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1.
J Infect Dis ; 187(4): 631-9, 2003 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-12599080

RESUMO

E5564 is a second-generation synthetic analogue of the lipid A component of endotoxin (lipopolysaccharide [LPS]). The ability of E5564 to block the toxic activity of LPS was assessed in a double-blind, placebo-controlled study. A bolus infusion of endotoxin (4 ng/kg) was administered to healthy subjects to induce a mild transient syndrome similar to clinical sepsis. Single E5564 doses of 50-250 microg ameliorated or blocked all of the effects of LPS in a dose-dependent manner. All E5564 dose groups had statistically significant reductions in elevated temperature, heart rate, C-reactive protein levels, white blood cell count, and cytokine levels (tumor necrosis factor-alpha and interleukin-6), compared with placebo (P<.01). In doses of > or = 100 microg, E5564 acted as an LPS antagonist and completely eliminated these signs. E5564 also blocked or ameliorated LPS-induced fever, chills, headache, myalgia, and tachycardia (P<.01). These results demonstrate that E5564 blocks the effects of LPS in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.


Assuntos
Endotoxemia/tratamento farmacológico , Lipídeo A/análogos & derivados , Lipídeo A/uso terapêutico , Adolescente , Adulto , Citocinas/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Humanos , Infusões Intravenosas , Lipídeo A/administração & dosagem , Lipopolissacarídeos/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade
2.
J Pharmacol Exp Ther ; 308(1): 175-81, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14566003

RESUMO

E5564 (alpha-D-glucopyranose) is a synthetic antagonist of bacterial endotoxin that has been shown to completely block human endotoxin response. Low doses of E5564 (0.35-3.5 mg) have a long pharmacokinetic half-life, but a surprisingly short ex vivo and in vivo pharmacodynamic half-life (generally less than several hours). To determine whether extended antagonistic activity can be achieved in vivo, this study assesses the pharmacodynamic activity of 4- and 72-h infusions of E5564 into normal volunteers. Administration of 3.5 mg of E5564/h x 72 h completely blocked effects of endotoxin challenge at the end of dosing (72 h), and at 48 and 72 h postdosing. Similarly, a 4-h infusion of E5564, 3 mg/h completely blocked endotoxin administered 8 h postdosing. A lower dose of E5564, 0.5 mg/h x 4 h, ameliorated but did not block most effects of endotoxin 8 h postdosing (p <0.05). Finally, the effect of varying plasma lipoprotein content on E5564 activity was studied in subjects having high or low cholesterol levels (>180 or <140 mg/dl) after 72-h infusion of 252 mg of E5564. No differences were observed. These results demonstrate that E5564 blocks the effects of endotoxin in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.


Assuntos
Endotoxemia/prevenção & controle , Lipídeo A/análogos & derivados , Lipídeo A/uso terapêutico , Lipopolissacarídeos/efeitos adversos , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Citocinas/metabolismo , Endotoxemia/induzido quimicamente , Endotoxemia/metabolismo , Endotoxinas , Humanos , Leucócitos/efeitos dos fármacos , Lipídeo A/efeitos adversos , Lipídeo A/farmacocinética , Masculino , Pessoa de Meia-Idade , Taquicardia/induzido quimicamente
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