Novel agents for mitigation of radiation-induced pulmonary injury

减轻辐射引起的肺损伤的新药

• 批准号: 7586482
• 负责人: LEO E GERWECK
• 金额: $ 95.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586482
• 关键词: Accidents; Breathing; Chest; Cyclophosphamide; Cytotoxic Chemotherapy; Data; Development; Devices; Dose; Drug Exposure; Event; Exposure to; External Beam Radiation Therapy; Fibrosis; Goals; Hematopoietic; Hepatitis; Hepatotoxicity; Histology; Human; Immune; Individual; Inflammation; Inflammatory; Injury; Life; Liquid substance; Lung; Malignant neoplasm of lung; Measures; Mus; Nuclear Weapon; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Plasma; Plethysmography; Production; Proteins; Radiation; Radiation Accidents; Radiation Pneumonitis; Radioisotopes; Respiratory physiology; Rodent; Rodent Model; Schedule; Syndrome; Time; Tissues; cytokine; gastrointestinal; improved; irradiation; mortality; novel; response

The overall goal of this project is to develop two novel agents - NOV-002 and NOV-205 - for the mitigation of radiation-induced pulmonary injury. In the event of a terrorist event or accident involving radiation, it is likely that some individuals will receive substantial radiation exposure to the lungs either from external radiation or inhaled radioisotopes, and the pulmonary injury could be lethal or life threatening. Hence, there is a need to develop efficacious, non-toxic agents as countermeasures to radiation-induced lung damage. Studies to date suggest that NOV-002 and NOV-205 have the potential to be such agents. Specifically, NOV-002 has been shown to increase survival of rodents exposed to lethal doses of radiation when administered after the irradiation, to have a positive impact on hematopoietic damage when given after irradiation or cyclophosphamide in rodents, and to improve hematopoietic parameters, and be well-tolerated, in humans treated with cytotoxic chemotherapy for lung cancer. NOV-205 has been shown to reduce tissue fibrosis, increase survival and normalize plasma levels of pro-inflammatory cytokines in rodent models of hepatotoxicity, and is in Phase I trials in hepatitis patients. Hence, aspects of radiation-induced lung damage that could be mitigated by NOV-002 or NOV-205 are cytokine production, inflammation, immune suppression, fibrosis and mortality. This application proposes a plan for further development of NOV-002 and NOV-205 for mitigation of radiation-induced pulmonary injury. Radiation dose response curves after localized thoracic irradiation in mice will be obtained for several endpoints of lung damage, including lethality, lung function measured by plethysmography, proteins in BAL fluid, and histology without and with each of the agents. The data will allow demonstration of the efficacy and calculation of dose reduction factors for each drug. Additionally, optimization of drug dose schedule will be conducted, with emphasis on determining how soon after radiation exposure the drugs must be administered to be effective and how frequently the agents must be given during the time course until lung damage would normally be seen. It is anticipated that this information will further these promising agents along the path to FDA approval as mitigators of radiation-induced pulmonary injury.

该项目的总体目标是开发两个新颖的代理商 - 11月2002年和11月205日 - 缓解辐射引起的肺损伤。如果发生恐怖事件或事故 涉及辐射，有些人可能会受到大量辐射的暴露 肺部来自外部辐射或吸入的放射性同位素，肺部损伤可能 致命或威胁生命。因此，有必要开发有效的，无毒的剂 对辐射引起的肺损伤的对策。迄今为止的研究表明，11月002和 11月205日有可能成为这样的代理商。具体来说，已显示11月002 增加暴露于致命剂量辐射的啮齿动物的存活率 辐照，在辐照后给予造血损伤的积极影响 啮齿动物中的环磷酰胺，并改善造血参数并耐受性良好 在接受肺癌细胞毒性化疗治疗的人类中。 11月205日已被证明 降低组织纤维化，增加存活率并归一化血浆促炎的水平 肝毒性啮齿动物模型中的细胞因子，并且正在肝炎患者的I期试验中。因此， 辐射引起的肺损伤的各个方面可能在11月2002年或11月205日减轻 细胞因子产生，炎症，免疫抑制，纤维化和死亡率。 该申请提出了一项计划，以进一步开发11月002和2015年11月205日 缓解辐射诱导的肺损伤。局部辐射剂量响应曲线 对于肺部损伤的几个终点，将获得小鼠的胸腔照射，包括 致死性，肺功能通过多体积学测量，BAL流体中的蛋白质和组织学测量 没有和每个代理商。数据将允许证明功效和 计算每种药物的剂量还原因子。另外，优化药物剂量 时间表将进行，重点是确定辐射暴露后多久 必须对药物进行有效的施用，并且必须给药多久 在时间过程中，通常会看到肺部损伤。预计这是 信息将进一步沿FDA批准的道路作为缓解者的这些有希望的代理商 辐射引起的肺损伤。