trans

458 MEDICAL IMPLICATIONS
are thought to be due to the release of worm
antigens in the central nervous system and
concomitant inflammatory responses.
Ivermectin
Ivermectin is the 22,23-dihydro derivative of
ivermectin B1, a macrocyclic lactone produced
by the actinomycete, Streptomyces avermitilis.
It was first developed as an insecticide and as a
veterinary drug for treatment and prevention
of nematode and arthropod infections in cattle
and domestic pets. It is well absorbed orally
and typically given as a single dose. Ivermectin
potentiates the opening of glutamate-gated
chloride channels in nematodes and arthropods.
The result is an influx of chloride. In
nematodes this is associated with paralysis of
the pharyngeal pumping motion. Ivermectin is
generally well tolerated in humans, but therapy
may be complicated by fever, pruritus,
arthralgias, myalgias and cutaneous edema,
due in part to release of worm antigens.
Future considerations
The availability of ivermectin and diethylcarbamazine
allows for the treatment of the
major filarial infections. Ivermectin is indicated
for onchocerciasis and is effective against
Mansonella streptocerca. Diethylcarbamazine
is the drug of choice for W. bancrofti, B. malayi,
L. loa and tropical pulmonary eosinophilia.
Both are active against Mansonella streptocerca.
Neither works against Mansonella perstans;
mebendazole is the drug of choice.
Diethylcarbamazine is administered orally over
14 to 21 days. A drug(s) that is active against
adult filariae, results in minimal or slow release
of antigens, and can be administered as a single
oral dose would be preferable.
Platyhelminths: trematodes
and cestodes
While trematodes and cestodes have, in general,
received the least attention from a biochemical
or molecular biological perspective,
therapy against them is excellent thanks to
large scale screening programs. The development
of praziquantel, a heterocyclic prazinoisoquinoline
derivative, stands among the great
therapeutic accomplishments of this century.
Its broad spectrum of activity revolutionized
the treatment of fluke and tapeworm infections.
Praziquantel is now the drug of choice
for schistosomiasis, most other fluke infections,
and intestinal tapeworms. It is active
against Schistosoma mansoni, S. hematobium,
S. japonicum, S. melongi and S. intercalatum. It
replaced several highly toxic drugs previously
used for S. mansoni and S. haematobium, and
in the case of S. japonicum, was the first drug
to be effective. The possibility of praziquanteltolerant
S. mansoni has been suggested by
reports of decreased cure rates in some areas,
but re-infection could not be excluded. Frank
resistance has not been confirmed.
Praziquantel is also recommended for the
treatment of the liver flukes, Clonorchis sinensis,
Opisthorchis viverinni, and Metorchis conjunctus,
the intestinal flukes Fasciolopsis buski,
Heterophes heterophes, Metagonimus yokogawi,
and Nanophyetus salmincola, and the
lung fluke Paragonimus westermani. Praziquantel
is well tolerated orally and administered
in three doses daily for one or two days
depending on the indication. Only Fasciola
hepatica, the sheep liver fluke, seems to be
resistant to praziquantel. The veterinary fasciolide,
triclabendazole, was effective, but production
recently ceased. Bithionol is now the
only drug available for treatment of F. hepatica.
All of the adult tapeworms that are
found in humans, including Taenia solium,
MEDICAL APPLICATIONS