Localized Metal Modulation as a First Line Treatment of Burn Injuries

局部金属调制作为烧伤的一线治疗

• 批准号: 8252621
• 负责人: Jerry Gin
• 金额: $ 29.73万
• 依托单位: LIVIONEX, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252621
• 关键词: 4 hydroxynonenal; Accounting; Acute; Aging; Aldehydes; Animals; Apoptosis; Area; Attenuated; Biochemical; Blood Platelets; Boxing; Burn injury; Calcium; Cell Death; Cell Membrane Permeability; Cell Respiration; Cell membrane; Cells; Cessation of life; Charge; Chelating Agents; Chronic; Church; Clinical Treatment; Clinical Trials; Complex; Dermal; Development; Disease; Distant; Dose; Down-Regulation; Drug Formulations; Drug Metabolic Detoxication; Early treatment; Edema; Enhancers; Enzymes; Event; Extracellular Matrix; Eye diseases; Fibroblasts; First Aid; Free Radical Scavengers; Grant; Growth Factor; Healed; Health Care Costs; Healthcare Systems; Home environment; Hospitalization; Hospitals; Human; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Iron; Knowledge; Lead; Lipid Peroxidation; Lipids; Lymphocyte; Matrix Metalloproteinases; Medical; Membrane; Metals; Methodology; Modeling; Necrosis; Neurosecretory Systems; North America; Organ failure; Outcome; Oxidants; Oxidative Stress; Pain; Patient Care; Patients; Phase; Play; Prevention; Proteins; Rattus; Reaction; Reactive Oxygen Species; Research; Role; Route; Safety; Scheme; Schools; Signal Transduction; Site; Small Business Innovation Research Grant; Speed; Staging; Stress; Superoxides; TNF gene; Technology; Testing; Texas; Thick; Time; Tissues; Topical application; Toxic effect; Toxin; United States; Universities; Vascular Cell Adhesion Molecule-1; Venous Insufficiency; Work; adduct; aldehyde dehydrogenase 1; autocrine; caspase-3; catalyst; cell type; cost; cytokine; cytotoxic; healing; heat injury; in vivo; injured; loss of function; macrophage; metal chelator; migration; neutrophil; novel; novel strategies; novel therapeutics; oxidation; oxidative damage; paracrine; peroxidation; prevent; response; wound

DESCRIPTION (provided by applicant): The proposed Phase I SBIR grant, Livionex Inc. will test and develop a novel approach for the early treatment of burn injuries. Livionex will leverage its knowledge in the use of localized metal modulation, particularly, the control of iron and calcium in the area of the injury, to attenuate the extreme degree of oxidative damage and inflammation that occurs early in the time frame of burn injury progression. Localized metal modulation to down regulate the inflammatory response post burn injuries is a path that has not been tried before. Livionex formulation (LF also designated as ME in our preliminary studies) consists of two GRAS components, a metal chelator and a membrane permeability enhancer. Since we have shown that topical application of ME crosses membranes and ameliorates ocular and dermal inflammation, a similar approach would work in burn injuries. This is also supported by anecdotal evidence that indicates the topical application of the LF slows the progression of the burn injury and has also shows early efficacy in a pilot clinical trial to treat inflammatory edema that results from chronic venous insufficiency. Increased amounts of oxidants generated endogenously early on in burns cause increased lipid peroxidation and iron dependent formation of cytotoxic lipid aldehydes, such as 4- hydroxynonenal (HNE) that can induce Ca/Fe-dependent toxic events. More ROS are generated in an autocrine/ paracrine fashion thus amplifying the oxidative and inflammatory damage in a cyclic manner. Thus early down-regulation of inflammation via localized metal modulation soon after the occurrence of the injury will speed healing. Utilizing a rat burn model and Drs Ansari and Herndon's expertise, and facilities at the University of Texas Medical Branch, we propose the following specific aims to show the efficacy of the approach: Specific Aim 1: Evaluate the efficacy of the Livionex formulation in the prevention of dermal full thickness burns (dose response and progression of burn injury over time). Specific Aim 2: Evaluate the effect of the time of treatment initiation after burn injury, on reducing the progression to full thickness burns. Successful completion of the proposed work will give us the grounds to proceed further and ultimately introduce a novel therapeutic strategy against burn injury. Such a topical therapy will have extensive application in hospitals, battle field and may end up being in every first-aid box at home, office and schools, as an early intervention for burn injuries. PUBLIC HEALTH RELEVANCE: Burns are a major cause of accidental death. Injuries from burns can be painful, require many months of treatment, and involve loss of function. Thermal injuries trigger an intense local and systemic inflammatory response. While it is transient systemically, burn wounds suffer from the effects of acute influx of inflammatory mediators and growth factors for an extended time. Burn research and the newest therapies focus on reducing this inflammatory response, intending to limit the progression of burns. Moderate to severe burn injuries requiring hospitalization account for approximately 100,000 of these cases, and about 5,000 patients die each year from burn related complications. Burn injuries incur a significant cost to the health care system in North America and worldwide. In the United States, current annual estimates show that more than US $18 billion is spent on specialized care of patients with major burn injuries. (Church 2006). The Livionex formulation has the potential to provide a novel early intervention to burn injuries that is not only safe and effective, but one that also reduces patient hardship and associated health care costs.

描述（由申请人提供）：拟定的第一阶段 SBIR 拨款，Livionex Inc. 将测试和开发一种烧伤早期治疗的新方法。 Livionex 将利用其在局部金属调节方面的知识，特别是控制损伤区域的铁和钙，以减轻烧伤损伤进展早期发生的极端程度的氧化损伤和炎症。通过局部金属调节来下调烧伤后的炎症反应是一种以前从未尝试过的途径。 Livionex 配方（LF 在我们的初步研究中也称为 ME）由两种 GRAS 成分组成：一种金属螯合剂和一种膜通透性增强剂。由于我们已经证明局部应用 ME 可以穿过细胞膜并改善眼部和皮肤炎症，因此类似的方法也适用于烧伤。这也得到了轶事证据的支持，这些证据表明局部应用 LF 可以减缓烧伤的进展，并且在一项试点临床试验中也显示出治疗慢性静脉功能不全引起的炎性水肿的早期疗效。 烧伤早期内源性产生的氧化剂数量增加，导致脂质过氧化增加和铁依赖性细胞毒性脂质醛的形成，例如可诱导 Ca/Fe 依赖性毒性事件的 4-羟基壬烯醛 (HNE)。更多的ROS以自分泌/旁分泌的方式产生，从而以循环方式放大氧化和炎症损伤。因此，在损伤发生后不久，通过局部金属调节来早期下调炎症将加速愈合。 利用大鼠烧伤模型以及 Ansari 和 Herndon 博士的专业知识以及德克萨斯大学医学分部的设施，我们提出以下具体目标来显示该方法的功效： 具体目标 1：评估 Livionex 制剂在预防中的功效真皮全层烧伤（剂量反应和烧伤随时间的进展）。 具体目标 2：评估烧伤后开始治疗的时间对减少全层烧伤进展的影响。成功完成拟议的工作将为我们进一步开展并最终推出针对烧伤的新型治疗策略提供基础。这种局部疗法将在医院、战场上得到广泛应用，并最终可能出现在家庭、办公室和学校的每个急救箱中，作为烧伤的早期干预措施。 公共卫生相关性：烧伤是意外死亡的主要原因。烧伤造成的伤害可能会很痛苦，需要数月的治疗，并且会导致功能丧失。热损伤引发强烈的局部和全身炎症反应。虽然它在全身上是短暂的，但烧伤创面会长时间受到炎症介质和生长因子急性流入的影响。烧伤研究和最新疗法的重点是减少这种炎症反应，旨在限制烧伤的进展。 其中约 100,000 例需要住院治疗的中度至重度烧伤，每年约有 5,000 名患者死于烧伤相关并发症。烧伤给北美和全世界的医疗保健系统带来了巨大的损失。在美国，目前每年估计有超过 180 亿美元用于严重烧伤患者的专门护理。 （教会2006）。 Livionex 配方有可能为烧伤提供一种新颖的早期干预措施，不仅安全有效，而且还可以减少患者的困难和相关的医疗费用。