Hagiwara M, Mikami T, Iwamura S, Miyazawa K, Kobayashi M, Miyasaka K
Pharmacological Research Department, Teikoku Hormone Mfg. Co., Ltd., Kawasaki, Japan.
Eur J Pharmacol. 1991 Jun 18;199(1):69-75. doi: 10.1016/0014-2999(91)90638-7.
Intrapleural injection of the ionophore A23187 in rats induced leukotriene (LT) production, prostaglandin E2 production, plasma exudation and leukocyte accumulation in the pleural cavity. We evaluated the inhibitory effects of orally administered drugs on 5-lipoxygenase activity by their ability to reduce the content of both peptido-LTs (LTC4, LTD4 and LTE4) and LTB4 in this model. TZI-41127, a novel selective 5-lipoxygenase inhibitor, significantly reduced the peptido-LTs and LTB4 content with ED50 values of 4.2 and 6.1 mg/kg, respectively, whereas it only reduced the prostaglandin E2 content (cyclooxygenase activity) by 31.1% even after 100 mg/kg. Phenidone inhibited 5-lipoxygenase activity more selectively than cyclooxygenase activity. BW755C inhibited cyclooxygenase activity more selectively than 5-lipoxygenase activity. Indomethacin selectively inhibited cyclooxygenase activity. These results suggest that: (1) A23187-induced pleurisy is an convenient in vivo model for studying drug effects on 5-lipoxygenase and cyclooxygenase activities and (2) TZI-41127 is an orally active and comparatively selective inhibitor of 5-lipoxygenase activity.
在大鼠胸腔内注射离子载体A23187可诱导白三烯（LT）生成、前列腺素E2生成、血浆渗出以及白细胞在胸腔内积聚。我们通过评估口服药物降低该模型中肽类白三烯（LTC4、LTD4和LTE4）及LTB4含量的能力，来评价其对5-脂氧合酶活性的抑制作用。新型选择性5-脂氧合酶抑制剂TZI-41127能显著降低肽类白三烯和LTB4的含量，其半数有效剂量（ED50）分别为4.2和6.1mg/kg，而即使在剂量为100mg/kg时，它也仅使前列腺素E2含量（环氧化酶活性）降低了31.1%。非那吡啶对5-脂氧合酶活性的抑制选择性高于环氧化酶活性。BW755C对环氧化酶活性的抑制选择性高于5-脂氧合酶活性。吲哚美辛选择性抑制环氧化酶活性。这些结果表明：（1）A23187诱导的胸膜炎是研究药物对5-脂氧合酶和环氧化酶活性影响的一种便捷的体内模型；（2）TZI-41127是一种口服活性且相对选择性的5-脂氧合酶活性抑制剂。
