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diagnostics (see Minimizing Harm below). Proof of safety with standard
primaquine dosing in G6PD normal patients is required for new part-
ners with primaquine in radical cure. As the harmful drug-drug interac-
tion between atabrine and pamaquine clearly demonstrated in 1943, similar
poor outcomes combining these families of compounds is possible. Lack of
PK/PD data on DHA-PP and primaquine impelled the day 28 dosing of
primaquine in the Indonesian study discussed. Concurrent administration
would be the preferred approach in order to maximize both possible syner-
gies and convenience of dosing. Blood schizontocides intended for partner-
ing with primaquine require PK/PD studies in healthy volunteers to guide
and affirm safe dosing strategies.
9.3. Proof of Effectiveness
As occurred with pamaquine nearly a century ago, malaria chemothera-
pists today strive to balance risk of harm against risk of poor adherence
with primaquine. A high-dose/short-duration regimen that generates fear
in patients and health care workers would likely prove as ineffective as low-
dose/long-duration strategies. In the absence of non-threatening doses of
primaquine or a practical means of excluding the vulnerable (see Section
9.4 ), this problem will persist. Malariologists should strive to develop the
evidence required to buttress strategies aimed at levels of effectiveness that
successfully challenge the hypnozoite reservoir in endemic zones. Miti-
gating fear, for example, may be accomplished with practical early detec-
tion of haemolysis and cessation of dosing. Likewise, demonstrations of the
impact of successful primaquine strategy in communities may provide the
motivation for providers and patients alike to strive for fuller adherence.
Confidence in the success of primaquine therapy, as in almost all human
endeavours, would inspire fuller commitment to it.
9.4. Minimizing Risk of Harm
Two 8-aminoquinoline drugs, primaquine and tafenoquine, represent the
only likely agents of anti-relapse therapy for the coming decade. The threat
that these drugs pose to unscreened patients with G6PDd severely limits
their effectiveness in combating endemic malaria. Shorter duration, higher
dose regimens of primaquine, like pamaquine before it, were not considered
because of the threat such dosing posed to unscreened G6PDd patients.
Tafenoquine progressed through 30 years of development almost solely on
the promise of shorter duration dosing and, presumably, assured exclusion of
G6PDd patients from perhaps catastrophic exposure to drug.
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