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: 8318853
• 负责人: DUANE D MILLER
• 金额: $ 35.65万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318853
• 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

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 proposal 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 γ-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).

无论是遭受核武器袭击的部队还是核袭击中的平民，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。在我们的提案中，我们 将评估两种新型药物的使用，以限制辐射和创伤联合的有害影响，我们将 针对受到中等剂量全身辐射的个体。我们的新代理是 由田纳西大学的研究人员开发。当对小鼠进行照射后长达 12 小时时 十八碳烯基硫代磷酸酯 (OTP) 经致死剂量的 γ 射线照射后可挽救细胞免于死亡， 减轻分泌性腹泻，增加白细胞和血小板计数，所有这些都可以减轻 混合辐射综合症并挽救生命。来自生物医学高级研究和的最新信息 开发机构透露，OTP 是唯一的低分子量化合物（也是仅有的两种低分子量化合物之一） 化合物）目前正在考虑获得 FDA 的快速批准。 KZ-41，我们的另一种新药，是一种 奎宁酸 (QA) 的有效类似物，奎尼酸 (QA) 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 具有强效的血管抗炎作用，促进血管 从损伤中恢复，并增加白细胞计数，使其成为潜在的优秀候选者 促进组织恢复和伤口修复的剂。我们应用程序的目标是开发一个 促进全身照射个体生存和伤口愈合的治疗策略 (TBI) 遭受外伤性机械损伤的人。我们的中心假设是 OTP 将努力增加 通过将细胞从程序性细胞死亡（由辐射暴露触发）中拯救出来并启动 血细胞计数增加，KZ-41 可以抑制外伤引起的炎症 并通过辐射暴露使伤口愈合进展到生长阶段和重塑阶段 达到正常愈合的效果。 R21阶段的具体目标 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、微血管损伤和修复的影响， 血液化学和血清细胞因子表达。 2. 我们将在临床上测试OTP和KZ-41单独和联合治疗的疗效，以及 实际上，辐射复合损伤后的相关时间点（12 和 24 小时）。 R33阶段的具体目标 3. 我们将研究主要化合物 QA 的化学变化，以寻找更有效的药物 具有更高的功效。 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）。