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 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.
Ikemura
T
T
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Manabe
H
H
Sasaki
Y
Y
Ishii
H
H
Onuma
K
K
Miki
I
I
Kase
H
H
Sato
S
S
Kitamura
S
S
Ohmori
K
K
D000123:Acetyltransferases / Q000187:drug effects; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D012898:Autacoids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D003990:Dibenzoxepins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism; D008055:Lipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D000069605:Olopatadine Hydrochloride; D010972:Platelet Activating Factor / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000187:drug effects
D018926:Anti-Allergic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D012898:Autacoids; D003990:Dibenzoxepins; D008055:Lipids; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000069605:Olopatadine Hydrochloride; D013929:Thromboxane B2; D000123:Acetyltransferases; C046035:1-alkylglycerophosphocholine acetyltransferase; D013930:Thromboxane-A Synthase