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
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
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
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.