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400 DRUG RESISTANCE
It is now estimated that almost half of the
world population is at risk from malaria. This
risk translates into an annual incidence rate of
some 400 million clinical cases and between
1.5 and 2.7 million deaths. Almost all of these
deaths are due to infection with Plasmodium
falciparum. Moreover the burden of this mortality
is seen in sub-Saharan Africa with young
children and pregnant mothers, deficient in an
adequate immune response to infection, being
by far the most at-risk groups.
Efforts to control malaria by targeting the
mosquito vector continue, but represent a
measure that at best may reduce malaria incidence.
Malaria vaccines may offer a long-term
solution to this disease but as yet a suitable
vaccine remains many years away. Thus our
principal tool in the control and treatment
of malaria is chemotherapy. The practice of
malaria chemotherapy has been in operation
over many centuries. Despite this, as we enter
the twenty-first century we find ourselves with
only a handful of anti-malarial drugs with potential
clinical utility. Moreover, parasite resistance
to almost all of these drugs has been identified
in wild parasite populations present in endemic
areas of the world. As with all parasitic diseases
targeting resource-poor areas of the world, the
situation is exacerbated by issues of drug affordability
and drug access.
Drug resistance in malaria is a major challenge.
Failure to understand the factors contributing
to resistance development in the field
and failure to elucidate the basic biological
mechanisms of resistance will have a devastating
impact on our ability to deal with this lifethreatening
infection.
Chloroquine
The 4-aminoquinoline chloroquine (Figure
16.2) was introduced into clinical medicine in
the 1940s and was the mainstay of malaria
control efforts until the development and
spread of resistance to the drug. Despite a general
perception to the contrary there remain
areas of the world where chloroquine is still
effective. Furthermore, chloroquine remains
the first choice anti-malarial drug in many parts
of the world even where its clinical effectiveness
has been seriously eroded. Against a parasitesusceptible
backdrop, chloroquine’s success
can be explained in terms of its affordability,
safety (when used as indicated), ease of use
and effectiveness. Chloroquine’s principal target
is the intraerythrocytic feeding trophozoite
stage.
The concept of chloroquine resistance was
not generally appreciated until some 15–20
years after the drug’s clinical introduction. It
was not until the late 1950s that reports of clinical
failure of chloroquine were reported independently
from SE Asia and South America.
Since these initial reports chloroquine resistance
has gradually spread to encompass all
malaria endemic regions of the world, with the
late 1970s marking the period when resistance
reached East Africa. In order to fully understand
chloroquine resistance it is important
to recognize that resistance acquisition took
many years to develop. Even then it only
occurred in a limited number of geographical
foci with their own transmission characteristics
and chloroquine treatment experiences. This
contrasts with drugs such as pyrimethamine,
where resistance has developed quickly and
independently on a number of occasions. This
difference must reflect the relative complexity
of the chloroquine resistance mechanism compared
to the simple point mutations in dhfr that
are associated with reduced pyrimethamine
sensitivity.
Parasites are generally referred to as chloroquine-resistant
or chloroquine-sensitive. This
definition may be acceptable from a clinical
stance, but from a biological perspective it fails
MEDICAL APPLICATIONS