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

• 批准号: 8546090
• 负责人: Garry John Southan
• 金额: $ 3.68万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 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/8546090
• 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

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）：该提案寻求对新药物治疗组合（TP）的评估和开发的支持，这些新药物代表了第一个被证明对急性氯吸入性损伤（CILI）临床前模型的复苏有效的分子。该TP包括4项技术，可解决关键的病理生理学目标，并已被证明对多种急性肺损伤有效：1）R-503，一种双功能聚（ADP-核糖）聚合酶（“PARP”）抑制剂-硫辛酸缀合物； 2) R-100，双官能有机硝酸盐和吡咯烷氮氧化物； 3) R-801，双功能线粒体钾-ATP 通道开放剂和吡咯烷氮氧化物； 4) R-901，一种细胞渗透性硫氧还蛋白模拟物。在 CILI 小鼠模型（400 ppm X 30 分钟）中，氯吸入结束后 15 分钟开始单药给药 R-503、R-801 或 R-901，使中性粒细胞浸润升高降低了 50-82%（p<0.0001），组织学损伤降低了 43-72%（p<0.001）。 R-100 同样可以有效地恢复局部和全身炎症模型中的急性肺损伤。目标#1：建立 TP 药物的最佳组合，确认其作用机制，并确定小鼠 CILI 复苏的治疗机会时间窗。对肺的组织学损伤、中性粒细胞浸润、脂质过氧化、还原剂浓度以及促炎和抗炎信号种类的表达进行评分。这些参数将与血浆和肺组织中 TP 药物的浓度相关，以构建指导大型动物和临床剂量的药效学曲线。最佳药物将被指定为 TP 候选者并进入大型动物研究。目标#2：通过对肺血管阻力、吸气峰值压、肺分流、肺淋巴流量以及肺组织的组织学和生化参数的影响进行评估，确认 TP 候选药物作为 CILI 绵羊模型救援疗法的有效性。目标#3：在毒理学、ADME/PK 和安全药理学 IND 支持研究中确定 TP 候选药物的急性安全性、稳定性和耐受性。在临床前环境中证明有效的复苏和安全性将为 CILI 临床治疗的开发奠定基础。