ozagrel and azelastine

We studied the role of arachidonic acid metabolites, histamine, and 5-HT in airway responses to trimellitic anhydride (TMA) in actively sensitized guinea pigs. Sensitization was produced by two intradermal injections of free TMA (0.1 ml of 0.3% TMA in corn oil). After 21 to 28 days, guinea pigs were anesthetized and challenged with intratracheal instillation of 0.5% TMA conjugated to guinea pig serum albumin (TMA-GPSA; 50 microliters). Lung resistance (RL) was measured to assess airflow obstruction, and the tissue content of Evans blue dye was measured to assess airway plasma exudation. Before challenge, sensitized animals were pretreated intravenously with inhibitors of different mediators: pyrilamine (antihistamine: 2 mg/kg, indomethacin (cyclooxygenase inhibitor: 10 mg/kg), OKY-046 (thromboxane synthetase inhibitor: 30 mg/kg), ICI-198,615 (leukotriene receptor antagonist: 10(-6) mol/kg), ketanserin (5-HT2 receptor antagonist: 1 mg/kg), or azelastine ("antiallergic agent": 1 mg/kg). Intratracheal instillation of TMA-GPSA induced a slowly progressing increase in RL and produced extravasation of Evans blue dye at all airway levels in sensitized animals. Pyrilamine and azelastine abolished the increase in RL induced by TMA-GPSA until 2.5 min after the challenge. Indomethacin and OKY-046 significantly attenuated the increase in RL 3 min after the challenge. ICI-198,615 and ketanserin did not significantly affect the increase in RL. Extravasation of Evans blue dye induced by TMA-GPSA was decreased by pyrilamine, azelastine and ICI-198,615 in main bronchi and intrapulmonary airways. Indomethacin, OKY-046 and ketanserin did not significantly affect the extravasation of dye into the airway tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Airway Resistance; Animals; Arachidonic Acid; Bronchi; Evans Blue; Exudates and Transudates; Guinea Pigs; Immunization; Indazoles; Indomethacin; Ketanserin; Male; Methacrylates; Permeability; Phthalazines; Phthalic Anhydrides; Pyrilamine; Respiratory Hypersensitivity; SRS-A; Thromboxane-A Synthase

Topics: Animals; Annexins; Asthma; Calcium-Binding Proteins; Cromolyn Sodium; Humans; Lipoxygenase Inhibitors; Methacrylates; Phosphodiesterase Inhibitors; Phospholipases A; Phthalazines; Protease Inhibitors; Respiratory Tract Infections; Thromboxane-A Synthase

IgE mediated type 1 hypersensitivity induces an immediate phase, during the minutes that follow contact with the allergen and is very often associated with a late phase that occurs during the hours that follow contact. The late phase of asthma induced by an IgE--dependent mechanism is linked with a cellular activation (lymphocytes, eosinophils) and release of different mediators (Paf Acether, LTB4, ECFA, MBP, EcP) from those of the immediate phase. Corticosteroids are well known as inhibitors of the late phase. Like cromoglycate, AZELASTINE inhibits both the immediate and late phases.

Topics: Adrenal Cortex Hormones; Animals; Asthma; Dogs; Eosinophils; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunoglobulin E; Methacrylates; Neutrophils; Phthalazines

We studied the effect of (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046.HCl), a specific thromboxane (TX) A2 synthetase inhibitor, on airway hyperresponsiveness of guinea pigs. OKY-046.HCl (30-100 mg/kg, intraduodenally (i.d.) or orally (p.o.)) suppressed dose dependently the airway hyperresponsiveness to acetylcholine (ACh) induced by formyl-methionyl-leucyl-phenylalanine (FMLP), platelet activating factor (PAF) and repetitive antigen. OKY-046.HCl (100 mg/kg) also inhibited the increase in TXB2 in bronchoalveolar lavage fluid (BALF) induced by FMLP, PAF and antigen. Aspirin 10 or 30 mg/kg i.d. or p.o.) suppressed the airway hyperresponsiveness induced by FMLP and PAF but not by antigen. Azelastine (10 mg/kg i.d.) was ineffective on PAF- and antigen-induced airway hyperresponsiveness. TXA2 mimetic drugs caused airway hyperresponsiveness that was not inhibited by OKY-046.HCl (30 mg/kg i.v.). Furthermore, OKY-046.HCl showed no effect on propranolol- and physostigmine-induced airway hyperresponsiveness which did not accompany TXB2 generation in BALF. The number of eosinophils in BALF increased after FMLP exposure, an effect which was not inhibited by OKY-046.HCl. These results suggest that OKY-046.HCl inhibits airway hyperresponsiveness by suppressing TXA2 generation. We suggest that OKY-046.HCl will be a new antiasthmatic drug.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Airway Resistance; Animals; Antigens; Aspirin; Bronchoalveolar Lavage Fluid; Guinea Pigs; Leukotriene E4; Methacrylates; N-Formylmethionine Leucyl-Phenylalanine; Phthalazines; Physostigmine; Platelet Activating Factor; Propranolol; Respiratory System; SRS-A; Thromboxane B2; Thromboxane-A Synthase