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TREATMENT OF PARASITIC DISEASES 451
Pentavalent antimony (stibogluconate
sodium and meglumine antimoniate)
Two pentavalent antimony-containing drugs,
stibogluconate sodium and meglumine antimoniate,
have been used for the treatment of
leishmaniasis. They are of comparable efficacy
and toxicity when administered on the basis
of their pentavalent antimony content. Their
efficacy varies by geographic region and the
infecting Leishmania species. Treatment failures
have become increasingly common in
patients infected with L. donovani in India
and with other Leishmania species in different
areas.
Both stibogluconate sodium and meglumine
antimoniate are available only for parenteral
use. They are administered on the
basis of their pentavalent antimony content,
20 mg of Sb v per kg body weight per day. The
mechanism of action is uncertain. Pentavalent
antimony appears to be concentrated in cells
of reticuloendothelial origin, the only site where
Leishmania resides in humans.
The pentavalent antimonial drugs have
important untoward effects. Chemical pancreatitis,
muscle and joint pain, fatigue, nausea,
weakness, leukopenia, thrombocytopenia
and rash are common. Severe pancreatitis can
occur. It seems to be more likely in persons
with chronic renal insufficiency. Most recipients
of pentavalent antimony evidence nonspecific
ST-T wave changes by ECG. Sudden
death, apparently due to cardiac arrhythmia,
can occur when doses greater than 20 mg Sb V
per kg body weight per day are administered,
or at lower doses in persons with underlying
heart disease.
Amphotericin B deoxycholate and
liposomal amphotericin B
Amphotericin B deoxycholate has been used
as an alternative to pentavalent antimony for
the treatment of leishmaniasis for decades.
Amphotericin binds to sterols and probably
damages the surface membrane of Leishmania
spp. in the same manner that it affects fungi.
The major problem with amphotericin B deoxycholate
has been the requirement for parenteral
administration over long periods of time, and
its toxicity, which includes fever, malaise and,
most importantly, dose-dependent renal toxicity
and accompanying electrolyte disturbances.
A recent advance has been the use of liposomal
amphotericin B for the treatment of visceral
leishmaniasis. Leishmania resides solely
in mononuclear phagocytes, and cells of reticuloendothelial
origin which preferentially take
up liposomes. In addition, liposomal amphotericin
B is substantially less toxic than amphotericin
B deoxycholate. Liposomal amphotericin
B was the first drug to receive FDA approval for
the treatment of visceral leishmaniasis. It is as
effective as pentavalent antimonials in the
treatment of antimony-susceptible strains of
L. donovani, and it is active against antimonyresistant
strains. Liposomal amphotericin B is
less toxic than either pentavalent antimonials
or amphotericin B deoxycholate. Although not
as extensively studied, other lipid-associated
amphotericin B preparations appear to act in
the same manner as liposomal amphotericin
B and have similar toxicity profiles. The major
factors limiting the use of liposomal amphotericin
B and lipid-associated preparations is
their cost and the requirement for parenteral
administration.
Future considerations
Over the years intense interest has focused
on new approaches to the treatment of leishmaniasis.
Immunotherapy has been of potential
interest. Leishmania is found only within
mononuclear phagocytes in humans and other
mammals. It is clear from animal models of
leishmaniasis and field studies in humans that
spontaneous resolution of infection and
MEDICAL APPLICATIONS