Statistical approaches to perform dissolution profile comparisons

Comparative dissolution testing is extensively used as a tool to evaluate equivalency between oral solid dosage forms. However the current official procedure to compare dissolution profiles, the f2 similarity factor, lacks solid statistical foundation and the statistical uncertainty is unknown. Additionally the limits to declare in vitro similarity with the current methodology (f2 ≥ 50) are arbitrary and not bound to any biopharmaceutical property; therefore it cannot be considered as a good predictor of the in vivo performance of formulations, especially in the case of extended release formulations. The aim of this work was to design, develop and explore two new statistical tests for comparing dissolution profiles. These tests have more statistical foundations than the current methodologies and exhibit the flexibility to be customized for a specific formulation. One test, the tolerated difference test (TDT) can be tailored to detect differences in the release profiles of extended release formulations that represent a lack of bioequivalence (or a significant difference in the performance in a combined dissolution permeability system). Customization of the dissolution profile comparison tests for ER formulations was possible by using the TDT without sacrificing its statistical properties (known and acceptable statistical uncertainty). In summary, a new approach to design and perform dissolution profile comparisons under typical principles of statistical experimental design is described. Four demonstrative examples of comparisons of ER formulations are presented.Vergleichende Untersuchungen des Auflösungsverhaltens werden häufig zur Bestimmung der Äquivalenz von oralen, festen Arzneiformen eingesetzt. Die derzeitige offizielle Prüfung, der f2-Test, verwendet hierfür den sogenannten similarity factor f2, dem jedoch eine solide statistische Grundlage fehlt und dessen statistische Unsicherheit nicht bekannt ist. Darüber hinaus sind bei diesem Test die Grenzen für die in-vitro-Ähnlichkeit (f2 < 50) willkürlich gewählt und nicht an biopharmazeutische Eigenschaften gebunden. Daher kann diese Methode nicht als eine gute Vorhersage für das in-vivo-Verhalten der untersuchten Arzneiformen angesehen werden. Dies gilt insbesondere für Arzneiformen mit verlängerter Wirkstofffreigabe. Das Ziel dieser Arbeit war die Entwicklung zweier neuer statistischer Tests zum Vergleich von Auflösungsprofilen. Im Vergleich zu momentan angewendeten Methoden besitzen diese beiden neuen Tests eine fundierte statistische Basis und verfügen über die Flexibilität, für spezifische Formulierungen angepasst werden zu können. Einer dieser Tests, der Tolerated Difference Test (TDT), kann so angepasst werden, dass solche Unterschiede zwischen den Dissolutionsprofilen von verlängert freisetzenden Formulierungen identifiziert werden, die auf mangelnde Bioäquivalenz hinweisen. Im Rahmen der vorliegenden Arbeit wird ein neuer Ansatz zur Entwicklung und Durchführung von Vergleichstests für Dissolutionsprofile beschrieben, die auf Prinzipien des statistischen experimentellen Designs basieren. Die Anwendungsmöglichkeiten werden anhand von vier Beispielen für verlängert freisetzende Formulierungen dargestellt

Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions

The antiplatelet agent clopidogrel is listed by the FDA as a strong clinical index inhibitor of cytochrome P450 (CYP) 2C8 and weak clinical inhibitor of CYP2B6. Moreover, clopidogrel is a substrate of—among others—CYP2C19 and CYP3A4. This work presents the development of a whole-body physiologically based pharmacokinetic (PBPK) model of clopidogrel including the relevant metabolites, clopidogrel carboxylic acid, clopidogrel acyl glucuronide, 2-oxo-clopidogrel, and the active thiol metabolite, with subsequent application for drug–gene interaction (DGI) and drug–drug interaction (DDI) predictions. Model building was performed in PK-Sim® using 66 plasma concentration-time profiles of clopidogrel and its metabolites. The comprehensive parent-metabolite model covers biotransformation via carboxylesterase (CES) 1, CES2, CYP2C19, CYP3A4, and uridine 5 0 -diphospho-glucuronosyltransferase 2B7. Moreover, CYP2C19 was incorporated for normal, inter mediate, and poor metabolizer phenotypes. Good predictive performance of the model was demon strated for the DGI involving CYP2C19, with 17/19 predicted DGI AUClast and 19/19 predicted DGI Cmax ratios within 2-fold of their observed values. Furthermore, DDIs involving bupropion, omeprazole, montelukast, pioglitazone, repaglinide, and rifampicin showed 13/13 predicted DDI AUClast and 13/13 predicted DDI Cmax ratios within 2-fold of their observed ratios. After publication, the model will be made publicly accessible in the Open Systems Pharmacology repository

A systems pharmacology model for inflammatory bowel disease

Motivation The literature on complex diseases is abundant but not always quantitative. This is particularly so for Inflammatory Bowel Disease (IBD), where many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. We propose the elaboration and validation of a logic network for IBD able to capture the information available in the literature that will facilitate the identification/validation of therapeutic targets. Results In this article, we propose a logic model for Inflammatory Bowel Disease (IBD) which consists of 43 nodes and 298 qualitative interactions. The model presented is able to describe the pathogenic mechanisms of the disorder and qualitatively describes the characteristic chronic inflammation. A perturbation analysis performed on the IBD network indicates that the model is robust. Also, as described in clinical trials, a simulation of anti-TNFα, anti-IL2 and Granulocyte and Monocyte Apheresis showed a decrease in the Metalloproteinases node (MMPs), which means a decrease in tissue damage. In contrast, as clinical trials have demonstrated, a simulation of anti-IL17 and anti-IFNγ or IL10 overexpression therapy did not show any major change in MMPs expression, as corresponds to a failed therapy. The model proved to be a promising in silico tool for the evaluation of potential therapeutic targets, the identification of new IBD biomarkers, the integration of IBD polymorphisms to anticipate responders and non-responders and can be reduced and transformed in quantitative model/s

Clinical Practice Guideline For The Prevention, Early Detection, Diagnosis, Management And Follow Up Of Type 1 Diabetes Mellitus In Patient Over 15 Years

Entidades participantes Agradecemos la participación de las instituciones, asociaciones y sociedades científicas, a través de sus representantes, por sus aportes y contribución en los diferentes procesos del desarrollo de la guía: Asociación Colombiana de Endocrinología, Diabetes y Metabolismo. Centro Nacional de Investigación en Evidencia y Tecnologías en Salud (Alianza CINETS).Revista Nacional - Indexad

Guía de práctica clínica para el diagnóstico, tratamiento y seguimiento de los pacientes mayores de 15 años diabetes mellitus tipo 1

La diabetes mellitus tipo 1 es una enfermedad que suele aparecer tempranamente, implicando que los pacientes convivan con ella por muchos años. Del adecuado control clínico que se logre, dependerán los resultados y como se trata de una condición con potenciales complicaciones serias, es imperativo tener claridad sobre su diagnóstico, tratamiento y seguimiento para minimizar impacto en morbilidad, calidad de vida y mortalidad.Pacientes mayores de 15 añoshttps://orcid.org/0000-0003-0960-9480https://orcid.org/0000-0002-1982-6799https://orcid.org/0000-0002-9013-5384N/

Ecos de la academia: Revista de la Facultad de Educación, Ciencia y Tecnología - FECYT Nro 6

Ecos de la academia, Revista de la Facultad de Educación Ciencia y Tecnología es una publicación científica de la Universidad Técnica del Norte, con revisión por pares a doble ciego que publica artículos en idioma español, quichua, portugués e inglés. Se edita con una frecuencia semestral con dos números por año.En ella se divulgan trabajos originales e inéditos generados por los investigadores, docentes y estudiantes de la FECYT, y contribuciones de profesionales de instituciones docentes e investigativas dentro y fuera del país, con calidad, originalidad y relevancia en las áreas de ciencias sociales y tecnología aplicada.Modelos multidimensionales del bienestar en contextos de enseñanza- aprendizaje: una revisión sistemática. Nuevas tendencias para el área académica de la Publicidad en la zona 1 del Ecuador. Propuesta de un curso de escritura académica bajo la base de modelos experienciales. Aproximación al estudio de las emociones. Seguimiento a egresados y graduados para actualizar el perfil de egreso y profesional. Impacto de la Gerencia de Calidad en el clima organizacional en Educación Básica. Comunicación efectiva del gerente educativo orientada al manejo de conflictos en el personal docente. Meritocracia: Democratización o exclusión en el acceso a la educación superior en Ecuador. Asertividad y desempeño académico en estudiantes universitarios. La creatividad en la formación profesional. Aspectos metodológicos en el proceso de enseñanza- aprendizaje de la gimnasia en estudiantes de Educación Física. English Language Learning Interaction through Web 2.0 Technologies. La sistematización de la práctica educativa y su relación con la metodología de la investigación. El ozono y la oxigenación hiperbárica: una vía para mejorar la recuperación en lesiones deportivas. La labor tutorial: Independencia del aprendizaje en el contexto universitario. Motivación hacia la profesión docente en la Enseñanza Secundaria. El uso académico de Facebook y WhatsApp en estudiantes universitarios... La educación superior en Ecuador: situación actual y factores de mejora de la calidad. El Proyecto de Investigación “Imbabura Étnica”

Resultados Semilleros de Investigación 2009-2010

La publicación recoge los doce informes finales de investigación presentados por los estudiantes de ocho Semilleros 1 y cuatro Semilleros 2, correspondientes a la convocatoria 2009–2010 y se constituye en el Número 25 de la Serie de Investigaciones en Construcción, si bien este es el primer Número publicado en formato digital que UNIJUS se permite poner a disposición no sólo de la comunidad universitaria, sino también de la sociedad colombiana e internacional, interesada en los temas estudiados por los jóvenes investigadores de la Facultad de Derecho, Ciencias Políticas y Sociales de la Universidad Nacional de Colombia

Measurement of B-c(2S)(+) and B-c*(2S)(+) cross section ratios in proton-proton collisions at root s=13 TeV

Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.Peer reviewe