Biology Reference
In-Depth Information
Antimalarial policy is prioritised towards eliminating the initial threat to
the patient and avoiding adverse outcomes, rather than preventing future
recurrences, which in most endemic settings are often regarded as inevi-
table. For this reason, the most important factor driving primaquine dosing
policy are concerns over its safety and tolerability rather than its treatment
efficacy. Primaquine has a well-described association with upper gastroin-
testinal discomfort. At a dose of more than 200 mg, all individuals complain
of immediate and severe cramping, but this proportion is reduced to 30% of
adults receiving 30 mg and 10% of those receiving 15 mg (
Clayman et al.,
1952
). Administering primaquine with food improves tolerance of even the
highest doses of the drug. In double blind randomized studies, 30 mg pri-
maquine daily for as long as 50 weeks was as well tolerated as chloroquine
or a placebo (
Baird et al., 2001
;
Weiss et al., 1995
).
An important constraint on the global deployment of primaquine is
its potential to cause haemolysis in patients with G6PDd, which typically
occurs in 2-15% (and up to 40%) of patients in endemic zones (
Nkhoma
et al., 2009
). Individuals who have <10% of normal enzyme activity may be
at risk of threatening haemolysis (
Pannacciulli et al., 1965
), but serious hae-
molysis has also occurred at higher levels of residual enzyme activity (
Ziai
et al., 1967
). Relative susceptibility to primaquine may not be characterized
on the basis of enzyme activity alone. Primaquine sensitivity phenotypes
have been characterized in only three of the many dozens of clinically
significant variants (A-, Mediterranean, and Mahidol variants). Much more
work is required to establish the relationship between the residual enzyme
activity and primaquine sensitivity phenotypes. This important issue is con-
sidered in greater depth in Chapter 4 of Volume B of this series.
Treatment of soldiers returning from the Korean War with vivax malaria
revealed that African-Americans were more prone to a relatively mild and
self-limiting primaquine-induced haemolysis compared to Caucasian sol-
diers. The 15 mg base daily dose (×14 days), while not efficacious against
the experimental challenges with the Chesson strain, was highly efficacious
against those Korean infections (
Baird and Hoffman, 2004
). The 15 mg reg-
imen in African-American soldiers caused relatively mild and self-limiting
haemolysis (
Alving et al., 1960
) and was thus adopted as the treatment of
choice in patients not screened for G6PDd. The US Navy and Army did
not begin routine screening of sailors and soldiers for G6PDd until 1981
and 2004, respectively. This regimen became the global standard of treat-
ment, although a 5-day regimen (15 mg daily) found favour in some nations
on the basis of a single poorly controlled trial (
Cedillos et al., 1978
). Only
