Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS

Autores
Pérez Montilla, Carlos Alberto; Moroni, Samanta; Gonzalez, N.; Moscatelli, Guillermo; Altcheh, Jaime Marcelo; García Bournissen, Facundo
Año de publicación
2019
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Background Nifurtimox (NFX) is one of the only 2 available drugs for the treatment of Chagas disease, a parasitic disease endemic to Latin America. In spite of widespread use of this medication, little is known regarding its metabolism, particularly in children.The objective of this study was to develop a method to identify NFX metabolites in human samples, and apply it to the discovery of NFX metabolites in urine from pediatric patients undergoing treatment for Chagas disease.Methods Urine was collected from 12 pediatric patients and 8 healthy volunteers (controls), and anonymized before analysis. Informed consent was obtained from all participants. Samples were aliquoted, deproteinized with ACN (BNZ as internal standard) and centrifuged in cold. 10% of supernatant in water was injected into a 1.8 µm C18 column and chromatographed in 3.5 min under a water/ACN gradient at 0.4 mL/min in a Shimadzu Nexera X2 UHPLC equipment. Species were positively ionized by a Turbo IonSpray source. Metabolites were identified and characterized by an ABSciex 6500 QTRAP spectrometer through Enhanced-Mass-Screening (EMS), Neutral-Loss (NL), Precursor-Ion (PREC), Enhanced-Product-Ion (EPI) and MS3 experiments. For chromatographic monitoring, parameters were optimized and the three most intense Multiple-Reaction-Monitoring (MRM) transitions were selected.Results Denitrated NFX conjugated with cysteine (M1) and N-acetyl-cysteine (M2), as well as other phase I metabolites like saturated nitrile (M3), hydroxyamide (M4), carboxylic acid (M5) or aldehyde (M6) were identified in most samples. The final MS/MS detection method was high reproducible and sensitive for all metabolites.Conclusions We found the main NFX metabolites in pediatric urine using a fast MS/MS method that can allow us to efficiently study the role of NFX and its metabolites in pediatric treatment response and the adverse drug reactions, and in combination with PK/PD experiments will facilitate future clinical trials, and possibly develop new therapeutic drug monitoring strategies.
Fil: Pérez Montilla, Carlos Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina
Fil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Gonzalez, N.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina
Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: García Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
European Society for Developmental Perinatal and Paediatric Pharmacology Congress
Basel
Suiza
European Society for Perinatal and Paediatric Pharmacology
Materia
NIFURTIMOX
METABOLITES
CHAGAS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/201764
Acceder
id CONICETDig_f3ee2a19887c31b7b3668bbe6afbf146
oai_identifier_str oai:ri.conicet.gov.ar:11336/201764
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MSPérez Montilla, Carlos AlbertoMoroni, SamantaGonzalez, N.Moscatelli, GuillermoAltcheh, Jaime MarceloGarcía Bournissen, FacundoNIFURTIMOXMETABOLITESCHAGAShttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Background Nifurtimox (NFX) is one of the only 2 available drugs for the treatment of Chagas disease, a parasitic disease endemic to Latin America. In spite of widespread use of this medication, little is known regarding its metabolism, particularly in children.The objective of this study was to develop a method to identify NFX metabolites in human samples, and apply it to the discovery of NFX metabolites in urine from pediatric patients undergoing treatment for Chagas disease.Methods Urine was collected from 12 pediatric patients and 8 healthy volunteers (controls), and anonymized before analysis. Informed consent was obtained from all participants. Samples were aliquoted, deproteinized with ACN (BNZ as internal standard) and centrifuged in cold. 10% of supernatant in water was injected into a 1.8 µm C18 column and chromatographed in 3.5 min under a water/ACN gradient at 0.4 mL/min in a Shimadzu Nexera X2 UHPLC equipment. Species were positively ionized by a Turbo IonSpray source. Metabolites were identified and characterized by an ABSciex 6500 QTRAP spectrometer through Enhanced-Mass-Screening (EMS), Neutral-Loss (NL), Precursor-Ion (PREC), Enhanced-Product-Ion (EPI) and MS3 experiments. For chromatographic monitoring, parameters were optimized and the three most intense Multiple-Reaction-Monitoring (MRM) transitions were selected.Results Denitrated NFX conjugated with cysteine (M1) and N-acetyl-cysteine (M2), as well as other phase I metabolites like saturated nitrile (M3), hydroxyamide (M4), carboxylic acid (M5) or aldehyde (M6) were identified in most samples. The final MS/MS detection method was high reproducible and sensitive for all metabolites.Conclusions We found the main NFX metabolites in pediatric urine using a fast MS/MS method that can allow us to efficiently study the role of NFX and its metabolites in pediatric treatment response and the adverse drug reactions, and in combination with PK/PD experiments will facilitate future clinical trials, and possibly develop new therapeutic drug monitoring strategies.Fil: Pérez Montilla, Carlos Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Gonzalez, N.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: García Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaEuropean Society for Developmental Perinatal and Paediatric Pharmacology CongressBaselSuizaEuropean Society for Perinatal and Paediatric PharmacologyOxford University Press2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/201764Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS; European Society for Developmental Perinatal and Paediatric Pharmacology Congress; Basel; Suiza; 2019; 1-2CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://adc.bmj.com/content/104/6/e16.2Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:27:15Zoai:ri.conicet.gov.ar:11336/201764instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:27:15.343CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS
title Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS
spellingShingle Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS
Pérez Montilla, Carlos Alberto
NIFURTIMOX
METABOLITES
CHAGAS
title_short Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS
title_full Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS
title_fullStr Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS
title_full_unstemmed Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS
title_sort Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS
dc.creator.none.fl_str_mv Pérez Montilla, Carlos Alberto
Moroni, Samanta
Gonzalez, N.
Moscatelli, Guillermo
Altcheh, Jaime Marcelo
García Bournissen, Facundo
author Pérez Montilla, Carlos Alberto
author_facet Pérez Montilla, Carlos Alberto
Moroni, Samanta
Gonzalez, N.
Moscatelli, Guillermo
Altcheh, Jaime Marcelo
García Bournissen, Facundo
author_role author
author2 Moroni, Samanta
Gonzalez, N.
Moscatelli, Guillermo
Altcheh, Jaime Marcelo
García Bournissen, Facundo
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv NIFURTIMOX
METABOLITES
CHAGAS
topic NIFURTIMOX
METABOLITES
CHAGAS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Background Nifurtimox (NFX) is one of the only 2 available drugs for the treatment of Chagas disease, a parasitic disease endemic to Latin America. In spite of widespread use of this medication, little is known regarding its metabolism, particularly in children.The objective of this study was to develop a method to identify NFX metabolites in human samples, and apply it to the discovery of NFX metabolites in urine from pediatric patients undergoing treatment for Chagas disease.Methods Urine was collected from 12 pediatric patients and 8 healthy volunteers (controls), and anonymized before analysis. Informed consent was obtained from all participants. Samples were aliquoted, deproteinized with ACN (BNZ as internal standard) and centrifuged in cold. 10% of supernatant in water was injected into a 1.8 µm C18 column and chromatographed in 3.5 min under a water/ACN gradient at 0.4 mL/min in a Shimadzu Nexera X2 UHPLC equipment. Species were positively ionized by a Turbo IonSpray source. Metabolites were identified and characterized by an ABSciex 6500 QTRAP spectrometer through Enhanced-Mass-Screening (EMS), Neutral-Loss (NL), Precursor-Ion (PREC), Enhanced-Product-Ion (EPI) and MS3 experiments. For chromatographic monitoring, parameters were optimized and the three most intense Multiple-Reaction-Monitoring (MRM) transitions were selected.Results Denitrated NFX conjugated with cysteine (M1) and N-acetyl-cysteine (M2), as well as other phase I metabolites like saturated nitrile (M3), hydroxyamide (M4), carboxylic acid (M5) or aldehyde (M6) were identified in most samples. The final MS/MS detection method was high reproducible and sensitive for all metabolites.Conclusions We found the main NFX metabolites in pediatric urine using a fast MS/MS method that can allow us to efficiently study the role of NFX and its metabolites in pediatric treatment response and the adverse drug reactions, and in combination with PK/PD experiments will facilitate future clinical trials, and possibly develop new therapeutic drug monitoring strategies.
Fil: Pérez Montilla, Carlos Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina
Fil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Gonzalez, N.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina
Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: García Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
European Society for Developmental Perinatal and Paediatric Pharmacology Congress
Basel
Suiza
European Society for Perinatal and Paediatric Pharmacology
description Background Nifurtimox (NFX) is one of the only 2 available drugs for the treatment of Chagas disease, a parasitic disease endemic to Latin America. In spite of widespread use of this medication, little is known regarding its metabolism, particularly in children.The objective of this study was to develop a method to identify NFX metabolites in human samples, and apply it to the discovery of NFX metabolites in urine from pediatric patients undergoing treatment for Chagas disease.Methods Urine was collected from 12 pediatric patients and 8 healthy volunteers (controls), and anonymized before analysis. Informed consent was obtained from all participants. Samples were aliquoted, deproteinized with ACN (BNZ as internal standard) and centrifuged in cold. 10% of supernatant in water was injected into a 1.8 µm C18 column and chromatographed in 3.5 min under a water/ACN gradient at 0.4 mL/min in a Shimadzu Nexera X2 UHPLC equipment. Species were positively ionized by a Turbo IonSpray source. Metabolites were identified and characterized by an ABSciex 6500 QTRAP spectrometer through Enhanced-Mass-Screening (EMS), Neutral-Loss (NL), Precursor-Ion (PREC), Enhanced-Product-Ion (EPI) and MS3 experiments. For chromatographic monitoring, parameters were optimized and the three most intense Multiple-Reaction-Monitoring (MRM) transitions were selected.Results Denitrated NFX conjugated with cysteine (M1) and N-acetyl-cysteine (M2), as well as other phase I metabolites like saturated nitrile (M3), hydroxyamide (M4), carboxylic acid (M5) or aldehyde (M6) were identified in most samples. The final MS/MS detection method was high reproducible and sensitive for all metabolites.Conclusions We found the main NFX metabolites in pediatric urine using a fast MS/MS method that can allow us to efficiently study the role of NFX and its metabolites in pediatric treatment response and the adverse drug reactions, and in combination with PK/PD experiments will facilitate future clinical trials, and possibly develop new therapeutic drug monitoring strategies.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Congreso
Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/201764
Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS; European Society for Developmental Perinatal and Paediatric Pharmacology Congress; Basel; Suiza; 2019; 1-2
CONICET Digital
CONICET
url http://hdl.handle.net/11336/201764
identifier_str_mv Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS; European Society for Developmental Perinatal and Paediatric Pharmacology Congress; Basel; Suiza; 2019; 1-2
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://adc.bmj.com/content/104/6/e16.2
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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