ANTIINFLAMMATORY PROPERTIES OF MIZOLASTINE AFTER ORAL-ADMINISTRATION ON ARACHIDONIC ACID-INDUCED CUTANEOUS REACTION IN THE RAT

The anti-inflammatory effect of mizolastine (GAS 108612-45-9, SL85.032 4-00), a new nonsedative histamine H-1-receptor antagonist, was assess ed in comparison to loratadine, terfenadine and pyrilamine. Intraplant ar injection of arachidonic acid (AA) into the rat paw was followed by a rapid and sustained (greater than or equal to 4 h) inflammatory oed ema. Mizolastine (0.1 to 10 mg/kg p.o.) inhibited in a dose-dependent manner the time course of the AA-induced paw inflammation as from the dose of 0.1 mg/kg p.o. This effect was maintained for at least the 4 h of observation (-44% at 0.3 mg/kg p.o.) suggesting a long lasting act ion of mizolastine. Although with higher maximal effect, a similar tim e course of response was observed with dexamethasone at 0.1 mg/kg p.o. In contrast, at anti-histamine doses, the histamine H-1-receptor anta gonists terfenadine (1 to 30 mg/kg p.o.), loratadine (10 mg/kg p.o.), and pyrilamine (10 mg/kg p.o.) failed to inhibit significantly the inf lammatory action of AA. Moreover, under conditions of H-1-receptors bl ockade (e.g. when co-administered with pyrilamine or loratadine (10 mg /kg p.o.), the inhibition by mizolastine (0.3 mg/kg) of AA-induced inf lammation was unchanged. This suggests that the anti-inflammatory effe ct of mizolastine was unrelated to its histamine H-1-receptor antagoni st properties. It is proposed that a primary effect on the lipoxygenas e pathway may contribute to this action of mizolastine. This is based on the observations that mizolastine inhibits 5-lipoxygenase activity in vitro. Furthermore, a high dose of mizolastine (50 mg/kg) did not a ffect the inflammatory response to carrageenin which is mediated by th e cyclooxygenase pathway. Together, these data indicate that mizolasti ne is orally effective in this animal model for cutaneous inflammation . Combined with its blockade of histamine H-1-receptors, this property may contribute to its possible use in allergic inflammation or other inflammatory states.