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parasites direct from the human host after short-term cultivation ( Tasanor
et al., 2006 ; Russell et al., 2003 ; Chotivanich et al., 2004 ; Druilhe et al.,
2007 ). A variety of methods have been used to quantify parasite growth,
including a modified schizont maturation test ( Russel et al., 2008 ), enzy-
matic assays ( Druilhe et al., 2007 ) and RTPCR ( Russell et al., 2003 ).
A major confounding factor in the interpretation of these results is a
marked stage specificity of action, which varies between drugs and Plasmo-
dium sp. This property has been demonstrated for chloroquine activity in P.
vivax , with parasites at trophozoite stage showing almost complete tolerance
of chloroquine ( Russel et al., 2008 ; Sharrock et al., 2008 ). IC 50 estimates
derived from parasite isolates with a high proportion of trophozoites are
likely to be far greater than the same isolate tested at predominantly ring
stage. Unlike P. falciparum infections, the parasitaemia of P. vivax presents
with most stages of development detectable in peripheral blood smears,
the degree of asynchronicity varying with inter-related host factors (such
as immunity and age of the patient) and local transmission intensity. The
in vitro drug response, therefore, needs to be interpreted according to the
initial stage composition of the parasite population and the duration of
the assay ( Russel et al., 2008 ). The differences in quantifying in vitro drug
susceptibility may explain some of the discrepancies between results of dif-
ferent laboratories, in which derived thresholds for chloroquine resistance
have varied from 22 to 100 nM ( Druilhe et al., 2007 ; Congpuong et al.,
2002 ; Suwanarusk et al., 2007 ).
The stage specificity of action of chloroquine although apparent in P. fal-
ciparum is far less pronounced than that observed in P. vivax . This may reveal
fundamental differences in the mechanism of action of the drug between
these two species. Chloroquine activity in P. falciparum is thought to act via
inhibiting haemozoin polymerisation, a central process by which young
ring forms detoxifying digested haemoglobin in the parasite food vacu-
ole. However, in P. vivax , haemozoin does not appear until more mature
trophozoite and schizont stages, the very stages which appear tolerant of
chloroquine. The findings of Nomura et al. (2001) emphasize fundamental
differences in the mechanism of resistance to chloroquine by these two
species and the need for deeper exploration of the cellular and molecular
processes underlying therapeutic failure by resistance.
Development of a standardized ex vivo assay for assessing the therapeu-
tic susceptibility of P. vivax needs to be a research priority. Recent funding
opportunities have stimulated renewed efforts aimed at generating labora-
tory methods capable of sustaining P. vivax in continuous ex vivo culture.
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