Ex vivo activity of the ACT new components pyronaridine and piperaquine in comparison with conventional ACT drugs against isolates of Plasmodium falciparum

Pascual, Aurélie; Parola, Philippe; Benoit‐Vical, Françoise; Simon, Fabrice; Malvy, Denis; Picot, Stéphane; Delaunay, Pascal; Basset, D.; Maubon, Danièle; Faugere, B.; Ménard, Guillaume; Bourgeois, Nathalie; Oeuvray, Claude; Didillon, Eric; Rogier, Christophe; Pradines, Bruno

doi:10.1186/1475-2875-11-45

Cited by 22 publications

(26 citation statements)

References 59 publications

(84 reference statements)

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“…Thus, after several years of extensive use of artesunate plus amodiaquine and of artemether plus lumefantrine as first-line treatments for P. falciparum malaria in Niger, there is no evidence of a decline in sensitivity to artemisinin. Our data are similar to those reported in Senegal and Congo and are consistent with findings of studies indicating a lack of decrease in sensitivity to artesunate in Gabon, Senegal, and Djibouti despite the extensive and growing use of ACT in these regions (12)(13)(14)(15)(16)(17)(18). A decrease in parasite susceptibility to artemisinin derivatives has been reported to date only in Southeast Asia along the border between Thailand and Cambodia.…”

supporting

confidence: 82%

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Ex Vivo Responses of Plasmodium falciparum Clinical Isolates to Conventional and New Antimalarial Drugs in Niger

Issaka

Salissou

Aliyu

et al. 2013

Antimicrob Agents Chemother

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Little is known about resistance of Plasmodium falciparum to antimalarials in Sahelian countries. Here we investigated the drug susceptibilities of fresh isolates collected in Niger post-deployment of artemisinin-based combination therapies (ACTs). We found that the parasites remained highly susceptible to new (dihydroartemisinin, lumefantrine, pyronaridine, and piperaquine) and conventional (amodiaquine and chloroquine) antimalarial drugs. The introduction of ACTs in 2005 and their further deployment nationwide have therefore not resulted in a decrease in P. falciparum susceptibilities to these antimalarials. The WHO estimates that 50% of the world's population is exposed to malaria. In 2010, 216 million cases and more than 650,000 deaths from malaria were reported. Despite a decrease in the number of confirmed cases in some parts of the world, the situation remains heterogeneous and worrying in Africa (1). Together with respiratory infections and diarrheal diseases, malaria is one of the leading causes of death in Niger. Malaria transmission rates are high, with a mean incidence of 80 cases per 1,000 inhabitants. Despite the complementary nature of interventions in the field, which have strengthened in recent years, the number of cases has steadily risen over the last 20 years, reaching three million in 2010 (2, 3). There are several reasons for the deterioration of the public health situation with regard to malaria, and the increase in resistance to antimalarial drugs is considered a key factor. In Niger, infections are currently treated with combinations of drugs including an artemisinin (ART) derivative (artemisinin-based combination treatment, or ACT) (4). Since 2005, ACT has been proposed as the first-line treatment for the management of uncomplicated malaria. The use of such treatments throughout Niger was greatly expanded in 2010 by the implementation of a Global Fund Affordable Malaria Facility mechanism (5). Thereby, the drug pressure exerted on Plasmodium falciparum increases the risk of selection of parasites with altered susceptibility to antimalarials. This seems to be inevitable, as demonstrated by recent observations in Asia, which have revealed the presence of parasites less sensitive to artemisinins (6). The risk of emerging resistance to ACT makes it necessary to monitor the susceptibilities of parasites to antimalarial drugs, particularly those used in combination with artemisinin derivatives, on a regular basis and to search for new molecules with antimalarial activity.In this context, a study was carried out in Niger in 2011, at Gaya in the Dosso region, 250 km south of Niamey (3.44°N, 11.9°E), to evaluate the response of P. falciparum isolates to lumefantrine (LUM) and amodiaquine diphosphate (AQ), both of which are widely used in the ACTs distributed in Niger. In addition, responses to alternative molecules, such as pyronaridine (PYD) and piperaquine (PIP), both currently not available in Niger, as well as dihydroartemisinin (DHA) and chloroquine (CQ), were investigated. P. falciparum is...

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supporting

confidence: 82%

“…These data demonstrate that the ACT components PIP and PYD have excellent antimalarial activity against Nigerien isolates. These activities are broadly similar to those reported in Africa (12)(13)(14)18). In Niger, the first cases of CQ resistance in vitro were reported at the end of the 1980s.…”

supporting

confidence: 68%

Ex Vivo Responses of Plasmodium falciparum Clinical Isolates to Conventional and New Antimalarial Drugs in Niger

Issaka

Salissou

Aliyu

et al. 2013

Antimicrob Agents Chemother

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“…P. falciparum isolates were collected from hospitalized patients with imported malaria from a malaria-endemic Dama et al 7 country. A significant positive correlation was shown between responses to PQP and Pyr responses and between PQP and MDAQ (Pascual et al, 2012). Ex-vivo isotopic study of P. falciparum clinical isolates to artemisinin derivatives and partner drugs in Niger (Issaka et al, 2013) showed that GMIC 50 s were below the resistance threshold.…”

Section: Studies Assessing In Vitro and Ex-vivo Efficacy Methods Of Amentioning

confidence: 90%

“…Optical microtest was the first in vitro method widely used (Price et al, 2010;Tanariya et al, 2000). Standard in vitro and ex-vivo isotopic methods were developed initially for conventional antimalarial drugs but these methods were used to monitor ACTs partner drugs efficacy (Lim et al, 2010;Mwai et al, 2009;Pascual et al, 2012;Pradines et al, 1998Pradines et al, , 2011. Because of biosafety concerns with radioactive reagents, and the high cost of equipment and reagents, fluorometric and ELISA methods were developed to monitor ACTs partner drugs.…”

Section: In Vitro/ex-vivo Methods For Acts Efficacy Evaluationmentioning

confidence: 99%

Methods for monitoring artemisinin-based combination therapies efficacy

Dama¹,

Djimdé²,

Doumbo³

2017

Clin. Rev. Opinions

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Plasmodium falciparum resistance to artemisinin and its derivatives is spreading in South-East Asia, and there is growing concern that this may reach other endemic countries. Methods used to assess P. falciparum resistance to artemisinin-based combination therapies (ACTs) are multiple and often divergent. This paper is a review of online accessible research publications from the past 20 years on ACTs, ranging from in vivo, in vitro/ex-vivo, molecular markers and pharmacokinetics studies. We highlight the procedures of the four main methods used for ACTs e f f i c a c y testing and provide a summary of published data. This review indicates that the most used method for ACT efficacy testing is the in vivo 28 days follow-up with molecular correction; the most widely used and reliable in vitro and ex-vivo method for artemisinin phenotyping is the ring stage survival assay from 0 to 3 h ring (RSA 0-3h ), and the main molecular marker of P. falciparum resistance to artemisinins are mutations on P. falciparum Kelch 13 propeller domain. Day 7 pharmacokinetics could help to predict resistance to artemether-lumefantrine and dihydroartemisinin-piperaquine. Findings from this review support that the combination of in vivo, in vitro/ex-vivo, molecular markers of drug resistance and day 7 PK levels of the partner drugs may be required for the optimal surveillance of artemisinin-based combination therapy efficacy in the field.

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“…One important difference between the ACT partner drugs and artemisinins is that the former act primarily against the early to mid trophozoite stages when hemoglobin degradation is at its peak, whereas artemisinins act against trophozoites as well as the early ring-stage parasites (53,54). For PND, studies with P. falciparum field isolates and culture-adapted lines show minimal crossresistance between this agent and the other ACT partner drugs, illustrating that resistance mechanisms that have evolved to drugs such as ADQ or the related 4-aminoquinoline chloroquine have not compromised PND efficacy (35,(55)(56)(57). These studies also show no evidence of significantly reduced activity against P. falciparum parasites that have acquired resistance to ADQ, chloroquine, or other related drugs.…”

Section: Figmentioning

confidence: 99%

Evidence for Pyronaridine as a Highly Effective Partner Drug for Treatment of Artemisinin-Resistant Malaria in a Rodent Model

Henrich

Saénz

Cremers

et al. 2014

Antimicrob Agents Chemother

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The increasing prevalence in Southeast Asia of Plasmodium falciparum infections with delayed parasite clearance rates, following treatment of malaria patients with the artemisinin derivative artesunate, highlights an urgent need to identify which of the currently available artemisinin-based combination therapies (ACTs) are most suitable to treat populations with emerging artemisinin resistance. Here, we demonstrate that the rodent Plasmodium berghei SANA strain has acquired artemisinin resistance following drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of artesunate or the active metabolite dihydroartemisinin. Using the SANA strain and the parental drug-sensitive N strain, we have interrogated the antimalarial activity of five ACTs, namely, artemether-lumefantrine, artesunate-amodiaquine, artesunatemefloquine, dihydroartemisinin-piperaquine, and the newest combination artesunate-pyronaridine. By monitoring parasitemia and outcome for 30 days following initiation of treatment, we found that infections with artemisinin-resistant P. berghei SANA parasites can be successfully treated with artesunate-pyronaridine used at doses that are curative for the parental drug-sensitive N strain. No other partner drug combination was as effective in resolving SANA infections. Of the five partner drugs tested, pyronaridine was also the most effective at suppressing the recrudescence of SANA parasites. These data support the potential benefit of implementing ACTs with pyronaridine in regions affected by artemisinin-resistant malaria.

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Ex vivo activity of the ACT new components pyronaridine and piperaquine in comparison with conventional ACT drugs against isolates of Plasmodium falciparum

Cited by 22 publications

References 59 publications

Ex Vivo Responses of Plasmodium falciparum Clinical Isolates to Conventional and New Antimalarial Drugs in Niger

Ex Vivo Responses of Plasmodium falciparum Clinical Isolates to Conventional and New Antimalarial Drugs in Niger

Methods for monitoring artemisinin-based combination therapies efficacy

Evidence for Pyronaridine as a Highly Effective Partner Drug for Treatment of Artemisinin-Resistant Malaria in a Rodent Model

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