Cui Xizhong, Li Yan, Moayeri Mahtab, Choi Gil H, Subramanian G M, Li Xuemei, Haley Michael, Fitz Yvonne, Feng Jing, Banks Steven M, Leppla Stephen H, Eichacker Peter Q
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Infect Dis. 2005 Feb 1;191(3):422-34. doi: 10.1086/427189. Epub 2004 Dec 22.
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.
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.
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.
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.
在动物模型中，用5H3（一种完全人源的针对保护性抗原的单克隆抗体（PA单克隆抗体））进行治疗，在接近炭疽杆菌致死毒素（LeTx）推注或活菌攻击时给药可提高生存率。然而，如果PA单克隆抗体即使在因LeTx导致休克和致死性发作后给药仍有益，则其在临床上将最具价值。
我们研究了在24小时LeTx输注开始时或开始后3、6、9或12小时给大鼠（n = 324）注射PA单克隆抗体与安慰剂的效果。
在接受安慰剂的大鼠中，非存活者的平均动脉血压（MBP）和心率（HR）在6小时时与存活者相比降低，然后进一步恶化，致死性在8小时时首次显现（中位数为16小时；范围为8 - 152小时）。在每个治疗时间点，PA单克隆抗体组的生存率均高于安慰剂组，尽管在较晚治疗时间点改善程度有所降低（时间效应，P = .001）。与安慰剂相比，PA单克隆抗体在治疗开始后的12小时内显著提高了MBP，但在3小时治疗时升高幅度最大；同样，PA单克隆抗体在所有治疗时间点均显著提高了HR。
在该大鼠模型中，在初次暴露于LeTx后长达6小时给予PA单克隆抗体可显著改善预后（在长达12小时给药时接近显著）。临床上，即使在因LeTx导致休克和致死性发作后给予PA单克隆抗体也可能有益。
