Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy

Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality. Objective: Our objective was to assess the impact of som...

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Autores Principales: Calderon-Ospina, Carlos-Alberto, Galvez, J. M., López-Cabra, C., Morales. N., Restrepo, Carlos M., Rodríguez, J., Aristizábal-Gutiérrez, F. A., Velez-van-Meerbeke, Alberto, Laissue, P., Fonseca-Mendoza, Dora Janeth
Formato: Artículo (Article)
Lenguaje:Inglés (English)
Publicado: Frontiers Media S.A. 2020
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Acceso en línea:https://repository.urosario.edu.co/handle/10336/24945
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spelling ir-10336-249452021-11-07T12:58:42Z Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy Calderon-Ospina, Carlos-Alberto Galvez, J. M. López-Cabra, C. Morales. N. Restrepo, Carlos M. Rodríguez, J. Aristizábal-Gutiérrez, F. A. Velez-van-Meerbeke, Alberto Laissue, P. Fonseca-Mendoza, Dora Janeth drug resistant epilepsy drug-related side effects and adverse reactions pharmacogenetics pharmacovigilance phenytoin Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality. Objective: Our objective was to assess the impact of some genetic factors and its possible association with treatment response and adverse drug reactions (ADRs) to phenytoin in 67 adult Colombian patients with epilepsy. Methods: We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: CYP2C9*2-c.430C>T (rs1799853), CYP2C9*3-c.1075A>C (rs1057910), ABCB1-c.3435T>C (rs1045642), and SCN1A-IVS5-91G>A (rs3812718), and their association with treatment response. Patients were followed for 1 year to confirm the existence of DRE (non-response) and ADRs using an active pharmacovigilance approach, followed by a consensus in order to classify ADRs according to causality, preventability, intensity and their relation with phenytoin dose, the duration of treatment, and susceptibility factors (DoTS methodology). Results: A little more than half of evaluated subjects (52.2%) were non-responding to phenytoin. Regarding the genotype-phenotype correlation there was no association between polymorphisms of SCN1A and ABCB1 and DRE (non-response) (p = 0.34), and neither with CYP2C9 polymorphisms and the occurrence of ADRs (p = 0.42). We only found an association between polymorphic alleles of CYP2C9 and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (p = 0.001). Alleles CYP2C9*2-c.430C>T and CYP2C9*3-c.1075A>C were identified as susceptibility factors to ADRs in 24% of patients. Conclusions: Decreased function alleles of CYP2C9 were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (p = 0.001). However, the genetic variants CYP2C9*2-c.430C>T, CYP2C9*3-c.1075A>C, ABCB1-c.3435T>C, and SCN1A-IVS5-91G>A, were not associated with treatment response in our study. © Copyright © 2020 Calderon-Ospina, Galvez, López-Cabra, Morales, Restrepo, Rodríguez, Aristizábal-Gutiérrez, Velez-van-Meerbeke, Laissue and Fonseca-Mendoza. 2020 2020-06-11T13:21:53Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 16639812 https://repository.urosario.edu.co/handle/10336/24945 eng info:eu-repo/semantics/openAccess application/pdf Frontiers Media S.A. instname:Universidad del Rosario reponame:Repositorio Institucional EdocUR
institution EdocUR - Universidad del Rosario
collection DSpace
language Inglés (English)
topic drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
spellingShingle drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
Calderon-Ospina, Carlos-Alberto
Galvez, J. M.
López-Cabra, C.
Morales. N.
Restrepo, Carlos M.
Rodríguez, J.
Aristizábal-Gutiérrez, F. A.
Velez-van-Meerbeke, Alberto
Laissue, P.
Fonseca-Mendoza, Dora Janeth
Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy
description Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality. Objective: Our objective was to assess the impact of some genetic factors and its possible association with treatment response and adverse drug reactions (ADRs) to phenytoin in 67 adult Colombian patients with epilepsy. Methods: We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: CYP2C9*2-c.430C>T (rs1799853), CYP2C9*3-c.1075A>C (rs1057910), ABCB1-c.3435T>C (rs1045642), and SCN1A-IVS5-91G>A (rs3812718), and their association with treatment response. Patients were followed for 1 year to confirm the existence of DRE (non-response) and ADRs using an active pharmacovigilance approach, followed by a consensus in order to classify ADRs according to causality, preventability, intensity and their relation with phenytoin dose, the duration of treatment, and susceptibility factors (DoTS methodology). Results: A little more than half of evaluated subjects (52.2%) were non-responding to phenytoin. Regarding the genotype-phenotype correlation there was no association between polymorphisms of SCN1A and ABCB1 and DRE (non-response) (p = 0.34), and neither with CYP2C9 polymorphisms and the occurrence of ADRs (p = 0.42). We only found an association between polymorphic alleles of CYP2C9 and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (p = 0.001). Alleles CYP2C9*2-c.430C>T and CYP2C9*3-c.1075A>C were identified as susceptibility factors to ADRs in 24% of patients. Conclusions: Decreased function alleles of CYP2C9 were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (p = 0.001). However, the genetic variants CYP2C9*2-c.430C>T, CYP2C9*3-c.1075A>C, ABCB1-c.3435T>C, and SCN1A-IVS5-91G>A, were not associated with treatment response in our study. © Copyright © 2020 Calderon-Ospina, Galvez, López-Cabra, Morales, Restrepo, Rodríguez, Aristizábal-Gutiérrez, Velez-van-Meerbeke, Laissue and Fonseca-Mendoza.
format Artículo (Article)
author Calderon-Ospina, Carlos-Alberto
Galvez, J. M.
López-Cabra, C.
Morales. N.
Restrepo, Carlos M.
Rodríguez, J.
Aristizábal-Gutiérrez, F. A.
Velez-van-Meerbeke, Alberto
Laissue, P.
Fonseca-Mendoza, Dora Janeth
author_facet Calderon-Ospina, Carlos-Alberto
Galvez, J. M.
López-Cabra, C.
Morales. N.
Restrepo, Carlos M.
Rodríguez, J.
Aristizábal-Gutiérrez, F. A.
Velez-van-Meerbeke, Alberto
Laissue, P.
Fonseca-Mendoza, Dora Janeth
author_sort Calderon-Ospina, Carlos-Alberto
title Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy
title_short Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy
title_full Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy
title_fullStr Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy
title_full_unstemmed Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy
title_sort possible genetic determinants of response to phenytoin in a group of colombian patients with epilepsy
publisher Frontiers Media S.A.
publishDate 2020
url https://repository.urosario.edu.co/handle/10336/24945
_version_ 1723228599649042432
score 12,131701