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）：炭疽、鼠疫和土拉热病等细菌生物恐怖剂的受害者经常因败血症和随后的多器官功能障碍综合征（MODS）而死亡。天花等病毒性生物恐怖因子还可因继发细菌感染而诱发全身炎症反应综合征 (SIRS) 和败血性休克。针对 SIRS 和 MODS 的有效治疗将使许多生物恐怖主义的受害者免遭悲惨的死亡。 越来越多的证据表明细胞因子和细胞因子介质、先天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质。迄今为止，经过针对个体脓毒症介质的药物的大量研究和临床试验，尚未有任何抗炎药物获得临床批准。该项目的目标是开发一种简单的基于体外吸附剂的单采系统，该系统可以广泛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。 一种治疗脓毒症的新疗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) 和血浆分离系统 (PF) 组成。体外研究表明，炎症性脓毒症介质如 TNF-α 在 20-25 ml/min 的情况下可被清除长达 6 小时，这完全是由于 PF 系统中吸附剂的吸附。 I 期试验表明，使用 DTPF 系统进行 2-6 小时的治疗后，八名脓毒症和多器官衰竭患者中的​​七名获得了生理改善。根据这项 I 期试验，基于吸附剂的粉末吸附剂分离术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前景，因为它既具有广谱性（去除促炎化合物和抗炎化合物），又可以通过去除与其循环浓度相关的物质进行自我调节。 该项目将修改 PF 体外血液分离系统治疗，使其成为一个独立的系统。将开发一种新的吸附剂混合物，并在实验室中使用各种脓毒症引发剂和介质进行测试。血浆和吸附剂的接触方式将发生改变，以提高系统的效率。抗凝方法改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求。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。