Source:http://linkedlifedata.com/resource/pubmed/id/12697095
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
6
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pubmed:dateCreated |
2003-4-16
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pubmed:abstractText |
E5564, a synthetic lipid A analogue, is a selective, highly active antagonist of endotoxin-mediated activation of immune cells. Preclinical research has indicated that E5564 can block endotoxin-mediated induction of cytokines and endotoxin or Gram-negative bacterial-induced death in animal models. Recent phase I clinical trials have focused on the ability of E5564 to block responsiveness to endotoxin. This was done in two ways: in vivo challenge of human volunteers with 4 ng/kg endotoxin, and by use of an ex vivo assay which utilizes blood drawn from volunteers administered E5564 and challenged with endotoxin at concentrations that ranged from 50 pg/ml to 10 ng/ml. In vivo, > or = 100 microg of E5564 completely blocked signs, symptoms and cytokines induced by concomitantly-administered endotoxin. In contrast, subjects receiving a 50 microg dose of E5564 demonstrated a graded response; cytokines were inhibited > or = 95%, but many signs and symptoms of endotoxemia were still evident. E5564 demonstrated a long pharmacokinetic half-life (> 30 h); however, ex vivo analysis indicated that while single doses of 350 microg induced a nearly complete block of the effects of 1 ng/ml endotoxin immediately upon E5564 administration, antagonistic activity declined rapidly (t(1/2) < 1 h). Similar results were obtained in vivo using a delayed endotoxin challenge. These results have driven us to examine antagonistic activity of E5564 in vivo and ex vivo after administration by continuous infusion or twice-daily dosing. Results from these multiple-dose studies indicate that under these conditions of administration, plasma levels of E5564 can be predictive of long-term pharmacodynamic activity.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:issn |
0968-0519
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
8
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
483-8
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pubmed:dateRevised |
2004-11-17
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pubmed:meshHeading |
pubmed-meshheading:12697095-Animals,
pubmed-meshheading:12697095-Cell Culture Techniques,
pubmed-meshheading:12697095-Cytokines,
pubmed-meshheading:12697095-Disease Models, Animal,
pubmed-meshheading:12697095-Half-Life,
pubmed-meshheading:12697095-Humans,
pubmed-meshheading:12697095-Lipid A,
pubmed-meshheading:12697095-Lipopolysaccharides,
pubmed-meshheading:12697095-Macrophages,
pubmed-meshheading:12697095-Mice
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pubmed:year |
2002
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pubmed:articleTitle |
Antagonism of in vivo and ex vivo response to endotoxin by E5564, a synthetic lipid A analogue.
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pubmed:affiliation |
Eisai Medical Research Inc., Teaneck, New Jersey 07666, USA. dan_rossignol@eisai.com
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pubmed:publicationType |
Journal Article
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