Biology Reference
In-Depth Information
the efficient harvest of as many sporozoites as possible derived from a single
patient at a single time, thus maximizing the number of assays that could
be evaluated without confounding by strain variability (Hoffman). This
approach requires an almost industrial approach to the problem.
Understanding and segregating tissue schizontocidal vs. hypnozoitocidal
activity is crucial in
ex vivo
assessment of hypnozoitocidal activity. Prevent-
ing the development of hypnozoites (tissue schizontocidal) fundamentally
differs from killing extant hypnozoites (hypnozoitocidal). Causal prophy-
laxis with primaquine, for example, likely works by killing active early liver
stages destined to be either primary tissue schizonts or hypnozoites. This is
tissue schizontocidal activity and is achieved at much lower doses relative to
standard radical cure of patients with acute vivax malaria (Section
4
). They
already harbour hypnozoites and primaquine therapy must destroy them.
Ex vivo
systems that demonstrate inhibition of hypnozoite formation by
drug exposure during or soon after introduction of sporozoites do not offer
insights relevant to radical cure. Systems capturing hypnozoitocidal activity
must demonstrate inhibition of hypnozoite activation by drugs introduced
to the system following their maturation to dormant hypnozoites. This rep-
resents a much steeper technical challenge than demonstration of inhibition
of hypnozoite formation.
8.3.2.1. Non-human primates
Plasmodium vivax
in non-human primates does not form viable hypnozoites,
with the exception of chimpanzees. This renders their evaluation for suscep-
tibility to primaquine virtually impossible by this means. Although techni-
cally feasible with chimpanzees, this approach would be extremely costly,
and socially and ethically challenging. Infecting a chimpanzee with an isolate
or strain would likely be a very rare event compelled by extreme scientific
interest, need, and potential benefit. Federal legislation being considered by
the US Congress in 2012, however, would prohibit such experimentation.
9. RESEARCH AND DEVELOPMENT URGENCIES
This chapter presents the complexities and challenges of the current
state of the diagnosis and treatment of vivax malaria. Failing chloroquine
and the challenge of deploying primaquine reliably in a safe and effective
manner, lie at the heart of vivax chemotherapeutics. However, progress has
been made, particularly in the past 5 years with a growing awareness among
malariologists of the importance of
P. vivax
. Long withheld fiscal resources
