Aoki M, Yamamoto S, Kobayashi M, Ohga K, Kanoh H, Miyata K, Honda K, Yamada T
Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba-shi, Ibaraki, Japan.
J Pharmacol Exp Ther. 2001 Apr;297(1):165-73.
YM976 is a novel and specific phosphodiesterase 4 inhibitor. In our previous report, we indicated that YM976 has less emetogenicity, a major adverse effect of PDE4 inhibitors, than rolipram. In the present study, we examined the antiasthmatic effects of YM976 in guinea pigs. YM976 orally administered exhibited inhibition of antigen-induced bronchoconstriction, airway plasma leakage, airway eosinophil infiltration, and airway hyperreactivity (AHR), with ED(50) values of 7.3, 5.7, 1.0, and 0.52 mg/kg, respectively. Rolipram also dose dependently suppressed these responses. Prednisolone suppressed eosinophil infiltration and AHR, whereas it failed to inhibit bronchoconstriction and plasma leakage. Theophylline moderately suppressed bronchoconstriction and edema, but neither eosinophil infiltration nor AHR. YM976 suppressed the peroxidase activity in the bronchoalveolar lavage fluid, and elevated the intracellular peroxidase activity and cAMP contents of infiltrated cells, suggesting that YM976 inhibited not only the infiltration but also the activation of leukocytes. In vitro studies revealed that YM976 potently suppressed eosinophil activation (EC(30) = 83 nM), and exerted a little relaxation on LTD(4)-precontracted tracheal smooth muscle (EC(50) = 370 nM). Rolipram exhibited a potent tracheal relaxation activity (EC(50) = 50 nM). In vivo studies indicated that the inhibitory effect of YM976 on LTD(4)-induced bronchospasm was marginal even at 30 mg/kg p.o., although rolipram significantly inhibited the bronchospasm at the same dose. These results suggested that YM976, unlike rolipram, showed the inhibition of antigen-induced airway responses due to anti-inflammatory effects, but not to direct tracheal relaxation. In conclusion, YM976 may have potential therapeutic value in the treatment of asthma through its anti-inflammatory activities.
YM976是一种新型的特异性磷酸二酯酶4抑制剂。在我们之前的报告中，我们指出YM976的致吐性比咯利普兰低，而致吐性是磷酸二酯酶4抑制剂的一种主要不良反应。在本研究中，我们检测了YM976对豚鼠的抗哮喘作用。口服给药的YM976可抑制抗原诱导的支气管收缩、气道血浆渗漏、气道嗜酸性粒细胞浸润和气道高反应性（AHR），其半数有效剂量（ED50）值分别为7.3、5.7、1.0和0.52mg/kg。咯利普兰也呈剂量依赖性地抑制这些反应。泼尼松龙可抑制嗜酸性粒细胞浸润和气道高反应性，但不能抑制支气管收缩和血浆渗漏。茶碱可适度抑制支气管收缩和水肿，但对嗜酸性粒细胞浸润和气道高反应性均无抑制作用。YM976可抑制支气管肺泡灌洗液中的过氧化物酶活性，并提高浸润细胞的细胞内过氧化物酶活性和环磷酸腺苷（cAMP）含量，这表明YM976不仅抑制了白细胞的浸润，还抑制了其活化。体外研究表明，YM976可有效抑制嗜酸性粒细胞活化（半数有效浓度（EC30）=83 nM），并对白三烯D4（LTD4）预收缩的气管平滑肌有轻微舒张作用（半数有效浓度（EC50）=370 nM）。咯利普兰表现出较强的气管舒张活性（半数有效浓度（EC50）=50 nM）。体内研究表明，即使口服剂量为30mg/kg，YM976对LTD4诱导的支气管痉挛的抑制作用也很微弱，而咯利普兰在相同剂量下可显著抑制支气管痉挛。这些结果表明，与咯利普兰不同，YM976通过抗炎作用而非直接的气管舒张作用来抑制抗原诱导的气道反应。总之，YM976可能因其抗炎活性而在哮喘治疗中具有潜在的治疗价值。
