What to expect and when: benznidazole toxicity in chronic Chagas' disease treatment.

Background: Benznidazole is one of the two most effective antiparasitic drugs for Chagas' disease treatment. However, knowledge about its toxicity profile is mostly based on post-marketing observational studies. Objectives: Our study combines data from two prospective clinical trials designed to assess the safety of the drug newly produced by ELEA Laboratories (Abarax®). Methods: Eligible participants were selected using a consecutive sampling strategy in the CINEBENZ and BIOMARCHA studies between 2013 and 2016 (EUDRACT 2011-002900-34 and 2012-002645-38, respectively, and clinicaltrials.gov NCT01755403 and NCT01755377, respectively). Enrolled subjects received treatment with 5 mg/kg/day benznidazole orally in two divided doses for 8 weeks and were followed up fortnightly. Results: We observed 305 adverse reactions in 85 of 99 participants (85.9%). Each patient had a median of three adverse reactions, 89.5% were mild and the median duration was 12 days. Most adverse reactions appeared in the first month of treatment except arthritis and peripheral neuropathy. Twenty-six patients did not complete treatment: 2 were withdrawn, 1 for ectopic pregnancy and 1 for epilepsy relapse due to cysticercosis; 2 were lost to follow-up; and 22 were owing to adverse reactions, two of them severe. We observed some unexpected adverse reactions that have not been described previously, such as psychiatric symptoms, erectile dysfunction, menstrual cycle alterations and lung infiltration. Conclusions: There is a very high frequency of adverse reactions to benznidazole. Most adverse reactions are mild, but the treatment burden is significant and unexpected reactions are not rare. Severe reactions are uncommon, but they can be life-threatening. Further studies are necessary to optimize treatment.

Reline aqueous solutions behaving as liquid mixtures of H-bonded co-solvents: microphase segregation and formation of co-continuous structures as indicated by Brillouin and 1H NMR spectroscopies.

Deep eutectic solvents (DESs) offer a suitable alternative to conventional solvents in terms of both performance and cost-effectiveness. Some DESs also offer certain green features, the greenness of which is notoriously enhanced when combined with water. Aqueous DES dilutions are therefore attracting great attention as a novel green medium for biotechnological processes, with the aqueous dilutions of reline - a DES composed of urea and choline chloride - being one of the most studied systems. Despite their macroscopic homogeneous appearance, both 1H NMR spectroscopic studies and molecular dynamics simulations have revealed the occurrence of certain dynamic heterogeneity at a microscopic molecular level. Ultrasonic measurements were also used with the aim of getting further insights but nonconclusive results were obtained. Herein, we have studied aqueous reline dilutions by Brillouin spectroscopy given its proved suitability for detecting local structure rearrangements in liquid mixtures of H-bonded co-solvents. Brillouin spectroscopy revealed the formation of a co-continuous structure resulting from local structure rearrangements and micro-segregation into aqueous and DES phases. Interestingly, there is agreement between 1H NMR and Brillouin spectroscopy when pointing to the DES content where microphase segregation and formation of co-continuous structures occurred.

Population pharmacokinetics of benznidazole in adult patients with Chagas disease.

The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h(-1)). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011-002900-34 and at ClinicalTrials.gov under number NCT01755403.).

Arthritis and benznidazole: more closely related than we thought.

Chagas disease is a parasitic infection that leads to a significant public health problem in countries where the disease is endemic and where it is nonendemic. Benznidazole is the most commonly used drug for the etiological treatment of Chagas disease. Patients treated with benznidazole suffer frequent adverse drug reactions. Although arthralgia is common, arthritis has been reported as a very rare side effect. The objective of this study was to describe arthritis in a cohort of Trypanosoma cruzi-infected patients treated with benznidazole.

Bronquiolitis: guia para el tratamiento con medicina basada en la evidencia / Bronquiolitis: guide by treatment in evidence based medicine

El objetivo de esta guia es proponer recomendaciones acerca del diagnóstico, los criterios de hospitalización y el tratamiento, en niños previamente sanos, quienes presentan bronquiolitis

Las interleucinas 6, 8 y 10 en la fase inicial de la pancreatitis aguda. Su utilidad pronóstica / Interleukins 6, 8 and 10 in the initial phase of acute pancreatitis. Their prognostic utility

Introducción. La pancreatitis aguda es una grave enfermedad que precisa para la instauración de un tratamiento acorde con la gravedad, de un diagnóstico evolutivo precoz. El objetivo de nuestro estudio ha sido determinar los valores de interleucina 6, 8 y 10 en la fase inicial de la enfermedad. Pacientes y método. Hemos realizado un estudio prospectivo de 29 pacientes agrupados en pancreatitis leve, de mediana gravedad o grave. Las determinaciones de interleucinas en sangre venosa se realizaron en los primeros 5 días de evolución, y la cuantificación se efectuó con técnicas de enzimoinmunoanálisis. Resultados. En la pancreatitis grave existió una elevación de las tres interleucinas, con un pico máximo a las 36 h del inicio de la enfermedad. Desde el segundo día, el descenso de valores fue continuado. A partir del tercer día, las interleucinas 8 y 10 se normalizaron, persistiendo las diferencias estadísticamente significativas en los valores de la interleucina 6. Conclusiones. La interleucina 6 es el marcador que con mayor fiabilidad nos permitirá predecir, desde el día de admisión del paciente, la evolución pronóstica de la pancreatitis (AU)

Use of a proteome strategy for tagging proteins present at the plasma membrane.

A plasma membrane (PM) fraction was purified from Arabidopsis thaliana using a standard procedure and analyzed by two-dimensional (2D) gel electrophoresis. The proteins were classified according to their relative abundance in PM or cell membrane supernatant fractions. Eighty-two of the 700 spots detected on the PM 2D gels were microsequenced. More than half showed sequence similarity to proteins of known function. Of these, all the spots in the PM-specific and PM-enriched fractions, together with half of the spots with similar abundance in PM fraction and supernatant, have previously been found at the PM, supporting the validity of this approach. Extrapolation from this analysis indicates that (i) approximately 550 polypeptides found at the PM could be resolved on 2D gels; (ii) that numerous proteins with multiple locations are found at the PM; and (iii) that approximately 80% of PM-specific spots correspond to proteins with unknown function. Among the later, half are represented by ESTs or cDNAs in databases. In this way, several unknown gene products were potentially localized to the PM. These data are discussed with respect to the efficiency of organelle proteome approaches to link systematically genomic data to genome expression. It is concluded that generalized proteomes can constitute a powerful resource, with future completion of Arabidopsis genome sequencing, for genome-wide exploration of plant function.

[Nutritional status of preschool children in Ciudad de La Habana from 1972 to 1993]. / Estado nutricional de preescolares de Ciudad de La Habana entre 1972 y 1993.

Two anthropometric surveys of children and adolescents have been carried out in Cuba with national samples. A third study done in the province of Ciudad de la Habana provided information on the physical characteristics of the population in that area and a baseline for the periodic evaluation of its nutritional status. This article compares the weight and height results obtained in these surveys for children 0 to 5 years old who lived in this province with the international reference standards proposed by WHO. The results show that, despite the economic difficulties the country has faced, the prevalence of malnutrition is low. In 1993, the prevalence of low height-for-age was 3.1%; that of low weight-for-height, 0.4%; and that of low weight-for-age, 1.5%. Overweight was the most common type of malnutrition, with a prevalence of 5.2%. Between 1972 and 1993, the prevalence of chronic malnutrition fell 32.6%, acute malnutrition was reduced by 69.2%; malnutrition of all types decreased by 44.4%; and overweight fell 48.5%.

[Puberal development in Cuban adolescents]. / Desarrollo puberal en adolescentes cubanos.

Within the sample of the National Investigation of Development and Growth in Cuba in 1972, the mean age of menarche in girls and the different stages of sexual development in both sexes were analyzed. For menarche, the status method was employed with logit analysis in a national aleatory sample that comprised 13,143 girls. The mean age for menarche was 13.01 +/- 0.02 years with a value of 12.77 for urban population and 13.26 for the rural. The study was also made by provinces. The sexual development, according with the stages of Tanner's method was investigated. The sample included about 26,000 individuals from 8 to 18 years old. The results obtained for the different percentiles with the logit analysis are offered. The importance that adolescents have a different maturation rhythm; precocious, average and late, becomes evident and the importance of the knowledge of these variants in normal individuals by the personnel in charge is pointed out.

PIP: The authors examine the different stages of sexual development in Cuban adolescents, including mean age at menarche in girls. Data are for 13,143 girls surveyed in the 1972 National Investigation of Development and Growth in Cuba (SUMMARY IN ENG)

Combinación del estudio y el trabajo en la formación de los profesionales de la salud / The combination of study and work in the formation of health professionals

En esta ponencia se aborda el análisis de las determinantes economicosociales en la evolución del concepto salud-enfermedad y en el ejercicio profesional, así como en los cambios en la organización de los servicios de salud y en la educación médica. Se hace un recuento histórico de la educación médica en Cuba, desde sus inicios hasta nuestros días, y se destaca la influencia de las relaciones de producción a través de los diferentes períodos. En este sentido se significa como el proceso revolucionario ha determinado profundos cambios en el cuadro de salud, que demandan y facilitan el desarrollo correspondiente del proceso enseñanza-aprendizaje y la aplicación del principio del estudio-trabajo para la formación más integral de los futuros profesionales de la salud (AU)