Anti-inflammatory properties of mizolastine after oral administration on arachidonic acid-induced cutaneous reaction in the rat.

The anti-inflammatory effect of mizolastine (CAS 108612-45-9, SL85.0324-00), a new non-sedative histamine H1-receptor antagonist, was assessed in comparison to loratadine, terfenadine and pyrilamine. Intraplantar injection of arachidonic acid (AA) into the rat paw was followed by a rapid and sustained (> or = 4h) inflammatory oedema. 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 action of mizolastine. Although with higher maximal effect, a similar time course of response was observed with dexamethasone at 0.1 mg/kg p.o. In contrast, at anti-histamine, doses, the histamine H1-receptor antagonists 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 inflammatory action of AA. Moreover, under conditions of H1-receptors blockade (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 inflammation was unchanged. This suggests that the anti-inflammatory effect of mizolastine was unrelated to its histamine H1-receptor antagonist properties. It is proposed that a primary effect on the lipoxygenase 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 affect the inflammatory response to carrageenin which is mediated by the cyclooxygenase pathway. Together, these data indicate that mizolastine is orally effective in this animal model for cutaneous inflammation. Combined with its blockade of histamine H1-receptors, this property may contribute to its possible use in allergic inflammation or other inflammatory states.