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TP508:A New Drug for Mitigating Lethal Effects of Radiation Exposure

TP508：一种减轻辐射暴露致命影响的新药

基本信息

批准号：
7808581
负责人：
Darrell H. Carney
金额：
$ 29.73万
依托单位：
CHRYSALIS BIOTHERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7808581
关键词：
Acetates Affect Animals Antibodies Apoptosis Attenuated Back Biological Assay Blast Cell Blood Body Surface Burn injury C57BL/6 Mouse Cessation of life Clinical Clinical Trials DNA Defect Dermal Development Devices Diabetic Foot Ulcer Diabetic mouse Disease Disease Progression Distal Dose Drug Formulations Drug Kinetics Emergency Situation Endothelial Cells Epithelial Epithelial Cells Exposure to FDA approved Flying body movement Fracture Functional disorder Genetic Goals Government Healed Heart Histology Human Imagery Immunohistochemistry Impaired wound healing Infection Inflammation Inflammatory Injection of therapeutic agent Injury Intestines Label Laboratories Lead Licensing Life Lung Measures Messenger RNA Mucous Membrane Multiple Organ Failure Mus Nitric Oxide Nuclear Peptides Pharmaceutical Preparations Phase Placebos Prevention Procedures Process Production Protocols documentation Radiation Radiation Injuries Radius Fractures Rattus Reperfusion Injury Reperfusion Therapy Risk Safety Saline Sampling Sepsis Serum Site Spleen Staging Staining method Stains Syndrome Technology Testing Therapeutic Thick Thrombin Time Tissue Sample Tissues Toxicology Up-Regulation Vascular Endothelial Growth Factors Western Blotting Work Wound Healing Wounds and Injuries angiogenesis animal data animal resource animal rule annexin A5 arginase arteriole attenuation base body system bone clinical efficacy combat crypt cell cytokine drug candidate healing human NOS3 protein injured interest jejunum mortality novel phase 1 study phase 2 study prevent public health relevance radiation effect repaired reproductive research study response safety study wound

项目摘要

DESCRIPTION (provided by applicant): With increasing risk of nuclear detonation there is a need for effective medicinal counter-measures that can be delivered after exposure to prevent radiation-induced mortality. Adding to this need, mortality increases significantly when radiation is combined with injury (RCI). Thousands of people injured by nuclear detonation are expected to die from what was considered a sub-lethal radiation exposure. Therefore, agents to mitigate effects of radiation and RCI must be developed and stockpiled for emergency use. TP508 (rousalatide acetate), a novel peptide drug that is currently in clinical trials with established safety and manufacturing, stimulates angiogenesis and tissue repair by attenuating inflammation, preventing apoptosis, stimulating nitric oxide (NO) production, and reversing endothelial dysfunction. Preliminary studies suggest that TP508 attenuates radiation-induced apoptosis, reverses radiation-induced endothelial dysfunction, and stimulates healing in irradiated rats. Because apoptosis, endothelial dysfunction, and delayed healing are associated with early radiation damage and subsequent effects leading to mortality, these results predict that TP508 treatment will counteract lethal effects of radiation and RCI in multiple tissues and at multiple points in the disease process. In this project, we will use gamma irradiated C57BL/6 mice to test the potential efficacy of TP508 as a countermeasure for radiation exposure and RCI. Specific aims for this Phase 1 project will be: 1) to determine whether TP508 application to wounds or injection into mice reduces mortality due to radiation or RCI, and if this treatment accelerates wound healing in these mice; and 2) to determine whether TP508 affects systemic manifestations of radiation and RCI that include increased cytokine production, cellular apoptosis, and endothelial dysfunction. These Phase 1 studies will determine whether TP508 has potential to become a medicinal countermeasure for radiation and RCI-induced mortality. If TP508 reduces radiation or RCI mortality, Phase 2 studies will be proposed to complete FDA requirements to initiate clinical trials with a goal of government licensing and National Stockpiling of this drug for emergency use. PUBLIC HEALTH RELEVANCE: Following a nuclear detonation the combination of radiation and traumatic injury is expected to be much more deadly that radiation alone. TP508, a novel peptide drug with established manufacturing and safety, works through mechanisms thought to counteract effects of radiation. In this project, we will determine whether TP508 can prevent lethal effects of radiation and injury in irradiated animals as a first major step in development and potential FDA approval of TP508 as a drug to reduce the risk of death from radiation exposure.

描述（由申请人提供）：随着核爆炸风险的增加，需要在暴露后提供有效的药物对抗措施，以防止辐射引起的死亡。除此之外，当辐射与损伤（RCI）结合时，死亡率显着增加。成千上万因核爆炸受伤的人预计将死于被认为是亚致命的辐射照射。因此，必须开发和储存减轻辐射和放射性氯化物影响的制剂，以备紧急使用。TP 508（醋酸罗丹明）是一种新型肽类药物，目前正在临床试验中，具有确定的安全性和生产能力，通过减轻炎症，防止细胞凋亡，刺激一氧化氮（NO）产生和逆转内皮功能障碍来刺激血管生成和组织修复。初步研究表明，TP 508减弱辐射诱导的细胞凋亡，逆转辐射诱导的内皮功能障碍，并刺激辐射大鼠的愈合。由于细胞凋亡、内皮功能障碍和延迟愈合与早期辐射损伤和导致死亡的后续效应相关，因此这些结果预测TP 508治疗将在疾病过程中的多个组织和多个点抵消辐射和RCI的致死效应。在本项目中，我们将使用伽马辐照的C57 BL/6小鼠来测试TP 508作为辐射暴露和RCI对策的潜在功效。该1期项目的具体目标是：1）确定TP 508应用于伤口或注射到小鼠中是否降低了由于辐射或RCI导致的死亡率，以及这种治疗是否加速了这些小鼠中的伤口愈合;以及2）确定TP 508是否影响辐射和RCI的全身表现，包括增加的细胞因子产生、细胞凋亡和内皮功能障碍。这些I期研究将确定TP 508是否有潜力成为辐射和RCI诱导死亡的药物对策。如果TP 508降低辐射或RCI死亡率，将提出2期研究以完成FDA要求，启动临床试验，目标是获得政府许可和国家储备该药物以供紧急使用。公共卫生相关性：在核爆炸之后，辐射和创伤性损伤的组合预计比单独的辐射更致命。TP 508是一种新型肽类药物，具有生产和安全性，通过被认为可以抵消辐射影响的机制发挥作用。在这个项目中，我们将确定TP 508是否可以防止辐射和辐射动物损伤的致命影响，作为开发和FDA批准TP 508作为降低辐射暴露死亡风险的药物的第一个主要步骤。