good efficacy of primaquine when administered with chloroquine, and
then they exploited the total dose effect in developing relatively safe dos-
ing regimens for undiagnosed G6PDd patients. That safety, however, was
demonstrated only in healthy adult volunteers, relatively few of them,
and only in African-Americans with the A-variant of relatively very mild
sensitivity to primaquine haemolytic toxicity ( Baird and Surjadjaja, 2011 ).
Their work nonetheless met the needs of American soldiers, the intended
beneficiaries of this Army-sponsored work. Shannon sat on the BMCS
and in 1946 expressed their efforts like this ( Shannon, 1946 ), ' The primary
purpose of the investigations has been, at all times, to satisfy specific needs of the
armed services '.
Primaquine was never adapted for use by poorly resourced nations
with endemic malaria. The currently prescribed doses derived directly
from US Army development programs not intended or optimized for
residents of endemic zones. The threat of haemolytic anaemia in undiag-
nosed G6PDd patients sharply restricts the effectiveness of this otherwise
extraordinarily useful and versatile drug. Chemotherapeutic explorations
aimed at finally adapting primaquine for use in poorly resourced systems
must consider Alving's chemotherapeutic principles in doing so. The first
two principles are considered below, and Chapter 4 of Volume B of this
series provides a full consideration of the singularly important problem of
G6PDd and primaquine therapy.
3.4. Total Dose Effect of Primaquine
In 1928 and 1930, Sinton and colleagues ( Sinton and Bird, 1928 ; Sinton
et al., 1930 ) described the successful treatment of vivax malaria deliv-
ering the same total dose of pamaquine over 21 days rather than the
recommended 5-10 days. They applied smaller doses of pamaquine over
longer periods as a means of mitigating pamaquine toxicity while incur-
ring higher risk of poor adherence. Higher doses over shorter duration
improved adherence but increased the risk of toxicity, and Sinton et al.
(1930) warned against the approach. As is explained later, striking the
same balance persists today in strategizing primaquine therapy for elimi-
nation. In 1946, Most et al. (1946a) chose 14 days as the appropriate bal-
ance between risk of harm and risk of poor adherence for pamaquine and
quinine therapy of vivax malaria. Because the therapeutic indices of the
candidate 8-aminoquinolines were not substantially higher than pama-
quine, this 14-day regimen was applied as the dosing standard in almost
all of the clinical trials of Alving et al.