Biology Reference
In-Depth Information
therapies for the acute attack and is likely to continue doing so. Necessary
drug discovery for vivax malaria is effectively limited to hypnozoitocides,
and so far, only the 8-aminoquinolines (and their attendant toxicity issues)
have shown broad activity as a class. However, that search has had important
limitations, and still does.
Pamaquine was not identified on the basis of screening for anti-
relapse activity. Likewise, primaquine was selected for superior activity
against relapse in humans from a field of just a few dozen candidate
8-aminoquinolines chosen solely on the basis of toxicity data irrelevant
to the G6PDd problem. Activity against hypnozoites and toxicity in
G6PDd erythrocytes never entered the development algorithm. An effort
by the US Army during the 1970s and 1980s, however, was informed by
screening diverse chemicals for anti-relapse activity against
P. cynomolgi
in rhesus monkeys. The broad failure of chemicals not belonging to the
8-aminoquinolines, and the broad success of those that did, brought res-
ignation to an enduring problem of haemolytic toxicity in radical cure
of vivax malaria.
The US Army faced this problem by striving to find a means of estimat-
ing relative haemolytic toxicity in a pre-clinical
in vitro
system (
Baird et al.,
1984
,
1986a
,
1986b
;
Baird, 1984
). The mechanism of primaquine-induced
haemolysis, at the time (and in some quarters, still) believed to be genera-
tion of an intracellular oxidizing stress generated by primaquine metabo-
lites, could not be reconciled with those
in vitro
data. Oxidative injury did
not correlate with the oxidative activity of 8-aminoquinolines, very similar
to methylene blue (
Baird, 1984
). An unknown mechanism of haemolysis
was at work in G6PDd red blood cells. The failure to elucidate that process
effectively crippled pre-clinical screening of 8-aminoquinoline candidates
for haemolytic toxicity. Tafenoquine advanced through development with
almost no understanding of its potential haemolytic toxicity relative to pri-
maquine. In 2012, more than 30 years after the entry of tafenoquine into
clinical studies that critical assessment awaits the completion of dose chal-
lenge studies in healthy G6PDd volunteers.
Drug discovery of hypnozoitocides, in the absence of a stroke of
extraordinary luck in the very limited screening capacity made available
with
P. cynomolgi
in rhesus macaques, will remain limited to 8-aminoquin-
olines. Discovery of a means of pre-clinical screening against haemolytic
toxicity will be an essential element of that complex task. That will likely
require elucidation of the molecular basis of 8-aminoquinoline haemo-
lytic toxicity and rational leveraging of that understanding in pre-clinical
screening.
