Lynn Melvyn, Rossignol Daniel P, Wheeler Janice L, Kao Richard J, Perdomo Carlos A, Noveck Robert, Vargas Ramon, D'Angelo Tony, Gotzkowsky Sandra, McMahon F Gilbert
Eisai Medical Research, Teaneck, New Jersey 07666-6741, USA.
J Infect Dis. 2003 Feb 15;187(4):631-9. doi: 10.1086/367990. Epub 2003 Feb 7.
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.
E5564是内毒素（脂多糖[LPS]）脂质A成分的第二代合成类似物。在一项双盲、安慰剂对照研究中评估了E5564阻断LPS毒性活性的能力。向健康受试者静脉推注内毒素（4 ng/kg）以诱发一种类似于临床败血症的轻度短暂综合征。50 - 250微克的单剂量E5564以剂量依赖方式改善或阻断了LPS的所有效应。与安慰剂相比，所有E5564剂量组的体温升高、心率、C反应蛋白水平、白细胞计数和细胞因子水平（肿瘤坏死因子-α和白细胞介素-6）均有统计学显著降低（P<0.01）。剂量≥100微克时，E5564作为LPS拮抗剂发挥作用并完全消除了这些体征。E5564还阻断或改善了LPS诱导的发热、寒战、头痛、肌痛和心动过速（P<0.01）。这些结果表明E5564在临床败血症的人体模型中阻断了LPS的效应，并表明其在治疗和/或预防临床败血症方面的潜力。
