A Novel Resuscitation for Hemorrhagic Shock: AM/AMBP-1

项目描述：这项SBIR第二阶段提案旨在进一步开发一种新的治疗方法 抢救严重创伤失血性休克伤员生命的方法。大多数创伤死亡 由于失血过多导致组织灌注量不足，或者 复苏后的炎症、感染和重要器官损伤。三叉神经痛的临床管理 失血性休克依靠大量快速输液来维持血压。然而， 大多数严重失血的受害者对补液反应不佳。的发展。 因此，迫切需要有效的策略来复苏创伤失血。市场 据估计，仅在美国，每年治疗出血的可能性就达100亿美元。我们最近做了 发现血管对肾上腺髓质素(AM)的反应性是一种新发现的有效血管活性物质 在大鼠失血后，多肽含量下降，而其新的结合蛋白(即， AMBP-1)。大鼠AM联合AMBP-1治疗后组织损伤和炎症反应减少 出血和大容量复苏，提示AM/AMBP-1可能是一种有益的治疗方法 在人类创伤中的方法。阻碍AM/AMBP-1作为治疗剂发展的一个障碍 失血性休克是大鼠蛋白在人类体内潜在的免疫原性。因此，主要的 我们第一阶段计划的目标是确定人AM/AMBP-1对出血的影响。 导致器官损伤、炎症和死亡。我们使用啮齿动物模型实现了这一里程碑 血压稳定的严重失血性休克。第一阶段项目的结果表明， 人AM/AMBP-1的疗效，从而确立了第二阶段的技术优势和可行性 项目。剂量-反应研究表明，人AM/AMBP-1的最高剂量在 一期工程对出血后有较好的保护作用。然而，极高的成本， 商品化的人类AMBP-1限制了它的进一步发展。为了克服这一障碍，我们有 以较低的成本成功地从人血清中分离纯化了AMBP-1。因此，我们继续 假设即使在低容量复苏的情况下，人AM/AMBP-1的给药也能改善 在严重失血后存活。在这个第二阶段的提案中，我们计划扩大人类生产 AMBP-1，进行额外的疗效研究，确定人类的最佳保护剂量 AM/AMBP-1用于出血，并进行药代动力学和毒理学评价。在……里面 为了将该技术推进到临床试验，人AM/AMBP-1的疗效在更多的临床上 将研究失控出血的相关模型。我们的最终目标是开发商业 人AM/AMBP-1作为创伤患者安全有效的复苏方法 严重失血，特别是用于在遥远的前线战场的战斗伤员护理。

PROJECT DESCRIPTION: This SBIR Phase II proposal is intended to further develop a novel therapeutic approach to save the lives of severely injured trauma victims with hemorrhagic shock. Most trauma deaths result either from insufficient tissue perfusion due to excessive blood loss, or the development of inflammation, infection, and vital organ damage following resuscitation. Clinical management of hemorrhagic shock relies on massive and rapid infusion of fluids to maintain blood pressure. However, the majority of victims with severe blood loss do not respond well to fluid restoration. The development of effective strategies for resuscitation of traumatic blood loss, therefore, is urgently needed. The market potential for hemorrhage treatment is estimated at >$10 billion/year in the US alone. We have recently discovered that vascular responsiveness to adrenomedullin (AM), a newly-discovered potent vasoactive peptide, decreases after hemorrhage in the rat, which is markedly improved by its novel binding protein (i.e., AMBP-1). Treatment with rat AM plus AMBP-1 reduces tissue injury and inflammatory responses after hemorrhage and large volume resuscitation, suggesting that AM/AMBP-1 may be a beneficial treatment approach in human trauma. One obstacle hampering development of AM/AMBP-1 as a therapeutic agent for hemorrhagic shock is the potential immunogenicity of rat proteins in humans. Accordingly, the primary objective of our Phase I proposal was to determine the effect of human AM/AMBP-1 on hemorrhage- induced organ injury, inflammation, and mortality. We have achieved this milestone using a rodent model of severe hemorrhagic shock with fixed blood pressure. The results of the Phase I project demonstrated the efficacy of human AM/AMBP-1, and thereby established the technical merit and feasibility of the Phase II project. The dose-response study showed that the highest dose of human AM/AMBP-1 proposed in the Phase I project achieved a better protection after hemorrhage. However, the extremely high cost of commercial human AMBP-1 limits its further development. To overcome this obstacle, we have successfully isolated and purified AMBP-1 from human serum at a much lower cost. We therefore continue to hypothesize that administration of human AM/AMBP-1, even with low volume resuscitation, improves survival after severe blood loss. In this Phase II proposal, we plan to scale up the production of human AMBP-1, conduct additional efficacy studies determining the optimal protective dosage of human AM/AMBP-1 in hemorrhage, and perform pharmacokinetic characterization and toxicological evaluation. In order to advance the technology to clinical trials, the efficacy of human AM/AMBP-1 in more clinically relevant models of uncontrolled hemorrhage will be studied. Our ultimate goal is to develop the commercial utilization of human AM/AMBP-1 as a safe and effective resuscitation approach for the trauma victim with severe blood loss, especially for the use in combat casualty care at the far-forward battlefield setting.