Late treatment with a protective antigen-directed monoclonal antibody improves hemodynamic function and survival in a lethal toxin-infused rat model of anthrax sepsis
Late treatment with a protective antigen-directed monoclonal antibody improves hemodynamic function and survival in a lethal toxin-infused rat model of anthrax sepsis
复制标题
DOI：
10.1086/427189
复制
发表时间：
2005-02-01
影响因子：
6.4
通讯作者：
Eichacker, PQ
中科院分区：
文献类型：
--
作者：
Cui, XZ;Li, Y;Eichacker, PQ
背景在动物模型中，当接近炭疽芽孢杆菌致死毒素（LeTx）推注或活菌激发时间时，用完全人保护性抗原导向单克隆抗体（PA-MAb）5 H3治疗可改善存活率。然而，用PA-MAb治疗将是最有价值的临床，如果它是有益的，甚至当由于LeTx的休克和致死性发作后给药。我们研究了PA-MAb与安慰剂在大鼠（n = 324）中给药的效果，在24小时LeTx输注开始后3、6、9或12小时。在接受安慰剂的大鼠中，与存活大鼠相比，6 h时死亡大鼠的平均动脉血压（MBP）和心率（HR）降低，然后进一步恶化，8 h时首次出现明显的致死性（中位数，16 h;范围，8-152 h）。在每个治疗时间，PA-MAb组的生存率均高于安慰剂组，尽管在以后的治疗时间内改善程度降低（P = 0.001，时间效应）。与安慰剂相比，PA-MAb在治疗开始后12 h内显著增加MBP，但在治疗3 h时增加最大;同样，PA-MAb在所有治疗时间均显著增加HR。在该大鼠模型中，PA-MAb在首次暴露于LeTx后6小时内给药（给药至12小时时接近显著性），可显著改善结局。在临床上，PA-MAb可能是有益的，即使在休克和致死性由于LeTx发作后给药。
Background. In animal models, treatment with 5H3, a fully human protective antigen-directed monoclonal antibody (PA-MAb), improved survival when administered close to the time of Bacillus anthracis lethal toxin (LeTx) bolus or live bacterial challenge. However, treatment with PA-MAb would be most valuable clinically if it were beneficial even when administered after the onset of shock and lethality due to LeTx.Methods. We investigated the effects of PA-MAb versus placebo administered in rats (n = 324) at the time of or 3, 6, 9, or 12 h after the initiation of a 24-h LeTx infusion.Results. In rats receiving placebo, mean arterial blood pressure (MBP) and heart rate (HR) were decreased in nonsurvivors, compared with those in survivors, at 6 h and then worsened further, with lethality first evident at 8 h (median, 16 h; range, 8-152 h). At each treatment time, survival rates were greater for PA-MAb than for placebo, although improvement was decreased at later treatment times (P = .001, for the effect of time). Compared with placebo, PA-MAb significantly increased MBP during the 12 h after the initiation of treatment, but the increase was greatest for treatment at 3 h; similarly, PA-MAb significantly increased HR at all treatment times.Conclusion. In this rat model, improvements in outcome due to PA-MAb were significant when it was administered up to 6 h (and approached significance when administered up to 12 h) after initial exposure to LeTx. Clinically, PA-MAb may be beneficial even when administered after the onset of shock and lethality due to LeTx.