Abstract
Rationale: PI3Kd is a lipid kinase involved in the activation, proliferation and differentiation of leukocytes and thus is an anti-inflammatory target for the treatment of asthma and COPD.
Aim: To describe the in vivo efficacy of a new PI3Kd inhibitor, LAS194223 in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rat by inhaled route compared to fluticasone.
Methods: The pharmacokinetic profile of LAS194223 was assessed by intratracheal administration in male Wistar rats using a Liquid MicroSprayer. Plasma and lung concentrations were measured at time points ranging from 0.01 to 24 h. LAS194223 was administered by i.t. route to OVA-sensitized Brown Norway rats 1 h prior to the OVA challenge and BAL as well as lung tissue for histological evaluation were obtained 24 h post challenge. Total and differential BAL cell counting were performed by Sysmex. Cytokine levels were measured using Luminex technology. PenH was measured by whole body plethysmography.
Results: In the OVA model intratracheal administration of LAS194223 inhibited OVA induced late asthmatic response (LAR), measuring PenH, by 79% at 1 mg/kg, dose-dependently inhibited the eosinophil, neutrophil counts and cytokine levels in BAL. In the lung tissue, it inhibited the alveolar inflammation, alveolar hemorrhages and interstitial edema.
Conclusions: The inhaled administration of the LAS194223 inhibits OVA induced changes in lung function and inflammation. Therefore, LAS194223 shows a promising profile for further characterization and suggests that PI3Kd inhibition, by inhaled route could be a potential treatment for asthma and COPD.
- © 2014 ERS