ozagrel and Asthma

Airway smooth muscle (ASM) is the effector cell in the bronchoconstrictory pathway. It is believed that the bronchoconstriction present in asthma is associated with changes in the airway milieu that affect ASM excitation-contraction coupling and Ca(2+)-handling. Asthmatics also react differently to ventilatory mechanical strain. Deep inspiration (DI), which produces bronchodilation in healthy individuals, is less effective in asthmatics, and even enhances bronchoconstriction in moderate to severely affected patients. Our laboratory has previously studied the mechanotransductory pathway of airway stretch-activated contractions (Rstretch) leading to DI-induced bronchoconstriction. We demonstrated the ability of agonists acting through thromboxane A2 (TxA2) receptors to amplify airway Rstretch responses. Despite the involvement of excitatory prostanoids in bronchoconstriction, clinical trials on treatments targeting TxA2-synthase inhibition and TP-receptor antagonism have produced mixed results. Studies in Western populations produced mostly negative results, whereas studies performed in Asian populations showed mostly positive outcomes. In this review, we discuss the role of TxA2-synthase inhibition and TP-receptor antagonism in the treatment of asthmatics. We present information regarding variations in study designs and the possible role of TP-receptor gene polymorphisms in previous study outcome discrepancies. Perhaps future studies should focus on asthmatic patients with DI-induced bronchoconstriction in particular, planting the seed for the individualized treatments for asthmatics.

Topics: Animals; Asthma; Bronchoconstriction; Cyclooxygenase Inhibitors; Humans; Methacrylates; Polymorphism, Genetic; Prostaglandin-Endoperoxide Synthases; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

Topics: Adult; Aged; Aged, 80 and over; Anti-Allergic Agents; Asthma; Benzoquinones; Chemical and Drug Induced Liver Injury; Enzyme Inhibitors; Female; Heptanoic Acids; Humans; Lung Diseases, Interstitial; Male; Methacrylates; Middle Aged; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane-A Synthase

COPD (Chronic Obstructive Pulmonary Disease) and bronchial asthma are two severe lung diseases which represent a major problem of world public health. Leukotrienes and prostanoids play an important role in the pathogenesis of pulmonary diseases. Prostanoids: prostaglandins (PGs) and thromboxane A2 (TXA2), the cyclooxygenase metabolites of arachidonic acid are implicated in the inflammatory cascade that occurs in asthmatic airways. Recently, the roles played by isoprostanes or prostaglandin-like compounds nonenzymatically generated via peroxidation of membrane phospholipids by reactive oxygen species, in particular F2-isoprostanes, in pulmonary pathophysiology have been highlighted. This article aims to provide an overview of the role of prostanoids and isoprostanes in the pathogenesis of COPD and asthma and to discuss the pharmacological strategies developed in prevention and/or treatment of these pathologies.

Topics: Animals; Asthma; Benzoquinones; Carbazoles; Enzyme Inhibitors; F2-Isoprostanes; Heptanoic Acids; Humans; Methacrylates; Prostaglandin Antagonists; Prostaglandin D2; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

Bronchial asthma is a disease defined by reversible airway obstruction, bronchial hyperresponsiveness and inflammation. In addition to histamine and acetylcholine, recent studies have emphasized the role of arachidonic acid metabolites (leukotrienes, prostaglandins and thromboxane A(2)) in the pathogenesis of asthma. Among these mediators, thromboxane A(2) (TXA(2)) has attracted attention as an important mediator in the pathophysiology of asthma because of its potent bronchoconstrictive activity. Thromboxane A(2) is believed to be involved not only in late asthmatic responses but also in bronchial hyperresponsiveness, a typical feature of asthma. Strategies for inhibition of TXA(2) include TXA(2) receptor antagonism and thromboxane synthase inhibition. Results of double-blind, placebo-controlled clinical trials have proven the efficacies of the thromboxane receptor antagonist seratrodast and the thromboxane synthase inhibitor ozagrel in the treatment of patients with asthma. Seratrodast and ozagrel are available in Japan for the treatment of asthma. Ramatroban, another thromboxane receptor antagonist, is currently under phase III clinical evaluation in Europe and Japan for the treatment of asthma. The pharmacological profiles of the thromboxane modulators may be improved by combination with leukotriene D(4) receptor antagonists. A multi-pathway inhibitory agent such as YM 158, which is a novel orally active dual antagonist for leukotriene D(4) and thromboxane A(2 )receptors, may have potent therapeutic effects in the treatment of bronchial asthma. Large scale clinical trials are necessary to further define the role of thromboxane modulators in the treatment of patients with asthma.

Topics: Anti-Asthmatic Agents; Asthma; Benzoquinones; Carbazoles; Heptanoic Acids; Humans; Methacrylates; Molecular Structure; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

Thromboxane A2 (TxA2) plays an important role in asthma. TxA2 are newly generated after cellular activation and are produced by not only platelets but also eosinophils, basophils, alveolar macrophages, and neutrophils. Pharmacological actions of TxA2 include potent bronchoconstriction, increased microvascular leakage, impairment of mucociliary clearance, and induction of airway hyperresponsiveness. Recent study demonstrated that TxA2 receptor antagonist decreased the number of eosinophils in bronchial biopsy specimens, suggesting that this type of agent possesses anti-inflammatory actions in asthma. Furthermore, addition of TxA2 synthase inhibitor significantly increased the PEF values in the persistent asthmatic patients despite the treatment with moderate-dose of inhaled corticosteroids. Therefore, these results suggest that TxA2 synthase inhibitor and receptor antagonist are useful for the treatment with symptomatic patients who had already been treated with inhaled corticosteroids.

Topics: Asthma; Benzoquinones; Bronchi; Bronchial Hyperreactivity; Eosinophils; Heptanoic Acids; Humans; Methacrylates; Practice Guidelines as Topic; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase

Thromboxane A2(TXA2), a platelet aggregator and vasoconstricter, has been implicated as a potential mediator of bronchial asthma. TXA2 induces potent contraction of airway smooth muscles and airway hyperresponsiveness. OKY-046 (ozagrel hydrochloride) is a specific inhibitor of TXA2 synthetase and a new antiasthmatic agent. In a phase III study ozagrel has shown significantly higher effect in ameliorating the asthma symptoms and reduced the dose of concomitant steroid therapy compared to azelastine hydrochloride. Both basical and clinical studies showed that TXA2 synthetase inhibitor is effective on airway hyperresponsiveness. In this review the role of TXA2 synthetase inhibitor in current asthma therapy, which is based on the Japanese guideline of allergic disorders, was discussed.

Topics: Asthma; Bronchial Hyperreactivity; Clinical Trials as Topic; Humans; Methacrylates; Thromboxane A2; Thromboxane-A Synthase

Acetaldehyde is thought to be a main factor of alcohol-induced asthma. The thromboxane (TX) synthetase inhibitor, ozagrel hydrochloride, inhibits acetaldehyde-induced bronchoconstriction in asthmatic patients. The present study evaluated the involvement of TXA(2) on alcoholic beverage-induced bronchoconstriction. Four patients with alcohol-induced asthma received ozagrel (400 mg for 4 days) or placebo using a single-blind, randomized, cross-over design. On two separate study days, each subject drank the same brand and volume of alcoholic beverage (beer or Japanese sake) and bronchoconstriction was assessed as the change in peak expiratory flow (PEF). The effect of ozagrel on the aerosolized challenge of acetaldehyde was investigated in the same subjects. Although aerosolized acetaldehyde-induced bronchoconstriction was significantly prevented by ozagrel, there were no differences in the time course of the decrease in PEF or the maximum fall in PEF after alcohol intake between placebo and ozagrel. We conclude that TXA(2) is not involved in alcoholic beverage-induced bronchoconstriction.

Topics: Acetaldehyde; Adult; Alcoholic Beverages; Asthma; Beer; Bronchial Provocation Tests; Bronchoconstriction; Humans; Male; Methacrylates; Middle Aged; Peak Expiratory Flow Rate; Sample Size; Thromboxane-A Synthase; Wine

We investigated the effect of thromboxane (TX) synthetase inhibitor, OKY-046, on bronchial hypersensitivity in 16 asthmatics by a double-blind, placebo-controlled, crossover trial. Bronchial sensitivity to methacholine was measured by Astograph. Blood samples were taken to measure plasma levels of TX metabolites. No significant differences of forced expiratory volume in 1 sec (FEV1), bronchial sensitivity, or bronchial reactivity were observed after OKY-046 administration, compared to baseline or after placebo. However, responders showed a significant decrease in the plasma TXB2/6-keto-PGF1alpha ratio as compared to nonresponders. Our data failed to confirm an inhibitory effect of OKY-046 on bronchial hypersensitivity, but suggested the importance of its therapeutic dose monitoring.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Asthma; Bronchial Hyperreactivity; Double-Blind Method; Enzyme Inhibitors; Female; Forced Expiratory Volume; Humans; Male; Methacrylates; Placebos; Spirometry; Thromboxane B2; Thromboxane-A Synthase

Leukotriene (LT) and thromboxane A2 (TXA2) receptor antagonists have been used in the treatment of asthma.. We examined the effects of an LT receptor antagonist, TXA2 receptor antagonist, and TXA2 synthetase inhibitor on bronchoprovocation test (BPT) in patients with mild-to-moderate atopic asthma.. BPT was performed four times in each of six asthmatics. Development of the immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) was confirmed on the first BPT (BPT1). After a 7-day washout period, an LT receptor antagonist (pranlukast, 450 mg/d), TXA2 receptor antagonist (seratrodast, 80 mg/d), or TXA2 synthetase inhibitor (ozagrel, 800 mg/d) was administered orally over 7 days at random using a cross-over method (BPT2-4). Blood levels of LTB4, LTC4, LTD4, 11-dehydrothromboxane B2, eosinophil cationic protein, and histamine were measured at reaction phases of pre-BPT, IAR, and LAR.. Administration of pranlukast suppressed IAR by 80.5% (p < 0.0001) and LAR by 54.6% (p = 0.0391). Ozagrel significantly suppressed IAR by 39.5% (p = 0.0413), but the fall in FEV1 was >20% (21.56+/-4.173%). Seratrodast did not suppress IAR or LAR. Blood levels of chemical mediators did not correlate with the suppressive effects of the tested drugs.. The LT receptor antagonist was considered to be the most effective. LT might play a more important role in the pathogenesis of asthma than TXA2. Our data showed that measurement of blood levels of chemical mediators is not useful in identifying the pathogenic mechanisms of asthma.

Topics: Administration, Oral; Adult; Anti-Asthmatic Agents; Antigens; Asthma; Benzoquinones; Blood Proteins; Bronchial Provocation Tests; Bronchoconstriction; Chromones; Cross-Over Studies; Eosinophil Granule Proteins; Female; Follow-Up Studies; Heptanoic Acids; Histamine; Humans; Leukotriene Antagonists; Male; Membrane Proteins; Methacrylates; Receptors, Leukotriene; Receptors, Thromboxane; Ribonucleases; Thromboxane B2; Thromboxane-A Synthase; Treatment Outcome

Cyclooxygenase products are released by chronic airway inflammation. Our working hypothesis for the present study was that prostanoids augment airway cough sensitivity. The effects of a cyclooxygenase inhibitor, indomethacin (100 mg.day-1 for 4 days), and a thromboxane synthesis inhibitor, OKY-046 (400 mg.day-1 for 4 days), on cough response to inhaled capsaicin were examined in eight patients with asthma, 10 patients with chronic bronchitis, and 10 normal subjects. Capsaicin cough threshold, the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough sensitivity. In asthmatics, the cough thresholds with indomethacin treatment (15.7 (GSEM 1.38) microM) and OKY-046 (10.2 (GSEM 1.20) microM) were significantly greater than the value with placebo (6.05 (GSEM 1.25) microM). In patients with chronic bronchitis, the cough threshold was significantly greater with indomethacin (5.94 (GSEM 1.50) microM) than with placebo (3.41 (GSEM 1.33) microM and OKY-046 2.97 (GSEM 1.43) microM). In normal subjects, the capsaicin cough threshold was not altered by indomethacin or OKY-046 treatment. These results support our hypothesis and suggest that thromboxane A2 may be one of the cyclooxygenase products augmenting airway cough sensitivity in asthma, but not in chronic bronchitis.

Topics: Adult; Aged; Asthma; Bronchial Provocation Tests; Bronchitis; Capsaicin; Chronic Disease; Cough; Cross-Over Studies; Cyclooxygenase Inhibitors; Double-Blind Method; Female; Humans; Indomethacin; Male; Methacrylates; Middle Aged; Respiratory Function Tests; Thromboxane-A Synthase; Treatment Outcome

Ozagrel (OKY-046), a selective inhibitor of thromboxane biosynthesis has been reported to reduce airway hyperresponsiveness in asthmatics. DSCG has been widely used for atopic, but not for non-atopic asthmatics. We evaluated the additive effect of combination therapy with DSCG and Ozagrel on nonatopic asthmatics. Fourteen asthmatics were divided into two groups. The patients in the O-D group were initially treated with Ozagrel (400 mg/day) for 4 weeks, and then DSCG (8 mg/day) was added for another 4 weeks. The patients in D-O group were initially treated with DSCG (8 mg/day), and then Ozagrel (400 mg/day) was added for 4 more weeks. TXB2, PGF2 alpha, PGE2, 6-keto-PGF1 alpha in sputum and 11-dehydro TXB2 in urine were measured before and after 4th and 8th weeks of therapy. Ozagrel decreased the metabolites of thromboxane and PGF2 alpha in sputum and urine. PGE2 in sputum tended to be increased by Ozagrel. DSCG did not affect mediators in sputum. Combination therapy with Ozagrel and DSCG showed the additive effect to single use on attack score and PF in non-atopic asthmatics.

Topics: Adult; Asthma; Cromolyn Sodium; Drug Therapy, Combination; Female; Histamine Antagonists; Humans; Male; Methacrylates; Middle Aged; Thromboxane-A Synthase

We recently reported that inhaled acetaldehyde causes bronchoconstriction indirectly via histamine release in patients with asthma. The purpose of this study was to investigate a role of thromboxane A2 in acetaldehyde-induced bronchoconstriction in asthmatic airways. We investigated the bronchial response to inhalation of ascending doses (5, 10, 20, and 40 mg/ml) of acetaldehyde in nine asthmatic subjects who were treated with placebo or OKY-046, a selective thromboxane A2 synthetase inhibitor, of 200 mg twice a day for 3 days, and 200 mg on the fourth day (test day) in a double-blind, randomized, placebo-controlled, crossover fashion. Percentage decreases in FEV1 caused by 20 and 40 mg/ml of acetaldehyde inhalation were significantly (p < 0.05 and p < 0.01, respectively) prevented by the pretreatment with OKY-046. Geometric mean value (geometric standard error of the mean) of acetaldehyde concentration producing a 20 percent fall in FEV1 (PC20-Ac-CHO) was significantly (p < 0.01) greater with the OKY-046 pretreatment (72.2 [1.1] mg/ml) than with the placebo pretreatment (19.8 [1.2] mg/ml). We conclude that thromboxane A2 is one of contributors to acetaldehyde-induced bronchoconstriction in asthmatic subjects. It suggests that thromboxane A2 may play an important role in endogenous histamine-induced bronchoconstriction caused by acetaldehyde in asthmatic airways. We believe that this is a first report on the interaction between endogenous histamine and thromboxane A2 in asthmatic subjects.

Topics: Acetaldehyde; Adult; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Cross-Over Studies; Depression, Chemical; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Methacrylates; Middle Aged; Statistics, Nonparametric; Thromboxane A2; Thromboxane-A Synthase; Vital Capacity

Topics: Acrylates; Asthma; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Humans; Methacrylates; Thromboxane-A Synthase

Thromboxane (Tx)A2 synthase inhibitors and thromboxane prostanoid (TP) receptor antagonists have been developed as anti-asthma drugs. TxA2 may contribute to airflow limitation and bronchial hyperresponsiveness, and these compounds have been demonstrated to improve them. However, it is not known whether TxA2 is involved in bronchial inflammation. To address this question, we explored the influences of OKY-046 (a TxA2 synthase inhibitor) and S-1452 (a TP receptor antagonist) on eosinophilic inflammation of the airways using a murine model. BALB/c mice sensitized with ovalbumin and challenged by repeated exposure to ovalbumin yielded marked eosinophilia in bronchoalveolar lavage fluid (BALF). Treatment with either compound significantly reduced the number of total cells and eosinophils in BALF in a dose-dependent manner. The production of interleukin (IL)-5, IL-2 and interferon (IFN)-gamma by antigen-stimulated splenic mononuclear cells (SMNC) was significantly decreased in mice treated with either compound compared to that in untreated mice. Furthermore, both compounds inhibited proliferation and cytokine production of SMNC in vitro. These results suggest that both OKY-046 and S-1452 are capable of inhibiting production of cytokines, which in turn inhibits eosinophil infiltration into the murine airway. Thus, both thromboxane A2 synthesis inhibitors and thromboxane prostanoid antagonists may be effective as anti-inflammatory drugs in the treatment of asthma.

Topics: Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cytokines; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Methacrylates; Mice; Mice, Inbred BALB C; Prostaglandin Antagonists; Pulmonary Eosinophilia; Thromboxane-A Synthase

The effect of Y-24180, a potent antagonist to-platelet-activating factor (PAF), was evaluated on the antigen-induced immediate asthmatic response (IAR) in actively sensitized guinea pigs that were pretreated with an antihistaminic agent, pyrilamine. Then, the effect was compared with that of other antiasthmatic agents. In a dose-dependent manner, Y-24180 (0.01-1 mg/kg, p.o.) suppressed the IAR, and WEB 2086 (0.1-10 mg/kg, p.o.), another PAF antagonist, also suppressed IAR in the same fashion as Y-24180. In contrast, AA-2414 (1-100 mg/kg,p.o.), a thromboxane A2 (TXA2) antagonist, was effective only at the beginning of the IAR and ONO-1078 (1-100 mg/kg, p.o.), a peptide leukotriene (pLT) antagonist, was effective only in the latter period, OKY-046, a TXA2 synthetase inhibitor, showed no significant suppression of the IAR at doses up to 100 mg/kg. Thus, PAF antagonists were more effective than the other agents tested in the present model for IAR. In a subsequent test, Y-24180 (1 mg/kg, p.o.) was confirmed to enhance the suppressive effects of theophylline (10 and 30 mg/kg, p.o.), procaterol (0.1 and 1 microgram/kg, i.v.), OKY-046 (100 mg/kg, p.o.) and ONO-1078 (100 mg/kg, p.o.) on the IAR. A combination of three agents, namely Y-24180 with OKY-046 and ONO-1078, completely suppressed the IAR. The results demonstrate that Y-24180 not only suppresses the IAR, but also enhances the suppressive effect of other antiasthmatic agents. Therefore, Y-24180 would be a clinically promising drug for the treatment of bronchial asthma.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Azepines; Benzoquinones; Bronchodilator Agents; Chromones; Drug Interactions; Drug Therapy, Combination; Guinea Pigs; Heptanoic Acids; Male; Methacrylates; Platelet Activating Factor; Theophylline; Triazoles

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

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

Etodolac, which inhibits the activity of cyclooxygenase, did not affect antigen-induced contractions of the trachea and lung parenchyma of guinea pigs. Indomethacin tended to enhance antigen-induced contractions of the trachea and significantly enhanced contractions of the lung parenchyma. The inhibitory activity of AA-861, a 5-lipoxygenase inhibitor, in antigen-induced contractions of the trachea and lung parenchyma was more potent than that of ozagrel, a thromboxane A2 (TXA2) inhibitor. Thus, lipoxygenase products played a more important role than TXA2 in antigen-induced contractions of the trachea and lung parenchyma. These results suggest that the enhancement of antigen-induced contractions by indomethacin might be due to an increase in anaphylactic release of lipoxygenase products through the inhibition of cyclooxygenase. Since etodolac did not enhance antigen-induced contractions, we attempted to determine whether or not etodolac inhibits 5-lipoxygenase. Etodolac was found to have no effect on 5-lipoxygenase activity. Therefore, the low adverse effect of etodolac on antigen-induced contractions of the airway may be due to its weak inhibition of cyclooxygenase in the airway. These results suggest that etodolac would have only a very slight, if any, adverse effect on the airway in patients with asthma.

Topics: Animals; Asthma; Benzoquinones; Disease Models, Animal; Etodolac; Guinea Pigs; Immunization, Passive; Indomethacin; Isoantigens; Lipoxygenase Inhibitors; Lung; Methacrylates; Muscle Contraction; Muscle, Smooth; Rabbits; Serum Albumin, Bovine; Thromboxane A2; Trachea

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

We attempted to obtain a new airway hyperresponsiveness model using DNP-Ascaris extract (DNP-Asc)-induced rat allergic asthma. Male Wistar rats were actively sensitized with DNP-Asc, and challenged in a non-anesthetized state by inhalation of the antigen for 10 min in a chamber. One, 6 and 24 hr after DNP-Asc challenge, the responsiveness of the airway smooth muscles to inhaled acetylcholine (ACh) was determined using a modified Konzett-Rössler method under anesthesia. Twenty four hr after the challenge, a significant and marked airway hyperresponsiveness was seen. The increase in airway responsiveness was significantly inhibited by pretreatments with a leukotriene antagonist, ONO-1078, and a thromboxane synthetase inhibitor, ozagrel, and tended to be inhibited by a PAF antagonist, CV-3988. The hyperresponsiveness induced by DNP-Asc challenge was accompanied by airway inflammation determined by dye exudation. From the above results, it is indicated that a model of airway hyperresponsiveness was established in rats with allergic asthma, and that the chemical mediators involved in the response might be leukotrienes, thromboxane A2 and PAF.

Topics: Acetylcholine; Animals; Ascaris; Asthma; Bronchial Hyperreactivity; Capillary Permeability; Chromones; Depression, Chemical; Dinitrophenols; Disease Models, Animal; Male; Methacrylates; Phospholipid Ethers; Platelet Activating Factor; Rats; Rats, Wistar; SRS-A; Thromboxane-A Synthase; Tissue Extracts

To clarify whether thromboxane A2 (TXA2) is involved in type III and IV allergy, or so called "cell-mediated allergy", we studied the effect of a specific TXA2 synthetase inhibitor, sodium ozagrel (OKY-046) on peripheral blood mononuclear cells and neutrophils in adult intractable asthmatics. The results revealed, firstly, that lymphocyte blastogenesis and interleukin-2 (IL-2) production from peripheral blood mononuclear cells stimulated by PHA and Candida antigen in intractable asthmatics was significantly suppressed dose-dependently by OKY-046. Secondly, there was a tendency that neutrophil chemotactic factor (NCF) and eosinophil chemotactic factor (ECF) from peripheral blood mononuclear cells stimulated by Candida antigen in intractable asthmatics were suppressed by OKY-046. Thirdly, leukotriene (LTC4) and superoxide (O2-) production from peripheral blood neutrophils in intractable asthmatics was significantly suppressed dose-dependently by OKY-046. That is, OKY-046 has a suppressive effect on type IV allergy caused by lymphocyte activation and on mediator release from neutrophils. These results suggest that TXA2 plays an important role in the development of bronchial asthma and OKY-046 might be a useful drug in the treatment of intractable asthmatics.

Topics: Adult; Aged; Asthma; Depression, Chemical; Dose-Response Relationship, Drug; Female; Humans; Interleukin-2; Interleukin-8; Lymphocyte Activation; Lymphocytes; Male; Methacrylates; Middle Aged; Neutrophils; SRS-A; Superoxides; Thromboxane-A Synthase

We examined the effect of a potent thromboxane (Tx) A2 receptor antagonist, calcium (1R, 2S, 3S, 4S)-(5Z)-7-(((phenylsulfonyl)amino)bicyclo[2.2.1] hept-2-yl)-5-heptenoate dihydrate (S-1452), on antigen- and various allergic-spasmogen-induced contractions of guinea pig lung parenchymal strips and on the increase in insufflation pressure, an index of bronchoconstriction, in anesthetized guinea pigs. In isolated guinea pig lung parenchymal strips, S-1452 showed competitive antagonism of the contractile activity of U-46619, a TxA2 mimetic, with a pA2 value of 8.9. The compound also inhibited the contraction induced by prostaglandin (PG) D2 and PGF2 alpha, but a TxA2 synthetase inhibitor, OKY-046, did not. In contrast, both drugs inhibited not only leukotriene (LT) D4-induced contraction but also antigen-induced contraction in the presence of a histamine antagonist. In anesthetized guinea pigs, oral administration of S-1452 markedly inhibited the bronchoconstrictions induced by intravenous injection of U-46619, PGD2, PGF2 alpha, LTD4 and platelet-activating factor (PAF) with ED50 values of 0.006, 0.031, 0.112, 0.033 and 0.115 mg/kg, respectively, but OKY-046 inhibited only that by LTD4 and PAF. Additionally, bronchoconstriction following intravenous injection of antigen was almost completely suppressed by S-1452 (0.1 mg/kg) and partially by OKY-046 (300 mg/kg) in passively sensitized guinea pigs which were treated with diphenydramine and propranolol. The inhibitory effect of S-1452 against U-46619-induced broncho-constriction persisted up to 7 h after oral administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Asthma; Bridged Bicyclo Compounds; Bronchoconstriction; Fatty Acids, Monounsaturated; Guinea Pigs; In Vitro Techniques; Lung; Male; Methacrylates; Muscle Contraction; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Thromboxane A2

In the present study, we investigated (1) whether airway responsiveness to inhaled histamine-aerosol could be induced during 7-d exposure of guinea pigs to 4 ppm NO2 and, if so, (2) whether thromboxane A2 may be involved in such increase. Female Hartley guinea pigs were divided into 6 groups (n = 15/group). Three groups were exposed to filtered air and the other 3 groups were exposed to NO2 for 1, 3, or 7 d (24 h/d). Baseline specific airway resistance (SRaw0) did not change significantly after exposure to 4 ppm NO2 or air. Airway responsiveness was determined 1 wk before the beginning of exposure and on the day of termination of the exposure. Prior to exposure to NO2, the EC200His, the concentrations of inhaled histamine necessary to double SRawNaCl (SRaw after inhalation of 0.9% NaCl), were 1.07 +/- 0.20, 1.30 +/- 0.20, and 1.01 +/- 0.18 mM for the 3 groups later given NO2 for 1, 3, and 7 d, respectively. Following exposure to NO2 for 1, 3, or 7 d, EC200His values were 1.42 +/- 0.25, 0.66 +/- 0.10 (p < .05), and 1.05 +/- 0.22 mM, respectively. These results show that 7-d exposure to 4 ppm NO2 induced a significant increase in airway responsiveness on d 3. Exposure to air had no significant effect on the airway responsiveness. This transient hyperresponsiveness was inhibited by a specific inhibitor of thromboxane synthetase, OKY 046. These results indicated that (1) a lower concentration (4 ppm) of NO2 than that previously reported can induce transient hyperresponsiveness in guinea pigs during appropriate long-term exposure, and (2) thromboxane A2 may play an important role in this transient airway hyperresponsiveness.

Topics: Administration, Inhalation; Air Pollutants; Airway Resistance; Animals; Asthma; Bronchial Hyperreactivity; Drug Hypersensitivity; Female; Guinea Pigs; Histamine; Lung; Methacrylates; Nitrogen Dioxide; Thromboxane A2; Thromboxane-A Synthase; Time Factors

Effects of a thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial hyperresponsiveness induced by subthreshold concentration of aerosolized thromboxane A2 analogue (STA2) were investigated in anesthetized, artificially ventilated guinea pigs in order to examine the role of the cyclooxygenase pathway in bronchial hyperresponsiveness. Pretreatment with aerosolized OKY-046 significantly inhibited the bronchial hyperresponsiveness to histamine, but pretreatment with intravenous indomethacin showed a tendency to potentiate bronchial hyperresponsiveness. These results suggest that subthreshold concentration of thromboxane A2 contributes to bronchial hyperresponsiveness through activating the cyclooxygenase pathway including thromboxane A2 synthesis, and that the released cyclooxygenase products have an inhibitory effect on the bronchial hyperresponsiveness in guinea pigs.

Topics: Aerosols; Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Dose-Response Relationship, Drug; Guinea Pigs; Indomethacin; Male; Methacrylates; Thromboxane A2

The effect of a thromboxane A2 synthetase inhibitor (OKY-046, 400 mg po/day) on mucociliary transport was investigated in 19 asthmatic patients. The nasal clearance time, as measured by the saccharin test, was prolonged in asthmatics (60.2 +/- 8.4 SE min) compared with normal controls (15.1 +/- 3.4 SE min). Within 4 weeks after OKY-046 administration, the nasal clearance time had improved (27.4 +/- 4.4 SE min, P less than .01) and the amount of sputum had decreased 30% (P less than .01). These results indicate that thromboxane A2 plays an important role in mucociliary transport in patients with asthma.

Topics: Aged; Asthma; Female; Forced Expiratory Volume; Humans; Male; Methacrylates; Middle Aged; Mucociliary Clearance; Nasal Mucosa; Sputum; 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

We studied the effects of OKY-046 on type I allergic reactions. OKY-046 (100 mg/kg) given orally suppressed antigen-induced bronchoconstriction and TXB2 generation in broncho alveolar lavage fluid in rats passively sensitized with anti-DNP-As monoclonal IgE. At the dose of 30 mg/kg given intraduodenally, it also inhibited antigen-induced bronchoconstriction in guinea pigs passively sensitized with anti DNP-As serum and actively sensitized with ovalbumin. However, aspirin (30 mg/kg) didn't suppressed them significantly. Azelastine (10 mg/kg) inhibited bronchoconstriction in passively sensitized rats and actively sensitized guinea pigs. In 48 hour homologous PCA reactions of rats and mice, oral administration of OKY-046 (300 mg/kg) and tranilast (100 mg/kg) suppressed the extravasated dye in the skin. OKY-046 decreased histamine release from passively sensitized rat peritoneal exudate cells. There was no effect of OKY-046 on SRS-A and leukotriene release from actively sensitized guinea pig lungs and passively sensitized rats. In conclusion, we think that OKY-046 should be an useful asthmatic drug or anti-allergic drug by oral administration.

Topics: Acrylates; Administration, Oral; Animals; Asthma; Bronchi; Depression, Chemical; Guinea Pigs; Histamine Release; Lung; Male; Methacrylates; Mice; Muscle Contraction; Muscle, Smooth; Passive Cutaneous Anaphylaxis; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2; 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

Topics: Acrylates; Arachidonic Acids; Asthma; Benzoquinones; Bronchoalveolar Lavage Fluid; Chromones; Cyclooxygenase Inhibitors; Humans; Indomethacin; Leukocytes; Lipoxygenase Inhibitors; Lung; Macrophages; Methacrylates; Quinones; Thromboxane-A Synthase

To determine whether the involvement of thromboxane A2 in bronchial hyperresponsiveness is specific to asthma, we examined the effects of a selective thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial responsiveness to methacholine in patients with bronchial asthma and chronic bronchitis. The provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20-FEV1) was measured before and after oral administration of OKY-046 and indomethacin in eight asthmatic and 10 bronchitic subjects. Baseline FEV1 value was not altered by OKY-046 or indomethacin. The geometric mean value of PC20-FEV1 increased significantly (p less than 0.005) from 1.78 to 4.27 mg/ml after OKY-046 in asthmatic subjects, but not in bronchitic subjects. On the other hand, PC20-FEV1 was not altered by indomethacin in all subjects. It was concluded that the involvement of thromboxane A2 in bronchial hyperresponsiveness may be specific to asthma.

Topics: Asthma; Bronchi; Bronchial Provocation Tests; Bronchitis; Chronic Disease; Female; Humans; Male; Methacholine Chloride; Methacholine Compounds; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane-A Synthase

To determine whether the involvement of thromboxane A2 in bronchial hyperresponsiveness (BHR) is specific to asthma, we examined the effects of a selective inhibitor of thromboxane synthetase (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial responsiveness to methacholine in normal subjects and patients with chronic bronchitis, diffuse bronchiectasis, and intrinsic bronchial asthma. The provocative concentration of methacholine producing a 20 percent fall in forced expiratory volume in 1 s (PC20-FEV1) was measured before and after oral administration of OKY-046 (2,600 mg over four days) and indomethacin (450 mg over three days) in ten normal, ten bronchitic, nine bronchiectatic, and eight asthmatic subjects, respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by OKY-046 or indomethacin. The geometric mean value of PC20-FEV1 increased significantly (p less than 0.005) from 1.78 to 4.27 mg/ml after OKY-046 in asthmatic subjects, but not in normal, bronchitic, or bronchiectatic subjects. On the other hand, PC20-FEV1 increased significantly (p less than 0.005) from 2.19 to 8.13 mg/ml after indomethacin in bronchiectatic subjects, but not in normal, bronchitic, or asthmatic subjects. We conclude that the involvement of thromboxane A2 in BHR may be specific to asthma, and bronchial responsiveness of bronchiectasis may be potentiated by inflammatory release of bronchoconstrictor prostaglandins except for thromboxane A2. Further studies using thromboxane A2 receptor antagonists are needed to confirm the conclusion.

Topics: Acrylates; Asthma; Bronchi; Bronchial Provocation Tests; Bronchiectasis; Bronchitis; Female; Forced Expiratory Volume; Humans; Indomethacin; Male; Methacholine Chloride; Methacholine Compounds; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane-A Synthase; Vital Capacity

We studied the inhibitory effects of OKY-046.HCl on PAF-induced airway hyperresponsiveness (AHR) in guinea pigs. 1) Inhalation of PAF (1 or 10 micrograms/ml) caused AHR to acetylcholine (ACh) aerosol and increased TXB2 generation in broncho-alveolar lavage fluid (BALF) at 30 min and 60 min, but the AHR and the TXB2 generation disappeared at 2 hr. OKY-046.HCl (100 mg/kg, intraduodenally) inhibited the AHR, which was accompanied by its inhibition of the TXB2 generation. However, no changes of 6-keto-PGF1 alpha in BALF were found. 2) There were no changes in the number of leukocytes; the activities of alkaline phosphatase, N-acetyl-beta-D-glucosaminidase, and lactate dehydrogenase; and the LTC4/D4/E4 in BALF. 3) In bronchus-lung preparations, PAF (1 microgram/min) also caused the AHR and increased TXB2 generation. OKY-046.HCl (100 micrograms/min) inhibited the AHR and TXB2 generation. 4) PAF (1 microgram/ml) evoked TXB2 generation in BALF from normal guinea pigs. OKY-046.HCl (10(-4)M) inhibited its increase. 5) Stable TXA2 (STA2, 1 ng/ml) inhalation also caused AHR to ACh at 30 min. STA2 (0.45 ng/min) also caused the AHR in bronchus-lung preparations. These results suggest that OKY-046.HCl can inhibit PAF-induced AHR by suppressing the generation of TXA2. We also supposed that TXA2 is released from lung parenchyma, airway epithelium and cell components in BALF.

Topics: Acrylates; Animals; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Guinea Pigs; In Vitro Techniques; Male; Methacrylates; Platelet Activating Factor; Thromboxane A2; Thromboxane-A Synthase

The effect of ozagrel (OKY-046), a selective thromboxane A2 synthetase inhibitor, on theophylline disposition was studied in 12 asthmatic patients. Ozagrel was administered at a dose of 200 mg twice daily for 24 weeks to 4 outpatients receiving oral theophylline medication. Blood samples were drawn from each patient visiting the hospital at one to four-week intervals. There were no clinical significant changes between the time course profiles of serum theophylline concentration during the treatment and those after the cessation of ozagrel dosing. In addition, another 8 hospitalized patients received a single intravenous infusion of aminophylline (200 mg as theophylline) before and after ozagrel treatment of 200 mg twice daily for 7 days. No statistical significant alteration in elimination half-life, total body clearance or volume of distribution of theophylline was observed by the administration of ozagrel. These results suggest that ozagrel does not inhibit the metabolism of theophylline despite having an imidazole ring in its chemical structure.

Topics: Acrylates; Adult; Aged; Asthma; Drug Interactions; Female; Half-Life; Humans; Male; Methacrylates; Middle Aged; Theophylline; Thromboxane-A Synthase

To elucidate the possible involvement of thromboxane A2 (TxA2) in airway hyperresponsiveness, we examined the effect of OKY-046, a potent and selective inhibitor of TxA2 synthetase, on airway hyperresponsiveness induced by ozone exposure in dogs. Ozone exposure (3 ppm, 2 hr) markedly increased airway responsiveness to inhaled methacholine without affecting basal respiratory resistance. Although ozone also caused a slight but significant increase in neutrophil number in the bronchoalveolar lavage fluid, there was no correlation between the level of airway hyperresponsiveness and increased neutrophil number. Although OKY-046 significantly inhibited the increases in airway hyperresponsiveness in a dose-dependent manner at doses ranging from 100 to 300 mg/kg, p.o., the compound did not affect the basal airway responsiveness and respiratory resistance at 300 mg/kg, p.o. Inhalation of the subthreshold concentration (i.e., the highest dose which did not cause bronchoconstriction) of STA2 (a stable TxA2 mimetic agent) elicited a significant increase in airway responsiveness to methacholine. These results suggest that TxA2 may play a role in mediating ozone-induced airway hyperresponsiveness. However, the accumulation of neutrophils in the airway lumen may not be essential for the development of airway hyperresponsiveness.

Topics: Acrylates; Animals; Asthma; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Methacrylates; Ozone; Thromboxane A2; Thromboxane-A Synthase

Bronchial hyperresponsiveness is one of the major clinical features of bronchial asthma. We previously reported that oral administration of a selective thromboxane synthetase inhibitor, OKY-046, reduced bronchial hyperresponsiveness to acetylcholine in asthmatic subjects. In this study, the effect of aerosol administration of OKY-046 on bronchial hyperresponsiveness was evaluated in ten inpatients with intrinsic asthma. Acetylcholine inhalation tests were performed before and after four days of inhalation of OKY-046 (100 mg/day). The provocative concentration of acetylcholine producing a 20 percent fall in forced expiratory volume in 1 s (PC20-FEV1) and that causing a 35 percent fall in respiratory conductance (PC35-Grs) were measured as indexes of bronchial responsiveness. There was a significant increase in PC20-FEV1 (p less than 0.001) and PC35-Grs (p less than 0.02) after inhalation of OKY-046 from 0.79 (GSEM, 1.41) Mg/ml and 0.96 (GSEM, 1.35) mg/ml to 1.20 (GSEM, 1.41) mg/ml and 1.74 (GSEM, 1.32) mg/ml, respectively. There was no significant difference in forced vital capacity (FVC), FEV1, or respiratory resistance (Rrs) baseline values before and after inhalation of OKY-046. Platelet aggregation was not inhibited by the treatment in other five inpatients. Thus, prophylactic administration of aerosol OKY-046 may be available for treatment of asthma by reduction of bronchial hyperresponsiveness. Further studies are needed to determine the optimum dose.

Topics: Acetylcholine; Acrylates; Administration, Inhalation; Aerosols; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Female; Forced Expiratory Volume; Humans; Male; Methacrylates; Middle Aged; Thromboxane-A Synthase

To determine whether O3 exposure increased airway responsiveness to antigen inhalation, we studied airway responsiveness to acetylcholine (ACh) and Ascaris suum antigen (AA) before and after O3 in dogs both sensitive and insensitive to AA. Airway responsiveness was assessed by determining the provocative concentration of ACh and AA aerosols that increased respiratory resistance (Rrs) to twice the base-line value. O3 (3 parts per million) increased airway responsiveness to ACh in dogs both sensitive and insensitive to AA, and it significantly decreased the ACh provocation concentration from 0.541 +/- 0.095 to 0.102 +/- 0.047 (SE) mg/ml (P less than 0.01; n = 10). AA aerosols, even at the highest concentration in combination with O3, did not increase Rrs in dogs insensitive to AA. However, O3 increased airway responsiveness to AA in AA-sensitive dogs and significantly decreased log AA provocation concentration from 2.34 +/- 0.22 to 0.50 +/- 0.17 (SE) log protein nitrogen units/ml (P less than 0.01; n = 7). O3-induced hyperresponsiveness to ACh returned to the base-line level within 2 wk, but hyperresponsiveness to AA continued for greater than 2 wk. The plasma histamine concentration after AA challenge was significantly higher after than before O3 (P less than 0.01). Intravenous infusion of OKY-046 (100 micrograms.kg-1.min-1), an inhibitor of thromboxane synthesis, inhibited the O3-induced increase in responsiveness to ACh, but it had no effects on the O3-induced increase in responsiveness to AA and the increase in the plasma histamine concentration. These results suggest that O3 increases susceptibility to the antigen in sensitized dogs via a different mechanism from that of O3-induced muscarinic hyperresponsiveness.

Topics: Acetylcholine; Aerosols; Airway Resistance; Animals; Antigens, Helminth; Ascaris; Asthma; Dogs; Female; Histamine; Male; Methacrylates; Ozone; Skin Tests; Thromboxane-A Synthase

To determine whether thromboxane A2 (TXA2) participates in allergen-induced asthmatic responses, we measured plasma TXB2 levels during allergen-induced immediate and late asthmatic responses (IAR and LAR) in atopic asthmatics. We also examined the effect of a TXA2 synthetase inhibitor, OKY-046, on the responses. Plasma TXB2 levels increased in both IAR and LAR, being 2.2 times higher in LAR than in IAR. Plasma TXB2 levels in LAR reached the peak 4 hours after allergen challenge when FEV1 had just begun to decrease in LAR. OKY-046 inhibited both IAR and LAR with decreased plasma TXB2 levels. We conclude that TXA2 is produced in allergen-induced asthmatic responses and participates in the responses, especially in inducing LAR.

Topics: Adult; Allergens; Asthma; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Male; Methacrylates; Thromboxane A2; Thromboxane-A Synthase; Time Factors

The effect of the thromboxane (TX) A2 synthetase inhibitor, OKY-046, on human leukocyte histamine release and bronchial hypersensitivity in asthmatic subjects was evaluated. It was found that OKY-046 inhibited IgE- and Ca2+ ionophore A23187-mediated leukocyte histamine release in a dose-dependent fashion (IC50: 1.0 and 3.0 X 10(-3) M, respectively) and that OKY-046 could diminish bronchial hypersensitivity, determined by leukotriene D4 inhalation, following a 2-week oral medication. These data suggest that the TXA2 synthetase inhibitor can produce favorable effects upon the course of immediate-type hypersensitivity reactions.

Topics: Acrylates; Asthma; Bronchial Provocation Tests; Calcimycin; Drug Evaluation; Female; Histamine Release; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Leukocytes; Male; Methacrylates; SRS-A; Thromboxane-A Synthase

The effect of OKY-046, a newly synthetized thromboxane A2 (TxA2) synthetase inhibitor, on IgE mediated experimental asthma in guinea pigs was investigated. Indomethacin, a cyclooxygenase inhibitor, and tranilast (N-5'), a potent anti-allergic agent, were used as comparative drugs. OKY-046 clearly improved asthmatic respiratory disorders in guinea pigs. Whereas indomethacin had no effect on the changes of asthmatic respiration, tranilast significantly inhibited the changes. OKY-046 inhibited the in vitro antigen-induced contraction of sensitized guinea pig lung parenchyma. This antigen-induced contraction was also inhibited by tranilast, but not by indomethacin. OKY-046 inhibited the contractions of lung parenchyma caused by leukotriene C4, D4 and E4 (LTC4, LTD4 and LTE4), but not by histamine. Indomethacin showed a biphasic action on the contractile responses caused by histamine and LTD4 Consequently, contractions due to either agonist at low concentrations were inhibited by indomethacin, but those at high concentrations were enhanced. Tranilast inhibited the contraction of lung parenchyma induced by a low concentration of LTD4 but not that produced by histamine. Moreover, OKY-046 inhibited an elevation of concentration of thromboxane B2 (TxB2) in guinea pig lung perfusate after infusion of LTC4 but did not affect the elevation of 6-keto-PGF1 alpha. OKY-046 had no effect on the antigen-induced release of histamine but it inhibited the release of the slow reacting substance of anaphylaxis (SRS-A) from sensitized chopped lung tissues. Indomethacin at a high concentration inhibited the release of histamine but did not affect the release of SRS-A. Tranilast clearly inhibited the release of both mediators. These results suggest that OKY-046 inhibits IgE mediated experimental asthma in guinea pigs and that its main mechanism is related to the inhibition of LT induced contraction of airway smooth muscle and the release of SRS-A from lung tissues.

Topics: Acrylates; Animals; Asthma; Female; Guinea Pigs; Histamine; Histamine Release; Indomethacin; Lung; Male; Methacrylates; Muscle Contraction; Respiration; SRS-A; Thromboxane-A Synthase

Since inhibition of cyclo-oxygenase precipitates asthmatic attacks in patients with aspirin idiosyncrasy, we have evaluated the effects of pharmacological inhibition of the next enzyme in arachidonic acid cascade, i.e., thromboxane synthetase. Twelve patients with aspirin-induced asthma received on 3 days increasing doses (25-400 mg) of an imidazole derivative, OKY-046, which specifically blocks TXA2 synthetase. Twelve healthy controls received a single dose of 400 mg OKY-046. The drug neither precipitated asthmatic attacks nor altered pulmonary function tests throughout a 24-hr observation period. Five of 12 patients, but none of the controls, developed nasal congestion, approximately 1 hr after ingestion of the inhibitor. Though initial platelet aggregation evoked by arachidonic acid or ADP did not differ between the two groups, inhibitory effects of 400 mg OKY-046 on the aggregability were more pronounced in the patients than in the controls. Thus, inhibition of TXA2 synthetase, contrary to inhibition of cyclo-oxygenase, does not affect bronchopulmonary function in patients with asthma and aspirin intolerance. It does, however, often produce nasal congestion, possibly through reorientation of prostanoid synthesis from TXA2 to PGD2. It remains to be established whether pronounced depressive effects of a TXA2 synthetase inhibitor on platelet aggregability constitute a treat of aspirin idiosyncrasy or is a more general phenomenon associated with bronchial asthma.

Topics: Adult; Arachidonic Acid; Arachidonic Acids; Aspirin; Asthma; Drug Hypersensitivity; Female; Humans; Male; Methacrylates; Middle Aged; Platelet Aggregation; Thromboxane-A Synthase

Topics: Acetylcholine; Acrylates; Adolescent; Adult; Asthma; Bronchi; Bronchial Provocation Tests; Female; Humans; Male; Methacrylates; Middle Aged; Respiration; SRS-A; Thromboxane-A Synthase

Since inhibition of cyclooxygenase precipitates asthmatic attacks in patients with aspirin idiosyncrasy, we have evaluated the effects of pharmacologic inhibition of thromboxane A2 (TXA2) synthetase, next to cyclooxygenase enzyme in arachidonic acid cascade. Sixteen patients with aspirin-induced asthma received increasing doses on 3 days (25 to 400 mg) of an imidazole derivative, OKY-046, which specifically blocks TXA2 synthetase. Twenty-three healthy control subjects received a single dose of 400 mg of OKY-046. In both patients and control subjects, the inhibitor at a dose of 400 mg produced (1) a pronounced fall in thromboxane B2 serum levels, (2) a rise in serum 6-keto-prostaglandin F1 alpha, and (3) a depression in platelet aggregability to arachidonic acid and adenosine diphosphate. The drug, however, neither precipitated attacks of asthma nor impaired pulmonary function tests throughout a 24-hour observation period. Five patients, but none of the control subjects, developed transient nasal congestion about 1 hour after taking the drug. Thus, inhibition of TXA2 synthetase, contrary to inhibition of cyclooxygenase, does not affect bronchopulmonary function in patients with asthma and aspirin intolerance.

Topics: Acrylates; Adult; Aspirin; Asthma; Female; Humans; Male; Methacrylates; Middle Aged; Respiratory Function Tests; Thromboxane A2

The effect of a selective thromboxane synthetase inhibitor, OKY-046, and a selective 5-lipoxygenase inhibitor, AA-861, on bronchial responsiveness to acetylcholine was studied in 23 asthmatic subjects. The provocative concentration of acetylcholine producing a 20% fall in forced expiratory volume in one second (PC20 FEV1) was measured before and after oral administration of OKY-046 (3000 mg over four days) and AA-861 (1100 mg over four days) and inhalation of OKY-046 (30 mg) in 10, 10, and nine asthmatic subjects respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by oral OKY-046, oral AA-861, or inhaled OKY-046. The geometric mean value of PC20 FEV1 increased significantly from 0.55 to 2.24 mg/ml after oral OKY-046, but was unchanged after inhalation of OKY-046 and after oral administration of AA-861. These results suggest that thromboxane A2 may play a part in bronchial hyperresponsiveness to acetylcholine.

Topics: Acetylcholine; Acrylates; Adult; Aged; Asthma; Benzoquinones; Bronchi; Bronchial Provocation Tests; Female; Humans; Male; Methacrylates; Middle Aged; Quinones