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  43. Nelwan EJ, Ekawati LL, Tjahjono B, Setiabudy R, Sutanto I, Chand K, Ekasari T, Djoko D, Basri H, Taylor WR, Duparc S, Subekti D, Elyazar I, Noviyanti R, Sudoyo H, Baird JK. Randomized trial of primaquine hypnozoitocidal efficacy when administered with artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax in Indonesia. BMC Med. 2015; 13: 294.Legends to FiguresFigure 1. Haemoglobin - methaemoglobin interconversion. The major factor contributing to reduction of methaemoglobin back to haemoglobin is the activity of the red cell NADH cytochrome B5 MetHb reductase. MetHb: methaemoglobin.
Figure 2: The figures show increasing levels of methaemoglobinaemia (as a proportion of the corresponding haemoglobin concentration) during radical curative treatment of vivax malaria with primaquine. On the left (Figure 2A) primaquine 30mg base/day was given to adults for 14 days either concurrently with quinine, or 28 days after a treatment dose of dihydroartemisinin-piperaquine (from Sutanto et al (21)). On the right (Figure 2B) primaquine was given to adults and children either at a dose of 0.5mg base/kg /day for 14 days or 1mg/kg/day for 7 days and patients were randomized to receive concurrent chloroquine or dihydroartemisinin-piperaquine (from Chu et al (22))
Figure 3: During the clinical investigations, conducted over 70 years ago in the USA, to develop new 8-aminoquinolines 18 different compounds were evaluated in addition to pamaquine, and later primaquine (23-25). Each was administered for 14 days concurrently with quinine. The volunteers were infected by multiple bites of A. quadrimaculatusinfected with the Chesson strain of P. vivax . The figure shows the relationship between the radical cure proportion and the average blood methaemoglobin concentration (%) measured in the last 4 days of treatment. The size of the circles is proportional to the number recruited as shown in the inset box.
Figure 4: Dose-response relationships for primaquine and tafenoquine in generating methaemoglobinaemia (21,22, 24-26, 28-32). The dose shown is the daily adult dose of primaquine, whereas for tafenoquine the dose shown is the total dose administered. The size of the circles is proportional to the number of patients or volunteers recruited as shown in the inset box.
Figure 5: Studies conducted during the development of primaquine which assessed the average methaemoglobin concentration (%) as a proportion of the haemoglobin concentration in the last 4 days of treatment in relation to the dosing of plasmoquine (pamaquine) (left) and primaquine (right) (11,33,37). These initial observations suggested that methaemoglobinaemia following primaquine, but not plasmoquine, was attenuated by concomitant administration of chloroquine or quinine. However, later studies (summarized in Figure 6) did not confirm this. The size of the circles is proportional to the number of patients or volunteers recruited as shown in the inset box.
Figure 6: More recent studies in which methaemoglobinaemia has been assessed after different dose regimens of primaquine whether given alone (26,39-41), or in combination with antimalarial drugs (18, 34, 37, 38), either to healthy volunteers, in antimalarial prophylaxis, or in the treatment of vivax malaria (15,19,21,22,24-26,28-32,37,42,43). These do not suggest attenuation of primaquine induced methaemoglobinaemia by concomitant antimalarial drugs (as reported by Clayman et al (37)), nor are there differences between healthy subjects and patients with malaria. The size of the circles is proportional to the number of patients or volunteers recruited as shown in the inset box.
Figure 7: Mean values of haemoglobin (g/dL) and methaemoglobin (%) in 12 normal and 12 African A- G6PD deficient volunteers given primaquine (from Brewer et al (26)).