ovalbumin and azelastine

Glucocorticoids are among the most effective drugs to treat asthma. However, the severe adverse effects associated generate the need for its therapeutic optimization. Conversely, though histamine is undoubtedly related to asthma development, there is a lack of efficacy of antihistamines in controlling its symptoms, which prevents their clinical application. We have reported that antihistamines potentiate glucocorticoids' responses in vitro and recent observations have indicated that the coadministration of an antihistamine and a synthetic glucocorticoid has synergistic effects on a murine model of allergic rhinitis. Here, the aim of this work is to establish if this therapeutic combination could be beneficial in a murine model of asthma. We used an allergen-induced model of asthma (employing ovalbumin) to evaluate the effects of the synthetic glucocorticoid dexamethasone combined with the antihistamine azelastine. Our results indicate that the cotreatment with azelastine and a suboptimal dose of dexamethasone can improve allergic lung inflammation as shown by a decrease in eosinophils in bronchoalveolar lavage, fewer peribronchial and perivascular infiltrates, and mucin-producing cells. In addition, serum levels of allergen-specific IgE and IgG1 were also reduced, as well as the expression of lung inflammatory-related genes IL-4, IL-5, Muc5AC, and Arginase I. The potentiation of dexamethasone effects by azelastine could allow to reduce the effective glucocorticoid dose needed to achieve a therapeutic effect. These findings provide first new insights into the potential benefits of glucocorticoids and antihistamines combination for the treatment of asthma and grants further research to evaluate this approach in other related inflammatory conditions.

Topics: Administration, Intranasal; Animals; Anti-Asthmatic Agents; Asthma; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Glucocorticoids; HEK293 Cells; Histamine H1 Antagonists, Non-Sedating; Humans; Lung; Mice; Ovalbumin; Phthalazines; Receptors, Glucocorticoid; Transcriptional Activation

This study aimed to explore the effects of curcumin on experimental allergic rhinitis in rats.. Twenty-eight male Wistar albino rats were randomly divided into four groups: a control group; a group in which allergic rhinitis was induced and no treatment given; a group in which allergic rhinitis was induced followed by treatment with azelastine hydrochloride on days 21-28; and a group in which allergic rhinitis was induced followed by treatment with curcumin on days 21-28. Allergy symptoms and histopathological features of the nasal mucosa were examined.. The sneezing and nasal congestion scores were higher in the azelastine and curcumin treatment groups than in the control group. Histopathological examination showed focal goblet cell metaplasia on the epithelial surface in the azelastine group. In the curcumin group, there was a decrease in goblet cell metaplasia in the epithelium, decreased inflammatory cell infiltration and vascular proliferation in the lamina propria.. Curcumin is an effective treatment for experimentally induced allergic rhinitis in rats.

Topics: Administration, Intranasal; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents, Non-Steroidal; Chondrocytes; Cilia; Curcumin; Eosinophils; Goblet Cells; Hyperemia; Hypertrophy; Male; Mast Cells; Metaplasia; Nasal Mucosa; Ovalbumin; Phthalazines; Random Allocation; Rats; Rats, Wistar; Rhinitis, Allergic; Sneezing

Urocortin (UCN), a newly identified, 40-amino-acid, corticotropin-releasing hormone (CRH) structurally related peptide, has been demonstrated to be expressed in the central nervous system and many peripheral tissues of rats and man. This study aimed to investigate the expression profile of UCN in rat lung and the effect of UCN on lung vascular permeability. The expression of UCN mRNA was detected by reverse transcriptase PCR (RT-PCR). UCN peptide was measured by immunohistochemistry and Western blot analysis. We found that both UCN mRNA and peptide were obviously expressed in rat lung. Immunohistochemistry results showed that UCN peptide is mainly expressed in bronchial epithelium mucosa and alveolar epithelium. We also found that rats receiving inhalation aerosol of UCN had a significant elevation of lung vascular permeability compared with rats receiving vehicle and ovalbumin (OVA) by the Evans blue (EB) technique. UCN aerosol inhalation resulted in obvious pulmonary congestion and edema observed under light microscope by hematoxylin and eosin (HE) staining. The nonselective peptide CRH receptor antagonist astressin markedly reduced lung vascular permeability triggered by UCN. Enhanced pulmonary vascular permeability induced by UCN was markedly inhibited by pretreatment with the mast-cell stabilizer cromolyn and histamine-1 (H1) receptor antagonist azelastine respectively, but not by the leukotriene receptor antagonist montelukast. In summary, in the present study, we demonstrated for the first time that UCN is expressed in rat lung and contributes to an increase in lung vascular permeability through activation of CRH receptors. Mast cells and histamine may be involved in this effect of UCN. Peripherally produced UCN in lung may act as an autocrine and paracrine proinflammatory factor.

Topics: Acetates; Administration, Inhalation; Aerosols; Animals; Blotting, Western; Bronchi; Capillary Permeability; Corticotropin-Releasing Hormone; Cromolyn Sodium; Cyclopropanes; Epithelium; Histamine H1 Antagonists; Immunohistochemistry; Leukotriene Antagonists; Lung; Male; Mast Cells; Ovalbumin; Peptide Fragments; Phthalazines; Pulmonary Alveoli; Quinolines; Rats; Rats, Sprague-Dawley; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfides; Urocortins

To examine the effects of a specific cysteinyl leukotriene (cysLT) antagonist, pranlukast, on allergic rhinitis, antigen-induced rhinitis in guinea pigs was modified by pretreatment with an cyclooxygenase inhibitor (indomethacin) followed by an H1-blocker (pyrilamine). Intranasal ovalbumin (OVA) administration in actively sensitized guinea pigs resulted in concentration-dependent increases in nasal permeability and nasal airway resistance (NAR). Although pyrilamine (1 mg/kg, i.v.) abolished these antigen-induced changes, pretreatment with indomethacin (5 mg/kg, i.v.) followed by pyrilamine enhanced these responses to a degree similar to that observed with OVA challenge alone. Analyses of nasal perfusate in indomethacin/pyrilamine-pretreated animals showed that cysLTs increased by 270.8%, whereas thromboxane B2 decreased by 88.3% as compared with those on challenged with OVA alone. Oral administration of pranlukast (1-10 mg/kg) dose-dependently prevented increases in nasal permeability and NAR of indomethacin/pyrilamine-pretreated animals. However, an anti-allergic agent, azelastine, did not affect these responses. These results indicate that pranlukast suppresses antigen-induced cysLT-mediated responses of allergic rhinitis in actively sensitized guinea pigs. A cysLT antagonist, pranlukast, may thus prevent cysLT-mediated symptoms of allergic rhinitis.

Topics: Airway Resistance; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Chromones; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Guinea Pigs; Histamine H1 Antagonists; Indomethacin; Leukotriene Antagonists; Nasal Mucosa; Ovalbumin; Phthalazines; Pyrilamine; Rhinitis, Allergic, Perennial; SRS-A; Thromboxane B2

The aims of these studies were to examine the effects of FCC5 (2-carboxamidino-1,2,3,4,10,14b-hexahydrodibenzo (c,f) pyrazino (1,2,-a) azepine HCl), an analogue of mianserin, on immediate type hypersensitivity reactions in-vitro. The actions of FCC5 were examined on the Schultz-Dale reaction of guinea-pig ileum and on histamine and leukotriene release from human- and guinea-pig-sensitized lung fragments. FCC5 (applied topically) was assessed for anti-inflammatory activity in-vivo against phorbol-12-myristate-13-acetate (PMA)-induced oedema in the mouse ear. FCC5 (IC50 = 0.17 microM) was a potent inhibitor of the Schultz-Dale reaction in-vitro, as assessed by a concentration-dependent attenuation of egg albumin-induced contractions of sensitized guinea-pig isolated ileum. Using human and guinea-pig isolated sensitized lung fragments, FCC5 (1-100 microM) attenuated antigen-induced release of sulphidopeptidoleukotrienes and histamine. FCC5 (50 micrograms topically) resembled mianserin and indomethacin in attenuating PMA-induced mouse ear inflammation. These properties together with previously published evidence of long lasting antihistamine properties in-vivo, suggest that FCC5 has therapeutic potential as an anti-allergic agent, especially in pathological conditions where an inflammatory component is present.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Drug Hypersensitivity; Drug Interactions; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Humans; Ileum; Injections, Intraperitoneal; Leukotrienes; Lung; Male; Mianserin; Mice; Muscle Contraction; Muscle, Smooth; Ovalbumin; Phthalazines; Serotonin Antagonists; Tetradecanoylphorbol Acetate

Azelastine prevents down-regulation of beta 2-receptors and adenylate cyclase and upregulation of alpha 1-adrenoceptors induced by repeated allergen challenge in the guinea pig lung. In the present study the protective effects of azelastine and salbutamol and a combination of both drugs was investigated using aeroallergen-induced acute allergic bronchoconstrictor responses in conscious, actively sensitized guinea pig. The drugs were given orally 1 h prior to challenge. The oral PD50 was 230 micrograms/kg for azelastine and 1200 micrograms/kg for salbutamol. Both drugs showed a synergistic protective effect with a PD50 of 60 micrograms/kg of azelastine plus 120 micrograms/kg of salbutamol indicating a reduction in the PD50 of azelastine by a factor of 4 and of salbutamol by a factor of 10. These findings may explain the reduction in the use of salbutamol and theophylline with azelastine by chronic asthmatics.

Topics: Administration, Oral; Albuterol; Animals; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Guinea Pigs; Male; Ovalbumin; Phthalazines

A simple, noninvasive, bias-flow ventilated wholebody plethysmographic technique and noninvasive pulmonary analyzer (Buxco dyspnea monitor) were used to quantitate allergic dyspnea in chronically sensitized freely moving guinea pigs. In this study, the effect of azelastine on aeroallergen-induced dyspnea in allergic guinea pigs was investigated. Aeroallergen challenge produced severe dyspnea which was characterized by a 390% increase in the amplitude of pseudo flow signal, a 93% increase in box pressure (delta P) and a 68% decline in relaxation time; these changes signify a tremendous increase in the effort of breathing. The oral administration of azelastine (1 mg/kg) two hours before aeroallergen provocation significantly inhibited allergic dyspnea in this acute allergic asthma model. This technique permits quantitative measurement of the severity of the airway allergic responses in freely moving guinea pigs.

Topics: Aerosols; Allergens; Animals; Asthma; Bronchodilator Agents; Dyspnea; Guinea Pigs; Male; Ovalbumin; Phthalazines; Plethysmography

1. In guinea-pigs previously sensitized with ovalbumin, the intra-plantar administration of the antigen induced dose-dependent and sustained oedema. An intense infiltrate of neutrophils and eosinophils was observed at the peak of the oedema (4 h). 2. Oedema induced by ovalbumin at the doses of 50 or 200 micrograms/paw was not inhibited by antihistamines (meclizine and cetirizine), a PAF antagonist (BN 50730), a cyclo-oxygenase inhibitor (indomethacin), a lipoxygenase inhibitor (MK-886), a dual type lipo- and cyclo-oxygenase inhibitor (NDGA), a bradykinin antagonist (Hoe 140) or the combination of cetirizine, MK-886, indomethacin and BN 50730. These drugs did inhibit paw oedema induced by their specific agonists or by carrageenin. These results suggest that histamine, PAF, prostaglandins, leukotrienes or bradykinin are not important in the development of immune paw oedema in guinea-pigs. 3. Dexamethasone (10 mg kg-1) inhibited oedema induced by ovalbumin (50 or 200 micrograms/paw, P < 0.05). This effect apparently does not result from inhibition of arachidonate metabolism, since indomethacin, MK-886 and NDGA were without effect. 4. Oedema induced by ovalbumin (50 or 200 micrograms/paw) was also inhibited by azelastine. This effect was not due to the anti-histaminic property of azelastine since two other potent-antihistamines, meclizine and cetirizine, were ineffective. 5. Intravenous injection of lipopolysaccharide (LPS) dose-dependently inhibited the oedema induced by ovalbumin (200 micrograms/paw). This effect could not be attributed to hypotension or leucopenia since the maximal dose applied (81 micrograms kg-1) did not induce significant changes in the blood pressure or in the white blood cell levels of the animals. It is suggested that the effect of LPS is mediated by the endogenous release of cytokines, including tumour necrosis factor (TNF alpha). Murine TNF alpha dose dependently(9-81 microg kg-1) inhibited the paw oedema induced by ovalbumin.7. The anti-oedematogenic effects of LPS and/or TNF alpha are possibly associated with their capacity to inhibit leucocyte emigration. Accordingly, guinea-pigs rendered leucopenic with vinblastine exhibited less intense oedema after ovalbumin. Vinblastine did not affect oedema induced by PAF or bradykinin,indicating that vascular responsiveness was not involved.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Dexamethasone; Edema; Enzyme-Linked Immunosorbent Assay; Foot; Guinea Pigs; Hypersensitivity; Immunoglobulin G; Leukocyte Count; Leukocytes; Leukopenia; Lipopolysaccharides; Male; Mice; Ovalbumin; Phthalazines; Platelet Aggregation Inhibitors; Tumor Necrosis Factor-alpha; Vinblastine

To define the role of platelet activating factor (PAF) in allergic rhinitis, we examined the effects of anti-PAF agents (WEB2086, SM10661) on the changes of nasal airway resistance (NAR) and nasal symptoms after topical antigen challenge in actively sensitized guinea pigs and compared these with the changes brought by anti-leukotriene (LT) agent (FPL 55712), 5-lipoxygenase inhibitor (E6080), anti-allergic agent (azelastine), and anti-histamine agent (mepyramine maleate). We noted biphasic increase in NAR after antigen challenge; the first peak, 146.3 +/- 4.3% at 10 min and the second peak, 163.3 +/- 7.8% at 240 min after antigen challenge. The first peak response of NAR was not affected by anti-PAF agents, anti-LT agent, 5-lipoxygenase inhibitor, or azelastine; it was slightly but significantly inhibited by anti-histamine. The second NAR response was significantly inhibited by anti-PAF agents, anti-LT agent, 5-lipoxygenase inhibitor, and azelastine, but was not affected by anti-histamine. The nasal symptoms which occurred within 30 min after antigen challenge were significantly inhibited by WEB2086, E6080, azelastine, and mepyramine, but were not affected by SM10661. Our results suggest that PAF activities and LTs may play an important role in the later phase increase of NAR after topical antigen challenge.

Topics: Airway Resistance; Animals; Azepines; Chromones; Guinea Pigs; Histamine H1 Antagonists; Immunization; Lipoxygenase Inhibitors; Male; Ovalbumin; Phthalazines; Platelet Activating Factor; Pyrilamine; Rhinitis, Allergic, Perennial; Sneezing; SRS-A; Thiazoles; Thiazolidines; Triazoles

Peptide leukotrienes have been suggested to play an important role in bronchial asthma. As antigen-induced bronchoconstrictions, airway hyperreactivity, and pulmonary eosinophil accumulation are characteristics of the pathology of asthma, we investigated the effect of a peptide leukotriene receptor antagonist, ONO-1078, on these responses using guinea-pig models of asthma. Oral administration of ONO-1078 (3 mg/kg) significantly inhibited slow-reacting substance of anaphylaxis-mediated bronchoconstriction induced by i.v. administered ovalbumin. ONO-1078 (30-100 mg/kg), when administered orally both 1 h before and 4 h after ovalbumin challenge, significantly reduced immediate- and late-phase asthmatic responses, with peak responses occurring immediately and 5-11 h after challenge with inhaled ovalbumin. Oral administration of ONO-1078 significantly reduced the airway hyperreactivity (10-30 mg/kg) and the pulmonary eosinophil accumulation (30-100 mg/kg) observed 4 and 24 h after ovalbumin challenge, respectively. These results suggest that ONO-1078 may be of therapeutic use for bronchial asthma.

Topics: Acetylcholine; Acute-Phase Reaction; Animals; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Bronchodilator Agents; Chromones; Disease Models, Animal; Guinea Pigs; Hypersensitivity; Immunization; Male; Ovalbumin; Phthalazines; Pulmonary Eosinophilia; Pyrilamine; SRS-A

The inhibition of the haematological alterations and prevention of death due to systemic anaphylaxis after antigen challenge were investigated in rats after various drug treatments. The i.v. injection of ovalbumin (250 micrograms/kg) into actively sensitized rats induced marked thrombocytopenia and haemoconcentration within 5 min and significant leukocytosis within 30 min, lasting for 2 h after the challenge. Pretreatment with meclizine or terfenadine (15-30 mg/kg i.p.) inhibited antigen-induced haemoconcentration, whereas WEB 2086 (2-10 mg/kg i.p.) and PCA 4248 (5-10 mg/kg p.o.), two platelet-activating factor (PAF) antagonists, interfered with thrombocytopenia only. Azelastine (1-20 mg/kg p.o.) dose dependently inhibited antigen-induced haemoconcentration and thrombocytopenia but failed to block leukocytosis. Azelastine also inhibited the thrombocytopenia observed after the i.v. administration of PAF (4 micrograms/kg). Administration of ovalbumin at a dose of 1.5 mg/kg resulted in a lethal anaphylactic reaction in about 85% of the rats. Pretreatment with WEB 2086 (10 mg/kg i.p.), meclizine (30 mg/kg i.p.) or both increased the survival rate from 15 to 57, 68 and 87%, respectively. Azelastine alone (20 mg/kg p.o.) completely blocked the lethal reaction. It was concluded that the ability of azelastine to antagonize histamine and PAF is important for its effectiveness against anaphylactic shock.

Topics: Anaphylaxis; Animals; Azepines; Dihydropyridines; Dose-Response Relationship, Drug; Hematocrit; Histamine H1 Antagonists; Leukocyte Count; Male; Meclizine; Ovalbumin; Phthalazines; Platelet Activating Factor; Platelet Count; Rats; Rats, Inbred Strains; Terfenadine; Triazoles

The in vivo effects of the antiallergic drug azelastine were investigated in sensitized guinea pigs. Topical administration of antigen into the nasal cavity produced an increase in nasal vascular permeability together with an increase in both the histamine and leukotriene C4 (LTC4) concentrations of nasal lavage fluid. Pre-treatment with azelastine significantly inhibited both the LTC4 release and the increase in nasal vascular permeability. These results suggest that azelastine inhibits the release of antigen-induced leukotrienes and increases nasal vascular permeability in vivo.

Topics: Animals; Capillary Permeability; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Immunization; Male; Ovalbumin; Phthalazines; Rhinitis, Allergic, Perennial; SRS-A

The effect of azelastine on platelet-activating factor (PAF)-induced bronchoconstriction and mediator release in isolated lungs from actively sensitised guinea-pigs was investigated. Guinea-pigs were actively sensitised with two s.c. injections of 10 micrograms ovalbumin in 1 mg Al (OH)3 at a 2-week interval. One week after the second injection, the lungs were removed and challenged intra-arterially with PAF or arachidonic acid. In some experiments lungs from non-immunised guinea-pigs were injected with PAF or histamine. Bronchoconstriction, the release of thromboxane (TX)B2 or leukotriene (LT)-like material and the histamine content of the effluent were evaluated. Azelastine was given s.c. at 10 or 100 micrograms/kg, 4 h before lung removal. Azelastine (100 micrograms/kg) did not inhibit PAF-induced bronchoconstriction and mediator release from lungs from non-immunised guinea-pigs. In contrast, the hyperresponsiveness to 1 ng PAF observed in lungs from actively sensitised animals was dose dependently inhibited by azelastine. Azelastine did not reduce the histamine-induced bronchoconstriction and consequent TXB2 release from lungs from immunised guinea-pigs, indicating that the protective effect exerted against hyperresponsiveness to PAF was not due to histamine antagonism. Azelastine also reduced arachidonic acid-induced bronchoconstriction and LT-like material release from sensitised lungs, regardless of the presence of indomethacin. These results suggest that inhibition of lung hyperresponsiveness to PAF by azelastine may result from an interference with leukotriene synthesis.

Topics: Animals; Arachidonic Acid; Bronchoconstriction; Guinea Pigs; Histamine; Immunization; Injections, Intra-Arterial; Leukotrienes; Lung; Male; Ovalbumin; Phthalazines; Platelet Activating Factor; Platelet Aggregation Inhibitors; Pulmonary Artery; Thromboxane B2

We examined the effect of ONO-1078, a peptide leukotriene antagonist, on antigen-induced airway microvascular leakage in ovalbumin-sensitized guinea pigs. When guinea pigs were pretreated with mepyramine, ovalbumin challenge increased vascular permeability to Evans blue dye in trachea, main bronchi and intrapulmonary airways. Oral administration of ONO-1078 significantly reduced microvascular leakage in intrapulmonary airways at doses more than 3 mg/kg, but not in trachea. Moreover, oral administration of ONO-1078 significantly reduced SRS-A mediated microvascular leakage into all airway tissues and was more effective in intrapulmonary airways at 3 mg/kg. Simultaneously, ONO-1078 also inhibited SRS-A mediated bronchoconstriction. On the other hand, azelastine (10 mg/kg, p.o.), an anti-asthma agent, failed to inhibit microvascular leakage into the airways. These results suggest that peptide leukotrienes may be important mediators of airway microvascular leakage, and that the inhibitory effect of ONO-1078 on antigen-induced airway microvascular leakage in addition to the blockade of bronchoconstriction may have therapeutic implications for bronchial asthma.

Topics: Analysis of Variance; Animals; Bordetella pertussis; Bronchodilator Agents; Capillary Permeability; Chromones; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Guinea Pigs; Male; Ovalbumin; Phthalazines; Respiratory Hypersensitivity; Respiratory Physiological Phenomena; Respiratory System; SRS-A

The interference of azelastine with pleurisy induced by antigen was investigated in actively sensitized rats. The antigenic challenge (ovalbumin, 12 micrograms/cavity) caused early plasma leakage, which peaked within 4 h, accompanied by intense neutrophil infiltration. Pleural exudate decayed 24 h after antigen provocation, when a long-lasting increase in the number of resident eosinophils was observed. Oral pretreatment with azelastine (1-10 mg/kg) dose dependently inhibited the vasopermeation (ED50 = 4.2 mg/kg) and reduced the pleural exudate (ED50 = 6.8 mg/kg) induced by the antigen. In contrast, azelastine (10 mg/kg) failed to modify the neutrophil influx observed at 4 h and the eosinophil accumulation detected at 24 h. Azelastine was also effective against rat pleurisy induced by either platelet-activating factor (PAF-acether), histamine or serotonin. It reduced exudation and the increase in the number of mononuclear cells, neutrophils and eosinophils observed 6 h after PAF-acether. Nevertheless, antagonism of PAF-acether may not be relevant to the inhibition observed in the present model of allergic pleurisy, as the inhibition was refractory to three distinct PAF-acether receptor antagonists. In contrast, like azelastine, the histamine H1 receptor antagonist meclizine and the dual histamine and serotonin receptor antagonist cyproheptadine blocked antigen-induced exudation and failed to interfere with cell influx. We conclude that the anti-exudatory activity of oral azelastine on antigen-induced pleurisy is consistent with it exerting direct effects against vasoactive amines, but is not related to an effect against leucocyte infiltration nor to its ability to inhibit PAF-acether.

Topics: Animals; Antigens; Female; Histamine; Histamine H1 Antagonists; Leukocytes; Male; Ovalbumin; Phthalazines; Platelet Activating Factor; Pleural Effusion; Pleurisy; Rats; Rats, Inbred Strains; Serotonin

Sequential changes in airway and adrenergic responsiveness after ovalbumin (OA) challenge were studied in guinea pigs. Airway responsiveness, alpha 1- and beta-adrenoceptor numbers and adenylate cyclase activity was determined after increasing doses of acetylcholine aerosol were administered before, 0, 3, 7, and 14 days after exposure to 2 percent OA or physiologic saline solution for 10 consecutive days. The antiasthmatic agent, azelastine (1 mg/kg/day, intraperitoneal), was administered for 14 days after the tenth exposure to OA in some animals. Airway responsiveness increased significantly after OA exposure, beta-adrenoceptor numbers decreased by 35 percent, and adenylate cyclase activity decreased by 54 percent (p less than 0.01). Values remained significantly different than control animals for 7 days and required 14 days to normalize completely. Azelastine decreased the recovery period to seven days. Azelastine may affect airway responsiveness, at least in part, by increasing beta-adrenergic responsiveness.

Topics: Acetylcholine; Adenylyl Cyclases; Animals; Bronchial Provocation Tests; Bronchoconstriction; Bronchodilator Agents; Guinea Pigs; Male; Ovalbumin; Phthalazines; Receptors, Adrenergic; Time Factors

Fluorescence polarisation technique was adapted to measure microviscosity in the bronchoalveolar lavage fluid (BAL) of guinea pigs. In sensitized guinea pigs, 20 hours after antigen challenge, the microviscosity of BAL was increased by 86%, suggesting that antigen-induced bronchospasm is followed by inflammatory events. Pretreatment with azelastine (3 mg/kg, p.o., 2 hours prior to antigen challenge) tended to normalize microviscosity in the bronchoalveolar lavage fluid obtained from challenged guinea pigs. The present results suggest that azelastine inhibits the increase of microviscosity of BAL, a symptom of the late phase reactions.

Topics: Animals; Bronchoalveolar Lavage Fluid; Guinea Pigs; Histamine H1 Antagonists; Immunization; Male; Ovalbumin; Phthalazines; Pyridazines; Viscosity

Azelastine is a phthalazinone derivative with a wide spectrum of pharmacological activities. Actively sensitized guinea pigs were used to examine the broncholytic effect of azelastine in vivo. Furthermore, the influence of azelastine on the production of arachidonic acid (AA) metabolites was investigated in vitro and compared to the effects of nordihydroguaiaretic acid (NDGA), indomethacin and ketotifen. In vivo, azelastine protected actively sensitized guinea-pigs against ovalbumin-induced bronchospasm with an ID50 of 0.08 mg/kg orally. Ketotifen was similarly active (ID50 = 0.05 mg/kg). Antigen-induced contraction of isolated tracheal rings of sensitized guinea-pigs was concentration-dependently inhibited by azelastine and NDGA with IC50-values of 94.1 and 34.2 mumol/l, respectively. Ketotifen exerted only weak inhibitory activity (18% at 100 mumol/l). The arachidonic acid-induced contraction of isolated guinea-pig tracheal rings was also inhibited both by azelastine (IC50 = 92.6 mumol/l) and NDGA (IC50 = 20.4 mumol/l). Ketotifen was inactive on this model. Antigen challenge of chopped lung tissue from sensitized guinea-pigs resulted in the release of cysteinyl-leukotrienes (LT) which were identified by reversed phase high pressure liquid chromatography (HPLC) as LTD4 and LTE4. The release of cysteinyl-LT from sensitized guinea-pig lung tissue induced by antigen challenge was concentration-dependently inhibited by azelastine (IC50 = 35.2 mumol/l) and NDGA (IC50 = 8.4 mumol/l) but not by ketotifen and indomethacin. By contrast, indomethacin caused a pronounced augmentation of cysteinyl-LT release. The concentration of indomethacin, which augmented cysteinyl-LT release by 50% was 0.19 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antigens; Arachidonic Acid; Arachidonic Acids; Bronchi; Guinea Pigs; Histamine H1 Antagonists; In Vitro Techniques; Indomethacin; Ketotifen; Leukotriene E4; Male; Masoprocol; Muscle Contraction; Ovalbumin; Phthalazines; Pyridazines; SRS-A; Thromboxane B2; Trachea

Contractile responses to acetylcholine were measured using isolated tracheae obtained from actively sensitized guinea pigs 0.5, 1, 5, 20, 24, 48 and 72 h after antigen challenge. Tracheal contractions to acetylcholine and to histamine were significantly increased 20 h but not 0.5, 1, 5, 24, 48 and 72 h after antigen challenge indicating bronchial hyperreactivity. When animals were pretreated with azelastine and then exposed to antigen challenge, concentration-response curve to acetylcholine did not differ from that obtained in control (non-challenged) tracheae. It is likely that azelastine is able to inhibit bronchial hyperresponsiveness to chemical mediators of bronchial asthma.

Topics: Acetylcholine; Animals; Antigens; Asthma; Bronchi; Guinea Pigs; Histamine; Histamine H1 Antagonists; Muscle Contraction; Ovalbumin; Phthalazines; Pyridazines; Trachea

The influence of aerosolized azelastine on acute lung anaphylaxis in actively sensitized guinea pigs (experimental asthma model) was studied. Azelastine administered as an aerosol produced significant inhibition of acute lung anaphylactic responses, ie, the reduction in dynamic lung compliance and an increase in pulmonary airway resistance. These data showed that regardless of the method of sensitization and time of administration (immediately or 15 minutes before antigen challenge), aerosolized azelastine affords significant protection against acute lung anaphylaxis. The inhibition of acute lung anaphylaxis by aerosolized azelastine in the guinea pig asthma model may be due to (1) inhibition of the synthesis/release of chemical mediators, eg, histamine and leukotrienes, etc and/or (2) antagonism of the pharmacologic mediators at the receptor site in respiratory smooth muscles.

Topics: Aerosols; Anaphylaxis; Animals; Antigens; Asthma; Disease Models, Animal; Guinea Pigs; Injections, Intraperitoneal; Injections, Intravenous; Lung; Male; Ovalbumin; Phthalazines; Pyridazines

The ability of azelastine to inhibit IgE-mediated allergic histamine release from the peritoneal mast cells of actively sensitized rats was investigated and compared with selected antiallergic agents. Azelastine added simultaneously with the allergic stimuli (ovalbumin, OA, 10 micrograms/ml + phosphatidylserine, PS, 10 micrograms/ml) or preincubated with cells for 10 min prior to antigen challenge produced similar concentration-dependent inhibition of allergic histamine release. The IC50s (microM) following 10-min preincubation were as follows: azelastine = 4.8; astemizole = 86.3; ketotifen = 112.2; diphenhydramine = 133 and theophylline = 2040.3. At IC50 level azelastine was about 18, 23, 28 and 425 times as effective as astemizole, ketotifen (newer histamine H1-receptor antagonists), diphenhydramine (a traditional H1-receptor antagonist), and theophylline (a phosphodiesterase inhibitor), respectively. Sodium cromoglycate in a concentration range or 1-1000 microM (0 or 10-min preincubation) failed to exert any inhibitory effect. These data showed that among six drugs tested azelastine is the most potent inhibitor of allergic histamine release from rat peritoneal mast cells.

Topics: Animals; Astemizole; Benzimidazoles; Diphenhydramine; Histamine Release; Hypersensitivity; Immunoglobulin E; Ketotifen; Male; Mast Cells; Ovalbumin; Phosphatidylserines; Phthalazines; Pyridazines; Rats; Rats, Inbred Strains; Theophylline