trans

TREATMENT OF PARASITIC DISEASES 449
Compared to the other drugs used for the treatment
of African trypanosomiasis, eflornithine
is relatively well tolerated. Adverse effects are
usually mild and reversible. They include anemia,
thrombocytopenia, leukopenia, nausea,
vomiting, diarrhea and convulsions. Interestingly,
given its mechanism of action, eflornithine
is now being produced for topical
application as a depilatory.
Unfortunately, the large amount of drug
needed and production costs have limited its
profitability and availability. As a result, production
of eflornithine for the treatment of
African trypanosomiasis has ceased, but limited
supplies of the drug are available. Even
though production may resume in the future
with support from government or nongovernment
agencies, an expensive drug such
as eflornithine is not likely to be used for the
treatment of any disease if residents of impoverished
areas are required to pay for it.
Suramin
Suramin has activity against both T. b. gambiense
and T. b. rhodesiense. It does not cross the
blood–brain barrier, and it is therefore useful
only for the hemolymphatic stage of infection.
The precise mechanism of action is not known,
but suramin is a polyanionic molecule that
complexes with and inhibits a number of
enzymes. The anti-trypanosomal effects correlate
with inhibition of the parasite’s glycerol-3-
phosphate oxidase and glycerol-3-phosphate
dehydrogenase, two enzymes that are involved
in energy metabolism.
Suramin is a toxic drug. Fever and allergic
reactions are common. Immediate reactions
include nausea, vomiting, shock, loss of consciousness
and occasionally death. Other sideeffects
include renal dysfunction, exfoliative
dermatitis, stomatitis, paresthesias, photophobia,
peripheral neuropathy, blood dyscrasias,
shock and optic atrophy. Untoward effects
seem to be more severe in malnourished hosts
and in persons with pre-existing kidney and
liver disease.
Pentamidine
Pentamidine isethionate, a diamidine, is active
against T. b. gambiense and T. b. rhodesiense
in the bloodstream and lymph nodes, but
it does not cross the blood–brain barrier. It
has also been widely used as an alternative
to trimethoprim–sulfamethoxazole for the
treatment of Pneumocystis carinii pneumonia.
Pentamidine must be administered parenterally,
either by slow intravenous infusion or by
intramuscular injection. An oral preparation is
not available.
Its mechanism of action against trypanosomes
is uncertain. Pentamidine is
known to bind to DNA in a non-intercalative
manner. It also poisons trypanosomal topoisomerase
II, resulting in linearization of minicircle
DNA in the kinetoplast. It has other
effects that may be relevant to its anti-parasitic
action, including decreased amounts of membrane
phospholipids and altered polyamine
function through a reduction in the activity of
ornithine decarboxylase.
Pentamidine is associated with a number
of side-effects, which include tachycardia,
nausea, vomiting, dizziness, facial flushing,
breathlessness and a metallic taste. Severe
hypotension can result if it is given too rapidly
by intravenous infusion. Hypoglycemia due
to pancreatic beta-cell damage and insulin
release can be severe and occasionally fatal.
Insulin-dependent diabetes mellitus may follow
in patients experiencing beta-cell damage.
Reversible azotemia, hypocalcemia and hyperkalemia
and bone marrow suppression occur.
Fatal cases of pancreatitis have been reported
in persons with AIDS who have received
pentamidine.
MEDICAL APPLICATIONS