Ikemura T, Manabe H, Sasaki Y, Ishii H, Onuma K, Miki I, Kase H, Sato S, Kitamura S, Ohmori K
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Int Arch Allergy Immunol. 1996 May;110(1):57-63. doi: 10.1159/000237311.
The effects of (Z)-11-[(3-dimethylamino)propylidene]-6,11-dihydrodibenz [b.e.]oxepin-2-acetic acid monohydrochloride (KW-4679), an orally active antiallergic drug, on the production of platelet-activating factor (PAF), leukotriene (LT) and thromboxane (TX) induced by Ca2+ ionophore A23187 were examined. KW-4679 at 10 microM reduced the amount of cell-associated PAF by 52.8% in human polymorphonuclear leukocytes (PMNs). KW-4679 (1-100 microM) also inhibited the release of both LTB4 and TXB2, a stable metabolite of TXA2, by human PMNs in a concentration-dependent manner, but did not influence the release of beta-glucuronidase. The 50% inhibitory concentration (IC50) values for LTB4 and TXB2 release were 5.9 and 6.0 microM, respectively. In guinea pig eosinophils, KW-4679 inhibited the release of peptide LTs at a concentration higher than 10 microM (IC50 = 66.9 microM). KW-4679 failed to inhibit PAF acetyltransferase, 5-lipoxygenase and TX synthase, but inhibited the arachidonic acid release by human PMNs in a concentration-dependent manner in a similar concentration as that inhibiting production or release of lipid mediators (IC50 = 19.5 microM). These results indicate that KW-4679 suppresses LTs and TX release and PAF formation by reducing arachidonic acid release from phospholipids, probably through interference with phospholipase A2. The inhibitory action of KW-4679 on PAF, LT and TX production is a beneficial effect of an antiallergic drug.
对口服活性抗过敏药物（Z）-11-[(3-二甲氨基)亚丙基]-6,11-二氢二苯并[b.e.]氧杂环庚英-2-乙酸盐酸盐（KW-4679）对钙离子载体A23187诱导的血小板活化因子（PAF）、白三烯（LT）和血栓素（TX）生成的影响进行了研究。10微摩尔的KW-4679可使人类多形核白细胞（PMN）中与细胞相关的PAF量减少52.8%。KW-4679（1-100微摩尔）还以浓度依赖性方式抑制人类PMN释放LTB4和TXB2（TX A2的稳定代谢产物），但不影响β-葡萄糖醛酸酶的释放。LTB4和TXB2释放的50%抑制浓度（IC50）值分别为5.9和6.0微摩尔。在豚鼠嗜酸性粒细胞中，KW-4679在高于10微摩尔的浓度时抑制肽类LT的释放（IC50 = 66.9微摩尔）。KW-4679未能抑制PAF乙酰转移酶、5-脂氧合酶和TX合酶，但以浓度依赖性方式抑制人类PMN释放花生四烯酸，其浓度与抑制脂质介质生成或释放的浓度相似（IC50 = 19.5微摩尔）。这些结果表明，KW-4679可能通过干扰磷脂酶A2减少磷脂中花生四烯酸的释放，从而抑制LT和TX的释放以及PAF的形成。KW-4679对PAF、LT和TX生成的抑制作用是一种抗过敏药物的有益作用。
