Background: Azelastine, oxatomide, and ketotifen are used for patients
with allergic diseases. These drugs inhibit the release of chemical m
ediators including the leukotrienes; however, the mechanism involved i
s unclear. Objective: To clarify the mechanism of inhibition, we inves
tigated the effects of three drugs on the function of phospholipase A(
2), 5-lipoxygenase, leukotriene C-4 synthase, and leukotriene A(4) hyd
rolase, which are all catabolic enzymes involved in synthesizing leuko
triene C-4 and leukotriene B-4 in rat basophilic leukemia (RBL)-1 cell
s. Methods and Results: The production of leukotriene C-4 and leukotri
ene B-4 was measured by high performance liquid chromatography (HPLC).
All three drugs inhibited the production of leukotriene C-4 and leuko
triene Bq when cells were stimulated with A23187. All three drugs also
inhibited the A23187-stimulated release of H-3-arachidonic acid from
membrane phospholipids. Azelastine inhibited the production of leukotr
iene C-4, but not leukotriene B-4, when either arachidonic acid or leu
kotriene A(4) free acid was used as the substrate in our cell free sys
tem. Oxatomide and ketotifen did not inhibit the synthesis of either l
eukotriene C-4 or leukotriene B-4 in the same cell free study. Conclus
ion: Results indicated that oxatomide and ketotifen inhibit the produc
tion of leukotriene C-4 and leukotriene B-4 by inhibiting phospholipas
e A(2) activity, whereas, azelastine inhibits the leukotriene C-4 prod
uction by inhibiting phospholipase A(2) and leukotriene C-4 synthase.