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Lipoxins and novel 15‐epi‐lipoxin analogs display potent anti‐inflammatory actions after oral administration
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Lipoxins and novel 15‐epi‐lipoxin analogs display potent anti‐inflammatory actions after oral administration
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Journal Article
Lipoxins and novel 15‐epi‐lipoxin analogs display potent anti‐inflammatory actions after oral administration
2004
Overview
Lipoxins (LX) and aspirin‐triggered 15‐epi‐lipoxins (ATL) exert potent anti‐inflammatory actions. In the present study, we determined the anti‐inflammatory efficacy of endogenous LXA4 and LXB4, the stable ATL analog ATLa2, and a series of novel 3‐oxa‐ATL analogs (ZK‐996, ZK‐990, ZK‐994, and ZK‐142) after intravenous, oral, and topical administration in mice. LXA4, LXB4, ATLa2, and ZK‐994 were orally active, exhibiting potent systemic inhibition of zymosan A‐induced peritonitis at very low doses (50 ng kg−1–50 μg kg−1). Intravenous ZK‐994 and ZK‐142 (500 μg kg−1) potently attenuated hind limb ischemia/reperfusion‐induced lung injury, with 32±12 and 53±5% inhibition (P<0.05), respectively, of neutrophil accumulation in lungs. The same dose of ATLa2 had no significant protective action. Topical application of ATLa2, ZK‐994, and ZK‐142 (∼20 μg cm−2) prevented vascular leakage and neutrophil infiltration in LTB4/PGE2‐stimulated ear skin inflammation. While ATLa2 and ZK‐142 displayed approximately equal anti‐inflammatory efficacy in this model, ZK‐994 displayed a slower onset of action. In summary, native LXA4 and LXB4, and analogs ATLa2, ZK‐142, and ZK‐994 retain broad anti‐inflammatory effects after intravenous, oral, and topical administration. The 3‐oxa‐ATL analogs, which have enhanced metabolic and chemical stability and a superior pharmacokinetic profile, provide new opportunities to explore the actions and therapeutic potential for LX and ATL. British Journal of Pharmacology (2004) 143, 43–52. doi:10.1038/sj.bjp.0705912
Publisher
Blackwell Publishing Ltd,Nature Publishing
Subject
/ Animals
/ Anti-Inflammatory Agents, Non-Steroidal - pharmacology
/ Biological and medical sciences
/ delivery
/ Inflammation - prevention & control
/ lipoxins
/ Lipoxins - administration & dosage
/ Lung Diseases - prevention & control
/ Male
/ Mice
/ Peritonitis - chemically induced
/ Peritonitis - prevention & control
/ Pharmacology. Drug treatments
/ Reperfusion Injury - pathology
/ Reperfusion Injury - prevention & control
/ skin
