Short Report: Lack of Prediction of Amodiaquine Efficacy in Treating Plasmodium Falciparum Malaria by in Vitro Tests

Aubouy, Agnès; Mayombo, J.; Keundjian, A.; Bakary, Mohamed; Bras, J. Le; Deloron, Philippe

doi:10.4269/ajtmh.2004.71.294

Cited by 18 publications

(13 citation statements)

References 17 publications

(22 reference statements)

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“…This may account for the lack of an association. The relation between AQ in vivo efficacy and in vitro DEAQ susceptibility may be confounded by interindividual variations in pharmacokinetic factors, such as the metabolism of AQ to DEAQ by CYP2C8 (55,56), and the complex dynamics between AQ, DEAQ, and possibly other metabolites (57). In vitro susceptibility to artemisinins and in vivo efficacy of artesunate have been associated (5), but inconsistently (4).…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum Polymorphisms Associated with Ex Vivo Drug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin

Dahlström

Aubouy

Maïga-Ascofaré

et al. 2014

Antimicrob Agents Chemother

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h Artemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association of Plasmodium falciparum polymorphisms and ex vivo drug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n ‫؍‬ 96), fixed-dose artesunate-amodiaquine (n ‫؍‬ 96), and sulfadoxine-pyrimethamine (n ‫؍‬ 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed. pfcrt, pfmdr1, pfmrp1, pfdhfr, and pfdhps polymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates by Plasmodium lactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC 50 ) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC 50 s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome.

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Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum Polymorphisms Associated with Ex Vivo Drug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin

Dahlström

Aubouy

Maïga-Ascofaré

et al. 2014

Antimicrob Agents Chemother

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“…This finding is of particular concern, because the use of AQ-containing combinations has been shown to select for infections that are less responsive to AQ in Uganda (24). However, no clear relationship was observed between the treatment response and the in vitro IC 50 of AQ in Gabon, and selection of this type does not seem to be occurring in Niger, while resistances to AQ have already been reported in some other African countries (25,26). Similarly, no sign of a decrease in susceptibility to LUM has been detected.…”

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confidence: 99%

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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“…Para la cloroquina, dicho punto de corte fue establecido hace más de 25 años por comparación directa de los resultados obtenidos in vivo e in vitro, mientras que para los demás antipalúdicos, generalmente se han calculado con base solamente en los resultados in vitro, con el promedio más dos desviaciones estándar (29); por lo tanto, no se ha validado su importancia frente a los resultados in vivo, lo cual constituye un factor que explica la falta de concordancia entre las pruebas de eficacia terapéutica y de susceptibilidad in vitro que se ha reportado en los diferentes estudios (11,12,(29)(30)(31). Todo esto indica que, más importante que conocer la proporción de aislamientos resistentes a un medicamento, es medir la CI 50 , lo cual permitirá determinar la sensibilidad basal de los parásitos a un fármaco, evaluar el cambio en dicha sensibilidad en el tiempo y, con estos datos, guiar mejor los estudios de eficacia terapéutica (2).…”

Section: Discussionunclassified

Susceptibilidad in vitro de aislamientos colombianos de Plasmodium falciparum a diferentes antipalúdicos

Blair¹,

Arango²,

Fonseca³

2008

biomedica

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Introducción. Los estudios de susceptibilidad in vitro de Plasmodium falciparum a los medicamentos antipalúdicos son herramientas importantes para vigilar la utilidad de esos medicamentos; tales estudios son escasos en Colombia. Objetivo. Evaluar la susceptibilidad in vitro de aislamientos colombianos de P. falciparum a cloroquina, amodiaquina, mefloquina, quinina y artesunato. Materiales y métodos. Se obtuvieron aislamientos clínicos de P. falciparum en varias regiones colombianas. De cada antipalúdico se probaron siete diluciones dobles seriadas, por duplicado, con la técnica HRP-2 y las cepas FCB2 (resistente a cloroquina) y NF54 (sensible a cloroquina) como controles. Se utilizaron las concentraciones inhibitorias 50 (CI 50 ) mayor de 100, 80, 64, 500 y 10,5 nM como puntos de corte para clasificar la resistencia a cloroquina, amodiaquina, mefloquina, quinina y artesunato, respectivamente. Resultados. Se evaluaron 25 aislamientos: 72% de Urabá, 8% de Bajo Cauca y 20% de la Costa Pacífica. Las CI 50 promedio de cloroquina, amodiaquina, mefloquina, quinina y artesunato fueron 422,9; 131,4; 56,3; 269,7 y 1,88 nM, respectivamente, y la proporción de aislamientos resistentes fue, en el mismo orden, 76%, 16%, 32%, 24% y 4%. Conclusiones. La baja sensibilidad a la cloroquina concuerda con otros estudios in vitro y con la baja eficacia terapéutica in vivo. Aunque 96% de los aislamientos fueron sensibles a artesunato, éste y otros estudios han observado aislamientos con disminución de la sensibilidad a las artemisininas (CI 50 >10,5 nM), lo que sugiere que el uso indiscriminado de estos medicamentos pone en riesgo su efectividad y podría dejarnos sin opciones para el tratamiento del paludismo por P. falciparum.Palabras clave: malaria/terapia, Plasmodium falciparum, antipalúdicos, resistencia a las drogas, Colombia

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Short Report: Lack of Prediction of Amodiaquine Efficacy in Treating Plasmodium Falciparum Malaria by in Vitro Tests

Cited by 18 publications

References 17 publications

Plasmodium falciparum Polymorphisms Associated with Ex Vivo Drug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin

Plasmodium falciparum Polymorphisms Associated with Ex Vivo Drug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin

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

Susceptibilidad in vitro de aislamientos colombianos de Plasmodium falciparum a diferentes antipalúdicos

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