title: The effect of azelastine on neutrophil and eosinophil generation of superoxide.
abstract: Azelastine is a new investigational drug used to treat rhinitis and asthma. In addition to described actions that include inhibition of immunologic release of histamine from mast cells and basophils, blockade of smooth muscle contraction to various spasmogenic mediators, and relaxation of airway smooth muscle, azelastine has been ascribed anti-inflammatory properties. To understand further the mechanisms by which azelastine may regulate inflammation, its effect on neutrophil and eosinophil superoxide (O2-) generation was evaluated. Purified suspension of neutrophils (greater than 95% pure) and eosinophils (greater than 85% pure) were isolated from human peripheral blood samples by continuous density gradients of Percoll. The isolated granulocyte suspensions (1 x 10(5) cells) were added to 96-well microtiter plates in the presence of cytochrome c, activated by either N-formyl-methionyl-leucyl-phenylalanine, phorbol myristate acetate, calcium ionophore A23187, or opsonized zymosan particles; O2- generation was measured by the reduction of cytochrome c. We found that azelastine significantly inhibited both neutrophil and eosinophil generation of O2- in a dose-dependent fashion (10(-7) to 10(-5) mol/L) with each activator except zymosan. Furthermore, the degree to which azelastine suppressed O2- was similar in neutrophils and eosinophils. Thus, azelastine, in concentrations achieved therapeutically, inhibited granulocyte generation of O2-. This anti-inflammatory effect may also be beneficial in the treatment of asthma.
authors.affiliation: University of Wisconsin Medical School, Madison 53792.
authors.forename: W
authors.initials: W
authors.lastname: Busse
authors.forename: B
authors.initials: B
authors.lastname: Randlev
authors.forename: J
authors.initials: J
authors.lastname: Sedgwick
mesh_terms: D000328:Adult; D000001:Calcimycin; D004804:Eosinophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005609:Free Radicals; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010793:Phthalazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate; D015054:Zymosan
chemical_list: D005609:Free Radicals; D006634:Histamine H1 Antagonists; D010793:Phthalazines; D011724:Pyridazines; D013481:Superoxides; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015054:Zymosan; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; C020976:azelastine