Azelastine Reduces Mediators of Inflammation in Patients with Nasal Polyps
Department of Medical Informatics, University of Cologne, Germany.Allergy and Asthma Proceedings (Impact Factor: 3.06). 11/1998; 19(6):379-83. DOI: 10.2500/108854198778612663
Nasal polyps affect approximately 4% of the population in the western world. The etiology of this disease is unknown, although inflammatory mechanisms may play an important role. In preceding studies we and others have shown that besides H1-antagonism, azelastine influences the immigration and activation of inflammatory cells. In this open label study in 16 patients with nasal polyps and perennial mite-allergic rhinitis, the effect of azelastine nasal spray twice daily 0.14 mg to each nostril on recurrence of nasal polyposis after endonasal surgery was evaluated. One patient dropped out after 3 months, unwilling to take further medication. Clinical and laboratory data of 15 patients were recorded over 25 weeks in a total of seven visits. Of these one patient needed nasal budesonide during the 4 weeks between visits 3 and 4. All other patients did not take any steroids before inclusion into the trial or during the 6-month observation period. Concentrations of eosinophil cationic protein (ECP) for eosinophils, myeloperoxidase (MPO) for neutrophils and tryptase for mast cells were determined in nasal secretions before and after eight and 25 weeks of treatment using double antibody radioimmunoassays, because these have been demonstrated to be good inflammatory markers in nasal diseases. Mean concentrations of MPO decreased from 2724 ng/mL to 1610 ng/mL (p = 0.0015) over the entire treatment period. ECP decreased from 458 ng/mL to 264 ng/mL (p = 0.0342). Tryptase decreased from 37.9 ng/mL to 22.4 ng/mL (p = 0.0574). These data were consistent with a significant decrease in clinical symptoms. Thus, azelastine seems to have an inhibitory effect on eosinophil and neutrophil activation in patients with nasal polyps and mite allergy.
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ABSTRACT: The H(1) antagonist azelastine is used in nasal sprays for the treatment of allergic rhinitis, but its therapeutic efficacy in vasomotor rhinitis is unknown. We performed a multicenter randomized double-blind placebo-controlled study of the efficacy and tolerance of azelastine nasal spray in 89 adult patients with vasomotor rhinitis (confirmed by negative Phadiatop). Following a washout period, patients were treated for 15 days with one puff three times daily per nostril of azelastine (n = 44) or placebo (n = 45) nasal spray. Efficacy was evaluated by the reduction in symptomatology and by rhinoscopy. Intent-to-treat analysis revealed better results in the azelastine group for all assessed symptoms; the significance level was reached for nasal obstruction on day 15 (p = 0.042). Using per protocol analysis (in 85 patients complying with the protocol), the significance level was reached for nasal obstruction on day 15 (p = 0.017) and for the percentage of success in rhinorrhea (p = 0.023). In the azelastine group, rhinoscopy examination showed a significantly higher reduction in the inflammatory level and edema of the nasal mucosa (p = 0.03 and 0.02 for VAS on day 15 respectively, per protocol analysis). General efficacy assessment by the physician and the patient was in favor of azelastine (with significance levels <0.01). No drowsiness or serious adverse event was reported, and the frequency of mouth dryness and headaches was similar in the two treatment groups. The present study demonstrates the efficacy of azelastine nasal spray in the treatment of vasomotor rhinitis. The best achieved results were a decrease in nasal obstruction and mucosal edema. Further studies are required to investigate if this therapeutic benefit results from H(1) antagonism or from another, not well-characterized pharmacological action of azelastine.
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ABSTRACT: Mast cells are involved in early- and late-phase reactions by releasing vasoactive molecules, proteases, and cytokines. Certain histamine-1 receptor antagonists and other antiallergic drugs seem to inhibit the release of mediators from rat and human mast cells. Azelastine and olopatadine are antiallergic agents present in the ophthalmic solutions azelastine hydrochloride (Optivar, Asta Medica/Muro Pharmaceuticals, Tewksbury, MA), and olopatadine hydrochloride (Patanol, Alcon Laboratories, Fort Worth, TX), respectively. We investigated the effect of these drugs on interleukin-6 (IL-6), tryptase, and histamine release from cultured human mast cells (CHMCs). CHMCs were grown from human umbilical cord blood-derived CD34+ cells in the presence of stem cell factor and IL-6 for 14 to 16 weeks. Sensitized CHMCs were pretreated with various concentrations of azelastine or olopatadine for 5 minutes. CHMCs were then challenged with anti-immunoglobulin E, and the released mediators were quantitated. The greatest inhibition of mediator release was seen with 24 microM azelastine; this level of inhibition was matched with the use of 133 microM olopatadine. At this concentration, these drugs inhibited IL-6 release by 83% and 74%, tryptase release by 55% and 79%, and histamine release by 41% and 45%, respectively. Activated CHMCs were characterized by numerous filopodia that were inhibited by both drugs as shown by electron microscopy. These results indicate that azelastine and olopatadine can inhibit CHMCs activation and release of IL-6, tryptase, and histamine. On an equimolar basis, azelastine was a more potent inhibitor than olopatadine.
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ABSTRACT: Mast cells play an important role in allergic inflammation by releasing vasoactive molecules, proteases and cytokines. Corticotropin-releasing hormone (CRH) and its structural analogue urocortin (Ucn) were shown to trigger skin mast cell activation and vascular permeability. We investigated the effect of acute stress on rat skin vascular permeability and CRH secretion, as well as the effect of intradermal CRH, and that of two histamine-1 receptor antagonists, azelastine and olopatadine, on vascular permeability. Rats were stressed by restraint and vascular permeability was assessed by extravasation of (99)Tc-gluceptate, while mast cell activation was determined by skin rat mast cell protease-1 (RMCP-1) content. Skin CRH content was evaluated by ELISA. The effect of intradermal injection of CRH and Ucn, as well as that of two histamine-1 receptor antagonists, azelastine and olopatadine, was assessed by Evan's blue extravasation. Purified rat peritoneal mast cells (RPMCs) were also pretreated with azelastine (24 microM) or olopatadine (133 microM) for 5 min before challenge with compound 48/80 (0.5 microg/ml) for 30 min. Histamine secretion was measured fluorometrically. Intracellular Ca(2+) ions were evaluated in RPMCs loaded with calcium crimson and stimulated with compound 48/80. Acute stress increased skin vascular permeability and CRH content, while it decreased RMCP-1. Intradermal injection of CRH or Ucn induced substantial Evan's blue extravasation that was inhibited by pretreatment with azelastine (24 microM) and olopatadine (133 microM). Both antihistamines also inhibited histamine release and intracellular increase of Ca(2+) ions from RPMCs stimulated by compound 48/80. These results indicate that acute stress increases skin CRH that can trigger mast cell-dependent vascular permeability, effects inhibited by certain histamine-1 receptor antagonists, possibly acting to reduce intracellular Ca(2+) ion levels.
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