The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin

Duraisingh,; Jones, P.; Sambou, I; Seidlein, Lorenz von; Pinder, Margaret; Warhurst, David C.

doi:10.1016/s0166-6851(00)00201-2

Cited by 255 publications

(262 citation statements)

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“…33 This disproportionate presence of Tyr-86 may partly explain the lack of correlation between the pfmdr1 polymorphisms and drug resistance. If Tyr-86 were a marker for increased sensitivity to synthetic amino alcohols and artemisinin derivatives, as suggested by Duraisingh and others, 18 it may explain the absence of Cameroonian isolates that are resistant in vitro to these drugs, but it does not explain the concomitant increased resistance to chloroquine and quinine observed in the Gambian isolates, in particular the presence of 22 (39%) of 56 Cameroonian isolates carrying Tyr-86 that were sensitive in vitro to chloroquine. This discordance between the Gambian and Cameroonian isolates may be due to the difference in the epidemiology of drug-resistant P. falciparum or difference in the in vitro assay methodology.…”

Section: Discussionmentioning

confidence: 95%

“…19 In studies involving field isolates, Tyr-86 was associated with increased sensitivity to mefloquine, halofantrine, and artemisinin derivatives and resistance to chloroquine and quinine in Gambian isolates, but the same mutation was associated with increased sensitivity to mefloquine alone in Thailand. 18,26 Thus, it seems that, at present, there is still no single pfmdr1 allelic profile that clearly distinguishes between sensitive and resistant parasites.…”

Section: Discussionmentioning

confidence: 99%

“…15,16 However, more recent data have suggested that specific mutations in the pfmdr1 gene, which were initially thought to be associated with chloroquine resistance, may confer cross-resistance to quinine, mefloquine, halofantrine, and artemisinin derivatives. [17][18][19] In the face of contradictory data from different studies, we conducted the present study with the aim to assess the possible correlation between in vitro drug sensitivity pattern of clinical isolates and pfmdr1 profile and establish the baseline pfmdr1 sequence data in Cameroon.…”

Section: Introductionmentioning

confidence: 99%

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Molecular epidemiology of malaria in Cameroon. X. Evaluation of PFMDR1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives.

Basco¹,

Ringwald²

2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. Mutations at five positions in the Plasmodium falciparum multidrug-resistance gene 1 (pfmdr1), initially thought to confer resistance to chloroquine, have been associated with in vitro resistance to amino alcohols and artemisinin derivatives in more recent studies. To assess the possible association between drug resistance phenotype and pfmdr1 polymorphisms and establish the baseline pfmdr1 sequence data in Yaoundé, Cameroon, the in vitro drug sensitivity pattern was determined for 64 clinical isolates by isotopic microtest. The pfmdr1 alleles were determined by a polymerase chain reaction and automatic sequencing. A large majority of isolates carried Tyr-86 (88%) and Phe-184 (91%) alleles. With the exception of one isolate with mixed codon 1246, all isolates had wild-type alleles Ser-1034, Asn-1042, and Asp-1246. There was no statistical association between codons 86 and 184 and in vitro response to chloroquine, amino alcohols, and artemisinin derivatives (P > 0.05). Our data do not seem to support the hypothesis that mutations in codons 86 and 184 influence the in vitro response to these drugs. Further monitoring of both in vitro response and pfmdr1 polymorphisms is required to evaluate the potential role played by other pfmdr1 alleles in the determination of drug resistance in Africa.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular epidemiology of malaria in Cameroon. X. Evaluation of PFMDR1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives.

Basco¹,

Ringwald²

2002

The American Journal of Tropical Medicine and Hygiene

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“…En conclusión, la gran prevalencia en nuestro estudio del alelo Asn 86, tanto en casos de respuesta adecuada como de falla al tratamiento, no nos permite afirmar que la presencia del alelo se relacione con uno u otro evento, como lo informan diversos autores (6,32,36,37). Con respecto a la distribución geográfica de alguno de los polimorfismos, podemos afirmar que, a diferencia de lo reportado en África y Asia, el alelo silvestre es mucho más frecuente en nuestras poblaciones de P. falciparum.…”

Section: Tratamientounclassified

“…Algunos estudios in vitro sugieren que el alelo mutado 86 TIr incrementa la sensibilidad y no la resistencia a la mefloquina y a otros medicamentos como la halofantrina y la artemisinina (36,39); sin embargo, esta afirmación es inconsistente con el resultado de nuestro estudio, en el cual observamos una respuesta clínica adecuada al tratamiento con mefloquina de 96% y el alelo 86 TIr se encontró solo o en combinación con el silvestre en 4,6% de las muestras. La observación de este alelo mutante se realizó en muestras de pacientes con respuestas clínicas adecuadas y representaron 2,8% del total de los pacientes con respuesta clinica adecuada.…”

Section: Tratamientounclassified

Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia

et al. 2007

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Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia Paula Montoya, Alberto Tobón, Silvia Blair, Jaime Carmona, Amanda Maestre Grupo de Malaria, Sede de Investigación Universitaria, Universidad de Antioquia, Medellín, ColombiaIntroducción. El gen pfmdr1 de Plasmodium falciparum se describió como un gen de resistencia a diversos antipalúdicos. Sin embargo, no se han estudiado el papel de su polimorfismo en la respuesta terapéutica al tratamiento con antipalúdicos en Colombia, ni su relación con paludismo grave. Objetivos. Este trabajo determinó la asociación entre los polimorfismos Asn 86 Tir y Asp 1246 Tir del gen pfmdr1 con la respuesta terapéutica a cloroquina, amodiaquina y mefloquina, en tres municipios antioqueños, y la asociación de estos polimorfismos con paludismo grave en muestras de pacientes del municipio de Tumaco. Materiales y métodos. Los polimorfismos del gen pfmdr1 se determinaron mediante amplificación de ácidos nucleicos y análisis con enzimas de restricción. Resultados. El alelo silvestre Asn 86 se encontró en 97% (137/141) de las muestras en el estudio de respuesta terapéutica a cloroquina, amodiaquina y mefloquina; no se observó ninguna asociación entre su presencia y la falla terapéutica como sí lo reportan otros autores. El alelo 1246 Tir se encontró en una alta proporción en el estudio de respuesta terapéutica, tanto en las muestras del día cero como en los del día de la falla después del tratamiento con los antipalúdicos. Conclusiones. Los polimorfismos 86 Tir y 1246 Tir en el gen pfmdr1 no son útiles como factores de predicción de falla terapéutica o paludismo grave en los municipios estudiados. Este estudio describe por primera vez la presencia del alelo 86 Tir en cuatro muestras clínicas de Suramérica.Palabras clave: Plasmodium falciparum/efectos de drogas, antipalúdicos/uso terapéutico, malaria, cloroquina, amodiaquina, mefloquina. Polymorphisms of the pfmdr1 gene in field samples of Plasmodium falciparum and their association with therapeutic response to antimalarial drugs and severe malaria in ColombiaIntroduction. The pfmdr1 gene of Plasmodium falciparum has been described as a gene conferring resistance to several antimalarial drugs. In particular, polymorphisms on specific codons have been associated with resistance and treatment failure with cloroquine, amodiaquine and mefloquine. However, the role of these polymorphisms in treatment response to antimalarials remains unexplored in Colombia. Furthermore, the relationship of these polymorphisms to severe malaria is unknown. Objective. This work studied the association of the Asn 86 Tyr and Asp 1246 Tyr pfmdr1 polymorphisms with response to cloroquine, amodiaquine and mefloquine treatment in three municipalities of Antioquia, and severe malaria cases from the municipality Tumaco. Materials and methods.The polymorphisms were assessed by nucleic acid amplification followed by restriction length polymorphism analysis. Result...

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ABC Proteins Involved in Protozoan Parasite Resistance

Pradines

2009

ABC Transporters and Multidrug Resistance

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The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin

Cited by 255 publications

References 35 publications

Molecular epidemiology of malaria in Cameroon. X. Evaluation of PFMDR1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives.

Molecular epidemiology of malaria in Cameroon. X. Evaluation of PFMDR1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives.

Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia

ABC Proteins Involved in Protozoan Parasite Resistance

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