Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, dose-ranging trial

Eziefula, Alice C; Bousema, Teun; Yeung, Shunmay; Kamya, Moses R.; Owaraganise, Asiphas; Gabagaya, Grace; Bradley, John; Grignard, Lynn; Lanke, Kjerstin; Wanzira, Humphrey; Mpimbaza, Arthur; Nsobya, Samuel L.; White, Nicholas J.; Webb, Emily L.; Staedke, Sarah G.; Drakeley, Chris

doi:10.1016/s1473-3099(13)70268-8

Cited by 103 publications

(144 citation statements)

References 37 publications

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“…There were no betweengroup differences in initial asexual parasite clearance in the main trial (29), so this phenomenon is unlikely to have been influential in the present substudy. In addition, and in support of the validity of our findings, the gametocyte carriage times in the two groups (13 and 20 days in the artemether-lumefantrine and artemisininnaphthoquine groups, respectively) are in accord with those in studies that have used the same mathematical model (12.8 days after artemether-lumefantrine in Ugandan children ages 1 to 10 years [39], 13.4 days after treatment with sulfadoxine-pyrimethamine plus artesunate [SP-AS] in Kenyan children ages 0.5 to 10 years [4], and 28 days in a young Tanzanian cohort also treated with SP-AS [4]). …”

Section: Discussionsupporting

confidence: 88%

“…In areas with a high entomological inoculation rate, artemether-lumefantrine may reduce the likelihood of posttreatment transmission (40), albeit at the cost of late recurrences of asexual forms, especially P. vivax where this species is transmitted (29). Single-dose primaquine kills P. falciparum gametocytes and has been proposed as an addition to P. falciparum treatment to reduce transmission (39). However, given its potential hemolytic toxicity and questions regarding the most suitable socioeconomic and epidemiologic settings for it use, it is currently not a part of currently recommended therapy for P. falciparum infection (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

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Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

Karl

Laman

Moore

et al. 2015

Antimicrob Agents Chemother

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gQuantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated Plasmodium falciparum and/or Plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral P. falciparum gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/l for artemether-lumefantrine and 61/l for artemisinin-naphthoquine (P < 0.001). The median time for P. falciparum gametocyte density to fall to <2.5/l (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (P < 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days; P < 0.001) and had a longer median P. falciparum gametocyte carriage time per individual (20 versus 13 days; P < 0.001). Clearance of P. vivax gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed P. vivax gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential P. falciparum transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses P. vivax recurrence and consequent gametocytemia. Intraerythrocytic development of Plasmodium spp. comprises asexual reproduction, which underlies host pathophysiology or sexual reproduction (gametocyte formation) that is essential for malaria transmission. Apart from distinctive morphology, gametocytes have many characteristics that set them apart from asexual stages. Plasmodium falciparum gametocytes have a much longer life span in the circulation and, through metabolic inactivity during the mature phase, reduced antimalarial drug sensitivity (1-3). Artemisinin drugs have greater gametocytocidal activity than conventional agents, such as chloroquine, sulfadoxine, and pyrimethamine, in P. falciparum infections (4-7). As their half-lives are relatively short, this greater potency arises largely from their ability to destroy a wider range of early-stage gametocytes, presumably at their sequestration sites (4, 8). However, the exact effect of antimalarial drugs on the viability of more mature P. falciparum gametocytes that continue to circulate after treatment is unc...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

Karl

Laman

Moore

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…At the time malaria patients seek medication, there would already be late stage IV and V gametocytes circulating in their system (Eziefula et al, 2014). Late stage gametocytes particularly make a scientifically credible stage to block transmission as they are the only form of P. falciparum capable of infecting a female Anopheles mosquito (Sinden et al, 2012a).…”

Section: Discussionmentioning

confidence: 99%

In vitro inhibition of Plasmodium falciparum early and late stage gametocyte viability by extracts from eight traditionally used South African plant species

Moyo

Botha

Nondaba

et al. 2016

Journal of Ethnopharmacology

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“…Later in the same year, the WHO Malaria Advisory Committee modified their recommendation to a single 0.25-mg/kg PQ dose to alleviate concerns of serious toxicity in patients with glucose-6-phosphate dehydrogenase deficiency and in consideration of the benefits of disseminating PQ as a transmission blocking drug to a high proportion of patients within a population. In vivo studies conducted in Southeast Asia and Africa showed that PQ added to ACTs for treating P. falciparum malaria exhibited effective gametocyte clearance in patients (6)(7)(8)(9). Even when added to non-artemisinin-based regimens, PQ (Ͼ0.4 mg/kg) was able to drastically reduce the proportions of people with detectable gametocytemia (10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

Cabrera

2015

Antimicrob Agents Chemother

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Currently, the World Health Organization recommends addition of a 0.25-mg base/kg single dose of primaquine (PQ) to artemisinin combination therapies (ACTs) for Plasmodium falciparum malaria as a gametocytocidal agent for reducing transmission. Here, we investigated the potential interactions of PQ with the long-lasting components of the ACT drugs for eliminating the asexual blood stages and gametocytes of in vitro-cultured P. falciparum strains. Using the SYBR green I assay for asexual parasites and a flow cytometry-based assay for gametocytes, we determined the interactions of PQ with the schizonticides chloroquine, mefloquine, piperaquine, lumefantrine, and naphthoquine. With the sums of fractional inhibitory concentrations and isobolograms, we were able to determine mostly synergistic interactions for the various PQ and schizonticide combinations on the blood stages of P. falciparum laboratory strains. The synergism in inhibiting asexual stages and gametocytes was highly evident with PQ-naphthoquine, whereas synergism was moderate for the PQ-piperaquine, PQ-chloroquine, and PQ-mefloquine combinations. We have detected potentially antagonistic interactions between PQ and lumefantrine under certain drug combination ratios, suggesting that precautions might be needed when PQ is added as the gametocytocide to the artemether-lumefantrine ACT (Coartem).A sexual multiplication of the malaria parasites in human blood is associated with the morbidity and mortality due to the disease. The gametocyte, the sexual stage of the parasites, is the obligatory link perpetuating the parasite's life cycle into the Anopheles vectors. While most antimalarial drugs target the asexual intraerythrocytic stages of the malaria parasites, it has been increasingly recognized that drugs with actions on the gametocyte stages are critical for severing this transmission link (1, 2). In particular, interruption of malaria transmission is a major challenge for malaria elimination (3). Among the currently used antimalarial drugs, primaquine (PQ) is the only one with gametocytocidal activity on late-stage gametocytes (4). This drug has been used since the 1950s primarily in combination with chloroquine (CQ) as a radical cure for preventing relapses due to Plasmodium vivax. Presently, it is used in combination with CQ or artemisinin combination therapies (ACTs) for radical cure of relapsing malaria parasites due to P. vivax and Plasmodium ovale. In 2012, the World Health Organization (WHO) recommended the addition of a single dose of 0.74 mg/kg PQ as a gametocytocidal agent to reduce P. falciparum transmission in low-transmission settings, particularly in areas under the threat of artemisinin resistance (5). Later in the same year, the WHO Malaria Advisory Committee modified their recommendation to a single 0.25-mg/kg PQ dose to alleviate concerns of serious toxicity in patients with glucose-6-phosphate dehydrogenase deficiency and in consideration of the benefits of disseminating PQ as a transmission blocking drug to a high proportion of patien...

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Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, dose-ranging trial

Abstract: Wellcome Trust and the Bill & Melinda Gates Foundation.

Cited by 103 publications

References 37 publications

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

In vitro inhibition of Plasmodium falciparum early and late stage gametocyte viability by extracts from eight traditionally used South African plant species

In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

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