Catalytic antioxidant for hemorrhagic shock

描述（由申请人提供）： 该第二阶段SBIR提案旨在进一步开发一种新的治疗方法，以挽救严重创伤患者的出血性休克（HS）。在一小部分创伤中，由于重要功能的不可逆丧失或大量失血，可以肯定会导致致命的结局。然而，紧急复苏通常是可能的。这些受害者能活到住院治疗，并能得到现代重症监护和手术的充分好处。尽管进行了液体复苏和手术修复血管和实质损伤，但并非所有接受治疗的患者都能在HS中存活。该人群成功结局的主要障碍是心血管衰竭的发生，在这种情况下，HS导致严重低血压，对补液和正性肌力药物支持无效。大量证据表明，HS诱导的组织损伤是由自由基一氧化氮和超氧阴离子及其反应产物过氧亚硝酸盐（一种有毒氧化剂）的生物合成的深刻改变介导的。我们正在开发新型的金属卟啉基分子，作为过氧亚硝酸盐分解催化剂。早期开发的化合物FP 15在缺血再灌注损伤的实验模型中具有保护作用。基于这些数据，I期资助提案的中心目标是确定药理学过氧亚硝酸盐分解可以改善失血性休克啮齿动物模型的血流动力学、代谢功能、终末器官损伤和存活率。我们已经解决了这一目标，通过表征的催化剂在大鼠模型的严重固定压力HS的药效学概况。第一阶段应用的结果证明了下一代有效卟啉催化抗氧化剂WW-85的功效，从而确立了当前项目的技术优点和可行性。在目前的II期资助申请中，我们计划在临床相关的啮齿动物和大型动物模型中进行额外的疗效研究，以测试WW-85的不受控制的出血性休克。该研究的其他目的包括制剂和稳定性工作，以及化合物的药代动力学和代谢表征，以及毒理学评价，以将该技术推进到人体临床试验阶段。

DESCRIPTION (provided by applicant): This Phase II SBIR proposal is intended to further develop a new therapeutic approach to save the lives of severely injured trauma victims with hemorrhagic shock (HS). In a small proportion of trauma, a fatal outcome is assured due to the irreversible loss of vital functions or massive blood loss. Frequently, however, emergent resuscitation is possible. These victims survive to hospitalization and are able to receive the full benefits of modern intensive care and surgery. In spite of fluid resuscitation and surgery to repair vascular and parenchymal injuries, however, not all treated patients survive HS. The principal impediment to a successful outcome in this population is the development of cardiovascular failure, a condition in which HS results in profound hypotension refractory to fluid replacement and inotropic support. There is substantial evidence that HS - induced tissue injury is mediated by profound alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion, and their reaction product peroxynitrite, a toxic oxidant. We are developing novel metalloporphyrin-based molecules that act as peroxynitrite decomposition catalysts. An early development compound, FP15, was protective in experimental models of ischemia-reperfusion injury. Based on these data, the central objective of the Phase I grant proposal was to establish that pharmacological peroxynitrite decomposition can improve hemodynamics, metabolic function, end-organ injury, and survival in a rodent model of hemorrhagic shock. We have addressed this objective by characterizing the pharmacodynamic profile of the catalysts in a rat model of severe fixed-pressure HS. The results of the Phase I application demonstrated the efficacy of WW-85, a next generation potent porphyrinic catalytic antioxidant, and thereby established the technical merit and feasibility of the current project. In the current Phase II grant application, we plan to conduct additional efficacy studies testing WW-85 in clinically relevant rodent and large animal models of uncontrolled hemorrhagic shock. Additional aims of the study include formulation and stability work, as well as pharmacokinetic and metabolic characterization of the compound, and toxicological evaluation, in order to advance the technology to the stage of human clinical testing.