Pheresis Treatment of Bioterrorism-Induced Sepsis

描述（由申请人提供）：炭疽、鼠疫和兔热病等细菌性生物恐怖剂的受害者经常死于败血症和随后的多器官功能障碍综合征（MODS）。病毒性生物恐怖剂，如天花，也可以诱发全身炎症反应综合征（SIRS）和败血性休克，因为继发性细菌感染。SIRS和MODS的有效治疗将使许多生物恐怖主义的受害者免于悲惨的死亡。 越来越多的证据表明，细胞因子和细胞因子介质，由先天免疫系统产生的循环因子，作为脓毒症相关组织损伤和死亡的关键介质。迄今为止，在针对个体脓毒症介质的药物的大量研究和许多临床试验之后，还没有抗炎剂被临床批准。本项目的目标是开发一种简单的基于山梨醇的体外分离系统，该系统可以广泛地降低血浆中促炎和抗炎脓毒症介质的水平，并阻止脓毒症后器官衰竭的恶化过程。 一种新的脓毒症治疗方法已经在脓毒症和多器官衰竭患者的I期临床试验中进行了测试。该系统（Biologic-DTPF）由串联的透析系统（DT）和分离系统（PF）组成。体外研究表明，完全由于PF系统中吸附剂的吸附，以20- 25 ml/min的速度清除炎症性脓毒症介质（如TNF-α）长达6小时。I期试验表明，使用DTPF系统进行2-6小时的一次治疗导致8名脓毒症和多器官衰竭患者中的7名生理改善。基于这项I期试验，似乎基于山梨醇的粉末吸附剂分离法有可能改变治疗期间血液中细胞因子的浓度，并改善脓毒症和多器官衰竭患者的结局。这种疗法在免疫调节领域提供了新的前景，因为它既具有广谱性（去除促炎和抗炎化合物），又通过去除与其循环浓度相关的物质进行自我调节。 本项目将通过使其成为独立系统来修改PF体外血液分离系统治疗。将开发一种新的吸附剂混合物，并在实验室中与各种各样的脓毒症引发剂和介质进行测试。将改变等离子体与吸附剂的接触方式，以提高系统的效率。抗凝方法将变更为局部柠檬酸盐抗凝。现有PF系统的安全系统将进行修改，以满足独立系统的需要。最后，将使用脓毒症动物模型来检查整个系统的有效性和安全性。

DESCRIPTION (provided by applicant): Victims of bacterial bioterrorism agents such as anthrax, plague, and tularemia die very often because of septicemia and subsequent multiple organ dysfunction syndrome (MODS). Viral bioterrorism agents such as smallpox can also induce Systemic Inflammatory Response Syndrome (SIRS) and septic shock because of secondary bacterial infections. An effective therapy for SIRS and MODS would spare many of the victims of bioterrorism from a tragic death. Escalating evidence has implicated cytokines and cytokines mediators, circulating factors produced by the innate immune system, as critical mediators of sepsis-related tissue injury and death. To date, after much research and many clinical trials of drugs targeting individual sepsis mediators, no anti-inflammatory agent has been clinically approved. The goal of this project is to develop a simple extracorporeal sorbent-based pheresis system that can broadly diminish level of pro-inflammatory and anti-inflammatory sepsis mediators from plasma, and halt the downhill course of organ failure after sepsis. A novel treatment for sepsis has already been tested in Phase I clinical trials in patients with sepsis and multiple organ failure. This system, the Biologic-DTPF, consisted of a dialysis system (DT) and a pheresis system (PF) in series. In vitro studies indicated clearance of inflammatory sepsis mediators like TNF-alpha at 20- 25 ml/min for up to 6 hours, due entirely to adsorption by sorbent in the PF system. The Phase I trial indicated that one treatment of 2-6 hours with the DTPF system resulted in physiologic improvement in seven of eight patients with sepsis and multiple organ failure. Based on this Phase I trial, it appears that sorbent-based pheresis with powdered sorbent has the potential to alter cytokine concentrations in blood during therapy and improve the outcome of patients with sepsis and multiple organ failure. This therapy offers new promise in the field of immuno-modulation because it is both broad-spectrum (removing both pro and anti inflammatory compounds) and self-regulating by removing substances in relation to their circulating concentrations. This project will modify the PF extracorporeal pheresis system treatment by making it a stand-alone system. A new sorbent mixture will be developed and tested in the laboratory with a broad assortment of sepsis initiators and mediators. The means of contacting plasma and sorbent will be changed to improve the efficacy of the system. The anticoagulation method will be changed to regional citrate anticoagulation. The safety systems of the existing PF system will be modified to meet the needs of the stand-alone system. Finally, an animal model of sepsis will be used to check efficacy and safety of the entire system.