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In silico assessment of drug safety in human heart applied to late sodium current blockers

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In silico assessment of drug safety in human heart applied to late sodium current blockers

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dc.contributor.author Trénor Gomis, Beatriz Ana es_ES
dc.contributor.author Gomis-Tena Dolz, Julio es_ES
dc.contributor.author Cardona Urrego, Karen Eliana es_ES
dc.contributor.author Romero Pérez, Lucia es_ES
dc.contributor.author Rajamani, Sridharan es_ES
dc.contributor.author Belardinelli, Luiz es_ES
dc.contributor.author Giles, Wayne R. es_ES
dc.contributor.author Saiz Rodríguez, Francisco Javier es_ES
dc.date.accessioned 2016-07-15T14:04:21Z
dc.date.available 2016-07-15T14:04:21Z
dc.date.issued 2013-07-01
dc.identifier.issn 1933-6950
dc.identifier.uri http://hdl.handle.net/10251/67665
dc.description.abstract Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (INaL) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K+ current (IKr). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of IKr/INaL ratio of steady-state block of drug candidates on “torsadogenic” biomarkers. The O’Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of INaL and IKr were evaluated. “Safety plots” were developed to illustrate the value of the specific biomarker for selected combinations of IC50s for IKr and INaL of potential drugs. The reference biomarkers at baseline changed depending on the “drug” specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of INaL) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle. es_ES
dc.description.sponsorship This work was supported by (1) Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica, (2) Plan Avanza en el marco de la Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion del Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), (3) Programa de Apoyo a la Investigacion y Desarrollo (PAID-06-11-2002) de la Universidad Politecnica de Valencia, (4) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana and (5) Gilead Sciences, Ltd. en_EN
dc.language Inglés es_ES
dc.publisher Landes Bioscience es_ES
dc.relation.ispartof Channels es_ES
dc.rights Reserva de todos los derechos es_ES
dc.subject Anti-arrhythmic es_ES
dc.subject Drug safety es_ES
dc.subject Multi-channel block es_ES
dc.subject Reverse rate-dependence es_ES
dc.subject Late sodium current es_ES
dc.subject Transmural dispersion of repolarization es_ES
dc.subject.classification TECNOLOGIA ELECTRONICA es_ES
dc.title In silico assessment of drug safety in human heart applied to late sodium current blockers es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.4161/chan.24905
dc.relation.projectID info:eu-repo/grantAgreement/MITURCO//TSI-020100-2010-0469/ES/LocMoTIC. Localización del Origen de Arritmias Cardíacas Mediante Modelado y Tecnologías de la Información y Comunicaciones/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/UPV//PAID-06-11-2002/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/GVA//PROMETEO%2F2012%2F030/ES/MEJORA EN LA PREVENCION Y TRATAMIENTO DE PATOLOGIAS CARDIACAS A TRAVES DE LA MODELIZACION MULTI-ESCALA Y LA SIMULACION COMPUTACIONAL (DIGITAL HEART)/ es_ES
dc.rights.accessRights Abierto es_ES
dc.contributor.affiliation Universitat Politècnica de València. Instituto Interuniversitario de Investigación en Bioingeniería y Tecnología Orientada al Ser Humano - Institut Interuniversitari d'Investigació en Bioenginyeria i Tecnologia Orientada a l'Ésser Humà es_ES
dc.contributor.affiliation Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica es_ES
dc.description.bibliographicCitation Trénor Gomis, BA.; Gomis-Tena Dolz, J.; Cardona Urrego, KE.; Romero Pérez, L.; Rajamani, S.; Belardinelli, L.; Giles, WR.... (2013). In silico assessment of drug safety in human heart applied to late sodium current blockers. Channels. 7(4):1-14. https://doi.org/10.4161/chan.24905 es_ES
dc.description.accrualMethod S es_ES
dc.relation.publisherversion http://dx.doi.org/10.4161/chan.24905 es_ES
dc.description.upvformatpinicio 1 es_ES
dc.description.upvformatpfin 14 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 7 es_ES
dc.description.issue 4 es_ES
dc.relation.senia 259537 es_ES
dc.identifier.eissn 1933-6969
dc.identifier.pmid 23696033 en_EN
dc.identifier.pmcid PMC3989354 en_EN
dc.contributor.funder Gilead Sciences es_ES
dc.contributor.funder Generalitat Valenciana es_ES
dc.contributor.funder Ministerio de Industria, Turismo y Comercio es_ES
dc.contributor.funder Universitat Politècnica de València es_ES
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