Effective dosing of lipid A analogue E5564 in rats depends on the timing of treatment and the route of Escherichia coli infection.
Effective dosing of lipid A analogue E5564 in rats depends on the timing of treatment and the route of Escherichia coli infection.
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脂质 A 类似物 E5564 在大鼠中的有效剂量取决于治疗时间和大肠杆菌感染途径。
DOI：
10.1086/500147
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Eichacker,PeterQ
中科院分区：
文献类型：
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作者：
Solomon,StevenB;Cui,Xizhong;Gerstenberger,Eric;Danner,RobertL;Fitz,Yvonne;Banks,StevenM;Natanson,Charles;Eichacker,PeterQ
背景E5564是一种竞争性脂质A拮抗剂，可抑制内毒素刺激的炎症，目前正在脓毒症患者中进行研究。方法我们在大肠杆菌攻击的大鼠中测试了临床相关变量，包括治疗时间和感染途径，是否影响E5564的有效剂量。结果所有E5564剂量（0.3、1.0、2.0和3.0 mg/kg血管内推注，随后每小时输注推注剂量的10%，持续24 h），在血管内注射前1 h给药E。colichallenge同样降低了死亡风险。将E5564的开始时间延迟至血管内注射后1或3 h。colichallenge显著降低了测试剂量的有益效果。然而，增加E5564的剂量逆转了延迟治疗的一些疗效损失（P = 0.004，随着1小时剂量的增加，获益增加）。在支气管内或腹膜内（血管外）E。大肠杆菌激发后，E5564的有效给药模式与血管内给药模式相反。大肠杆菌挑战（对于相互作用，P =.001）-较低剂量的E5564是有益的，而较高剂量则不是（0.03、0.3、1.0、2.0和3.0 mg/kg推注，随后输注）（P = 0.05，1小时时随着剂量的增加，获益减少）结论这些发现表明，为了获得最大的临床获益，E5564应尽早给药，血管内感染时应上调剂量，血管外感染时应下调剂量
BackgroundE5564, a competitive lipid A antagonist, inhibits endotoxin-stimulated inflammation and is under study in patients with sepsisMethodsWe tested whether clinically relevant variables, including the timing of treatment and the route of infection, influenced the effective dosing of E5564 inEscherichia coli–challenged ratsResultsAll E5564 doses (0.3, 1.0, 2.0, and 3.0 mg/kg intravascular bolus followed by 10% of the bolus dose infused hourly for 24 h) administered 1 h before intravascularE. colichallenge similarly reduced the risk of death. Delaying the start of E5564 to 1 or 3 h after intravascularE. colichallenge significantly reduced the beneficial effect of the doses tested. However, increasing the dose of E5564 reversed some loss of efficacy for delayed treatment (P=.004, for increasing benefit with increasing dose at 1 h). During intrabronchial or intraperitoneal (extravascular)E. colichallenge, the pattern of effective E5564 dosing was the inverse of that for intravascularE. colichallenge (P=.001, for the interaction)—lower doses of E5564 were beneficial and higher doses were not (0.03, 0.3, 1.0, 2.0, and 3.0 mg/kg bolus followed by infusion) (P=.05, for decreasing benefit with increasing dose at 1 h)ConclusionThese findings suggest that, for maximal clinical benefit, E5564 should be given early and that dosing should be adjusted upward for intravascular infection and downward for extravascular infection