ovalbumin and ozagrel

ONO-1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A(2) (TxA(2)) synthase inhibitory activity. We investigated the effect of ONO-1301 on development of airway allergic inflammation.. Mice sensitized and challenged to ovalbumin (OVA) received ONO-1301, OKY-046 (TxA(2) synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO-1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty-four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function.. Mice that received ONO-1301 showed significantly lower AHR, airway eosinophilia, T-helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle-treated mice. These effects of ONO-1301 were mostly reversed by CAY10449. BMDCs treated with ONO-1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells.. These data suggest that ONO-1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti-inflammatory drug in the treatment of asthma.

Topics: Animals; Bronchial Hyperreactivity; Dendritic Cells; Disease Models, Animal; Epoprostenol; Female; Inflammation; Methacrylates; Mice; Mice, Inbred BALB C; Ovalbumin; Pyridines; Thromboxane-A Synthase; Thromboxanes

Effects of Y-24180 on antigen-induced asthmatic responses were evaluated in actively sensitized guinea pigs and the effects were compared with those of several anti-asthmatic drugs.. Male Hartley guinea pigs were used.. Guinea pigs were actively sensitized with ovalbumin and were pretreated with pyrilamine Y-24180 was orally administered to the animals 3 h and others were 1 h before the antigen challenge.. The airway hyperresponsiveness was measured according to the method of Konzett and Rössler with some modifications. The immediate asthmatic response (IAR) and late asthmatic response (LAR) were measured by the oscillation method. Inflammatory cells infiltrated into the lungs were counted after the bronchoalveolar lavage.. Under oral administration before or after the challenge with antigen, Y-24180, OKY-046, and ONO-1078 suppressed the antigen-induced airway hyperresponsiveness. Moreover, Y-24180, ONO-1078, AA-2414, and theophylline suppressed both the IAR and LAR, but OKY-046 only suppressed the LAR. Among the test drugs, only Y-24180 and theophylline suppressed the antigen-induced accumulation of eosinophils in the bronchoalveolar lavage fluid.. The data indicate practical participation of PAF in the development of antigen-induced asthmatic responses in animals, and usefulness of Y-24180 in the clinical treatment of asthma as well as other anti-asthmatic drugs.

Topics: Administration, Oral; Aerosols; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Azepines; Benzoquinones; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Chromones; Enzyme Inhibitors; Guinea Pigs; Heptanoic Acids; Histamine Antagonists; Leukotriene Antagonists; Male; Methacrylates; Ovalbumin; Platelet Membrane Glycoproteins; Pyrilamine; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Serine Proteinase Inhibitors; Signal Transduction; Theophylline; Thromboxane-A Synthase; Triazoles

We studied the effects of apafant (WEB 2086 BS), a specific and potent platelet activating factor (PAF) receptor antagonist, on the early and late airway responses in conscious and actively sensitized guinea pigs. An increase in airway resistance (Rs) was seen 1 min after the inhaled antigen challenge (early airway response), followed by another increase in Rs which peaked between 4 and 8 h after the provocation (late airway response). Oral administration of apafant as well as theophylline inhibited both early and late airway responses. Ozagrel, an inhibitor of thromboxane A2 synthetase, salbutamol, a beta2-adrenoceptor agonist, and dexamethasone significantly inhibited either the early or the late airway response only. Disodium cromoglycate inhibited neither the early nor the late airway response. The results showed that apafant inhibited both the early and late airway responses in sensitized guinea pigs and its effect was comparable or superior to that of anti-asthmatic drugs used clinically.

Topics: Administration, Inhalation; Administration, Oral; Adrenergic beta-Agonists; Airway Resistance; Albuterol; Animals; Anti-Asthmatic Agents; Azepines; Bronchodilator Agents; Cromolyn Sodium; Dexamethasone; Drug Interactions; Glucocorticoids; Guinea Pigs; Histamine Antagonists; Histamine H1 Antagonists; Methacrylates; Metyrapone; Ovalbumin; Platelet Aggregation Inhibitors; Plethysmography; Pyrilamine; Theophylline; Thromboxane-A Synthase; Triazoles; Vaccination

The therapeutic effect of a thromboxane A2 (TXA2) synthetase inhibitor on asthma is still controversial. This study was aimed at clarifying its effect on asthmatic reactions in guinea pigs. Both ovalbumin (OVA)- and platelet activating factor (PAF)-induced dual phase airway spasm and hyperreactivity in guinea pigs were used as the asthma model. Our results demonstrated that aerosol administration of OKY-046 could inhibit both OVA- and PAF-induced late phase bronchoconstriction and airway hyperreactivity to methacholine in OVA sensitized guinea pigs. PAF administration could also induced dual phase bronchoconstriction in normal guinea pigs. Similarly, late phase airway spasm and airway hyperreactivity after PAF exposure was also blocked by OKY-046. In conclusion, aerosol administration of OKY-046 is a safe and effective way to modulate OVA- and PAF-induced asthmatic reactions. The protective effect of OKY-046 on OVA- and PAF-induced late phase bronchoconstriction and airway hyperreactivity indicates that TXA2 might play an important role in the late phase asthmatic reaction and airway hyperreactivity. The normalization of PAF-induced airway hyperreactivity by OKY-046 also indicates that PAF induced airway inflammation might be through the generation of TXA2.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Dose-Response Relationship, Drug; Guinea Pigs; Histamine Antagonists; Male; Methacrylates; Ovalbumin; Platelet Activating Factor; Thromboxane-A Synthase; Time Factors

We established an experimental model of late asthmatic response (LAR) using conscious guinea pigs actively sensitized by antigen aerosol inhalation. In actively sensitized guinea pigs, antigen challenge by aerosol inhalation caused an immediate increase in specific airway resistance (SRaw) (immediate airway response; IAR) followed by a LAR which occurred 4 to 8 hr after antigen challenge. SRaw in the challenged animals was still increased 23 hr after antigen challenge. Examination of bronchoalveolar lavage (BAL) fluid and histology of the lungs revealed increases in eosinophils and neutrophils during LAR. The beta-2 agonist salbutamol inhibited only IAR and not LAR. Dexamethasone inhibited LAR but not IAR. A low dose of theophylline had little effect on both IAR and LAR. A novel thromboxane A2 (TXA2) receptor antagonist, AA-2414, orally administered before antigen challenge dose-dependently inhibited both IAR and LAR, and oral administration of AA-2414 after the IAR inhibited LAR. Also, thromboxane synthetase inhibitors, CV-4151 and OKY-046, reduced both IAR and LAR. Salbutamol significantly reduced the increase in neutrophils in BAL fluid, and dexamethasone significantly reduced the increase in eosinophils and neutrophils in BAL fluid. Theophylline also reduced the increase in eosinophils in BAL fluid. However, AA-2414 did not inhibit the accumulation of these inflammatory cells in BAL fluid or the airway tissues. These results suggest that asthmatic responses in guinea pigs are similar to those in asthmatic subjects and that TXA2 plays an important role in both IAR and LAR but not in inflammatory cell infiltration in this model of allergic asthma.

Topics: Acetylcholine; Airway Resistance; Animals; Antibodies; Asthma; Benzoquinones; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Fatty Acids, Monounsaturated; Guinea Pigs; Heptanoic Acids; Leukocytes; Male; Methacrylates; Ovalbumin; Pyridines; Theophylline; Thromboxane A2

The anti-asthmatic effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate) , a specific thromboxane A2 (TXA2) synthase inhibitor, were investigated in the ovalbumin-sensitized guinea pig asthmatic model. Although CS-518 slightly inhibited (about 25%) whole bronchoconstriction, it significantly inhibited the antigen-induced bronchoconstriction mediated by slow-reacting substance of anaphylaxis (SRS-A), which was not reduced by chlorpheniramine, a histamine H1 antagonist. On the other hand, indomethacin, a cyclooxygenase inhibitor, potentiated the SRS-A-mediated constriction. CS-518 strongly, and indomethacin slightly, suppressed the leukotriene D4-induced bronchoconstriction. CS-518 clearly inhibited the antigen-induced airway hyperresponsiveness, but this compound had no effect on the airway hyperresponsiveness induced by U-46619, a TXA2-mimetic agent, and propranolol. These results suggest that CS-518 suppresses the development of bronchoconstriction and airway hyperresponsiveness in asthmatic models by inhibition of TXA2 synthesis with the concomitant increase in bronchodilating prostaglandins such as prostaglandin E2 and prostaglandin I2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Chlorpheniramine; Disease Models, Animal; Guinea Pigs; Indomethacin; Male; Methacrylates; Ovalbumin; Propranolol; Prostaglandin Endoperoxides, Synthetic; SRS-A; Thiophenes; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

The effect of a peptide leukotriene receptor antagonist ONO-1078 on the production of thromboxane (Tx) B2 induced by leukotriene (LT) D4 and antigen challenge was examined in guinea pig lungs. LTD4 (1-1,000 nM) induced a concentration-dependent production of TxB2 in non-sensitized guinea pig lungs and ovalbumin challenge (0.01-100 micrograms/ml) produced TxB2 and peptide leukotrienes in a concentration-dependent manner in ovalbumin-sensitized guinea pig lungs. ONO-1078 inhibited LTD4 (100 nM)-induced TxB2 production with the IC50 value of 0.24 microM. Furthermore, ONO-1078 inhibited antigen (10 micrograms/ml)-induced TxB2 production with the IC50 value of 0.14 microM without effect on the production of peptide leukotrienes. These results suggest that ONO-1078 may prevent the antigen-induced production of TxB2 through the blockade of the activation of receptors by endogenously generated peptide leukotrienes.

Topics: Animals; Antigens; Bordetella pertussis; Chromones; Dose-Response Relationship, Drug; Guinea Pigs; Indomethacin; Kinetics; Lung; Male; Methacrylates; Ovalbumin; SRS-A; Thromboxane B2; Thromboxane-A Synthase

Topics: Acrylates; Animals; Guinea Pigs; Indomethacin; Lung; Methacrylates; Ovalbumin; Reference Values; Thromboxane-A Synthase