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Lipoxins and novel 15‐epi‐lipoxin analogs display potent anti‐inflammatory actions after oral administration
Author(s) -
Bannenberg Gerard,
Moussignac RoseLaure,
Gronert Karsten,
Devchand Pallavi R,
Schmidt Birgitta A,
Guilford William J,
Bauman John G,
Subramanyam Babu,
Daniel Perez H,
Parkinson John F,
Serhan Charles N
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705912
Subject(s) - pharmacology , oral administration , inflammation , pharmacokinetics , zymosan , chemistry , peritonitis , lipoxin , medicine , immunology , biochemistry , in vitro
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 LXA 4 and LXB 4 , 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. LXA 4 , LXB 4 , 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 μ g kg −1 ). Intravenous ZK‐994 and ZK‐142 (500 μ g 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 μ g cm −2 ) prevented vascular leakage and neutrophil infiltration in LTB 4 /PGE 2 ‐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 LXA 4 and LXB 4 , 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