{"id":115340,"date":"2014-06-03T00:00:00","date_gmt":"2014-06-03T00:00:00","guid":{"rendered":""},"modified":"2014-06-03T00:00:00","modified_gmt":"2014-06-03T00:00:00","slug":"busqueda-de-nuevas-variantes-geneticas-con-relevancia-en-la-farmacogenetica-del-acenocumarol-para-la-creacion-de-un-algoritmo-cla%c2%adnico-genetico-de-prediccion-de-dosis-estable-valoracion-de-su-ap","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/medicina-interna\/busqueda-de-nuevas-variantes-geneticas-con-relevancia-en-la-farmacogenetica-del-acenocumarol-para-la-creacion-de-un-algoritmo-cla%c2%adnico-genetico-de-prediccion-de-dosis-estable-valoracion-de-su-ap\/","title":{"rendered":"B\u00fasqueda de nuevas variantes gen\u00e9ticas con relevancia en la farmacogen\u00e9tica del acenocumarol para la creaci\u00f3n de un algoritmo cl\u00ednico\/gen\u00e9tico de predicci\u00f3n de dosis estable. valoraci\u00f3n de su aplicaci\u00f3n en la dosificaci\u00f3n al inicio del tratamiento en pacientes con fibrilaci\u00f3n auricular"},"content":{"rendered":"<h2>Tesis doctoral de <strong> Juan  Jose Cerezo Manchado <\/strong><\/h2>\n<p>Resumen  objetivos: a lo largo de esta tesis doctoral hemos comprobado la influencia que tienen los polimorfismos rs9923231 de vkorc1, rs1799853 y rs1057910 de cyp2c9 y rs2108622 de cyp4f2 en el control del tratamiento con acenocumarol al inicio de la terapia.  El primer objetivo (b\u00fasqueda de nuevas variantes g\u00e9nicas que influyeran en la dosis estable de la terapia oral anticoagulante, de cara a incluirlas en un futuro algoritmo), concluimos que dada la baja frecuencia de las nuevas variantes encontradas y de la peque\u00f1a mejora que supone su incorporaci\u00f3n al algoritmo de predicci\u00f3n de dosis ( 1%), no encontramos argumentos que justifiquen su inclusi\u00f3n en dichos m\u00e9todos predictivos. Al abordar el segundo objetivo valoramos cu\u00e1les eran los principales factores cl\u00ednicos y gen\u00e9ticos que ten\u00edan mayor relevancia para un control \u00f3ptimo de la terapia oral al inicio del tratamiento. Con estos datos posteriormente elaboramos un algoritmo de predicci\u00f3n de dosis estable, en lo que ser\u00eda el tercer objetivo.  metodos: se realiz\u00f3 un estudio retrospectivo de cohortes en la anticoagulaci\u00f3n unidad de terapia, hospital morales meseguer (murcia, espa\u00f1a). El estudio fue aprobado por las juntas de \u00e9tica de la investigaci\u00f3n en la instituci\u00f3n. Los pacientes que reciben tratamiento anticoagulante con acenocumarol terapia se hacen pruebas de elegibilidad en la base de datos de nuestra anticoagulaci\u00f3n unidad de terapia. En primer lugar, se seleccionaron aquellos pacientes que ten\u00edan tratamiento iniciado con acenocumarol en nuestra cl\u00ednica ambulatoria constituyendo la cohorte primaria. En segundo lugar, hemos validado el algoritmo en una segunda poblaci\u00f3n (cohorte de validaci\u00f3n) de los pacientes que est\u00e1n siendo controlados en nuestra unidad. Algunos pacientes con valores perdidos por lo menos uno de los determinantes o los que no alcanzan un fase estable dentro de un a\u00f1o despu\u00e9s del inicio de la terapia.  resultados: en cuanto al primer objetivo concluimos que dada la baja frecuencia de las nuevas variantes encontradas y de la peque\u00f1a mejora que supone su incorporaci\u00f3n al algoritmo de predicci\u00f3n de dosis ( 1%), no encontramos argumentos que justifiquen su inclusi\u00f3n en dichos m\u00e9todos predictivos. en cuanto al segundo objetivo, los resultados de este trabajo muestran que el inr a las 72 horas del inicio de la terapia es un potente predictor de los principales objetivos de la misma, sobre-anticoagulaci\u00f3n y dosis estable a los tres meses del inicio. Adicionalmente, adem\u00e1s del efecto bien conocido de los polimorfismos de vkorc1 y cyp2c9, el polimorfismo rs2108622 de cyp4f2 tiene un efecto significativo en la sobre-dosificaci\u00f3n de acenocumaro durante los primeros tres meses de tratamiento.   en cuanto al tercer objetivo, con nuestros datos, el mejor modelo de predicci\u00f3n de dosis incluye factores cl\u00ednicos (edad y superficie corporal) y gen\u00e9ticos (polimorfismos de vkorc1, cyp2c9 y cyp4f2) y explica hasta el 50% de la variaci\u00f3n de la dosis. Este algoritmo resulta especialmente \u00fatil para pacientes que necesitan dosis extremas de acenocumarol (?7mg\/semana y ?25mg\/semana), ya que proporciona una estimaci\u00f3n en un rango de \u00c2\u00b120% de la dosis real. Dado que estos pacientes son los que normalmente necesitan m\u00e1s tiempo para su estabilizaci\u00f3n y son los que con m\u00e1s frecuencia sufren efectos adversos derivados del tratamiento, puede ser relevante emplear este algoritmo en la pr\u00e1ctica cl\u00ednica en nuestra poblaci\u00f3n y finalmente, aunque fuera del cuerpo principal de esta tesis, realizamos un estudio aleatorizado donde comprobamos la eficacia y seguridad de nuestro algoritmo de predicci\u00f3n de dosis comparado con el sistema habitual de dosificaci\u00f3n en dos grupos de pacientes. De los resultados de este trabajo se concluye que la inclusi\u00f3n del valor del inr a las 72 horas en el sistema de dosificaci\u00f3n que tiene en cuenta  la informaci\u00f3n gen\u00e9tica es crucial para que este esquema sea superior al m\u00e9todo cl\u00e1sico en los objetivos analizados (porcentaje de pacientes con dosis estable, porcentaje de inrs en rango y tiempos para alcanzar ambos objetivos). Sin embargo, a los 6 meses de inicio del tratamiento, la valoraci\u00f3n de estos objetivos se iguala en ambas ramas, de donde podemos concluir que la informaci\u00f3n gen\u00e9tica es especialmente relevante al inicio de la terapia (3 primeros meses). Tras este periodo, otros factores inherentes a los pacientes van modulando la dosis necesaria para estar en inr terap\u00e9utico.    summary objectives : throughout this thesis we have tested the influence of the vkorc1 rs9923231 , rs1799853 and rs1057910 and rs2108622 cyp2c9 polymorphisms of cyp4f2 in the control treatment acenocumarol the beginning of therapy. The first objective ( finding new gene variants that influenced the stable dose of oral anticoagulant therapy , in order to include them in a future algorithm) , we conclude that given the low frequency of new variants found and small improvement achieved its join the dose prediction algorithm ( ? 1%) , we find arguments that justify their inclusion in such predictive methods . In addressing the second objective value which were the main clinical and genetic factors were most important for optimal control of oral therapy at baseline . With these data subsequently developed a prediction algorithm stable dose , in what would be the third objective . methods : a retrospective cohort study was performed on anticoagulation therapy unit , hospital morales meseguer (murcia , spain ) . The study was approved by the boards of research ethics in the institution. Patients receiving anticoagulant therapy with acenocoumarol eligibility tests are done in the database of our anticoagulation therapy unit . First, those patients who had started treatment with acenocoumarol in our outpatient clinic constituting the primary cohort were selected. Second, we validated the algorithm in a second population ( validation cohort ) of patients being monitored in our unit. Some patients with missing at least one of the key or the failure to achieve a stable phase within one year after the initiation of therapy values . results : regarding the first objective we conclude that given the low frequency of new variants found and small improvement achieved by incorporating the prediction algorithm dose ( ? 1%) , we find arguments that justify their inclusion in such predictive methods . regarding the second objective , the results of this work show that the inr at 72 hours after initiation of therapy is a powerful predictor of the main objectives of the same , over- anticoagulation and stable at three months of starting dose . Additionally , besides the well known effect of cyp2c9 and vkorc1 polymorphisms , of cyp4f2 rs2108622 polymorphism has a significant effect on the over- dosing of acenocumaro during the first three months of treatment . as for the third goal, with our data, the best prediction model includes clinical dose (age and body surface area) and genetic factors (polymorphisms of vkorc1 , cyp2c9 and cyp4f2 ) and explains up to 50 % of the variation in dose. This algorithm is especially useful for patients who need extreme acenocumarol dose ( ? And ? 7mg\/semana 25mg\/semana ) , providing an estimate within a range of \u00c2\u00b1 20% of the actual dose . Since these patients are normally need more time to stabilize and are the most frequently suffer adverse effects from treatment , may be relevant to use this algorithm in clinical practice in our population and finally , even if the main body of this thesis , we conducted a randomized study in which the efficacy and safety check of our prediction algorithm compared with the usual dose dispensing system on two groups of patients. From the results of this study concluded that the inclusion of the value of the inr at 72 hours in the metering system that takes into account genetic information is crucial in this scheme is higher than the classical method in the objectives analyzed ( percentage of patients with stable dose , percentage of inrs in range and times for both targets ) . However, at 6 months of starting treatment , assessment of these objectives is equal in both directions, from which we can conclude that genetic information is particularly relevant to the initiation of therapy ( first 3 months) . After this period, other factors inherent to patients will be necessary to modulate the inr in therapeutic doses .<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>B\u00fasqueda de nuevas variantes gen\u00e9ticas con relevancia en la farmacogen\u00e9tica del acenocumarol para la creaci\u00f3n de un algoritmo cl\u00ednico\/gen\u00e9tico de predicci\u00f3n de dosis estable. valoraci\u00f3n de su aplicaci\u00f3n en la dosificaci\u00f3n al inicio del tratamiento en pacientes con fibrilaci\u00f3n auricular<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 B\u00fasqueda de nuevas variantes gen\u00e9ticas con relevancia en la farmacogen\u00e9tica del acenocumarol para la creaci\u00f3n de un algoritmo cl\u00ednico\/gen\u00e9tico de predicci\u00f3n de dosis estable. valoraci\u00f3n de su aplicaci\u00f3n en la dosificaci\u00f3n al inicio del tratamiento en pacientes con fibrilaci\u00f3n auricular <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Juan  Jose Cerezo Manchado <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Murcia<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 06\/03\/2014<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li>Vanesa Roldan Schilling<\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: Jos\u00e9 Antonio Paramo fernandez <\/li>\n<li>Jos\u00e9 Mateo arranz (vocal)<\/li>\n<li>dolors T\u00ed\u00a0ssies penella (vocal)<\/li>\n<li>Francisco Mar\u00edn ortu\u00f1o (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Juan Jose Cerezo Manchado Resumen objetivos: a lo largo de esta tesis doctoral hemos comprobado la influencia [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-gradient":""}},"footnotes":""},"categories":[139,8235],"tags":[228222,196223,18182,51496,228221,119966],"class_list":["post-115340","post","type-post","status-publish","format-standard","hentry","category-medicina-interna","category-murcia","tag-dolors-ti-ssies-penella","tag-francisco-marin-ortuno","tag-jose-antonio-paramo-fernandez","tag-jose-mateo-arranz","tag-juan-jose-cerezo-manchado","tag-vanesa-roldan-schilling"],"_links":{"self":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/posts\/115340","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/comments?post=115340"}],"version-history":[{"count":0,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/posts\/115340\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/media?parent=115340"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/categories?post=115340"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.deberes.net\/tesis\/wp-json\/wp\/v2\/tags?post=115340"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}