Lipoxins and novel 15‐epi‐lipoxin analogs display potent anti‐inflammatory actions after oral administration
G Bannenberg, RL Moussignac… - British journal of …, 2004 - Wiley Online Library
G Bannenberg, RL Moussignac, K Gronert, PR Devchand, BA Schmidt, WJ Guilford…
British journal of pharmacology, 2004•Wiley Online LibraryLipoxins (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) …
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) …
- 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
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