thromboxane-b2 and seratrodast

It has been reported that the biosynthesis of thromboxane A2 (TXA2) is enhanced in platelets in the presence of chronic obstructive pulmonary disease (COPD), and 11-dehydro-TXB2, a urinary metabolite of thromboxane, also increases in blood. In the present study, seratrodast (CAS 112665-43-7, Bronica), a TXA2 receptor antagonist, was administered to 14 patients with chronic pulmonary emphysema in the stable phase for 8 weeks. Respiratory distress was evaluated in the attending physicians' judgments using the Hugh-Jones (H-J) classification, and also by the patients themselves using the Borg scale. Respiratory function tests, including forced vital capacity (FVC), percent of one second forced expiratory volume (FEV1.0%), arterial blood gases during respiration of room air, and peak expiratory flows (PEF) (morning and evening), and measurement of plasma 11-denhydro-TXB2 and TXB2 levels were performed before and 8 weeks after the start of administration, as well as at the time of the start of administration. The results revealed significant improvement of respiratory distress, evaluated on both the H-J classification and the Borg scale, at week 8. Although no significant changes were observed in plasma TXB2 levels, the plasma 11-dehydro-TXB2 level significantly decreased at week 8. Among the respiratory function parameters examined, only FVC was significantly improved. These results indicated that seratrodast is useful for the improvement of respiratory distress in patients with chronic pulmonary emphysema in the stable phase.

Topics: Aged; Aged, 80 and over; Anti-Asthmatic Agents; Benzoquinones; Carbon Dioxide; Chronic Disease; Dyspnea; Female; Forced Expiratory Volume; Heptanoic Acids; Humans; Immunoglobulin E; Male; Middle Aged; Oxygen; Peak Expiratory Flow Rate; Prostaglandin Antagonists; Pulmonary Emphysema; Respiratory Function Tests; Smoking; Thromboxane A2; Thromboxane B2

Thromboxane (TX) A2 is an important bronchoconstrictor in the pathogenesis of asthma. Seratrodast, known as AA-2414, is a new oral TXA2 receptor antagonist which is currently prescribed in asthma therapy in Japan. However its clinical effects have been very different in individual subjects. To assess whether the clinical efficacy of TXA2 antagonist is predictable on the basis of urinary arachidonic acid metabolites in urine of patients with asthma, an open and multicentre trial was conducted. Fifty adult asthmatic subjects (women/men = 28/22) were enrolled [resting mean forced expiratory volume in 1 sec (FEV1)% was 82%; range, 50-96%]. Urinary levels of 11-dehydro-TXB2, leukotriene (LT) E4, 2,3-dinor-6-keto-prostaglandin F1alpha and creatinine in 3-h urine collected in the morning at the start of seratrodast (80 mg day(-1), once a day at evening for 4 weeks) were measured. Responders were defined by improvements of asthma symptoms score and peak expiratory flow rate (PEFR). Of the 50 subjects, 45 completed this study. Eighteen patients were responders and the other 27 were nonresponders. There were no significant differences between the two groups in patients' characteristics, baseline lung functions, treatments and baseline urinary eicosanoids. The 11-dehydro-TXB2/LTE4 ratio of responders was significantly higher (P = 0.0091) than that of non-responders (mean +/- SE, 7.49+/-0.71 vs. 5.09+/-0.67). Eleven patients out of 18 responders agreed to continue this drug for 6 months, the 11-dehydro-TXB2/LTE4 ratio decreased during this period, but not significantly. Our data demonstrated that responders and non-responders to TXA2 receptor antagonist existed in patients with asthma, and it suggests that the ratio of urinary eicosanoids might be a possible predictor of the effects of TXA2 receptor antagonist.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Anti-Asthmatic Agents; Asthma; Benzoquinones; Creatinine; Eicosanoids; Female; Forced Expiratory Volume; Heptanoic Acids; Humans; Leukotriene E4; Male; Middle Aged; Peak Expiratory Flow Rate; Receptors, Thromboxane; Thromboxane B2

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

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Oral; Adolescent; Adult; Benzoquinones; Body Weight; Double-Blind Method; Heptanoic Acids; Humans; Leukotriene B4; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Quinones; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

Cigarette smoking is one of the risk factors for chronic obstructive pulmonary disease (COPD). In this study, we investigated the effects of thromboxane A2 (TxA2) receptor antagonists on airway mucus production induced by cigarette smoke. Rats were exposed to cigarette smoke 1h/day, 6 days/week for 4 weeks. Seratrodast (2, 5, 10mg/kg day) was administered intragastrically prior to smoke exposure. Thromboxane B2 (TxB2) in the bronchoalveolar lavage fluid and lung tissues was determined by enzyme immunoassay. Airway mucus production was determined by alcin-blue/periodic acid sthiff (AB-PAS) staining, Muc5ac immunohistochemical staining, and RT-PCR. The phosphorylation of ERK and p38 was evaluated by Western blotting. Seratrodast reduced the overproduction of TxB2 in both bronchoalveolar lavage fluid and lung tissues. Cigarette smoke exposure markedly increased AB/PAS-stained goblet cells and rat Muc5ac expression in the airway, which was significantly attenuated by seratrodast administration. The induced phosphorylation of ERK and p38 was also attenuated by seratrodast. TxA2 receptor antagonist could reduce Muc5ac production induced by cigarette smoke in vivo, possibly through the mitogen-activated protein kinases (MAPK) signaling pathway.

Topics: Animals; Anti-Asthmatic Agents; Benzoquinones; Bronchoalveolar Lavage Fluid; Heptanoic Acids; Lung; Male; Mitogen-Activated Protein Kinases; Mucin 5AC; Mucus; Nicotiana; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane A2, Prostaglandin H2; Smoke; Thromboxane B2

Little is known about any changes in cerebral hemodynamics, during and after abdominal aortic cross-clamping and unclamping, especially in the cerebral microcirculation. We studied the effects of abdominal aortic cross-clamping and unclamping on cerebral pial vessel diameter in the presence or absence of the thromboxane (Tx)A(2) receptor antagonist using a closed cranial window in 27 rabbits. Although infrarenal aortic cross-clamping did not affect pial vessel diameter, release of a 20-min aortic cross-clamp caused pial arterioles to dilate and then constrict. A significant constriction persisted for at least 60 min (maximum, -17% for large [> or =75 micro m] and -28% for small arterioles [<75 micro m] compared with baseline). Topical administration of a TxA(2) receptor antagonist, seratrodast, at 10(-7) M and 10(-6) M, significantly attenuated the constriction of large and small arterioles (at 60 min, -9% and -13% constriction for 10(-7) M, and -6% and -7% for 10(-6) M). Release of a 20-min aortic cross-clamp induced a sustained pial arteriolar constriction. Because this unclamping-induced vasoconstriction was attenuated by topical administration of seratrodast, it was likely partially mediated via the washout of TxA(2) produced in the ischemic region during the clamp and after cross-clamp release.. Abdominal aortic unclamping after a 20-min clamp caused an initial dilation followed by a sustained constriction of pial arterioles. Seratrodast, a thromboxane A(2) receptor antagonist, attenuated the vasoconstriction suggesting that it is at least partly mediated by thromboxane A(2) washed out from the region rendered ischemic by clamping.

Topics: Animals; Aorta, Abdominal; Arterioles; Benzoquinones; Blood Pressure; Carbon Dioxide; Cerebrovascular Circulation; Constriction; Heart Rate; Hemodynamics; Heptanoic Acids; Hydrogen-Ion Concentration; Microcirculation; Prostaglandin Antagonists; Rabbits; Receptors, Thromboxane; Thromboxane B2

Seratrodast, an antagonist to thromboxane A2 (TXA2) receptors, is not always effective in patients with bronchial asthma. In fact, some respond definitely to this drug while others not. In the present study, to clarify the predictability of the clinical effects of Seratrodast, we investigated whether there is a correlation between the levels of TXB2 and 11-DHTXB2, both of which are metabolites of TXA2, in urine and sputum taken before the administration and the clinical effects seen after initiation of the treatment. Baseline concentrations of TXA2 metabolites in urine/sputum were not significantly different between responders and non-responders. However, 4 cases who had remarkably responded to Seratrodast had significantly higher baseline 11-DHTXB2 levels than the rest of the patients. These results suggested that bronchial asthma patients with high urinary 11-DHTXB2 levels could markedly respond to Seratrodast treatment.

Topics: Adult; Aged; Anti-Asthmatic Agents; Asthma; Benzoquinones; Female; Heptanoic Acids; Humans; Male; Middle Aged; Prostaglandin Antagonists; Sputum; Thromboxane A2; Thromboxane B2

The effects of YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl )propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene D(4) and thromboxane A(2) receptors, on antigen-induced increases in airway resistance were investigated in mediator-controlled novel asthmatic models using actively sensitized guinea pigs. While the predominant mediator was thromboxane A(2), complete inhibition of cyclooxygenase induced mediation by cysteinyl-leukotrienes. About 1-mg/kg indomethacin induced a state where both mediators participated equally. YM158 inhibited increases in resistance whether only one or both mediators were involved. When leukotriene D(4) and thromboxane A(2) equally participated, ED(50) values for 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4 H-1-benzo pyran hemihydrate (pranlukast; 3.9 mg/kg) and 7-(3,5,6-trimethyl-1, 4-benzoquinon-2-yl)-7-phenylheptanoic acid (seratrodast; 2.1 mg/kg) were similar to that for YM158 (8.3 mg/kg), although those effects on the corresponding mediator-induced reaction were 10 times stronger than those of YM158. Additionally, the maximum inhibition of YM158 was stronger than those of either single receptor antagonist. In conclusion, YM158 has a potentially greater efficacy in wider types of experimental asthmatic models than single receptor antagonists.

Topics: Administration, Oral; Airway Resistance; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Asthma; Benzoquinones; Chromones; Dose-Response Relationship, Drug; Guinea Pigs; Heptanoic Acids; Indomethacin; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Leukotriene E4; Lipid Metabolism; Lung; Male; Membrane Proteins; Ovalbumin; Receptors, Leukotriene; Receptors, Thromboxane; Tetrazoles; Thiazoles; Thromboxane B2; Time Factors

The airway of asthmatic patients is hyperresponsive to various stimuli in vivo. There are, however, only a few reports that compared the in vivo responsiveness of asthmatic patients and non-asthmatic subjects to those of lung parenchyma in vitro.. To compare the contractile response, release of various chemical mediators, and responsiveness to drugs in samples of lung parenchyma excised from asthma patients with those of non-asthmatic subjects.. Human lung parenchymal strips were subjected to passive sensitization with sera of 5+ RAST titer to mites. The strip was suspended in a magnus bath containing a buffer solution. Parenchymal contraction was induced by PGF2 alpha. After washing, the baseline concentrations of thromboxane B2 (TXB2), leukotriene (LT), and histamine were measured in each bath and then contraction was induced by the addition of a mite antigen. The concentrations of TXB2, LT, and histamine were measured after contraction. The inhibitory effects of TXA2 synthetase inhibitor (DP-1904) and TXA2 receptor antagonist (AA-2414) were also evaluated in both tissue samples.. There were no significant differences between lung parenchymal tissues of asthmatic and non-asthmatic patients with regard to PGF2 alpha-induced contraction, antigen-induced contraction, release of chemical mediators, and the response to drugs.. Unlike the response in vivo, there are no differences in the response to stimuli in vitro between lung parenchymal tissues of asthmatic and non-asthmatic patients.

Topics: Aged; Airway Resistance; Animals; Antigens; Ascaris; Asthma; Benzoquinones; Dinoprost; Dogs; Female; Heptanoic Acids; Histamine Release; Humans; Immune Sera; Immunization, Passive; Leukotrienes; Lung; Male; Middle Aged; Mites; Muscle Contraction; Muscle, Smooth; Radioallergosorbent Test; Smoking; Thromboxane B2; Thromboxane-A Synthase

We hypothesized that AA-2414, a novel thromboxane receptor blocker with antioxidant properties, would inhibit peroxide-induced vasoconstriction in the isolated perfused human placental cotyledon. In study 1, placental cotyledons (n = 5) were perfused serially for 20- min intervals with control KrebsRinger-bicarbonate (KRB) buffer, t-butyl hydroperoxide (Px; 100 microM), KRB buffer, and KRB buffer containing Px to which progressively increasing concentrations of AA-2414 were added (1 x 10(-8) to 1 x 10(-4) mol/l). In study 2, placental cotyledons (n = 6) were perfused with control KRB buffer, Px alone, KRB buffer, 1 x 10(-5) mol/l AA-2414 alone, Px plus AA-2414, and Px alone. Compared with control, perfusion with Px significantly increased perfusion pressure, vascular resistance, and the maternal and fetal secretion rates of lipid peroxides, thromboxane B2 (TXB2) and 6-keto prostaglandin F1alpha. In study 1, AA-2414 + Px produced a dose-response inhibition of Px-induced increases in perfusion pressure, vascular resistance, and maternal secretion of lipid peroxides and TXB2. In study 2, perfusing AA-2414 at a dose of 1 x 10(-5) mol/l completely inhibited Px-induced vasoconstriction and increases in lipid peroxide and TXB2 secretion rates, but only partially inhibited the increase in 6-keto prostaglandin F1alpha secretion. We conclude that AA-2414 inhibited peroxide-induced vasoconstriction in the human placenta, as well as peroxide- induced increases in the placental secretion rates of lipid peroxides and thromboxane, but only partially inhibited peroxide-induced increases in the placental secretion rate of prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Antioxidants; Benzoquinones; Blood Pressure; Dose-Response Relationship, Drug; Female; Fetus; Heptanoic Acids; Humans; In Vitro Techniques; Peroxides; Placenta; Pregnancy; Receptors, Thromboxane; Regional Blood Flow; Thromboxane B2; Vascular Resistance; Vasoconstriction

The effects were studied of three novel thromboxane A2 (TXA2) receptor antagonists (S-1452, AA-2414 and ONO-3708) on the increase in pulmonary pressure caused by Forssman anaphylaxis in guinea-pigs. Three TXA2 antagonists at doses of between 1 and 10 mg/kg administered orally 1 h before the challenge clearly inhibited the pulmonary pressure increase. At a dose of 10 mg/kg, all three antagonists inhibited the pulmonary pressure increase caused by leukotriene D4 (LTD4) and U-46619, but not that caused by histamine. The decrease in peripheral platelet counts caused by Forssman anaphylaxis was also clearly inhibited by the three TXA2 antagonists. However, the decreased peripheral leukocyte counts were unaffected by the three agents. The decrease in serum complement activity (CH50) was inhibited by S-1452 and AA-2414 at a dose of 10 mg/kg. In bronchoalveolar lavage fluid (BALF), significant increases in eosinophils and neutrophils were observed after Forssman anaphylaxis. Three TXA2 antagonists at a dose of 10 mg/kg (except for AA-2414 on eosinophils) did not affect the changes of leukocyte counts in BALF. Moreover, increases in the TXB2 and 6-keto-PGF1 alpha levels of the BALF brought about by Forssman anaphylaxis were unaffected by the three TXA2 receptor antagonists. Histamine and LTD4 were not changed in the BALF after Forssman anaphylaxis. These results indicate the efficacy of TXA2 receptor antagonists on the increase in pulmonary pressure caused by Forssman anaphylaxis in guinea-pigs by direct antagonism to released TXA2.

Topics: 6-Ketoprostaglandin F1 alpha; Airway Resistance; Anaphylaxis; Animals; Antibodies, Heterophile; Benzoquinones; Bridged Bicyclo Compounds; Bronchoalveolar Lavage Fluid; Fatty Acids, Monounsaturated; Guinea Pigs; Heptanoic Acids; Histamine; Leukocyte Count; Male; Platelet Count; Quinones; Receptors, Prostaglandin; Receptors, Thromboxane; SRS-A; Thromboxane A2; Thromboxane B2

To clarify the role of thromboxane (TX) A2 in arterial thrombus formation, we examined the antithrombotic effects of both a TXA2 synthetase inhibitor (CV-4151) and a TXA2 receptor antagonist (AA-2414) on the rabbit common carotid artery thrombosis which was induced by injury of the endothelium by treatment with 0.25% pronase solution. CV-4151 (1,10 mg/kg, p.o.) and AA-2414 (10 mg/kg, p.o.) significantly inhibited thrombus formation. Furthermore, the combined use of CV-4151 and AA-2414 (0.1 mg/kg, p.o. each) significantly inhibited thrombus formation, though these drugs at the same doses had no effect when administered singly. The plasma level of 11-dehydro TXB2 increased significantly during thrombus formation, and CV-4151 (10 mg/kg) markedly inhibited this increase. There was a significant correlation between the in vivo antithrombotic effects of these drugs and their ex vivo inhibitory effects on arachidonic acid-induced platelet aggregation. The antithrombotic effect of CV-4151 also correlated significantly with its ability to inhibit the production of serum TXA2. These results show that TXA2 may play an important role in the thrombus formation in arterial thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Benzoquinones; Carotid Artery Thrombosis; Disease Models, Animal; Endothelium, Vascular; Fatty Acids, Monounsaturated; Heptanoic Acids; Male; Platelet Aggregation; Pyridines; Quinones; Rabbits; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

We studied the effect of AA-2414, a TXA2 receptor antagonist, on platelet function in 12 asthmatic patients, 6 males and 6 females, whose mean age was 43.6 years. AA-2414 was orally administered to each patient at 20 mg/day for two weeks and then at 40 mg/day for the following two weeks. Platelet aggregation, plasma concentration of TXB2, and serum concentrations of AA-2414 and its metabolites were measured before and after the administration of each dose. Platelet aggregation induced by U-46619 (an analogue of PGH2), STA2 (a stable analogue of TXA2) and arachidonic acid with the administration of AA-2414 was significantly inhibited. The degree of this inhibition was proportional to the serum level of the drug. Plasma concentration of TXA2 tended to be lowered by administration of AA-2414, but it was not statistically significant. Eight (75.0%) of the 12 patients showed clinical improvement. In the cases where the drug was ineffective, the inhibition of platelet aggregation after administration of AA-2414 was less than in those cases where it was effective. We conclude that AA-2414 might exert its antiplatelet and antiasthmatic effects through antagonism of the TXA2 receptor. Investigation of the response to AA-2414 may be useful in assessing the clinical effect of this compound.

Topics: Administration, Oral; Adolescent; Adult; Aged; Asthma; Benzoquinones; Heptanoic Acids; Humans; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Quinones; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane B2