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）：无论是暴露于核武器的部队还是核攻击中的平民，大多数幸存者很可能会遭受辐射和机械、血管或热损伤的综合伤害。在我们的应用中，我们将评估两种新型药物的使用，以限制辐射和创伤相结合的有害影响，并且我们将针对暴露于中等剂量全身辐射的个体。我们的新型药物是由田纳西大学的研究人员开发的。当对受致死剂量 β-辐射照射的小鼠进行辐射后长达 12 小时时，十八碳烯基硫代磷酸酯 (OTP) 可以挽救细胞免于死亡，减轻分泌性腹泻，增加白细胞和血小板计数，所有这些加在一起可以减弱混合辐射综合症并拯救生命。来自生物医学高级研究与开发局的最新信息显示，OTP 是目前 FDA 考虑快速批准的唯一低分子量化合物（也是仅有的两种化合物之一）。 KZ-41 是我们的另一种新药，是奎宁酸 (QA) 的有效类似物，奎宁酸是草药猫爪草热水提取物中的活性成分。我们的初步数据表明，KZ-41 具有有效的血管抗炎作用，促进血管从损伤中恢复，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绝佳候选者。我们应用的目的是开发一种治疗策略，以促进遭受全身照射（TBI）且遭受创伤性机械损伤的个体的生存和伤口愈合。我们的中心假设是，OTP 将通过拯救细胞免于程序性细胞死亡（由辐射暴露引发）并启动血细胞计数增加来提高存活率，而 KZ-41 将阻止由创伤性伤口损伤和辐射引起的炎症暴露使伤口愈合能够进展到正常愈合的生长阶段和重塑阶段。 R21 阶段具体目标 1. 建立辐射复合损伤大鼠模型。该模型将用于表征全身照射对伤口愈合、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. 我们将在放射复合损伤后的临床和实践相关时间点（12 和 24 小时）分别和联合测试 OTP 和 KZ-41 治疗的功效。 R33 阶段特定目标 3. 我们将研究主要化合物 QA 的化学变化，以寻找更有效、更高效的药物。 4. 我们将优化新型药物的化学参数，以确保易用性（例如口服给药）。我们将开发一种治疗策略，使用新型 OTP 和 KZ-41 药物，这将促进全身辐射和创伤性损伤后的生存和伤口愈合。 OTP 将致力于提高存活率，并且 KZ-41 将阻止伤口/辐射引起的炎症，从而使伤口能够通过正常的愈合过程。