INHIBITION OF IGE-MEDIATED AND NON-IGE-MEDIATED HISTAMINE-RELEASE FROM HUMAN BASOPHIL LEUKOCYTES IN-VITRO BY A HISTAMINE H-1-ANTAGONIST, DESETHOXYCARBONYL-LORATADINE

Loratadine, a new nonsedating histamine H-1-antagonist, has been shown to inhibit immunologic release of inflammatory mediators in addition to its H-1-receptor blocking properties. After oral administration the agent is metabolized primarily to desethoxycarbonyl-loratadine (DCL). The basic piperidine, DCL, is readily soluble in water whereas the no nbasic urethane, loratadine, is insufficiently soluble in water for so me in vitro investigations. Therefore we used the metabolite, DCL, to study its influence on in vitro leukocyte histamine release (LHR) in 2 4 allergic and 22 nonallergic subjects. IgE-mediated and calcium ionop hore A23187-induced LHR were inhibited by DCL in a dose-dependent fash ion (values of drug concentration to induce 30% inhibition after stimu lation with inhalant antigen, anti-IgE, concanavalin A, and calcium io nophore A23187 were 6, 8, 5, and 11 mu mol/L, respectively). Higher co ncentrations of DCL caused mediator release in all subjects (n = 45, 3 0 mu mol/L DC: 11% +/- 2% LHR, 100 mu mol/L DCL: 35% +/- 1% LHR), abol ishing any inhibitory effect of the drug. Rapid onset of inhibition by 10 mu mol/L DCL was found in kinetic studies (n = 10). The inhibition of anti-IgE-induced histamine secretion was synergistically increased by simultaneous preincubation of DCL with the potent histamine H-2-ag onist, FRA-19. Additional data indicate that the inhibition of LHR by DCL might involve biochemical events that occur after cellular Ca++ in flux because LHR induced by N-formyl-methionyl-leucyl-phenylalanine or the phorbol ester, 12-O-tetradecanoyl phorbol-12-acetate, was not sig nificantly affected by DCL.