Introduction
Hepatic latency in vivax and ovale malarias requires treatment with
8-aminoquinoline drugs in order to prevent recurrent attacks called
relapses (a therapy called radical cure). The first 8-aminoquinoline
(variously named plasmoquine, plasmochin, or pamaquine) was discovered
nearly one hundred years ago. Within four years of the reported
discovery and introduction, Sinton and colleagues working in Northern
India discovered that the combination of quinine and plasmoquine was
effective in preventing late recurrences (presumed relapses) ofPlasmodium vivax malaria (1,2). This efficacy against late
attacks of vivax malaria was very slow to be accepted by international
authorities (notably the malaria commission of the League of Nations)
and malaria experts. Plasmoquine was not well tolerated at the doses
required for radical cure– abdominal pain and vomiting were dose
limiting, and “cyanosis” was noted with higher doses (3-5). It was
also observed that about 10% of patients of African or Asian origin
developed significant haemolytic anaemia (5). The cyanosis following
pamaquine therapy was caused by methaemoglobinaemia, and the sporadic
severe haemolytic anaemia was later identified as resulting from the
oxidant drug susceptibility of erythrocytes with reduced
glucose-6-phosphate dehydrogenase (G6PD) activity. During the Second
World War recurrent vivax malaria in the Indo-Burman and Pacific
theatres of war was a major threat to soldiers on both sides. An
intensive research effort, based in the United States, set out to
discover more effective and better tolerated 8-aminoquinolines.
Pharmacometric studies in volunteers infected with P. vivax(notably the frequent relapse Chesson strain originating in New Guinea)
and in rhesus monkeys infected with P. cynomolgi continued after
the end of the Second World War, and ultimately led to the replacement
of pamaquine by primaquine in 1951 during the Korean war (6). These
large and detailed pioneering volunteer studies recorded a wealth of
valuable information.