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。本地BPI 与多种革兰氏阴性菌的内毒素结合， 抑制内毒素介导的细胞效应，如TNF。我们的假设是 积极或剧烈地给予BPI可以增强我们的自然 对有毒细菌产物如内毒素的防御 中和作用和清除率的提高使用我们的犬类模型 设盲、对照、随机试验，两个治疗组：一个 每6小时接受2 mg/kg BPI，共3次给药，另一次给药 （对照）接受类似数量的车辆中使用的 以类似的方式制备BPI，我们评估BPI是否 改变存活率菌血症和内毒素血症我们追踪生存， 连续血流动力学，CBCs，血液化学，乳酸，定量 血培养TNF和内毒素水平重组人BPI， 由Incyte Pharmaceuticals提供。我们 发现BPI在狗体内的半衰期约为20分钟， 比通常报道的小动物高。不幸的是在 这只犬的感染性休克模型，BPI总体上没有变化 存活率、血流动力学和TNF水平或菌血症。但我们 发现在动物接受BPI或 对照治疗，BPI治疗的动物具有更长的存活时间 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症的潜在治疗药物 冲击.

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.