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  • 1
    ISSN: 1420-908X
    Keywords: Interleukin-8 ; Staphylococcal enterotoxin A ; Macrophages ; Neutrophils ; Inflammation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Since Staphylococcus aureus is an important human pathogen, and infection of the lungs in characterized by neutrophil infiltration we studied the role of a staphylococcal toxin, enterotoxin A (SEA) on the synthesis and secretion of IL-8 by human alveolar macrophages. As SEA concentration was increased, the IL-8 accumulation in the macrophage conditioned medium increased. The concentration of mRNA encoding IL-8 was also elevated in the macrophage in response to increases in SEA concentration. Although the monocytic cell line U937 was able to respond to SEA and secrete IL-8, treatment with PMA prior to SEA stimulation increased the IL-8 accumulation around fifty fold indicating that maturation of the undifferentiated cell to a more macrophage-like cell facilitated IL-8 accumulation. Stimulating human alveolar macrophages with high concentrations of SEA caused an increase in IL-1 accumulation. However, when the cells were incubated with SEA in the presence of IL-1 receptor antagonist, there was no decrease in IL-8 accumulation. Addition of a neutralizing anti-IL-8 monoclonal antibody to the culture medium of SEA-stimulated macrophages significantly reduced the neutrophil chemotactic activity of the medium. These studies showed that IL-8 is a major neutrophil chemotaxin from human alveolar macrophages stimulated with SEA.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1420-908X
    Keywords: Interleukin-8 ; Inhibitor ; Sepsis ; Neutrophils ; Lung
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Staphylococcal enterotoxin A (SEA) is a superantigen, produced by some strains ofStaphylococcus aureus (S. aureus), which can cause a variety of clinical manifestations ranging from food poisoning to shock. SEA can also stimulate human alveolar macrophages to produce interleukin-8 (IL-8), a member of the α-chemokine subfamily that activates and is chemotactic for neutrophils. In these studies we showed that in rabbits, intravenous SEA significantly decreased the circulating white blood cell population from a baseline value of 6409±2027×103 cells/ml to 1943±862×103 cells/ml in 7 h. There was a concommitent increase in IL-8 in the circulating plasma (baseline: 60±34 pg/ml, 7 h post SEA: 109±64 pg/ml). The increase in circulating IL-8 was accompanied by a much greater increase in the IL-8 concentration of the epithelial lining fluid (ELF) where the IL-8 increased from 0.05±0.08 ng/ml (control) to 13.8±9.3 ng/ml (SEA treated). The increase in IL-8 concentration in the alveolar spaces was paralleled by an increase in both the percentage of neutrophils (1.4±0.9% (control) to 26.0±10.8% (SEA treated)) and total number of neutrophils (0.04±0.02×106/ml (control) to 4.8±3.3 106/ml (SEA treated)) in the airspaces, and the numbers of neutrophils in the ELF correlated with the IL-8 concentration r=0.62, p=0.006). When antileukinate, a hexapeptide which inhibits the binding of IL-8 to neutrophils, was administered to animals receiving SEA, the IL-8 concentration in the ELF (14.8±10.7 ng/ml) was not significantly different from the concentration of IL-8 in those animals receiving SEA alone). However, both the percentage of neutrophils (9.5±3.2%), and the total number of neutrophils (1.3±1.0×106/ml) in the ELF following SEA and antileukinate administration was significantly lower than in animals which only received SEA (p〈0.05). The findings suggest that SEA released into the circulation during a Staphylococcal infection can cause an inflammatory reaction in the lung. Since this reaction is at least partially mediated by IL-8, antileukinate may have pharmacologic potential in reducing the inflammatory reaction.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1041
    Keywords: Felodipine ; Nitrendipine ; Nifedipine ; pharmacokinetics ; stereoselectivity ; enantiomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all given as an oral dose of 20 mg in solution) have been investigated in a randomised cross-over study in 12 healthy male subjects using stereoselective assays. Both felodipine and nitrendipine exhibited stereoselective pharmacokinetics. On average, the AUCs of the active (S)-enantiomers of felodipine and nitrendipine were 139% and 104% higher than those of their optical antipodes, but the elimination half-lives of the enantiomers of each racemate were not different. The AUCs of nifedipine, rac-felodipine, rac-nitrendipine and of their enantiomers were highly correlated (all r〉0.83), suggesting closely related rate limiting steps in the in vivo first-pass metabolism of these high-clearance drugs. Stereoselectivity was only a minor contributor to inter-individual variability in the oral pharmacokinetics of these compounds in healthy subjects.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1041
    Keywords: Felodipine ; Nitrendipine ; Nifedipine ; enantiomers ; blood pressure ; heart rate ; concentration-effect relationship ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all 20 mg solution p.o.) on non-invasively measured blood pressure and heart rate were investigated in a randomised, double-blind, cross-over study in 12 normotensive, young, healthy males. Compared to baseline values, heart rate increased more after rac-felodipine treatment (+47% at maximum) than rac-nitrendipine (+40%) and nifedipine (+38%); only small and variable changes in blood pressure were observed with any of the drugs. The baseline-corrected area under the heart rate-time curve up to 4 h after the administration of rac-felodipine was 197% and 180% larger than after nifedipine and rac-nitrendipine treatment, respectively. The effects on heart rate could be fitted individually to a sigmoidal Emax-model without hysteresis for all drugs under investigation. The relative potencies of the unbound drugs for their indirect effects on heart rate were 1:7:43 for nifedipine, rac-nitrendipine and rac-felodipine, respectively. The active (S)-enantiomers of felodipine and nitrendipine appeared to be 9-and 60-times as potent as nifedipine in this respect, assuming no (inter)activity of the (R)-enantiomers. Individual and mean changes in blood pressure were small, they were not related to plasma concentrations, and did not differ between treatments.
    Type of Medium: Electronic Resource
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