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.