Bifunctional Modulation of Redox Imbalance for Treatment of Septic Shock

氧化还原失衡的双功能调节治疗感染性休克

基本信息

批准号：
8050752
负责人：
Garry John Southan
金额：
$ 24.37万
依托单位：
RADIKAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8050752
关键词：
Accounting Acute Address Adverse event Aftercare American Anabolism Animal Model Animals Antibiotics Arginine Biological Blood Vessels Blood flow Canis familiaris Cardiovascular system Caring Cessation of life Choking Clinical Clinical Treatment Consumption Diffusion Dose Drainage procedure Drug Delivery Systems Drug Kinetics Enzymes Epithelial Excision Fatal Outcome Free Radicals Functional disorder Future Glucose Gold Hospitalization Hour Hydrogen Peroxide Injury Intensive Care Units Ischemia Length of Stay Lipid Peroxidation Liquid substance Lung Lung Inflammation Lymphatic Lymphoma Mechanical ventilation Mediating Medical Microcirculation Micronucleus Tests Mission Mitochondria Modeling Multiple Organ Failure Mus Muscle Tonus NADPH Oxidase Neutrophil Infiltration Nitric Oxide Nitrogen Outcome Oxidation-Reduction Oxygen Oxygen measurement, partial pressure, arterial Peripheral Permeability Peroxonitrite Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Placebo Control Pneumonia Poly Adenosine Diphosphate Ribose Production Protein Isoforms Pseudomonas aeruginosa Pulmonary Vascular Resistance Pyrrolidines Randomized Rattus Reaction Reactive Oxygen Species Respiratory Insufficiency Safety Secondary to Sepsis Septic Shock Sheep Shock Shunt Device Signs and Symptoms Small Business Innovation Research Grant Smoke Inhalation Injury Superoxide Dismutase Superoxides Technology Testing Therapeutic Tight Junctions Tissues Toxicogenetics Toxicokinetics Toxicology Translating Trauma United States National Institutes of Health Water Xanthine Oxidase base catalase catalyst clinically relevant extracellular hemodynamics human NOS2A protein human NOS3 protein improved innovation lung injury man mimetics mortality neurobehavioral novel pressure prevent pulmonary arterial hypertension pyrrolidine respiratory small molecule tetrahydrobiopterin treatment effect wet lung

项目摘要

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.

描述（由申请人提供）：每年在美国的败血症计算> 500k住院，其中一半将发展为致命的结果。由于没有批准的药物可深刻改善预后的药物，因此护理的主要是支持液体，氧气，机械通气和抗生素。败血症是由自由基一氧化氮和超氧化物阴离子的生物合成改变介导的广泛的组织损伤驱动的。这两个自由基物种的失衡会导致细胞外水的分布，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，窒息微循环血流，触发动脉高压和肺动脉高压，并提高内皮耐药性。尽管有积极的支持，但败血症可能会发展到循环崩溃的状态，并在死亡前广泛的组织功能障碍和多器官衰竭。成功治疗败血症需要同时补充一氧化氮并去除超氧化物。 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催化剂。结合起来，这些功能使R-100可以去除有毒的活性氧，并递送一氧化氮，而不会产生过氧亚硝酸盐的混杂作用。在内毒素血症的致命鼠模型中，R-100治疗阻止了败血症的体征和症状，并产生了100％的生存率，而对照组中的生存率为0％。现在，我们建议扩展这些观察结果，并验证R-100在与创伤相关性败血性休克的金标准卵子模型中的功效。具体目的：在创伤相关败血症的卵巢模型中确定R-100的功效。我们将进行一项安慰剂对照的卵子研究，其中通过急性吸入损伤和铜绿假单胞菌肺炎诱发麻醉，机械通风的美利奴绵羊在麻醉，机械通风的美利奴绵羊中诱发呼吸不足和败血性休克。 R-100的治疗将在创伤后1小时开始，并持续24小时。 R-100预计1）通过降低湿/淋巴引流，脂质过氧化，嗜中性粒细胞浸润，过氧亚硝酸盐产生以及聚（ADP-核糖）形成以及2改善血液动力学和空气压力，通过降低肺动脉压力和pul脉管降压，通过降低湿度和2的形成，预计R-100会阻塞肺部炎症和损伤。这些实验治疗效果预计将在临床环境中转化为机械通气的持续时间较短，重症监护室的加速放电以及降低全因30天死亡率。公共卫生相关性：败血症是重症监护病房死亡率的主要原因，也是未满足的医疗需求。唯一获得败血性冲击的疗法的益处有限，而且很少有处方。我们正在开发一种针对这种疾病的基本机制的新型药物，并将在临床上与大型动物模型中测试该药物。