thromboxane-b2 and nafagrel

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cross-Over Studies; Enzyme Inhibitors; Female; Humans; Imidazoles; Indomethacin; Lupus Nephritis; Male; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

A marked and sustained bronchoconstriction after antigen challenge was produced in actively sensitised guinea pigs, and correlated with increments of thromboxane (TX) A2 level in both the plasma and bronchoalveolar lavage fluid. DP-1904 given orally relieved the bronchoconstriction and increase in TXA2 in a dose-dependent manner. In platelet-depleted animals, antigen-induced bronchoconstriction and TXA2 release in the plasma were significantly reduced compared to those of non-platelet-depleted animals, indicating that platelets are a major cell source of TXA2 production, the remainder originating from the other cells excluding platelets. In the platelet-deprived animal, DP-1904 showed further significant inhibition of the constriction and plasma TXA2 level, and therefore likely inhibits TXA2 synthesis of various cells, including platelets, in the bloodstream. The results suggested that TXA2 is an important mediator responsible for producing antigen-induced bronchoconstriction, and endogenously originated from various cells including platelets in guinea pigs.

Topics: Animals; Anti-Asthmatic Agents; Antigens; Asthma; Blood Platelets; Enzyme Inhibitors; Guinea Pigs; Imidazoles; Male; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The contractile activity and mobilisation of arachidonic acid metabolites in response to the antigen challenge were studied in isolated lung parenchymal tissue from the actively sensitised guinea pig. The sustained constriction of the lung tissue was evoked by the antigen, associated with significant liberation of TXB2, histamine and p-LTs. Other prostanoids (PGF2 alpha, PGD2, PGE2 and 6-keto-PGF1 alpha) were also released by the antigen challenge. DP-1904, an inhibitor of TX synthetase, significantly suppressed the late phase of the antigen-induced constriction. DP-1904 was potent to inhibit the production of TXB2, while DP-1904 accelerated the formation of PGF2 alpha, PGE2 and 6-keto-PGF1 alpha, presumably indicating the alternative changes of dilatory metabolites to the spasmogenic component. Mepyramine and FPL-77512 augmented the effect of DP-1904. AA-861 inhibited the antigen-induced constriction of the lung parenchymal tissue by inhibiting the release of p-LTs and TXB2. Pretreatment of the lung parenchymes with anti-guinea pig platelet serum, in order to deplete the platelets, did not affect the generation of TXB2 both in resting and also in the antigen-stimulated status, indicating that TXA2 is produced in the topical pulmonary tissue. It is concluded that DP-1904 inhibits the parenchymal contraction through potent inhibition of TXA2 generation, associated with significant elevation in PGE2 and PGI2.

Topics: Animals; Anti-Asthmatic Agents; Antigens; Benzoquinones; Bronchoconstriction; Chromones; Enzyme Inhibitors; Guinea Pigs; Imidazoles; In Vitro Techniques; Lipoxygenase Inhibitors; Lung; Male; Pyrilamine; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The effect of DP-1904, a novel thromboxane (TX) synthetase inhibitor, on airway hyperresponsiveness was studied in actively sensitized guinea-pigs. Airway hyperresponsiveness to intravenous ACh was observed at 3 and 7 h after aerosolized antigen challenge. In the model, a significant correlation between increases of respiratory resistance and microvascular leakage was observed, corresponding to the elevation of TXB2 in bronchoalveolar lavage fluid (BALF) in the early phase. DP-1904, at doses of 3 mg/kg or higher given orally one hour prior to the antigen challenge, inhibited the TXB2 production and the development of airway hyperresponsiveness in the early phase. Further, DP-1904 significantly suppressed the accumulation of lymphocytes in BALF and airway hyperresponsiveness in the late phase, although it only slightly decreased the mobilization of eosinophils and neutrophils. The results suggest that TXA2 is possibly involved in the development of airway hyperresponsiveness, and DP-1904 prevented the airway hyperresponsiveness via inhibition of TXA2 production and regulation of inflammatory cells.

Topics: Acetylcholine; Animals; Bronchoalveolar Lavage; Dinoprostone; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guinea Pigs; Imidazoles; Lymphocytes; Male; Respiratory Hypersensitivity; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Time Factors

Abnormalities of prostanoid metabolism, which may affect renal function, were studied in lupus nephritis. The subjects were 31 patients with lupus nephritis, ten with non-renal SLE, and four with renal, non-SLE collagen disease. Urinary levels of various prostanoids, thromboxane B2(TXB2), 11-dehydro-TXB2, 6-keto-PGF1 alpha,2,3-dinor-6-keto-PGF1 alpha and PGE2, and plasma level of 11-dehydro-TXB2, were determined. The effects of four days' dosing of a selective thromboxane A2 (TXA2) synthetase inhibitor, DP-1904 (DP), on prostanoid metabolism, were also studied. Urinary excretion of TXB2, which reflects the renal production of TXA2, was significantly increased in patients with lupus nephritis as compared with non-renal SLE (p < 0.05). The urinary TXB2/6-keto-PGF1 alpha ratio was also increased in lupus nephritis as compared with non-renal SLE or healthy controls (p < 0.01), indicating a prostanoid imbalance, which may lead to impaired renal function and subsequent pathology. The urinary TXB2/6-keto-PGF1 alpha ratio in these lupus nephritis patients showed negative correlations with Ccr and positive correlations with anti-DNA antibody titer (p < 0.001). DP was administered orally (400 mg/day, given in two divided doses) for four days to eight lupus nephritis patients. The urinary excretion of TXB2 and urinary TXB2/6-keto-PGF1 alpha ratio were decreased after one to two days of treatment in all patients. An increase in creatinine clearance used as a measure of renal function was observed in four of eight patients. Furthermore, no side effects were elicited during the four days of treatment. The conclusion reached were that the abnormal prostanoid metabolism observed in lupus nephritis could aggravate renal function through hemodynamic mediation, and that the deviated metabolism was reversible and, at least partially, corrected by a TXA2 synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Enzyme Inhibitors; Female; Humans; Imidazoles; Kidney Diseases; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Prostaglandins; Reference Values; Regression Analysis; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

Several mediators are released from mast cells during allergic reactions. These substances cause contraction of airway smooth muscles, increase the permeability of blood vessels, and enhance mucous secretion. Among these mediators, thromboxane A2 (TXA2) has a particularly strong bronchoconstrictive effect.. We examined antigen-induced contraction of excised human lungs and the suppressive effects of TXA2 synthetase inhibitor on TXA2 release.. Human lung parenchymal strips were subjected to passive sensitization with sera of 5+ RAST titer to the mite. They were suspended in magnus baths, to which buffer and 10(-4) to 10(-8) M of DP-1904, an inhibitor of TXA2 synthetase, were added. Following the measurement of TXB2 and leukotriene (LT) concentrations in each bath, parenchymal contraction was induced by the addition of a mite antigen. The concentration of TXB2 and LT was measured after contraction.. Antigen-induced release of TXB2 was significantly suppressed by DP-1904 in a concentration-dependent manner. DP-1904 did not inhibit parenchymal contraction and the release of LT.. Antigen-induced parenchymal contraction was not suppressed by inhibition of TXA2 release, suggesting that DP-1904 may not be effective in asthma.

Topics: Aged; Animals; Antigens; Bronchoconstriction; Dose-Response Relationship, Immunologic; Enzyme Inhibitors; Female; Humans; Imidazoles; Leukotrienes; Lung; Male; Middle Aged; Mites; Muscle Contraction; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A2 synthase inhibitor, was evaluated using an experimental model of membranous nephropathy, viz. accelerated passive Heymann nephritis in which the glomerular injury is mediated by immune complexes. DP-1904 markedly inhibited the develop-ent of glomerular alteration as well as the elevation of proteinuria and plasma creatinine. When the treatment was started from the 22nd day, at which time proteinuria is fully developed, DP-1904 showed beneficial effects on proteinuria and glomerular histopathological changes. DP-1904 apparently decreased the deposition of both rabbit immunoglobulin G and rat immunoglobulin G on glomerular basement membrane in nephritic rats. A single administration of DP-1904 restored the decreased renal tissue blood flow, inhibited glomerular thromboxane B2 production and increased glomerular prostaglandin E2 and 6-keto prostaglandin F1 alpha production in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of idiopathic membranous nephropathy and that the beneficial effect of this drug may be due to the elimination of glomerular immune deposits and to an increase in renal tissue blood flow related to amelioration of the abnormal metabolism of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibodies; Azathioprine; Creatinine; Dinoprostone; Drug Interactions; Enzyme Inhibitors; Glomerulonephritis; Imidazoles; Immunoglobulin G; Immunosuppressive Agents; Kidney Glomerulus; Male; Methacrylates; Proteinuria; Rabbits; Rats; Rats, Sprague-Dawley; Renal Circulation; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A2 synthetase inhibitor, was compared with that of OKY-046, using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane nephritis. Test drugs were given p.o. once daily from the day after the the development of glomerular alteration as well as the elevation of proteinuria and plasma cholesterol. On the other hand, OKY-046 (20 mg/kg per day), a thromboxane A2 synthetase inhibitor, significantly inhibited only deterioration in the glomeruli. DP-1904 and OKY-046 inhibited glomerular thromboxane B2 production and increased glomerular prostaglandin E2 and 6-keto prostaglandin F1 alpha production in normal and nephritic rats. Both drugs inhibited the increase in platelet aggregability, restored decreased renal tissue blood flow to a near-normal level and decreased the deposition of rat immunoglobulin G on glomerular basement membrane in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of proliferative glomerulonephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Basement Membrane; Cholesterol; Dinoprostone; Fluorescent Antibody Technique; Imidazoles; Kidney Glomerulus; Male; Methacrylates; Nephritis, Interstitial; Platelet Aggregation; Proteinuria; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

Spontaneously hypertensive rats (SHR) were injected with streptozotocin (STZ-SHR) to induce diabetes. The effect of DP-1904, a thromboxane A2 synthetase inhibitor, on diabetic nephropathy was then studied by administering it for 5 months (1 or 10 mg/kg). DP-1904 did not affect renal 6-keto prostaglandin (PG)F1 alpha production in STZ-SHR, but markedly inhibited renal thromboxane (TX) B2 production, so that the 6-keto PGF1 alpha/TXB2 ratio was significantly increased (P less than 0.05). STZ-SHR showed significant uraemia and proteinuria, plus increases in urinary gamma-glutamyl-transpeptidase and urinary N-acetyl-beta-glucosaminidase. DP-1904 significantly decreased (P less than 0.01) the urinary changes. STZ-SHR also showed an increase in mesangial periodic acid-Schiff-positive substance and in relative renal weight, both of which were significantly inhibited by DP-1904 (P less than 0.05). Thus, DP-1904 inhibited both TXB2 production and the progression of renal damage in STZ-SHR.

Topics: Acetylglucosaminidase; Animals; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Nephropathies; gamma-Glutamyltransferase; Heart Rate; Hypertension; Imidazoles; Kidney; Prostaglandins; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

In an effort to characterize an interaction between the eicosanoids and sympathoadrenal system on platelet aggregation, we tried to determine if a sustained thromboxane A2 (TXA2) synthase inhibition would modulate changes in eicosanoid formation, catecholamine concentration, and platelet aggregation induced by a physical stress. We measured thromboxane B2 (TXB2), 11-dehydro-TXB2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), norepinephrine, and epinephrine in vivo and platelet aggregation ex vivo before and after a treadmill exercise with and without the oral doses (400 mg twice daily for 7 days) of a new selective TXA2 synthase inhibitor (DP-1904) in nine healthy male subjects. The exercise tests performed on the pretreatment day (day 0) and posttreatment day (day 7) gave a similar result. DP-1904 caused a decrease in serum and urinary TXB2 and urinary 11-dehydro-TXB2 (p less than 0.001 to p less than 0.01) and an increase in serum 6-keto-PGF1 alpha (p less than 0.001 to p less than 0.05) throughout the dosing interval on days 4 and 7. Despite the drug effect on eicosanoid formation at rest and after exercise, the exercise-induced plasma norepinephrine and epinephrine concentrations did not differ between days 0 and 7. The 7-day treatment decreased (p less than 0.01) platelet aggregation induced both by adenosine diphosphate and by collagen at rest. However, the exercise increased (p less than 0.01) platelet aggregation by the two aggregators, resulting in the disappearance of the drug-induced antiaggregatory effects observed at rest. The treatment with a TXA2 synthase inhibitor does not appear to attain the antithrombotic action during an exercise despite the occurrence of a sustained endoperoxide shunting.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Chromatography, High Pressure Liquid; Epinephrine; Humans; Imidazoles; Male; Norepinephrine; Physical Exertion; Platelet Aggregation; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antigens; Asthma; Bronchoconstriction; Guinea Pigs; Imidazoles; In Vitro Techniques; Lung; Ovalbumin; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

The effects of DP-1904, a thromboxane (TX) A2 synthase inhibitor, on renal function were investigated by analysis of prostanoid metabolism in hydronephrotic and ischemic rat kidney models, and in isolated perfused normal and hydronephrotic rat kidneys. The increase in production of TXB2 in hydronephrotic or ischemic kidneys was significantly suppressed by intraperitoneal DP-1904 (10 mg/kg), with the 6-keto-prostaglandin F1 alpha to TXB2 ratio being significant increased. Urine volume, glomerular filtration rate and renal plasma flow were all improved. DP-1904 (0.3 micrograms/min) blocked the effects of infused arachidonic acid on isolated perfused normal rat kidneys thus reducing TXB2 levels and perfusion pressure but the pressor response to norepinephrine or angiotensin II remained unchanged. In isolated perfused hydronephrotic rat kidneys, DP-1904 suppressed the increase in perfusion pressure and TXB2 production caused by platelet-activating factor. These findings suggested that DP-1904 improved renal failure by specifically inhibiting TXA2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Hydronephrosis; Imidazoles; Ischemia; Kidney; Male; Perfusion; Rats; Rats, Inbred Strains; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor, and its effects on ex-vivo prostanoid formation have been studied in groups of Japanese normal male volunteers, who received repeated oral doses of 200 mg every 12 h for 4 doses, or 400 mg every 24 h for 2 doses, or 200 mg every 12 h for 14 doses. The drug was well tolerated by all subjects without evidence of adverse reactions. Repeated administration showed no significant changes in half-lives, tmax values, cmax values and AUC values. DP-1904 did not exhibit time-dependent kinetics. Its plasma levels were lower than the quantifiable level (50 ng mL-1) at 12 h after each dose. These data suggest no significant accumulation of DP-1904 in normal volunteers. DP-1904 reduced the serum thromboxane B2 by about 80% during the medication, the serum concentrations returning to about 44, 75 and 20% of the predrug control values at 36 h after the last 200 mg doses and 48 h after the last 400 mg dose.

Topics: Administration, Oral; Adult; Chromatography, High Pressure Liquid; Half-Life; Humans; Imidazoles; Male; Metabolic Clearance Rate; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

The effects of a new thromboxane A2 synthetase inhibitor (DP-1904) on electrical stability of the heart were tested in anesthetized, open chest dogs. The incidence of spontaneous ventricular arrhythmias, ventricular refractory period and ventricular fibrillation threshold (VFT) during ligation of the left anterior descending coronary artery (LAD) for 180 min and after reperfusion were measured as indices of stability. Ventricular fibrillation and ventricular tachycardia occurred spontaneously after ligation of LAD in 56% of 9 control dogs and 29% of 7 dogs which received intravenous DP-1904 (100 mg) before ligation of LAD (n.s.). In the control group, the ventricular refractory period decreased in the ischemic region; consequently, the difference in refractory period duration between the ischemic and non-ischemic regions (i.e., dispersion) increased 30 min after coronary ligation (7 +/- 9 ms vs 32 +/- 17 ms, p less than 0.05). The dispersion at 30 min after coronary ligation, though, was not affected in the DP-1904 treated group (2 +/- 4 ms vs 10 +/- 9 ms, n.s.). The VFT (determined with pulse trains) decreased from 28 +/- 5 mA to 15 +/- 11 mA (p less than 0.05) 30 min after coronary ligation in the control group, but was not affected (30 +/- 0 mA vs 27 +/- 4 mA) in the DP-1904 group. The plasma concentration of thromboxane B2 decreased after DP-1904 administration (baseline vs 30 min after coronary ligation: 475 +/- 165 pg/ml vs 165 +/- 74 pg/ml, n = 3, p less than 0.05), while the concentration of 6-keto-prostaglandin F1 alpha increased gradually. In conclusion, DP-1904 prevents a decline in electrical stability in the ischemic region of the canine heart during coronary occlusion.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Coronary Vessels; Dogs; Electrophysiology; Female; Heart Rate; Heart Ventricles; Imidazoles; Ligation; Male; Naphthalenes; Refractory Period, Electrophysiological; Reperfusion; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase; Ventricular Fibrillation

The disposition of a new thromboxane synthetase inhibitor, 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904) upon administration of a single 200-mg oral dose to normal Japanese volunteers was studied. DP-1904 proved to be rapidly absorbed from the gastrointestinal tract and converted to its ester glucuronide, which appeared in plasma within 30 min after dosing. The AUCs of DP-1904 and its ester glucuronide were 7.23 +/- 0.54 and 7.93 +/- 0.86 micrograms.h/ml (mean +/- S.E., n = 5), respectively. Both compounds were also eliminated very rapidly from the body (half-lives greater than 60 min). The primary route of elimination was renal, with 52.1 +/- 2.2 and 37.6 +/- 1.6% of the dose being excreted in the urine as the unchanged form and the glucuronide conjugate within 48 h, respectively. The cumulative fecal excretion rates of DP-1904 up to 48 h after dosing were approximately 0.5%. The main metabolite of DP-1904 in humans was DP-1904 glucuronide. Serum thromboxane (TX) B2 levels were reduced more than 98% within 1 h after dosing. There was still more than 75% suppression of serum TXB2 levels at 12 h after dosing. At 72 h TXB2 concentrations returned to control levels. These data indicate that DP-1904 is a potent and long-acting thromboxane synthetase inhibitor.

Topics: Adult; Feces; Half-Life; Humans; Imidazoles; Male; Naphthalenes; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor and its effects on ex-vivo prostanoid formation were studied in Japanese normal male volunteers, who received orally a single 10, 20, 50, 100, 200, 400 or 800 mg dose. The drug was well tolerated by all subjects without evidence of any adverse reactions. The absorption of DP-1904 from gastro-intestinal tract was rapid. After oral doses of 10-800 mg of the drug given to volunteers in the fasted state, the mean maximum drug concentrations in plasma (Cmax) (mean +/- s.e., n = 5) of 0.215 (+/- 0.041), 0.399 (+/- 0.037), 1.47 (+/- 0.22), 2.86 (+/- 0.22), 4.66 (+/- 0.58), 7.28 (+/- 0.72) and 16.9 (+/- 2.6) micrograms mL-1 were reached within 1 h. DP-1904 concentrations declined monophasically after Cmax with half lives of 30-40 min. These half lives were independent of the administered doses. The mean area under the concentration-time curves (AUCs) increased from 0.398 (+/- 0.038) to 30.0 (+/- 2.7) micrograms h mL-1 as the dose increased from 10 to 800 mg. Linear relations between the doses and Cmax and AUCs were observed. The correlation coefficients for Cmax and AUC were 0.930 and 0.960, respectively. The apparent oral clearance (CL/F) and renal clearance (CLR) did not change significantly as dose increased from 10 to 800 mg. The kinetics of DP-1904 proved to be linear in the dose range studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Humans; Imidazoles; Male; Middle Aged; Naphthalenes; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase