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Beyond Hydroxyurea




 

GMHC Treatment Issues 1995 Sep 1; 9(9): 2

Hydroxyurea may simply be the first of a series of compounds that inhibit cellular enzymes to suppress HIV and increase the antiviral activity of nucleoside analogs such as AZT or ddI. Some of these other drugs also inhibit ribonucleotide reductase (RR), but a few have other mechanisms of action. Like hydroxyurea, most of these drugs are cytotoxic.

Two newer drugs, didox and trimidox, are much more potent inhibitors of RR than hydroxyurea. The published data on didox and trimidox largely concern retrovirus models in mice, including the murine Immunodeficiency Model (MAIDS). In one model, trimidox inhibited reverse transcriptase activity by 90 percent. In the MAIDS model, the compound significantly extended mouse survival as compared to placebo.1 Trimidox is not yet in clinical trials, but didox has been well tolerated in phase II clinical trials for breast and other cancers. The drug has not been given to people on a daily chronic basis, but chronic use is well tolerated in baboons with sickle cell anemia. Molecules for Health, developer of these two drugs, plans to conduct soon a Swedish trial of daily didox monotherapy in ten people with HIV. It will then proceed to combination therapy trials if the results are encouraging.

Another approach is to inhibit thymidylate synthetase (TS), which plays a major role in the synthesis of thymidine, the nucleoside that AZT and d4T mimic. Two cancer drugs are known to inhibit TS: fluorouracil (5-FU or Efudex), and floxuridine (FUdr). Researchers at the National Cancer Institute have shown in vitro that FUdr has significant anti-HIV activity at doses currently used in chemotherapy. Better, doses almost one-ninth as much increase the amount of d4T's triphosphated active metabolite in the cell ten-fold. At the same low dose of FUdr, the amount of d4T required to inhibit HIV decreases eight-fold.2 All these cancer chemotherapeutics, including hydroxyurea, are very toxic drugs that cause bone marrow toxicities and can kill activated lymphocytes. However, if extremely low doses are sufficient to provide a competitive advantage to the nucleoside analogs, clinical investigation of these compounds is more than justified.

Other, safer drugs may also increase the activity of the nucleoside analogs. Ribavirin has long been known to increase the formation of ddI's active metabolite (again, the triphosphate) and to boost the effect of ddI in cell culture studies, probably by inhibiting other cellular enzymes (such as 5�-monophosphate dehydrogenase).3 In an NIH-sponsored pharmacokinetic pilot study of the combination of ribavirin and ddI (ACTG 231), the ribavirin/ddI combination was shown to be well tolerated. Further, the fifteen study participants exhibited a median 1.1 log (92 percent) viral load reduction at week twelve.4 The researchers argued that further study of ddI plus ribavirin is merited since the combination proved to have greater antiviral activity than is normally reported for ddI monotherapy. Ribavirin, which has had a controversial history as an anti-HIV agent, is approved in an aerosolized form for respiratory syncytial virus infections in children. An oral formulation is currently in phase III studies for hepatitis C. It is also available from the PWA Health Group in New York.

Dipyridamole (Persantine), a blood thinning drug long used in heart disease, has also been shown to potentiate the activity of nucleoside analogs by reducing the entry of competing natural nucleosides into the cell. A five-day American study of the combination of two doses of dipyridamole (600 mg or 450 mg a day) plus AZT (600 mg a day) in eleven people with HIV took place in the early nineties.5 The combination caused moderate, transient headaches and nausea which went away in most patients within four days, although the nausea was considered severe enough to preclude use of the higher dose.

The dipyridamole concentrations attained in the study participants' blood with the lower dose were comparable to levels that increased AZT's effect by ten fold in the test tube. A fourteen-day French study in twelve people with HIV, using 600 mg a day of AZT and 450 mg of dipyridamole reported similar findings.6 The American researchers concluded that the further studies are needed to establish the long-term safety and activity of the AZT plus dipyridamole. Such studies may be long in coming since the researchers have been unable to secure financial support from the dipyridamole's manufacturer, Boehringer Ingelheim. The drug's patent has expired, which may be the reason for Boehringer's lack of interest.

1. Elford H et al. AIDS Research and Human Retroviruses, Aug 1 1995; 11(supplement 1, abstract 384):160.

2. Wen-Yi G et al. AIDS Research and Human Retroviruses, Aug 1 1995; 11(supplement 1, abstract 387):161.

3. Balzarini J et al. Journal of Biological Chemistry, Nov 15, 1991; 266(32):21509-14.

4. Japour AJ et al. Second National Conference on Human Retroviruses and Related Infections. January 29-February 2, 1995; (abstract 266):103.

5. Hendrix C et al. Antimicrobial Agents and Chemotherapies, May 1994 38(5):1036-40.

6. Livrozet JM et al. Tenth International Conference on AIDS. Aug 1994; 1(abstract PB0250):205.



 


Copyright © 1995 -Gay Men's Health Crisis, Publisher. All rights reserved to Gay Men's Health Crisis (GMHC) Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, INC. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 Email GMHC. Visit GMHC

Information in this article was accurate in September 1, 1995. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.