Multifunctional therapeutics for treatment of acute chlorine inhalational injury

描述（由申请人提供）：本提案寻求对新型药物治疗组合（TP）的评价和开发的支持，这些药物代表了第一批被证明在急性氯吸入性损伤（CILI）临床前模型复苏中有效的分子。TP包括4种技术，可解决关键病理生理学靶点，并已证明在广泛的急性肺损伤中有效：1）R-503，一种双功能多聚（ADP-核糖）聚合酶（“PARP”）抑制剂-硫辛酸缀合物; 2）R-100，双功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;和4）R-901，细胞可渗透的硫氧还蛋白模拟物。在CILI的鼠模型中（400 ppm X 30 min），在氯吸入结束后15 min开始的R-503、R-801或R-901的单一药剂递送使中性粒细胞浸润的升高降低50-82%（p<0.0001），并使组织学损伤降低43-72%（p<0.001）。R-100在局部和全身炎症模型中同样有效地复苏了急性肺损伤。目标一：建立TP药物的最佳组合，确认其作用机制，并确定小鼠CILI复苏的治疗时间窗。将对肺的组织学损伤、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物质的表达进行评分。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给药的药效学特征。最佳药物将被指定为TP候选药物，并进行大型动物研究。目标二：通过对肺血管阻力、吸气峰压、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绵羊模型补救治疗的疗效。目的#3：在毒理学、ADME/PK和安全药理学IND使能研究中确定TP候选药物的急性安全性、稳定性和耐受性。在临床前环境中有效复苏和安全性的证明将为CILI的临床治疗的开发提供基础。

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.