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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：Radikal Therapeutics (RTX) 发明了一种新型双功能一氧化氮 (NO) 供体和氧化还原催化剂 (R-190)，用于治疗啮齿动物和绵羊的内毒素血症和革兰氏阴性休克模型。阴性杆菌感染性休克、R-190 治疗性复苏可改善临床相关终点的结果，包括血流动力学、在 LD100 内毒素血症小鼠模型中，LPS 给药后，R-100 或 R-190 剂量依赖性地阻断肾、肺和肝损伤 73-90%，并抑制肝脏、肺和肝脏的组织学损伤。在假单胞菌感染性休克的绵羊模型中，肾、肺和肠道的存活率提高了 75-90%，并确保了 100% 的存活率。 R-190 复苏可恢复血流动力学和氧合。拟议的工作范围将在临床相关的感染性休克模型中构建 PD 曲线，设计和实施释放和跟踪活性药物成分的方法，并开发 R-190 和 R-190 的生物分析方法。目标#1：在败血症绵羊模型中建立 R-190 的药效学 (PD) 曲线 RTX 将进行一项安慰剂对照随机研究，其中会产生败血性休克。在机械通气雄性美利奴羊的 LD100 模型中，通过静脉注射途径接种铜绿假单胞菌。我们将开展研究，以确定 R-190 在败血症羊中的剂量反应、时间窗口和安全性。任务#1：将 R-190（30、100 和 300 mg/kg IV q6h IV）与载体对照进行比较然而，初始剂量在菌血症发作后 1 小时给药，以确定提供最佳结果的最低剂量（“LDPOO”），每 6 小时测量一次 R-190 血浆水平，以将药物浓度与功效联系起来。 2：我们将通过在发病后 1、2、4、8、12 或 24 小时（以 LDPOO 剂量）开始 R-190 治疗来确定治疗时间窗的持续时间。菌血症发生后 48 小时将评估血流动力学、氧合和通气参数，以确定对 R-190 的反应：开发释放和释放的分析方法。确定杂质和降解物，从而确定最佳储存条件，并在用于绵羊研究之前确定剂量配方。为此，将按照 ICH 指南制定分析方法，并确定 R-190 API 和给药溶液的储存条件和稳定性。目标 3：开发定量 R-190 及其代谢物的生物分析方法。血浆 RTX 将构建 R-190 血浆浓度及其代谢物与药理活性相关的药效学曲线，将开发具有 LOQ 的强大生物分析 LC-MS/MS 方法。比现有方法少 2 个对数，允许在低 ng/mL 水平下鉴定和定量血浆 R-190 及其主要代谢物。我们将验证该方法的线性、精密度和准确度，并定义血浆制备和分析的条件。优化该方法可靠性的存储。