Modelling primaquine-induced haemolysis in G6PD deficiency

Watson, James A; Taylor, Walter R. J.; Ménard, Didier; Kheng, Sim; White, Nicholas J.

doi:10.7554/elife.23061

Cited by 49 publications

(45 citation statements)

References 22 publications

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“…The coarse-resolution analysis discussed here bears important limitations which need to be addressed through further development. G6PD deficiency is considered as a single universally preclusive condition, without accounting for the possibility of a protective effect of G6PD deficiency against infection, or of alternative treatment regimens which may be safely administered to P. vivax patients with certain levels of G6PD deficiency, such as 8 weekly dosing or a variable daily-dosing regimen [ 17 ]. The G6PD population estimates used came from a mapping analysis published in 2012 [ 3 ], since when there has been increased commitment to P. vivax elimination and the need to increase access to safe radical cure treatment [ 18 , 19 ].…”

Section: More Work On the Primaquine Ineligibility Problemmentioning

confidence: 99%

Primaquine ineligibility in anti-relapse therapy of Plasmodium vivax malaria: the problem of G6PD deficiency and cytochrome P-450 2D6 polymorphisms

Baird

Battle

Howes

2018

Malar J

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The hypnozoite reservoir of Plasmodium vivax represents both the greatest obstacle and opportunity for ultimately eradicating this species. It is silent and cannot be diagnosed until it awakens and provokes a clinical attack with attendant morbidity, risk of mortality, and opportunities for onward transmission. The only licensed drug that kills hypnozoites is primaquine, which attacks the hypnozoite reservoir but imposes serious obstacles in doing so—at hypnozoitocidal doses, it invariably causes a threatening acute haemolytic anaemia in patients having an inborn deficiency in glucose-6-phosphate dehydrogenase (G6PD), affecting about 8% of people living in malaria endemic nations. That problem excludes a large number of people from safe and effective treatment of the latent stage of vivax malaria: the G6PD deficient, pregnant or lactating women, and young infants. These groups were estimated to comprise 14.3% of populations resident in the 95 countries with endemic vivax malaria. Another important obstacle regarding primaquine in the business of killing hypnozoites is its apparent metabolism to an active metabolite exclusively via cytochrome P-450 isozyme 2D6 (CYP2D6). Natural polymorphisms of this allele create genotypes expressing impaired enzymes that occur in over 20% of people living in Southeast Asia, where more than half of P. vivax infections occur globally. Taken together, the estimated frequencies of these primaquine ineligibles due to G6PD toxicity or impaired CYP2D6 activity composed over 35% of the populations at risk of vivax malaria. Much more detailed work is needed to refine these estimates, derive probabilities of error for them, and improve their ethnographic granularity in order to inform control and elimination strategy and tactics.

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Section: More Work On the Primaquine Ineligibility Problemmentioning

confidence: 99%

Primaquine ineligibility in anti-relapse therapy of Plasmodium vivax malaria: the problem of G6PD deficiency and cytochrome P-450 2D6 polymorphisms

Baird

Battle

Howes

2018

Malar J

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“…One important mechanism of PQ toxicity in patients is related to the G6PD enzyme, wherein the persons with an inherited deficiency of G6PD may suffer severe side effects, in particular hemolytic anemia [40,41]. We therefore asked whether the favorable cytotoxicity profile of novel compounds 10 is retained or abolished in G6PD-deficient cells, in comparison to PQ and the most promising previous PQ derivatives from series 3 and 5.…”

Section: Cytotoxicity In G6pd-deficient Cellsmentioning

confidence: 99%

Machine learning prioritizes synthesis of primaquine ureidoamides with high antimalarial activity and attenuated cytotoxicity

Levatić

Pavić

Perković

et al. 2018

European Journal of Medicinal Chemistry

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Primaquine (PQ) is a commonly used drug that can prevent the transmission of Plasmodium falciparum malaria, however toxicity limits its use. We prepared five groups of PQ derivatives: amides 1a-k, ureas 2a-k, semicarbazides 3a,b, acylsemicarbazides 4a-k and bis-ureas 5a-v, and evaluated them for antimalarial activity in vitro against the erythrocytic stage of P. falciparum NF54. Particular substituents, such as trityl (in 2j and 5r) and methoxybenzhydryl (in 3b and 5v) were associated with a favorable cytotoxicity-to-activity ratio. To systematically link structural features of PQ derivatives to antiplasmodial activity, we performed a quantitative structure-activity relationship (QSAR) study using the Support Vector Machines machine learning method. This yielded a highly accurate statistical model (R = 0.776 in cross-validation), which was used to prioritize novel candidate compounds. Seven novel PQ-ureidoamides 10a-g were synthesized and evaluated for activity, highlighting the benzhydryl ureidoamides 10e and 10f derived from p-chlorophenylglycine. Further experiments on human cell lines revealed that 10e and 10f are an order of magnitude less toxic than PQ in vitro while having antimalarial activity indistinguishable from PQ. The toxicity profile of novel compounds 10 toward human cells was particularly favorable when the glucose-6-phosphate dehydrogenase (G6PD) was inhibited, while toxicity of PQ was exacerbated by G6PD inhibition. Our work therefore highlights promising lead compounds for the development of effective antimalarial drugs that may also be safer for G6PD-deficient patients. In addition, we provide computational inferences of antimalarial activity and cytotoxicity for thousands of PQ-like molecular structures.

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“…Treatment of the blood stages of acute vivax malaria relies on the schizontocidal agent chloroquine (CHQ) in most parts of the world, and is safe in pregnancy [7]. Relapse prevention is achieved with the 8-aminoquinolines primaquine (PMQ) or tafenoquine (TQ), both active against P. vivax hypnozoites [7,8] and contra-indicated in pregnancy as the glucose-6-phosphate dehydrogenase (G6PD) status of the fetus cannot be determined antenatally in most malaria endemic settings.…”

Section: Introductionmentioning

confidence: 99%

Vivax malaria in pregnancy and lactation: a long way to health equity

Brummaier

Gilder

Gornsawun

et al. 2020

Malar J

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Background: The Sustainable Development Goals (SDG) call for increased gender equity and reduction in malariarelated mortality and morbidity. Plasmodium vivax infections in pregnancy are associated with maternal anaemia and increased adverse perinatal outcomes. Providing radical cure for women with 8-aminoquinolines (e.g., primaquine) is hindered by gender-specific complexities. Case presentation: A symptomatic episode of vivax malaria at 18 weeks of gestation in a primigravid woman was associated with maternal anaemia, a recurrent asymptomatic P. vivax episode, severe intra-uterine growth restriction with no other identifiable cause and induction to reduce the risk of stillbirth. At 5 months postpartum a qualitative glucose-6-phosphate dehydrogenase (G6PD) point-of-care test was normal and radical cure with primaquine was prescribed to the mother. A 33% fractional decrease in haematocrit on day 7 of primaquine led to further testing which showed intermediate phenotypic G6PD activity; the G6PD genotype could not be identified. Her infant daughter was well throughout maternal treatment and found to be heterozygous for Mahidol variant. Conclusion: Adverse effects of vivax malaria in pregnancy, ineligibility of radical cure for pregnant and postpartum women, and difficulties in diagnosing intermediate levels of G6PD activity multiplied morbidity in this woman. Steps towards meeting the SDG include prevention of malaria in pregnancy, reducing unnecessary exclusion of women from radical cure, and accessible quantitative G6PD screening in P. vivax-endemic settings.

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Modelling primaquine-induced haemolysis in G6PD deficiency

Cited by 49 publications

References 22 publications

Primaquine ineligibility in anti-relapse therapy of Plasmodium vivax malaria: the problem of G6PD deficiency and cytochrome P-450 2D6 polymorphisms

Primaquine ineligibility in anti-relapse therapy of Plasmodium vivax malaria: the problem of G6PD deficiency and cytochrome P-450 2D6 polymorphisms

Machine learning prioritizes synthesis of primaquine ureidoamides with high antimalarial activity and attenuated cytotoxicity

Vivax malaria in pregnancy and lactation: a long way to health equity

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