trans

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prevention of re-infection are associated with
activation of macrophages by interferon- in
concert with other cytokines of the TH1 type.
A logical extension from these findings was
the use of recombinant interferon- for the
treatment of human leishmaniasis. Unfortunately,
interferon- was not curative when
used alone, but the combination of interferon-
and pentavalent antimony was effective in
cases where antimony alone had failed. Interestingly,
‘immunotherapy’, in which a crude
leishmanial promastigote antigen preparation
is administered concurrently with BCG, results
in slow healing of cutaneous leishmaniasis. It is
possible that effective immunological manipulation
will emerge as the treatment of choice
for leishmaniasis in the future. It is also likely
that an effective anti-leishmanial vaccine will
eventually be developed.
Over the years a number of case reports and
uncontrolled case series have suggested that
various antibiotics and other drugs might be
effective. Interpretation was difficult because
cutaneous leishmaniasis eventually heals spontaneously.
Without appropriate controls, data
suggesting a positive outcome are difficult to
interpret. More recently, well controlled trials
indicate that locally applied heat is effective in
the treatment of cutaneous leishmaniasis, but
it is difficult to administer. Ketoconazole and
itraconazole, both azole antifungals, also have
some activity against selected Leishmania spp.
However, none of these drugs or approaches
has proven to be sufficiently effective to be recommended
for general clinical use.
Three experimental approaches are worthy
of further discussion. In the first, elegant studies
of pyrazolopyrimidines demonstrated how
a detailed understanding of the parasite’s biochemistry
could lead to rational drug design.
In the second, the synthesis of inhibitors
selectively active against leishmanial topoisomerase
II was shown to be possible. And third,
the development of an anti-cancer drug,
miltefosine, appears particularly promising in
studies of human visceral leishmaniasis in
India.
Pyrazolopyrimidines (allopurinol and
allopurinol ribonucleoside)
The metabolism of purines in trypanosomes
and leishmania differs significantly from that
in humans. Leishmania and trypanosomes
rely on salvage pathways to obtain purine
analogs, whereas humans synthesize purines
de novo. Certain purine analogs are metabolized
by parasites to nucleotides and aminated
to analogs of adenine nucleotides. These stop
protein synthesis and result in breakdown of
RNA. Pyrazolo[3,4-d]-pyrimidines, such as
allopurinol and allopurinol ribonucleoside,
are aminated to adenine nucleotide analogs
in this manner. They have been shown to kill
Leishmania spp. and T. cruzi in vitro and in
animal models. Activity was also demonstrated
in a study of American cutaneous leishmaniasis,
but the efficacy was not sufficient for these
drugs to be recommended for routine clinical
use. Nonetheless, the development of the
pyrazolopyrimidines illustrates how differences
in metabolic pathways between parasites
and humans can potentially be exploited
in the development of new approaches to
chemotherapy.
Topoisomerase II inhibitors
Building on studies of topoisomerase II in trypanosomes,
leishmanial topoisomerase II has
been cloned, sequenced and studied. Selective
activators and inhibitors that are lethal
for Leishmania have been synthesized. They
appear to act in a manner similar to the fluoroquinolone
antibiotics, such as ciprofloxacin,
that inhibit topoisomerase II (which is known
as DNA gyrase) in susceptible bacteria. The
findings suggest that specific topoisomerase
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