy in children: an attempt to improve the effects of the elimination diet with an immunomodulating agent (thymomodulin). A double-blind clinical trial. Immunopharmacology and Immunotoxicology. 1989; volume 11, number 1, pages 131-142. Kouttab NM, Prada M, and Cazzola P. Dept of Pathology, Roger Williams General Hospital, Providence, Rhode Island. Thymomodulin: biological properties and clinical applications. Medical Oncology and Tumor Pharmacotherapy. 1989; volume 6, number 1, pages 5-9. Bagnato A, Brovedani P, Comina P, and others. Servizio di Fisiopatologia Respiratoria, Ospedale di Codroipo, Udine, Italy. Long-term treatment with thymomodulin reduces airway hyperresponsiveness to methacholine. Annals of Allergy. May 1989; volume 62, number 5, pages 425-428. Paroli M, Balsano C, Valesini G, Biffoni M, Perrone A, and Barnaba V. In vitro effect of alpha-interferon and thymomodulin on natural killer activity in patients with AIDS-related complex. [Italian, with English abstract.] Ann. Ital. Med. Int. January-March 1988; volume 3, number 1, pages 39-42. Vasilopoulos G, Porwit A, Lauren L, Reizenstein P, and Cazzola P. Hematology Laboratory, Karolinska Hospital, Stockholm, Sweden. The effect of a calf thymus acid lysate on bone marrow cell growth in vitro. Immunopharmacology and Immunotoxicology. 1988; volume 10, number 4, pages 523-536. Longo F, Lepore L, Agosti E, and Panizon F. Istituto per l'Infanzia "Burlo Garofolo," Trieste, Italia. Evaluation of the effectiveness of thymomodulin in children with recurrent respiratory infections. [Italian, with English abstract.] Pediatr. Med. Chir. November-December 1988, volume 10, number 6, pages 603-607. Colizzi V, Cazzola P, and Mazzanti P. Institute of Microbiology, University of Pisa, Italy. The combined administration of thymomodulin and interleukin 2 reverses T- cell unresponsiveness in mice infected with Mycobacterium bovis-BCG. International Journal of Immunopharmacology. 1988; volume 10, number 3, pages 271-275. Montagna D, Maccario R, Nespoli L, Mazzanti P, and Cazzola P. Department of Pediatrics, University of Pavia, Italy. Thymomodulin enhances in vitro natural killer (NK) activity of human cord blood lymphocytes (CBL). Thymus. 1988; volume 11, number 3, pages 201-205. Cantelli-Forti G, Hrelia P, Scotti M, Scornavacche V, and Prada M. Institute of Pharmacology, University of Bologna, Italy. Mutagenicity studies on thymomodulin. Arzneimittelforschung. November 1987; volume 37, number 11, pages 1269-1273. Cazzola P, Mazzanti P, and Kouttab NM. Ellem Industria Farmaceutica s.p.a., Milan, Italy. Update and future perspectives of a thymic biological response modifier (Thymomodulin). Immunopharmacol. Immunotoxicol. 1987; volume 9, numbers 2-3, pages 195-216. Valesini G, Barnaba V, Benvenuto R, Balsano F, Mazzanti P, and Cazzola P. Instituto Clinica Medica I, University of Rome La Sapienza, Milan, Italy. A calf thymus acid lysate improves clinical symptoms and T-cell defects in the early stages of HIV infection: second report. Eur. J. Cancer Clin. Oncol. December 1987; volume 23, number 12, pages 1915-1919. Marzari R, Mazzanti P, Cazzola P, and Pirodda E. Universita degli Studi di Bologna, Istituto di Clinica Otorinolaringologica. Perennial allergic rhinitis. Prophylaxis of acute episodes using thymomodulin. Minerva Med. November 30, 1987; volume 78, number 22, pages 1675- 1681. Vettori G, Lazzaro A, Mazzanti P, and Cazzola P. Prevention of recurrent respiratory infections in adults. Minerva Med. September 15, 1987; volume 78, number 17, pages 1281-1289. Fiocchi A, Borella E, Riva E, and others. A double-blind clinical trial for the evaluation of the therapeutical effectiveness of a calf thymus derivative (Thymomodulin) in children with recurrent respiratory infections. Thymus. 1986; volume 8, number 6, pages 331-339. Cappellari A, Galvan D, Bagarella M, Busolo R, Corradi G, and Cazzola P. Scanning electron microscopy study of changes induced by thymomodulin on the morphology of mononuclear elements of peripheral blood from healthy subjects and patients with neoplasms. [Italian, with English abstract.] Boll Ist Sieroter Milan. 1986; volume 65, number 4, pages 290-297. Genova R, and Guerra A. Thymomodulin in management of food allergy in children. International Journal of Tissue Reactions. 1986; volume 8, number 3, pages 239-242. Poli G, Secchi C, Bonizzi L, and Guttinger M. Stimulation of the antibody response after treatment with thymomodulin in mice immunodepressed with cyclophosphamide and in aging mice. International Journal of Tissue Reactions. 1986; volume 8, number 3, pages 231-238. Segatto O, Secchi C, Berrini A, and Natali PG. Thy 1.2 antigen inducing capacity of a calf thymus acid hydrolysate and its fractions. International Journal of Tissue Reactions. 1986; volume 8, number 3, pages 225-229. Calsini P, Mocchegiani E, and Fabris N. Broncho-Asthmatic Centre, Poggiosecco Hospital, INRCA, Florence, Italy. The pharmacodynamics of thymomodulin in elderly humans. Drugs Exp. Clin. Res. 1985; volume 11, number 9, pages 671-674. Galli M, Crocchiolo P, Negri C, Caredda F, Lazzarin A, and Moroni M. Clinic for Infectious Diseases, University of Milan, Italy. Attempt to treat acute type B hepatitis with an orally administered thymic extract (thymomodulin): preliminary results. Drugs Exp. Clin. Res. 1985; volume 11, number 9, pages 665-669. Genova R, and Guerra A. A thymus extract (thymomodulin) in the prevention of childhood asthma. [Italian, with English abstract.] Pediatr. Med. Chir. September-October 1983; volume 5, number 5, pages 395-402. Part II -- Thymomodulin Articles Largely Unknown in the U.S. Baroni MG, Fiore V, Maestripieri PL, and others. Instituto II Clinica Medica, Policlinico Umberto I, University of Rome, Rome, Italy. Therapy with a thymic extract and reduced recurrence of low urinary tract infections in patients with diabetes mellitus. Acta Thermographica. 1993; volume 19, number 3, pages 283-294. Lantero S, Oddera S, Silvestri M, and Rossi GA. Divisione di Pneumologia, Istituto G. Gaslini, Genova Italy. Biological response modifiers. [Italian, with English abstract.] Lotta Contro Tuberculosi Malattie Polmonari Sociali. 1993; volume 63, numbers 1-2, pages 35-38. Garattini S, and Garattini L. Economia Sanitaria 'A. Valenti', Istituto di Ricerche Farmacologiche, 'Mario Negri', Milan Italy. Pharmaceutical prescriptions in four European countries. Lancet. 1993; volume 342, number 8881, pages 1191- 1192. Chirigos MA, and De Simone C. Immunoregulatory biological response modifiers: Effect of cytokines on septic shock. Mediators of Inflammation. 1993; volume 2, supplement 1, pages S5-S10. Hadden JW. Division of Immunopharmacology, Department of Medicine, Univ. South Florida Medical College, Tampa, USA. Immunostimulants. Immunology Today. 1993; volume 14, number 6, pages 275-280. Garbin F, Eckert K, and Maurer HR. Institut fur Pharmazie, Freie Universitat, Berlin, Germany. A semi-automatic microassay to measure human tumor clonogenic growth in vitro. Int. J. Oncol. 1993; volume 2, number 3, pages 357-361. Catena E, Grassi C, and Grossi E. Efficacy of treatment with thymomodulin in the prophylaxis of exacerbations in COPD patients with cell-mediated deficit. G. Ital. Mal. Torace. 1992; volume 46, number 3, pages 193-202. Zuddas AA, Zanetti L, Gavazzoni GB, and others. Primario Div. ORL, Ospedale Civile, Manerbio, Italy. Seasonal allergic oculorhinitis: Prophylaxis with thymomodulin. [Italian, with English abstract.] Otorinolaringologia. 1992; volume 42, number 5, pages 341-344. De Martino M, Galli L, and Vierucci A. Department of Pediatrics, Clinical Immunology Unit, University of Florence, Italy. May children with recurrent respiratory infections be a test bed of immunomodulators? Pharmacological Research. 1992; volume 26, supplement 2, pages 156-159. Czaplicki J, Blonska B, Religa Z, and Salomon DR. The lack of hyperacute xenogeneic heart transplant rejection in a human. Journal of Heart and Lung Transplantation. 1992; volume 11, number 21, pages 393-397. Motta G, Antonelli A, and Cis C. Thymomodulin in the prevention of postoperative immunodepression. [Italian, with English abstract.] Otorinolaringologia. 1992; volume 42, number 1, pages 49-54. Adolph T, Baumstummler B, and Zoch E. Fachrichtung 3.3 -- Medizinische Biochemie, Medizinische Fakultat, Universitat des Saarlandes, Germany. Electron microscopy on the surface of lymphocytes (Molt-3) with the TFX-peptides beta(a), beta(b) and beta(c). [German, with English abstract.] Dtsch. Z. Onkol. 1992; volume 24, number 1, pages 18-21. Pecora R, Cherubini V, Milani G, and Bartolotta E. Paediatric Department, S. Lucia Hospital, Recanati Italy. Decreased IgE circadian variation in atopic children treated with an orally administered thymic derivative (thymomodulin). Int. J. Immunotherapy. 1991; volume 7, number 3, pages 149-151. De Pra M, and Oberti F. Ospedale Generale Provinciale, Divisione di Pediatria, Carrara, Italy. Infantile sinusitis. Clinical comment on the basis of a ten-year series of patients. [Italian, with English abstract.] Minerva Pediatria. 1990; volume 42, number 12, pages 515-530. Chirigos MA, Kouttab NM, Bersani C, and others. U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, USA. Immune cell modulation by thymic derivatives. Eos. Riv. Immunol. Immunofarm. 1990; volume 10, number 4, pages 131-132. Pesic MC, Czarnecki J, and Kornaszewski W. Institute for Immunology and Thymus Research, Bad Harzburg, Germany. Immunoprophylaxis and/or immunotherapy with thymic hormones in HIV-seropositive asymptomatic subjects and in AIDS patients. Archives of AIDS Research. (current title, Archives of STD - HIV Research). 1990; volume 4, numbers 3-4, page 218. Kruscic S, Lilic D, and Brkic S. Clinical Institute for Geriatrics, Clinical Hospital Centre 'Zvezdara', Belgrade Yugoslavia. NK activity assay in patients with viral myocarditis. Period. Biol. 1990; volume 92, number 1, pages 113-114. Galli L, De Martino M, and Azzari C. Centro di Allergologia e di Immunologia Clinica, Clinica Pediatrica III, Universita di Firenze, Firenze, Italy. Clinical trial on thymomodulin in children with recurrent respiratory infections. [Italian, with English abstract.] Pediatr. Med. Chir. 1990; volume 12, number 3, pages 229-232. Cadrobbi P, Crivellaro C, Marranconi F, and others. Divisione Malattie Infettive, Padova, Italy. Treatment of pediatric chronic hepatitis B and delta. [Italian.] Basi. Razion. Ter. 1990; volume 20, number 5, pages 339-343. Czaplicki J, Blonska B, and Cwiertka P. Department of Biology and Genetics, Silesian Academy of Medicine (SAM), Sosnowiec Poland. Embryonal and mature thymic extracts in heart transplant acute rejection treatment. Thymus. 1990; volume 15, number 3, pages 187-191. La Rosa M. Cattedra di Pediatria Preventiva e Sociale, Catania, Italy. Use of immunomodulating drugs in pediatric pulmonology. [Italian, with English abstract.] Pediatr. Med. Chir. 1989; volume 11, number 6, pages 649-652. Bartalucci S, Gemelli MT, Giorgi F, and others. Fourth Department of Internal Medicine, University of Florence, Florence, Italy. Efficacy of thymomodulin on leukocyte recovery in patients undergoing antiblastic chemotherapy. Current Therapeutic, Research Clinical and Experimental. 1989; volume 46, number 6, pages 1136-1141. Miglietta A, Coniglio D, Gravilli C, and others. Hospital Umberto I, Barletta, Italy. In vivo effect of oral thymomodulin on some immunological parameters in elderly subjects. Current Therapeutic Research, Clinical and Experimental. 1989; volume 45, number 5, pages 838-843. Ferrero ME, Marni A, Gaja G, and others. Istituto di Patologia Generale, Universita di Milano, Milano, Italy. Thymomodulin in vivo restores impaired metabolism induced in immune cells by isoflurane. Journal of Drug Development. 1989; volume 2, number 1, pages 55-60. Hermans P, and Clumeck N. Division of Infectious Diseases, St. Pierre University Hospital, Brussels, Belgium. Preliminary results on clinical and immunological effects of thymus hormone preparations in AIDS. Medical Oncology and Tumor Pharmacotherapy. 1989; volume 6, number 1, pages 55-58. Maiorano V, Chianese R, Fumarulo R, and others. Istituto di Fisiopatologia Respiratoria dell'Universita di Bari, Bari, Italy. Thymomodulin treatment in chronic bronchitis: Clinical improvement and restoration of production of superoxide anions by alveolar macrophages. [Italian.] Lotta Tuberculosi Malattie Polmonari Sociali. 1988; volume 58, numbers 3-4, pages 722-726. Matzeu M, Gramiccioni E, Mazzei L, and Bolzan Mariotti A. Istituto di Tisiologia e Malattie dell'Apparato Respiratorio, Universita degli Studi di Roma 'La Sapienza', Roma, Italy. Thymus extracts: Biologic characteristics and therapeutic results. [Italian, with English abstract.] Lotta Tuberculosi Malattie Polmonari Sociali. 1988; volume 58, numbers 3-4, pages 606-616. Terrizzi A, Di Somma C, Dato D, and others. Surgical Semeotics B, University of Genoa, Genoa, Italy. Thymomodulin prevents post-operative immunodepression measured by means of skin tests. Int. J. Immunother. 1988; volume 4, number 3, pages 193-198. Schoeller MC, Careddu P, Sandri MT, and Cazzola P. Clinica Pediatrica I, Universita di Milano, Milan, Italy. Recurrent respiratory infections in children: Prevention of acute episodes by oral administration of thymomodulin. Current Therapeutic Research, Clinical and Experimental. 1988; volume 44, number 4, pages 503-509. Ferrero ME, Marni A, Gaja G, and others. Istituto di Patologia Generale, University of Milan, Milan Italy. A calf thymus lysate (thymomodulin) in vitro restores impaired cellular metabolism induced by isoflurane. Journal of Drug Development. 1988; volume 1, number 1, pages 55-62. Sofia M, Molino A, Mormile M, and others. Clinica Tisiologica, Universita degli Studi di Napoli, II Facolta di Medicina e Chirurgia, Napoli, Italy. Chronic bronchitis: A double-blind clinical trial for the evaluation of the therapeutical effectiveness of orally administered thymomodulin in the prevention of acute attacks. [Italian, with English abstract.] G. Ital. Mal. Torace. 1988; volume 41, number 6, pages 339-342. Bortolotti F, Cadrobbi P, Crivellaro C, and others. Clinica Medica II of the University, Padua, Italy. Effect of an orally administered thymic derivative, thymodulin, in chronic type B hepatitis in children. Current Therapeutic Research, Clinical and Experimental. 1988; volume 43, number 1, pages 67-72. Dajbukat FJr, Uray Z. Pop D, and others. Clinica Odontoiatrica, Universita di Pavia, Pavia, Italy. 'Thymomodulin' in parodontal bone surgery. Riv. Ital. Biol. Med. 1987; volume 7, numbers 1-2, pages 76-80. Fiocchi A, Grasso U, Rottoli A, and others. Ellem Industria Farmaceutica SpA, 20123 Milan, Italy. A double blind clinical trial on the effectiveness of a thymic derivative (thymomodulin) in the treatment of children with atopic dermatitis. Int. J. Immunother. 1987; volume 3, number 4, pages 279-284. Cazzola P, Mazzanti P, and Bossi G. Department of Clinical Research, Ellem Industria Farmaceutica spa, Milan, Italy. In vivo modulating effect of a calf thymus acid lysate on human T lymphocyte subsets and CD4+/CD8+ ratio in the course of different diseases. Current Therapeutic Research, Clinical and Experimental. 1987; volume 42, number 6, pages 1011-1017. Andolina M, Dobrinz MG, Meraviglia L, and others. Institute of Clinical Paediatrics, University of Trieste, Trieste Italy. Myelopoiesis induction on human bone marrow precursor cells by a calf thymic derivative (thymomodulin): In vitro comparison with exogenous CSF. Int. J. Immunother. 1987; volume 3, number 2, pages 139-145. Segatto O, Berrini A, Cuomo M, and others. Laboratorio di Immunologia, Istituto Regina Elena, Rome, Italy. Thy 1.2 inducing activity of a partially purified calf thymus acid lysate. Int. J. Immunother. 1986; volume 2, number 4, pages 309-315. Gallo Curcio C, Barduagni A, Tonachella R, and others. Regina Elena Institute, Rome, Italy. Double blind randomized study on the effect of thymomodulin (TM) in chemoinduced myelodepression in cancer patients: Preliminary results. Int. J. Immunother. 1986; volume 2, number 2, pages 189-191. Calonghi GF. Primario della Divisione Malattie Infettive Arcispedale S. Maria Nuova, Reggio Emilia, Italy. Thymomodulin in infectious diseases. [Italian, with English abstract.] Eur. Rev. Med. Pharmacol. Sci. 1985; volume 7, number 4, pages 511-518. Porzio G, Lapenta M, Morlando L, and Russo P. Presidio Ospedaliero, U.S.L. N. 22, I Divisione di Medicina, Pozzuoli, Italy. Immunological studies in elderly subjects treated with thymomodulin. Eur. Rev. Med. Pharmacol. Sci. 1984; volume 6, number 3, pages 577-582. Kouttab NM, and Twomey JJ. Department of Pathology, Section of Pathobiology, University of Texas, Houston, USA. The pharmacodynamics of in vivo administered thymomodulin. Drugs Exp. Clin. Res. 1984; volume 10, number 12, pages 921-927. ***** Zerit (d4T) Approved FDA approval of d4T (brand name Zerit, chemical name stavudine) was announced June 27; the drug should reach pharmacies in July. Under the FDA's accelerated-approval regulations, this drug was approved on the basis of "surrogate markers" (improvement in blood work) plus safety data from the large parallel-track program -- while the longer trials needed to obtain statistical proof that the drug increases survival or reduces opportunistic infections are still ongoing. The package insert for d4T -- the "labeling" approved by the FDA, which defines the claims which can be made in marketing the drug -- provides an accessible overview of what was known about the drug when it was approved. A major controlled trial, in patients with at least six months (and usually longer) of prior AZT use, is now comparing two treatment strategies, switching to d4T vs. continuing on AZT. Data from 359 patients in this trial has been analyzed; after 12 weeks of treatment, those who switched to d4T had an average increase of 22 in their T-helper count, while those who continued on AZT had an average decrease of 22. Meanwhile, a large parallel-track program, sponsored by Bristol-Myers Squibb Company, the sponsor of d4T, provided the drug free to over 10,000 people who could not use either AZT or ddI. Those who entered this program were randomly assigned to either a 20 mg or 40 mg dose twice daily (or a smaller dose, depending on body weight). An interim analysis of data from 9,226 patients showed that the survival rate was about the same in the two dose groups. The main side effect of d4T is peripheral neuropathy, which was serious enough to require drug discontinuation or dose reduction in 15 percent of the volunteers in the controlled trial, and 21 percent in the parallel-track program. The neuropathy may worsen temporarily after the drug is discontinued. Because there is no data now available on whether d4T improves survival or reduces opportunistic infections, the drug "is indicated for the treatment of adults with advanced HIV infection who are intolerant of approved therapies with proven clinical benefit or who have experienced significant clinical or immunologic deterioration while receiving these therapies or for whom such therapies are contraindicated." A trial to compare d4T with AZT as initial therapy is now being planned, but no such trial has yet been started. The package insert (which unfortunately is usually not given to patients with the prescription, but will be generally available in the Physician's Desk Reference) also provides the following information about using d4T: * d4T can be taken without regard to meals. * Persons with decreased kidney function excrete d4T more slowly than normal, so their dose should be reduced; specific recommendations are given. * For persons with pre-existing liver dysfunction, no data is available, so no recommendations can be made. But there are recommendations for drug discontinuation or dose reduction if "clinically significant elevations of hepatic transaminases" occur during d4T treatment. * Because of unknown risks, d4T "should be used during pregnancy only if clearly needed," and mothers should discontinue breast feeding if they are using the drug. ***** Thymopentin (TP-5) Trial Starting, 34 U.S. Cities This trial will test whether thymopentin (also called TP-5, or Timunox), can slow the progression of HIV disease in AZT- experienced persons. Volunteers must be asymptomatic, with T-helper count from 100-400. They must have taken at least six months of prior AZT, and upon entry into the study may be receiving AZT, ddI, AZT+ddI, AZT+ddC, or no current antiretroviral treatment. There are also some exclusion criteria, including oral candidiasis. Note: Thymopentin is a small part -- five amino acids -- of a hormone produced by the thymus gland. Previous trials have suggested that thymopentin is safe; but the drug, perhaps erroneously, developed a community reputation as not being very effective. However, a trial in over 350 asymptomatic patients suggested that TP-5 might significantly slow disease progression [reported at the International Conference on AIDS, Berlin, July 6-11, 1993, poster #2144]. When comparing progression to ARC, AIDS, or death, it found only 2.7 such events per 100 person-years for patients taking AZT plus thymopentin, compared to 10.4 events for those taking AZT alone. When comparing progression to AIDS or death only (not including ARC, an obsolete concept which can be difficult to interpret consistently), for those patients with T-helper counts between 200 and 400, it found only one event in the thymopentin plus AZT group, compared to eight events with AZT alone. However, the total number of events was too small to provide conclusive proof that thymopentin slows the progression of HIV disease, and the FDA insisted on a followup trial to confirm the result, before the drug could be approved. The trial sites are in the following cities: Atlanta, GA; Austin, TX; Beverly Hills, CA; Bronx, NY; Brookline, MA; Chicago, IL (2 sites); Cleveland, OH; Coral Gables, FL; Dallas, TX; Ft. Lauderdale, FL; Greenwich, CT; Hampton, VA; Houston, TX; Indianapolis, IN; Kansas City, MO; Kirkland, WA; Miami Beach, FL; Milwaukee, WI; New Orleans, LA; New York, NY (4 sites); Philadelphia, PA (2 sites); Pittsburgh, PA; Redwood City, CA; San Diego, CA; San Francisco, CA (2 sites); San Juan, PR; Sherman Oaks, CA; St. Louis, MO; Stony Brook, NY; Sylmar, CA; Tampa, FL; Torrance, CA; Washington, DC; and Wichita, KS. For more information, including a contact person and phone number in a city convenient for you, call the AIDS Clinical Trials Information Service, 800/TRIALS-A. [Note 2: A separate trial, at only three sites (Tarzana, Pittsburgh, and San Francisco), is studying the effect of thymopentin on viral load and on lymphoproliferative responses. Volunteers can have any T-helper count under 400; they must be either asymptomatic or minimally symptomatic. More information about this trial is also available through 800/TRIALS-A.] AIDS TREATMENT NEWS, a twice-monthly newsletter, is available by subscription; about half of each issues is reprinted in the BAY TIMES. For a sample issue, call 800/TREAT-1-2, or send a self-addressed stamped envelope to: ATN, P.O. Box 411256, San Francisco, CA 94141. To protect your confidentiality, we mail first class without mentioning AIDS on the envelope.