Restoration of free radical homeostasis: novel therapy of septic shock

恢复自由基稳态：感染性休克的新疗法

• 批准号: 9342949
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 119.49万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9342949
• 关键词: 3-nitrotyrosine; Anabolism; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Bacteremia; Biochemical; Biological; Biological Markers; Blood flow; Choking; Clinical Research; Clinical Trials; Collaborations; Conscious; Creatinine; Creatinine clearance measurement; Critical Illness; Diagnosis; Dose; Endotoxemia; Epithelial; Evaluation; Excision; Excretory function; Formulation; Free Radicals; Functional disorder; Glucose; Glutathione Disulfide; Guidelines; High Pressure Liquid Chromatography; Histologic; Homeostasis; Impairment; Infiltration; Injury; Isoprostanes; Kidney; LCN2 gene; Liver; Lung; Measurement; Measures; Mechanics; Mediating; Medical; Methodology; Methods; Modeling; Multi-Institutional Clinical Trial; Muscle Tonus; Nitric Oxide; Nitric Oxide Donors; Nitrogen; Organ; Outcome; Outcome Measure; Outcome Study; Oxidation-Reduction; Oxygen; Patients; Peritonitis; Peroxonitrite; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Plasma; Preparation; Procedures; Prodrugs; Product R; Protocols documentation; Pseudomonas aeruginosa; Rattus; Reaction Time; Reference Standards; Reperfusion Injury; Resuscitation; Rodent; Route; Safety; Sepsis; Septic Shock; Serum; Sheep; Side; Sodium; Solid; Superoxides; Testing; Texas; Therapeutic; Therapeutic Agents; Tight Junctions; Time; Tissues; Toxicology; Universities; Vascular Smooth Muscle; Water; Work; analytical method; catalyst; chemokine; clinically relevant; cytokine; extracellular; hemodynamics; immunoreactivity; improved; improved outcome; liver injury; lung injury; male; model design; mouse model; novel; novel therapeutics; preclinical trial; public health relevance; pulmonary arterial hypertension; randomized placebo controlled trial; renal ischemia; response; restoration; septic

 DESCRIPTION (provided by applicant): Radikal Therapeutics (RTX) has invented a novel first-in-class bifunctional nitric oxide (NO) donor and redox catalyst (R-190) to treat septic shoc. In rodent and ovine models of endotoxemia and gram negative bacillary septic shock, therapeutic resuscitation with R-190 improves outcome across clinically-relevant endpoints, including hemodynamics, oxygenation, and end-organ injury. In an LD100 murine model of endotoxemia, post-LPS administration of R-100 or R-190 dose-dependently blocked renal, lung, and hepatic injury 73-90%, inhibited histologic damage in liver, kidney, lung, and gut by 75-90%, and assured 100% survival. In an ovine model of Pseudomonal septic shock, R-190 resuscitation restored hemodynamics and oxygenation. The proposed scope of work will construct a PD profile in a clinically-relevant septic shock model, design and implement methods to release and track the active pharmaceutical ingredient, and develop bioanalytical methods of R-190 and its metabolites. Aim #1: Establish the pharmacodynamic (PD) profile of R-190 in an ovine model of sepsis RTX will carry out a placebo-controlled randomized study wherein septic shock is produced in an LD100 model in mechanically-ventilated male Merino sheep administered an inoculum of Pseudomonas aeruginosa via an IV route. We will carry out studies in order to establish the dose-response, time-window, and safety of R-190 in the septic sheep. Task #1: R-190 (30, 100, and 300 mg/kg IV q6h IV) will be compared to vehicle control wherein the initial dose is delivered 1 h post onset of bacteremia, in order to establish the lowes dose providing optimal outcome ("LDPOO"). Plasma levels of R-190 will be measured q6h, to relate drug concentration to efficacy. Task #2: We will determine the duration of the therapeutic time window by initiating R-190 therapy 1, 2, 4, 8, 12, or 24 h (at the LDPOO dose) after the onset of bacteremia. Hemodynamic, oxygenation, and ventilatory parameters will be assessed q3h. Serum and tissue will be examined 48 h post onset of bacteremia for determination of response to R-190. Aim #2: Synthesize R-190. Develop analytical methods for release and stability. Define impurities and degradants and thereby define optimal storage conditions and dosing formulation. R-190 API material will be qualified prior to use in the ovine studies in order to assure identity and purity. Analytical methods will be developed following ICH guidelines for this purpose and to establish storage conditions and stability of the R-190 API and dosing solutions. Aim #3: Develop a bioanalytical methodology to quantitate R-190 and its metabolites in plasma RTX will construct a pharmacodynamic profile relating plasma concentrations of R-190 and its metabolites to pharmacologic activity. A robust bioanalytical LC-MS/MS approach will be developed with an LOQ 2 logs less than existing methods, allowing for identification and quantitation of plasma R-190 and its major metabolites at the low ng/mL level. We will qualify this approach for linearity, precision, and accuracy, and define the conditions of plasma preparation and storage that optimize reliability of this methodology.

 描述（应用程序提供）：Radikal Therapeutics（RTX）发明了一种新型的一流双功能一氧化氮（NO）供体和氧化还原催化剂（R-190）来治疗化粪池SHOC。在内毒素血症和革兰氏阴性休克的啮齿动物和卵巢模型中，具有R-190的治疗复苏可改善与临床相关的终点的预后，包括血液动力学，氧合和最终器官损伤。 LD100内毒素血症的鼠模型，LPS后LPS的R-100或R-190剂量依赖性地阻断肾脏，肺和肝损伤为73-90％，抑制了肝，肾脏，肺和肠道的组织学损害，并抑制75-90％的肠道损伤，并假设生存期为100％。在伪败血性休克的卵巢模型中，R-190复苏恢复了血液动力学和氧合。所提出的工作范围将在临床上与脓毒症相关模型，设计和实施方法中构建PD曲线，以释放和跟踪活性药物成分，并开发R-190及其代谢物的生物分析方法。 AIM＃1：建立R-190的药效学（PD）轮廓在败血症RTX的卵巢模型中将进行安慰剂对照的随机研究，其中在机械通风的雄性美利奴羊羊中，在LD100模型中产生了败血性休克，该模型由pseudomonasemonas aereguginosa covia aereperugiginosa via Ani iv Routeage。我们将进行研究，以建立败血症绵羊R-190的剂量反应，时端和安全性。任务＃1：R-190（30、100和300 mg/kg IV Q6H IV）与车辆对照进行比较，其中最初剂量在细菌发作后1小时输送，以确定可提供最佳结果的Lowes剂量（“ LDPOO”）。 R-190的血浆水平将测量Q6H，以与功效相关的药物浓度。任务2：我们将通过启动R-190治疗1、2、4、8、12或24 h（在LDPOO剂量下）确定治疗时间窗口的持续时间。血液动力学，氧合和通气参数将评估Q3H。细菌发作后48小时，将检查血清和组织，以确定对R-190的反应。目标＃2：合成R-190。开发用于释放和稳定性的分析方法。定义杂质和降解剂，从而定义最佳存储条件和给药公式。 R-190 API材料将在氧气研究中使用之前有资格 为此目的，将根据ICH指南制定分析方法，并建立R-190 API和剂量解决方案的存储条件和稳定性。 AIM＃3：开发一种生物分析方法来定量R-190及其在等离子体RTX中的代谢产物，将构建与R-190及其代谢物与药物活性的血浆浓度相关的药效学谱。强大的生物分析LC-MS/MS方法将使用小于现有方法的LOQ 2日志开发，从而可以在低Ng/mL水平下对等离子体R-190及其主要代谢物进行识别和定量。我们将有资格以线性，精度和准确性，并定义等离子体制备和存储的条件，以优化该方法的可靠性。