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be reduced to levels tolerated by all recipients '. However, the Army program
developing tafenoquine turned their energies to its use as an agent of pro-
phylaxis rather than radical cure. No further exploration of synergy of the
8-aminoquinolines against relapse occurred.
Through a fitful drug development program stretching over more than
three decades, the US Army abandoned tafenoquine for prophylaxis and
today GlaxoSmithKline (GSK) and the Medicines for Malaria Venture
(MMV) are developing the drug for radical cure of vivax malaria. In a series
of experiments using P. cynomolgi challenge in rhesus monkeys not designed
to detect the phenomenon, US Army scientists noted that the minimally
effective dose of tafenoquine could be reduced 10-fold when administered
with blood schizontocidal therapies ( Dow et al., 2011 ). Exploring co-drug
synergies with primaquine or tafenoquine may indeed yield safe 8-amino-
quinoline therapies against relapse, should drug developers at last commit
to the therapeutic principles laid down by Alving et al. over 60 years ago.
3.6. Chloroquine-Resistant Vivax Malaria
The emergence of resistance to chloroquine by the asexual blood stages
of P. vivax represents another important historical event that provides key
perspectives in managing the problem today. Although resistance to chlo-
roquine in P. falciparum appeared as early as the late 1950s, the first report
of this in P. vivax did not appear until 1989 ( Whitby et al., 1989 ). There are
several likely explanations for that seemingly long delay, one or all of which
may have played a role. These are described later in this chapter.
The onset of resistance to chloroquine, and its continuing emergence
today, profoundly impacts the treatment of vivax malaria and therefore its
management as a global problem. This single problem effectively unhinges
chemotherapeutics of the infection for the simple reason that there is only
a single proven means of radical cure, i.e. chloroquine and primaquine. That
60-year-old treatment has failed in much of malarious Southeast Asia and
now threatens South Asia, these areas accounting for over 80% of the global
burden of P. vivax .
The emergence of chloroquine-resistant vivax malaria impels clinical devel-
opment of new ways of achieving radical cure. A concerted effort to address
this problem has not been undertaken since the 1940s, when large-scale studies
in American prisoner volunteers were conducted. The choice of those subjects
should not be construed as having been a matter of convenience - freedom
from confounding by reinfection was essential to the successful development
of chloroquine-primaquine. Today the use of prisoner volunteers is not an
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