KW-4679 an antiallergic drug, inhibits the production of inflammatory lipids in human polymorphonuclear leukocytes and guinea pig eosinophils

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 mu M reduced the amount of cell-associated PAF by 52.8% in human polymorphonuclear leukocytes (PMNs). KW-4679 (1-100 mu M) also inhibited the release of both LTB(4) and TXB(2), a stable metabolite of TXA(2), by human PMNs in a concentration-dependent manner, but did not influence the release of beta-glucuronidase. The 50% inhibitory concentration (IC50) values for LTB(4) and TXB(2) release were 5.9 and 6.0 mu M, respectively. In guinea pig eosinophils, KW-4679 inhibited the release of peptide LTs at a concentration higher than 10 mu M (IC50 = 66.9 mu M) KW-4679 failed to inhibit PAF acetyltransferase, 5-lipoxygenase and TX synthase, but inhibited the arachidonic acid rlease by human PMNs in a concentration-dependent manner at a similar concentration as that inhibiting production or release of lipid mediators (IC50 = 19.5 mu M) 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 A(2). The inhibitory action of KW-4679 on PAF, LT and TX production is a beneficial effect of an antiallergic drug.