Formación entre pares. Experiencia digital sincrónica en tiempos de pandemia / Peer to peer education among internal medicine residents using digital platforms

BACKGROUND: COVID-19 impacted all areas of our society, and we took advantage of new technologies such as telemedicine to deliver information. Peer education is another tool that can be used. AIM: To report the experience of peer education among residents using a digital platform. MATERIAL AND METHODS: A digital educational program was devised in which third year residents exposed different relevant topics in internal medicine to their first year peers using Zoom. The educational process was evaluated using a Likert scale. RESULTS: A high level of satisfaction was found among the respondents according to the scale. Conclusions: There was a high level of satisfaction with the used methodology among first-year residents. A more exhaustive evaluation of this educational program should be worthwhile.

Phase I Study of Taminadenant (PBF509/NIR178), an Adenosine 2A Receptor Antagonist, with or without Spartalizumab (PDR001), in Patients with Advanced Non-Small Cell Lung Cancer.

PURPOSE: The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non-small cell lung cancer (NSCLC). Taminadenant (PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response. PATIENTS AND METHODS: In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80-640 mg, orally, twice a day) with or without spartalizumab (anti-programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination. RESULTS: During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea [n = 1 (4.0%) each; 640 mg], and in the combination group were pneumonitis [n = 2 (8.0%); 160 and 240 mg] and fatigue and alanine/aspartate aminotransferase increase [n = 1 (4.0%) each; 320 mg]; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively. CONCLUSIONS: Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status.

ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non-Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges.

PURPOSE: Central nervous system metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges. PATIENTS AND METHODS: Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses. RESULTS: Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6-52.0), 30.0% (16.6-46.5), 50.0% (21.1-78.9), and 59.1% (43.2-73.7); whole-body DCR (95% CI): 66.7% (50.5-80.4), 82.5% (67.2-92.7), 66.7% (34.9-90.1), and 70.5% (54.8-83.2); intracranial ORRs (95% CI): 39.3% (21.5-59.4), 27.6% (12.7-47.2), 28.6% (3.7-71.0), and 51.5% (33.5-69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6-41.4) and DCR was 66.7% (95% CI, 41.0-86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood-brain barrier. CONCLUSIONS: Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease. See related commentary by Murciano-Goroff et al., p. 2477.

[Peer to peer education among internal medicine residents using digital platforms]. / Formación entre pares. Experiencia digital sincrónica en tiempos de pandemia.

BACKGROUND: COVID-19 impacted all areas of our society, and we took advantage of new technologies such as telemedicine to deliver information. Peer education is another tool that can be used. AIM: To report the experience of peer education among residents using a digital platform. MATERIAL AND METHODS: A digital educational program was devised in which third year residents exposed different relevant topics in internal medicine to their first year peers using Zoom. The educational process was evaluated using a Likert scale. RESULTS: A high level of satisfaction was found among the respondents according to the scale. CONCLUSIONS: There was a high level of satisfaction with the used methodology among first-year residents. A more exhaustive evaluation of this educational program should be worthwhile.

Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study.

BACKGROUND: Several paediatric malignancies, including anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumour (IMT), neuroblastoma, and rhabdomyosarcoma, harbour activation of anaplastic lymphoma kinase (ALK) through different mechanisms. Here, we report the safety, pharmacokinetics, and efficacy of ceritinib in paediatric patients with ALK-positive malignancies. METHODS: This multicentre, open-label, phase 1 trial was done at 23 academic hospitals in ten countries. Children (aged ≥12 months to <18 years) diagnosed with locally advanced or metastatic ALK-positive malignancies that had progressed despite standard therapy, or for which no effective standard therapy were available, were eligible. ALK-positive malignancies were defined as those with ALK rearrangement, amplification, point mutation, or in the case of rhabdomyosarcoma, expression in the absence of any genetic alteration. Eligible patients had evaluable or measurable disease as defined by either Response Evaluation Criteria in Solid Tumours, version 1.1 for patients with non-haematological malignancies, International Neuroblastoma Response Criteria scan for patients with neuroblastoma, or International Working Group criteria for patients with lymphoma. Other eligibility criteria were Karnofsky performance status score of at least 60% for patients older than 12 years or Lansky score of at least 50% for patients aged 12 years or younger. This study included a dose-escalation part, followed by a dose-expansion part, in which all patients received treatment at the recommended dose for expansion (RDE) established in the dose-escalation part. Both parts of the study were done in fasted and fed states. In the dose-escalation part, patients were treated with once-daily ceritinib orally, with dose adjusted for body-surface area, rounded to the nearest multiple of the 50 mg dose strength. The starting dose in the fasted state was 300 mg/m2 daily and for the fed state was 320 mg/m2 daily. The primary objective of this study was to establish the maximum tolerated dose (ie, RDE) of ceritinib in the fasted and fed states. The RDE was established on the basis of the incidence of dose-limiting toxicities in patients who completed a minimum of 21 days of treatment with safety assessments and at least 75% drug exposure, or who discontinued treatment earlier because of dose-limiting toxicity. Overall response rate (defined as the proportion of patients with a best overall response of complete response or partial response) was a secondary endpoint. Activity and safety analyses were done in all patients who received at least one dose of ceritinib. This trial is registered with ClinicalTrials.gov (NCT01742286) and is completed. FINDINGS: Between Aug 28, 2013, and Oct 17, 2017, 83 children with ALK-positive malignancies were enrolled to the dose-escalation (n=40) and dose-expansion (n=43) groups. The RDE of ceritinib was established as 510 mg/m2 (fasted) and 500 mg/m2 (fed). 55 patients (30 with neuroblastoma, ten with IMT, eight with ALCL, and seven with other tumour types) were treated with ceritinib at the RDE (13 patients at 510 mg/m2 fasted and 42 patients at 500 mg/m2 fed). The median follow-up was 33·3 months (IQR 24·8-39·3) for patients with neuroblastoma, 33·2 months (27·9-35·9) for those with IMT, 34·0 months (21·9-46·4) for those with ALCL, and 27·5 months (22·4-36·9) for patients with other tumour types. An overall response was recorded in six (20%; 95% CI 8-39) of 30 patients with neuroblastoma, seven (70%; 33-93) of ten patients with IMT, six (75%; 35-97) of eight patients with ALCL, and one (14%; <1-58) of seven patients with other tumours. The safety profile of ceritinib was consistent with that observed in adult patients. All patients had at least one adverse event. Grade 3 or 4 adverse events occurred in 67 (81%) of 83 patients and were mostly increases in aminotransferases (alanine aminotransferase increase in 38 [46%] patients and aspartate aminotransferase increase in 27 [33%] patients). At least one serious adverse event was reported in 40 (48%) of 83 patients and 31 (37%) of 83 patients had at least one grade 3 or 4 serious adverse event. 14 (17%) deaths occurred during the study, of which 12 were on-treatment deaths and two were after 30 days of the last dose. Of the 12 on-treatment deaths, ten were due to disease progression (neuroblastoma), one due to sepsis, and one due to intractable hypotension. INTERPRETATION: Ceritinib 500 mg/m2 once daily with food is the recommended dose for paediatric patients with ALK-positive malignancies. Ceritinib showed promising preliminary antitumour activity in patients with ALK-positive refractory or recurrent IMT or ALCL, and in a subset of patients with relapsed or refractory neuroblastoma, with a manageable safety profile. Our data support the notion that ALK inhibitors should be considered in therapeutic strategies for paediatric patients with malignancies with genetic ALK alterations. FUNDING: Novartis Pharmaceutical Corporation.

Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug-drug interaction study in patients with ALK + advanced tumors.

PURPOSE: Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively. METHODS: This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily. RESULTS: Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC. CONCLUSION: Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.

Development and validation of an LC-MS/MS method for the quantitative analysis of the adenosine A2a receptor antagonist NIR178 and its monohydroxy metabolite in human plasma: Application to clinical pharmacokinetics.

We report a selective LC-MS/MS method for the simultaneous quantitative determinations of the adenosine A2a receptor antagonist NIR178 (NIR178) and its major metabolite NJI765 in human plasma. Sample preparation steps involved protein precipitation, sample evaporation and reconstitution using a plasma sample volume of 0.1 ml plasma. Separation was achieved in 10 min on an Acquity UPLC BEH C18 1.7 µm, 2.1 × 50 mm column heated at 60°C with a gradient elution at 0.6 ml/min mobile phase made of water and acetonitrile both acidified with 0.1% formic acid. The detection was performed in positive ion mode and quantification based on multiple reaction monitoring. The linear response range was 1.00-1,000 ng/ml using a 1/x2 weighting factor. The intra- and inter-day accuracies (bias %) and intra- and inter-day precisions (CV, %) obtained for NIR178 and NJI765 were within the acceptance criteria. The normalized NIR178 and NJI765 matrix factor calculated from six lots of normal, lipemic and hemolyzed plasmas ranged from 0.97 to 1.05. The normalized recoveries of both NIR178 and NJI765 compared with their internal standards were consistent and reproducible with a CV ≤8.0. This method was successfully applied to support pharmacokinetic studies in adult patients with cancer.

The structure of a prokaryotic viral envelope protein expands the landscape of membrane fusion proteins.

Lipid membrane fusion is an essential function in many biological processes. Detailed mechanisms of membrane fusion and the protein structures involved have been mainly studied in eukaryotic systems, whereas very little is known about membrane fusion in prokaryotes. Haloarchaeal pleomorphic viruses (HRPVs) have a membrane envelope decorated with spikes that are presumed to be responsible for host attachment and membrane fusion. Here we determine atomic structures of the ectodomains of the 57-kDa spike protein VP5 from two related HRPVs revealing a previously unreported V-shaped fold. By Volta phase plate cryo-electron tomography we show that VP5 is monomeric on the viral surface, and we establish the orientation of the molecules with respect to the viral membrane. We also show that the viral membrane fuses with the host cytoplasmic membrane in a process mediated by VP5. This sheds light on protein structures involved in prokaryotic membrane fusion.

Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers.

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases.

The Ferric uptake regulator (Fur) and iron availability control the production and maturation of the antibacterial peptide microcin E492.

Microcin E492 is a pore-forming bacteriocin with toxic activity against Enterobacteriaceae, which undergoes amyloid aggregation as a mechanism to regulate its toxicity. To be active, it requires the posttranslational attachment to the C-terminus of a glycosylated enterochelin derivative (salmochelin), a process carried out by the proteins MceC, MceI and MceJ encoded in the MccE492 gene cluster. Both microcin E492 and salmochelin have a proposed role in the virulence of the bacterial pathogen Klebsiella pneumoniae. Besides, enterochelin is produced as a response to low iron availability and its synthesis is controlled by the global iron regulator Fur. Since the production of active microcin E492 depends on enterochelin biosynthesis, both processes could be coordinately regulated. In this work, we investigated the role of Fur in the expression of the microcin E492 maturation genes mceCJI. mceC was not regulated by Fur as it occurs with its homolog iroB in Salmonella enterica. We demonstrated that mceJI along with the previously uncharacterized gene mceX are transcribed as a single mRNA, and that Fur binds in vivo to a Fur box located upstream of the mceX-mceJI unit. Also, we established that the expression of these genes decreased in a condition of high iron availability, while this effect is abrogated in a Δfur background. Furthermore, our results indicated that MceX acts as a negative regulator of microcin E492 structural gene expression, coupling its synthesis to the iron-dependent regulatory circuit. Consequently, fur or mceX overexpression led to a significant decrease in the antibacterial activity of cells producing microcin E492. Altogether these results show that both the expression of microcin E492 maturation genes mceJI, and MceX the negative regulator of microcin E492 synthesis, are coordinated with the enterochelin production by Fur, depending on the iron levels in the medium.

Development and Qualification of a Drug-Disease Modeling Platform to Characterize Clinically Relevant Endpoints in Type 2 Diabetes Trials.

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease characterized by persistently elevated blood glucose concentration (hyperglycemia). We developed a mechanistic drug-disease modeling platform based on data from more than 4,000 T2DM subjects in seven phase II/III clinical trials. The model integrates longitudinal changes in clinically relevant biomarkers of glycemic control with information on baseline disease state, demographics, disease progression, and different therapeutic interventions, either when given alone or as add-on combination therapy. The model was able to simultaneously characterize changes in fasting plasma glucose, fasting serum insulin, and glycated hemoglobin A1c following administration of sulfonylurea, metformin, and thiazolidinedione as well as disease progression in clinical trials ranging from 16-104 weeks of treatment. The mechanistic components of this generalized mechanism-based platform, based on knowledge of pharmacology, insulin-glucose homeostatic feedback, and diabetes pathophysiology, allows its application to be further expanded to other antidiabetic drug classes and combination therapies.

Bacterial Tubulins A and B Exhibit Polarized Growth, Mixed-Polarity Bundling, and Destabilization by GTP Hydrolysis.

Bacteria of the genus Prosthecobacter express homologs of eukaryotic α- and ß-tubulin, called BtubA and BtubB (BtubA/B), that have been observed to assemble into filaments in the presence of GTP. BtubA/B polymers are proposed to be composed in vitro by two to six protofilaments in contrast to that in vivo, where they have been reported to form 5-protofilament tubes named bacterial microtubules (bMTs). The btubAB genes likely entered the Prosthecobacter lineage via horizontal gene transfer and may be derived from an early ancestor of the modern eukaryotic microtubule (MT). Previous biochemical studies revealed that BtubA/B polymerization is reversible and that BtubA/B folding does not require chaperones. To better understand BtubA/B filament behavior and gain insight into the evolution of microtubule dynamics, we characterized in vitro BtubA/B assembly using a combination of polymerization kinetics assays and microscopy. Like eukaryotic microtubules, BtubA/B filaments exhibit polarized growth with different assembly rates at each end. GTP hydrolysis stimulated by BtubA/B polymerization drives a stochastic mechanism of filament disassembly that occurs via polymer breakage and/or fast continuous depolymerization. We also observed treadmilling (continuous addition and loss of subunits at opposite ends) of BtubA/B filament fragments. Unlike MTs, polymerization of BtubA/B requires KCl, which reduces the critical concentration for BtubA/B assembly and induces it to form stable mixed-orientation bundles in the absence of any additional BtubA/B-binding proteins. The complex dynamics that we observe in stabilized and unstabilized BtubA/B filaments may reflect common properties of an ancestral eukaryotic tubulin polymer.IMPORTANCE Microtubules are polymers within all eukaryotic cells that perform critical functions; they segregate chromosomes, organize intracellular transport, and support the flagella. These functions rely on the remarkable range of tunable dynamic behaviors of microtubules. Bacterial tubulin A and B (BtubA/B) are evolutionarily related proteins that form polymers. They are proposed to be evolved from the ancestral eukaryotic tubulin, a missing link in microtubule evolution. Using microscopy and biochemical approaches to characterize BtubA/B assembly in vitro, we observed that they exhibit complex and structurally polarized dynamic behavior like eukaryotic microtubules but differ in how they self-associate into bundles and how this bundling affects their stability. Our results demonstrate the diversity of mechanisms through which tubulin homologs promote filament dynamics and monomer turnover.

Complicaciones presentadas en pacientes mayores de 65 años ingresados por fractura de cadera en un hospital andaluz de tercer nivel / Complications presented in patients over 65 years admitted for hip fracture in an Andalusian tertiary hospital

Objetivo: Conocer las complicaciones que se han producido en pacientes mayores de 65 años, ingresados en un hospital andaluz de tercer nivel durante el año 2012, con diagnóstico principal de fractura de cadera. Metodología: Diseño: Se realizó un estudio descriptivo transversal. Ámbito, periodo y sujetos de estudio: Pacientes ingresados en el año 2012 mayores de 65 años con diagnóstico principal de fractura de cadera. Variables principales: Morbimortalidad recogida en el CMBD, analizada en función de otras variables que influyen en su aparición según la bibliografía (edad, sexo, comorbilidad, etc). Análisis estadístico de las variables con comparación de medias y proporciones con los programas estadísticos Epidat y G-Stat de uso libre. Resultados: La media de edad fue de 83,16 (6,68) años, y de estancia 10,2 días. La mortalidad fue del 4,99%. Las fracturas extracapsulares fueron más frecuentes que las intracapsulares, 64,24% y 35,76% respectivamente. La estancia media preoperatoria, 3,5 días. El tratamiento más frecuente la osteosíntesis, con un 62,6%. La complicación más frecuente, excluyendo el éxitus, “complicaciones quirúrgicas- vías urinarias”. El total de pacientes complicados fue del 8,7%, incluyendo los fallecidos. El sexo masculino, la edad avanzada y la demora quirúrgica se asocian con aparición de complicaciones. Los porcentajes más altos de complicación se dieron en pacientes con tres comorbilidades asociadas. Conclusión: La presencia de complicaciones en el período de hospitalización de pacientes ancianos ingresados por fractura de cadera se relaciona con sexo masculino, edad avanzada, demora quirúrgica y mayor número de comorbilidades (AU)

Purpose: To know the complications that occurred in patients over 65 years admitted to an Andalusian tertiary hospital during 2012 with a primary diagnosis of hip fracture. Methodology: Design: Cross-sectional study. Scope, period and cohort: Patients admitted in 2012 over 65 years with a primary diagnosis of hip fracture. Main outcomes: Morbidity and mortality collected in the Andalusian Minimum Data Set , analyzed in terms of other variables that influence their occurrence according to the literature (age, sex, comorbidity, etc). Instruments: Statistical analysis has been done with Epidat and G-Stat, statistical free software, to get and compare means and proportions of the variables. Results: The mean age was 83.16(6.68) years old. The mortality rate was 4.99%. The average length of stay was 10.2 days. Extracapsular fractures were more frequent than intracapsular ones, 64.24% and 35.76% respectively. The average preoperative stay was 3.5 days. The most frequent treatment was osteosynthesis, with 62.6%. The most common complication, excluding exitus, was “surgical urinary tract complications”. Total complicated patients was 8.7%, including the deceased. Male gender, older age and surgical delay was associated with development of complications. The highest percentages of complications occurred in patients with three comorbidities. Conclusion: The presence of complications during the period of hospitalization of elderly patients admitted for hip fracture is associated with male gender, older age, surgical delay and more comorbidities (AU)

Producción científica en Educación en Enfermería en Brasil y España: Un estudio comparativo / Science production in nursing education in Brazil and Spain: A comparative study

Objetivo: Conocer el estado del arte de la producción científica relacionada con la Educación en Enfermería en Brasil y España. Método: Investigación documental, descriptiva, exploratoria, retrospectiva y de naturaleza cuantitativa. Período: 2000-2010. Ámbito: Base de datos LILACS (Brasil) y CUIDEN (España). Análisis: Categorización: 1.Temática: Proceso Enseñanza-Aprendizaje, Currículum, Docentes, Evaluación, Alumnos e Historia de la Educación en Enfermería; 2.Tipo de estudio: investigación, revisión, reflexión y relato de experiencia; estadística descriptiva. Resultados: LILACS fueron analizados 490 artículos. El año de mayor producción fue el 2007; en destaque la categoría "Proceso Enseñanza-Aprendizaje". CUIDEN fueron utilizados 247 artículos; mayor producción en 2009; categoría destacada "Alumno". Conclusión: La producción científica analizada en Brasil y España presenta aspectos semejantes, tanto en la presencia de estudios de diversas naturalezas, como en la evolución de las transformaciones sociales. Se percibe un creciente aumento del número de publicaciones en ambos países, aunque todavía, insuficientes en relación con sus particularidades

Objective: know the state of the art of scientific literature on nursing education in Brazil and Spain. Method: The research was documentary, descriptive, exploratory, retrospective, quantitative. Period: 2000-2010. Scope: LILACS database (Brazil) and CUIDEN (Spain). Analysis: categorization: 1. thematic: Teaching- Learning Process, Curriculum, Teachers, Evaluation, Students and History of Nursing Education, 2. Type of study: research, review, reflection and experience report; descriptive statistics. Results: LILACS 490 articles were analyzed. The highest production year was 2007; highlighted the category "Teaching-Learning Process." CUIDEN was used 247 articles; higher production in 2009; category highlighted "Students". Conclusion: The scientific production in Brazil and Spain analyzed presents aspects similar both in the presence of various types of studies, such as its evolution and social transformation. We can see an increasing number of publications in both countries, however, still insufficient when viewed in its particularities

Enhanced penetration of moxifloxacin into rat prostate tissue evidenced by microdialysis.

Moxifloxacin is reported to have increased distribution into the prostate compared with older fluoroquinolones such as norfloxacin and ciprofloxacin, being able to reach tissue-to-plasma concentration ratios greater than unity. However, most of these studies use tissue homogenates derived from biopsy samples, which can lead to overestimation of free concentrations as fluoroquinolones tend to accumulate in the intracellular space. The aim of this study was to investigate moxifloxacin pharmacokinetics in rat prostate interstitial fluid by microdialysis. Tissue pharmacokinetics was assessed by implanting a small microdialysis catheter in the prostate gland. Blood samples were simultaneously collected for assessing plasma pharmacokinetics. Analysis of plasma (N=154) and microdialysis (N=344) concentrations after a single intravenous dose of 6 or 12mg/kg moxifloxacin was conducted in the non-linear mixed-effect modelling software NONMEM v.6 as well by a non-compartmental approach. Moxifloxacin showed a significant tissue distribution in the prostate (AUCprostate,ISF/fu·AUCplasma=1.24±0.37), 59% higher than the value obtained for levofloxacin in a previous study. A three-compartment model with non-linear kinetics could adequately describe moxifloxacin pharmacokinetics in terms of curve fitting and precision in parameter estimation. The developed pharmacokinetic model indicates that passive diffusion and active transport are the mechanisms involved in moxifloxacin distribution to the prostate. These findings suggest that moxifloxacin could be a better alternative to levofloxacin for the treatment of chronic bacterial prostatitis owing to its enhanced tissue penetration and higher AUCtissue/MIC ratios, even though it is not yet approved by the US FDA for this indication.

Population pharmacokinetic modeling of the unbound levofloxacin concentrations in rat plasma and prostate tissue measured by microdialysis.

Levofloxacin is a broad-spectrum fluoroquinolone used in the treatment of both acute and chronic bacterial prostatitis. Currently, the treatment of bacterial prostatitis is still difficult, especially due to the poor distribution of many antimicrobials into the prostate, thus preventing the drug to reach effective interstitial concentrations at the infection site. Newer fluoroquinolones show a greater penetration into the prostate. In the present study, we compared the unbound levofloxacin prostate concentrations measured by microdialysis to those in plasma after a 7-mg/kg intravenous bolus dose to Wistar rats. Plasma and dialysate samples were analyzed using a validated high-pressure liquid chromatography-fluorescence method. Both noncompartmental analysis (NCA) and population-based compartmental modeling (NONMEM 6) were performed. Unbound prostate tissue concentrations represented 78% of unbound plasma levels over a period of 12 h by comparing the extent of exposure (unbound AUC0-∞) of 6.4 and 4.8 h·µg/ml in plasma and tissue, respectively. A three-compartment model with simultaneous passive diffusion and saturable distribution kinetics from the prostate to the central compartment gave the best results in terms of curve fitting, precision of parameter estimates, and model stability. The following parameter values were estimated by the population model: V1 (0.38 liter; where V1 represents the volume of the central compartment), CL (0.22 liter/h), k12 (2.27 h(-1)), k21 (1.44 h(-1)), k13 (0.69 h(-1)), Vmax (7.19 µg/h), kM (0.35 µg/ml), V3/fuprostate (0.05 liter; where fuprostate represents the fraction unbound in the prostate), and k31 (3.67 h(-1)). The interindividual variability values for V1, CL, Vmax, and kM were 21, 37, 42, and 76%, respectively. Our results suggest that levofloxacin is likely to be substrate for efflux transporters in the prostate.

Esteroides e infección en trauma craneoencefálico / Infectious complications in steroid recipients for cns trauma

Estudio descriptivo retrospectivo que busca valorar la frecuencia de infección en trauma craneoencefálico que fue manejado con esteroides. Se recolectó una muestra de 153 pacientes y de las historias clínicas se extrajeron las variables demográficas (edad, género, mortalidad) y las características clínicas (infección, uso de esteroides). Los resultados no evidenciaron aumento de la frecuencia de infecciones en los pacientes con trauma craneoencefálico que recibieron manejo con esteroides...

This descriptive retrospective study sought to assess the frequency of infectious complications in steroid recipients for central nervous system (CNS) trauma. A sample of 153 patients was collected and demographic variables (age, gender, mortality) and clinical features (infection, steroid use) were obtained from medical records. Results did not evidence an increase in the frequency of infectious complications in patients treated with steroids for CNS trauma...

Validated stability-indicating RP-HPLC method for the determination of rimonabant in a pharmaceutical dosage form.

A simple RP-HPLC method was developed and validated for the determination of rimonabant in a pharmaceutical dosage form. The separation was performed on a C18 column (150 x 4.6 mm id, 5 microm) with acetonitrile-water (75 + 25, v/v) mobile phase. The detection was achieved with a diode array detector at 215 nm. The method was linear in the concentration range of 0.5-50 microg/mL (r = 1) with an LOQ of 0.24 microg/mL. The specificity and stability-indicating capability of the method were proved through forced degradation studies, and it was shown that there was no increase of the cytotoxicity. Rimonabant was exposed to hydrolytic, oxidative, and photolytic stress conditions, and the samples were analyzed by the proposed method. Under optimized conditions, rimonabant was successfully separated from its degradation products within 10 min, and the resolution was found to be greater than 2. The RSD values for intraday and interday precision were always less than 2%. Interday accuracy ranged from 98.1 to 101.7% (RSD = 1.0%). Moreover, method validation demonstrated acceptable results for sensitivity and robustness. The method was applied for the quantitative analysis of rimonabant in a tablet dosage form to demonstrate its use for improving the QC of pharmaceuticals containing this drug.

HPLC determination of bezafibrate in human plasma and its application to pharmacokinetics studies.

An isocratic high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of bezafibrate in biological fluids. Bezafibrate was separated on a C(18) analytical column (150 x 4.6 mm i.d., 5 microm particle size) with 0.01 M phosphate buffer (pH 3.5)-acetonitrile-methanol (50:40:10) as mobile phase at a flow rate of 1.0 mL/min. The UV detector was set to 230 nm. Bezafibrate was extracted from human plasma using a simple liquid-liquid extraction with tert-butyl methyl ether. Parameters such as linearity, precision, accuracy, recovery, specificity, and stability were evaluated by method validation studies. All the parameters remained within acceptable limits. The validated procedure was linear in the concentration range of 0.2-50 microg/mL. The proposed method used for individual drug determinations is applicable for therapeutic monitoring purposes as well as for use in pharmacokinetic investigations. As an example, the practical quantification limit for bezafibrate in plasma was about 0.05 microg/mL with precision of 10.2% and accuracy of 112.6%. The method was applied in a study of the pharmacokinetics of bezafibrate in six healthy volunteers, who ingested a single oral dose of 200 mg.