Pheresis Treatment of Bioterrorism-Induced Sepsis

描述（由申请人提供）：炭疽、鼠疫和土拉菌病等细菌性生物恐怖制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）。由于继发性细菌感染，天花等病毒生物恐怖主义制剂也可诱发系统性炎症反应综合征（SIRS）和感染性休克。对SIRS和MODS的有效治疗将使许多生物恐怖主义受害者免于悲惨的死亡。

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.