Pheresis Treatment of Bioterrorism-Induced Sepsis

描述(申请人提供)：炭疽病、鼠疫和兔热病等细菌生物恐怖因子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)。病毒生物恐怖因子，如天花，也可诱发全身炎症反应综合征(SIRS)和感染性休克，因为继发性细菌感染。对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体是由天然免疫系统产生的循环因子，是脓毒症相关组织损伤和死亡的关键介体。到目前为止，在针对单个脓毒症介质的药物进行了大量研究和临床试验后，尚未有抗炎药获得临床批准。本项目的目标是开发一种简单的体外吸入剂为基础的止血系统，该系统可以广泛降低血浆中促炎症和抗炎脓毒症介质的水平，并阻止脓毒症后器官衰竭的下行过程。 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。生物DTPF系统由串联的透析系统(DT)和静注系统(PF)组成。体外研究表明，炎性脓毒症介质如肿瘤坏死因子-α以20-25ml/min的速度清除长达6小时，完全是由于PF系统中的吸着剂的吸附。I期试验表明，DTPF系统一次治疗2-6小时后，8名脓毒症和多器官衰竭患者中有7人的生理状况得到改善。基于这项I期试验，基于吸着剂和粉末状吸入剂的静脉注射似乎有可能在治疗过程中改变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预后。这种疗法在免疫调节领域提供了新的希望，因为它既是广谱的(去除促炎和抗炎化合物)，又是自我调节的，通过去除与其循环浓度有关的物质。 该项目将对PF体外循环治疗系统进行改进，使其成为一个独立的系统。将开发一种新的吸着剂混合物，并在实验室中与各种败血症启动剂和介体一起进行测试。改变等离子体与脱硫剂的接触方式，提高系统的效率。抗凝方法改为局部柠檬酸盐抗凝。将对现有PF系统的安全系统进行改造，以满足独立系统的需要。最后，将使用败血症的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.