IPL576,092, a novel anti-inflammatory compound, inhibits leukocyte infiltration and changes in lung function in response to allergen challenge.

Abstract

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 microg/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.

• Authors: C E Kasserra, P Harris, G R Stenton, W Abraham, J M Langlands
• Journal: Pulmonary pharmacology & therapeutics (Pulm Pharmacol Ther) Vol. 17 Issue 5 Pg. 309-18 ( 2004) ISSN: 1094-5539 [Print] England
• PMID: 15477127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Anti-Inflammatory Agents
• IPL576,092
• Sterols

Topics

• Airway Resistance (drug effects)
• Allergens
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Bronchial Hyperreactivity (prevention & control)
• Bronchoalveolar Lavage
• Bronchoalveolar Lavage Fluid (cytology)
• Bronchoconstriction (drug effects)
• Female
• Guinea Pigs
• Leukocytes (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Models, Animal
• Rats
• Sheep
• Sterols (pharmacology)