leukotriene-b4 and ozagrel

The influence of OKY-046, which is a thromboxane (TxA2) synthetase inhibitor, was studied in patients with exercise-induced asthma (EIA). When OKY-046 was administered to 11 patients with EIA-positive (EIA+) asthma, 7 patients showed an effect of the inhibition of airway contraction. As the mechanism of action, inhibition of TxA2 production and acceleration of PGI2 were considered, since OKY-046 has no bronchodilation action. In other words, the fact that TxA2 was a mediator of EIA had been made clear, but it was also found that it had no association as a mediator of leukotrienes (LTC4 and LTB4) in EIA.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Asthma, Exercise-Induced; Drug Evaluation; Exercise Test; Female; Humans; Leukotriene B4; Male; Methacrylates; SRS-A; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Biologically active substances, such as prostaglandins, thromboxanes, and leukotrienes, which are metabolites involved in the arachidonic acid cascade, are detected in herniated disc samples obtained from patients with lumbar disc herniation. However, little is known concerning the relationships between these substances and clinical symptoms such as radicular pain. Thromboxane A2 (TXA2) induces not only potent platelet aggregation, but also blood vessel contraction. Leukotriene B4 (LTB4), a potent chemotactic agent, plays a role in inflammatory reactions by recruiting neutrophils and lymphocytes. The purpose of this study was to examine the roles of TXA2 and LTB4 in the hyperalgesia induced by application of nucleus pulposus to the lumbar nerve root in the rat. TXA2 synthetase inhibitor and LTB4 receptor antagonist, which were injected into the epidural space, decreased mechanical hyperalgesia at both three and seven days after epidural injection. There were no significant differences in sensitivity to noxious thermal stimuli following application of the nucleus pulposus or an epidural injection. Epidural injection of LTB4 receptor antagonist and/or TXA2 synthetase inhibitor may attenuate the painful radiculopathy due to lumbar disc herniation. In conclusion, our findings suggest that TXA2 and LTB4 may play significant roles in mechanical hyperalgesia induced by autologous nucleus pulposus.

Topics: Animals; Disease Models, Animal; Enzyme Inhibitors; Hyperalgesia; Intervertebral Disc Displacement; Leukotriene B4; Male; Methacrylates; Motor Activity; Phenylpropionates; Rats; Rats, Sprague-Dawley; Receptors, Leukotriene B4; Shoulder Pain; Thromboxane A2; Thromboxane-A Synthase

As part of our research for the development of novel antiinflammatory drug candidates, we have designed and synthesized a series of (E)-3-(1,4-benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid derivatives as dual inhibitors of 5-lipoxygenase (5-LO) and thromboxane (TX) A2 synthetase. In order to increase the absorption after oral administration, we introduced a carboxylic acid moiety into the 1,4-benzoquinone skeleton, which has 5-LO-inhibitory character. Introduction of a 3-pyridylalkyl group at the double bond of the 1,4-benzoquinonyl propenoic acid moiety afforded good to moderate inhibitory activities against the production of leukotriene (LT) B4 and TXA2 while not significantly inhibiting that of prostaglandin E2 by glycogen-induced peritoneal cells of rat (in vitro). The length of the methylene chain of the 3-pyridylalkyl group influenced the inhibition of LTB4 and TXB2 production. An increase of lipophilicity by introducing a more lipophilic alkoxy group did not markedly increase the inhibitory activity on LTB4 production. The position of alkoxy group on the 1,4-benzoquinone skeleton played an important role in TXA2 synthetase inhibition. Compounds such as 20c (E6700) with an appropriate alkoxy group and proper length of methylene side chain, together with a polar substituent (carboxylic acid), showed good inhibition of both 5-LO and TXA2 synthetase and possess a variety of pharmacologically beneficial effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoquinones; Blood Platelets; Cells, Cultured; Humans; Hydroxyurea; Leukotriene B4; Lipoxygenase Inhibitors; Magnetic Resonance Spectroscopy; Methacrylates; Molecular Structure; Neutrophils; Pyridines; Rats; Structure-Activity Relationship; Thromboxane B2; Thromboxane-A Synthase

Thromboxanes (Txs) were implicated as possible participants in the altered microvascular permeability of acute lung injury when the Tx synthase inhibitor, OKY-046, was reported to prevent pulmonary edema induced by phorbol myristate acetate (PMA). Recently, however, we found that OKY-046, at a dose just sufficient to block Tx synthesis in intact dogs, did not prevent PMA-induced pulmonary edema but rather merely reduced it modestly. The present study was designed to explore other mechanisms whereby OKY-046 might prevent PMA-induced pulmonary edema. The finding that 5-lipoxygenase (5-LO) metabolites of arachidonic acid were increased within the lung after PMA administration, coupled with the report that OKY-046 inhibited slow-reacting substance of anaphylaxis formation, permitted formulation of the hypothesis that OKY-046, at a dose in excess of that required to inhibit Tx synthesis, inhibits the formation of a product(s) of 5-LO and, thereby, prevents edema formation. In vehicle-pretreated pentobarbital-anesthetized male mongrel dogs (n = 4), PMA (20 micrograms/kg i.v.) increased pulmonary vascular resistance (PVR) from 4.4 +/- 0.3 to 26.3 +/- 8.8 mmHg.l-1 x min (P < 0.01) and extravascular lung water from 6.7 +/- 0.5 to 19.1 +/- 6.2 ml/kg body wt (P < 0.05). Concomitantly, both TxB2 and leukotriene B4 (LTB4) were significantly increased in the lung. Pretreatment with OKY-046 (100 mg/kg i.v., n = 8) prevented PMA-induced increases in TxB2, LTB4, and pulmonary edema formation but did not prevent the increase in PVR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonate 5-Lipoxygenase; Cardiac Output; Dogs; Extravascular Lung Water; Leukocyte Count; Leukotriene B4; Male; Methacrylates; Oxygen; Pulmonary Edema; Tetradecanoylphorbol Acetate; Thromboxane-A Synthase; Thromboxanes

Derivatives of arachidonic acid have been found to play a role in the reperfusion injury of various tissues. These compounds have a broad spectrum of activity, including modulation of white blood cell response to injured tissue. This study was designed to determine the effect of thromboxane and lipoxygenase derivatives on the local and systemic response to ischemia and reperfusion of skeletal muscle. Fifteen dogs were separated into three groups and subjected to gracilis muscle ischemia followed by 2 hours of reperfusion. One group served as controls, one group was treated with OKY-046 (a thromboxane synthetase inhibitor), and one group was treated with diethylcarbamazine (a lipoxygenase inhibitor). White blood cell activation as measured by superoxide anion production, and eicosanoid levels were measured both in the gracilis venous effluent and central venous circulation. These results were compared to infarct size in the gracilis muscle. OKY-046 significantly reduced thromboxane production in both the central venous (102 +/- 30 to 31 +/- 9 pg/ml, p less than 0.05) and gracilis samples (107 +/- 22 to 25 +/- 6 pg/ml, p less than 0.005). This was accompanied by a reduced white cell activation in the central venous blood (15 +/- 1 to 10 +/- 1 nmol O2-, p less than 0.05), but did not affect infarct size or white cell activation in the gracilis. Conversely, diethylcarbamazine significantly reduced both white cell activation (16 +/- 1 to 10 +/- 1 nmol O2-, p less than 0.005) and infarct size in the gracilis muscles (61.6% +/- 4.5% to 28.5% +/- 8.6%, p less than 0.01), as well as reduced systemic white blood cell activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Cell Survival; Diethylcarbamazine; Dogs; Female; Ischemia; Leukotriene B4; Male; Methacrylates; Muscles; Neutrophils; Reperfusion Injury; Superoxides; Thromboxane B2; Thromboxane-A Synthase

The effect of platelet-activating factor (acetyl glyceryl ether phosphorylcholine; PAF), a potent inflammatory mediator, on airway responsiveness was studied. In six dogs airway responsiveness was determined by measuring the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance (RL) by 5 cm H2O X L-1 X s, before and after inhalation of PAF (1 mg). PAF caused a 2.3-fold increase in RL (P less than .001) that lasted approximately 30 min. Airway hyperresponsiveness was maximal at 3 hr (mean 3.7-fold increase, P less than .001), persisted at 6 hr (P less than .005) and disappeared by 24 hr. Inhalation of 0.9% NaCl had no effect on RL or on responsiveness. PAF caused an 8-fold increase in neutrophil recovery in bronchoalveolar lavage fluid at 3 hr. OKY-046, a thromboxane synthetase inhibitor, inhibited PAF-induced bronchoconstriction and hyperresponsiveness but did not alter the increase in neutrophil recovery. We tested the specificity of the effect of OKY-046 on the release of cyclooxygenase products from canine neutrophils in vitro; OKY-046 suppressed PAF-induced generation of thromboxane and caused a small increase in prostaglandin F2 alpha release. The studies suggest that the airway hyperresponsiveness induced by PAF may depend on thromboxane generation.

Topics: Animals; Bronchi; Dogs; In Vitro Techniques; Leukotriene B4; Methacrylates; Neutrophils; Platelet Activating Factor; Respiratory System; Thromboxanes

The myotropic activities of PAF-acether, leukotriene B4, leukotriene D4 and histamine were compared on superfused guinea-pig lung parenchymal strip and were shown to have the following order of potency: PAF-acether greater than LTD4 greater than LTB4 greater than histamine. The contractile response of the lung parenchyma to PAF-acether was inhibited by aspirin, imidazole and OKY-046, which suggested that thromboxane A2 might play a mediator role in PAF-induced contractions. Neither an antagonist of leukotriene D4, FPL-55712, nor an antihistamine, mepyramine, had any effect on PAF contractions. The activity of a novel antagonist of PAF-acether, BN 52021, was also studied on superfused lung parenchyma contracted by histamine, leukotriene B4, leukotriene D4 and PAF-acether. This compound was without effect on the histamine response but it slightly reduced the contractions elicited by leukotriene D4 and potentiated those by leukotriene B4. BN 52021 (7.1 X 10(-6) M) inhibited by 63% the contraction induced by 5.7 X 10(-13) M PAF-acether and by 52% that induced by 5.7 X 10(-10) M PAF-acether and kadsurenone (8.4 X 10(-6) M), another PAF-acether antagonist, inhibited the same PAF-induced contractions by 75% and 20% respectively.

Topics: Animals; Aspirin; Benzofurans; Chromones; Diterpenes; Ginkgolides; Guinea Pigs; Histamine; Imidazoles; Lactones; Leukotriene B4; Lignans; Lung; Male; Methacrylates; Muscle Contraction; Muscle, Smooth; Plant Extracts; Platelet Activating Factor; Prostaglandin Antagonists; Pyrilamine; SRS-A

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

In superfusion experiments, the complement peptide C5a-desArg and the leukotriene B4 (LTB4) enhanced adhesion of guinea pig polymorphonuclear leukocytes to autologous aortic strips (threshold at about 10(-8) M, maximal effects at 10(-7) M). C5a-desArg acted primarily by stimulation of the leukocytes: pretreatment of them with the peptide abolished their response by deactivation, whereas pretreatment of the endothelium did not affect adhesion. However, the endothelium obviously cooperated in the response: enhanced adhesion was obtained only when the leukocytes were exposed to C5a-desArg while in contact with the endothelium. The cooperation is most probably due to release of arachidonic acid from endothelium and formation of lipoxygenase products (LTB4?) therefrom by the stimulated leukocytes. Incubation of leukocytes with nordihydroguaiaretic acid or with relatively high concentrations of indomethacin--both known to inhibit lipoxygenases-- lowered the effect of C5a-desArg, but not that of LTB4 nor the spontaneous adhesion. On the other hand, the stable prostacyclin analogue ZK 36 374 decreased C5a-desArg-induced adhesion, while pretreatment of the aortic strips with indomethacin increased it. These results suggest that endogenous prostacyclin may also play a role in this system by reducing adhesion.

Topics: Animals; Aorta; Arachidonic Acid; Arachidonic Acids; Cell Adhesion; Chemotactic Factors; Complement C5; Complement C5a; Cyclooxygenase Inhibitors; Guinea Pigs; Humans; Leukotriene B4; Lipoxygenase Inhibitors; Methacrylates; Neutrophils; Thromboxane-A Synthase

We studied the effect of leukotriene B4 aerosols on airway responsiveness to inhaled acetylcholine aerosols and on the cellular components and cyclooxygenase metabolites in bronchoalveolar lavage fluid in dogs. Inhalation of leukotriene B4 aerosols had no effect on resting total pulmonary resistance but increased airway responsiveness, an effect that was maximum in 3 h and that returned to control levels within 1 wk. Three hours after leukotriene B4, the number of neutrophils and the concentration of thromboxane B2 recovered in lavage fluid increased markedly. Pretreatment with the thromboxane synthase inhibitor OKY-046 prevented the increases in airway responsiveness and in thromboxane B2 but did not alter neutrophil chemotaxis. Thus we speculate that leukotriene B4 causes neutrophil chemotaxis and release of thromboxane B2, which increases airway responsiveness.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Aerosols; Airway Resistance; Animals; Chemotaxis, Leukocyte; Dinoprost; Dinoprostone; Dogs; Leukotriene B4; Methacrylates; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Prostaglandins F; Pulmonary Alveoli; Respiratory System; Thromboxane B2; Thromboxane-A Synthase; Time Factors