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TREATMENT OF PARASITIC DISEASES 445
P. falciparum. Primaquine has gametocytocidal
activity against all four Plasmodium species
that infect humans, but this does not have therapeutic
relevance for the infected individual.
Primaquine is well absorbed orally. The
major toxicity is hemolysis in persons with
glucose-6-phosphate dehydrogenase (G-6-PD)
deficiency. It is recommended that recipients
be tested for G-6-PD deficiency before use
unless they have previously taken the drug
without adverse effect. Gastrointestinal sideeffects
occur, but usually do not necessitate the
discontinuation of therapy. Rare complications
include granulocytopenia or agranulocytosis.
Artemisinin and its derivatives
The emergence of multi-drug resistant P. falciparum
has fueled the search for new antimalarial
compounds. Extensive study of the
Chinese herbal anti-malarial, qinghaosu, led
to the characterization of artemisinin and a
number of derivatives including artesunate
and artemether. They act rapidly against multidrug
resistant P. falciparum, are relatively inexpensive
to produce, and are generally well
tolerated. They are usually administered with
mefloquine or another anti-malarial to prevent
relapse and the development of resistance.
Their short half-lives and association with
neurotoxicity after chronic administration in a
dog model mean that they are unlikely to be
used for malaria prophylaxis. Although not yet
licensed in the United States, artemisinin derivatives
are now used for P. falciparum infection
in Thailand, other areas of Southeast Asia, and
elsewhere in the world.
Artemisinin and its derivatives are endoperoxide-containing
drugs. Depending on the
compound, they are administered enterally,
intramuscularly or intravenously. Their mechanism(s)
of action are not entirely clear. In the
presence of intra-parasitic iron, they are thought
to be converted to free radicals and other intermediates
that alkylate malaria proteins or
damage parasite membranes. The artemisinin
derivatives arrest the development of parasites
in erythrocytes and prevent cytoadherence and
rosetting of infected erythrocytes.
Artemisinin derivatives are generally well
tolerated. Side-effects are infrequent and mild.
They include transient liver enzyme elevations,
gastrointestinal complaints, drug fever
and leukopenia. Central pontine demyelination
has been reported in dogs treated chronically
at high doses.
Future considerations
The propensity of Plasmodium species to
develop drug resistance suggests that it is only
a matter of time until they become resistant to
currently available medications. Resistance
has already developed to chloroquine, mefloquine,
quinine, pyrimethamine and sulfonamides
among P. falciparum and to a lesser
degree P. vivax in various regions of the world. In
fact, cross-resistance between pyrimethamine
and trimethoprim appears to be occurring as a
result of the extensive use of trimethoprim–
sulfamethoxazole prophylaxis in patients with
AIDS in Africa. In response to the known
development of resistance, combinations of
anti-malarial drugs are now being considered
in order to treat organisms potentially resistant
to one or the other and theoretically to reduce
the development of resistance. Artemisinin
derivatives have been administered with mefloquine
or other anti-malarial drugs for this
reason.
Efforts are urgently needed to identify new
anti-malarial drugs, even among known antiparasitic
drugs. For example, diamidine compounds
including pentamidine have recently
been shown to have anti-malarial activity, apparently
by binding to and preventing breakdown
MEDICAL APPLICATIONS