Experimental Antivirals

Dozens of different potential antivirals were mentioned in
presentations at the Sixth International Conference on AIDS. But
usually the results were too sketchy to be useful, or otherwise
relevant to only a handful of specialists.

If we were asked to name one "sleeper" at the Conference --
one project which we believe may have great importance but which
received little attention -- it would be the work on melanins,
described below. It is too early to know if this treatment will
be useful -- but it would be easy to find out.

By contrast, the paper on Chinese medicines with anti-HIV
activity in laboratory tests (below) did attract attention --
partly because virologist David Ho, known for his work on plasma
viremia, assisted in the project. As with melanins, we
highlighted this work because it offers practical advantages. A
medicine already in routine human use can clearly be developed
faster as an AIDS/HIV treatment than a new chemical never used
before. But Chinese medicines may be unpatentable, and they fit
poorly into the Western medical-industrial complex, so the
research needed is hard to fund. Community-based organizations
should pay special attention to treatments which could be
developed rapidly, but may not be developed at all without
community pressure.

Readers should note that this article is based mainly on
information presented at the Conference, as we have not had time
to contact the researchers or do other followup.

For information on how to obtain the Conference abstracts
and tapes referred to in this issue, see "Obtaining Conference
Information," under Announcements.



Melanins

This work, by researchers at Vanderbilt University Medical
School, could easily be missed, because the interesting
information appeared for only one day on the poster presentation
itself (poster #Th.A. 228), not in the published abstract or in
an article published by the investigators. To anyone not at the
poster that day, melanins would look like just another of the
dozens of potential treatments which appear promising in
laboratory tests and ought to be investigated further for
possible human use for treating AIDS.

Melanins are pigments which are already found in the body in
hair, skin, and eyes. Although recognized for at least 60 years,
their chemical structure is not known, and no therapeutic use for
these chemicals has been found. The melanins which occur
naturally in the body are insoluble in water, but the synthetic
forms studied as an anti-HIV treatment are soluble. Melanins are
easy to make, can be given orally, and are inexpensive.

The published abstract (reference above) reported that small
concentrations of melanins (0.3 to 10 ug/ml) blocked infection of
human T-helper cells with HIV in laboratory tests; three
different cell lines and three different viruses (including HIV-
2) were used. A more detailed report of the same work was
published in April of this year. (Montefiori, D. C. and others.
Inhibition of human immunodeficiency virus type 1 replication and
cytopathicity by synthetic soluble catecholamine melanins in
vitro. Biochemical and Biophysical Research Communications,
volume 168, number 1, pages 200-205, April 16, 1990.) The
mechanism of action is not known, but melanins did not inhibit
reverse transcriptase, so clearly they work entirely differently
than AZT. (One test suggested that they probably did not get
inside the cells.)

Another report, apparently of research too recent for
inclusion in the published abstract or the journal article,
appeared only on the poster itself. Synthetic melanins were
given to mice in their drinking water, and their urine had anti-
HIV activity even when diluted up to 200 times; control urine of
mice given plain water had no effect. The mice showed no
toxicity from the chemical, and they ate and drank as much as the
control mice during the five-day test. (Much larger doses of
melanin given by injection did kill mice, however, and the
researchers estimated the lethal dose for the animals at between
one and ten grams per kilogram of body weight.)

Comment: Although this research is preliminary and much
uncertainty remains, we find it especially significant that urine
concentration 200 times that needed to show anti-HIV activity
could be achieved with no apparent harm to the animals (blood
concentrations were not reported). Other reasons why this work
deserves high-priority followup is that melanins are considered
relatively innocuous, can be given orally (at least in the animal
tests), are very easy to produce (the synthesis could be carried
out in a high school chemistry lab), and are inexpensive. Also,
since melanins work very differently than the available
antivirals like AZT, combinations might be especially effective.

Many questions can be raised. Melanins worked with
laboratory cell lines and viruses; would they work with fresh
cells and viruses from patients? What is the toxicity of these
chemicals in humans? And melanins may interact with certain
antibiotics or other drugs; how might this complicate their use?

Yet the existing information suggests a strong possibility
that melanins might have an important impact on AIDS/HIV
treatment worldwide. We are concerned that this opportunity may
not be realized, since under the commercial and regulatory
structure of drug development in the United States it will take
years before any standard drug could become available from this
early research -- due to delays with patents, business
negotiations, corporate restructuring, etc., as well as Federal
requirements such as excessive animal tests which should not be
allowed to impede progress in an emergency. Scattered reforms
have been made, but no one has studied the practical operation of
drug development from beginning to end, or has the authority
necessary to make the changes needed to meet the AIDS emergency
effectively.

We suggest that community-based and other research
organizations -- including institutions outside of the United
States -- investigate melanins further, and proceed if justified
to develop this information into a practical AIDS/HIV treatment.



Chinese Medicines

At the UCLA School of Medicine and Cedars-Sinai Medical
Center in Los Angeles, 57 injectable Chinese medicines were
screened against HIV in laboratory-cell cultures; 10 showed
activity (poster #Th.A. 237). These ten were then screened
against primary HIV-1 isolates (and also against HIV-2). Using
primary isolates is important because recently it has been found
that tests with cells and viruses which have lived for years in
laboratories -- the ones most convenient for scientists to use --
can show very different results than the same tests with cells
and viruses taken recently from patients.

In the first phase of testing (using cultured cells and
viruses), the therapeutic index (ratio between the concentration
which was effective and that which was harmful to the cells)
ranged from 22 to 333. Of the ten drugs which passed the first
test, the two with the greatest therapeutic index were Injection
Yin Huang (333), and Injection Co. Dan Shen (174). We do not
have the result of the second-phase tests.

Comment: Treatments based on Chinese medicine are usually
ignored in the U. S. drug-development system. The cultural bias
of Western science and medicine is to isolate one or more pure
chemicals which are effective, and then hopefully synthesize them
-- adding years of research time when an adequate herbal
treatment may already be available.

Community-based research organizations could make a major
and cost-effective contribution by organizing professional
investigation of and advocacy for treatments which, due to
cultural or commercial biases, are unlikely to get a prompt
hearing otherwise. Then small phase I/II trials could obtain
initial information about effectiveness in patients, using
standard measurements such as T-helper counts, and p24 antigen
and antibody levels. These trials could be conducted easily when
the treatments being tested are already in widespread human use.