ANTIANAPHYLACTIC ACTIVITY OF THE NOVEL SELECTIVE HISTAMINE H-1 RECEPTOR ANTAGONIST MIZOLASTINE IN THE RODENT

The anti-anaphylactic/anti-histamine activity of mizolastine (CAS 1086 12-45-9, SL 85.0324), a novel histamine H-1 receptor antagonist devoid of sedative properties, has been evaluated in the rat, mouse and guin ea pig. Mizolastine inhibited the passive cutaneous anaphylactic react ion caused by ovalbumin challenge in the rat (ED(50) = 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 (ED(50) = 0.07 mg/kg p.o.). Mizolastine prot ected actively sensitized guinea pigs from anaphylactic mortality, bro nchospasm and respiratory difficulties (increase in pulmonary resistan ce) preceding this event and from morphological modifications at doses from 0.05 mg/kg i.v. The pharmacological activity of mizolastine is l inked to a selective blockade of histamine H-1 receptors as indicated by the ability of this compound to antagonize rat paw edema induced by the subplantar injection of histamine (ED(50) = 0.5 mg/kg p.o.) but n ot that induced by the injection of serotonin or bradykinin. Mizolasti ne also antagonized the increase in cutaneous capillary permeability c aused by the intradermal injection of histamine (-80% at 0.3 mg/kg p.o .) and compound 48/80 (ED(50) = 1.1 mg/kg p.o.) but not that induced b y serotonin in the rat. In the guinea pig, mizolastine antagonized i.v . histamine-induced bronchoconstriction (ED(50) = 0.03 mg/kg p.o.) and histamine-induced vascular permeability and edema in trachea and bron chi (ED(50) less than or equal to 0.05 mg/kg i.v.). Moreover, at highe r doses, mizolastine antagonized the bronchospasm caused by systemic i njection of platelet-activating factor (PAF) and leukotriene D-4 (LTD( 4)) (ED(50)'s = 0.30 and 3.0 mg/ kg p.o., respectively). However, mizo lastine only weakly antagonized bronchospasm induced by aerosolized PA F (-67% at 50 mg/kg p.o.), failed to antagonize (up to 3 mg/kg i.v.) P AF-induced microvascular permeability of the tracheal mucosa in the gu inea pig and was a weak inhibitor of PAF-induced platelet aggregation in the rabbit (IC50 = 74 mu mol/l). In addition to antagonizing histam ine H-1 receptors, mizolastine also inhibits the release of histamine during allergic reactions in tissues. Thus, mizolastine antagonizes th e antigen-induced in vivo release of histamine from mast cells in bron choalveolar lavages of actively sensitized guinea pigs (minimal effect ive dose 0.3 mg/kg p.o.) and the release of histamine from mast cells in the peritoneal fluid of passively sensitized rats (ED(50) = 0.9 mg/ kg iv.). In these various models, mizolastine was more potent than lor atadine and terfenadine but less potent than ketotifen. The apparent h alf-life for the pharmacological actions of mizolastine ranged from 6 to 8 h. These data altogether indicate that mizolastine is highly effe ctive in animal models for allergy and asthma. The mechanism of the an ti-anaphylactic effect of this compound is likely to involve direct an tagonism of the actions of allergic mediators at their target sites as well as inhibition of histamine release from mast cells.