Comparative effectiveness of two lipid emulsions in preventing retinopathy of prematurity in preterm infants requiring parenteral nutrition. / [Artículo traducido] Efectividad comparativa de 2 emulsiones lipídicas en la prevención de la retinopatía del prematuro en neonatos pretérmino que requieren nutrición parenteral.

OBJECTIVES: The main aim was to compare the effects of two parenteral lipid emulsions on retinopathy of prematurity (ROP) incidence, severity, and need for treatment. Secondary aim was to compare the effect on weight gain in the first 6 weeks of life. METHODS: Single-center, observational, retrospective study analyzing preterm infants with a gestational age < 31 weeks and a birth weight < 1,251 g, born between April 2015 and December 2018. The infants' medical records were reviewed to collect clinical data. Parenteral nutrition details were obtained from the hospital pharmacy database. RESULTS: In total, 180 patients were included: 90 received ClinOleic® and 90 received SMOFlipid®. No significant differences were observed for the incidence of ROP (40% in ClinOleic® group and 41% in SMOFlipid® group, p=0.88) or ROP requiring treatment (4% and 10% respectively, p=0.152). Weekly weight gain was similar in the two groups. CONCLUSIONS: This study showed no difference between the two groups regarding ROP, ROP requiring treatment or weekly weight gain in the first 6 weeks of life.

Microbiological quality of pediatric oral liquid formulations / Calidad microbiológica de las formulaciones orales líquidas pediátricas

The oral administration of drugs to the pediatric population involves the extemporaneous preparation of liquid formulations. These formulations have studies on their physicochemical stability, but they often lack microbiological studies. The objective of this study is to check the microbiological quality of five oral liquid formulations prepared with different excipients, which represent five major combinations, in two conditions: kept unopened until the day of the test, and in a multi-dose vial opened daily. The formulations were prepared according to standard operating procedures. Half of each batch was packaged in vials that remained closed until the day of testing, and the other half in a single container which was opened daily. Both the vials and the containers had been previously sterilized. Microbiological tests were performed weekly during the first month of the study, and then every two weeks, until the expiration date. The microbiological quality of oral liquid formulations is determined by the Royal Spanish Pharmacopoeia. The conclusion was that none of the formulations prepared that were packaged in sterilized containers became contaminated, either in unopened vials or in multi-dose containers when they were opened daily (AU)

La administración oral de fármacos a la población pediátrica implica la preparación de fórmulas líquidas extemporáneas. Estas fórmulas tienen estudios de estabilidad fisicoquímica pero en muchas ocasiones carecen de estudios microbiológicos. El objetivo del estudio es comprobar la calidad microbiológica de cinco fórmulas orales líquidas, preparadas con diferentes excipientes, que representan mayoritariamente cinco combinaciones, en dos condiciones: conservadas sin abrir hasta el día del análisis y abriendo diariamente el envase multidosis. Se prepararon las fórmulas según los procedimientos normalizados de trabajo. La mitad del lote de cada fórmula se envasó en viales que estuvieron cerrados hasta el día del análisis y la otra mitad en un solo frasco que se abría diariamente. Tanto los viales como los frascos para el envasado estaban esterilizados previamente. El análisis microbiológico se realizó cada semana durante el primer mes de estudio y después cada dos semanas hasta llegar al periodo de caducidad. La calidad microbiológica de las fórmulas orales líquidas viene marcada por la Real Farmacopea Española. Se concluye que ninguna de las fórmulas elaboradas envasadas en contenedores esterilizados se contaminó ni en los viales cerrados ni en los frascos multidosis cuando se abrieron diariamente (AU)

[Pica diagnosis during pregnancy and micronutrient dificiency in Argentine women]. / Diagnóstico de pica durante el embarazo y deficiencia de micronutrientes en mujeres argentinas.

OBJECTIVE: To evaluate by biochemical parameters iron and zinc nutritional status in women with and without pica diagnosis during pregnancy. METHODOLOGY: During puerperium 109 women were evaluated at Fiorito Hospital, Argentina. Pica diagnosis was made in 42 women while 67 did not refer the practice. Fasting blood samples were obtained and analyzed in a hematology analyzer for values of red blood cells, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and hematocrit. Serum zinc and erythrocyte zinc was analyzed by atomic absorption spectrophotometry. RESULTS: Substances consumed during pica practice were: earth, ice, brick, paper, desinfectant and dog food. Women with pica diagnosis had higher a rate of family history of pica and personal antecedents of pica in childhood (OR: 15.9). Sociodemographic and anthropometric characteristics and neonatal birth weight were similar between both groups, although women with pica diagnosis had lower values in mean corpuscular volume (p = 0,008), mean corpuscular hemoglobin (p = 0,009) and erythrocyte zinc (0,008). Applying a logistic regression model, erythrocyte zinc was the only biochemical indicator associated with pica practice (p = 0,028). CONCLUSIONS: At puerperium, women with pica during pregnancy could have lower levels in biochemical parameters for iron and zinc status so we suggest that early diagnosis of pica could help to identify micronutrient deficient.

Evaluación de un programa de valoración de adherencia al tratamiento antirretroviral / Evaluation of a program for assessing adherence to antiretroviral treatment

Introducción: Una baja adherencia al tratamiento antirretroviral (TARV) es la causa más frecuente de fracaso terapéutico tanto en niños como en adultos que viven con el VIH, siendo especialmente importante durante la adolescencia. En consecuencia, cualquier análisis de la efectividad del TARV deberá considerarse incompleto si no incluye una evaluación de la adherencia. El objetivo de este estudio es evaluar la utilidad de un programa de valoración de la adherencia al TARV en una población de pacientes pediátricos infectados por el VIH. Pacientes y métodos: Se trata de un estudio observacional y transversal, dentro del «Programa de educación sanitaria para la optimización de la adherencia en pacientes pediátricos con VIH», que forma parte del proyecto «No estoy solo». La adherencia se estudió simultáneamente mediante una combinación de diferentes métodos: entrevista personal, evolución de la carga viral y del recuento de linfocitos TCD4+, determinación de concentraciones plasmáticas de fármacos y registros de dispensación de farmacia. Resultados: Se incluyó un total de 20 pacientes (50% mujeres, edad mediana: 14,5 años). Se obtuvo un porcentaje de adherencia completa informada por el propio paciente o cuidador del 90% (IC 95%: 70-97,2%); sin embargo, el porcentaje medio de adherencia según los registros de dispensación fue significativamente inferior (83,3%; DE=32,88). La media de principios activos/día y de medicamentos/día fue de 3,5 (DE=0,83) y 5,5 (DE=2,72), respectivamente. Hubo una relación inversa entre el n.° de medicamentos/día y las puntuaciones de adherencia (F=13,8; p=0,002). Ninguno de los métodos de evaluación se relacionó de manera estadísticamente significativa con la adherencia, presentando la determinación de concentraciones plasmáticas una tendencia a la significación. Conclusiones: La adherencia global al TARV fue elevada y se vio favorecida por el uso de pautas posológicas sencillas. La adherencia informada por el paciente y/o el cuidador sobreestimó la verdadera adherencia al TARV. Recomendamos la utilización simultánea de diversos métodos de valoración de la adherencia en los niños y adolescentes que viven con el VIH (AU)

Introduction: Poor adherence to antiretroviral treatment (ART) is the commonest cause of treatment failure in children and adults living with HIV, and this is especially important during adolescence. Therefore, any analysis of ART effectiveness in children should include an evaluation of adherence to ART. The aim of this study is to assess the usefulness of an ART adherence monitoring program in an HIV-infected paediatric population. Patients and methods: An observational and cross-sectional study was performed, within the framework of the “Health Education Program for Optimising Adherence in Paediatric Patients with HIV”, which is part of the “I am not alone” project. Adherence was assessed simultaneously by different methods: personal interview, therapeutic drug monitoring, pharmacy dispensing records and evolution of viral load and T CD4+ lymphocyte count. Results: Twenty patients were included (50% female, median age 14.5 years). Percentage of self-reported full adherence was 90% (95% CI: 70-97.2%); however, the median adherence percentage according to pharmacy dispensing records was significantly lower (83.3%, SD=32.88). The average of drugs and dosage forms per day were 3.5 (SD=0.83) and 5.5 (SD=2.72), respectively. There was an inverse relationship between the number of dosage forms per day and adherence scores (F=13.8; P=0.002). No single method was statistically related to adherence, although therapeutic drug monitoring showed a trend towards significance. Conclusions: Global adherence to ART was high and was easier with simpler regimens. Self-reported adherence overestimated real adherence to ART in our cohort. The simultaneous use of different methods to assess adherence is recommended in HIV-infected children (AU)

[Evaluation of a program for assessing adherence to antiretroviral treatment]. / Evaluación de un programa de valoración de adherencia al tratamiento antirretroviral.

INTRODUCTION: Poor adherence to antiretroviral treatment (ART) is the commonest cause of treatment failure in children and adults living with HIV, and this is especially important during adolescence. Therefore, any analysis of ART effectiveness in children should include an evaluation of adherence to ART. The aim of this study is to assess the usefulness of an ART adherence monitoring program in an HIV-infected paediatric population. PATIENTS AND METHODS: An observational and cross-sectional study was performed, within the framework of the "Health Education Program for Optimising Adherence in Paediatric Patients with HIV", which is part of the "I am not alone" project. Adherence was assessed simultaneously by different methods: personal interview, therapeutic drug monitoring, pharmacy dispensing records and evolution of viral load and T CD4+ lymphocyte count. RESULTS: Twenty patients were included (50% female, median age 14.5 years). Percentage of self-reported full adherence was 90% (95% CI: 70-97.2%); however, the median adherence percentage according to pharmacy dispensing records was significantly lower (83.3%, SD=32.88). The average of drugs and dosage forms per day were 3.5 (SD=0.83) and 5.5 (SD=2.72), respectively. There was an inverse relationship between the number of dosage forms per day and adherence scores (F=13.8; P=.002). No single method was statistically related to adherence, although therapeutic drug monitoring showed a trend towards significance. CONCLUSIONS: Global adherence to ART was high and was easier with simpler regimens. Self-reported adherence overestimated real adherence to ART in our cohort. The simultaneous use of different methods to assess adherence is recommended in HIV-infected children.

[Osmolality of oral liquid dosage forms to be administered to newborns in a hospital]. / Osmolalidad de las formas farmacéuticas orales líquidas en un hospital para su aplicación en neonatos.

OBJECTIVE: Oral administration of hypertonic solutions can contribute to intestinal damage in the initial stages of neonatal necrotizing enterocolitis. The purpose of this study is to determine the osmolality of oral liquid dosage forms used in a division of neonatology and to establish some recommendations for their dilution. METHOD: The osmolality of 26 oral liquid dosage forms has been measured using the freezing-point depression method. RESULTS: Oral liquid dosage forms used in the division of neonatology present an osmolality greater than 350 mOsm/kg H2O. 19.2% of all the analysed forms presented an osmolality lower than 1500 mOsm/kg H2O, 80.7% were over that figure, while 23% presented an extremely high osmolality (> 5,000 mOsm/kg H2O). CONCLUSIONS: Knowledge of osmolality of oral liquid dosage forms in the division of neonatology enables the risk of intestinal aggression caused by enteral administration of the medication to be assessed.

microRNAs and the regulation of glucose and lipid metabolism.

Over recent years, metabolic disorders such as type 2 diabetes have finally become recognized as a major challenge to global health. The attention of scientists therefore has to focus on improving our understanding of the molecular mechanisms behind these diseases and towards the design of new drug therapy strategies. The pathophysiology of diabetes is undoubtedly complex, oftentimes characterized by varying states of insulin resistance and impaired beta-cell function; however, the identification of new pathways is constantly improving our understanding of the disease. We and others have recently shown that microRNAs (miRNAs) can play a role in insulin secretion and glucose homostasis. Thus, in this review, we will discuss the potential role of miRNAs in type 2 diabetes and related metabolic diseases.

Osmolalidad de las formas farmacéuticas orales líquidas en un hospital para su aplicación en neonatos / No disponible

Objetivo: La administración oral de soluciones hipertónicaspuede participar en la lesión intestinal en la fase inicial de la enterocolitisnecrotizante neonatal. El objetivo del estudio es determinarla osmolalidad de las fórmulas farmacéuticas orales líquidasutilizadas en una unidad de neonatología y establecer recomendacionesde dilución.Método: Se ha medido la osmolalidad de 26 fórmulas farmacéuticasorales líquidas por el método de descenso crioscópico.Resultados: Las fórmulas farmacéuticas orales líquidas utilizadasen la unidad de neonatología presentan una osmolalidad superiora 350 mOsm/kg H2O. Del total analizado, el 19,2% de las fórmulaspresentaban una osmolalidad inferior a 1.500 mOsm/kgH2O, el 80,7% superior y el 23% presentaban una osmolalidadextremadamente alta (> 5.000 mOsm/kg H2O).Conclusiones: El conocimiento de la osmolalidad de las fórmulasfarmacéuticas orales líquidas administradas en la unidad deneonatología permite valorar el riesgo de agresividad intestinalque produce la administración enteral de la medicación

Objective: Oral administration of hypertonic solutions can contributeto intestinal damage in the initial stages of neonatal necrotizingenterocolitis. The purpose of this study is to determine the osmolalityof oral liquid dosage forms used in a division of neonatologyand to establish some recommendations for their dilution.Method: The osmolality of 26 oral liquid dosage forms hasbeen measured using the freezing-point depression method.Results: Oral liquid dosage forms used in the division ofneonatology present an osmolality greater than 350 mOsm/kgH2O. 19.2% of all the analysed forms presented an osmolalitylower than 1500 mOsm/kg H2O, 80.7% were over that figure,while 23% presented an extremely high osmolality (> 5,000mOsm/kg H2O).Conclusions: Knowledge of osmolality of oral liquid dosageforms in the division of neonatology enables the risk of intestinalaggression caused by enteral administration of the medication tobe assessed

[Administration of anti-infective agents through the inhaled route]. / Administración de antiinfecciosos por vía inhalatoria.

OBJECTIVE: To report the doses of inhaled anti-infective agents described in the literature for both the adult and paediatric population. In the case of anti-infective agents which were not approved for inhaled administration, to propose the optimum manner in which these should be prepared in order to achieve osmolality and pH values as similar as possible to physiological values. METHOD: A search was carried out of Pubmed (between 1960 and 2005) for each of the anti-infective agents using the words "inhalation OR inhaled OR aerosol OR aerosolized OR nebulized". We also consulted text books, Micromedex and the technical specifications of the pharmaceutical products. Nebulised solutions were prepared using the drugs for which information was found. The drugs approved for inhaled administration were prepared according to the manufacturers recommendations. For anti-infective agents which were not approved for inhaled administration, the raw materials and the branded drug products for intravenous administration available at our hospital were diluted using physiological saline solution and/or water for injection up to a final volume of 4-5 ml. The osmolality and pH values of all the solutions were measured. The optimum form of preparation was considered to be one with values as close as possible to between 150 and 550 mOsm/kg for osmolatity osmolality and 7 +/- 0.5 for pH. RESULTS: Information about doses of 18 inhaled anti-infective agents was found (12 antibiotics, 5 antifungals and 1 antiviral); paediatric doses were described in 9 of these. Three of the anti-infective agents reviewed were approved for inhaled use in adult patients and four in paediatric patients. Of the 48 recommendations for dilution suggested for administration, two had an osmolality > 1,100 mOsm/kg and 5 an osmolality of < 100 mOsm/kg. Two dilutions had a pH > 8 and 14 a pH < 5. CONCLUSIONS: There is limited literature regarding the doses of anti-infective agents for inhaled administration. The majority of anti-infective agents are not approved for inhaled administration. The dilution of the raw material or proprietary drugs with water or physiological saline solution for intravenous administration achieved solutions with appropriate osmolality in the majority of cases. Some of the solutions have extreme osmolality and/or pH levels, implying that it is reasonable to expect a greater risk of bronchospasm.

Administración de antiinfecciosos por vía inhalatoria / No disponible

Objetivo: Describir las dosis de los antiinfecciosos inhalados descritas en la literatura tanto en la población adulta como en la pediátrica. Para aquellos antiinfecciosos que no tienen la vía inhalatoria aprobada, proponer la forma óptima de preparación para conseguir una osmolaridad y un pH lo más cercano posible a los valores fisiológicos. Método: Se realizó una búsqueda en PubMed (entre 1960 y 2005) con cada uno de los antiinfecciosos y las palabras "inhalation OR inhaled OR aerosol OR aerosolized OR nebulized". También se consultaron libros de texto, Micromedex y las fichas técnicas de las especialidades farmacéuticas. De los fármacos que se encontró información se prepararon las soluciones para nebulizar. Los fármacos con vía inhalada aprobada se prepararon según las recomendaciones del laboratorio fabricante. Para los antiinfecciosos que no tienen la vía inhalatoria aprobada se prepararon diluciones de la materia prima o de las presentaciones comerciales por vía intravenosa disponibles en nuestro hospital con solución salina fisiológica y/o agua para inyección hasta un volumen final de 4-5 ml. Se midió la osmolaridad y pH de todas las soluciones. Se consideró como forma óptima de preparación, la más próxima posible a una solución de una osmolaridad entre 150 y 550 mOsm/kg y a un pH de 7 ± 0,5. Resultados: Se encontró información sobre dosificación por vía inhalatoria de 18 antiinfecciosos (12 antibióticos, 5 antifúngicos y 1 antivírico), de los cuales en 9 se describe la dosis pediátrica. Tres de los antiinfecciosos revisados tienen la vía inhalatoria aprobada en adultos y 4 en pediatría. De las 48 recomendaciones de dilución propuestas para la administración, dos tienen una osmolaridad > 1.100 mOsm/kg y 5 una osmolaridad 8 y 14 un pH < 5. Conclusiones: La información bibliográfica sobre las dosificaciones de los antiinfecciosos por vía inhalatoria es escasa. La mayoría de antiinfecciosos no tienen aprobada la administración por vía inhalatoria. La dilución de la materia prima o de las especialidades por vía intravenosa con agua o solución salina fisiológica consigue soluciones con osmolaridad adecuada en la mayoría de los casos. Algunas de las soluciones tienen valores extremos de osmolaridad y/o pH con lo que cabe esperar un riesgo mayor de broncoespasmo

Objective: To report the doses of inhaled anti-infective agents described in the literature for both the adult and paediatric population. In the case of anti-infective agents which were not approved for inhaled administration, to propose the optimum manner in which these should be prepared in order to achieve osmolality and pH values as similar as possible to physiological values. Method: A search was carried out of Pubmed (between 1960 and 2005) for each of the anti-infective agents using the words “inhalation OR inhaled OR aerosol OR aerosolized OR nebulized”. We also consulted text books, Micromedex and the technical specifications of the pharmaceutical products. Nebulised solutions were prepared using the drugs for which information was found. The drugs approved for inhaled administration were prepared according to the manufacturers’ recommendations. For anti-infective agents which were not approved for inhaled administration, the raw materials and the branded drug products for intravenous administration available at our hospital were diluted using physiological saline solution and/or water for injection up to a final volume of 4-5 ml. The osmolality and pH values of all the solutions were measured. The optimum form of preparation was considered to be one with values as close as possible to between 150 and 550 mOsm/kg for osmolatity osmolality and 7 ± 0.5 for pH. Results: Information about doses of 18 inhaled anti-infective agents was found (12 antibiotics, 5 antifungals and 1 antiviral); paediatric doses were described in 9 of these. Three of the antiinfective agents reviewed were approved for inhaled use in adult patients and four in paediatric patients. Of the 48 recommendations for dilution suggested for administration, two had an osmolality > 1,100 mOsm/kg and 5 an osmolality of 8 and 14 a pH < 5. Conclusions: There is limited literature regarding the doses of anti-infective agents for inhaled administration. The majority of anti-infective agents are not approved for inhaled administration. The dilution of the raw material or proprietary drugs with water or physiological saline solution for intravenous administration achieved solutions with appropriate osmolality in the majority of cases. Some of the solutions have extreme osmolality and/or pH levels, implying that it is reasonable to expect a greater risk of bronchospasm

[Pharmacokinetic interaction between valproic acid and meropenem]. / Interacción farmacocinética entre ácido valproico y meropenem.

Several reports have described a decrease in valproic acid (VPA) serum concentrations when carbapenem therapy is administered. The exact mechanism of this pharmacokinetic interaction is unknown, although several experimental studies have been carried out in animals. Because of these interactions, plasma concentrations of VPA in these patients should be monitored and, whenever possible, VPA or carbapenem therapy should be substituted by other drugs. We describe the cases of two epileptic children who simultaneously received meropenem and VPA. Concentrations of VPA decreased to subtherapeutic levels. We review the various mechanisms for this interaction proposed to date, as well as all reported cases.

[Dosage of drugs for cerebrospinal administration]. / Dosificación de fármacos en administración cerebroespinal.

OBJECTIVE: To review the most appropriate doses and routes within cerebrospinal - intrathecal, intraventricular, epidural - administration for drugs most commonly used in daily practice as reported in the literature, with particular emphasis on pediatric use. METHOD: A systematic, sequential, repetitive search of tertiary sources primarily and then primary sources in MEDLINE (Pubmed) and GOOGLE by combining each individual drug name with "intrathecal OR intraventricular OR epidural", and then differentiating between data referring to the pediatric and adult populations. RESULTS: In all, 28 drugs within 5 groups are described: anti-infectious, analgesic, and anti-neoplastic agents, corticoids, and other. Doses are categorized by population type: pediatric (newborns, infants, children) and adult. CONCLUSIONS: The relevance of this administration route and its potential use do not correlate with its scant reporting in the literature, except for anti-infectious, analgesic and cytostatic agents. Only five of these drug types are officially approved for cerebrospinal administration according to their prescribing information (polymyxin B, colistin, cytarabine, baclofen and morphine). Of these, only polymyxin B and colistin are indicated for the whole of the pediatric population.

Dosificación de fármacos en administración cerebroespinal / Dosage of drugs for cerebrospinal administration

Objetivo: Revisar las dosis y las vías más adecuadas dentro de la administración cerebroespinal -intratecal, intraventricular y epidural de los fármacos más usados en la práctica clínica diaria, descritos en la literatura, con especial énfasis en la utilización pediátrica. Método: Búsqueda sistemática y secuencial, consultando en primer lugar fuentes terciarias y posteriormente fuentes primarias a través de repetidas búsquedas en Medline (Pubmed) y en el buscador Google, cruzando el nombre de cada uno de los fármacos con 'intrathecal OR intraventricular OR epidural' y diferenciando los datos referidos a la población pediátrica y a la adulta. Resultados: Se describen 28 fármacos, divididos en 5 grupos: antiinfecciosos, analgésicos, antineoplásicos, corticoides y otros. Las dosis se clasifican según población: pediátrica (neonatos, lactantes y niños) y adulta. Conclusiones: La importancia de esta vía de administración y sus usos potenciales no se correlacionan con la escasa bibliografía publicada. Son excepción: antiinfecciosos, analgésicos y citostáticos. Tan sólo cinco de los fármacos citados tienen reconocida oficialmente la vía de administración cerebroespinal en la ficha técnica (polimixina B, colistina, citarabina, baclofeno y morfina). De ellos, sólo polimixina B y colistina la tienen en la totalidad de la población pediátrica

Objective: To review the most appropriate doses and routes within cerebrospinal – intrathecal, intraventricular, epidural –administration for drugs most commonly used in daily practice as reported in the literature, with particular emphasis on pediatric use. Method: A systematic, sequential, repetitive search of tertiary sources primarily and then primary sources in MEDLINE (Pubmed) and GOOGLE by combining each individual drug namewith 'intrathecal OR intraventricular OR epidural', and then differentiating between data referring to the pediatric and adult populations. Results: In all, 28 drugs within 5 groups are described: antiinfectious, analgesic, and anti-neoplastic agents, corticoids, and other. Doses are categorized by population type: pediatric (newborns,infants, children) and adult. Conclusions: The relevance of this administration route andits potential use do not correlate with its scant reporting in the literature,except for anti-infectious, analgesic and cytostatic agents. Only five of these drug types are officially approved for cerebrospinal administration according to their prescribing information (polymyxin B, colistin, cytarabine, baclofen and morphine). Of these, only polymyxin B and colistin are indicated for the whole of the pediatric population

[Drug use in a neonatal ICU: a prospective study]. / Utilización de medicamentos en una UCI neonatal: estudio prospectivo.

INTRODUCTION: Many drugs prescribed in pediatric units do not meet the conditions of use defined in their corresponding prescription information sheets, or their use has not been approved by the Spanish Health Authorities. The lack of clinical trials in children, and of adequate dosage forms, reduces drug safety, assuming both the physician and the pharmacist the responsibility for the drug use. OBJECTIVE: To assess drug prescription status within a neonatal intensive care unit in a third-level hospital. MATERIAL AND METHODS: A 3-months prospective study was performed, and information was collected from all admitted children along four time periods. Sixty-one complete therapies were evaluated, with a total of 236 drugs prescribed. Fifty percent were off-label, 13% were unlicensed, and 37% were correctly used. CONCLUSIONS: These figures resemble those from, similar studies carried out in other European hospitals. This is therefore a common practice resulting from the need to treat. Health authorities should encourage clinical trials so that drug therapies for children become evidence-based.

Utilización de medicamentos en una UCI neonatal: estudio prospectivo / Drug use in a neonatal ICU: a prospective study

Introducción: Muchos de los fármacos pautados en unidades pediátricas, no siguen las condiciones de uso marcadas en su correspondiente ficha técnica (fármacos denominados “off-label”)o no están autorizados por la Dirección General de Farmacia y Productos Sanitarios (“unlicensed”). La falta de ensayos clínicos en niños y de formulaciones adecuadas, disminuye la seguridad de uso de los medicamentos, recayendo la responsabilidad en el médico y el farmacéutico. Objetivo: Evaluar la situación de la prescripción de medicamentos dentro de la unidad de cuidados intensivos neonatal en un hospital de tercer nivel. Material y métodos: Para ello se realizó un estudio prospectivo de tres meses de duración, recogiéndose la información de todos los niños ingresados en un total de cuatro cortes. Se evaluaron 61 tratamientos completos, con un número total de 236 fármacos pautados. El 50% fue “off-label”, el 13% “unlicensed” y el 37% se utilizaba bajo las condiciones correctas. Conclusiones: Esta cifra se asemeja a la de estudios similares realizados en hospitales europeos. Es por tanto un práctica habitual que resulta de la necesidad de tratar al paciente. Las autoridades sanitarias deben incentivar la realización de ensayos clínicos para que los tratamientos farmacológicos en niños estén basados en la evidencia

Introduction: Many drugs prescribed in pediatric units do not meet the conditions of use defined in their corresponding prescription information sheets, or their use has not been approvedby the Spanish Health Authorities. The lack of clinical trials in children, and of adequate dosage forms, reduces drug safety,assuming both the physician and the pharmacist the responsibility for the drug use. Objective: To assess drug prescription status within a neonatal intensive care unit in a third-level hospital. Material and methods: A 3-months prospective study was performed, and information was collected from all admitted children along four time periods. Sixty-one complete therapies were evaluated, with a total of 236 drugs prescribed. Fifty percent were “off-label”, 13% were“unlicensed”, and 37% were correctly used. Conclusions: These figures resemble those from, similar studies carried out in other European hospitals. This is therefore a common practice resulting from the need to treat. Health authorities should encourage clinical trials so that drug therapies for children become evidence-based

Leptin concentrations in hirsute women with polycystic ovary syndrome or idiopathic hirsutism: influence on LH and relationship with hormonal, metabolic, and anthropometric measurements.

BACKGROUND: The known association between leptin, obesity and insulin action suggests that leptin may have a role in polycystic ovarian syndrome (PCOS) but this has only been addressed peripherally. METHODS: We assessed the influence of leptin on LH and investigated the relationship between leptin and body mass index (BMI), waist:hip ratio (WHR), androgen concentrations, fasting insulin and insulin:glucose ratio (IGR) in 27 women with PCOS and in 20 age- and weight-matched women with regular, ovulatory menstrual cycles and idiopathic hirsutism (IH). RESULTS: Leptin concentrations were significantly higher in obese PCOS women than in normal weight women with either PCOS or IH (P = 0.0028), but did not differ between obese women with PCOS and IH. WHR, insulin concentrations and IGR were significantly higher in obese PCOS patients in comparison with the three other groups. In IH patients, the association between leptin concentrations and WHR was lost after adjustment for BMI. In PCOS patients, a significant correlation was observed between leptin and fasting insulin concentrations, IGR, WHR and LH. After adjustment for BMI, only the correlation with LH remained significant. A stepwise regression model was set up with LH as the dependent variable to test the hypothesis that the concentrations of leptin might be modulating the concentrations of LH in PCOS patients. The relationship of LH concentrations with IGR was found to be BMI dependent. In contrast, leptin concentrations contributed negatively and significantly to LH concentrations, independently of either BMI or IGR. CONCLUSIONS: We speculate that the known attenuation in basal or stimulated response of LH in obese PCOS patients might be related to leptin resistance, which could influence LH hypersecretion. In IH ovulatory patients, normal LH concentrations suggest the presence of preserved regulatory mechanisms of GnRH pulsatility. Further studies are needed to specifically investigate the proposed correlation between leptin and GnRH modulation in PCOS.

Differences in tissue-specific and embryonic expression of mouse Ceacam1 and Ceacam2 genes.

The intercellular adhesion molecule CEACAM1, also known as C-CAM1 (where CAM is cell-adhesion molecule), can function as a tumour suppressor in several carcinomas, including those of the prostate, breast, bladder and colon. This suggests that CEACAM1 may play an important role in the regulation of normal cell growth and differentiation. However, there is no direct evidence to support this putative function of CEACAM1. To elucidate its physiological function by targeted gene deletion, we isolated the Ceacam genes from a mouse 129 Sv/Ev library. Although there is only one Ceacam1 gene in humans and one in rats, two homologous genes (Ceacam1 and Ceacam2) have been identified in the mouse. Our sequence analysis revealed that the genes encoded nine exons and spanned approx. 16-17 kb (Ceacam1) and 25 kb (Ceacam2). The genes were highly similar (79.6%). The major differences in the protein-coding regions were located in exons 2, 5 and 6 (76.9%, 87.0% and 78.5% similarity respectively). In addition, introns 2, 5 and 7 were also significantly different, being 29.7%, 59.8% and 64.5% similar respectively. While most of these differences were due to nucleotide substitutions, two insertions of 418 and 5849 bp occurred in intron 2 of Ceacam2, and another two insertions of 1384 and 197 bp occurred in introns 5 and 7 respectively. To determine whether functional redundancy exists between Ceacam1 and Ceacam2, we examined their expression in 16 mouse tissues by using semi-quantitative reverse transcription-PCR. As in human and rat, in the mouse Ceacam1 mRNA was highly abundant in the liver, small intestine, prostate and spleen. In contrast, Ceacam2 mRNA was only detected in kidney, testis and, to a lesser extent, spleen. Reverse transcription-PCR using testis RNA indicated that Ceacam2 in the testis is an alternatively spliced form containing only exons 1, 2, 5, 6, 8 and 9. In the mouse embryo, Ceacam1 mRNA was detected at day 8.5, disappeared between days 9.5 and 12.5, and re-appeared at day 19. On the other hand, no Ceacam2 mRNA was detected throughout embryonic development. The different tissue expression patterns and regulation during embryonic development suggest that the CEACAM1 and CEACAM2 proteins, although highly similar, may have different functions both during mouse development and in adulthood.

The differential effects of pp120 (Ceacam 1) on the mitogenic action of insulin and insulin-like growth factor 1 are regulated by the nonconserved tyrosine 1316 in the insulin receptor.

pp120 (Ceacam 1) undergoes ligand-stimulated phosphorylation by the insulin receptor, but not by the insulin-like growth factor 1 receptor (IGF-1R). This differential phosphorylation is regulated by the C terminus of the beta-subunit of the insulin receptor, the least conserved domain of the two receptors. In the present studies, deletion and site-directed mutagenesis in stably transfected hepatocytes derived from insulin receptor knockout mice (IR(-/-)) revealed that Tyr(1316), which is replaced by the nonphosphorylatable phenylalanine in IGF-1R, regulated the differential phosphorylation of pp120 by the insulin receptor. Similarly, the nonconserved Tyr(1316) residue also regulated the differential effect of pp120 on IGF-1 and insulin mitogenesis, with pp120 downregulating the growth-promoting action of insulin, but not that of IGF-1. Thus, it appears that pp120 phosphorylation by the insulin receptor is required and sufficient to mediate its downregulatory effect on the mitogenic action of insulin. Furthermore, the current studies revealed that the C terminus of the beta-subunit of the insulin receptor contains elements that suppress the mitogenic action of insulin. Because IR(-/-) hepatocytes are derived from liver, an insulin-targeted tissue, our observations have finally resolved the controversy about the role of the least-conserved domain of insulin and IGF-1Rs in mediating the difference in the mitogenic action of their ligands, with IGF-1 being more mitogenic than insulin.

Comparison of the intracellular trafficking of two alternatively spliced isoforms of pp120, a substrate of the insulin receptor tyrosine kinase.

pp120, a substrate of the insulin receptor tyrosine kinase, is a plasma membrane glycoprotein in the hepatocyte. It is expressed as two spliced isoforms differing by the presence (full length) or absence (truncated) of most of the intracellular domain including all phosphorylation sites. Because the two isoforms differ by their ability to regulate receptor-mediated insulin endocytosis and degradation, we aimed to investigate the cellular basis for this functional difference by comparing their intracellular trafficking. During its intracellular assembly, pp120 is transported from the trans-Golgi network to the sinusoidal domain of the plasma membrane before its final transcytosis to the bile canalicular domain. Because both isoforms are expressed in hepatocytes, we examined their intracellular trafficking in NIH 3T3 fibroblasts individually transfected with each isoform. Pulse-chase experiments demonstrated that most of the newly synthesized full-length isoform reached complete maturation at about 60 min of chase. By contrast, only about 40% of the newly synthesized truncated isoform underwent complete maturation, even at more prolonged chase. Moreover, a significant portion of the truncated isoform appeared to be targeted to lysosomes. Abolishing basal phosphorylation on Ser(503) by cAMP-dependent serine kinase by mutating this residue to alanine was correlated with incomplete maturation of full length pp120 in NIH 3T3 cells and hepatocytes. This finding suggests that the intracellular domain of pp120 contains information that regulates its vectorial sorting from the trans-Golgi network to the plasma membrane.

Insulin stimulates pp120 endocytosis in cells co-expressing insulin receptors.

pp120, a substrate of the insulin receptor tyrosine kinase, is a plasma membrane glycoprotein that is expressed in the hepatocyte as two spliced isoforms differing by the presence (full-length) or absence (truncated) of most of the intracellular domain including all phosphorylation sites. Co-expression of full-length pp120, but not its phosphorylation-defective isoforms, increased receptor-mediated insulin endocytosis and degradation in NIH 3T3 fibroblasts. We, herein, examined whether internalization of pp120 is required to mediate its effect on insulin endocytosis. The amount of full-length pp120 expressed at the cell surface membrane, as measured by biotin labeling, markedly decreased in response to insulin only when insulin receptors were co-expressed. In contrast, when phosphorylation-defective pp120 mutants were co-expressed, the amount of pp120 expressed at the cell surface did not decrease in response to insulin. Indirect immunofluorescence analysis revealed that upon insulin treatment of cells co-expressing insulin receptors, full-length, but not truncated, pp120 co-localized with alpha-adaptin in the adaptor protein complex that anchors endocytosed proteins to clathrin-coated pits. This suggests that full-length pp120 is part of a complex of proteins required for receptor-mediated insulin endocytosis and that formation of this complex is regulated by insulin-induced pp120 phosphorylation by the receptor tyrosine kinase. In vitro GST binding assays and co-immunoprecipitation experiments in intact cells further revealed that pp120 did not bind directly to the insulin receptor and that its association with the receptor may be mediated by other cellular proteins.