Pheresis Treatment of Bioterrorism-Induced Sepsis

生物恐怖主义引起的脓毒症的血液分离治疗

• 批准号: 6742356
• 负责人: STEPHEN R ASH
• 金额: $ 50.47万
• 依托单位: HEMOCLEANSE, INC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6742356
• 关键词: anticoagulants; bacterial disease; bioterrorism /chemical warfare; blood /lymphatic pharmacology; blood disorder chemotherapy; blood filtration; blood toxicology; blood treatment; cytokine; dogs; hemodialysis; hemodynamics; lipopolysaccharides; multiple organ failure; nonhuman therapy evaluation; plasmapheresis; secondary infection; septic shock; therapy design /development

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.

描述（由申请人提供）：细菌生物恐怖剂的受害者，例如炭疽，瘟疫和tular症，经常因败血症和随后的多器官功能障碍综合征（MODS）而死亡。病毒生物恐怖剂（例如天花）也可以诱导全身性炎症综合征（SIR）和败血性休克，因为继发细菌感染。对先生和国防部的有效疗法将使许多生物恐怖主义的受害者免于悲惨的死亡。 不断升级的证据暗示了细胞因子和细胞因子介质，这是由先天免疫系统产生的循环因子，作为败血症相关的组织损伤和死亡的关键介质。迄今为止，经过大量研究和许多针对单个脓毒症介质的药物的临床试验，尚未在临床上批准抗炎剂。该项目的目的是开发一个简单的基于吸附的基于吸附剂的门诊系统，该系统可以从血浆中广泛降低促炎和抗炎败血症介体的水平，并在脓毒症后阻止器官衰竭的下坡病程。 在I期临床试验中，已经在败血症和多器官衰竭患者中对败血症进行了新的治疗方法。该系统，即生物-DTPF，由串联的透析系统（DT）和网络处理系统（PF）组成。体外研究表明，以20-25 mL/min的速度清除了炎症性败血症介质（如TNF-Alpha）最多6小时，这完全是由于吸附剂吸附在PF系统中。第一阶段试验表明，使用DTPF系统进行2-6小时的治疗可导致八名败血症患者和多器官衰竭的七名患者中的七名进行生理改善。基于此I阶段试验，似乎基于吸附剂的吸附剂的粉状糖浆有潜力改变治疗过程中血液中的细胞因子浓度，并改善败血症患者和多器官衰竭的患者的预后。这种疗法在免疫调节领域提供了新的希望，因为它既是宽光谱（去除Pro和抗炎性化合物），并且通过去除与循环浓度相关的物质来自我调节。 该项目将通过使其成为独立系统来修改PF体外体育系统治疗。将在实验室开发和测试一种新的吸附混合物，并通过各种败血症的发起人和介体。接触等离子体和吸附剂的手段将更改以提高系统的功效。抗凝方法将更改为柠檬酸区域抗凝治疗。现有PF系统的安全系统将被修改以满足独立系统的需求。最后，将使用败血症的动物模型来检查整个系统的功效和安全性。