The anti-anaphylactic/anti-histamine activity of mizolastine (CAS 108612-45-9, SL 85.0324), a novel histamine H1 receptor antagonist devoid of sedative properties, has been evaluated in the rat, mouse and guinea pig. Mizolastine inhibited the passive cutaneous anaphylactic reduction caused by ovalbumin challenge in the rat (ED50 = 0.7 mg/kg i.v., 1.6 mg/kg p.o.) and effectively protected rats from the lethal shock induced by compound 48/80 (ED50 = 0.07 mg/kg p.o.). Mizolastine protected actively sensitized guinea pigs from anaphylactic mortality, bronchospasm and respiratory difficulties (increase in pulmonary resistance) preceding this event and from morphological modifications at doses from 0.05 mg/kg i.v. The pharmacological activity of mizolastine is linked to a selective blockade of histamine H1 receptors as indicated by the ability of this compound to antagonize rat paw edema induced by the subplantar injection of histamine (ED50 = 0.5 mg/kg p.o.) but not that induced by the injection of serotonin or bradykinin. Mizolastine also antagonized the increase in cutaneous capillary permeability caused by the intradermal injection of histamine (-80% at 0.3 mg/kg p.o.) and compound 48/80 (ED50 = 1.1 mg/kg p.o.) but not that induced by serotonin in the rat. In the guinea pig, mizolastine antagonized i.v. histamine-induced bronchoconstriction (ED50 = 0.03 mg/kg p.o.) and histamine-induced vascular permeability and edema in trachea and bronchi (ED50 < or = 0.05 mg/kg i.v.). Moreover, at higher doses, mizolastine antagonized the bronchospasm caused by systemic injection of platelet-activating factor (PAF) and leukotriene D4 (LTD4) (ED50's = 0.30 and 3.0 mg/kg p.o., respectively). However, mizolastine only weakly antagonized bronchospasm induced by aerosolized PAF (-67% at 50 mg/kg p.o.), failed to antagonize (up to 3 mg/kg i.v.) PAF-induced microvascular permeability of the tracheal mucosa in the guinea pig and was a weak inhibitor of PAF-induced platelet aggregation in the rabbit (IC50 = 74 mumol/l). In addition to antagonizing histamine H1 receptors, mizolastine also inhibits the release of histamine during allergic reactions in tissues. Thus, mizolastine antagonizes the antigen-induced in vivo release of histamine from mast cells in bronchoalveolar lavages of actively sensitized guinea pigs (minimal effective dose 0.3 mg/kg p.o.) and the release of histamine from mast cells in the peritoneal fluid of passively sensitized rats (ED50 = 0.9 mg/kg i.v.). In these various models, mizolastine was more potent than loratadine and terfenadine but less potent than ketotifen. The apparent half-life for the pharmacological actions of mizolastine ranged from 6 to 8 h.(ABSTRACT TRUNCATED AT 400 WORDS)