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Transcellular synthesis of cysteinyl leukotrienes and neutrophil-dependent cerebral edema
No full textSimultaneous investigation of the neuronal and vascular compartments in the guinea pig brain isolated in vitro
No full textWe describe a new method for studying the interactions between vascular tone changes and neuronal activity in the arterially perfused isolated brain of the adult guinea pig maintained in vitro. Electrophysiological recordings were performed in the piriform and entorhinal cortices with the entire arterial bed preserved or after vascular restriction to the territories of median and posterior cerebral arteries of one hemisphere. The changes in vascular tone were measured by means of a pressure transducer. The arterial pressure was 53.77+/-12.74 mmHg in control conditions at 30 degreesC. Intraluminal application of vasoactive drugs, such as the tromboxane A2 receptor agonist U46619 (0.1 microM) and 5-HT (3 microM), induced an increase in the resistance to perfusion pressure that was prevented by the selective antagonists. The preservation of the endothelial function was verified by inducing the release of endogenous endothelial relaxant factor after intraluminal application of 1 microM acetylcholine. The study of the reciprocal interactions between neuronal activity and vascular tone modifications demonstrated that evoked responses in the piriform and entorhinal cortices were not modulated by rapid changes of the vascular tone. A sustained and elevated plateau of vasoconstriction maintained for several minutes determined a cortical spreading depression. Epileptiform discharges induced in limbic cortices by GABAa receptor blockade were consistently associated with a vasodilation (8.26+/-2.8 mmHg). The results demonstrate that the in vitro isolated guinea pig brain preparation can be exploited for studying simultaneously neuronal activity and cerebrovascular motility
Tramadol anti-inflammatory activity is not related to a direct inhibitory action on prostaglandin endoperoxide synthases
No full textThe analgesic drug tramadol has been shown to relieve pain in inflammatory conditions, to inhibit the development of experimental inflammation, and to reduce prostaglandin (PG)E 2 concentrations in the inflammatory exudate. In this study, we evaluated the putative activity of tramadol to suppress prostaglandin endoperoxide synthase-1 (PGHS-1), and prostaglandin endoperoxide synthase-2 (PGHS-2) activities in human whole blood in vitro. Platelet thromboxane (Tx)B 2 production and monocyte PGE 2 production in LPS-stimulated blood were measured in samples incubated with different concentrations (300 ng/ml, 3 μg/ml, 30 μg/ml) of tramadol or its enantiomers. Neither tramadol nor the enantiomers inhibited the formation of arachidonic acid metabolites. Our results indicate that the anti-inflammatory effect of tramadol demonstrated in some models is not related to a direct inhibitory effect on the formation of prostanoids
Modulation of leukocyte-endothelial cell interaction and leukotriene dependent vasoconstriction by prostacyclin mimetics in the isolated rabbit heart
No full textLeukotriene modifiers: novel therapeutic opportunities in asthma
No full textCysteinyl leukotrienes (Cys-LT) are powerful proinflammatory autacoids that cause long-lasting bronchoconstriction, plasma leakage, increased mucus production; their biological activity suggests a prominent role in the etiopathology of asthma and several Cys-LT receptor antagonists and synthetase inhibitors have been developed as new antiasthmatic drugs. Zafirlukast was discovered by a mechanism-based approach to drug discovery; early structure-activity relationship analyses of the prototype SRS-A antagonist FPL-55712, lead to the identification of an indole-containing lead compound that was more specific than FPL-55712. Modifications were made on the lipid-like tail, indole backbone and acidic head region of this lead compound, resulting in potent and selective leukotriene receptor antagonists such as ICI-198615 and 204219 (zafirlukast). On the basis of successful results in preclinical asthma models, zafirlukast was recommended for clinical development and became the first leukotriene-modifier to be approved for the treatment of asthma. Leukotriene biosynthesis inhibitors (LSI) also represent a promising approach to the treatment of asthma and may theoretically provide a broader protection than Cys-LT receptor antagonists by inhibition of the synthesis of the two major leukotrienes, the Cys-LT and the chemotactic LTB4. The LSI BAY X-1005 is the result of a broad chemistry program that identified 15-HETE as an endogenous inhibitor of leukotriene synthesis and REV 5901 as a lead prototypic quinoline-based 5-lipoxygenase (5-LO) inhibitor. Clinical studies demonstrated the effectiveness of BAY X-1005 in experimental conditions such as allergen provocation and cold-air induced asthma. However, no consistent treatment effect in the overall asthma population (mild to moderately severe asthmatics) lead to discontinuation of its development
COX-1 AND PROSTACYCLIN PRODUCTION BY ENDOTHELIAL CELLS IN THE PRESENCE OF MILD OXIDATIVE STRESS
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