Preliminary in vitro assessment of pharmacokinetic drug-drug interactions of EST64401 and EST64514, two sigma-1 receptor antagonists.

EST64401 and EST64514 are two selective sigma-1 receptor ligands that showed a good profile in a lead optimization process for oral pain treatment. Their potential for pharmacokinetic-based drug-drug interactions was assessed to anticipate clinical interactions.Both compounds showed a low potential for CYP inhibition with percentages of inhibition <50% at 1 µM in recombinant human CYPs (CYP1A2, 2C9, 2C19, 2D6 and 3A4) and IC50 ≥75 µM for CYP3A4 and 2D6 in human liver microsomes.No CYP induction was observed for CYP1A2, 2B6 and 3A4 at concentrations ≤25 µM (EST64401) or ≤50 µM (EST64514) in human hepatocytes using as endpoints CYP activities and mRNA levels.More than one enzyme participated in compound metabolism. The main enzymes involved were CYP3A4 for EST64401 and CYP2D6 besides CYP3A4 for EST64514.Neither EST64401 nor EST64514 seemed to be substrates of P-gp or BCRP in Caco-2 cells (efflux ratio ≤2). Transporter inhibition was observed at concentrations ≥20 µM; EST64401 only inhibiting P-gp at higher concentrations (≥125 µM).Preliminary in vitro interaction studies suggest a similar profile for EST64401 and EST64514. Therefore, other properties will have to be considered for compound differentiation and selection for further development.

Hábitos alimentarios y estado nutricional en pacientes diabéticos con retinopatía que acuden a una Clínica Oftalmológica Privada de la ciudad de Asunción / Food habits and nutritional status in diabetic patients with retinopathy that attend a private Ophthalmological Clinic of the city of Asunción

La retinopatía diabética (RD) es una complicación microvascular crónica, específica de la diabetes. Es una causa importante de pérdida visual en adultos, con consecuencias médicas, sociales y financieras significativas. El objetivo fue evaluar los hábitos alimentarios y estado nutricional en diabéticos con retinopatía que acuden a la Clínica Vista 10 de la ciudad de Asunción entre setiembre y noviembre del año 2018. Estudio descriptivo, observacional de corte transverso que incluyó 50 pacientes, Siendo la mayor parte de ellos del sexo femenino (65%), la edad media fue de 62,8±11,3 años, el 66% (n=33) estaba casado con nivel educativo primario (n=20;40%) y vivía en Gran Asunción (n= 46; 92%). Respecto a la frecuencia de consumo de alimentos, se encontró que casi la totalidad de la población realizaba el desayuno (96%). El 70% consumía lácteos descremados menos de la cantidad recomendada. Solo un 20% consumía frutas todos los días. Un poco más de la mitad (52%) consumía verduras todos los días. El 70% consumía pescado por debajo de las recomendaciones establecidas, y el 78% consumía legumbres menos de la cantidad recomendada. Más de la mitad (58%) consumía alimentos integrales por debajo de las recomendaciones. El 54% consumía comida casera todos los días y el 56% realizaba la cena todos los días. Más de la mitad de los participantes presentó sobrepeso u obesidad. Los hábitos de la población son deficientes, en relación al consumo de frutas, lácteos según las recomendaciones de las Guías Alimentarias del Paraguay

Diabetic retinopathy (RD) is a chronic microvascular complication specific to diabetes. It is an important cause of visual loss in adults, with significant medical, social and financial consequences. The objective was to evaluate the dietary habits and nutritional status in diabetic atients with retinopathy who attend the Clínica Vista 10 in the city of Asunción between September and November of 2018. This was a descriptive, observational cross-sectional study The majority of the population studied was female (n = 33, 65%), the mean age was 62.8 ± 11.3 years, 66% (n = 33) was married and the highest percentage was presented primary education level(n = 20, 40%). According to the classification of the place of origin, most lived in Gran Asunción (n = 46, 92%). Regarding the frequency of food consumption, it was found that almost the entire population made breakfast(96%), 70% consumed low-fat dairy products less than the recommended amount. Only 20% consumed fruits every day. A little more than half(52%)consumed vegetables every day, 70% consumed fish below the established recommendations and 78% consumed legumes less than the recommended amount. More than half (58%) consumed whole food below the recommendations, 54% consumed home-cooked food every day and 56% made dinner every day. More than half of the population was overweight or obese. The habits of the population are deficient, in relation to the consumption of fruits, dairy products according to the recommendations of the Food Guides of Paraguay

Methyl-DEAE-dextran: a candidate biomaterial.

The full quaternisation of DEAE-dextran was successfully attempted and an application of the quaternised product was suggested. Commercial DEAE-dextran was reacted with iodomethane at 60 degrees C in the presence of NaOH. The raw product was purified by dialysis, during which the iodide ion was replaced by chloride. N-methylation and O-methylation resulted from the reaction. A second methylation step produced no further changes in the molecule. Alkalimetry indicated the absence of amino groups in the methylated polymer molecule, thus testifying to a complete quaternisation. N-acetylcysteine (AcCy) was neutralised with the polymer in the hydroxide form, thus obtaining the methyl DEAE-dextran salt of AcCy (Me-DEAE-dextran/AcCy), whereby an ophthalmic formulation for the treatment of the dry eye syndrome was prepared. For comparison, the neutral AcCy salt of commercial DEAE-dextran (DEAE-dextran/AcCy) was prepared. The AcCy content in Me-DEAE-dextran/AcCy was higher than in DEAE-dextran/AcCy (23 vs 13%), while the viscosity of a solution containing the salt concentration corresponding to the therapeutic AcCy concentration (4%w/v) was lower with the former compared to the latter salt (20.5 vs 23.9 mPa s). Both solutions were ipotonic (245 mOsm/kg), whereas the commercial Tirocular is strongly hypertonic (900 mOsm/kg) and irritant.

Entropy-based gene ranking without selection bias for the predictive classification of microarray data.

BACKGROUND: We describe the E-RFE method for gene ranking, which is useful for the identification of markers in the predictive classification of array data. The method supports a practical modeling scheme designed to avoid the construction of classification rules based on the selection of too small gene subsets (an effect known as the selection bias, in which the estimated predictive errors are too optimistic due to testing on samples already considered in the feature selection process). RESULTS: With E-RFE, we speed up the recursive feature elimination (RFE) with SVM classifiers by eliminating chunks of uninteresting genes using an entropy measure of the SVM weights distribution. An optimal subset of genes is selected according to a two-strata model evaluation procedure: modeling is replicated by an external stratified-partition resampling scheme, and, within each run, an internal K-fold cross-validation is used for E-RFE ranking. Also, the optimal number of genes can be estimated according to the saturation of Zipf's law profiles. CONCLUSIONS: Without a decrease of classification accuracy, E-RFE allows a speed-up factor of 100 with respect to standard RFE, while improving on alternative parametric RFE reduction strategies. Thus, a process for gene selection and error estimation is made practical, ensuring control of the selection bias, and providing additional diagnostic indicators of gene importance.

Manifestaçöes dermatológicas da esclerose sistêmica progressiva: relato de um caso / Dermatologic manifestations of progressive systemic sclerosis: report of a case

Os autores relatam um caso clínico com imagens fotográficas de uma paciente, com 51 anos de idade, em estágio avançado de Esclerose Sistêmica Progressiva (E.S.P.). A Esclerose Sistêmica Progressiva é uma doença que atinge, principalmente, o tecido conjuntivo com caráter sistêmico, sendo que as manifestaçoes dermatológicas sao as mais freqüentemente encontradas e de fácil visualizaçao.

Cloroquina: uso e paraefeitos em reumatologia / Chloroquine rheumatology: use and aftereffects in rheumatology

Os autores revisaram a literatura sobre Cloroquina, seu uso e paraefeitos. A seguir, apresentaram a sua experiência estudando 69 casos de pacientes com a artrite reumatóide, artrite reumatóide juvenil e lupus eritematoso sistêmico em uso de cloroquina. Os resultados condizem com os encontrados na literatura. Os paraefeitos enonctrados foram de pequena magnitude e a cloriquina foi considerada droga segura no tratamento a longo prazo em Artrite Reumatóide e Lupus Eritematoso Sistêmico.