Abstract
Primaquine is the only generally available anti-malarial that prevents relapse in vivax and ovale malaria, and the only potent gametocytocide in falciparum malaria. Primaquine becomes increasingly important as malaria-endemic countries move towards elimination, and although it is widely recommended, it is commonly not given to malaria patients because of haemolytic toxicity in subjects who are glucose-6-phosphate dehydrogenase (G6PD) deficient (gene frequency typically 3-30% in malaria endemic areas; >180 different genetic variants). In six decades of primaquine use in approximately 200 million people, 14 deaths have been reported. Confining the estimate to reports with known denominators gives an estimated mortality of one in 621,428 (upper 95% CI: one in 407,807). All but one death followed multiple dosing to prevent vivax malaria relapse. Review of dose-response relationships and clinical trials of primaquine in G6PD deficiency suggests that the currently recommended WHO single low dose (0.25 mg base/kg) to block falciparum malaria transmission confers a very low risk of haemolytic toxicity.
Highlights
Primaquine is an 8-aminoquinoline, a descendant of the first generally available synthetic anti-malarial plasmoquine
The downside is that they cause haemolysis in people who are glucose-6-phosphate dehydrogenase (G6PD) deficient
In some MDA programmes given to almost 300,000 people in Azerbaijan and Kunduz Province, northern Afghanistan (Mediterranean variant prevalence 5-10%), an interrupted regimen was used, designed so that haemolytic toxicity could be detected and managed
Summary
Primaquine is an 8-aminoquinoline, a descendant of the first generally available synthetic anti-malarial plasmoquine (plasmochin, pamaquine). In some MDA programmes given to almost 300,000 people in Azerbaijan (where the prevalence of G6PD deficiency, presumed Mediterranean variant, varied between 0 and 38.7%) and Kunduz Province, northern Afghanistan (Mediterranean variant prevalence 5-10%), an interrupted regimen was used, designed so that haemolytic toxicity could be detected and managed This was 15 mg primaquine (adult dose) once daily for four days, followed by three days without drug, primaquine for a further ten days [27]. Haemolysis following single-dose primaquine Haemolysis is self-limiting as primaquine is eliminated rapidly (t1/2 ~ five hours) This is exploited in the once weekly 0.75-mg base/kg radical cure regimen recommended for patients with vivax malaria and ‘mild’ G6PD variants [2,28], and the interrupted MDA regimens. These and other data are consistent with a ‘gene dosage’ effect as the African A- G6PD deficiency is less severe than the Mahidol and Viengchan variants, which in turn are less severe than the Mediterranean variant
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