Combined chloroquine, sulfadoxine/pyrimethamine and primaquine against Plasmodium falciparum in Central Java, Indonesia

Background P. falciparum gametocytes may persist after treatment with sulphadoxine-pyrimethamine (SP) plus artesunate (AS) and contribute considerably to malaria transmission. We determined the efficacy of SP+AS plus a single dose of primaquine (PQ, 0.75 mg/kg) on clearing gametocytaemia measured by molecular methods.MethodologyThe study was conducted in Mnyuzi, an area of hyperendemic malaria in north-eastern Tanzania. Children aged 3–15 years with uncomplicated P. falciparum malaria with an asexual parasite density between 500–100,000 parasites/µL were randomized to receive treatment with either SP+AS or SP+AS+PQ. P. falciparum gametocyte prevalence and density during the 42-day follow-up period were determined by real-time nucleic acid sequence-based amplification (QT-NASBA). Haemoglobin levels (Hb) were determined to address concerns about haemolysis in G6PD-deficient individuals.Results108 individuals were randomized. Pfs25 QT-NASBA gametocyte prevalence was 88–91% at enrolment and decreased afterwards for both treatment arms. Gametocyte prevalence and density were significantly lower in children treated with SP+AS+PQ. On day 14 after treatment 3.9% (2/51) of the SP+AS+PQ treated children harboured gametocytes compared to 62.7% (32/51) of those treated with SP+AS (p<0.001). Hb levels were reduced in the week following treatment with SP+AS+PQ and this reduction was related to G6PD deficiency. The Hb levels of all patients recovered to pre-treatment levels or greater within one month after treatment.ConclusionsPQ clears submicroscopic gametocytes after treatment with SP+AS and the persisting gametocytes circulated at densities that are unlikely to contribute to malaria transmission. For individuals without severe anaemia, addition of a single dose of PQ to an efficacious antimalarial drug combination is a safe approach to reduce malaria transmission following treatment.Trial RegistrationControlled-Trials.com ISRCTN61534963

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“…The addition of a single dose of PQ had no beneficial influence on the clearance of asexual parasites, as was described previously [36], [38].…”

Section: Discussionsupporting

confidence: 65%

Primaquine Clears Submicroscopic Plasmodium falciparum Gametocytes that Persist after Treatment with Sulphadoxine-Pyrimethamine and Artesunate

et al. 2007

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“…A dosing regimen of primaquine is currently being further tested as a potential transmission-reducing therapy (25). Although it has been previously shown that it effectively clears gametocytes in human patients (16), primaquine did not show significant activity in any of our assays. We observed only a small, statistically insignificant reduc- tion of the formation of stages I and II gametocytes and only at a relatively high concentration (5,000 nM).…”

Section: Discussionmentioning

confidence: 73%

The Spiroindolone Drug Candidate NITD609 Potently Inhibits Gametocytogenesis and Blocks Plasmodium falciparum Transmission to Anopheles Mosquito Vector

Pelt-Koops

Pett

Graumans

et al. 2012

Antimicrob Agents Chemother

117

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The global malaria agenda has undergone a reorientation from control of clinical cases to entirely eradicating malaria. For that purpose, a key objective is blocking transmission of malaria parasites from humans to mosquito vectors. The new antimalarial drug candidate NITD609 was evaluated for its transmission-reducing potential and compared to a few established antimalarials (lumefantrine, artemether, primaquine), using a suite of in vitro assays. By the use of a microscopic readout, NITD609 was found to inhibit the early and late development of Plasmodium falciparum gametocytes in vitro in a dose-dependent fashion over a range of 5 to 500 nM. In addition, using the standard membrane feeding assay, NITD609 was also found to be a very effective drug in reducing transmission to the Anopheles stephensi mosquito vector. Collectively, our data suggest a strong transmission-reducing effect of NITD609 acting against different P. falciparum transmission stages. P lasmodium falciparum malaria is responsible for almost 800,000 deaths and 250 million clinical cases annually (35). The number of deaths associated with malaria gradually went down in several countries of sub-Saharan Africa during the previous decade, thanks to increased financial investments, implementation of long-lasting-insecticide-impregnated bed nets, and artemisinin-based combination therapy (35). As expressed by the MalEra initiative, the global malaria agenda has undergone a reorientation from control of clinical cases to malaria elimination and eventually eradication (5).For decades, antimalarial drug development has been almost entirely focused on asexual blood stages, which are directly responsible for morbidity and mortality, while mostly ignoring the nonpathogenic life cycle stages responsible for malaria transmission and subsequent spread of parasites in the population. Transmission stages emerging from asexual blood stages follow a number of transformation steps and eventually appear in the blood circulation as mature stage V male and female gametocytes (6). Once these mature gametocytes are ingested by blood-feeding Anopheles mosquitoes, the sporogonic cycle is initiated by rapid transition of male and female gametocytes into gametes, instantly followed by fertilization. The formed oocysts finally release sporozoites that migrate to the mosquito salivary glands. Infected mosquitoes inject a small number of sporozoites into the human host with every blood meal. A drug that substantially reduces or preferably entirely blocks transmission of malaria from human to mosquito would be an important tool (5).Here we describe a series of in vitro assays performed to test the effects of drugs on the early and late development of laboratoryadapted P. falciparum strain NF54 as well as in vivo oocyst development in mosquitoes. Data are shown for the new antimalarial drug candidate NITD609 as well as a few established antimalarial drugs (lumefantrine, artemether, primaquine) (24). Lumefantrine and artemether were chosen due to being the two compounds of the ...

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“…Notwithstanding, CQ þ PQ combinations have a role against both tissue and blood-schizontocides that are to be deployed in endemic areas [67]. CQ, sulfadoxine/pyrimethamine and PQ were combined together in an early work, and while no effect on asexual stage parasitemia was apparent, clearance of gametocytes was significantly accelerated [68]. Bray et al analysed matched transfectants expressing mutant and wild-type alleles of the P. falciparum chloroquine resistance transporter (PfCRT) and concluded that PQ exerts its activity by blocking PfCRT, thus enhancing accumulation of CQ [69].…”

Section: Pq Combined With Other Drugsmentioning

confidence: 99%

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

321

308

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Combined chloroquine, sulfadoxine/pyrimethamine and primaquine against Plasmodium falciparum in Central Java, Indonesia

Cited by 23 publications

References 30 publications

Primaquine Clears Submicroscopic Plasmodium falciparum Gametocytes that Persist after Treatment with Sulphadoxine-Pyrimethamine and Artesunate

Primaquine Clears Submicroscopic Plasmodium falciparum Gametocytes that Persist after Treatment with Sulphadoxine-Pyrimethamine and Artesunate

The Spiroindolone Drug Candidate NITD609 Potently Inhibits Gametocytogenesis and Blocks Plasmodium falciparum Transmission to Anopheles Mosquito Vector

Primaquine revisited six decades after its discovery

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