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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 21 (1987), S. 355-357 
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The object of this study was to investigate the importance of omega oxidation in regulating leukotriene B4 (LTB4) levels in man. In human polymorphonuclear leukocytes metabolism of LTB4 was rapid but was critically dependent on PMN number: greater than 1.5×106 PMN/ml were required. Metabolism of LTB4 was blocked in the presence of plasma. In whole blood and in PMN-rich rheumatoid synovial fluids no significant metabolism of LTB4 was detected within 30 min at 37°C. We conclude that LTB4 metabolism at inflamed sites will be regulated both by cellular content and the degree of plasma exudation. In most pathological conditions rapid exchange with the micro-vasculature will be more important than metabolism in limiting LTB4 levels.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Formyl-methionyl-leucyl-phenylalanine (FMLP), platelet activating factor (PAF) and leukotriene B4 (LTB4) are potent activators of human neutrophils. Using human neutrophils prelabelled with the fluorescent indicator dye, Quin 2, or with [32P]-orthophosphate, we examined the effects of these stimuli on intracellular free calcium concentration, [Ca2+]i, and, on various indices of phosphoinositide metabolism, including [32P]-phosphatidic acid (PtdA) formation. The concentration-dependence of the observed changes in [Ca2+]i or [32P]-PtdA were then compared to stimulus-induced aggregation and enzyme release (β-N-acetylglucosaminidase (NAG) and lysozyme). FMLP, PAF and LTB4 caused a concentration-dependent elevation of [Ca2+]i, aggregation and enzyme release. However, unlike FMLP and PAF, LTB4 (≦2.5 μM) did not cause significant formation of [32P]-PtdA. The concentration response curves for agonist-induced elevation of [Ca2+]i lie to the left of those for aggregation and enzyme release. FMLP and PAF also caused an elevation of [Ca2+]i at concentrations lower than those required to elicit [32P]-PtdA formation. These observations suggest that [Ca2+]i elevationper se cannot mediate human neutrophil functional responses to FMLP, PAF and LTB4. Consequently there may exist other mediator(s) that act in concert with [Ca2+]i or are triggered by [Ca2+]i elevation to promote human neutrophil activation. Both the elevation of [Ca2+]i and the formation of these putative mediator(s) in response to LTB4 apparently occur independently of inositol phospholipid hydrolysis.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of medicinal chemistry 34 (1991), S. 1028-1036 
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Methoxyalkyl thiazoles are novel 5-lipoxygenase inhibitors which are neither redox agents nor iron chelators and are exemplified by ICI211965 [1-(3-naphth-2-ylmethoxy)phenyl)-1-(thiazol-2-yl)propyl methyl ether]. ICI211965 potently inhibits LTC4 synthesis in murine macrophages (IC50=0.0085 μM) and its selectivity with respect to cyclo-oxygenase (〉5800) is greater than any previously reported lipoxygenase inhibitor. ICI211965 also selectively inhibits LTB4 synthesis by human bloodin vitro (IC50=0.45 μM) and rat bloodex vivo (ED50=10 mg/Kg, p.o.). Methoxyalkyl thiazoles exhibit a tight structure activity relationship and resolution of a chiral member of the series demonstrates that 5-lipoxygenase inhibition resides largely in one enantiomer. Methoxyalkyl thiazoles represent the first class of agents for which 5-lipoxygenase inhibition is mediated by specific, enantioselective interaction with the enzyme.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 34 (1991), S. 121-124 
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tolfenamic acid and tenidap have been reported to be dual inhibitors of cyclo-oxygenase and 5-lipoxygenase. In this study inhibition of 5-lipoxygenase by tenidap and tolfenamic acid in plasma-free leukocyte suspensions (IC50 values=10 μM) required concentrations more than 100 fold higher than those which inhibited cyclo-oxygenase (IC50 values=0.05 and 0.02 μM respectively). The potencies of tolfenamic acid and tenidap as cyclo-oxygenase inhibitors were markedly reduced in blood (IC50=6.5 and 10 μM respectively) and neither significantly inhibited 5-lipoxygenase. Since both drugs also failed to inhibit 5-lipoxygenase in rat bloodex vivo, we conclude that, at physiological levels of plasma proteins, tolfenamic acid and tenidap are selective cyclo-oxygenase inhibitors.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 24 (1988), S. 114-119 
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Polymorphonuclear leukocytes (PMNL) are prominent at sites of acute inflammation. Their infiltration is stimulated under pathological conditions by a variety of agents which include bacteria, immune complexes and complement derived chemotactic peptides. Recently attention was focussed on the 5-lipoxygenase product leukotriene B4 (LTB4) which has been demonstrated to induce the key features associated with an acute inflammatory reaction. However, evidence supporting a pro-inflammatory role for LTB4, and therefore the anti-inflammatory efficacy of 5-lipoxygenase inhibitors, is largely circumstantial. Moreover, there are concerns that other chemotactic factors, notably C5a, may compensate for the absence of LTB4. Here we challenge this view and, on the basis of recent experimental and clinical data suggest that LTB4 does not simply duplicate the activity of C5a. Instead we propose that their predominant site(s) of action differ in such a way that they may synergise in mediating PMNL recruitment.
    Type of Medium: Electronic Resource
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