IPL576,092, a novel anti-inflammatory compound, inhibits leukocyte infiltration and changes in lung function in response to allergen challenge.
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.
Inflazyme Pharmaceuticals Ltd, 425-5600 Parkwood Way, Richmond, BC, Canada V6V 2M2. ckass@inflazyme.com
C E
CE
Kasserra
P
P
Harris
G R
GR
Stenton
W
W
Abraham
J M
JM
Langlands
D000403:Airway Resistance / Q000187:drug effects; D000485:Allergens; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000517:prevention & control*; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects*; D005260:Female; D006168:Guinea Pigs; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D051381:Rats; D012756:Sheep; D013261:Sterols / Q000494:pharmacology*
D000485:Allergens; D000893:Anti-Inflammatory Agents; C467961:IPL576,092; D013261:Sterols