Biology Reference
In-Depth Information
Malaria drug developers may solve the problem of 8-aminoquinoline
toxicity in G6PDd patients by simply mining the phenomenon of co-drug
synergy to discover, perhaps, a co-drug (whether it happens to be a blood
schizontocide or not) that provides complete efficacy against hypnozoites
at doses below the threshold of harm to the most sensitive G6PDd variants.
This phenomenon, recognized in 1955 as the hypnozoitocide development
program was drawing to a close, was not further leveraged to improve the
therapeutic index of primaquine. Schmidt began an exploration of co-drug
synergy in the 1980s for that expressed purpose, but the Army abandoned
tafenoquine for radical cure in favour of a chemoprophylaxis development
strategy. A full exploration of co-drug synergy with primaquine and tafeno-
quine should at last be carried out.
Alving's unpublished 1949 report (
Alving et al., 1949
) to his sponsors
describing the complete abrogation of severe haemolytic sensitivity to an
8-aminoquinoline (isopentaquine) by the addition of methylene blue to
the treatment suggests yet another approach. Rather than dose reduction,
detoxifying the 8-aminoquinoline at standard dosing appears possible.
Ironically, the logical starting point for that exploration is precisely that
which launched modern antimalarial drugs - the aniline dye methylene
blue. This compound is a licensed therapy for a number of indications,
including reversal of the profound methaemoglobinemia of nitrite poi-
soning. It is at least plausible that this therapeutic effect could uncouple
the oxidative events that lead to 8-aminoquinoline-induced haemolysis.
Confirming and optimizing this effect at high doses of primaquine, along
with co-formulation, would perhaps provide universally safe and effective
therapy against relapse.
Another approach to minimizing harm is to effectively exclude those at
risk. Among patients and subjects considered good candidates for the treat-
ment, the 8-aminoquinolines are remarkably safe and well tolerated when
administered with food, even in relatively massive doses (e.g. a 200 mg sin-
gle dose (
Clayman et al., 1952
) or 30 mg daily for 50 weeks (
Fryauff et al.,
1995
)). A point-of-care G6PD diagnostic device would open up high-dose/
short-duration dosing for most patients. Such development is at last under-
way and shows promise (
Kim et al., 2011a
).
9.5. New Drug Discovery
Unless the new blood schizontocides being discovered for falciparum
malaria fail against vivax malaria, there is no practical need for such discov-
ery solely for
P. vivax
. That highly sophisticated pipeline has produced good
