Bifunctional Modulation of Redox Imbalance for Treatment of Septic Shock

描述(由申请人提供)：在美国，每年有50万人因脓毒症住院，其中一半将发展为致命后果。由于目前还没有得到批准的可以显著改善预后的药物，因此主要的护理手段是支持性的液体、氧气、机械通风和抗生素的管理。脓毒症是由广泛的组织损伤引起的，这种损伤是由自由基、一氧化氮和超氧阴离子的生物合成改变所介导的。这两种自由基的失衡导致细胞外水分布发生重大变化，扰乱上皮和内皮紧密连接，损害内皮功能和血管平滑肌张力，阻断微循环血流，触发肺动脉高压，增加内皮通透性。尽管有积极的支持，脓毒症可能会进展到循环衰竭的状态，死亡前会出现广泛的组织功能障碍和多器官衰竭。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。为了满足这一未得到满足的临床需求，Radikal Treeutics正在开发R-100，这是一种新型药物，由两个基于氧化还原的部分共价连接而成：1)释放一氧化氮的有机硝基血管扩张剂，以及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。这些功能结合在一起，使R-100能够去除有毒的活性氧物种并提供一氧化氮，而不会产生产生过氧亚硝酸盐的混杂效应。在致死性内毒素血症小鼠模型中，R-100治疗阻止了败血症的迹象和症状，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，并在创伤相关败血症休克的黄金标准绵羊模型中验证R-100的有效性。具体目的：建立创伤相关性脓毒症绵羊模型，观察R-100的疗效。我们将开展一项安慰剂对照绵羊研究，通过急性烟雾吸入性损伤和铜绿假单胞菌肺炎在麻醉、机械通气的美利奴绵羊中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，持续24小时。R-100有望1)通过减少湿/干比、淋巴引流、脂质过氧化、中性粒细胞渗透、过氧亚硝酸盐生成和多聚(ADP-核糖)形成来阻止肺部炎症和损伤，以及2)通过降低肺血管阻力、吸气峰值压力和肺分流来改善血流动力学和气道压力。这些实验性的治疗效果有望在临床环境中转化为更短的机械通气时间，加速重症监护病房的出院，并降低全因30天的死亡率。 公共卫生相关性：败血症是重症监护病房死亡的主要原因，也是未得到满足的主要医疗需求。唯一被批准的感染性休克的治疗方法是有限的，很少开出处方。我们正在开发一种针对这种情况的基本机制的新药，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.