Searchlight Vol. 3, no. 1

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By Henry E. Chang, Clinical Research Specialist

Ketoconazole and Diet Coke
Ketoconazole (trade name: Nizoral) is an approved
antifungal drug used for the treatment of systemic or
topical fungal infections such as candidiasis, candiduria, blastomycosis, coccidiodomycosis, and
histoplasmosis. While ketoconazole is employed in
many different clinical situations, its absorption is
often poor and requires adequate stomach acid.
Most people with AIDS, in particular those who are
taking antacids or H-2 blockers such as cimetidine
(Tagamet), have lower levels of stomach acid which
leads to diminished absorption of ketoconazole. The
drug package insert recommends that the tablets be
dissolved in 4 ml of 0.2 N HC1 or hydrochloric acid
before ingestion. Alternatively, many physicians recommend dissolving ketoconazole tablets in orange
juice. While using orange juice as a dilutent may be
a logical approach, its effectiveness on drug dissolution has not been examined.
A study conducted by Dr. E. F. Sugar and colleagues
at the Boston University Medical Center compared
the ability of nine different beverages and HC1 to dissolve 200 mg ketoconazole tablets. Refrigerated
beverages and HC1 were added to individual flasks
containing ketoconazole tablets, and then stirred vigorously three times. After six minutes, the beverages
were discarded and what remained of the tablets was
recovered from the flasks. Intact ketoconazole
tablets were recovered from two samples, lemonade
and orange juice. Minimal drug residue was left by
Coke Classic, Diet Sprite, Polar Seltzer (carbonated
water) and iced tea, and none in the Diet Coke and
HCl flask. Due to acid damage to the teeth, most
physicians are reluctant to recommend their patients
ingest HC1. The results from this study suggest that
one might see a better absorption of the ketoconazole in the carbonated drinks or iced tea.
DNCB
Topical dinitrochlorobenzene (DNCB) is a contact
sensitizing agent used in color photography.
Interestingly, DNCB acts as a potent immune modulator of dendritic cells under cell culturing conditions. Dendritic cells serve as the primary antigenpresenting cells of the human immune system.
Although few in number, these cells can be found in
a variety of human tissues including blood, thymus,
lung, skin, gut, and tonsil. A growing body of evidence suggests that as much as 25% of dendritic
cells are heavily infected with HIV in patients with
AIDS. Conversely, it is estimated that less than 0.2%
of CD4+ T cells become infected with HIV during the
course of the disease. Thus, dendritic cells may
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function as a major reservoir for HIV. Topical application of DNCB may reverse the immune dysfunction
seen in AIDS by modulating dendritic cells and stimulating cellular immune function.
In a small controlled clinical study, Dr. Raphael
Stricker and colleagues at the California Pacific
Medical Center in San Francisco with collaborators
from the University of California at San Francisco,
found a significant increase in patients' CD8+ T cell
counts (from a mean of 1,095 cells/pl to a mean of
1,255 cells/pl), while CD4+ T cell counts remained
unchanged from 3 to 18 months after DNCB treatment. Surprisingly, RNA PCR tests revealed an average of 10-fold reduction in patients' HIV viral loads
over the same treatment period. This pilot study has
demonstrated that DNCB may be a safe treatment for
individuals in the early stages of H1V infection.
Treatment with topical DNCB results in a transient
increase in CD8+ T-cells without changing CD4+ Tcell counts. However, the long-term effect of DNCB
on CD8 T-cells and HIV replication deserves further
investigation.
New Class of Anti-HIV Agents
Dr. Sylvia Lee-Huang and colleagues at the New York
University School of Medicine have isolated and purifled three inhibitors of HIV from Euphorbiaceae
himalaya seeds and carnation leaves. These proteins, GAP 31 from himalaya seeds and DAPs 30 and
32 from carnation leaves, possess potent anti-HIV
activity with little toxicity to normal cells in culture
and in mice. The effects of GAP 31, DAP 30, and
DAP 32 on HIV infection were measured by their
ability to inhibit syncytium or giant cell formation.
The dose required to achieve a 50% reduction in
giant cell formation was 0.28, 0.83, and 0.76 nM for
GAP 31, DAP 30, and DAP 32, respectively. These
proteins also inhibit HIV p24 antigen production and
viral replication.
The actual mechanism of anti-HIV action of these
compounds remains to be elucidated. The results
from this preliminary study suggest that these proteins exert their effects at different stages of the IV
life cycle, inhibiting both viral infection and replication. Because of the high therapeutic indices of
these compounds, it is likely that these proteins may
play important therapeutic roles in the treatment of
AIDS.
Prodrug of PMEA
In the last issue of Searchlight (Nov/Dec, 1992),
Gilead Sciences' PMEA was first discussed here as an

agent with broad spectrum antiviral activities. A
recent article published in AntiviralResearch by a
group of researchers at Bristol-Myers Squibb summarized the findings of a PMEA prodrug which
seems to have a greater antiviral potency than the
original PMEA compound.
PMEA is currently administered intravenously,
because the effectiveness of oral PMEA has been
reported to be very low (between 1% and 11%), in
animal models. This low oral bioavailability is
thought to make it a poor candidate for penetrating
the cellular surface. To overcome these effects, a
PMEA prodrug was made using an organic compound, thus enabling better penetration. The use of
the PMEA prodrug greatly enhanced its potency
against the herpes simplex virus type 1 and type 2 by
50-fold and 150-fold respectively when compared
with PMEA. Less dramatic differences were
observed against HIV and CMV. The results of the
study may alter the current preferred route of PMEA
administration from intravenous to an oral formulation for future clinical trials.
A Wish List
In our continuing effort to keep overhead
expenses to a minimum, your support in
the form of a donation of a piece of furniture or equipment-or the money needed
to purchase it-means that we can serve
our trial volunteers and the community
even better. If you are inspired by any of
the items on our Wish List below, please
call the SEARCH Alliance office.

* Laser Printer
(preferably
Laserwriter II
or comparable)
*Macintosh
Computers
*Lateral File
Cabinet
SPostal Scale
(one with a fivepound capacity)
*Conference
Table
*Heavy Duty Copy
Machine
SFiling Cabinets

*Bookcases
*Blackboard
(green or white
will also do)
*Refrigerator
*Books for
SEARCH's
Medical Library
*Dual Coffee
Machine (two
pots)
*Desktop
Laminating
Machine
*Desktop
Labelmaker

C0 ' C,0. SEARCHLIGHT

January/February,1998

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