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.