Bifunctional Modulation of Redox Imbalance for Treatment of Septic Shock

描述（由申请人提供）：脓毒症每年在美国占> 50万例住院治疗，其中一半将进展为致命结局。由于没有批准的药物可以显著改善预后，因此主要的护理是支持性输液、吸氧、机械通气和抗生素。脓毒症是由自由基一氧化氮和超氧阴离子生物合成的改变介导的广泛组织损伤驱动的。这两种自由基物质的不平衡产生细胞外水分布的重大变化，破坏上皮和内皮紧密连接，损害内皮功能和血管平滑肌张力，阻塞微循环血流，引发肺动脉高压，并提高内皮通透性。尽管有积极的支持，脓毒症可能进展到循环衰竭的状态，广泛的组织功能障碍和多器官功能衰竭之前死亡。脓毒症的成功治疗需要同时补充一氧化氮和清除超氧化物。为了解决这一未满足的临床需求，Radikal Therapeutics正在开发R-100，这是一种由两个基于氧化还原的部分共价连接形成的新型药物：1）释放一氧化氮的有机硝基血管扩张剂，和2）作为超氧化物歧化酶模拟物、过氧化氢酶模拟物和过氧亚硝酸盐分解催化剂的吡咯烷氮氧化物。结合起来，这些功能允许R-100去除有毒的活性氧物质并提供一氧化氮，而不会产生过氧亚硝酸盐的混淆效应。在致死性内毒素血症小鼠模型中，R-100治疗预防了脓毒症的体征和症状，并产生了100%的存活率，而对照组的存活率为0%。我们现在建议扩展这些观察结果，并验证R-100在创伤相关脓毒性休克金标准绵羊模型中的疗效。具体目的：确定R-100在创伤相关脓毒症绵羊模型中的疗效。我们将进行一项安慰剂对照绵羊研究，在麻醉、机械通气的美利奴绵羊中通过急性烟雾吸入性损伤和铜绿假单胞菌肺炎诱导呼吸功能不全和感染性休克。R-100治疗将在创伤后1小时开始，并持续24小时。预计R-100可1）通过降低湿/干比、淋巴引流、脂质过氧化、中性粒细胞浸润、过氧亚硝酸盐生成和聚（ADP-核糖）形成来阻断肺部炎症和损伤，2）通过降低肺血管阻力、吸气峰压和肺分流来改善血流动力学和气道压力。这些实验性治疗效果预计将在临床环境中转化为更短的机械通气持续时间、加速从重症监护室出院和降低30天全因死亡率。 公共卫生相关性：脓毒症是重症监护室死亡的主要原因，也是一个主要的未满足的医疗需求。唯一批准的治疗感染性休克的方法是有限的好处，很少规定。我们正在开发一种针对这种疾病基本机制的新药，并将在临床相关的大型动物模型中测试这种药物。

DESCRIPTION (provided by applicant): Sepsis accounts for > 500K hospitalizations in the USA yearly, of which half will progress to a fatal outcome. Because there are no approved pharmaceutical agents that profoundly improve outcome, the mainstay of care is supportive administration of fluids, oxygen, mechanical ventilation, and antibiotics. Sepsis is driven by widespread tissue injury mediated by alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion. The imbalance of these two free radical species produces major changes in the distribution of extracellular water, disrupts epithelial and endothelial tight junctions, impairs endothelial function and vascular smooth muscle tone, chokes off microcirculatory blood flow, triggers pulmonary arterial hypertension, and raises endothelial permeability. Despite aggressive support, sepsis may progress to a state of circulatory collapse, with widespread tissue dysfunction and multiple organ failure prior to death. A successful treatment of sepsis requires the simultaneous replenishment of nitric oxide and removal of superoxide. To address this unmet clinical need, Radikal Therapeutics is developing R-100, a novel agent formed from the covalent linkage of two redox-based moieties: 1) an organic nitrovasodilator that releases nitric oxide, and 2) a pyrrolidine nitroxide that acts as a superoxide dismutase mimetic, a catalase mimic, and a peroxynitrite decomposition catalyst. In combination, these functionalities allow R-100 to remove toxic reactive oxygen species and deliver nitric oxide without the confounding effect of producing peroxynitrite. In a lethal murine model of endotoxinemia, R-100 treatment prevented signs and symptoms of sepsis and produced 100% survival, vs. 0% survival in controls. We now propose to extend these observations and validate the efficacy of R-100 in a gold-standard ovine model of trauma-associated septic shock. Specific Aim: Establish the efficacy of R-100 in an ovine model of trauma-associated sepsis. We will carry out a placebo-controlled ovine study in which respiratory insufficiency and septic shock are induced in anesthetized, mechanically-ventilated Merino sheep via acute smoke inhalation injury and Pseudomonas aeruginosa pneumonia. Treatment with R-100 will be initiated 1 hour after trauma and continued for 24 hours. R-100 is expected to 1) block lung inflammation and injury, by reducing wet/dry ratio, lymphatic drainage, lipid peroxidation, neutrophil infiltration, peroxynitrite production, and poly (ADP-ribose) formation, and 2) improve hemodynamics and airway pressures, by reducing pulmonary vascular resistance, peak inspiratory pressure, and pulmonary shunt. These experimental treatment effects are expected to translate in the clinical setting into shorter duration of mechanical ventilation, accelerated discharge from the intensive care unit, and reduced all-cause 30 day mortality. PUBLIC HEALTH RELEVANCE: Sepsis is a leading cause of mortality in the intensive care unit and a major unmet medical need. The sole approved therapy for septic shock is of limited benefit and rarely prescribed. We are developing a novel drug that targets the basic mechanisms of this condition and will test this agent in a clinically-relevant large animal model.