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Primaquine: the risks and the benefits.

Ashley EA, Recht J, White NJ - Malar. J. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. nickw@tropmedres.ac.

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.

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Related in: MedlinePlus

G6PD-deficient red cell survival following daily primaquine dosing. G6PD-deficient red cell survival was assessed by 51Cr labelling and transfusion into G6PD-normal healthy recipients (15 mg/day or 45 mg single dose in Mahidol or Viengchan variants, 30 mg/day Mediterranean variant, and a range of doses in African A- variant). The corresponding haematocrit reductions following continuous dosing (or in the green bar, a single dose) in G6PD-deficient subjects are shown in the inset [17, 21–24, 37].
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Fig2: G6PD-deficient red cell survival following daily primaquine dosing. G6PD-deficient red cell survival was assessed by 51Cr labelling and transfusion into G6PD-normal healthy recipients (15 mg/day or 45 mg single dose in Mahidol or Viengchan variants, 30 mg/day Mediterranean variant, and a range of doses in African A- variant). The corresponding haematocrit reductions following continuous dosing (or in the green bar, a single dose) in G6PD-deficient subjects are shown in the inset [17, 21–24, 37].

Mentions: Primaquine is metabolized in vivo via cytochrome P450 to reactive intermediates (mainly through CYP2D6) thought to mediate both anti-malarial and haemolytic effects [34]. These active intermediates have not been characterized definitively. Individuals with CYP2D6 genetic polymorphisms conferring reduced enzyme activity may have reduced primaquine efficacy [35, 36]. The relationships between primaquine dose, duration and haemolysis were characterized in detail for the G6PD A-variant in healthy adult volunteers. A clear dose-response relationship was evident; increasing daily doses up to 45 mg progressively shortened red cell survival (Figure 2) [21]. Dosing 45 mg daily could cause severe anaemia whilst 15 mg daily caused only mild anaemia. Taking 30 mg/day for 14 days in the African A- variant resulted in approximately the same degree of haemolysis as 15 mg/day in the Mahidol or Viengchan variants, with no further decline in haemoglobin during the second week of drug administration (Figure 1). 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.Figure 2


Primaquine: the risks and the benefits.

Ashley EA, Recht J, White NJ - Malar. J. (2014)

G6PD-deficient red cell survival following daily primaquine dosing. G6PD-deficient red cell survival was assessed by 51Cr labelling and transfusion into G6PD-normal healthy recipients (15 mg/day or 45 mg single dose in Mahidol or Viengchan variants, 30 mg/day Mediterranean variant, and a range of doses in African A- variant). The corresponding haematocrit reductions following continuous dosing (or in the green bar, a single dose) in G6PD-deficient subjects are shown in the inset [17, 21–24, 37].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230503&req=5

Fig2: G6PD-deficient red cell survival following daily primaquine dosing. G6PD-deficient red cell survival was assessed by 51Cr labelling and transfusion into G6PD-normal healthy recipients (15 mg/day or 45 mg single dose in Mahidol or Viengchan variants, 30 mg/day Mediterranean variant, and a range of doses in African A- variant). The corresponding haematocrit reductions following continuous dosing (or in the green bar, a single dose) in G6PD-deficient subjects are shown in the inset [17, 21–24, 37].
Mentions: Primaquine is metabolized in vivo via cytochrome P450 to reactive intermediates (mainly through CYP2D6) thought to mediate both anti-malarial and haemolytic effects [34]. These active intermediates have not been characterized definitively. Individuals with CYP2D6 genetic polymorphisms conferring reduced enzyme activity may have reduced primaquine efficacy [35, 36]. The relationships between primaquine dose, duration and haemolysis were characterized in detail for the G6PD A-variant in healthy adult volunteers. A clear dose-response relationship was evident; increasing daily doses up to 45 mg progressively shortened red cell survival (Figure 2) [21]. Dosing 45 mg daily could cause severe anaemia whilst 15 mg daily caused only mild anaemia. Taking 30 mg/day for 14 days in the African A- variant resulted in approximately the same degree of haemolysis as 15 mg/day in the Mahidol or Viengchan variants, with no further decline in haemoglobin during the second week of drug administration (Figure 1). 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.Figure 2

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. nickw@tropmedres.ac.

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.

Show MeSH
Related in: MedlinePlus