Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: results of phase IIIb BALLET trial in Spain

Background: Everolimus with exemestane has shown promising activity in patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant advanced breast cancer. It is necessary, therefore, to characterize the safety profile of this new combination in the real-world clinical setting and in the broadest possible population. Patients and methods: Post-menopausal women with HR-positive HER2-negative advanced breast cancer progressing after prior non-steroidal aromatase inhibitors (NSAIs) were included. The objectives of this analysis were to evaluate the safety profile of this combination in a subset of Spanish patients in the BALLET trial and to characterize grade 3 and 4 adverse events (AEs) in routine clinical practice in Spain. Results: Between September 2012 and July 2013, 429 patients (20% of the overall study population) were included in the BALLET study in 52 hospitals in Spain, of whom 100 (23%) were ≥ 70 years. The median treatment duration was 3.14 and 3.03 months for exemestane and everolimus, respectively. The most common reasons for discontinuation of treatment were local reimbursement of everolimus (43%), followed by disease progression (31%) and the incidence of AEs (15%). The most frequent AEs causing permanent discontinuation were pneumonitis (4%), asthenia (2%) and stomatitis (2%). Overall, 87% of patients experienced at least one AE of any grade, 30% of patients at least one grade 3 AE and 2% of patients a grade 4 AE. Conclusion: The safety profile in Spanish patients of the BALLET trial is consistent with the results obtained in the overall population of the trial, as well as in previous clinical trials

No disponible

Effects of wortmannin on cardioprotection exerted by ischemic preconditioning in rat hearts subjected to ischemia-reperfusion

Ischemic preconditioning (IPC) is one of the most powerful interventions to reduce ischemia-reperfusion injury. The aim of the present study was to investigate the involvement of the phosphatidylinositol-3-kinases (PI3Ks) family in cardioprotection exerted by IPC and the relationship between preservation of mitochondrial morphology and ATP synthesis capacity. In this regard, macroautophagy (autophagy) is considered a dynamic process involved in the replacement of aged or defective organelles under physiological conditions. IPC consisted of four 5-min cycles of ischemia-reperfusion followed by sustained ischemia. Wortmannin (W), a PI3K family inhibitor, was added to the perfusion medium to study the involvement of autophagy in the beneficial effects of IPC. In the present study, LC3-II/I expression was significantly increased in the IPC group when compared with the control group. The hearts subjected to IPC showed greater degradation of p62 than control groups, establishing the existence of an autophagic flow. Electron microscopy showed that IPC preserves the structural integrity of mitochondria after ischemia and at the end of reperfusion. Moreover, hearts subjected to IPC exhibited increased mitochondrial ATP synthesis. The beneficial effects of IPC were abolished by W in all trials of this study, abolishing the differences between the IPC and control groups. These results suggest that IPC could partly reduce injury by ischemia-reperfusion (I/R) by decreasing mitochondrial damage and promoting autophagy. Since W is a nonspecific inhibitor of the PI3Ks family, further research is required to confirm participation of PI3K in the response to IPC (AU)

No disponible

Posible interacción exemestano con clopidogrel / Possible interaction between exemestane and clopidogrel

No disponible

El uso de propionato de fluticasona inhalado no parece modificar la historia natural del asma en niños menores de cinco años con sibilancias / Inhaled flucticasone doesn´t seem to modify natural history of asthma in wheezy children under five

No disponible

Disfagia en paciente joven con historia de atopia / Dysphagia in young patient with an atopic background

No disponible

Asma. El control como meta del tratamiento / Asthma: control as therapeutic goal

No disponible

Eficacia broncodilatadora de la asociación de salmeterol y tiotropio en pacientes con EPOC / Bronchodilator efficacy of combined salmeterol and tiotropium in patients with chronic obstructive pulmonary disease

OBJETIVO: Los broncodilatadores continúan siendo los fármacos más eficaces para el control de los síntomas de la enfermedad pulmonar obstructiva crónica (EPOC). Recientemente se ha añadido un anticolinérgico de acción larga, el bromuro de tiotropio, al arsenal terapéutico de esta enfermedad. No existen estudios que hayan asociado 2 broncodilatadores de acción sostenida. El objetivo de este estudio ha sido comprobar si la asociación de salmeterol y tiotropio a pacientes con EPOC mejora la función pulmonar respecto a cuando se administran aislados. PACIENTES Y MÉTODOS: Se incluyó en el estudio a 22 pacientes diagnosticados de EPOC (20 varones), con una edad media de 64 años. Se excluyó a los fumadores activos. El volumen espiratorio forzado en el primer segundo (FEV1) medio (± desviación estándar) fue un 43 ± 14% del teórico. Todos los pacientes tenían amplia experiencia en el uso de los dispositivos de inhalación. Se realizaron 3 combinaciones terapéuticas de forma aleatoria durante una semana: a) fluticasona (500 µg/12 h), salmeterol (50 µg/12 h) y placebo; b) fluticasona, tiotropio (18 µg/24 h) y placebo, y c) fluticasona, salmeterol y tiotropio. Al final de cada período se realizó una espirometría forzada entre las 8.30 y las 9.00 h, antes de la inhalación de la combinación y 2 h después de ésta. Durante toda la semana se recogió el pico de flujo matutino inmediatamente antes de la inhalación de los fármacos, dejando 48 h de lavado entre cada asociación. RESULTADOS: Todos los pacientes finalizaron el protocolo. No hubo diferencias significativas en el FEV1 tanto valle como postinhalación con salmeterol y tiotropio (FEV1 valle: 1,17 ± 0,55 frente a 1,19 ± 0,49 l; FEV1 postinhalación: 1,32 ± 0,65 frente a 1,29 ± 0,61 l). En todos los casos el FEV1 postinhalación fue significativamente superior al FEV1 valle. La combinación de fluticasona, salmeterol y tiotropio se mostró superior a las otras 2 tanto en el FEV1 valle como postinhalación (FEV1 valle: 1,32 ± 0,56 l, p < 0,03 en ambos casos; FEV1 postinhalación: 1,49 ± 0,68 l, p < 0,001 en los 2 casos). El pico de flujo también fue significativamente mayor con la combinación de los 2 broncodilatadores (345 frente a 291 l/m y 311 l/m, respectivamente; p < 0,04 en ambos casos). No hubo efectos secundarios reseñables. CONCLUSIONES: La asociación de salmeterol y tiotropio unidos a fluticasona en pacientes con EPOC de grado moderado- grave es más eficaz en términos de mejoría funcional respiratoria que cualquiera de los 2 broncodilatadores dados de forma aislada

OBJECTIVE: Bronchodilators are still the most effective drugs for controlling the symptoms of chronic obstructive pulmonary disease (COPD). Tiotropium bromide, a longacting anticholinergic drug, has recently been added to the therapeutic arsenal for the disease. To date, there have been no studies combining 2 long-acting bronchodilators. The aim of the present trial was to determine whether the combination of salmeterol and tiotropium improved lung function in COPD patients more than either of them alone. PATIENTS AND METHODS: Twenty-two patients (20 men) diagnosed with COPD, with a mean age of 64 years, were enrolled in this cross-over trial. Active smokers were excluded. Mean (SD) forced expiratory volume in 1 second (FEV1) was 43% (14%) of predicted. All patients were experienced in the use of inhalers. The following 3 therapeutic combinations were randomly assigned to be administered for a 1-week period: a) fluticasone (500 µg/12 h), salmeterol (50 µg/12 h) and placebo; b) fluticasone, tiotropium (18 µg/24 h), and placebo; and c) fluticasone, salmeterol, and tiotropium. At the end of each period, forced spirometry was performed before inhalation of the therapeutic combination (between 8:30 AM and 9:30 AM) and 2 hours after inhalation. Throughout the week, morning peak flow rates measured immediately before inhalation were recorded, and there was a 48-hour wash-out period between each therapeutic combination. RESULTS: All the patients completed the protocol. There were no significant differences in preinhalation or postinhalation FEV1 with salmeterol compared to tiotropium (preinhalation FEV1, 1.17 [0.55] L compared to 1.19 [0.49] L; postinhalation FEV1, 1.32 [0.65] L compared to 1.29 [0.61] L). In all cases postinhalation FEV1 was significantly higher than preinhalation FEV1. The combination of fluticasone, salmeterol, and tiotropium proved superior to the other 2 combinations with respect to both preinhalation FEV1 and postinhalation FEV1 (preinhalation FEV1, 1.32 [0.56] L, [P<.03 in both comparisons]; postinhalation FEV1, 1.49 [0.68] L [P<.001 in both comparisons]). Peak flow rate was also significantly higher with the combination of the 2 bronchodilators (345 L/min compared to 291 L/min and 311 mL, respectively [P <.04 in both cases]). There were no notable side effects. CONCLUSIONS: In terms of improvement in lung function, the combination of salmeterol and tiotropium together with fluticasone is more effective in patients with moderate-to-severe COPD than either of the 2 bronchodilators administered alone

The effect of montelukast on eosinophil apoptosis: induced sputum findings of patients with mild persistent asthma

Background: Apoptosis may be important in limiting airway eosinophilia. Treatment with leukotriene antagonists decreases the number of eosinophils in both peripheral blood and sputum. Aim: To assess the effect of montelukast on eosinophil apoptosis in a group of patients with mild persistent asthma (MPA) and to compare this effect with the apoptotic effect of fluticasone propionate (FP). Methods: Randomly selected patients with MPA (n = 22) who had not taken anti-inflammatory therapy within the preceding 12 months were included in the study. The sputum induction procedure was performed and the patients were divided into two groups: group 1 (n = 10) received FP 250 mg/day and group 2 (n = 22) received montelukast 10 mg/day orally for 4 weeks. Sputum induction was repeated after the treatment period. The resulting cytospin slides were stained by Wright’s stain and morphologic changes in apoptotic eosinophils were assessed by the use of light microscopy by two blinded expert pathologists. Serum soluble Fas ligand (sFasL) concentrations were measured by an ELISA method at baseline and after treatment in both groups, as well as in a group of healthy subjects. Results: In within-group comparisons, the apoptotic ratio (AR) increased at the end of the study period in group 1 (p = 0.05). In the group treated with FP the ratio of sputum eosinophils significantly decreased (p = 0.02), and the AR significantly increased (p 0.05). Conclusion: Our findings demonstrate that 4 weeks’ treatment with a CysLT receptor antagonist (montelukast) resulted in an increase in eosinophil apoptosis comparable to that produced by FP, suggesting that induction of apoptosis may be a potential mechanism for the mode of action of CysLT receptor antagonists in asthma

Contexto: La apoptosis puede ser importante para limitar los eosinófilos de las vías respiratorias. El tratamiento con antagonistas de los leucotrienos reduce el número de eosinófilos tanto en la sangre periférica como en el esputo. Objetivo: Evaluar el efecto del montelukast (M) sobre la apoptosis eosinofílica en un grupo de pacientes con asma leve persistente (ALP) para compararlo con el efecto apoptótico del propionato de fluticasona (PF). Métodos: Para el estudio se seleccionaron aleatoriamente pacientes con ALP (n = 22) que no habían recibido terapia antiinflamatoria durante los 12 meses previos. Tras proceder a la inducción del esputo, los pacientes se dividieron en dos grupos: uno recibió 250 mg/día de propionato de fluticasona (grupo 1, n = 10) y el otro 10 mg/día de M por vía oral (grupo 2, n = 12) durante 4 semanas. Tras el período de tratamiento se repitió la inducción del esputo. Los preparados resultantes obtenidos por citocentrifugación se tiñeron con colorante de Wright y dos patólogos expertos que desconocían el origen de las muestras las observaron al microscopio de luz para evaluar los cambios morfológicos de los eosinófilos apoptóticos. Se midieron las concentraciones séricas del ligando Fas soluble (sFasL) mediante el método ELISA antes y después del tratamiento en ambos grupos, midiéndose simultáneamente en un grupo de sujetos sanos. Resultados: Comparando los resultados en un mismo grupo, el índice apoptótico (IA) aumentó al final del período de estudio en el grupo 1 (p = 0,05). En el grupo tratado con PF, el índice de eosinófilos en el esputo disminuyó significativamente (p = 0,02), mientras que hubo un aumento significativo del IA (p 0.05). Conclusión: Nuestros hallazgos demuestran que un tratamiento de cuatro semanas con un antagonista de los receptores de Cis-LT, el montelukast, produce un aumento de la apoptosis eosinofílica comparable al que produce el propionato de fluticasona, lo que sugiere que la inducción de la apoptosis puede ser un mecanismo de acción de los antagonistas de los receptores de Cis-LT en el asma

The comparision of the efficacy of fluticasone propinate with cetirizine in perenneal allergic rhinitis

Background: allergic rhinitis is an IgE mediated hypersensitivity reaction of the nasal mucosa characterised by nasal discharg, obstruction, and pruritus. Patients and methods: in this study, 43 patients with perenneal allergic rhinitis were enrolled in order to compare the efficacy of Fluticasone Propionate (FP), a corticosteroid nasal spray, with Cetirizine, a systemic oral antihistaminic preparation, wich is suposed to have nonsteroidal antiinflammatory activity. Cetirizine (10 mg daily as a single dose) was administered to 22 patient for 45 days. On the other hand, FP (400 mg/day) was administered into each nostril twice a day in the remaining 21 patients for 45 days. Skin test was obtained from each patient before therapy. Total eosinophil count, eosinophil count in nasal smear, electrorhinomanometric investigation, PGE2 and ratio of LTC4 to LTD4 both in the serum and in the nasal secretions were determined before and after therapy. In addition, percentage of eosinophils, and mast cells count in the biopsy specimens taken from anterior edge of middle choncha were evaluated before and after therapy, and than the results were graded for each patients. Results: when we compared the eosinophil count in nasal smear, eosinophil percentage and total eosinophil parameters between two groups, it was shown that FP was more effective than Cetirizine. On the other hand, when we compared the ratio of LTC4 to LTD4 in serum and nasal smear, level of PGE2 and mast cell and nasal airway resistance measured by ERM, there were non statistical difference between two groups. Conclusion: these results suggest that FP and Cetirizine may be used alternatively in case of an adverse reaction to any of them (AU)

Fundamento: la rinitis alérgica es una reacción de hipersensibilidad de la mucosa nasal, mediada por IgE, y caracterizada por secreción, obstrucción y prurito nasal.Pacientes y métodos: en este estudio se incluyeron 43 pacientes con rinitis alérgica perenne con el objetivo de comparar la eficacia de propionato de fluticasona (PF), un corticoide administrado en nebulización nasal, con cetiricina, un antihistamínico sistémico administrado por vía oral, que supuestamente carece de actividad antiinflamatoria no esteroide. A 22 pacientes se les administró cetirizina (10 mg/día en una sola dosis) durante 45 días. A los 21 pacientes restantes se aplicó PF (400 g/día) 2 veces al día en cada ventana nasal durante 45 días.Antes del tratamiento se efectuaron pruebas cutáneas a todos los pacientes. Antes y después del tratamiento se hicieron: recuentos de eosinófilos en sangre y frotis nasal; en suero y secreción nasal se determinaron PGE2 y la relación LTC4/LTD4, y además se realizó estudio electrorrinomanométrico.Además, antes y después del tratamiento, se evaluaron el porcentaje de eosinófilos y el recuento de mastocitos en las biopsias obtenidas a partir del borde anterior del cornete medio.Resultados: cuando comparamos el recuento de eosinófilos en el frotis nasal, porcentaje de eosinófilos y recuento total de eosinófilos entre ambos grupos, se puso de manifiesto que PF fue más eficaz que cetiricina. Por otra parte, cuando comparamos el cociente LTC4:LTD4 en suero y frotis nasal, valores de PGE2 y recuento de mastocitos y la resistencia de las vías respiratorias nasales determinadas mediante ERM, no se detectaron diferencias estadísticamente significativas entre ambos grupos.Conclusión: los resultados del presente estudio demuestran que ambos fármacos pueden utilizarse alternativamente en caso de reacciones adversas a cualquiera de ellos (AU)

Fluticasone propionate and budesonide does not influence bone metabolism in the long term treatment of asthma

Background: inhaled corticosteroids (ICS) are recommended in the treatment of asthmatic patients. They have been said to be efficacious in the treatment of asthma in respect to cortisol and bone metabolism. Methods: the effects of the two inhaled corticosteroid, budesonide (BUD) and fluticasone propionate (FP) on bone metabolism, morning cortisol and their effects on the clinical parameters (FEV1, diurnal variation of peak expiratory flow rate = PEFR and log PC20) were examined in a group of 16 asthmatic patients. Eight patients used 800 μg/daily BUD and 8,400 μg/daily FP during 6 months period.Results: both BUD and FP improved clinical parameters as determined by FEV1 (p < 0.05) and PEFR (p < 0.01). There was no difference in respect to log PC20 values in either group (p > 0.05). Both treatments didn't change morning cortisol (p < 0.05). Both FP and BUD didn't change any indices of bone formation as determined by serum alkalin phosphatase, bone alkalin phosphatase, osteocalcin and carboxyterminal propeptide of type 1 procollagen and bone resorption as determined by urinary calcium and deoxypyridinoline (p > 0.05). ln addition there was no significant effect on calcium and phosphate metabolism (serum calcium, phosphate and parathyroid hormone). Conclusion: as a result, having no adverse effect on bone metabolism and adrenal function, in the regard to clinical efficacy, FP is as effective as the double dose of BUD on PEFR and FEV1 (AU)

Antecedentes: en el tratamiento de pacientes asmáticos se recomiendan corticoides inhalados (CSI).Se ha documentado que son eficaces en el tratamiento del asma con respecto al cortisol y al metabolismo óseo.Métodos: en un grupo de 16 pacientes asmáticos, se examinaron los efectos de dos corticoides inhalados, budesonida (BUD) y propionato de fluticasona (PF), sobre el metabolismo óseo, cortisol matutino y sus efectos sobre los parámetros clínicos (FEV1) y variación diurna de la tasa de flujo espiratorio máximo (PEFR y log PC20). Durante un período, de 6 meses, 8 pacientes utilizaron 800 g/día de BUD y 8, 400 g/día de PF.Resultados: tanto la BUD como el PF mejoraron los parámetros clínicos según lo determinado mediante el FEV1 (p 0,05). Ninguno de ambos tratamientos modificó los valores de cortisol matutino (p 0,05). Además, no se identificó un efecto significativo sobre el metabolismo del calcio y del fosfato (valores séricos de calcio, fosfato y paratormona).Conclusión: como consecuencia, puesto que el PF carece de efectos adversos sobre el metabolismo óseo y la función suprarrenal, desde un punto de vista clínico, es tan eficaz como una dosis doble de BUD sobre el PEFR y el FEV1 (AU)

Insuficiencia suprarrenal secundaria a dosis altasde fluticasona inhalada / Adrenocortical suppression after high doses of inhaled fluticasone

No disponible