RESUMEN
BACKGROUND: POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF). METHODS: Two studies, one in healthy volunteers (HVs, doses 20 to 960â¯mg) and one in subjects with CF (doses 80 to 320â¯mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow® nebuliser. PK was evaluated over a period of 24â¯h. In addition, NE activity in CF sputum was measured. RESULTS: After single doses, POL6014 was safe and well tolerated up to 480â¯mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with Cmax between 0.2 and 2.5⯵M in HVs and between 0.2 and 0.5⯵M in subjects with CF. Tmax was reached at approximately 2-3â¯h. Mean POL6014 levels in CF sputum rapidly reached 1000⯵M and were still above 10⯵M at 24â¯h. >1-log reduction of active NE was observed at 3â¯h after dosing. CONCLUSION: Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing. TRIAL REGISTRATION: European Medicines Agency EudraCT-Nr. 2015-001618-83 and 2016-000493-38.
Asunto(s)
Fibrosis Quística , Inhibidores Enzimáticos , Elastasa de Leucocito/antagonistas & inhibidores , Compuestos Macrocíclicos , Esputo/enzimología , Administración por Inhalación , Adulto , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Pruebas de Enzimas/métodos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Voluntarios Sanos , Humanos , Pulmón/metabolismo , Pulmón/fisiopatología , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/efectos adversos , Compuestos Macrocíclicos/farmacocinética , Masculino , Nebulizadores y VaporizadoresRESUMEN
BACKGROUND: Recent studies have yielded heterogeneous results regarding the relationship between vitamin D and atopic conditions. The aim of this study was to investigate the association between serum vitamin D level and the prevalence of eczema in German children and adolescents. METHODS: Data were drawn for children aged 1-17 from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), a nationwide cross-sectional representative survey. 25-hydroxyvitamin D (25(OH)D) serum concentration was measured in 9838 individuals with eczema and categorized into quartiles. We investigated the association of vitamin D level and eczema by means of logistic regression models. RESULTS: Weighted prevalence of eczema was 13.5% (95% confidence interval (CI) 12.6-14.4%). Mean vitamin D level was significantly higher in those with eczema compared with those without (P < 0.0001). Logistic regression revealed an inverse association between low levels of vitamin D and eczema (multivariate OR for quartile 1 vs quartile 2: 0.76 (95% CI 0.61-0.94)). CONCLUSIONS: This study suggests that low serum vitamin D level is inversely associated with eczema in German children and adolescents. Prospective studies are required to confirm this result, to discuss a potential opportunity for prevention of eczema.