CYP3A5*3 and CYP3A4*22 Cluster Polymorphism Effects on LCP-Tac Tacrolimus Exposure: Population Pharmacokinetic Approach

The aim of the study is to develop a population pharmacokinetic (PopPK) model and to investigate the influence of CYP3A5/CYP3A4 and ABCB1 single nucleotide polymorphisms (SNPs) on the Tacrolimus PK parameters after LCP-Tac formulation in stable adult renal transplant patients. The model was developed, using NONMEM v7.5, from full PK profiles from a clinical study (n = 30) and trough concentrations (C0) from patient follow-up (n = 68). The PK profile of the LCP-Tac formulation was best described by a two-compartment model with linear elimination, parameterized in elimination (CL/F) and distributional (CLD/F) clearances and central compartment (Vc/F) and peripheral compartment (Vp/F) distribution volumes. A time-lagged first-order absorption process was characterized using transit compartment models. According to the structural part of the base model, the LCP-Tac showed an absorption profile characterized by two transit compartments and a mean transit time of 3.02 h. Inter-individual variability was associated with CL/F, Vc/F, and Vp/F. Adding inter-occasion variability (IOV) on CL/F caused a statistically significant reduction in the model minimum objective function MOFV (p < 0.001). Genetic polymorphism of CYP3A5 and a cluster of CYP3A4/A5 SNPs statistically significantly influenced Tac CL/F. In conclusion, a PopPK model was successfully developed for LCP-Tac formulation in stable renal transplant patients. CYP3A4/A5 SNPs as a combined cluster including three different phenotypes (high, intermediate, and poor metabolizers) was the most powerful covariate to describe part of the inter-individual variability associated with apparent elimination clearance. Considering this covariate in the initial dose estimation and during the therapeutic drug monitoring (TDM) would probably optimize Tac exposure attainments

Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration. Having previously demonstrated that antisense oligonucleotides against miR-218 boost MBNL1 expression and rescue phenotypes in disease models, here we provide preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myotubes. In HSALR, antagomiR-218 reached 40-60 pM 2weeks after injection, rescued molecular and functional phenotypes in a dose- and time-dependent manner, and showed a good toxicity profile after a single subcutaneous administration. In muscle tissue, antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the proportion of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient cells. Importantly, miR-218 was found to be upregulated in DM1 muscle biopsies, pinpointing this microRNA (miRNA) as a relevant therapeutic target.This work was funded by research grants from Instituto de Salud Carlos III, including funds from FEDER, to M.P.-A. and B.L. (PI17/00352) and HR17-00268 (TATAMI project) from the “la Caixa” Banking Foundation to R.A. I.G.-M. was funded by the Precipita Project titled “Desarrollo de una terapia innovadora contra la distrofia miotónica,” E.C.-H. and J.M.F.-C. were supported by the post-doctoral fellowships APOSTD/2019/142 and APOSTD/2017/088 from the Fondo Social Europeo for science and investigation, while J.E.-E. was the recipient of a Santiago Grisolia fellowship (Grisolip2018/098) from the Generalidad Valenciana. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020). Antibody MB1a (4A8) was provided by MDA Monoclonal Antibody Resource

Spatial and temporal facies evolution of a Lower Jurassic carbonate platform, NW Tethyan margin (Mallorca, Spain)

The variety of depositional facies of a Lower Jurassic carbonate platform has been investigated on the island of Mallorca along a transect comprising six stratigraphic profiles. Twenty-nine facies and sub-facies have been recognized, grouped into seven facies associations, ranging in depositional environment from supratidal/terrestrial and peritidal to outer platform. Spatial and temporal (2D) facies distribution along the transect reflects the evolution of the carbonate platform with time showing different facies associations, from a broad peritidal platform (stage 1) to a muddy open platform (stage 2), and finally to a peritidal to outer carbonate platform (stage 3). Stage 1 (early Sinemurian to earliest late Sinemurian) corresponds to a nearly-flat peritidal-shallow subtidal epicontinental platform with facies belts that shifted far and fast over the whole study area. The evolution from stage 1 to stage 2 (late Sinemurian) represents a rapid flooding of the epicontinental shallow platform, with more open-marine conditions, and the onset of differential subsidence. During stage 3 (latest Sinemurian), peritidal and shallow-platform environments preferentially developed to the northeast (Llevant Mountains domain) with a rapid transition to middle-outer platform environments toward the northwest (Tramuntana Range domain). Stages 1 and 3 present facies associations typical of Bahamian-type carbonates, whereas stage 2 represents the demise of the Bahamian-type carbonate factory and proliferation of muddy substrates with suspension-feeders. The described platform evolution responded to the interplay between the initial extensional tectonic phases related to Early Jurassic Tethyan rifting, contemporaneous environmental perturbations, and progressive platform flooding related to the Late Triassic–Early Jurassic worldwide marine transgression and associated accommodation changes

Profundización en metodologías y espacios docentes innovadores

Fac. de FilologíaFALSEsubmitte

Meeting Point: methods and spaces for the flipped classroom

Desarrollo de programas formativos centrados en los estudiantes gracias a la mejora de la calidad de los recursos materiales y del personal docente e investigador.Vicerrectorado de CalidadFac. de FilologíaFALSEsubmitte

Universidad y sociedad: comunicación e integración en empresas e instituciones públicas y organizaciones no lucrativas. Renovación y vanguardia

Depto. de Teorías y Análisis de la ComunicaciónFac. de Ciencias de la InformaciónFALSEsubmitte

Caracterización del fenotipo y de la capacidad migratoria de los linfocitos en pacientes con leucemia mieloide crónica tratados con desatinib y efectos de este fármaco sobre el endotelio vascular

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 07-06-2019Esta tesis tiene embargado el acceso al texto completo hasta el 07-12-2020Dasatinib es un inhibidor de BCR-ABL de segunda generación que se usa como fármaco de primera línea en la leucemia mieloide crónica, y a cuya gran eficacia contribuyen efectos terapéuticos poco caracterizados sobre una inmunidad deficitaria por la acción crónica de la neoplasia. Por ello, en este trabajo nos hemos propuesto caracterizar, mediante citometría de flujo multiparamétrica, los cambios inmunofenotípicos que se producían durante la enfermedad, durante el tratamiento con dasatinib, y durante la linfocitosis que habitualmente induce el fármaco y que se propone como uno de sus principales efectos inmunomoduladores. Nuestros resultados demuestran que los principales efectos de la enfermedad son la disminución de CD62L y CCR7, en correspondencia con la disminución de TN. Por otra parte, al diagnóstico, los linfocitos NK presentan un fenotipo más maduro que el de sujetos sanos. Dasatinib es capaz de revertir total o parcialmente los déficits que se detectan al diagnóstico y además tiene efectos per se sobre algunas subpoblaciones linfocitarias como el aumento de HLA-DR. La caracterización de la linfocitosis demostró que el aumento de linfocitos tras la toma del fármaco tiene lugar a expensas de un aumento de LT efectores y su correspondiente disminución de TN en SP, así como de un aumento de células NK más diferenciadas. Para intentar explicar la linfocitosis, nos planteamos que el fármaco estuviese afectando a la migración linfocitaria de los LT hacia órganos linfoides secundarios y observamos que los LT de nuestros pacientes migraban menos hacia CCL19 y 21 tras dos horas de la toma del fármaco; la causa era la disminución de la proporción de los LT CCR7+ en SP y no un efecto directo de dasatinib sobre la capacidad migratoria o la expresión de CCR7. En cuanto a la asociación de la respuesta terapéutica a dasatinib y los parámetros inmunológicos pudimos comprobar que el valor absoluto de los LT CD8+ al diagnóstico se asocia a una respuesta molecular temprana. Por otro lado, dasatinib produce efectos adversos graves como el derrame pleural y la hemorragia intestinal, que conllevan la interrupción del tratamiento y cuya patogénesis se desconoce. Por ello, y a través de distintos abordajes experimentales, comprobamos que dasatinib produce una importante desorganización del citoesqueleto de actina de células endoteliales HUVEC que se acompaña de una pérdida de las uniones homotípicas que abre espacios entre las células adyacentes. Este efecto tiene lugar de forma rápida, es dosis-dependiente y reversible. Su mecanismo molecular incluye la fosforilación de la cadena ligera de la miosina que probablemente se traduce en la activación de la NMII y en un aumento de la contractilidad celular. Experimentos de permeabilidad in vivo confirmaron que dasatinib produce una pérdida de la función de barrera del endotelio vascular. En resumen, los datos aportados en esta tesis contribuyen al conocimiento de los efectos de la LMC y del tratamiento crónico con dasatinib sobre el sistema inmunitario, lo que es de crucial importancia en uno de los cánceres hematológicos en el que el potencial curativo del SI es más evidente. Además, la identificación, al menos en parte, de las causas de los efectos adversos más graves de dasatinib puede mejorar notablemente el manejo terapéutico de estos pacientes

Self-learning of Biopharmacy and Pharmacokinetic computer software

Uno de los pilares de la Biofarmacia y Farmacocinética es el tratamiento de datos, para lo que resulta imprescindible el conocimiento de programas informáticos estadísticos y de regresión no lineal. Estos son ampliamente usados en nuestra Unidad y forman parte de las destrezas prácticas que el alumno debe adquirir. Debido a las dificultades presentadas por los alumnos en la comprensión de ambas disciplinas, nos hemos planteado realizar una guía de apoyo virtual, sobre el uso del programa de regresión no lineal WinNonLin®. Dicho material estará a disposición del alumno a través de la plataforma virtual moodle para que pueda ser consultado antes de realizar las prácticas de la asignatura. Para valorar la utilidad de este material de apoyo como herramienta TIC, se han realizado una encuesta a profesores y alumnos vinculados a la Unidad, que son los usuarios principales de estas herramientas informáticas. Los resultados de las encuestas reflejaron su agrado y facilidad de compresión, de tal forma que para el próximo curso 2011-2012 se colgará en moodle para todos los alumnos de grado.One of the most important tasks in the biopharmaceutical and pharmacokinetics area is data management, being the statistical and non linear regression software widely used. Those IT skills should be acquired by students in practical lessons, but due to the comprehension difficulties showed, the Biopharmaceutical and Pharmacokinetics Unit of University of Barcelona elaborated a virtual guidance about the use of WinNonLin®, non-linear regression software. This guidance will be used to solve student’s queries by the virtual campus Moodle, before the attending sessions. The main software users, professors and internal students, were polled about the usefulness of this guide. The survey conclusions emphasized its easy understanding and its utility, therefore all students, who were inscribed in Biopharmaceutics and Pharmacokinetic subject, will have access to this guidance next term

The Domestic Environment and the Lung Mycobiome

This study analyzes the relationship between the mycobiome of the Lower Respiratory Tract (LRT) and the fungi in the domestic environment. Samples studied consisted of Broncho-Alveolar Lavage (BAL) from 45 patients who underwent bronchoscopy for different diagnostic purposes, and dust and air from the houses (ENV) of 20 of them (44.4%). Additionally, five bronchoscopes (BS) were also analyzed and negative controls were included for every procedure. All samples were processed for DNA extraction and cultures, which were performed in Sabouraud Dextrose and Potato Dextrose Agar. The fungal Internal Transcribed Spacer (ITS2) was sequenced by the Solexa/Illumina system and sequences were analyzed by QIIME 1.8.0 and compared with the UNITE Database for identification. The similarity between the two fungal communities (BAL and ENV) for a specific patient was assessed via the percentage of coincidence in the detection of specific operational taxonomic units (OTUs), and about 75% of co-occurrence was detected between the mycobiome of the LRT and the houses. Cultures confirmed the presence of the core mycobiome species. However, the low rate of isolation from BAL suggests that most of its mycobiome corresponds to non-culturable cells. This likely depends on the patient’s immune system activity and inflammatory status.This research was funded by the Spanish Association for Respiratory Diseases (SEPAR) through their grant program RESPIRA with number PII026/2016. E. Revelles (2015-16) and J. Adsuar (2018) received a grant from the Spanish Ministry of Education for their contribution in this work. E. Gómez-Imbernon received a grant from the University Miguel Hernandez for his contribution to this work (2017)