PT  - JOURNAL ARTICLE
AU  - Motonori Aoki
AU  - Masahiro Fukunaga
AU  - Minetake Kitagawa
AU  - Kazumi Hayashi
AU  - Tatsuaki Morokata
AU  - Go Ishikawa
AU  - Satoshi Kubo
AU  - Toshimitsu Yamada
TI  - Effect of a Novel Anti-Inflammatory Compound, YM976, on Antigen-Induced Eosinophil Infiltration into the Lungs in Rats, Mice, and Ferrets
DP  - 2000 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1149--1155
VI  - 295
IP  - 3
4099  - http://jpet.aspetjournals.org/content/295/3/1149.short
4100  - http://jpet.aspetjournals.org/content/295/3/1149.full
SO  - J Pharmacol Exp Ther2000 Dec 01; 295
AB  - We evaluated the effects of YM976, a selective inhibitor of phosphodiesterase type 4, on antigen-induced eosinophil infiltration into the lungs in rats, mice, and ferrets. In rats, YM976 inhibited the accumulation of eosinophils at an oral ED50 value of 1.7 mg/kg, and in C57Black/6 mice, exhibited a dose-dependent inhibition at an ED50 value of 5.8 mg/kg. In the same dose range in the same mouse model, YM976 suppressed interleukin-5 production. We then compared the inhibitory effect of chronic administration with that of single administration in another rat model of eosinophilia induced by repeated antigen exposure. YM976 administered chronically offered more potent inhibition (ED50 = 0.32 mg/kg p.o.) than a single dose (1.4 mg/kg p.o.). These results indicated that chronic administration is more effective in antigen-induced eosinophilia than a single administration. Emetogenicity is known to be a major adverse effect of phosphodiesterase type 4 inhibitors. We compared the anti-inflammatory activity of YM976 with its emetic activity in ferrets, in which it dose dependently suppressed eosinophil infiltration at an ED50value of 1.2 mg/kg, but induced no emesis at 10 mg/kg. This suggested that the compound exhibits a considerable dissociation between its anti-inflammatory and emetic effects. In summary, YM976 inhibited eosinophil infiltration in a dose-dependent manner in rats, mice, and ferrets. In ferrets, it suppressed antigen-induced eosinophil infiltration without emesis. Additionally, we demonstrated that the inhibitory effect on eosinophil infiltration was increased by chronic administration. In conclusion, YM976 is a promising drug for the treatment of diseases involving eosinophil activity, such as asthma. The American Society for Pharmacology and Experimental Therapeutics