IPL576,092, a lead compound from a novel class of polyhydroxylated sterols, was tested in models of allergen-induced bronchoconstriction and airway inflammation. In a rat ovalbumin lung inflammation model, orally administered IPL576,092 significantly inhibited the challenge-mediated increase in total bronchoalveolar lavage leukocyte numbers, and macrophage and lymphocyte infiltration (1-10 mg/kg/day). There was a similar trend towards inhibition of eosinophil and neutrophil accumulation. Sheep were treated with IPL576,092 by inhalation (400 μg/kg/day), and lung resistance and airway hyper-responsiveness (AHR) were determined after Ascaris suum challenge. IPL576,092 significantly reduced the early and late phase bronchoconstrictor responses by 63±4.6 and 84±4.6%, respectively. IPL576,092 also blocked AHR (2.2±5.7% change from pre-challenge PC400), whereas control animals showed a 62.2±2.6% decrease in the PC400 (p<0.05). Oral IPL576,092 (5 mg/kg/day) also significantly decreased hyper-reactivity in mice. In a guinea pig model, IPL576,092 (5 mg/kg/day) significantly protected against allergen-induced increases in lung resistance (11.4±2.3 control versus 4.8±01.5 IPL576,092, area under the curve) and inhibited the increase in lung elastance (280±58 control versus 167±52 IPL576,092, p<0.05). IPL576,092, unlike dexamethasone, did not significantly decrease rat serum corticosterone levels or thymus and spleen weights, supporting a mechanism of action different from classic glucocorticoids. IPL576,092 significantly attenuates characteristics of an asthmatic response, indicating therapeutic potential for this drug class.
- Airway hyperresponsiveness
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine