interleukin-8 and azelastine

Azelastine (azelastine hydrochloride) was orally administered to 43 patients with recurrent aphthous ulcers (RAU), and its clinical effects and in vitro influence on leukocytes were examined. During at least 6 months after drug treatment, no oral ulcers occurred in 7 patients, and an improvement of the oral condition was exhibited in all except 4 of the remaining patients. The frequency of occurrence of RAU was significantly reduced, from 1.7 +/- 0.9 to 0.9 +/- 0.5 times/month, and ulcer duration and oral irritation were also significantly reduced from 12.5 +/- 2.5 and 7.5 +/- 2.4 days to 9.8 +/- 2.6 and 5.3 +/- 2.4 days, respectively. Neutrophils from patients treated with Azelastine generated a suppressed volume of superoxide (O2-). Suppression of O2- generation and chemiluminescence by in vitro Azelastine was also confirmed to occur in a dose-dependent manner. Furthermore, the production of TNF-alpha and GM-CSF in lymphocytes was suppressed in the presence of Azelastine, and the drug protected sheep red blood cells and epithelial tumor cell lines against hydrogen peroxide impairment and hypotonic shock. These clinical and experimental results lead to the conclusion that improvement of RAU by Azelastine depends on the protection of cell membranes and the suppression of leukocyte-function, including reactive oxygen generation.

Topics: Adolescent; Adult; Aged; Cell Survival; Child; Erythrocytes; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-1; Interleukin-8; Leukocytes; Leukocytes, Mononuclear; Lipoxygenase Inhibitors; Luminescent Measurements; Male; Middle Aged; Neutrophils; Oxides; Phthalazines; Recurrence; Stomatitis, Aphthous; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

For locally acting drugs, an extended residence time in the nasal cavity is desirable and related to a prolonged effect. We sought to develop a model for comparative determination of intranasal pharmacokinetics. We embedded human respiratory tissue into a solid matrix and coated the surface with artificial nasal fluid. Nasal spray suspensions of fluticasone propionate (FP) and budesonide (Bud) as well as a solution of azelastine hydrochloride (AZ) were applied onto the surface and removed after 30 min to simulate mucociliary clearance. As exemplary anti-inflammatory measure, we evaluated the inhibition of IL-8 release from epithelial cells. FP and Bud were initially bound to the same extent to the tissue gel while AZ displayed a more 4-fold higher binding than FP or Bud. After equilibrium with plasma, approximately 5-fold higher tissue concentrations of AZ compared to FP and 77-fold higher levels in relation to Bud were determined. This tissue retention revealed an excellent correlation with the volume of distribution of the respective drugs (r=0.9999, p ≤ 0.05). The inhibitory effect of FP on IL-8 release was approximately 5-fold more pronounced compared to AZ. The present model realistically mirrors conditions in vivo where solubility and tissue absorption of intranasally applied drugs compete with mucociliary clearance mechanisms.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Administration, Inhalation; Administration, Intranasal; Aerosols; Androstadienes; Anti-Allergic Agents; Anti-Inflammatory Agents; Budesonide; Cell Line, Tumor; Delayed-Action Preparations; Epithelial Cells; Fluticasone; Glucocorticoids; Histamine Antagonists; Humans; Interleukin-8; Lung; Lung Neoplasms; Mucociliary Clearance; Nasal Lavage Fluid; Nasal Sprays; Phthalazines; Rhinitis, Allergic, Seasonal

Mast cells are involved in allergic inflammation by secreting histamine, proteases and several cytokines, including interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha) and IL-8. Certain histamine-1 receptor antagonists, such as azelastine present in the ophthalmic solution Optivar, have been reported to inhibit histamine and tryptase secretion, but its effect on inflammatory cytokine release from normal human umbilical cord blood-derived cultured mast cells (hCBMC) are not well known.. We investigated the effect of azelastine on the secretion of IL-6, TNF-alpha and IL-8 from hCBMC, as well as its possible mechanism of action. hCBMC sensitized with IgE were pretreated for 5 min with azelastine at 0.01, 0.1, 1, 3, 6, 12, 24, or 60 microM of Optivar, before stimulation with anti-IgE for 6 h. Optivar vehicle without azelastine was used as control. Cytokines were measured by ELISA, intracellular calcium levels by calcium indicators confocal, and nuclear factor-kappaB (NF-kappaB) by electromobility shift assay.. Stimulation with anti-IgE led to substantial secretion of IL-6, TNF-alpha and IL-8. Preincubation for 5 min resulted in almost maximal inhibition with 6 microM azelastine for TNF-alpha (80%), with 24 microM for IL-6 (83%) and 60 microM for IL-8 (99%); the vehicle solution at the same concentrations as Optivar had no effect. Stimulation with anti-IgE increased intracellular Ca2+ level and induced NF-kappaB expression in hCBMC, which was inhibited by 24 microM azelastine.. Azelastine inhibited hCBMC secretion of IL-6, TNF-alpha and IL-8, possibly by inhibiting intracellular Ca2+ ions and NF-kappaB activation. Azelastine may, therefore, be helpful in treating allergic inflammation.

Topics: Calcium; Cells, Cultured; Histamine H1 Antagonists; Humans; Interleukin-6; Interleukin-8; Mast Cells; NF-kappa B; Phthalazines; Tumor Necrosis Factor-alpha

The mechanism of exercise-induced asthma (EIA) is still controversial, although the role of chemical mediator is strongly suspected. In the present study, 50 asthmatic patients were observed after exercise on bicycle ergometer during dry air breathing, and changes of plasma histamine and neutrophil chemotactic factor (NCF) were measured and effect of anti-allergic drugs was examined. 31 patients developed postexertional bronchoconstriction and their % reduction of FEV1 after exercise correlated significantly with the degree of airway hyperresponsiveness to inhaled methacholine determined by Astograph. Plasma histamine levels were examined in 20 EIA positive cases and 13 EIA negative cases, but no significant changes were observed between pre- and post-histamine levels in either group. On the other hand, NCF was elevated significantly after exercise in both EIA positive and negative cases, but postexertional NCF levels were significantly higher in EIA positive than in EIA negative cases. The relationship between % increase of NCF and the % reduction of FEV1 after exercise was significant (r = 0.472, p less than 0.05). DSCG and Azelastine protected the development of EIA in 14 out on 19 cases and 7 out of 12 cases, respectively. Pretreatment with DSCG significantly reduced the increase of NCF after exercise. These results indicates that one of the chemical mediator, NCF, may play an important role in producing postexertional bronchoconstriction in asthmatic patients.

Topics: Adolescent; Adult; Asthma; Asthma, Exercise-Induced; Chemotactic Factors; Female; Histamine; Histamine H1 Antagonists; Humans; Interleukin-8; Male; Middle Aged; Phthalazines