Inclusão da ractopamina na nutrição de peixes: revisão de literatura / Inclusion of ractopamine in fish nutrition: literature review / Inclusión de ractopamina en nutrición de peces: revisión de literatura

A demanda da população mundial por produtos aquáticos esta se incrementando, enquanto que a produção da pesca extrativa reduzindo, alcançando em muitos casos, seu máximo potencial produtivo. Como consequência, não será possível em curto prazo, sustentar o fornecimento de produtos aquáticos, direcionado a uma população que constantemente cresce e demanda pescados. O setor produtivo segue a tendência atual de outros sistemas de produção animal, os quais vêm buscando o aumento da produtividade, de maneira sustentável, do ponto de vista econômico e ambiental, requerendo, principalmente, o aporte da nutrição para contribuir com essa tendência. Os estudos com os aditivos adicionados a dieta dos animais de cativeiro é uma estratégia que tem demonstrado alto potencial para sua inclusão na aquicultura, havendo a possibilidade de um aumento nos índices produtivos e/ou melhora na qualidade do produto para o consumidor. A ractopamina é um aditivo classificado como um agonista beta-adrenérgico e seu mecanismo de ação esta associado com efeitos sobre o metabolismo dos peixes que diminuem o acúmulo de gorduras, por meio da inibição da lipogêneses e estimulo da lipólise, e por mecanismos que favorecem a síntese de proteínas muscular. Os estudos realizados até o momento comprovam que existem alterações metabólicas nos peixes, embora, não se tem encontrado, em todos os estudos, diferenças significativas nos índices zootécnicos, para assim, estabelecer seu uso na indústria. A realização de mais pesquisas é necessária para o melhor entendimento da ractopamina na alimentação dos peixes, sobretudo, no entendimento dos receptores e mecanismos de ação dos peixes.(AU)

The demand of the global population for aquatic products is increasing while the production of extractive fisheries is reducing, and, in many cases, even reaching its maximum productive potential. As a consequence, it will not be possible in the short term to sustain the supply of aquatic products aimed at a population in constant growth and in demand for fish. The productive sector follows the current trend of other animal production systems, which have been seeking to sustainably increase productivity from an economic and environmental point of view, mainly requiring the contribution of nutrition to this trend. Studies with additives to the diet of captive animals is a strategy that has shown high potential for inclusion in aquaculture, with the possibility of an increase in production rates and/or improvement in the quality of the product for the consumer. Ractopamine is an additive classified as a beta-adrenergic agonist and its mechanism of action is associated with effects on fish metabolism that reduce the accumulation of fats through the inhibition of lipogenesis and stimulation of lipolysis, and by mechanisms that favor the synthesis of muscle protein. The studies carried out so far prove that there are metabolic changes in fish, although no significant differences have been found in zootechnical indexes in order to establish its use in the industry. Further research is required for a better understanding of ractopamine in fish nutrition, especially in understanding the receptors and mechanisms of action in fish.(AU)

La demanda de la población mundial por productos acuáticos va en aumento, mientras que la producción de la pesca extractiva se reduce, alcanzando, en muchos casos, su máximo potencial productivo. Como consecuencia, no será posible en corto plazo sostener el suministro de productos acuáticos, dirigidos a una población que crece constantemente y demanda pescado. El sector productivo sigue la tendencia actual de otros sistemas de producción animal, que han venido buscando incrementar la productividad, de manera sostenible, desde el punto de vista económico y ambiental, requiriendo, principalmente, del aporte de la nutrición para contribuir a esa tendencia. Los estudios con aditivos agregados a la dieta de animales en cautiverio es una estrategia que ha mostrado un alto potencial para su inclusión en la acuicultura, con posibilidad de incremento en los índices de producción y/o mejora en la calidad del producto para el consumidor. La ractopamina es un aditivo clasificado como agonista beta-adrenérgico y su mecanismo de acción está asociado con efectos sobre el metabolismo de los peces que reducen la acumulación de grasas, a través de la inhibición de la lipogénesis y estimulación del lipólisis, y por mecanismos que favorecen la síntesis de proteínas musculares. Los estudios realizados hasta el momento prueban que existen cambios metabólicos en los peces, aunque en todos los estudios no se han encontrado diferencias significativas en los índices zootécnicos, con el fin de establecer su uso en la industria. Se necesita más investigación para comprender mejor la ractopamina en la nutrición de los peces, especialmente para comprender los receptores y los mecanismos de acción en los peces.(AU)

Severe hypokalemia secondary to abuse of ß-adrenergic agonists in a pediatric patient: Case report / Hipocalemia grave secundária a abuso de agonistas ß-adrenérgicos em paciente pediátrico: relato de caso

ABSTRACT This study reports a case of a 13-year-old male with a 3-year history of severe and intermittent hypokalemia episodes of unknown origin, requiring admission to the intensive care unit (ICU) for long QT syndrome (LQTS), finally diagnosed of redistributive hypokalemia secondary to the abuse of β-adrenergic agonists in the context of a probable factitious disorder.

RESUMO O presente estudo relata o caso de um jovem de 13 anos de idade com histórico, há três anos, de episódios de hipocalemia grave intermitente de origem desconhecida, internado em unidade de terapia intensiva (UTI) por síndrome do QT longo (SQTL). O paciente foi diagnosticado com hipocalemia por redistribuição secundária ao abuso de agonistas β-adrenérgicos, em contexto de provável transtorno factício.

Bronchodilator test in extreme old age: Adverse effects of short-acting beta-2 adrenergic agonists with clinical repercussion and bronchodilator response.

OBJECTIVE: To evaluate chronological age as a limiting factor to perform the bronchodilator test, determine significant adverse effects of short-acting beta 2 agonists with clinical repercussions, and assess bronchodilator response in extreme-old-age patients who undergo the spirometry test. METHODS: This is a cross-sectional and retrospective study. The sample was extracted from the database (spirometer and respiratory questionnaire) of a pulmonary function service. Patients over 90 years old were included in the research, and we evaluated their bronchodilator response and its significant adverse effects that may have clinical repercussions related to the bronchodilator. RESULTS: A sample of 25 patients aged 92.12 ± 2.22 years (95% CI, 91.20 - 93.04), with a minimum age of 90 years and a maximum of 97 years and a predominance of females with 72% (18/25). The bronchodilator test was performed in 84% (21/25) of the patients. The bronchodilator response was evaluated in 19 of the 21 patients (90.47%) who underwent the bronchodilator test. Two tests did not meet the criteria of acceptability and reproducibility. No clinical adverse effects were observed with the bronchodilator medication (salbutamol) during or after the exam. CONCLUSIONS: Chronological age is not a limiting factor for the bronchodilator test, short-acting beta-2 agonists did not present adverse effects with significant clinical repercussion and were useful in the diagnosis and therapeutic guidance of extreme-old-age patients.

Bronchodilator test in extreme old age: Adverse effects of short-acting beta-2 adrenergic agonists with clinical repercussion and bronchodilator response

SUMMARY OBJECTIVE: To evaluate chronological age as a limiting factor to perform the bronchodilator test, determine significant adverse effects of short-acting beta 2 agonists with clinical repercussions, and assess bronchodilator response in extreme-old-age patients who undergo the spirometry test. METHODS: This is a cross-sectional and retrospective study. The sample was extracted from the database (spirometer and respiratory questionnaire) of a pulmonary function service. Patients over 90 years old were included in the research, and we evaluated their bronchodilator response and its significant adverse effects that may have clinical repercussions related to the bronchodilator. RESULTS: A sample of 25 patients aged 92.12 ± 2.22 years (95% CI, 91.20 - 93.04), with a minimum age of 90 years and a maximum of 97 years and a predominance of females with 72% (18/25). The bronchodilator test was performed in 84% (21/25) of the patients. The bronchodilator response was evaluated in 19 of the 21 patients (90.47%) who underwent the bronchodilator test. Two tests did not meet the criteria of acceptability and reproducibility. No clinical adverse effects were observed with the bronchodilator medication (salbutamol) during or after the exam. CONCLUSIONS: Chronological age is not a limiting factor for the bronchodilator test, short-acting beta-2 agonists did not present adverse effects with significant clinical repercussion and were useful in the diagnosis and therapeutic guidance of extreme-old-age patients.

RESUMO OBJETIVOS: Avaliar se idade cronológica é um fator limitante para realizar prova broncodilatadora, determinar efeitos adversos significativos com repercussão clínica dos beta-2 agonistas de curta ação e avaliar a resposta broncodilatadora na espirometria, na velhice extrema. MÉTODOS: Estudo transversal, retrospectivo. Amostra extraída do banco de dados (espirômetro e questionário respiratório) de um serviço de função pulmonar. Incluídos na pesquisa pacientes com ≥90 anos, sendo avaliados a resposta broncodilatadora e efeitos adversos significativos com repercussão clínica ao broncodilatador. RESULTADOS: Amostra de 25 pacientes com idade de 92,12 ± 2,22 anos (IC 95%; 91,20 - 93,04), idade mínima de 90 anos e máxima de 97 anos, predominando o sexo feminino, com 72% (18/25). A prova broncodilatadora foi realizada em 84% (21/25) dos pacientes. A avaliação da resposta ao broncodilatador foi feita em 19 dos 21 pacientes (90,47%) que realizaram a prova broncodilatadora, uma vez que dois desses exames não preencheram os critérios de aceitabilidade e reprodutibilidade. A resposta broncodilatadora foi significativa em 10,52% (2/19) dos pacientes, ambos portadores de pneumopatia obstrutiva. Não foram observados efeitos adversos com repercussão clínica da medicação broncodilatadora (salbutamol) durante ou após sua realização. CONCLUSÕES: A idade cronológica não é um fator limitante para a realização da prova broncodilatadora, os beta-2 agonistas de curta ação não apresentaram efeitos adversos com repercussão clínica significativa e foram bastante úteis para auxiliar no diagnóstico e orientação terapêutica na velhice extrema.

Severe hypokalemia secondary to abuse of ß-adrenergic agonists in a pediatric patient: Case report.

This study reports a case of a 13-year-old male with a 3-year history of severe and intermittent hypokalemia episodes of unknown origin, requiring admission to the intensive care unit (ICU) for long QT syndrome (LQTS), finally diagnosed of redistributive hypokalemia secondary to the abuse of ß-adrenergic agonists in the context of a probable factitious disorder.

Níveis de ractopamina e sua influência sobre o desempenho e características de carcaça de suínos em terminação / Ractopamine levels and its influence on performance and carcass characteristics of finishing pigs

Aumentar a quantidade de carne na carcaça de suínos tem sido o objetivo não somente da indústria, como também do produtor de suínos, uma vez que melhora a rentabilidade e diminui os custos de produção. Neste sentido, objetivou-se com essa pesquisa avaliar o desempenho e as características de carcaça de suínos em terminação suplementados com diferentes níveis de ractopamina na dieta. Foram utilizados 60 suínos (30 machos castrados e 30 fêmeas), com peso inicial médio de 75,0 Kg alojados em baias de piso parcialmente ripado. O delineamento experimental foi em blocos casualizados com três níveis de ractopamina 0, 5 e 10 ppm, totalizando três tratamentos e dez repetições, com dois animais (um macho e uma fêmea) por baia (parcela experimental). Foram realizadas análises de desempenho (peso final, ganho de peso médio diário, consumo de ração médio diário e conversão alimentar) e de qualidade de carcaça (rendimento de carcaça, rendimento de carne na carcaça, espessura de toucinho e profundidade de lombo). A suplementação de 10 ppm de ractopamina na dieta de suínos em terminação aumentou o rendimento de carne na carcaça e reduziu a espessura de toucinho. Assim, conclui-se que a suplementação de 10 ppm de ractopamina na dieta de suínos em terminação melhora as características de carcaça.(AU)

Increasing the amount of meat in the pig carcass has been the goal not only of the industry but also of the pig producer as it improves profitability and reduces production costs. In this sense, the objective of this research was to evaluate the performance and carcass characteristics of finishing pigs supplemented with different levels of ractopamine in the diet. Sixty 60 pigs (30 castrated males and 30 females) were used, with a mean initial weight of 75.0 kg housed in partially slatted stalls. The experimental design was a randomized block with three ractopamine levels (0, 5 and 10 ppm), totaling three treatments and ten replicates, with two animals (one male and one female) per pen (experimental plot). There were analyzed animals performance (final weight, average daily weight gain, daily feed intake and feed conversion) and carcass quality (carcass yield, carcass meat yield, backfat thickness and loin depth). The supplementation of 10 ppm of ractopamine in the finishing pig diet increased the meat yield in the carcass and reduced the backfat thickness. Thus, it is concluded that the supplementation of 10 ppm of ractopamine in the finishing pig diet improves the carcass traits.(AU)

Níveis de ractopamina e sua influência sobre o desempenho e características de carcaça de suínos em terminação / Ractopamine levels and its influence on performance and carcass characteristics of finishing pigs

Aumentar a quantidade de carne na carcaça de suínos tem sido o objetivo não somente da indústria, como também do produtor de suínos, uma vez que melhora a rentabilidade e diminui os custos de produção. Neste sentido, objetivou-se com essa pesquisa avaliar o desempenho e as características de carcaça de suínos em terminação suplementados com diferentes níveis de ractopamina na dieta. Foram utilizados 60 suínos (30 machos castrados e 30 fêmeas), com peso inicial médio de 75,0 Kg alojados em baias de piso parcialmente ripado. O delineamento experimental foi em blocos casualizados com três níveis de ractopamina – 0, 5 e 10 ppm, totalizando três tratamentos e dez repetições, com dois animais (um macho e uma fêmea) por baia (parcela experimental). Foram realizadas análises de desempenho (peso final, ganho de peso médio diário, consumo de ração médio diário e conversão alimentar) e de qualidade de carcaça (rendimento de carcaça, rendimento de carne na carcaça, espessura de toucinho e profundidade de lombo). A suplementação de 10 ppm de ractopamina na dieta de suínos em terminação aumentou o rendimento de carne na carcaça e reduziu a espessura de toucinho. Assim, conclui-se que a suplementação de 10 ppm de ractopamina na dieta de suínos em terminação melhora as características de carcaça.

Increasing the amount of meat in the pig carcass has been the goal not only of the industry but also of the pig producer as it improves profitability and reduces production costs. In this sense, the objective of this research was to evaluate the performance and carcass characteristics of finishing pigs supplemented with different levels of ractopamine in the diet. Sixty 60 pigs (30 castrated males and 30 females) were used, with a mean initial weight of 75.0 kg housed in partially slatted stalls. The experimental design was a randomized block with three ractopamine levels (0, 5 and 10 ppm), totaling three treatments and ten replicates, with two animals (one male and one female) per pen (experimental plot). There were analyzed animals performance (final weight, average daily weight gain, daily feed intake and feed conversion) and carcass quality (carcass yield, carcass meat yield, backfat thickness and loin depth). The supplementation of 10 ppm of ractopamine in the finishing pig diet increased the meat yield in the carcass and reduced the backfat thickness. Thus, it is concluded that the supplementation of 10 ppm of ractopamine in the finishing pig diet improves the carcass traits.

Ractopamine hydrochloride induces behavioral alterations and oxidative status imbalance in zebrafish.

The occurrence of ractopamine (RAC) hydrochloride in water bodies is of significant concern due to its ecological impacts and toxicity to humans. RAC hydrochloride is a ß-adrenergic agonist drug used as a feed additive to (1) improve feed efficiency, (2) rate of weight gain, and (3) increase carcass leanness in animals raised for their meat. This drug is excreted by animals in urine and introduced into the environment affecting nontarget organisms including fish. In wastewater released from farms, RAC concentrations were detected from 0.124 µg/L to 30.1 µg/L, and in levels ranging from 1.3 × 10-5 to 5.4 × 10-4 µg/L in watersheds. The aim of this study was to examine the effects of exposure to RAC at 0.1, 0.2, 0.85, 8.5, or 85 µg/L dissolved in water on behavior and oxidative status in adult zebrafish. At 0.85 µg/L, RAC treatment increased exploratory behavior of zebrafish; while at 8.5 µg/L, decreased locomotor and exploratory activities were noted. With respect to oxidative stress biomarkers, results showed that RAC at 0.2 µg/L induced lipid peroxidation and elevated total thiol content in zebrafish brain. All drug tested concentrations produced a fall in nonprotein thiol content. Finally, RAC at 0.85, 8.5, or 85 µg/L increased catalase enzyme activity. Our results demonstrated that the exposure to RAC induced behavioral alterations and oxidative stress in zebrafish.

Eficacia y seguridad del uso de bromuro de tiotropio en el tratamiento de pacientes con asma severa no controlada con ics/laba y ltra, y no tributarios a teofilina / Efficacy and safety of the use of tiotropium bromide in the treatment of patients with severe asthma not controlled with ics / laba and ltra, and not tributaries to theophylline

INTRODUCCIÓN: El presente dictamen presenta la evaluación de tecnología de la eficacia y seguridad de bromuro de tiotropio en el tratamiento de dolor neuropático. El asma es una enfermedad respiratoria crónica que se manifiesta de manera heterogénea entre los que la padecen, usualmente caracterizada por inflamación crónica de las vías aéreas. El asma puede ser clasificado como leve, moderada o severa. La severidad del asma se evalúa de manera retrospectiva y está en función del tratamiento requerido para controlar los síntomas y exacerbaciones. La prevalencia global de asma se ha estimado entre 1% y 16% en la población entre 13 y 14 años de edad, aunque varían entre países por la ausencia de una definición de asma universal. En cuanto a la población adulta general, en Estados Unidos, la prevalencia de asma se estima cerca al 8%, mientras que la prevalencia de asma en adultos mayores de 65 años se encuentra entre 4% y 8%. El asma severa se da en 5-10% del total de casos de asma. TECNOLOGIA SANITARIA DE INTERÉS: El bromuro de tiotropio, también llamado únicamente tiotropio, es un agente anticolinérgico de acción prolongada que presenta afinidad especifica por los receptores muscarínicos (M 1 a M 5 ), particularmente por los subtipos M 1 y M 3 . La acción del bromuro de tiotropio se da a nivel de vías áreas, donde inhibe los receptores muscarínicos de músculo liso, lo cual tiene como resultado la broncodilatación. A los medicamentos de su clase se les conoce como antagonistas muscarínicos de acción prolongada (LAMA, por sus siglas en inglés). METODOLOGIA: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de de bromuro de tiotropio en el tratamiento de asma severa en las bases de datos de PubMed, TRIPDATABASE, The Cohrane Library y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como Organización mundial de la Salud (OMS), National Institute for Health and Care Excellence (NICE), Scottish Medicines Consortium (SMC), Canadian Agency for Drugs and Technologies in Health (CADTH), Instituto de efectividad clínica y sanitaria (IECS), Instituto de Evaluación de Tecnología en Salud (IETS); y especializados en neumología como American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), Asociación Latinoamericana de Tórax (ALAT), National Heart, Lung and Blood Institute (NHLBI), British Thoracic Society (BTS). RESULTADOS: En la actualidad el Petitorio Farmacológico de EsSalud cuenta con ICS, LABA, LTRA y teofilina para el tratamiento de pacientes con asma severa. Sin embargo, existe un grupo de pacientes en quienes el tratamiento con dosis máximas de ICS más LABA y terapia complementaria con LTRA o teofilina no ha logrado controlar la enfermedad, en ellos se requiere contar con otras alternativas de tratamiento. Adicional a ello, existen pacientes para quienes alguna de las terapias complementarias está contraindicada, dejando de ser una opción adicional de tratamiento. En este contexto, se ha solicitado al IETSI la evaluación del uso fuera del petitorio de bromuro de tiotropio. El bromuro de tiotropio, también llamado únicamente tiotropio, es un agente anticolinérgico de acción prolongada que presenta afinidad especifica por los receptores muscarínicos (M 1 a M 5 ). La acción del fármaco se da a nivel de vías áreas, donde inhibe los receptores muscarínicos del músculo liso, generando broncodilatación. A los medicamentos de su clase se les conoce como antagonistas muscarínicos de acción prolongada (LAMA, por sus siglas en inglés). A la fecha (Julio 2017) la evidencia identificada en relación al uso de bromuro de tiotropio en el tratamiento de asma severa corresponde a dos GPC (GINA 2017 y BTS/SIGN 2016), una ETS (SMC), un documento de consejo (NICE), un metanálisis (MA), y dos ECAs gemelos (PrimoTinA I y II). Las GPC de GINA y BTS/SIGN son homogéneas en sus recomendaciones. Así, ambas GPC mencionan el uso de tiotropio como una alternativa de tratamiento complementario en pacientes con asma pobremente controlada a pesar del uso de dosis máximas de ICS más LABA, al mismo nivel que el uso de LTRAs o teofilina. Dichas recomendaciones responden indirectamente a la pregunta PICO de interés del dictamen en la medida en que no especifican el uso consecutivo de las alternativas mencionadas frente a ausencia de mejoría de los síntomas, por lo que no hacen referencia específicamente a la población de interés del dictamen. Tanto el MA como los ensayos gemelos PrimoTinA I y II evidencian que el uso de tiotropio como terapia complementaria no ofrece ningún beneficio sobre el uso de ICS/LABA en cuanto a las variables de relevancia clínica como la ocurrencia de exacerbaciones, la calidad de vida y el control de la enfermedad, en pacientes con asma severa. Ambos estudios (el MA y los ensayos) constituyen evidencia indirecta para responder a la pegunta PICO ya que incluyen únicamente a la población de asmáticos que ha recibido ICS/LABA o solo ICS, mientras que la población de la pregunta PICO incluye también a aquellos que han recibido además LTRAs y no son tributarios a teofilina. A pesar de ser evidencia indirecta, es posible aplicar dichos resultados a la población de interés del dictamen ya que se observan resultados no favorables en una población que ha recibido menos líneas de tratamiento, por lo que se esperaría que en una población que ha pasado por más tratamientos este resultado negativo se mantenga. A manera de información adicional de relevancia, los elaboradores de las guías resaltan que para pasar a una siguiente alternativa de tratamiento es necesario corroborar la adherencia a los tratamientos empleados previamente, así como la ausencia de factores externos irritantes que puedan provocar exacerbaciones y la presencia de comorbilidades no controladas apropiadamente. Asimismo, hacen hincapié en que se debe evaluar la técnica empleada por los pacientes al usar el inhalador, ya que ello influye grandemente en la eficacia del fármaco. CONCLUSIÓN: El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) no aprueba el uso de bromuro de tiotropio en pacientes con asma severa no controlada con ICS/LABA y LTRAs y no tributarios a teofilina.

[Safety of beta-agonists in asthma]. / Seguridad de los beta 2 agonistas (ß2a) en asma bronquial.

Beta 2 agonist bronchodilators (ß2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The ß2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting ß2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting ß2 agonists (LABAs) The long-acting bronchodilators ß2A (Long acting ß2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

Los broncodilatadores beta 2 agonistas (ß2A) forman parte muy importante en el farmacoterapia del asma bronquial, una enfermedad que avanza en el mundo de manera epidémica. Los ß2A son prescritos a millones de personas en el mundo, por consiguiente los aspectos de seguridad son de interés público. Los broncodilatadores ß2A de acción corta (Short-Acting ß2 Agonists o SABA) como salbutamol inhalatorio, según las evidencias actuales, confirman su seguridad en su uso como fármaco de rescate o a demanda. Los broncodilatadores ß2A de acción prolongada (Long-Acting ß2 Agonists o LABA) se utilizan asociados a corticoides inhalatorios, como medicamentos controladores de exacerbaciones de accesos asmáticos, por razones de seguridad los LABAs no se recomienda su uso como monoterapia.

Seguridad de los beta 2 agonistas (ß2a) en asma bronquial. / [Safety of beta-agonists in asthma].

Beta 2 agonist bronchodilators (ß2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The ß2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting ß2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting ß2 agonists (LABAs) The long-acting bronchodilators ß2A (Long acting ß2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

Seguridad de los beta 2 agonistas (ß2a) en asma bronquial / [Safety of beta-agonists in asthma].

Beta 2 agonist bronchodilators (ß2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The ß2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting ß2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting ß2 agonists (LABAs) The long-acting bronchodilators ß2A (Long acting ß2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease.

BACKGROUND: Both inhaled steroids (ICS) and long-acting beta(2)-agonists (LABA) are used in the management of chronic obstructive pulmonary disease (COPD). This updated review compared compound LABA plus ICS therapy (LABA/ICS) with the LABA component drug given alone. OBJECTIVES: To assess the efficacy of ICS and LABA in a single inhaler with mono-component LABA alone in adults with COPD. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search was November 2011. SELECTION CRITERIA: We included randomised, double-blind controlled trials. We included trials comparing compound ICS and LABA preparations with their component LABA preparations in people with COPD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risk of bias and extracted data. The primary outcomes were exacerbations, mortality and pneumonia, while secondary outcomes were health-related quality of life (measured by validated scales), lung function, withdrawals due to lack of efficacy, withdrawals due to adverse events and side-effects. Dichotomous data were analysed as random-effects model odds ratios or rate ratios with 95% confidence intervals (CIs), and continuous data as mean differences and 95% CIs. We rated the quality of evidence for exacerbations, mortality and pneumonia according to recommendations made by the GRADE working group. MAIN RESULTS: Fourteen studies met the inclusion criteria, randomising 11,794 people with severe COPD. We looked at any LABA plus ICS inhaler (LABA/ICS) versus the same LABA component alone, and then we looked at the 10 studies which assessed fluticasone plus salmeterol (FPS) and the four studies assessing budesonide plus formoterol (BDF) separately. The studies were well-designed with low risk of bias for randomisation and blinding but they had high rates of attrition, which reduced our confidence in the results for outcomes other than mortality.Primary outcomes There was low quality evidence that exacerbation rates in people using LABA/ICS inhalers were lower in comparison to those with LABA alone, from nine studies which randomised 9921 participants (rate ratio 0.76; 95% CI 0.68 to 0.84). This corresponds to one exacerbation per person per year on LABA and 0.76 exacerbations per person per year on ICS/LABA. Our confidence in this effect was limited by statistical heterogeneity between the results of the studies (I(2) = 68%) and a risk of bias from the high withdrawal rates across the studies. When analysed as the number of people experiencing one or more exacerbations over the course of the study, FPS lowered the odds of an exacerbation with an odds ratio (OR) of 0.83 (95% CI 0.70 to 0.98, 6 studies, 3357 participants). With a risk of an exacerbation of 47% in the LABA group over one year, 42% of people treated with LABA/ICS would be expected to experience an exacerbation. Concerns over the effect of reporting biases led us to downgrade the quality of evidence for this effect from high to moderate.There was no significant difference in the rate of hospitalisations (rate ratio 0.79; 95% CI 0.55 to 1.13, very low quality evidence due to risk of bias, statistical imprecision and inconsistency). There was no significant difference in mortality between people on combined inhalers and those on LABA, from 10 studies on 10,680 participants (OR 0.92; 95% CI 0.76 to 1.11, downgraded to moderate quality evidence due to statistical imprecision). Pneumonia occurred more commonly in people randomised to combined inhalers, from 12 studies with 11,076 participants (OR 1.55; 95% CI 1.20 to 2.01, moderate quality evidence due to risk of bias in relation to attrition) with an annual risk of around 3% on LABA alone compared to 4% on combination treatment. There were no significant differences between the results for either exacerbations or pneumonia from trials adding different doses or types of inhaled corticosteroid.Secondary outcomes ICS/LABA was more effective than LABA alone in improving health-related quality of life measured by the St George's Respiratory Questionnaire (1.58 units lower with FPS; 2.69 units lower with BDF), dyspnoea (0.09 units lower with FPS), symptoms (0.07 units lower with BDF), rescue medication (0.38 puffs per day fewer with FPS, 0.33 puffs per day fewer with BDF), and forced expiratory volume in one second (FEV(1)) (70 mL higher with FPS, 50 mL higher with BDF). Candidiasis (OR 3.75) and upper respiratory infection (OR 1.32) occurred more frequently with FPS than SAL. We did not combine adverse event data relating to candidiasis for BDF studies as the results were very inconsistent. AUTHORS' CONCLUSIONS: Concerns over the analysis and availability of data from the studies bring into question the superiority of ICS/LABA over LABA alone in preventing exacerbations. The effects on hospitalisations were inconsistent and require further exploration. There was moderate quality evidence of an increased risk of pneumonia with ICS/LABA. There was moderate quality evidence that treatments had similar effects on mortality. Quality of life, symptoms score, rescue medication use and FEV(1) improved more on ICS/LABA than on LABA, but the average differences were probably not clinically significant for these outcomes. To an individual patient the increased risk of pneumonia needs to be balanced against the possible reduction in exacerbations.More information would be useful on the relative benefits and adverse event rates with combination inhalers using different doses of inhaled corticosteroids. Evidence from head-to-head comparisons is needed to assess the comparative risks and benefits of the different combination inhalers.

Safety of long-acting ß agonists for the treatment of asthma: clearing the air.

Concerns about the safety of long-acting ß2-agonist (LABA) therapy, has led to the appearance of multiple publications and recommendations. This review critically examines the available clinical evidence and safety requirements for LABA use. On the basis of nearly 20 systematic reviews and databases, the authors conclude that LABA monotherapy significantly increases the risk of asthma-related adverse effects. We also conclude that the use of LABAs concomitantly with inhaled corticosteroids (ICS) significantly reduces asthma hospitalisations and is not associated with life-threatening events and asthma-related deaths, especially when concurrent use of LABAs and ICS can be reasonably assured (use of a single inhaler device). An appropriate clinical study would require an extremely large sample, making it impractical. Finally, some of the new US Food and Drug Administration (FDA) recommendations have caused confusion and do not appear to be fully evidence based. Although limited by low statistical power, the evidence supports the use of LABAs plus ICS in a single inhaler device (to increase adherence and reduce the potential use of LABA monotherapy) for all patients (not only children) with moderate to severe asthma.

Beta 2 agonistas de acción prolongada en el tratamiento del asma en niños / Long acting beta 2 agonists in the treatment in children with asthma

A pesar del uso de corticoides inhalados en el tratamiento del asma bronquial existe un número variable de pacientes que no logran el control de su enfermedad. En estos casos, una de las alternativas terapéuticas propuesta por diversas guías clínicas es la adición de beta 2 agonistas de acción prolongada. Este articulo, revisa las características farmacológicas, posibles efectos adversos y las indicaciones en niños.

Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review.

BACKGROUND: Safety of long-acting beta agonists (LABA) has been questioned and recent evidence suggested a detrimental effect on asthma control as well as an increased risk of death. OBJECTIVE: To evaluate the safety of regular use of LABA compared with placebo or LABA added to inhaled corticosteroids (ICS) compared with ICS in persistent asthma. METHODS: Randomized studies from MEDLINE, EMBASE, and Cochrane Controlled Trials Register were identified. Additionally, AstraZeneca, GlaxoSmithKline, Novartis and FDA clinical trials databases were searched. Primary outcomes were asthma exacerbations (AE) requiring systemic corticosteroids or hospitalization, life-threatening exacerbations and asthma-related deaths. RESULTS: We identified 92 randomized clinical trials with 74,092 subjects. LABA (as monotherapy) reduced exacerbations requiring corticosteroids (Relative Risk [RR]=0.80; 95% CI, 0.73-0.88), without detrimental effects on hospitalizations or life-threatening episodes. Contrarily, LABA showed a significant increase in asthma-related deaths (Relative Risk=3.83; 95% CI, 1.21-12.14). Subgroup analysis suggests that children, patients receiving salmeterol, and a duration of treatment>12 weeks are associated with a higher risk of serious adverse effects; also there was a protective effect of concomitant use of ICS. On the other hand, combination of LABA/ICS reduced exacerbations (RR=0.73; 95% CI, 0.67-0.79), and hospitalizations (RR=0.58, 95% CI, 0.45-0.74). Combined therapy was also equivalent to ICS in terms of life-threatening episodes and asthma-related deaths. Again, children and use of salmeterol were associated with an increased risk of some severe outcomes as compared with adults and formoterol users, respectively. CONCLUSIONS: This review reinforced the international recommendations in terms of the use of LABA remains the preferred add-on therapy to ICS for patients whose disease cannot adequately controlled with ICS, and that LABA cannot be prescribed as a monotherapy. Nevertheless, in spite of the protective effect of the ICS, children and salmeterol use still show an increased risk of non-fatal serious adverse events.

Isoproterenol induces primary loss of dystrophin in rat hearts: correlation with myocardial injury.

The mechanism of isoproterenol-induced myocardial damage is unknown, but a mismatch of oxygen supply vs. demand following coronary hypotension and myocardial hyperactivity is the best explanation for the complex morphological alterations observed. Severe alterations in the structural integrity of the sarcolemma of cardiomyocytes have been demonstrated to be caused by isoproterenol. Taking into account that the sarcolemmal integrity is stabilized by the dystrophin-glycoprotein complex (DGC) that connects actin and laminin in contractile machinery and extracellular matrix and by integrins, this study tests the hypothesis that isoproterenol affects sarcolemmal stability through changes in the DGC and integrins. We found different sensitivity of the DGC and integrin to isoproterenol subcutaneous administration. Immunofluorescent staining revealed that dystrophin is the most sensitive among the structures connecting the actin in the cardiomyocyte cytoskeleton and the extracellular matrix. The sarcomeric actin dissolution occurred after the reduction or loss of dystrophin. Subsequently, after lysis of myofilaments, gamma-sarcoglycan, beta-dystroglycan, beta1-integrin, and laminin alpha-2 expressions were reduced followed by their breakdown, as epiphenomena of the myocytolytic process. In conclusion, administration of isoproterenol to rats results in primary loss of dystrophin, the most sensitive among the structural proteins that form the DGC that connects the extracellular matrix and the cytoskeleton in cardiomyocyte. These changes, related to ischaemic injury, explain the severe alterations in the structural integrity of the sarcolemma of cardiomyocytes and hence severe and irreversible injury induced by isoproterenol.

Exercise training prevents beta-adrenergic hyperactivity-induced myocardial hypertrophy and lesions.

BACKGROUND: Sustained beta-adrenoreceptor activation promotes cardiac hypertrophy and cellular injury. AIMS: To evaluate the cardioprotective effect of exercise on damage induced by beta-adrenergic hyperactivity. METHODS: Male Wistar rats were randomised into four groups (n=8 per group): sedentary non-treated control (C), sedentary treated with isoproterenol 0.3 mg/kg/day administered subcutaneously for 8 days (I), exercised non-treated (E) and exercised plus isoproterenol administered during the last eight days of exercise (IE). Exercised animals ran on a treadmill for 1 h daily 6 times a week for 13 weeks. RESULTS: Isoproterenol caused increases in left ventricle (LV) wet and dry weight/body weight ratio, LV water content and cardiomyocyte transverse diameter. Additionally, isoproterenol induced severe cellular lesions, necrosis, and apoptosis, increased collagen content and reduced capillary and fibre fractional areas. Notably, all of these abnormalities were completely prevented by exercise. CONCLUSION: Our data have demonstrated that complete cardioprotection is possible through exercise training; by preventing beta-adrenergic hyperactivity-induced cardiac hypertrophy and structural injury.