Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar

Detalhes bibliográficos
Autor(a) principal: Pernaute-Lau, Leyre
Data de Publicação: 2021
Outros Autores: Morris, Ulrika, Msellem, Mwinyi, Mårtensson, Andreas, Björkman, Anders, Gil, Jose Pedro
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/131182
Resumo: Funding Information: Open Access funding provided by Karolinska Institute. The work was funded by the Swedish Research Council [Grant ref. VR-2014-3134] and the Erling-Persson Family Foundation [Grant ref. 4-3031/2018]. L.P.L. is recipient of a fellowship from BioSys PhD programme PD65-2012 (Ref SFRH/BD/142860/2018) from Fundação para a Ciência e Tecnologia (Portugal). Publisher Copyright: © 2021, The Author(s).
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spelling Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in ZanzibarAdverse eventsArtesunate–amodiaquineCYP2C8Cytochrome P450EfficacyPlasmodium falciparumParasitologyInfectious DiseasesSDG 3 - Good Health and Well-beingFunding Information: Open Access funding provided by Karolinska Institute. The work was funded by the Swedish Research Council [Grant ref. VR-2014-3134] and the Erling-Persson Family Foundation [Grant ref. 4-3031/2018]. L.P.L. is recipient of a fellowship from BioSys PhD programme PD65-2012 (Ref SFRH/BD/142860/2018) from Fundação para a Ciência e Tecnologia (Portugal). Publisher Copyright: © 2021, The Author(s).Background: The anti-malarial drug, amodiaquine, a commonly used, long-acting partner drug in artemisinin-based combination therapy, is metabolized to active desethyl-amodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). The CYP2C8 gene carries several polymorphisms including the more frequent minor alleles, CYP2C8*2 and CYP2C8*3. These minor alleles have been associated with decreased enzymatic activity, slowing the amodiaquine biotransformation towards DEAQ. This study aimed to assess the influence of these CYP2C8 polymorphisms on the efficacy and tolerability of artesunate–amodiaquine (AS–AQ) treatment for uncomplicated Plasmodium falciparum malaria in Zanzibar. Methods: Dried blood spots on filter paper were collected from 618 children enrolled in two randomized clinical trials comparing AS–AQ and artemether-lumefantrine in 2002–2005 in Zanzibar. Study participant were under five years of age with uncomplicated falciparum malaria. Human CYP2C8*2 and CYP2C8*3 genotype frequencies were determined by PCR-restriction fragment length polymorphism. Statistical associations between CYP2C8*2 and/or CYP2C8*3 allele carriers and treatment outcome or occurrence of adverse events were assessed by Fisher’s exact test. Results: The allele frequencies of CYP2C8*2 and CYP2C8*3 were 17.5 % (95 % CI 15.4–19.7) and 2.7 % (95 % CI 1.8–3.7), respectively. There was no significant difference in the proportion of subjects carrying either CYP2C8*2 or CYP2C8*3 alleles amongst those with re-infections (44.1 %; 95 % CI 33.8–54.8) or those with recrudescent infections (48.3 %; 95 % CI 29.4–67.5), compared to those with an adequate clinical and parasitological response (36.7 %; 95 % CI 30.0-43.9) (P = 0.25 and P = 0.31, respectively). However, patients carrying either CYP2C8*2 or CYP2C8*3 alleles were significantly associated with an increased occurrence of non-serious adverse events, when compared with CYP2C8 *1/*1 wild type homozygotes (44.9 %; 95 % CI 36.1–54.0 vs. 28.1 %; 95 % CI 21.9–35.0, respectively; P = 0.003). Conclusions: CYP2C8 genotypes did not influence treatment efficacy directly, but the tolerability to AS–AQ may be reduced in subjects carrying the CYP2C8*2 and CYP2C8*3 alleles. The importance of this non-negligible association with regard to amodiaquine-based malaria chemotherapy warrants further investigation.Global Health and Tropical Medicine (GHTM)Instituto de Higiene e Medicina Tropical (IHMT)RUNPernaute-Lau, LeyreMorris, UlrikaMsellem, MwinyiMårtensson, AndreasBjörkman, AndersGil, Jose Pedro2022-01-20T03:33:42Z2021-122021-12-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/131182eng1475-2875PURE: 33048820https://doi.org/10.1186/s12936-021-03620-6info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T05:09:43Zoai:run.unl.pt:10362/131182Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:46:59.804645Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar
title Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar
spellingShingle Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar
Pernaute-Lau, Leyre
Adverse events
Artesunate–amodiaquine
CYP2C8
Cytochrome P450
Efficacy
Plasmodium falciparum
Parasitology
Infectious Diseases
SDG 3 - Good Health and Well-being
title_short Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar
title_full Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar
title_fullStr Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar
title_full_unstemmed Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar
title_sort Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar
author Pernaute-Lau, Leyre
author_facet Pernaute-Lau, Leyre
Morris, Ulrika
Msellem, Mwinyi
Mårtensson, Andreas
Björkman, Anders
Gil, Jose Pedro
author_role author
author2 Morris, Ulrika
Msellem, Mwinyi
Mårtensson, Andreas
Björkman, Anders
Gil, Jose Pedro
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Global Health and Tropical Medicine (GHTM)
Instituto de Higiene e Medicina Tropical (IHMT)
RUN
dc.contributor.author.fl_str_mv Pernaute-Lau, Leyre
Morris, Ulrika
Msellem, Mwinyi
Mårtensson, Andreas
Björkman, Anders
Gil, Jose Pedro
dc.subject.por.fl_str_mv Adverse events
Artesunate–amodiaquine
CYP2C8
Cytochrome P450
Efficacy
Plasmodium falciparum
Parasitology
Infectious Diseases
SDG 3 - Good Health and Well-being
topic Adverse events
Artesunate–amodiaquine
CYP2C8
Cytochrome P450
Efficacy
Plasmodium falciparum
Parasitology
Infectious Diseases
SDG 3 - Good Health and Well-being
description Funding Information: Open Access funding provided by Karolinska Institute. The work was funded by the Swedish Research Council [Grant ref. VR-2014-3134] and the Erling-Persson Family Foundation [Grant ref. 4-3031/2018]. L.P.L. is recipient of a fellowship from BioSys PhD programme PD65-2012 (Ref SFRH/BD/142860/2018) from Fundação para a Ciência e Tecnologia (Portugal). Publisher Copyright: © 2021, The Author(s).
publishDate 2021
dc.date.none.fl_str_mv 2021-12
2021-12-01T00:00:00Z
2022-01-20T03:33:42Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/131182
url http://hdl.handle.net/10362/131182
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1475-2875
PURE: 33048820
https://doi.org/10.1186/s12936-021-03620-6
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
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dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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