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Guinea pigs were sensitized and boostered with i.p. injections of ovalbumin (OA) 10 micrograms + Al(OH)3 100 mg. Thirteen days after the last injection animals (800-1100 g) were placed in bias flow ventilated whole body plethysmographs and allowed to stabilize for 2 h. Lung function was recorded for up to 2 h before and 5 h after aeroallergen challenge (OA 20 mg/ml, 60 s, 20 psi) by a noninvasive pulmonary analyzer for unrestrained rodents. Aeroallergen challenge produced immediate dyspnea and gasping (peaking between 8 and 17 min). Gasping was associated with an increase in amplitude in the box pressure fluctuations (93%), and in the slope of the fluctuations (391%). Respiratory rate increased (103 to 175 breaths/min, 78%), the product of breathing rate times box pressure amplitude increased (161 to 432, 180%). Relaxation time (the time it takes the box pressure signal to drop from its peak to 1/3 of its peak value) declined (0.16 to 0.05 s, 72%). All of these lung dysfunction changes were highly significant (p < 0.001). Lung dysfunction persisted for 60 to 120 min after challenge. One of 8 animals tested died within 10 min. None of the animals exhibited late asthmatic responses during the 5 h post-challenge period. Based on these data we conclude that this technique allows quantitative analysis of dyspnea, gasping, and an abnormal pattern (waveform) of breathing.(ABSTRACT TRUNCATED AT 250 WORDS)

Azelastine, an orally effective antiasthmatic agent, has been reported to inhibit antihistamine-resistant, leukotriene-mediated allergic bronchoconstriction in guinea pigs. This suggests that azelastine might act through inhibition of leukotriene (LT) C₄/D₄ synthesis. We have examined the effect of azelastine on allergic and nonallergic histamine secretion and LTC₄ formation. Azelastine and the known 5-lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861, exerted concentration-dependent inhibition of allergic LTC₄ formation in chopped lung tissue from actively sensitized guinea pigs and calcium ionophore A23187-stimulated LTC₄ synthesis in mixed peritoneal cells from rats. Azelastine also produced concentration-dependent inhibition of allergic and nonallergic histamine secretion from rat peritoneal mast cells. The ability of azelastine to inhibit allergic and nonallergic histamine secretion and LTC₄ generation may contribute to its mode of action and its therapeutic efficacy.

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Azelastine hydrochloride, chemically known as 1(2H)-phthalazinone, 4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepine-4-yl)-, monohydrochloride, is a novel, orally effective, long-acting, antiallergic/antiasthmatic agent. The ability of azelastine and selected antiallergic drugs to inhibit SRS-A (leukotriene)-mediated acute lung anaphylaxis in guinea pigs (Konzett-Rossler method) was investigated. Azelastine and ketotifen were administered p.o. 2 and 24 h before antigen challenge; disodium cromoglycate (DSCG) was administered i.v. immediately before antigen challenge. The oral dose of azelastine required to inhibit leukotriene-mediated allergic bronchospasm by 50% (ID50: mg/kg) was 0.063 at 2 h and 0.120 at 24 h. Ketotifen at a dose of 0.05 to 10 mg/kg at 2 and 24 h, p.o., as well as DSCG at a dosage of 0.3 to 10 mg/kg at 0 min, i.v., produced weak, inconsistent and nondose-related antianaphylactic effects. Azelastine is an orally effective and long-acting inhibitor of in vivo synthesis and/or release of leukotrienes.