ciclesonide and Disease-Models--Animal

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

The long-acting anticholinergic tiotropium has recently been registered for the treatment of asthma, and its use is associated with a reduction in exacerbation frequency. Anti-inflammatory and anti-remodeling effects of tiotropium have been demonstrated in in vitro and in vivo models. Because tiotropium treatment is used in combination with inhaled corticosteroids, potential additive effects between the two would be clinically relevant. Therefore, the aim of this study was to investigate additive effects between tiotropium and ciclesonide on airway inflammation and remodeling in guinea pig models of asthma.. Guinea pigs (n = 3-8/group) were sensitized and challenged with ovalbumin in an acute (single challenge) and a chronic model (12 weekly challenges) of allergic asthma. Animals were treated with vehicle, nebulized tiotropium (0.01-0.3 mM) and/or intranasally instilled ciclesonide (0.001-1 mg/kg) before each challenge. Bronchoalveolar lavage fluid and lungs were collected for analysis of airway inflammation and remodeling.. Tiotropium and ciclesonide treatment, alone or in combination, did not inhibit airway inflammation in the acute asthma model. In a dose-finding study, low doses of tiotropium and ciclesonide inhibited airway eosinophilia and airway smooth muscle thickening in the chronic asthma model. Threshold doses of 0.01 mM tiotropium (nebulizer concentration) and 0.01 mg/kg ciclesonide were selected to investigate potential additive effects between both drugs. At these doses, tiotropium and ciclesonide did not inhibit airway eosinophilia or airway smooth muscle thickening when administered alone, but significantly inhibited these allergen-induced responses when administered in combination.. Combined treatment with low doses of tiotropium and ciclesonide inhibits airway inflammation and remodeling in a guinea pig model of chronic asthma, suggesting that combined treatment with anticholinergics and corticosteroids may have anti-inflammatory and anti-remodeling activity in allergic airway diseases. Since tiotropium is registered as a therapy for asthma added on to corticosteroid treatment, these beneficial effects of the combination therapy may be clinically relevant.

Topics: Administration, Inhalation; Airway Remodeling; Animals; Anti-Allergic Agents; Asthma; Bronchodilator Agents; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guinea Pigs; Male; Ovalbumin; Pregnenediones; Tiotropium Bromide; Treatment Outcome