Effects of drugs combining H1 and H2 receptor antagonist activity on histamine release and life threatening anaphylactoid reactions in pigs

Abstract

Two recently synthetized drugs combining H1- and H2-receptor antagonist activity in a single molecule (alitidine, clophetidine) were compaired for their potency in preventing histamine release and lifethreatening anaphylactoid reactionin vivo with the usually tested H1/H2-blocker combination dimetindene/cimetidine. Saline premedication in a fourth group served as control. Anaesthetized and ventilated pigs were administered H1/H2-blockers or placebo and 500 ml of blood were removed. Subsequently, 500 ml saline solution containing 1 mg/kg compound 48/80 for initiating histamine release were rapidly reinfused (n=15 pigs per group). The system proved reliable in creating hypotension and histamine release in the placebo group. The extent of histamine release did not differ between the placebo, alitidine and dimetindene/cimetidine groups. However, clophetidine was shown to be effective in preventing increases in plasma histamine after compound 48/80. Tachycardia was almost completely prevented by dimetindene/cimetidine, was diminished by clophetidine, but was not affected by alitidine. Hypotension following 48/80 was best reversed by clophetidine. This investigation suggests that clophetidine is a most promising drug in preventing histamine release and its circulatory effects in a pig anaphylactoid shock model. It requires, however, further quantitative confirmation in experiments with a two-group design only, since the analysis of variance is less suitable for the extreme variation of the plasma-histamine values after administration of compound 48/80.