Aoki M, Fukunaga M, Kitagawa M, Hayashi K, Morokata T, Ishikawa G, Kubo S, Yamada T
Inflammation Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba-shi, Ibaraki, Japan.
J Pharmacol Exp Ther. 2000 Dec;295(3):1149-55.
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.
我们评估了磷酸二酯酶4型选择性抑制剂YM976对大鼠、小鼠和雪貂抗原诱导的嗜酸性粒细胞浸润到肺部的影响。在大鼠中，YM976以1.7mg/kg的口服半数有效剂量（ED50）抑制嗜酸性粒细胞的聚集，在C57BL/6小鼠中，以5.8mg/kg的ED50值呈现剂量依赖性抑制。在同一小鼠模型的相同剂量范围内，YM976抑制白细胞介素-5的产生。然后，我们在另一个由反复抗原暴露诱导的嗜酸性粒细胞增多的大鼠模型中比较了长期给药与单次给药的抑制效果。长期给药的YM976比单次给药（口服1.4mg/kg）具有更强的抑制作用（口服ED50 = 0.32mg/kg）。这些结果表明，长期给药在抗原诱导的嗜酸性粒细胞增多方面比单次给药更有效。已知致吐性是磷酸二酯酶4型抑制剂的主要不良反应。我们在雪貂中比较了YM976的抗炎活性与其催吐活性，在雪貂中，它以1.2mg/kg的ED50值剂量依赖性地抑制嗜酸性粒细胞浸润，但在10mg/kg时未引起呕吐。这表明该化合物在其抗炎和催吐作用之间表现出相当大的解离。总之，YM976在大鼠、小鼠和雪貂中以剂量依赖性方式抑制嗜酸性粒细胞浸润。在雪貂中，它抑制抗原诱导的嗜酸性粒细胞浸润而不引起呕吐。此外，我们证明长期给药可增强对嗜酸性粒细胞浸润的抑制作用。总之，YM976是一种有前途的药物，可用于治疗涉及嗜酸性粒细胞活性的疾病，如哮喘。
