ozagrel and Chronic-Disease

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

The mechanisms of excessive sputum production are only partially understood. We speculated that a selective thromboxane (Tx) A2 synthetase inhibitor, OKY-046, now used in the treatment of asthma in Japan, could decrease excess sputum production in patients with chronic airways disease. To test this hypothesis, we carried out a double-blind, placebo-controlled study of the effects of OKY-046, administered orally at 400 mg.day-1, on the sputum of patients with chronic bronchitis and patients with diffuse panbronchiolitis. Patients treated with OKY-046 showed a significant decrease (22%) in sputum volume after 1 month, and a 39% decrease after 3 months. Although the rheological properties of the sputum and the concentrations of fucose and immunoglobulin (Ig) A in the sputum remained unchanged, significant decreases were observed in the concentrations of total protein, albumin, sialic acid and phospholipid. Since albumin and fucose are chemical markers of plasma exudation and mucus secretion, respectively, whilst sialic acid and phospholipid are derived both from serum and mucus, our results indicate that this TxA2 synthetase inhibitor reduced sputum volume by inhibiting microvascular leakage in the airway. OKY-046 may, therefore, be of value in the treatment of chronic bronchitis and diffuse panbronchiolitis.

Topics: Adult; Aged; Bronchiolitis; Bronchitis; Chronic Disease; Double-Blind Method; Enzyme Inhibitors; Female; Humans; Male; Methacrylates; Middle Aged; Respiratory Function Tests; Rheology; Sputum; Thromboxane A2; Thromboxane-A Synthase

Topics: Adult; Chronic Disease; Creatinine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Kidney Transplantation; Male; Methacrylates; Prospective Studies; Thromboxane-A Synthase; Time Factors

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

Ciclosporin A (CsA) is a potent immunosuppressive agent which is extremely effective in controlling allograft rejection and in the treatment of autoimmune disease and nephrotic syndrome. Unfortunately, its use is limited by chronic, irreversible nephrotoxicity. Administration of CsA induces renal vasoconstriction, causing a reduction in renal blood flow. An alteration of the prostaglandin-thromboxane cascade may be involved in the vasoconstriction. We studied the role of thromboxane A2 in CsA nephrotoxicity and the ability of a thromboxane synthase inhibitor, OKY-046, to reduce the CsA nephrotoxicity. Daily administration of CsA 25 mg/kg for 28 days to Sprague-Dawley rats resulted in increased excretion of urinary thomboxane B2 (47.9+/-11.5 vs. 27.2+/-9.7 ng/24 h; p<0.05) and decreased creatinine clearance (0.25+/-0.07 vs. 0.43+/-0.17ml/min/100 g; p<0.01) as compared with administration of vehicle only. Histologically, large numbers of lysosomes in the tubular epithelium were characteristic. Coadministration of OKY-046 prevented both the rise in urinary thromboxane B2 excretion (40.0+/-11.8 ng/24 h) and the reduction in the creatinine clearance (0.44+/-0.11 ml/min/100 g). The severity of the histological changes was significantly diminished. Selective inhibition of thromboxane production with OKY-046 may be valuable in the attenuation of CsA nephrotoxicity.

Topics: Animals; Chronic Disease; Cyclosporine; Drug Evaluation, Preclinical; Enzyme Inhibitors; Kidney Diseases; Male; Methacrylates; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane-A Synthase

We studied the effects of the thromboxane-synthetase inhibitor ozagrel in 22 patients with chronic persistent coughing who did not have airwayhyperresponsiveness. Treatment with ozagrel (400 mg/day for 2 weeks) reduced coughing in 12 patients. Sputum from the patients in whom ozagrel was effective had a higher percentage of lymphocytes and a lower percentage of neutrophils than did sputum from those in whom ozagrel was not effective. Furthermore, in the former group the capsaicin cough threshold increased but in the latter it did not change consistently. These data indicate that thromboxane A2 may contribute to coughing associated with lymphocytic airway inflammation.

Topics: Adult; Aged; Bronchial Hyperreactivity; Chronic Disease; Cough; Enzyme Inhibitors; Female; Humans; Male; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane-A Synthase

A 25-year-old woman complained of coughing for over 8 weeks. The coughing was not relieved by a bronchodilator (beta 2-adrenoceptor agonist; clenbuterol), and anti-allergic agent (azelastine), or an inhaled corticosteroid. The thromboxane synthetase inhibitor ozagrel completely abolished her cough. In this case, thromboxane A2 may have contributed to the coughing.

Topics: Adult; Antitussive Agents; Chronic Disease; Cough; Female; Humans; Methacrylates; Thromboxane A2; Thromboxane-A Synthase

Topics: Arterial Occlusive Diseases; Aspirin; Chronic Disease; Epoprostenol; Fatty Acids, Monounsaturated; Humans; Methacrylates; Polydeoxyribonucleotides; Pyridines; Thromboxane A2; 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

There has been no useful treatments for chronic vascular rejection (CVR) after kidney transplantation until now. Recently, however, some reports have suggested that the thromboxane A2 synthetase inhibitor, OKY-046, is useful in reducing proteinuria in nephrotic syndrome and preventing progression of CVR. Five patients with CVR (serum creatinine range: 1.7-2.6 mg/dl) were treated with OKY-046 for over one year and the effect of OKY-046 was evaluated. One patient developed acute rejection and another renal hypertension during this study. Except for the cases of acute rejection and renal hypertension, serum creatinine slightly decreased in 1 case and remained unchanged in 2 cases. Urinary excretion of protein and thromboxane B2 decreased significantly but prostaglandin E2 did not change in the treatment of the deterioration with OKY-046. We concluded that OKY-046 was effective in preventing graft function and decreasing urinary protein excretion in kidney transplant recipients with CVR.

Topics: Acrylates; Chronic Disease; Female; Graft Rejection; Humans; Kidney; Kidney Transplantation; Male; Methacrylates; Prostaglandins E; Proteinuria; Thromboxane B2; Thromboxane-A Synthase

Topics: Acrylates; Chronic Disease; Epoprostenol; Graft Rejection; Humans; Kidney Transplantation; Methacrylates; Thromboxane-A Synthase; Ticlopidine; Time Factors; Vascular Diseases

Topics: Acrylates; Chronic Disease; Female; Glomerulonephritis; Humans; Male; Methacrylates; Thromboxane A2; Thromboxane-A Synthase