Multifunctional therapeutics for treatment of acute chlorine inhalational injury

治疗急性氯气吸入性损伤的多功能疗法

基本信息

批准号：
8336844
负责人：
Garry John Southan
金额：
$ 68.16万
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：
2011-09-21 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8336844
关键词：
Acetylcysteine Acute Acute Lung Injury Address Adherence Adverse effects Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antidotes Antihypertensive Agents Antioxidants Apoptosis Attenuated Biochemical Biodiversity Breathing CXCL9 gene Canis familiaris Cardiovascular system Cells Characteristics Chlorine Clinic Clinical Cytochrome P450 Development Dose Drug Formulations European Evaluation Exposure to Foundations Free Radicals Histologic Human Immune Infarction Infiltration Inflammation Inflammatory Injury Interleukin-10 Kidney Kinetics Lipid Peroxidation Lung Lymphoma Mediating Metabolic Metabolism Mission Mitochondria Modeling Multiple Trauma Mus Myocardial Necrosis Neutrophil Infiltration Nitrates Nitric Oxide Nuclear Oral Ovalbumin Oxidants Oxidation-Reduction Pathway interactions Peroxonitrite Pharmaceutical Preparations Pharmacodynamics Pharmacology Plasma Poly(ADP-ribose) Polymerases Potassium Pre-Clinical Model Property Pulmonary Vascular Resistance Rattus Reducing Agents Resuscitation Safety Sheep Shock Shunt Device Signal Transduction Societies Structure of parenchyma of lung Sulfhydryl Compounds Superoxides TNF gene Technology Testing Therapeutic Thioctic Acid Thioredoxin Time TimeLine Tissues Toxicogenetics Toxicology Treatment Efficacy Validation Zymosan catalase catalyst chlorine gas conditioning drug candidate in vivo indium arsenide inhibitor/antagonist innovation lymph flow manufacturing scale-up micronucleus mimetics mitochondrial K(ATP) channel mortality neurobehavioral neutrophil novel placebo controlled study pre-clinical pressure professor respiratory smoke inhalation therapeutic target

项目摘要

DESCRIPTION (provided by applicant): This proposal seeks support for the evaluation and development of a therapeutic portfolio (TP) of novel agents that represent the first molecules proven effective in the resuscitation of a pre-clinical model of acute chlorine inhalational injury (CILI). The TP comprises 4 technologies that address key pathophysiological targets and have proven effective in a broad range of acute lung injuries: 1) R-503, a bifunctional poly (ADP-ribose) polymerase ("PARP") inhibitor- lipoic acid conjugate; 2) R-100, a bifunctional organic nitrate and pyrollidine nitroxide; 3) R-801, a bifunctional mitochondrial potassium-ATP channel opener and pyrollidine nitroxide; and 4) R-901, a cell-permeable thioredoxin mimetic. In a murine model of CILI (400 ppm X 30 min), single-agent delivery of R-503, R-801, or R-901 initiated 15 min AFTER the end of chlorine inhalation reduced the elevation in neutrophil infiltration by 50-82% (p<0.0001) and histologic injury by 43-72% (p<0.001). R-100 has likewise effectively resuscitated acute lung injury in regional and systemic models of inflammation. Aim #1: Establish the optimal combination of TP agents, confirm their mechanism of action, and define the therapeutic time window of opportunity for resuscitation of murine CILI. Lungs will be scored for histologic injury, neutrophil infiltration, lipid peroxidation, reductant concentrations, and the expression of pro- and anti-inflammatory signaling species. These parameters will be correlated with the concentrations of the TP agents in plasma and lung tissue to construct a pharmacodynamic profile that will guide large animal and clinical dosing. The optimal agent will be designated as the TP candidate and advanced to large animal studies. Aim #2: Confirm the efficacy of the TP candidate as a rescue therapy in an ovine model of CILI, as assessed by the impact on pulmonary vascular resistance, peak inspiratory pressure, pulmonary shunt, lung lymph flow, and histologic and biochemical parameters of lung tissue. Aim #3: Establish the acute safety, stability, and tolerance of the TP candidate in toxicology, ADME/PK, and safety pharmacology IND-enabling studies. Demonstration of potent resuscitation and safety in the pre-clinical setting will provide the foundation for development of a clinical therapeutic for CILI.

描述（由申请人提供）：该提案寻求支持和开发新型药物的治疗组合（TP），该药物代表了第一个分子被证明有效地复苏了急性氯的临床前模型，急性氯含量损伤（CILI）。 TP包括4种针对关键病理生理靶标的技术，并在广泛的急性肺损伤中有效：1）R-503，一种双功能聚（ADP-核糖）聚合酶（“ PARP”）抑制剂 - 脂肪酸 - 脂肪酸偶联物； 2）R-100，一种双功能有机硝酸盐和硝基氮氧化物； 3）R-801，一种双功能线粒体钾通道开口机和氮氮氧化物； 4）R-901，一种可渗透的硫氧还蛋白模拟物。在CILI的鼠模型（400 ppm x 30分钟）中，氯气吸入结束后15分钟启动了R-503，R-801或R-901的单代药物递送，将中性粒细胞浸润的升高降低了50-82％（P <0.0001）和43-72％（P <0.0001）（P <0.0001）（P <0.0001）（P <0.0001）（P <0.0001）（P <0.0001）（P <0.0001）（P <0.001）（P <0.001）（P <0.001）。 R-100同样有效地在炎症的区域和全身性模型中恢复了急性肺损伤。 AIM＃1：建立TP代理的最佳组合，确认其作用机理，并定义鼠CILI复苏的治疗时间窗口。肺部将在组织学损伤，中性粒细胞浸润，脂质过氧化，还原剂浓度以及促疾病和抗炎信号传导物种的表达中评分。这些参数将与血浆和肺组织中TP药物的浓度相关，以构建一种可以指导大型动物和临床剂量的药效学特征。最佳剂将被指定为TP候选者，并升级为大型动物研究。 AIM＃2：确认TP候选者作为CILI烤箱模型中的救援疗法的功效，如对肺血管耐药性，峰值灵感压力，肺分流，肺淋巴流量以及肺组织的组织学和生物化学参数的影响所评估。 AIM＃3：建立TP候选者在毒理学，ADME/PK和安全药理学方面的急性安全性，稳定性和耐受性。在临床前环境中的有效复苏和安全性的演示将为开发CILI的临床治疗性提供基础。