ciclesonide and Acute-Lung-Injury

SARS-CoV-2 viremia is associated with increased acute lung injury (ALI) and mortality in children and adults. The mechanisms by which viral components in the circulation mediate ALI in COVID-19 remain unclear. We tested the hypothesis that the SARS-CoV-2 envelope (E) protein induces Toll-like receptor (TLR)-mediated ALI and lung remodeling in a model of neonatal COVID-19. Neonatal C57BL6 mice given intraperitoneal E protein injections revealed a dose-dependent increase in lung cytokines [interleukin 6 (

Topics: Acute Lung Injury; Animals; Child; COVID-19; Endothelial Cells; Glucocorticoids; Humans; Lipopolysaccharides; Mice; Mice, Inbred C57BL; SARS-CoV-2; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Transforming Growth Factor beta; Viral Envelope; Viremia

The pulmonary fate of inhaled poorly water-soluble drugs is not entirely clear. In this study, the main objective was to investigate the in vivo inhalation biopharmaceutics in the aspects of dissolution, mucociliary clearance, absorption and tissue binding using intratracheally administered budesonide and ciclesonide suspensions as model drugs. In doing so, this study first developed a method to differentiate between dissolved and undissolved ciclesonide in the lungs for evaluating in vivo dissolution. Following deposited in rat airways, the drug particles underwent rapid dissolution and mucociliary clearance, leading to the complete removal of drugs from the airways within 2 h and a limited absorption time less than 2 h. Upon dissolution, budesonide and ciclesonide were taken up and retained in the lung tissues for up to 12 h and 24 h, respectively. The in vivo dissolution profiles in the airways exhibited the sameness as the in vitro counterparts in a 0.5% sodium dodecyl sulfate solution as indicated by the similarity factor f2. The efficacy results in a lipopolysaccharide induced lung injury model showed that the duration of local anti-inflammatory was dependent on the drug levels in the lung tissues, but not on the in vitro/in vivo dissolution and plasma pharmacokinetics. The present results demonstrated that ciclesonide suspension has the potential to achieve once-daily dosing for nebulization therapy and the in vitro dissolution profile has limited usefulness in predicting in vitro-in vivo correlation.

Topics: Acute Lung Injury; Administration, Inhalation; Animals; Anti-Inflammatory Agents; Budesonide; Disease Models, Animal; Drug Liberation; Glucocorticoids; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Nebulizers and Vaporizers; Pregnenediones; Rats; Rats, Wistar; Solubility; Suspensions; Time Factors; Tissue Distribution