The effects of isofloxythepin, a dibenzo[b,f] thiepin derivative, on the central and peripheral histamine systems were compared with those of chlorpromazine and haloperidol. The three drugs examined all inhibited both the histamine-induced contraction of guinea pig ileum and the specific [3H]mepyramine binding to guinea pig brain membranes in a dose-dependent manner. The effectiveness in inhibiting these reactions was in the order of: chlorpromazine>isofloxythepin> haloperidol. The histamine-induced relaxation of rat uterus, which is mediated by H2-receptors, was not affected by isofloxythepin. The effect of isofloxythepin on the pargyline-induced accumulation of tele-methylhistamine in the mouse brain was indicative of a decrease in histamine turnover, whereas chlorpromazine and haloperidol were devoid of such effects. Isofloxythepin inhibited both the lethal effect of histamine injected i.v. in mice and histamine-induced edema in rat hind paws far more strongly than chlorpromazine or haloperidol did. These results show that isofloxythepin is a neuroleptic with H1-antagonist properties, which are intermediate in potency between those of chlorpromazine and haloperidol, and also it may have an inhibitory action on histamine turnover in the brain. Protection against the lethal effect of histamine and the inhibition of histamine edema by isofloxythepin may largely be due to mechanisms other than the blocking of H1-receptors.
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