BACTERICIDAL-PERMEABILITY INCREASING PROTEIN IN A CANINE MODEL OF SEPTIC SHOCK

BPI是由人中性粒细胞产生的55-Kda蛋白。天然BPI结合至 内毒素的各种革兰氏阴性细菌和抑制 内毒素介导的细胞效应如TNF。我们的假设是BPI 强烈或强烈的刺激可以增强我们的自然防御能力 针对毒性细菌产物如内毒素，导致增加的 中和和清除利用我们的犬类模型， 两个治疗组的对照、随机试验：一个接受2 mg/kg BPI，每6小时一次，共3次给药，其他（对照） 在制备BPI时使用的溶媒量相似， 以类似的方式，我们评估了BPI是否会改变存活率、菌血症和 内毒素血症我们跟踪了存活率，连续血流动力学，血细胞计数， 化学、乳酸盐、定量血培养、TNF和内毒素 程度.使用Incyte Pharmaceuticals提供的重组人BPI 本实验我们发现BPI在狗体内的半衰期为 大约20分钟，高于通常报告的较小 动物不幸的是，在这个感染性休克的犬模型中，BPI没有 改变总生存率、血流动力学和TNF水平或菌血症。 然而，我们发现，在动物接受 与对照组相比，BPI组动物的存活时间更长 与对照相比。一种半衰期更长的BPI制剂正在开发中。 制造的。因此，由于早期死亡率下降， 内毒素水平降低，我们计划进一步研究更长时间的 BPI制剂作为脓毒症和脓毒性休克的潜在治疗剂。

BPI is a 55-Kda protein produced by human neutrophils. Native BPI binds to endotoxins from a variety of gram-negative bacteria and inhibits endotoxin-mediated cellular effects as TNF. Our hypothesis is that BPI given prophylactically or acutely could bolster our natural defenses against toxic bacterial products such as endotoxin resulting in increased neutralization and clearance. Using our canine model in a blinded, controlled, randomized trial with two treatment groups: one receiving 2 mg/kg BPI every 6 h for a total of 3 doses and the other (controls) receiving similar amounts of the vehicle used in the preparation of BPI in a similar manner, we evaluated whether BPI alters survival, bacteremia and endotoxemia. We followed survival, serial hemodynamics, CBCs, blood chemistries, lactate, quantitative blood cultures, TNF and endotoxin levels. Recombinant human BPI, provided by Incyte Pharmaceuticals was used in this experiment. We found that in the dog BPI had a half life of approximately 20 minutes, higher than the usually reported in smaller animals. Unfortunately, in this canine model of septic shock, BPI did not change overall survival, hemodynamics and TNF levels, or bacteremia. However, we found that during the time during which animals were receiving BPI or control therapies, BPI-treated animals had greater survival times compared to controls. A BPI preparation with longer half life is being manufactured. Thus, since early mortality rates were decreased, and endotoxin levels were lowered, we plan to further investigate a longer acting BPI preparation as a potential therapy for sepsis and septic shock.