Treatment with KZ-41 and OTP promotes wound healing in a radiation combined injur

KZ-41 和 OTP 治疗可促进放射复合损伤的伤口愈合

• 批准号: 8145683
• 负责人: DUANE D MILLER
• 金额: $ 36.56万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145683
• 关键词: Amides; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Asses; Attenuated; Biomechanics; Biopharmaceutics; Blood Cell Count; Blood Chemical Analysis; Blood Vessels; Cat' s Claw; Cell Death; Cells; Chemicals; Data; Dermal; Diarrhea; Doctor of Pharmacy; Doctor of Philosophy; Dose; Drug Kinetics; Drug usage; Ensure; Epithelial; Exposure to; Goals; Growth; Growth Factor; Healed; Hematopoietic; Hour; Individual; Inflammation; Injury; Leukocytes; Lysophospholipids; Mechanics; Medical; Modeling; Molecular Weight; Mus; Muscle; Nuclear; Nuclear Weapon; Oral; Pharmaceutical Preparations; Phase; Phospholipids; Platelet Count measurement; Process; Quinic Acid; Radiation; Radiation Syndromes; Rattus; Recovery; Research; Research Personnel; Serum; Strategic Planning; Survivors; Tennessee; Time; Tissues; Trauma; Treatment Efficacy; United States National Institutes of Health; Universities; Variant; Water; White Blood Cell Count procedure; Whole-Body Irradiation; Work; Wound Healing; Wounds and Injuries; analog; authority; cytokine; efficacy testing; healing; heat injury; irradiation; lysophosphatidic acid; novel; oxidative damage; repaired; research and development; thiophosphate; tool; treatment strategy; wound

DESCRIPTION (provided by applicant): Whether it is troops exposed to nuclear weapons or civilians in a nuclear attack, the majority of the survivors will most likely suffer from combined radiation and mechanical, vascular, or thermal injury. In our application we will asses the use of two novel agents that limit the harmful effect of combined radiation and trauma and we will target individuals who were exposed to moderate doses of total body irradiation. Our novel agents were developed by researchers at the University of Tennessee. When applied up to 12 h post-irradiation in mice irradiated with lethal doses of ?-irradiation, Octadecenyl thiophosphate (OTP) rescues cells from death, attenuates secretory diarrhea, increases white blood cell and platelet counts, which all put together attenuate the mixed radiation syndrome and save lives. Recent information from the Biomedical Advanced Research and Development Authority reveals that OTP is the only low-molecular-weight compound (and one of only two compounds) currently under consideration for fast-track approval by the FDA. KZ-41, our other novel drug, is a potent analog of quinic acid (QA), which is an active ingredient in hot water extracts of the herbal cat's claw. Our preliminary data indicate that KZ-41 has potent vascular anti-inflammatory effects, promotes vascular recovery from injury, and increases white blood cell count, making it an excellent candidate as a potential agent that facilitate tissue recovery and wound repair. The objective of our application is to develop a treatment strategy that will promote survival and wound healing in individuals exposed to total body irradiation (TBI) who suffer from traumatic mechanical injury. Our central hypothesis is that OTP will work to increase survival by rescuing cells from programmed cell death (triggered by radiation exposure) and initiating an increase in blood cell counts and that KZ-41 will arrest the inflammation induced by the traumatic wound injury and by radiation exposure allowing the wound healing to progress to the growth and then remodeling phases of normal healing. R21 Phase Specific Aims 1. Develop a radiation combined injury rat model. The model will be used to characterize the effect of total body irradiation on wound healing, wound biomechanics, microvascular damage and repair, blood chemistry, and serum cytokine expression. 2. We will test the efficacy of treatment with OTP and KZ-41, separately and combined at clinically, and practically, relevant time points (12 and 24 hours) post radiation combined injury. R33 Phase Specific Aims 3. We will investigate chemical variations of our main compound QA to search for more potent agents with higher efficacy. 4. We will optimize chemical parameters of our novel agents to ensure ease of use (such oral delivery). We will develop a treatment strategy, using the novel OTP and KZ-41 agents, which will promote survival and wound healing following exposure to total body irradiation and traumatic injury. OTP will work to increase survival and that KZ-41 will arrest the wound/radiation-induced inflammation allowing the wound to progress through the normal healing process.

描述（由申请人提供）：无论是在核袭击中暴露于核武器还是平民的部队，大多数幸存者最有可能遭受辐射和机械，血管或热损伤的综合遭受。在我们的应用中，我们将评估两种限制辐射和创伤的有害作用的新型药物的使用，我们将针对暴露于中等剂量全身照射的个体。我们的新型代理商是由田纳西大学的研究人员开发的。当在用致死剂量的？辐照剂量辐照的小鼠中施用多达12小时的辐射时，甲基磷酸二甲苯基（OTP）会使细胞免于死亡，减轻分泌性腹泻，增加白细胞和血小板的数量，从而增加肿瘤的混合辐射综合征和挽救生命。生物医学高级研发局的最新信息表明，OTP是目前正在考虑的唯一低分子量化合物（也是仅有的两种化合物之一），以获得FDA的快速通道批准。 KZ-41是我们的另一种新型药物，是奎尼酸（QA）的有效类似物，它是草药猫爪的热水提取物中的一种活性成分。我们的初步数据表明，KZ-41具有有效的血管抗炎作用，可促进损伤中的血管恢复并增加白细胞计数，使其成为促进组织恢复和伤口修复的潜在药物的出色候选者。我们应用的目的是制定一种治疗策略，该策略将促进受到创伤性机械损伤的全身照射（TBI）的个体的生存和伤口愈合。我们的核心假设是，OTP将通过从程序性细胞死亡中拯救细胞（通过辐射暴露引发）并启动血细胞计数增加来提高存活率，并且KZ-41会阻止创伤伤口受伤引起的炎症和辐射暴露，从而使伤口愈合可以恢复到正常愈合的正常愈合相。 R21相特异性目标1。开发辐射组合的损伤大鼠模型。该模型将用于表征全身辐射对伤口愈合，伤口生物力学，微血管损伤和修复，血液化学和血清细胞因子表达的影响。 2。我们将分别在临床和实际上，相关的时间点（12和24小时）结合损伤的临床和相关时间点（12和24小时），分别在临床上和相关时间点（12和24小时）测试治疗的疗效。 R33阶段特定目的3。我们将研究主要化合物质量检查的化学变化，以寻找具有较高疗效的更有效的剂。 4。我们将优化新型药物的化学参数，以确保易用性（这样的口服递送）。我们将使用新型的OTP和KZ-41药物制定一种治疗策略，该药物将在暴露于全身辐射和创伤性损伤后促进生存和伤口愈合。 OTP将有助于提高生存率，并且KZ-41将阻止伤口/辐射引起的炎症，从而使伤口通过正常的愈合过程进行。