ozagrel and 2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid

Topics: Angina Pectoris; Aspirin; Coronary Disease; Epoprostenol; Humans; Hypertension; Methacrylates; Myocardial Infarction; Oxidoreductases; Platelet Aggregation; Thromboxane-A Synthase; Thromboxanes; Urokinase-Type Plasminogen Activator

Thromboxane (Tx) inhibition prevents pulmonary leukostasis after acid aspiration. This observation prompted study of polymorphonuclear leukocyte (PMN) accumulations and products of cyclooxygenase. Experiments were conducted with a skin abrasion preparation. Five groups of six rabbits were pretreated intravenously with: (1) placebo, (2) ibuprofen, (3) imidazole and two other Tx syntase inhibitors, (4) OKY 1555, or (5) OKY 046. Zymosan-activated serum (ZAS) and leukotriene B4 were used as chemotaxins and balanced salt solution as control. After pretreatment with placebo, PMN accumulation in leukotriene B4 sites was 2130 +/- 874 PMN/mm3 (mean +/- SD). Pretreatment with ibuprofen, imidazole, or OKY 046 decreased (p less than 0.05) accumulations to 205 +/- 139 PMN/mm3, 485 +/- 387 PMN/mm3, and 504 +/- 260 PMN/mm3, respectively. In ZAS sites, placebo pretreatment led to 2006 +/- 866 PMN/mm3, while the ibuprofen, imidazole, and OKY 046 groups had decreased (p less than 0.05) responses of 295 +/- 218 PMN/mm3, 444 +/- 477 PMN/mm3, and 386 +/- 151 PMN/mm3, respectively. Pretreatment with OKY 1555 did not produce significant reductions in response. Six animals in each group received intradermal injections of the two chemotaxins or Hank's balanced salt solution. Reduction in PMN accumulations after cyclooxygenase and Tx inhibition were similar to those observed in the skin abrasion preparation. Pretreatment with either ibuprofen, imidazole, or OKY 046 resulted in a decreased concentration of Tx in abrasion fluid exudate in response to leukotriene B4, 275 +/- 164 pg/ml, 460 +/- 144 pg/ml, and 440 +/- 260 pg/ml, respectively, as compared with 1168 +/- 380 pg/ml in the placebo group. The reduced responses were not the result of a decrease in regional perfusion as measured by 133Xe washout. The in vitro chemotactic response of PMN to leukotriene B4 and ZAS was unchanged after incubation in either ibuprofen, imidazole, OKY 1555, or OKY 046. These data show that cyclooxygenase and Tx syntase are integrally associated with PMN accumulations.

Topics: Animals; Chemotaxis, Leukocyte; Cyclooxygenase Inhibitors; Ibuprofen; Imidazoles; Male; Methacrylates; Neutrophils; Premedication; Prostaglandin-Endoperoxide Synthases; Rabbits; Skin; Skin Tests; Thromboxane A2; Thromboxane-A Synthase

We investigated the effects of OKY-046 and OKY-1580, thromboxane A2 (TxA2) synthetase inhibitors, on plasma levels of 6-keto PGF1 alpha and TxB2 in anesthetized dogs with experimentally induced air embolism. The percentage increase of tracheal pressure induced by room air infusion was suppressed significantly by premedication with OKY-046. The percentage increase of pulmonary artery blood pressure was suppressed significantly by premedication with OKY-046 compared to that in control group. By room air infusion after the premedication with OKY-046 and OKY-1580, systemic artery blood pressure did not show any significant changes. Plasma 6-keto PGF1 alpha level showed a marked increase by an intravenous infusion of room air, and such an increase became more predominant by the premedication with OKY-046 and OKY-1580. On the other hand, plasma TxB2 level showed a marked increase by an intravenous infusion of room air, and such an increase became less predominant by the premedication with OKY-046 and OKY-1580. These results may suggest that OKY-046 and OKY-1580 are not only TxA2 synthetase inhibitors but also PGI2 synthetase accelerators and are useful drugs for treatment and prevention of thromboembolism.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Anesthesia; Animals; Blood Pressure; Dogs; Embolism, Air; Methacrylates; Pulmonary Artery; Pulmonary Embolism; Thromboxane B2; Thromboxane-A Synthase

The effects of sodium-(E)-3-(4-(3-pyridylmethyl)phenyl)-2-methyl propenoate (OKY-1581) and (E)-3-(4-(imidazolylmethyl)phenyl)-2-propenoic acid (OKY-046), potent inhibitors to thromboxane A2 synthetase, on peroxisomal beta-oxidation and on lipid levels of liver and serum in the rat were studied. When the animals were administered with OKY-1581 at the dose levels of 100 and 500 mg/kg body weight for 2 weeks, the activity of peroxisomal beta-oxidation increased 2.2- and 6.3-fold respectively. Catalase activity increased 1.3-fold, whereas D-amino acid oxidase (DAAO) and urate oxidase activities did not change. Carnitine acetyltransferase and carnitine palmitoyltransferase activities also increased 2.2- - 4.1-fold and 2.7- - 4.2-fold respectively. These changes of the enzymes related to lipid metabolism were also confirmed by the results of a cell fractionation study. Moreover, the induction of peroxisome proliferation-associated polypeptide having a molecular weight of 80000, which is a bifunctional enzyme in the peroxisomal beta-oxidation system was also observed electrophoretically in the light mitochondrial fraction of the liver of OKY-1581-treated rat. The contents of triglyceride and cholesterol in the serum decreased. These results indicated that the action of OKY-1581 in enhancing hepatic peroxisomal-oxidation is similar to that of a potent hypolipidemic peroxisome proliferator such as clofibrate. On the other hand, differing from OKY-1581, OKY-046 at the dose level of 500 mg/kg for 2 weeks showed no effect on serum and liver lipid levels and on the activities of the peroxisomal enzymes, including a cyanide-insensitive fatty acyl-CoA oxidizing system and carnitine acetyl transferase.

Topics: Acrylates; Animals; Clofibrate; Hypolipidemic Agents; Lipid Metabolism; Liver; Male; Methacrylates; Microbodies; Mitochondria, Liver; Organ Size; Oxidation-Reduction; Rats; Rats, Inbred Strains; Thromboxane-A Synthase

Topics: Acrylates; Binding Sites; Drug Interactions; Humans; Methacrylates; Protein Binding; Serum Albumin; Thromboxane-A Synthase

The prevention of cerebral vasospasm with OKY-046, an imidazole derivative and a thromboxane synthetase inhibitor, was studied co-operatively at ten neurosurgical services. Intravenous administrations of 2, 5 or 10 mu/kg/minute of OKY-046 were given continuously from the earliest possible day to the 14th SAH-day to 82 patients with ruptured cerebral aneurysm. Sixty-eight patients (83%) showed moderate to high high-density (SAH) in their initial CTs. Angiographic vasospasms were seen in 58 patients, representing 71% of all cases or 81% of the 72 cases for which angiograms were available: the vasospasms of 45 patients (55 or 63%) were moderate to severe. Symptomatic vasospasm occurred, however, only in 27 patients (33%): in 18 of those cases, moreover, the symptoms were mild or transient. The conditions of the patients at one month after the SAH were classified into 9 grades from 0 (normal) to 8 (deceased). Fifty-two patients (63%) were classified as 0 or 1, and 64 (78%) as better than 3 (possible daily life unaided). The administration of OKY-046 was proven to decrease TXB2 in the blood. This paper emphasizes the effectiveness of the drug for symptomatic vasospasm, and supports our previous contention that cerebral microthrombosis may play an important role in the pathogenesis of cerebral vasospasm.

Topics: Acrylates; Adult; Aged; Drug Eruptions; Female; Hemorrhage; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Meclofenamic Acid; Methacrylates; Middle Aged; Recurrence; Subarachnoid Hemorrhage; Thromboxane-A Synthase

Leukotrienes (LT) LTA4, LTB4, LTC4, LTD4 and LTE4 induced marked contractions of guinea pig lung parenchymal strips mounted in organ baths. These contractions were inhibited differentially (40-50% for LTA4, LTC4, LTD4 and LTE4, and 90% for LTB4) by indomethacin (20 micrograms.ml-1; 55.9 microM). Two novel inhibitors of thromboxane synthetase (OKY-1581 and OKY-046) reduced the myotropic activity of the lung strips and the release of prostaglandins and thromboxanes from the perfused guinea pig lungs stimulated by LTB4 and LTD4. The release of cyclooxygenase products prostaglandin F2 alpha, thromboxane B2 and 12-hydroxyheptadecatrienoic acid by guinea pig lungs following stimulation with LTB4 and LTD4 was also measured by gas chromatography-mass spectrometry. The role of prostaglandins and thromboxanes in the lung actions of leukotrienes was confirmed using a cascade superfusion system and classical organ baths. Although prostaglandins and thromboxanes contribute to the contractile effect of LTB4 on the guinea pig lung whereas they may play a lesser role in the action of the peptidoleukotrienes (approx. 40-50%), stimulation of their release by the peptidoleukotrienes is many times more effective than by LTB4.

Topics: Animals; Arachidonic Acids; Dinoprost; Female; Gas Chromatography-Mass Spectrometry; Guinea Pigs; Indomethacin; Leukotriene A4; Leukotriene B4; Leukotriene E4; Lung; Male; Methacrylates; Prostaglandin-Endoperoxide Synthases; Prostaglandins F; SRS-A; Thromboxane B2

Aspirin (acetylsalicylic acid) was chronically infused i.v. into dogs at a low dose (0.1 mg/kg/hr) using a surgically implanted Alzet osmotic pump. The time course for inhibition of cyclooxygenase and for its recovery after removal of the pump were followed in washed platelet preparations and in kidney medulla microsomes using [14C]arachidonic acid metabolism. Chronic acetylsalicylic acid infusion inhibited platelet cyclooxygenase 60% after 1 day of treatment and 95% after 3 days. Recovery of platelet arachidonate metabolism after removal of the osmotic pump was very rapid (T 1/2 = 0.9 days). Renal cyclooxygenase was also completely inhibited after 3 days but showed a slower recovery rate (T 1/2 = 2.8 days). Therefore, canine platelets, unlike human platelets, recover more rapidly from acetylsalicylic acid inhibition than do the kidneys. We have also established a whole blood method to study the effective time course of thromboxane synthetase inhibitors. The relative potencies for inhibiting platelet thromboxane synthetase after i.v. bolus administration of the agents studied was OKY-1581 greater than OKY-046 = dazoxiben much greater than Ro 22-7878. The effective half-life of OKY-1581, OKY-046 and dazoxiben was 2 hr while the half-life of Ro 22-7878 was 0.5 hr.

Topics: Animals; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Dogs; Dose-Response Relationship, Drug; Kidney; Methacrylates; Oxidoreductases; Thromboxane-A Synthase

We investigated the effect of the thromboxane synthetase inhibitors, OKY-046 and OKY-1580, on the action of bronchoactive agents in guinea pig tracheal strips, and on arachidonic acid metabolism in isolated perfused guinea pig lung lobes. OKY-046 and OKY-1580 attenuated histamine-, serotonin-, acetylcholine-, bradykinin- and prostaglandin F2- induced contractile responses in guinea pig tracheal strips dose-dependently and potentiated isoproterenol-, salbutamol- and prostaglandin E2-induced relaxation in guinea pig tracheal strips dose-dependently. In addition, OKY-046 and OKY-1580 inhibited the biosynthesis of thromboxane A2 and accelerated the production of 6-keto prostaglandin F1 from arachidonic acid in isolated perfused guinea pig lung lobes. The above results suggest that OKY-046 and OKY-1580 might be useful therapeutic agents for the treatment of pulmonary thromboembolism and chronic obstructive lung diseases.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Bronchodilator Agents; Guinea Pigs; Histamine; In Vitro Techniques; Lung; Male; Methacrylates; Oxidoreductases; Thromboxane-A Synthase; Trachea

Topics: Acrylates; Animals; Arachidonic Acids; Dose-Response Relationship, Drug; Guinea Pigs; In Vitro Techniques; Lung; Male; Methacrylates; Muscle Contraction; Muscle, Smooth; Oxidoreductases; Thromboxane A2; Thromboxane-A Synthase; Trachea

Topics: Acrylates; Adult; Angina Pectoris; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Oxidoreductases; Physical Exertion; Platelet Aggregation; Reference Values; Thromboxane B2; Thromboxane-A Synthase

We examined the effects of thromboxane synthetase inhibition with OKY-1581 and OKY-046 on pulmonary hemodynamics and lung fluid balance after thrombin-induced intravascular coagulation. Studies were made in anesthetized sheep prepared with lung lymph fistulas. Pulmonary intravascular coagulation was induced by i.v. infusion of alpha-thrombin over a 15 min period. Thrombin infusion in control sheep resulted in immediate increases in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), which were associated with rapid 3-fold increase in pulmonary lymph flow (Qlym) and a delayed increase in lymph-to-plasma protein concentration (L/P) ratio, indicating an increase in the pulmonary microvascular permeability to proteins. Thrombin-induced intravascular coagulation also increased arterial thromboxane B2 (a metabolite of thromboxane A2) and 6-keto-PGF1 alpha concentrations (a metabolite of prostacyclin). Both OKY-1581 and OKY-046 prevented thromboxane B2 and 6-keto-PGF1 alpha generation. The initial increments in Ppa and PVR were attenuated in both treated groups. The increases in Qlym were gradual in the treated groups but attained the same levels as in control group. However, the increases in Qlym were associated with decreases in L/P ratio. In both treated groups, the leukocyte count decreased after thrombin infusion but then increased steadily above the baseline value, whereas the leukocyte count remained depressed in the control group after thrombin. These studies indicate that a part of the initial pulmonary vasoconstrictor response to thrombin-induced intravascular coagulation is mediated by thromboxane generation. In addition, thromboxane may also contribute to the increase in lung vascular permeability to proteins that occurs after intravascular coagulation and this effect may be mediated by a thromboxane-neutrophil interaction.

Topics: Acrylates; Animals; Blood Pressure; Disseminated Intravascular Coagulation; Humans; Leukocyte Count; Methacrylates; Oxidoreductases; Platelet Count; Pulmonary Circulation; Sheep; Thrombin; Thromboxane-A Synthase; Vascular Resistance

Thromboxane (TX) synthetase activity was selectively inhibited by (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046) and sodium (E)-3-[4-(3-pyridylmethyl)phenyl]-2-methyl-propenoate (OKY-1581) (OKYs). Their IC50 for the rabbit platelet enzyme were found to be 11nM and 3nM respectively. Arachidonic acid (AA) or collagen induced platelet aggregation, and generated TXA 2 and prostaglandins (PGs) in rabbit platelets. OKYs inhibited platelet aggregation and TXA2 generation without affecting PGs generation, while aspirin inhibited platelet aggregation, and TXA2 and PGs generation. There was a parallel relation between the degree of inhibition of platelet aggregation and TXA2 generation by OKYs, but the inhibitory effects of aspirin on platelet aggregation was related to that on both TXA2 and PGs generation. However, OKYs and aspirin did not inhibit ADP-induced platelet aggregation which did not involve the generation of TXA2 and PGs. These results suggested that TXA2 generation is related to platelet aggregation induced by AA or collagen, and that the inhibitory effect of OKYs on platelet aggregation is due to the inhibition of TX synthetase.

Topics: Animals; Aspirin; Cytochrome P-450 Enzyme System; Epoprostenol; In Vitro Techniques; Intramolecular Oxidoreductases; Male; Methacrylates; Oxidoreductases; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Rabbits; Sheep; Thromboxane-A Synthase; Time Factors

To elucidate the role of thromboxane A2 in the development of endotoxin shock following administration of endotoxin, the effects of three thromboxane A2 synthetase inhibitors, (E)-3-(4-(1-imidazolyl)phenyl)-2-propenoic acid hydrochloride monohydrate (OKY-046), sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methylacrylate (OKY-1581) and imidazole were examined. Intravenous administration of E. Coli endotoxin (3 mg/kg) produced shock and all rats died within ten hours. Pretreatment with thromboxane A2 synthetase inhibitors markedly improved the survival rates. The untreated endotoxin shock group showed marked increase in thromboxane B2 levels in the venous blood, while no such changes were seen in the pretreated groups. There were no statistically significant differences in 6-keto prostaglandin F1 alpha levels in the venous blood. In the untreated shock group, microthrombi were observed in 64% of the glomeruli in the kidneys two hours after endotoxin injection. In the groups pretreated with OKY-046, OKY-1581 and imidazole, microthrombi were seen only in 22, 19 and 24%, respectively. Thus, thromboxane A2 plays an important role in the development of endotoxin shock and thromboxane A2 synthetase inhibitors, in particular OKY-046 and -1581, are prophylactic.

Topics: Animals; Fibrinogen; Glucuronidase; Kidney; Male; Methacrylates; Oxidoreductases; Platelet Count; Rats; Rats, Inbred Strains; Shock, Septic; Thrombosis; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Effects of new inhibitors of thromboxane synthetase, (E)-3-([1-imidazolmethyl) phenyl]-2-propenoic acid and (E)-3-[4-(pyridylmethyl) phenyl]-2-methyl-2-propenoic acid on cyclical reduction of flow in the partially constricted coronary artery were examined in anesthetized beagle dogs. Intravenous injections of both agents with a dose of 20 mg/Kg eliminated the cyclical reduction induced by constriction in the majority of experiments. However, they failed to eliminate the cyclical reduction induced by indomethacin. Indomethacin-induced reduction was eliminated by prostaglandin I2 in all experiments. It is suggested that thromboxane A2 acted as an accelerator in the cyclical reduction of coronary flow induced by coronary constriction, but did not in the reduction induced by indomethacin.

Topics: Acrylates; Animals; Constriction; Coronary Circulation; Coronary Vessels; Dogs; Epoprostenol; Indomethacin; Methacrylates; Oxidoreductases; Thromboxane A2; Thromboxane-A Synthase