Biology Reference
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The success of these will have a huge impact in transforming the current
ex vivo assays into a more robust in vitro test that will permit its application
repeatedly to the same parasite isolate. However, despite its limitations, the
current schizont maturation assay has shown utility in discriminating para-
site populations with different degrees of chloroquine resistance ( Hasugian
et al., 2009 ; Suwanarusk et al., 2007 ; Chotivanich et al., 2009 ), characteriz-
ing drug susceptibility profiles ( Chotivanich et al., 2009 ; Suwanarusk et al.,
2008 ) and the screening of susceptibility to therapeutic agents ( Price et al.,
2010 ; Lek-Uthai et al., 2008 ; Marfurt et al., 2011a , 2011b ). This work per-
mits definitive drug resistance phenotyping, and thus, the vitally important
search for its genetic determinants.
8.2.2. Genetic basis of P. vivax drug resistance
Preliminary studies on drug resistance in P. vivax have focused on the ortho-
logues of the transporter genes pfcrt and pfmdr1 , known to be key determi-
nants in P. falciparum resistance. The role of pvcrt-o in chloroquine-resistant
P. vivax is not immediately apparent. Nomura et al. (2001) compared pfcrt
homologues from a number of species and although synteny was observed
between P. falciparum and P. vivax , they found no relationship between muta-
tions in pvcrt-o and the clinical. Using an experimental system, in which
pvcrt-o was transfected into P. falciparum , Sa et al. (2006) demonstrated a
potential role for pvcrt-o in chloroquine transport across membranes, a thre-
onine mutation at position 76 in their Dictyostelium system being associ-
ated with impaired accumulation of chloroquine. However, the relationship
between pvcrt-o sequence and either clinical or in vitro phenotype was not
apparent in studies of more than 330 field isolates from Thailand, Indonesia
and Madagascar ( Barnadas et al., 2008 ; Suwanarusk et al., 2007 ). An interest-
ing study of returning travellers with severe vivax malaria contracted from
the Brazilian Amazonia, found twofold increased pvmdr1 copy number and
21-fold increased copy number of pvcrt-0 compared to a patient with non-
severe vivax malaria ( Fernandez-Becerra et al., 2009 ). No studies have eval-
uated the role of pvcrt-o amplification as a marker of CQR in this parasite.
More progress has been made correlating CQR P. vivax with single-
nucleotide polymorphisms of pvmdr1 . Field studies of a large number of
clinical isolates demonstrated that aY976F pvmdr1 polymorphism was pres-
ent in nearly all patients presenting to a clinic in Papua Indonesia, where
high-grade CQR is known to be present ( Suwanarusk et al., 2007 ). The
same study showed that the same mutation was only present in 25% of iso-
lates in Thai isolates from an area where chloroquine retains high efficacy,
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