Primaquine synergises the activity of chloroquine against chloroquine-resistant P. falciparum

Bray, Patrick G.; Deed, Samantha; Fox, Emma; Kalkanidis, Martha; Mungthin, Mathirut; Deady, Leslie W.; Tilley, Leann

doi:10.1016/j.bcp.2005.07.021

Cited by 67 publications

(74 citation statements)

References 47 publications

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“…In clinical studies, artemether-LMF treatments have been found to select for wildtype pfcrt K76 (43,44), pfmdr1 N86 (43,45), and N1042 (45) alleles, as well as increased pfmdr1 copy numbers (40,46). Our finding of the PQ-CQ synergistic interaction in the CQR Dd2 strain was different from the additive effect observed earlier in the same strain (28), but similar to another observation in the CQR K1 strain (25). As speculated earlier, the inconsistent results for PQ-CQ interactions in different parasite strains may be due to other unknown factors rather than to the pfcrt mutations (28).…”

Section: Discussionsupporting

confidence: 76%

“…Here, we investigated the interactions between PQ and the longer-acting schizonticide in commonly used ACTs in both asexual parasites and latestage gametocytes. Compared to the other antimalarials tested, PQ is clearly a weak blood stage schizonticide (17,19,25,28,29). However, besides its tissue schizonticide activity targeting relapsing malaria parasites, it has evident gametocytocidal activity and shortens gametocyte carriage times in vivo (6-8, 11, 12, 30).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

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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“…Over half a century, PQ and CQ have been routinely associated for the radical cure of P. vivax infections in most countries in Latin America. The finding that PQ reverses CQ resistance in P. falciparum 39 suggests that a similar effect might occur in P. vivax isolates simultaneously exposed to both drugs. Accordingly, all 22 published reports of CQ-resistant P. vivax infections acquired in South America refer to patients to whom PQ was either given after CQ treatment, for several reasons, or not administered at all.…”

Section: Discussionmentioning

confidence: 96%

Recurrent Parasitemias and Population Dynamics of Plasmodium vivax Polymorphisms in Rural Amazonia

Orjuela-Sánchez¹,

Silva²,

Silva‐Nunes³

et al. 2009

The American Journal of Tropical Medicine and Hygiene

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Abstract. Clinical trials documented alarming post-treatment Plasmodium vivax recurrence rates caused by recrudescence of surviving asexual blood stages, relapse from hypnozoites, or new infections. Here we describe high rates of P. vivax recurrence (26-40% 180 days after treatment) in two cohorts of rural Amazonians exposed to low levels of malaria transmission after a vivax malaria episode treated with chloroquine-primaquine. Microsatellite analysis of 28 paired acute infection and recurrence parasites showed only two pairs of identical haplotypes (consistent with recrudescences or reactivation of homologous hypnozoites) and four pairs of related haplotypes (sharing alleles at 11-13 of 14 microsatellites analyzed). Local isolates of P. vivax were extraordinarily diverse and rarely shared the same haplotype, indicating that frequent recurrences did not favor the persistence or reappearance of clonal lineages of parasites in the population. This fast haplotype replacement rate may represent the typical population dynamics of neutral polymorphisms in parasites from low-endemicity areas.

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“…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]. Moreover, the alternative administration of PQ and CQ sequentially instead of simultaneously is clinically viable, and may constitute a cost-effective way of treating CQ-resistant malaria [70].…”

Section: Pq Combined With Other Drugsmentioning

confidence: 99%

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

322

308

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Primaquine synergises the activity of chloroquine against chloroquine-resistant P. falciparum

Cited by 67 publications

References 47 publications

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

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

Recurrent Parasitemias and Population Dynamics of Plasmodium vivax Polymorphisms in Rural Amazonia

Primaquine revisited six decades after its discovery

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