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438 MEDICAL IMPLICATIONS
transmission to others. Eradication of parasites
in an entire population remains the long-term
goal. Eosinophilia, which is not typically present
in protozoal infections, is often observed when
worms migrate through tissues.
The helminths are divided into nematodes
(roundworms) and platyhelminths (flat worms).
Roundworms can be further subdivided into
those that reside as adults in the human intestinal
tract and those that reside in tissue. The
platyhelminths are further subdivided into the
trematodes or flukes, and cestodes or tapeworms.
The outcome of any parasitic infection
depends on the genetically determined virulence
of the infecting parasite and the genetically
determined innate and acquired immune
responses of its host. Much needs to be learned
about the virulence factors of parasites, but
advances have been made. For example, the
mechanisms by which hookworms anticoagulate
host blood so that it will flow through
their gastrointestinal tracts have been worked
out. As virulence traits are understood, potential
points of intervention will likely emerge.
The sequencing of genomes of major parasitic
pathogens should expedite these efforts. The
genetic approach to analysis of virulence is
given in Chapter 6.
With virtually all parasitic infections, there is
a spectrum of disease. Some humans mount
effective host defenses and either eradicate the
invading pathogen or substantially limit its
numbers. For example, under conditions of
apparently comparable transmission, intestinal
helminths are not evenly distributed in the
population. Some persons have heavy burdens
while others have a limited number of worms.
Recent epidemiological data from family studies
of intestinal helminthic infections suggest that
genetically determined variations in human
susceptibility account for much of the variation.
A review of the innate and acquired human
host defenses effective against various parasites
is beyond the scope of this chapter, but
it is important to remember that the effects of
chemotherapy must be viewed in the broad
context of the host–parasite interaction.
Some anti-parasitic drugs act on molecules
that are unique to the parasite. Others act
preferentially against parasite enzymes. For
example, pyrimethamine inhibits both plasmodial
and human dihydrofolate reductase,
but it is greater than 1000-fold more active
against the parasite enzyme. Other drugs are
effective by virtue of differences in their distribution
between parasites and humans. In the
case of chloroquine, the drug is concentrated
in infected erythrocytes, resulting in high concentrations
in parasitophorous vacuoles. Differences
in metabolism render some drugs toxic
to parasites, but not to humans. For example,
electron transport proteins with low redox
potential in anaerobic organisms like Entamoeba
histolytica reduce metronidazole. It
thus acts as an electron sink, depriving the
parasite, but not the host, of the required
reducing equivalents.
An overview of the major parasitic diseases
and the drugs that are currently used to treat
them reveals substantial differences in efficacy
and toxicity. Protozoal pathogens currently provide
the greatest challenge for chemotherapy.
As discussed in Chapter 16, evolving drug resistance
has been a major problem among Plasmodium
species that cause malaria. The drugs
now used to treat Chagas disease, African trypanosomiasis,
and leishmaniasis are variably
effective and have substantial toxicity. In contrast,
while the helminths are among the least
studied of the parasitic pathogens, highly active,
broad spectrum, relatively non-toxic, recently
recognized drugs are currently available to treat
most of them.
The historical background, current status
of chemotherapy and potential future
MEDICAL APPLICATIONS