trans

450 MEDICAL IMPLICATIONS
Melarsoprol
Melarsoprol, or Mel B, is a trivalent arsenical.
It has the distinction of being one of the most
toxic drugs administered to humans. It is used
for the treatment of central nervous system
trypanosomiasis. Melarsoprol is given intravenously.
A small, but adequate concentration
of the drug is found in the central nervous system.
Melarsoprol is thought to enter the parasite
through an adenosine transporter, and
like other arsenicals, reacts with sulfhydryl
groups to inactivate enzymes. It may act differentially
on the parasite’s pyruvate kinase.
Reactive encephalopathy is the most feared
complication with melarsoprol and can cause
death in as many as 4–6% of those treated.
The syndrome is characterized by headache,
dizziness, mental dullness, confusion, ataxia
and grand mal seizures with progression to
obtundation and coma. It is thought to be due
at least in part to an immunologic reaction.
Corticosteroids such as prednisolone or prednisone
reduce the risk of encephalopathy and
mortality. Other untoward effects are common
with melarsoprol and include allergic reactions
such as rash and fever, abdominal pain,
vomiting, arthralgias, a Guillain–Barré-like
syndrome, hepatitis and renal toxicity. Severe
hemolysis can occur in patients with G-6-PD
deficiency. Erythema nodosum has been
reported in patients who were concurrently
infected with Mycobacterium leprae.
Future considerations
The first priority in African sleeping sickness is
to secure adequate supplies of eflornithine for
the treatment of T. b. gambiense infection. Its
production for oral and intravenous administration
has ceased, but it is now being used
topically as a depilatory, which raises the possibility
that the manufacturer could donate supplies
in the future. It would be advantageous to
have a drug with a similar mechanism of
action, but with greater potency and improved
pharmacodynamics.
Even with adequate supplies of eflornithine,
there would still be substantial problems in
the treatment of T. b. rhodesiense infections. The
organism is resistant to eflornithine, and the
drugs available to treat it are highly toxic.
The African trypanosomes evade humoral
host defenses by antigenic variation of surface
glycoproteins, as discussed in Chapter 5. An
attractive target for novel chemotherapeutic
interventions would be the parasite’s mechanism
of antigenic mimicry. If the switch in variant
surface glycoproteins were blocked, host
defenses would probably be effective in eliminating
infection. Other alternatives include
targeting the kinetoplast, as discussed in reference
to T. cruzi above. It is conceivable that
new drugs developed for one kinetoplastid will
be found to have activity against others.
Leishmania spp. (cutaneous, mucosal and
visceral leishmaniasis)
Pentavalent antimonials have been used for
decades for the treatment of cutaneous,
mucosal and visceral leishmaniasis. They are
also associated with substantial toxicity, and
there has been evidence of increasing resistance
among Leishmania spp. in widely scattered
areas. Amphotericin B deoxycholate and
pentamidine isethionate have been effective,
but toxic, alternatives. Major advances have
been made in the treatment of visceral leishmaniasis
in recent years. The most dramatic
was the introduction of liposomal amphotericin
B for the treatment of visceral leishmaniasis.
It recently became the first drug approved
by the US Food and Drug Administration for
this indication. A number of alternative drugs
and therapeutic approaches have been examined
over the years and are discussed below.
MEDICAL APPLICATIONS