The ability of azelastine to inhibit allergic histamine release from rabbit mixed leukocytes was studied and compared with selected antiallergic drugs. Azelastine, ketotifen, diphenhydramine, theophylline and disodium cromoglycate (DSCG) produced concentration-dependent inhibition of allergic histamine release from rabbit basophils. The concentrations inhibiting histamine release by 50% (IC50; microM) were as follows: azelastine = 4.5; ketotifen = 9.5; diphenhydramine = 18.9; theophylline = 56.9; DSCG = greater than 1,000. DSCG was added to the cells immediately prior to antigen challenge. All other drugs were preincubated for a period of 10 min prior to antigen challenge. At the IC50 level, azelastine is about 2, 4, 13 and greater than 200 times as effective as ketotifen, diphenhydramine, theophylline and DSCG, respectively. The IC50 of azelastine following 0, 10 and 30 min preincubation were 2.4, 1.9 and 3.5 microM, respectively. These observations showed: (1) azelastine is capable of acting rapidly on basophils and of inhibiting allergic histamine secretion, and (2) the prolongation of the preincubation time of azelastine up to 30 min with rabbit leukocytes did not exhibit any sign of tachyphylaxis (loss of activity). In conclusion, azelastine is a potent inhibitor of allergic histamine secretion from the leukocytes of ragweed-sensitized rabbits.