Population pharmacokinetic modelling of imatinib in healthy subjects receiving a single dose of 400 mg

Purpose: Imatinib is indicated for treatment of CML, GIST, etc. The population pharmacokinetics (popPK) of imatinib in patients under long-term treatment are reported in literature. Data obtained from bioequivalence trials for healthy subjects were used to evaluate the influence of demographic and pharmacogenetic factors on imatinib pharmacokinetics (PK) in a collective without concurrent drugs, organ dysfunction, inflammation etc. In addition, the differences in PK between the healthy subjects and a patient cohort was examined to identify possible disease effects. Methods: 26 volunteers were administered orally with single dose of 400 mg imatinib. 16–19 plasma samples per volunteer were collected from 0.5 up to 72 h post-dose. The popPK was built and post hoc estimates were compared with previously published PK parameters evaluated by non-compartmental analysis in the same cohort. The predictivity of the model for data collected from 40 patients with gastrointestinal stromal tumors at steady state was evaluated. Results: The popPK was best described by a two-compartment transit model with first-order elimination. No significant covariates were identified, probably due to the small cohort and the narrow range of demographic covariates; CYP3A5 phenotypes appeared to have some influence on the clearance of imatinib. Good agreement between non-compartment and popPK analyses was observed with the differences of the geometric means/ median of PK estimates below 10%. The model indicated lower clearance for patients compared to healthy volunteers (p value < 0.01). Conclusion: The two-compartment transit model adequately describes the absorption and distribution of imatinib in healthy volunteers. For patients, a lower clearance of imatinib compared to healthy volunteer was estimated by the model. The model can be applied for dose individualization based on trough concentrations assuming no significant differences in absorption between patients and healthy volunteersThis work was part of the master these of Yi-Han Chien. There was no funding for this work. P. Zubiaur’s contract with CIBERehd is fnanced by the “Infraestructura de Medicina de Precisión asociada a la Ciencia y Tecnología (IMPaCT, IMP/00009)”, Instituto de Salud Carlos III (ISCIII

Plasticity analysis by synchrotron radiation in a Mg97Y2Zn1 alloy with bimodal grain structure and containing LPSO phase

© 2015 Acta Materialia Inc. All rights reserved. Deformation behaviour has been examined by synchrotron radiation diffraction in an extruded magnesium - long-period-stacking-order phase alloy comprising three components of microstructure. The variation of internal strains and intensities of the important crystallographic planes of the two phases has been examined during compression at several temperatures. The long-period-stacking-order phase remains elastic to stresses beyond the macroscopic yield stress while deformation in the magnesium matrix is dominated by twinning and basal slip, with the coarse-grained regions deforming plastically at stresses well below the macroscopic yield stress while regions with fine grain size deform plastically only at much higher stresses.We would like to acknowledge financial support of the Spanish Ministry of Education and Science under project number MAT2012-34135. We would like to acknowledge the expert support of Miguel Acedo and Edurne Laurin for assistance with the extrusion processing and the metallographical preparation, respectively.Peer Reviewe

The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice

[Aims/hypothesis]: Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. [Methods]: We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. [Results]: Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. [Conclusions/interpretation]: Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes.This work was funded by H2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant Agreement 721236, European Commission). We also acknowledge grants RTI2018-094052-B-100/ AEI/10.13039/501100011033 (Ministerio de Ciencia e Innovación y Fondo Europeo de Desarrollo Regional [FEDER]) and S2017/BMD-3684 (Comunidad de Madrid, Spain), and grants from Fundación Ramón Areces (Spain) and CIBERDEM (ISCIII, Spain)

Caracterización mecánica y comportamiento a la oxidación del Ni3A1 procesado por vía pulvimetalúrgica : influencia del tamaño de partícula y de la implantación iónica

El objetivo de la investigación realizada ha consistido en la síntesis y caracterización del intermetalico ni3al para tratar de mejorar sus propiedades mecánicas, especialmente la ductilidad, y el comportamiento a oxidación mediante su procesado por técnicas pulvimetalurgicas (solidificación rápida por atomización por gas seguida de compactación isostatica en caliente) y el empleo de tratamientos superficiales (implantación ionica). La síntesis y procesado de las aleaciones ha sido completamente realizada en el departamento de metalurgia física del centro nacional de investigaciones metalúrgicas (cenim). La memoria se ha dividido en tres capítulos: síntesis y procesado, comportamiento mecánico y comportamiento frente a la oxidación. En el primer capítulo se recogen todos los detalles experimentales de la obtención del material y se caracteriza mediante microscopía óptica (mo), electrónica de barrido (meb) y de transmisión la microestructura tanto de los polvos solidificados rápidamente mediante atomización por argón, como del material consolidado por hip. Las propiedades mecánicas del intermetálico se estudian mediante ensayos de tracción en el intervalo 25-1000g c. Se analiza la influencia que ejercen en dichas propiedades la temperatura de compactación, la geometría de la probeta, el tamaño de partícula del compacto y la implantación de los iones al, cr y ce. También se investiga la influencia de la velocidad de deformación en la ductilidad del intermetalico, en el intervalo de temperaturas intermedias (350-500g c). Por ultimo, en el tercer capitulo, se estudia el comportamiento a la oxidación del material implantado y sin implantar en de un amplio intervalo de temperaturas (535-1020g c). Mediante termogravimetrías se calculan las cinéticas de oxidación, y la naturaleza de los productos de oxidación se determina mediante difracción de rayos-x y mo, meb y microanálisis por dispersión de energía. En el caso del material sin implantar se analiza la influencia del tamaño de partícula en el comportamiento a la oxidación

Comportamiento mecánico de la aleación AZ31 reforzada con nanofibras de carbono

En este trabajo se ha estudiado el efecto de la adición de nanofibras de carbono en las propiedades mecánicas de la aleación AZ31 procesada por una ruta pulvimetalúrgica convencional. Se prepararon tres materiales, AZ31, AZ31- 1 % C y AZ31-2 % C. Tras una mezcla mecánica de las nanofibras con los polvos de AZ31, se precompactaron en frío y se extruyeron a 350 °C. Los tres presentan una microestructura recristalizada con un tamaño de grano similar, fino aunque algo heterogéneo. Los tres materiales presentan una débil textura de fibra con el plano basal paralelo a la dirección de extrusión. Las propiedades mecánicas a tracción únicamente se ven afectadas por la presencia de nanofibras a 100 °C superando los materiales reforzados en un 30 % a los valores de límite elástico y resistencia de la aleación sin reforzar.Peer Reviewe

Microstructural characterisation and thermal stability of IVIg-2.3 %wt Zr alloy synthetised by Physical Vapour Deposition (PVD)

8 páginas, 9 figuras, 1 table.[ES] El objetivo del trabajo es estudiar la microestructura y estabilidad térmica de la aleación Mg-2,3 %wt Zr, crecida mediante deposición física en fase vapor. Las principales técnicas experimentales empleadas en este estudio son la calorimetría diferencial de barrido y la microscopía electrónica de transmisión. La aleación, en la condición estado de depósito (as-deposited)y es una solución sólida de átomos de circonio en magnesio. La microestructura de la aleación está caracterizada por granos alargados en la dirección de crecimiento. Los granos crecen con la dirección [0001] paralela a la dirección de crecimiento del depósito. Durante un calentamiento continuo del depósito, se observan tres transformaciones exotérmicas que se han asociado a restauración, precipitación del circonio en la matriz de magnesio y oxidación. Se calculó, mediante el análisis de Kissinger, que la energía de activación para el proceso de precipitación es de 138 kjmol-1.[EN] The objective of this work has been the study of the microstructure and the thermal stability of the alloy Mg-2.3 %Zr grown by Physical Vapour Deposition. This study has been carried out by Differential Scanning Calorimetry and Transmission Electron Microscopy. The alloy in the "as-deposited" condition consists oí a solid solution of zirconium atoms in the magnesium matrix. The microstructure of the alloy is characterised by elongated grains oriented in the growth direction. These grains grow with the [0001] direction parallel to the deposit growth direction. During a continuous heating, the deposit shows three exothermal transformations which have been associated with a recovery process, the zirconium precipitation in the magnesium matrix and oxidation at high temperatures. The activation energy for the precipitation reaction calculated from Kissinger analysis is 139 kjmol-1.Este trabajo ha sido financiado por la CICYT Proyecto MAT 981620-CE.Peer reviewe

Improvement of oxidation behavior of a Ti-48Al-2Cr alloy by a nitridation treatment

The effect of a nitridation treatment for 10 hr at 800°C on the oxidation resistance of a Ti-48Al-2Cr (at.%) alloy in air at 800°C was evaluated. Results prove that nitridation decreases by about 40% the total mass gain of non-nitrided material, although the oxidation mechanism is the same for both materials. The oxidation can be divided into two stages. The formation of a nonprotective mixed alumina-rutile scale during the transient stage results in a high oxidation rate. A further decrease in the oxidation rate arises from the establishment of an external alumina-rich layer during the steady stage. The main difference between the scale developed on both materials is the continuous nature of the nitride layer present in the nitrided material during the entire exposure. The thin continuous nitride layer formed during the nitridation treatment acts beneficially as a diffusion barrier, preventing oxygen dissolution in the α2-Ti3Al phase during the transient stage. Furthermore, the oxygen gradient through the oxide scale is kept low, because no oxygen is removed at the scale-alloy interface. © 2001 Plenum Publishing Corporation.Peer Reviewe

Oxidation behavior of a fine-grained chromium-containing Ni3 Al alloy prepared by powder metallurgy

The oxidation behavior of a fine-grained Cr-containing Ni3Al based alloy was evaluated between 500 and 1000°C for exposures up to 2000 h. The alloy showed low oxidation rates over the entire temperature interval due to the formation of a thin protective alumina layer. The growth of this healing layer was promoted by both the fine microstructure of the alloy and the chromium additions. Rapid formation of the alumina layer was observed even at temperatures as low as 500°C. During the whole exposure at temperatures below 800°C the alumina layer remained adherent. However, at 800 and 900°C some spalling was observed. Usually, spalling took place at the core of the alumina layer but not at the oxide/metal interface. © 2006 Springer Science+Business Media, Inc.Peer Reviewe

Influence of 1 and 5 wt% TiC additions on the oxidation behaviour of pure tungsten

The influence of 1 and 5 wt% of TiC nanoparticles on the oxidation behaviour of reinforced tungsten has been evaluated up to 700 °C in dry air. Isothermal thermogravimetric tests prove that the addition of 5 wt% of TiC particles is detrimental, increasing the mass gain of pure tungsten by a factor of ten. TiC particles act as stress concentrators, facilitating microcracking events within the scale and promoting decohesion between TiC-free boundaries and TiC-containing regions of the material. Compared to pure tungsten, lowering TiC addition to 1 wt% significantly improves the oxidation resistance at 700 °C by reducing about seven times the mass gain, while at 600 °C both materials exhibit similar resistance. At 700 °C, the presence of 1 wt% of TiC particles inhibits massive microcracking events occurring in the scale formed on pure tungsten, rendering the oxide scale denser and more protective.This research has been supported by the Regional Government of Madrid through TECHNOFUSIÓN(III)CM (S2018/EMT-4437) and the Ministerio de Economía y Competitividad of Spain (ENE2015-70300-C3-2-R MINECO/FEDER) and programs. The authors acknowledge the expert support of A. García and A. Tomás from the CENIM Microscopy Laboratory

Influence of grain and phase orientation on the oxidation behaviour of a Ti–46Al–1Cr–0.2Si alloy

Peer reviewe