Uso de micofenolato mofetilo fuera de registro en enfermedades inmunomediadas / Off-label use of mycophenolate mofetil in immune-mediated diseases

BACKGROUND: Mycophenolate mofetil (MMF) is a largely used immunosuppressive agent in the prevention of transplant rejection and lupus nephritis. Its use has been extended to other immune-mediated diseases (ID). AIM: To assess the off-label use of MMF, its performance as a glucocorticoid sparing agent, the therapeutic response, and its adverse effects. MATERIAL AND METHODS: A retrospective study was performed. One hundred-seven patients aged 58 ± 16 years (83% females) who received MMF for ID in off label uses between 2016 and 2018 were included. The study variables were cause of MMF indication, sex, age, use as a first- or second-line treatment and maintenance dosing. The cumulative doses of glucocorticoids six months before and after MMF indication were compared. RESULTS: MMF was used as a second-line therapy in 66 patients (62%). The mean maintenance dose of MMF was 1,500 ± 540 mg/day. Prednisone cumulative doses were 3,908 ± 2,173 and 1,672 ± 1,083 milligrams six months before and six months after starting MMF, respectively (p < 0.01). Adverse effects were identified in 21 (20%) cases, none of them serious. CONCLUSIONS: Mycophenolate has a favorable response profile as a second line immunosuppressive agent. It is effective as a glucocorticoid sparing drug. The safety profile is also favorable as adverse effects were scanty and mild.

Segundo estudio de consumo de benzodiazepinas en una población uruguaya (2014-2018): el problema avanza / Second study on the use of benzodiazepines in a Uruguayan population (2014-2018): the problem advances / Segundo estudo de consumo de benzodiazepínicos em uma população uruguaia (2014-2018): o problema avança

Resumen: Introducción: las benzodiazepinas (BZD) constituyen uno de los grupos farmacológicos más prescritos. La forma de uso y el riesgo de aumento de efectos adversos evitables a partir del amplio uso, pueden representar en sí mismos problemas de salud pública. Objetivos: conocer el consumo de BZD en una población uruguaya en el período 2014-2018. Métodos: se realizó un estudio de utilización de medicamentos para evaluar el consumo de BZD por vía oral, a través del dato de dispensación de farmacias de instituciones de salud, mediante la variable DHD (dosis diaria definida/1.000 habitantes/día). Resultados: participaron siete instituciones, representando el 65% de la población uruguaya. Las DHD globales fueron 116,05, 114,36, 117,32, 131,17 y 124,4 DHD para los años 2014, 2015, 2016, 2017 y 2018 respectivamente, con un aumento de 7% en el período. Conclusiones: el consumo de BZD a nivel nacional entre 2014 y 2018 persiste elevado y superior al estudio previo realizado entre 2010 y 2012. Comparado con otros países, los valores para Uruguay se encuentran entre los más altos. Es necesario que todos los actores relevantes de la cadena del medicamento desarrollen estrategias para controlar la situación.

Summary: Introduction: benzodiazepines (BZD) constitute one of the most widely prescribed pharmacological groups. The use modality and the risk of increase of avoidable adverse effects resulting from wide consumption may represent a public health problem in itself. Objectives: to learn about the use of benzodiazepine in a Uruguayan population between 2014 and 2018. Method: a study was conducted on the use of medications to evaluate BZD consumption administered orally, by consulting dispensing of pharmacies in the health institutions, through the DHD variable (daily human doses/1.000 inhabitants/day). Results: 7 institutions participated in the study, representing 65% of the Uruguayan population. Global DHD were 116.05, 114.36, 117.32, 131.17 and 124.4 for 2014, 2015, 2016, 2017 and 2018 respectively, with a 7% increase in the period of study. Conclusions: the use of benzodiazepines was still high at the national level between 2014 and 2018 and greater than the figure found in the previous study, conducted between 2010 and 2012. Compared to other countries, Uruguayan figures are among the highest. All relevant actors in the drug chain need to develop strategies to control the situation.

Resumo: Introdução: os benzodiazepínicos (BZD) constituem um dos grupos farmacológicos mais prescritos. A forma de uso e o risco de aumento dos efeitos adversos evitáveis pelo uso extensivo podem representar, por si só, problemas de saúde pública. Objetivos: conhecer o consumo de BZD em uma população uruguaia no período 2014-2018. Métodos: foi realizado um estudo de uso de medicamentos para avaliar o consumo de BZD por via oral, utilizando dados da dispensação em farmácias de instituições de saúde, utilizando a variável DHD (dose diária definida/1000 habitantes/dia). Resultados: dados de sete instituições foram estudados, representando 65% da população uruguaia. Os DHDs globais foram 116,05, 114,36, 117,32, 131,17 e 124,4 DHDs para os anos de 2014, 2015, 2016, 2017 e 2018 respectivamente, com aumento de 7% no período. Conclusões: o consumo de BZD em nível nacional entre 2014 e 2018 continua alto e é superior aos resultados de um estudo anterior realizado entre 2010 e 2012. Quando comparados com outros países, os valores para o Uruguai estão entre os mais altos. É necessário que todos os atores relevantes da cadeia de medicamentos desenvolvam estratégias para controlar a situação.

Running With Scissors: Evolutionary Conflicts Between Viral Proteases and the Host Immune System.

Many pathogens encode proteases that serve to antagonize the host immune system. In particular, viruses with a positive-sense single-stranded RNA genome [(+)ssRNA], including picornaviruses, flaviviruses, and coronaviruses, encode proteases that are not only required for processing viral polyproteins into functional units but also manipulate crucial host cellular processes through their proteolytic activity. Because these proteases must cleave numerous polyprotein sites as well as diverse host targets, evolution of these viral proteases is expected to be highly constrained. However, despite this strong evolutionary constraint, mounting evidence suggests that viral proteases such as picornavirus 3C, flavivirus NS3, and coronavirus 3CL, are engaged in molecular 'arms races' with their targeted host factors, resulting in host- and virus-specific determinants of protease cleavage. In cases where protease-mediated cleavage results in host immune inactivation, recurrent host gene evolution can result in avoidance of cleavage by viral proteases. In other cases, such as recently described examples in NLRP1 and CARD8, hosts have evolved 'tripwire' sequences that mimic protease cleavage sites and activate an immune response upon cleavage. In both cases, host evolution may be responsible for driving viral protease evolution, helping explain why viral proteases and polyprotein sites are divergent among related viruses despite such strong evolutionary constraint. Importantly, these evolutionary conflicts result in diverse protease-host interactions even within closely related host and viral species, thereby contributing to host range, zoonotic potential, and pathogenicity of viral infection. Such examples highlight the importance of examining viral protease-host interactions through an evolutionary lens.

Evaluación del consumo en antidepresivos en la población uruguaya entre 2010 y 2014 / Evaluation of antidepressant use in the Uruguayan population between 2010 and 2014 / Avaliação do uso de antidepressivos na população uruguaia entre 2010 e 2014

Resumen: Objetivo: conocer el consumo de antidepresivos en la población uruguaya en el período 2010-2014. Material y método: se realizó un estudio de utilización de medicamentos para evaluar el consumo de antidepresivos utilizando el dato de dispensación de medicamentos de las farmacias de las instituciones participantes. Se utilizó la variable dosis diaria definida (DDD) por 1.000 habitantes/día (DHD). Resultados: se incluyó el 69% de la población uruguaya. Las DHD globales de antidepresivos para los años 2010, 2011, 2012, 2013 y 2014 fueron: 26,49, 29,71, 30,17, 30,79 y 32,55 (promedio en los 5 años: 30,04) siendo el aumento porcentual global en dicho período de 22,88%. Los ISRS fueron el grupo de antidepresivos más consumidos. Sertralina fue el antidepresivo más consumido en los 5 años de estudio (DHD 13,65), y el de mayor aumento porcentual fue duloxetina, seguido por escitalopram. Conclusión: el consumo de antidepresivos a nivel nacional en el período analizado es inferior al constatado en otros países, con una tendencia al aumento. Éste puede ser visto como una señal para la evaluación evolutiva en el periodo 2015-2020 y para realizar análisis de las prácticas de prescripción y actuales indicaciones, utilizando otras metodologías como los estudios de prevalencia o estudios de indicación-prescripción o de prescripción-indicación.

Abstract: Objective: to learn about antidepressant use in the Uruguayan population between 2010 and 2014. Method: the use of drugs was studied to evaluate the consumption of antidepressants by analysing the dispensing of drugs in the pharmacies that are part of the participating institutions. The study used the defined daily dose variable (DDD) by 1.000 inhabitants/day (DHD). Results: 69% of the Uruguayan population was included in the study. The global antidepressant dose by inhabitants per day for 2010, 2011, 2012, 2013 and 2014 was 26,49, 29,71, 30,17; 30,79 and 32,55 respectively (average in the five years 30,4) being the global increase of percentage 22,88%5 for that period. The SSRIs (selective serotonin reuptake inhibitor) were the most widely used group of antidepressants. Sertraline was the antidepressant of greatest consumption in the 5 years of the study (DHD 13,65), and the one that presented the highest percentage increase was duloxetine, followed by escitalopram. Conclusion: antidepressant use at the national level during the period analysed is lower than that seen in other countries, although a tendency to increase was found. This may be interpreted as a sign for the need to evaluate the evolution in the 2015-2020 period, and to conduct studies on prescription practices and current indications using other methodologies, such as prevalence studies or indication-prescription or prescription-indication studies.

Resumo: Objetivo: conhecer o consumo de antidepressivos na população uruguaia no período 2010-2014. Material e método: foi realizado um estudo sobre o uso de medicamentos para avaliar o consumo de antidepressivos a partir dos dados de dispensação de medicamentos nas farmácias das instituições participantes. Foi utilizada a variável dose diária definida (DDD) por 1.000 habitantes/dia (DHD). Resultados: 69% da população uruguaia foram incluídas. Os DHDs globais de antidepressivos para os anos de 2010, 2011, 2012, 2013 e 2014 foram: 26,49, 29,71, 30,17; 30,79 e 32,55 (média nos 5 anos, 30,04) sendo o aumento percentual global no referido período de 22,88%. Os inibidores seletivos da recaptação da serotonina foram o grupo de antidepressivos mais amplamente utilizado. A sertralina foi o antidepressivo mais utilizado nos 5 anos do estudo (DHD 13,65), e o que apresentou maior aumento percentual foi a duloxetina, seguida do escitalopram. Conclusão: o consumo de antidepressivos em nível nacional no período analisado é inferior ao encontrado em outros países, com tendência de aumento. Isto pode ser visto como um sinal para a avaliação evolutiva no período 2015-2020 e para a realização de análises das práticas de prescrição e indicações atuais, utilizando outras metodologias como estudos de prevalência ou estudos de indicação-prescrição ou prescrição-indicação.

Perfil epidemiológico de las intoxicaciones por antidepresivos recibidas en el Centro Información y Asesoramiento Toxicológico uruguayo en el período 2010-2012 / Epidemiological profile in poisoning with antidepressants cases received at the Poison Information and Advice Center (Centro Información y Asesoramiento Toxicológico) in Uruguay between 2010 and 2012

Introducción: la depresión es una de las principales causas mundiales de discapacidad. Datos nacionales mostraron que 10,6% de la población consumió en alguna oportunidad algún antidepresivo. La importancia de la exposición de este grupo terapéutico en la sociedad se puede ver reflejada, entre otros aspectos, en la frecuencia en que se encuentran implicados en intoxicaciones. Objetivo: el objetivo de este estudio fue describir el perfil epidemiológico de las intoxicaciones por antidepresivos recibidas por el Centro de Información y Asesoramiento Toxicológico (CIAT) entre los años 2010 y 2012. Metodología: estudio observacional retrospectivo en el cual se analizaron las consultas de intoxicaciones que involucraron un antidepresivo, registradas en el CIAT entre 2010-2012. Resultados: se recibieron 32.565 consultas toxicológicas en el período analizado. Los antidepresivos fueron implicados como agente tóxico causal en 2.523 (7,7%). La mayoría de las intoxicaciones ocurrieron en pacientes de sexo femenino (75,4%), adultos (79,3%) y fueron de causa intencional (90%). El antidepresivo más frecuentemente implicado fue sertralina (38%). La totalidad de las intoxicaciones severas (54; 2,1%) implicaron más de un fármaco. Se registró un solo caso fatal. Conclusiones: el perfil de intoxicaciones por antidepresivos en Uruguay entre 2010 y 2012 es similar al reportado en series internacionales y apoya el ya conocido riesgo de los antidepresivos de segunda generación. Si bien en número escaso, se destaca la exposición a estos medicamentos en menores de 18 años, sobre todo menores de 5 años, lo que requiere mayor caracterización. (AU)

Introduction: Depression is one of the main global causes of disability. National data showed that 10.6% of the population once consumed some kind of antidepressant. It is important to focus on this therapeutic group since, among other aspects, they are frequently involved in cases of poisoning. Objective: The study aims to describe the epidemiological profile of poisoning with antidepressants of individuals who consulted at the Poison Information and Advice Center (Centro Información y Asesoramiento Toxicológico (CIAT) between 2010 and 2012. Methodology: Observational, retrospective study whereby consultations for poisoning involving antidepressants recorded in the CIAT between 2010 and 2012, were analysed. Results: 32565 poisoning consultations were received in the period under the study. Antidepressants were the causing poisoning agent in 2523 cases 7.7%. Most cases of poisoning occurred in female patients (75.4%), adults (79.3%), and were intentional in 90% of cases. The most frequently involved antidepressant was sertraline (38%). All cases of severe poisoning (54, accounting for 2.1%) involved more than one drug. Only one death was recorded. Conclusions: The profile of poisoning with antidepressants in Uruguay, between 2010 and 2012 is similar to that reported in international series and supports the already known risk of second generation antidepressants. Despite figures being low, we point out the exposure of the population younger than 18 years old, in particular younger than 5 years old, to these drugs, what calls for characterization.

Introdução: a depressão é uma das principais causas mundiais de deficiências. Dados nacionais mostraram que 10,6% da população consumiu em algum momento um antidepressivo. A importância da exposição deste grupo terapêutico na sociedade pode ser vista, entre outros aspectos, na frequência em que se encontram implicados em intoxicações. Objetivo: o objetivo deste estudo foi descrever o perfil epidemiológico das intoxicações por antidepressivos recebidas no Centro de Información y Asesoramiento Toxicológico (CIAT) entre 2010 e 2012. Metodologia: estudo observacional retrospectivo no qual foram analisadas as consultas por intoxicações registradas no CIAT entre 2010-2012 que estavam relacionadas a um antidepressivo, Resultados: no período analisado foram recebidas 32565 consultas toxicológicas. Os antidepressivos foram identificados como agente tóxico causal em 2523 (7,7%). As maiorias das intoxicações foram em pacientes de sexo feminino (75,4%), adultos (79,3%) e tiveram causa intencional (90%). O antidepressivo mais frequentemente implicado foi a sertralina (38%). Todas as intoxicações severas (54; 2,1%) foram devidas a mais de um fármaco. Somente um caso registrado foi fatal. Conclusões: o perfil das intoxicações por antidepressivos no Uruguai entre 2010 e 2012 é similar ao descrito em series internacionais e reforça o risco conhecido dos antidepressivos de segunda geração. Embora o número seja escasso, destaca-se a exposição de menores de 18 anos, sobre todo menores de 5 anos a estes medicamentos o que implica na necessidade de uma melhor caracterização.

Effect of Ki-67 assessment in the distribution of breast cancer subtypes: Evaluation in a cohort of Latin American patients.

Breast cancer (BC) is a heterogeneous disease composed of four main subtypes with distinct clinical and epidemiological features. Although several reports have described the distribution of BC subtypes in Latin America, the majority of them have not included the cellular marker, Ki-67, in the immunohistochemical (IHC) panel. The aim of the present study was to describe the distribution of BC subtypes in a cohort of Latin American women using an IHC panel with Ki-67. A prospective cohort of 580 patients in three centers of Peru (the Hospital Nacional Edgardo Rebagliatti Martins, the Hospital Nacional Guillermo Almenara Irigoyen, the Hospital Nacional Alberto Sabogal, Lima) and one in Uruguay (Instituto Nacional del Cáncer, Montevideo) were evaluated. BC phenotypes were classified according to an IHC panel: Estrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki-67. Silver in situ hybridization was used when the HER2 status, as determined by IHC, was equivocal. The associations between the BC phenotypes and their clinicopathological features were evaluated. ER was positive in 65% of the cases (n=377), and PgR in 50% (n=203). In total, 79.1% (n=459) were HER2-negative, 19.8% (n=115) were HER2-positive and 1% (n=6) had an equivocal status. With respect to Ki-67, 44.7% of the patients exhibited staining in >14% of the tumor cells (n=259). The distribution of subtypes was as follows: Luminal A, 31.9% (n=183); luminal B, 35% (n=201); HER2, 12.1% (n=70); and triple-negative, 20.9% (n=120). When Ki-67 was not included in the panel, the frequency of luminal A was 41.1% and luminal B, 25.8% (9.2% of the cases were misclassified). Ki-67 was most highly expressed in triple-negative and HER2 tumors. Inclusion of Ki-67 in the IHC panel to assign subtypes revealed a higher frequency of luminal B tumors than was reported previously for Latin American women with BC, whereas the distribution of triple-negative and HER2 tumors were similar to that previously reported. In conclusion, these results demonstrated that excluding Ki-67 from the panel of IHC markers may lead to an underestimation of the rates of luminal B tumors.

Uso racional de benzodiacepinas: hacia una mejor prescripción / Rational use of benzodiazepines: towards a better prescription

RESUMEN Las benzodiacepinas constituyen un grupo de fármacos de amplia prescripción en la práctica clínica. Sus efectos farmacológicos son compartidos pero su perfil farmacocinética modifica su utilidad en los diferentes escenarios clínicos. Su prescripción irracional es un problema de salud pública mundial, siendo el uso crónico y los riesgos asociados al mismo un claro ejemplo de este patrón de uso no apropiado. Están sujetas a interacciones farmacológicas frecuentes y existen poblaciones más vulnerables a sus efectos adversos, como los ancianos. Algunos de sus efectos adversos más notorios son las caídas y la aparición de dependencia y tolerancia asociado a un incorrecto uso crónico, con la aparición de síndromes de discontinuación si estese interrumpe en forma brusca. Existen pautas de uso racional que deben conocerse al realizar su prescripción

ABSTRACT Benzodiazepines are a drug group widely prescribed in clinical practice. Its pharmacological effects are shared but their pharmacokinetic profile changes their usefulness in different clinical scenarios. Benzodiazepines irrational prescribing is a global public health concern, including chronic consumption and its associated risks. They are subject to frequent drug-drug interactions, and there are recognized risk populations, such as the elderly. Some of its most frequently adverse reactions include falls and the emergence of dependence and tolerance associated with chronic use. Rational use guidelines must be known in order to improve benzodiazepines prescription

Consumo de benzodiazepinas en la población uruguaya: un posible problema de salud pública / Consumption of benzodiazepines in the Uruguayan population: a possible public health problem

Resumen Objetivo: conocer el consumo de benzodiazepinas en Uruguay entre 2010 y 2012. Material y método: se realizó un estudio de utilización de medicamentos para evaluar el consumo de benzodiazepinas usando la dispensación de las farmacias de las instituciones participantes. Se utilizó la variable dosis diaria definida (DDD) por 1.000 habitantes/día (DHD). Se compararon las DHD anuales según el perfil hipnótico o ansiolítico y el subsector de asistencia, público o privado. Resultados: se incluyó el 62% de la población uruguaya. Las DHD globales de benzodiazepinas para los años 2010, 2011 y 2012 fueron 74,97, 75,17 y 71,14 DDD/1.000 personas/día, respectivamente (promedio 73,76). La benzodiazepina ansiolítica más consumida en el período analizado fue alprazolam (promedio 25,09). La benzodiazepina hipnótica más consumida fue flunitrazepam (promedio 18,69). Incluyendo clonazepam, esta fue la benzodiazepina más consumida (promedio 36,51) y los valores de consumo global aumentan a 106,36, 110,86 y 113,61 DDD/1.000 personas/día, respectivamente (promedio 110,28). Clonazepam fue la que presentó mayor incremento (35,29%), mientras que midazolam (-46,15%) y diazepam (-18,83%) fueron las que descendieron en mayor medida. El subsector público contribuyó principalmente al consumo global y el privado fue el que mayor aumento porcentual tuvo. Conclusión: Uruguay presenta un elevado consumo de benzodiazepinas, similar al hallado en otros países, pudiendo constituir un problema de salud pública. Este dato constituye el primero disponible en nuestro país y será útil para realizar futuras comparaciones. Es necesario implementar estrategias a nivel nacional que favorezcan un uso racional de benzodiazepinas.

Abstract Objective: To quantify and evaluate benzodiazepines consumption in Uruguay between 2010 and 2012. Method: A study of utilization of drugs was conducted to assess benzodiazepines consumption in our population. Drug utilization data refers to oral benzodiazepines dispensed by the pharmacy departments from the participating health institutions. The unit of measurement was the defined daily doses (DDD) per 1000 inhabitants per day (DHD). DHD of hypnotic and anxiolytic benzodiazepines and DHD from public and private health care institutions were compared. Results were described as absolute values and percentage of changes. Results: Sixty two percent of the Uruguayan population was included in the study. Global DHD for 2010, 2011 and 2012 were 74.97, 75.17 and 71.14 (mean 73.76) DDD/1000 inhabitants/day respectively. Alprazolam was the most widely consumed anxiolytic benzodiazepine (mean 25.09) and flunitrazepam was the most commonly consumed hypnotic benzodiazepine (mean 18.69). If clonazepam is included, it becomes the most commonly consumed benzodiazepine (mean 36.51) and global DHD increases up to 106.36, 110.86 and 113.61 (mean 110.28) DDD/1000 inhabitants/day respectively. Clonazepam showed the higher consumption increase from 2010 to 2012 (35.29%), while the use of midazolam (-46.15%) and diazepam (-18.83%) gradually decreased. Public health institutions were responsible for most of the general consumption, whereas private institutions showed the higher increase in benzodiazepines consumption during the evaluated period. Conclusions: Uruguay showed high benzodiazepines consumption, similar to that reported by other countries and it seems to be an issue of public health concern. These are the first available benzodiazepines consumption data in our country and will be useful to perform future comparisons.

Resumo Objetivo: conhecer o consumo de benzodiazepinas no Uruguai no período 2010-2012. Material e método: foi realizado um estudo sobre a utilização de medicamentos para avaliar o consumo de benzodiazepinas usando a dispensação nas farmácias das instituições participantes. A variável dose diária definida (DDD) por 1.000 habitantes/dia (DHD) foi utilizada. As DHD anuais foram comparadas segundo o perfil, hipnótico ou ansiolítico, e subsector de assistência, público ou privado. Resultados: 62% da população uruguaia foi incluída. As DHD globais de benzodiazepinas para os anos 2010, 2011 e 2012 foram 74,97, 75,17 e 71,14 DDD/1.000 pessoas/dia, respectivamente (média 73,76). A benzodiazepina ansiolítica mais consumida no período analisado foi alprazolam (média 25,09) e a hipnótica com maior consumo foi flunitrazepam (média 18,69). Incluindo clonazepam, esta foi a benzodiazepina mais consumida (média 36,51) e os valores de consumo global aumentam a 106,36, 110,86 e 113,61 DDD/1.000 pessoas/dia, respectivamente (média 110,28). O clonazepam foi a que apresentou o maior incremento (35,29%), sendo que o midazolam (-46,15%) e o diazepam (-18,83%) as que apresentaram uma maior redução de consumo. O subsector público contribuiu principalmente ao consumo global e o privado o que apresentou o maior aumento porcentual. Conclusão: o Uruguai apresenta um consumo elevado de benzodiazepinas, similar ao descrito em outros países, podendo ser um problema de saúde pública. Estes dados são os primeiros disponíveis no nosso país e serão úteis para futuras comparações. É necessário implementar estratégias a nível nacional que favoreçam um uso racional de benzodiazepinas.