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

BPI是一种由人类中性粒细胞产生的55 KDA蛋白质。本地BPI绑定到 多种革兰氏阴性菌的内毒素及其抑制作用 内毒素介导的细胞效应，如肿瘤坏死因子。我们的假设是BPI 预防性或尖锐地给予可以增强我们的自然防御能力 对抗内毒素等有毒细菌产物，导致增加 中和和清除。在盲区使用我们的犬科动物模型， 两个治疗组的随机对照试验：一组接受2 BPI每6小时1次，共3次，另1次(对照组) 在#年收到相同数量的用于编制BPI的车辆 以类似的方式，我们评估了BPI是否改变了存活率、菌血症和 内毒素血症。我们观察了存活率、系列血流动力学、CBCS、血液 化学、乳酸、定量血培养、肿瘤坏死因子和内毒素 级别。使用Incell PharmPharmticals提供的重组人BPI 在这个实验中。我们发现在狗体内，BPI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 改变总体存活率、血流动力学和肿瘤坏死因子水平，或菌血症。 然而，我们发现，在动物接受 BPI或对照疗法，BPI处理的动物有更长的存活时间 与对照组相比。一种半衰期更长的BPI制剂正在研制中 制造的。因此，由于早期死亡率下降， 内毒素水平有所降低，我们计划进一步调查更长时间 将BPI制剂作为脓毒症和感染性休克的潜在治疗方法。

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.