mometasone-furoate and Pneumonia

Understanding the relationship between dose, lung exposure, and drug efficacy continues to be a challenging aspect of inhaled drug development. An experimental inhalation platform was developed using mometasone furoate to link rodent lung exposure to its in vivo pharmacodynamic (PD) effects.. We assessed the effect of mometasone delivered directly to the lung in two different rodent PD models of lung inflammation. The data obtained were used to develop and evaluate a mathematical model to estimate drug dissolution, transport, distribution, and efficacy, following inhaled delivery in rodents and humans.. Mometasone directly delivered to the lung, in both LPS and Alternaria alternata rat models, resulted in dose dependent inhibition of BALf cellular inflammation. The parameters for our mathematical model were calibrated to describe the observed lung and systemic exposure profiles of mometasone in humans and in animal models. We found that physicochemical properties, such as lung fluid solubility and lipophilicity, strongly influenced compound distribution and lung retention.. Presently, we report on a novel and sophisticated mathematical model leading to improvements in a current inhaled drug development practices by providing a quantitative understanding of the relationship between PD effects and drug concentration in lungs.

Topics: Administration, Inhalation; Aerosols; Alternaria; Alternariosis; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Dosage Calculations; Humans; Lipopolysaccharides; Lung; Lung Diseases, Fungal; Male; Models, Biological; Mometasone Furoate; Pneumonia; Rats, Inbred BN; Rats, Sprague-Dawley; Species Specificity; Tissue Distribution

Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury.

Topics: Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Budesonide; Chlorine; Glucocorticoids; Mice; Mice, Inbred Strains; Mometasone Furoate; Neutrophil Infiltration; Pneumonia; Pregnadienediols; Pulmonary Edema