Inhibition of allergic and nonallergic leukotriene C4 formation and histamine secretion by azelastine: implication for its mechanism of action.
Azelastine, an orally effective antiasthmatic agent, has been reported to inhibit antihistamine-resistant, leukotriene-mediated allergic bronchoconstriction in guinea pigs. This suggests that azelastine might act through inhibition of leukotriene (LT) C4/D4 synthesis. We have examined the effect of azelastine on allergic and nonallergic histamine secretion and LTC4 formation. Azelastine and the known 5-lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861, exerted concentration-dependent inhibition of allergic LTC4 formation in chopped lung tissue from actively sensitized guinea pigs and calcium ionophore A23187-stimulated LTC4 synthesis in mixed peritoneal cells from rats. Azelastine also produced concentration-dependent inhibition of allergic and nonallergic histamine secretion from rat peritoneal mast cells. The ability of azelastine to inhibit allergic and nonallergic histamine secretion and LTC4 generation may contribute to its mode of action and its therapeutic efficacy.
Chand
N
N
Department of Pharmacology, Wallace Laboratories, Cranbury, N.J.
Pillar
J
J
Nolan
K
K
Diamantis
W
W
Sofia
R D
RD
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D016227:Benzoquinones; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016593:Terfenadine
D001559:Benzhydryl Compounds; D016227:Benzoquinones; D007166:Immunosuppressive Agents; D010793:Phthalazines; D011724:Pyridazines; D011809:Quinones; D013189:SRS-A; D016593:Terfenadine; D009637:Masoprocol; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; C020976:azelastine