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

描述（由申请人提供）：无论是暴露在核武器下的部队还是遭受核攻击的平民，大多数幸存者极有可能遭受辐射和机械、血管或热损伤的综合伤害。在我们的应用程序中，我们将评估两种限制辐射和创伤联合有害影响的新型药物的使用，我们将针对暴露于中等剂量全身照射的个体。我们的新型药物是由田纳西大学的研究人员开发的。当在照射后12小时应用致死剂量的？-辐照，十八烯基硫代磷酸酯（OTP）拯救细胞免于死亡，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，减轻混合辐射综合征，挽救生命。来自生物医学高级研究与发展管理局的最新信息显示，OTP是目前FDA正在考虑的唯一一种低分子量化合物（也是仅有的两种化合物之一）。KZ-41，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，促进血管损伤恢复，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优秀候选人。我们的应用目的是开发一种治疗策略，以促进遭受创伤性机械损伤的全身照射（TBI）个体的生存和伤口愈合。我们的中心假设是，OTP将通过从程序性细胞死亡（由辐射暴露引发）中拯救细胞并启动血细胞计数的增加来提高存活率，KZ-41将阻止创伤性伤口损伤和辐射暴露引起的炎症，使伤口愈合进展到正常愈合的生长和重塑阶段。R21阶段具体目标建立辐射复合损伤大鼠模型。该模型将用于描述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. 我们将在放射联合损伤后的临床和实际相关时间点（12小时和24小时）分别测试OTP和KZ-41单独和联合治疗的疗效。R33阶段具体目标我们将研究我们的主要化合物QA的化学变化，以寻找更有效的药物。4. 我们将优化我们的新药的化学参数，以确保使用方便（如口服）。我们将开发一种治疗策略，使用新的OTP和KZ-41药物，这将促进全身照射和创伤性损伤后的生存和伤口愈合。OTP将提高生存率，KZ-41将阻止伤口/辐射诱导的炎症，使伤口通过正常的愈合过程进展。

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.