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

• Published in: International archives of allergy and immunology Vol. 110; no. 1; p. 57
• Main Authors: Ikemura, T, Manabe, H, Sasaki, Y, Ishii, H, Onuma, K, Miki, I, Kase, H, Sato, S, Kitamura, S, Ohmori, K
• Format: Journal Article
• Language: English
• Published: Switzerland 01.01.1996
• Subjects: Acetyltransferases - drug effects; Animals; Anti-Allergic Agents - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arachidonic Acid - secretion; Autacoids - antagonists & inhibitors; Autacoids - biosynthesis; Dibenzoxepins - pharmacology; Enzyme Activation - drug effects; Eosinophils - drug effects; Eosinophils - metabolism; Eosinophils - secretion; Guinea Pigs; Humans; Leukotriene B4 - secretion; Lipids - antagonists & inhibitors; Lipids - biosynthesis; Lipoxygenase Inhibitors; Male; Neutrophils - drug effects; Neutrophils - metabolism; Olopatadine Hydrochloride; Platelet Activating Factor - biosynthesis; Thromboxane B2 - secretion; Thromboxane-A Synthase - drug effects
• ISSN: 1018-2438
• 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.