Effect of a novel anti-inflammatory compound, YM976, on antigen-induced eosinophil infiltration into the lungs in rats, mice, and ferrets.
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 ED(50) value of 1.7 mg/kg, and in C57Black/6 mice, exhibited a dose-dependent inhibition at an ED(50) 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 (ED(50) = 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 ED(50) value 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.
Aoki
M
M
Inflammation Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba-shi, Ibaraki, Japan. aokim@yamanouchi.co.jp
Fukunaga
M
M
Kitagawa
M
M
Hayashi
K
K
Morokata
T
T
Ishikawa
G
G
Kubo
S
S
Yamada
T
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000941:Antigens / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000517:prevention & control; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D005289:Ferrets; D015848:Interleukin-5 / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011239:Prednisolone / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D020889:Rolipram / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000941:Antigens; D015848:Interleukin-5; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011744:Pyrimidinones; C414544:YM 976; D011239:Prednisolone; D020889:Rolipram