Biology Reference
In-Depth Information
may be characterized as a deeply flawed drug. Even more remarkable, that
product remains the only therapeutic option against a serious disease that
threatens 40% of humanity.
3.3. Primaquine
Historical perspectives on the development of primaquine provide crucial
insights today as momentum builds to apply it more aggressively in reach-
ing the goals of elimination of malaria transmission (
Baird, 2010
;
Marsh,
2010
;
Feachem et al., 2010
). Knowledge of the activity of 8-aminoquino-
lines against relapse predated compelling evidence of hypnozoites (although
the likely existence of such had been broadly accepted by the 1930s). This
remained true through the BMCS efforts to replace pamaquine, and pre-
clinical screening of compounds for this activity was not possible. The
BMCS instead focused screening on toxicity in rats, dogs and monkeys,
and in so doing, wholly missed the G6PDd key to that problem. Clinical
trials on humans involving only a few dozen compounds assessed safety
and efficacy. Those trials led to discovery of G6PDd as the basis of the most
important toxicity associated with these compounds (
Beutler, 2008
). That
understanding, however, occurred only after the selection and licensing of
primaquine (in 1956). In effect, there has yet to be a systematic exploration
of chemical classes for activity against hypnozoites and superior safety in
G6PDd patients.
The research conducted principally by Alf S. Alving et al. at the Uni-
versity of Chicago involved the clinical vetting of the 8-aminoquinoline
candidates in experimentally challenged prisoner volunteers at the Stat-
eville Penitentiary at nearby Joliet, Illinois (
Comfort, 2009
). In addition
to singling out primaquine as the superior compound, those investigators
described three important therapeutic principles with 8-aminoquinolines
against relapse:
(1)
Total dose effect: whether administered as a single dose or multiple
doses over as much as 8 weeks, primaquine provides good efficacy
against relapse.
(2)
Co-drug synergy: the efficacy of primaquine hinges upon the blood
schizontocidal partner drug, even if that drug alone exerts no apparent
effect on relapse.
(3)
Safety: the haemolytic toxicity of the 8-aminoquinolines is attributable
to an inborn X-linked deficiency of G6PD.
These principles guided Alving et al. in the development of chloroquine
and primaquine for radical cure of vivax malaria. They demonstrated
