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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Fecha de publicación:
2020
Institución:
Universidad del Rosario
Repositorio:
Repositorio EdocUR - U. Rosario
Idioma:
eng
OAI Identifier:
oai:repository.urosario.edu.co:10336/24945
Acceso en línea:
https://repository.urosario.edu.co/handle/10336/24945
Palabra clave:
drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
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id EDOCUR2_8caa1daa47ee0cb1e69d78c43dddbc8e
oai_identifier_str oai:repository.urosario.edu.co:10336/24945
network_acronym_str EDOCUR2
network_name_str Repositorio EdocUR - U. Rosario
repository_id_str
spelling 79733068600d163aa7c-843e-4722-85be-c5d5ff93a660df775774-e39f-4966-851c-2fdd63e3ba987623c620-4d5d-4738-87e0-43bd49e8e31719331819600fe6ddb63-56e9-4266-aad9-bbd3f72517b3c891e15b-c1fb-405c-aa96-c15c45f7c23d79141398600f27097fd-56db-4d27-91ed-7ffc57f6a046520948256002020-06-11T13:21:53Z2020-06-11T13:21:53Z2020Background: 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.application/pdf16639812https://repository.urosario.edu.co/handle/10336/24945engFrontiers Media S.A.Frontiers in PharmacologyVol. 11Frontiers in Pharmacology, ISBN: 16639812, Vol.11, No. (2020); pp. -https://www.scopus.com/inward/record.uri?eid=2-s2.0-85085200819&doi=10.3389%2ffphar.2020.00555&partnerID=40&md5=a0d4afbdb79a544dd87b1e308801baccAbierto (Texto Completo)http://purl.org/coar/access_right/c_abf2instname:Universidad del Rosarioreponame:Repositorio Institucional EdocURdrug resistant epilepsydrug-related side effects and adverse reactionspharmacogeneticspharmacovigilancephenytoinPossible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With EpilepsyarticleArtículohttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_6501Calderón Ospina, Carlos AlbertoGalvez, J. M.López-Cabra, C.Morales. N.Restrepo Fernández, Carlos MartínRodríguez, J.Aristizábal-Gutiérrez, F. A.Vélez van Meerbeke, Alberto FranciscoLaissue, P.Fonseca Mendoza, Dora Janeth10336/24945oai:repository.urosario.edu.co:10336/249452021-11-07 07:58:42.988https://repository.urosario.edu.coRepositorio institucional EdocURedocur@urosario.edu.co
dc.title.spa.fl_str_mv Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy
title Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy
spellingShingle Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy
drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
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
dc.subject.keyword.spa.fl_str_mv drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
topic drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
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.
publishDate 2020
dc.date.accessioned.none.fl_str_mv 2020-06-11T13:21:53Z
dc.date.available.none.fl_str_mv 2020-06-11T13:21:53Z
dc.date.created.spa.fl_str_mv 2020
dc.type.eng.fl_str_mv article
dc.type.coarversion.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.coar.fl_str_mv http://purl.org/coar/resource_type/c_6501
dc.type.spa.spa.fl_str_mv Artículo
dc.identifier.issn.none.fl_str_mv 16639812
dc.identifier.uri.none.fl_str_mv https://repository.urosario.edu.co/handle/10336/24945
identifier_str_mv 16639812
url https://repository.urosario.edu.co/handle/10336/24945
dc.language.iso.none.fl_str_mv eng
language eng
dc.relation.citationTitle.none.fl_str_mv Frontiers in Pharmacology
dc.relation.citationVolume.none.fl_str_mv Vol. 11
dc.relation.ispartof.spa.fl_str_mv Frontiers in Pharmacology, ISBN: 16639812, Vol.11, No. (2020); pp. -
dc.relation.uri.spa.fl_str_mv https://www.scopus.com/inward/record.uri?eid=2-s2.0-85085200819&doi=10.3389%2ffphar.2020.00555&partnerID=40&md5=a0d4afbdb79a544dd87b1e308801bacc
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.acceso.spa.fl_str_mv Abierto (Texto Completo)
rights_invalid_str_mv Abierto (Texto Completo)
http://purl.org/coar/access_right/c_abf2
dc.format.mimetype.none.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Frontiers Media S.A.
institution Universidad del Rosario
dc.source.instname.spa.fl_str_mv instname:Universidad del Rosario
dc.source.reponame.spa.fl_str_mv reponame:Repositorio Institucional EdocUR
repository.name.fl_str_mv Repositorio institucional EdocUR
repository.mail.fl_str_mv edocur@urosario.edu.co
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