ono-4057 and ozagrel

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

Platelet-activating factor (PAF) is a potent proinflammatory compound potentially involved in the pathogenesis of inflammatory disorders, including bronchial asthma. To elucidate the pathophysiologic roles of PAF in bronchial asthma, we studied airway responsiveness in transgenic mice overexpressing PAF receptor. In the transgenic mice, PAF-induced airway smooth muscle contraction was demonstrated by physiologic and morphometric analyses, whereas there was no significant response in the littermate control group. The PAF-elicited bronchoconstriction in the transgenic mice was significantly reduced not only by a PAF receptor antagonist (WEB-2086) but also by a thromboxane synthesis inhibitor (indomethacin or ozagrel), an inhibitor of 5-lipoxygenase-activating protein (MK-886), or a cysteinyl leukotriene (LT) antagonist (pranlukast). LTB4 receptor antagonist (ONO-4057), however, had no effect on the PAF-induced responses. The transgenic mice showed a bronchial hyperreactivity to methacholine challenge, which was also inhibited by pretreatment with either thromboxane synthesis inhibitor or cysteinyl LT antagonist. These observations suggest that both thromboxane A2 and cysteinyl LTs (LTC4, LTD4, and LTE4) are involved in the bronchial responses to PAF or cholinergic stimulus in mice. The transgenic mice overexpressing PAF receptor may provide an appropriate model to study various PAF-related lung diseases, including bronchial asthma.

Topics: Animals; Azepines; Bronchi; Bronchial Hyperreactivity; Chromones; Indoles; Indomethacin; Leukotriene Antagonists; Leukotrienes; Lipoxygenase Inhibitors; Lung; Methacrylates; Mice; Mice, Transgenic; Phenylpropionates; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Leukotriene B4; Thromboxanes; Triazoles

We examined the effects of eicosanoid antagonists on colonic damage induced by trinitrobenzene sulfonic acid (TNB) in a rat inflammatory bowel model. TNB (30 mg) dissolved in 0.25 ml of 50% ethanol, was given intrarectally. The appropriate doses of ONO-1078 (a leukotriene C4D4 antagonist), ONO-4057 (a leukotriene B4 antagonist), and OKY-046 (a thromboxane A2 synthetase inhibitor) were given to obtain the same blood level, either 4 h before (pre-treatment model) or 24 h after (the post-treatment model) the administration of TNB (n = 8 in all groups). Drugs were given once daily for 6 days through a gastric feeding tube. Autopsy was performed on the 7th day. Colonic damage was assessed in terms of colonic damage scores, and myeloperoxidase (MPO) activity and eicosanoid concentrations in colonic tissues were measured. Compared with the group given TNB alone, the colonic damage score was reduced to 10% in the pre-treatment model with ONO-1078, but the score was not reduced in other groups, MPO activity was not changed in any group. The concentration of leukotriene C4 was reduced with ONO-1078 treatment, in both pre- and post-treatment models. These results demonstrated that a leukotriene C4D4 antagonist reduced colonic inflammation; however, its anti-inflammatory effect was limited in this colitis model.

Topics: Animals; Chromones; Colon; Disease Models, Animal; Eicosanoids; Female; Inflammatory Bowel Diseases; Leukotriene C4; Leukotriene D4; Methacrylates; Peroxidase; Phenylpropionates; Rats; Rats, Sprague-Dawley; SRS-A; Thromboxane-A Synthase; Trinitrobenzenesulfonic Acid

Topics: Animals; Chromones; Colon; Inflammation; Inflammatory Bowel Diseases; Methacrylates; Phenylpropionates; Rats; SRS-A