Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH. METHODS AND RESULTS: Increased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH. CONCLUSION: This study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH.

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension.

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.

Comparación de la biodisponibilidad y la farmacocinética entre dos formulaciones de tabletas de metforminade 850 mg en voluntarios colombianos sanos / Bioavalaibility and pharmacokinetic comparison of two formulations of metformin 850 mg tablets in healthy Colombian volunteers

Purpose: The aim of this study was to compare the bioavailability of two formulations of metformin 850 mg tablets: Glucophage® from Merck Santè laboratories (reference product) and Metformin from Winthrop Pharmaceuticals de Colombia SA (test product) in healthy Colombian volunteers.Methods: A random, double blind, two-period, two-week wash out period, crossover study was performed in 24 healthy male and female volunteers for a single 850-mg dose of metformin tablets administrated with 240 ml of water after 12 hours of fasting. Once the drug was administrated, blood samples were collected before and within 24 hour, and plasma metformin concentration was determined by using a validated HPLC method. Pharmacokinetic parameters such as Cmax, AUC0-96h, AUC0-∞, and Tmax were determined. The formulations were considered bioequivalent if the logarithmic mean ratios of ln-transformed Cmax and AUC0-∞ values were within the equivalence range of 80%-125%.Results: ANOVA analysis of the ln-transformed Cmax and AUC0-∞ indicated that none of the effects examined (formulation, period, within and between-subjet variances and carry over) was statistically significant. The mean (±SD) of Cmax 1217.38 (± 251.72) ng/ml vs. 1305.25 (± 301.06) ng/ml, AUC0-96h 1363.49 (± 315.51) ng.h/ml vs. 1584.82 (± 368.75) ng.h/ml, AUC0-∞, 7155.75 (± 1440.74) ng.h/ml vs. 7777.08 (± 1896.49) ng.h/ml, and Tmax 2.57 (± 0.93) h vs. 2.22 (± 0.94) h were obtained with test and reference formulations, respectively. These pharmacokinetic parameters presented differences with the results from other published papers. The 90% confidence interval of the logarithmic ratio of AUC0-∞ and Cmax was within the range of 80-125%.Conclusions: In this study in healthy Colombian volunteers, a single 850-mg dose of metformin tablet test formulation met the criteria for bioequivalence to the reference formulation based on pharmacokinetic parameters AUC0-∞ and Cmax.

Objetivo: El objetivo de este estudio es comparar la bioequivalencia de dos formulaciones de tabletas de metformina de 850 mg: Glucophage® del Laboratorio Merck Santè (producto de referencia) y metformina de Laboratorios Winthrop Pharmaceuticals de Colombia SA (producto de prueba), en voluntarios colombianos sanos.Métodos: Se realizó un estudio aleatorizado, doble ciego, cruzado, en dos períodos y con un tiempo de lavado de dos semanas, en 24 voluntarios sanos, hombres y mujeres, que recibieron una dosis única de metformina de 850 mg, con 240 ml de agua, después de 12 horas de ayuno. Luego de la administración del medicamento, se recolectaron muestras de sangre durante 24 horas y las concentraciones plasmáticas de metformina se determinaron con un método de HPLC validado. Se calcularon los parámetros farmacocinéticos: Cmax, AUC0-96h, AUC0-∞, y Tmax. Las formulaciones se consideraron bioequivalentes si la relación de la media transformada a ln de Cmax y AUC0-∞ estaba dentro del rango de bioequivalencia de 80% a 125%.Resultados: El Anova de los datos transformados a ln de Cmax y AUC0-∞ indicaron que ninguno de los efectos analizados (formulación, período, variación intra e intersujetos y arrastre) fueron estadísticamente significativos. La media (±SD) de los parámetros obtenidos para los productos de prueba y de referencia, respectivamente, fueron: Cmax 1217.38 (± 251.72) ng/ml vs. 1305.25 (± 301.06) ng/ml, AUC0-96h 1363.49 (± 315.51) ng.h/ml vs. 1584.82 (± 368.75) ng.h/ml, AUC0-∞, 7155.75 (± 1440.74) ng.h/ml vs. 7777.08 (± 1896.49) ng.h/ml, and Tmax 2.57 (± 0.93) h vs. 2.22 (± 0.94) h. El intervalo de confianza de la relación logarítmica del AUC0∞ y Cmax se encontró dentro del rango de 80% a 125%.

Interheart, un estudio de casos y controles sobre factores de riesgo de infarto del miocardio en el mundo y América Latina / Interheart: a case and control study about risk factors for myocardial infarction worldwide and Latin America

Las enfermedades cardiovasculares son la primera causa de muerte a nivel mundial y en América Latina. El estudio INTERHEART es un estudio diseñado para comparar la importancia de los diferentes factores de riesgo de Infarto del Miocardio a nivel mundial. Material y Método: es un estudio de casos incidentes y controles realizado en 52 países. Los casos eran pacientes que ingresaron con un primer Infarto y los controles fueron pareados por sexo, edad y centro. En ambos grupos se determinó datos demográficos, nivel socioeconómico, estilo de vida, factores psicosociales, historia personal y familiar de enfermedad cardiovascular y factores de riesgo. Se midió índice cintura cadera y Apolipoproteina B y ApoA1. Resultados: A nivel mundial la asociación más fuerte ocurrió con tabaquismo actual (OR 2,87) y relación ApoB/ApoA1 elevada (OR 3,25, quintil superior vs inferior), seguida de factores psicosociales (OR 2,67), historia de diabetes (OR 2,37) e historia de hipertensión (OR 1,91). En América Latina los factores más prevalentes fueron obesidad abdominal, tabaquismo y niveles de ApoB/ApoA1 en el tercil superior. La asociación más fuerte con OR de 2,81 correspondió a historia de hipertensión arterial y a estrés permanente. El consumo diario de frutas y/o verduras y el ejercicio regular tuvieron un efecto protector similar con OR 0,63 (0,51-0,78) y 0,67 (0,55-0,82). El mayor riesgo atribuible poblacional, se debió a obesidad abdominal: 45,8% (35,8-56,2), niveles elevados de Apo B/ApoA1: 40,8 % (30,3-52,2) y tabaquismo: 38.4% (32,8-44,4). En América Latina y el mundo esto factores explican aproximadamente el 90% de los infartos. Conclusión: Los factores de riesgo conocidos permiten explicar casi la totalidad del riesgo de infarto del miocardio a nivel mundial y en América Latina. Su control tendrá un impacto significativo en el control de esta enfermedad...

Cardiovascular diseases are the main cause of death in the world and Latin America. The INTERHEART study was designed to assess the importance of different risk factors for myocardial infarction worldwide. Material and Methods: this is an incident case and control study performed in 52 countries. Cases were patients admitted with a first myocardial infarction. Controls were paired by gender, age and center. In both group demographic data, socioeconomic status, lifestyle, psychosocial factors, personal and family medical cardiovascular story and risk factors were determined. Waist to hip ratio and Apolipoprotein B and ApoA1 were measured. Results: worldwide the strong association was with active smoking (OR 2,87) and increased ApoB/ApoA1 ratio (OR 3,25, upper vs. lower quintile), followed by psychosocial factors (OR 2,67), history of diabetes (OR 2,37) and history of hypertension (OR 1,91). In Latin America the highest prevalence was for abdominal obesity, smoking and ApoB/ApoA1 in the upper tertile. The stronger association was with history of hypertension and permanent stress (OR 2,81. Daily fruit and vegetables consumption and exercise had a similar protective effect, OR 0,63 (0,51-0,78) and 0,67 (0,55-0,82) respectively. The highest population attributable risk was due to abdominal obesity 45.8% (35,8-56,2), increased levels of Apo B/ApoA1 ration: 40,8 % (30,3-52,2) and smoking: 38,4% (32,8-44,4). In Latin America and the rest of the World these factors explained approximately 90% of the myocardial infarctions. Conclusion: known risk factors can explain almost all the myocardial infarction risk in the World and in Latin America. Risk factor control may have a significant impact in the myocardial infarction impact worldwide...

Estudio de bioequivalencia de clonazepam, tabletas de 2 mg, en voluntarios sanos colombianos / Bioequivalence study of clonazepam 2 mg tablets in colombian healthy volunteers

Con el fin de determinar la bioequivalencia de dos formulaciones de tabletas de 2 mg de clonazepam: Sedatril®/Clonazepam MK (Tecnoquímicas S. A., Cali, Colombia) como producto de prueba y Rivotril® (Roche Químicos e Farmacéuticas S. A., Río de Janeiro, Brasil), como producto de referencia, se realizó un estudio de bioequivalencia en 26 voluntarios sanos. Los productos de prueba y de referencia se administraron en condiciones de ayuno de acuerdo con un diseño cruzado aleatorio de dosis única, con dos secuencias, dos tratamientos y un período de lavado de 28 días. Las muestras de sangre se obtuvieron desde las 0 hasta las 96 horas después de la administración del medicamento. Los niveles plasmáticos de clonazepam se determinaron con un método validado por cromatografía líquida de alta eficiencia con detección ultravioleta (HPLC/UV, siglas en inglés). Los parámetros farmacocinéticos ABC0-96, ABC0-∞, Cmax, Tmax, t1/2, and ke se determinaron de los perfiles plasmáticos concentración-tiempo por el método no compartimental. El test de bioequivalencia se realizó con los datos transformados a logaritmo natural (ln) de ABC0-∞ and Cmax. Los intervalos de confianza del 90 por ciento para la relación producto de prueba/producto de referencia fueron de 87,9 por ciento a 103,6 por ciento y 84,4 por ciento a 104,0 por ciento, respectivamente. Estos resultados estuvieron dentro de los rangos de aceptación del 80,0 por ciento al 125 por ciento, establecidos por la FDA y se concluyó que ambos productos son bioequivalentes.

In order to determine the bioequivalence of two formulations of clonazepam 2 mg tablets: Sedatril®/ Clonazepam MK (Tecnoquímicas S. A., Cali, Colombia) as a test product and Rivotril® (Roche Químicos e Farmacêuticas S. A., Rio de Janeiro, Brazil) as a reference product, a bioavailability study was performed in 26 healthy volunteers. Test and reference products were administered under fasting conditions following a single dose, two-sequences, two treatments, crossover randomized design with a 28-day-washout period. Blood samples were obtained from 0 to 96 hours after dosing. Plasma clonazepam levels were determined by a validated high performance liquid chromatography with UV detection method (HPLC/UV). ABC0-96, ABC0-∞, Cmax, Tmax, t1/2, and ke, pharmacokinetic parameters were determined from plasma level-time profiles by a noncompartmental method. ln-trasformed ABC0-∞ and Cmax were tested for bioequivalence. 90%-confidence intervals for test/reference ratio of these parameters were 87.9% to 103.6% and 84.4% to 104.0%, respectively. These results were within the FDA acceptance range of 80% to 125% and it was concluded that both products were bioequivalent.