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).

无论是暴露在核武器下的部队，还是遭受核攻击的平民，大多数都是幸存者