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:
  • 金额:
    $ 68.16万
  • 依托单位:
  • 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

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):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。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Garry John Southan其他文献

Garry John Southan的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Garry John Southan', 18)}}的其他基金

Thioredoxin mimicry: novel treatment of toxicant-mediated inhalational lung injur
硫氧还蛋白拟态:毒物介导的吸入性肺损伤的新治疗方法
  • 批准号:
    8735374
  • 财政年份:
    2014
  • 资助金额:
    $ 68.16万
  • 项目类别:
A Hybrid PARP Inhibitor and Redox Catalyst for Lung Transplantation
用于肺移植的混合 PARP 抑制剂和氧化还原催化剂
  • 批准号:
    8248350
  • 财政年份:
    2012
  • 资助金额:
    $ 68.16万
  • 项目类别:
Bifunctional Nitric Oxide Donor Refractory to Nitrate Tolerance
双功能一氧化氮供体难以耐受硝酸盐
  • 批准号:
    8248629
  • 财政年份:
    2012
  • 资助金额:
    $ 68.16万
  • 项目类别:
Peroxynitrite Decomposition Catalyst and Nitric Oxide Donor for Endotoxemia
过氧亚硝酸盐分解催化剂和一氧化氮供体治疗内毒素血症
  • 批准号:
    8248638
  • 财政年份:
    2012
  • 资助金额:
    $ 68.16万
  • 项目类别:
A Thioredoxin Mimetic for Radiocontrast Nephropathy
用于放射性对比肾病的硫氧还蛋白模拟物
  • 批准号:
    8308855
  • 财政年份:
    2012
  • 资助金额:
    $ 68.16万
  • 项目类别:
Bifunctional Modulation of Redox Imbalance for Treatment of Septic Shock
氧化还原失衡的双功能调节治疗感染性休克
  • 批准号:
    8050752
  • 财政年份:
    2011
  • 资助金额:
    $ 68.16万
  • 项目类别:
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:
    8539619
  • 财政年份:
    2011
  • 资助金额:
    $ 68.16万
  • 项目类别:
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:
    8692787
  • 财政年份:
    2011
  • 资助金额:
    $ 68.16万
  • 项目类别:
Bifunctional Redox Agent for the Treatment of PPHN
用于治疗 PPHN 的双功能氧化还原剂
  • 批准号:
    8195649
  • 财政年份:
    2011
  • 资助金额:
    $ 68.16万
  • 项目类别:
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
  • 财政年份:
    2011
  • 资助金额:
    $ 68.16万
  • 项目类别:

相似海外基金

Combinatorial cytokine-coated macrophages for targeted immunomodulation in acute lung injury
组合细胞因子包被的巨噬细胞用于急性肺损伤的靶向免疫调节
  • 批准号:
    10648387
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
Lung epithelial cell-derived C3 in acute lung injury
肺上皮细胞衍生的 C3 在急性肺损伤中的作用
  • 批准号:
    10720687
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
Examining the role of TRMT1 and tRNA methylation in acute lung injury and ARDS
检查 TRMT1 和 tRNA 甲基化在急性肺损伤和 ARDS 中的作用
  • 批准号:
    10719249
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
Inducible HMGB1 antagonist for viral-induced acute lung injury.
诱导型 HMGB1 拮抗剂,用于治疗病毒引起的急性肺损伤。
  • 批准号:
    10591804
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
MAP2K1 AND MAP2K2 IN ACUTE LUNG INJURY AND RESOLUTION
MAP2K1 和 MAP2K2 在急性肺损伤中的作用及缓解
  • 批准号:
    10741574
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
Development of a new treatment for COVID-19-related acute lung injury targeting the microbiota-derived peptide corisin
针对微生物群衍生肽 corisin 开发治疗 COVID-19 相关急性肺损伤的新疗法
  • 批准号:
    23K07651
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Probing immunovascular mechanobiology in pneumonia-associated acute lung injury at the single capillary level
在单毛细血管水平探讨肺炎相关急性肺损伤的免疫血管力学生物学
  • 批准号:
    10679944
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
The amyloid precursor protein protects against acute lung injury
淀粉样前体蛋白可预防急性肺损伤
  • 批准号:
    10575258
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
Role of macrophages and miRNA in regulating lung macrophage polarization and lung pathogenesis during respiratory virus-induced acute lung injury in normal and diabetic Syrian hamsters.
正常和糖尿病叙利亚仓鼠呼吸道病毒引起的急性肺损伤期间巨噬细胞和 miRNA 在调节肺巨噬细胞极化和肺部发病机制中的作用。
  • 批准号:
    10701207
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
Roles of N-glycans on neutrophil beta2 integrins in progression of acute lung injury
N-聚糖对中性粒细胞β2整合素在急性肺损伤进展中的作用
  • 批准号:
    10837431
  • 财政年份:
    2023
  • 资助金额:
    $ 68.16万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了