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

失血性休克的新型复苏：AM/AMBP-1

• 批准号: 6991043
• 负责人: RONGQIAN WU
• 金额: $ 15万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-03 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6991043
• 关键词: binding proteins; drug design /synthesis /production; hemorrhage; hemorrhagic shock; inflammation; injury; laboratory rat; peptide hormone; resuscitation; trauma; vasodilators

DESCRIPTION (provided by applicant): Trauma causes approximately 150,000 deaths per year, and is the leading cause of death in the population between ages 1 to 44 in the United States. The resulting loss of productive life years exceeds that of any other disease, with estimated societal costs of >$450 billion annually. Most trauma deaths result from insufficient tissue perfusion due to excessive blood loss. Clinical management of trauma victims currently relies on massive and rapid infusion of fluids, to which a large number of such victims often do not respond. The development of effective strategies for resuscitation of severe traumatic blood loss therefore is critically 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 recently-discovered potent vasoactive peptide, decreases after hemorrhage in rats, 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. It remains unknown, however, whether human AM plus human AMBP-1 is also beneficial and, if so, whether their administration with the reduced resuscitation fluid volume decreases mortality after hemorrhage. We therefore hypothesize that administration of human AM/AMBP-1, even with low volume resuscitation, improves survival after severe blood loss. The primary objective of this project, therefore, is to demonstrate the feasibility of further development of human AM/AMBP-1 as a novel therapeutic agent to reduce hemorrhage-induced organ injury, inflammation, and mortality in a rat model of hemorrhage. The proposed studies should provide useful feasibility information for further developing AM/AMBP-1 as an effective therapy for the treatment of hemorrhagic shock. Our ultimate goal (Phase IISBIR and beyond) 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.

描述(由申请人提供)： 创伤每年造成约15万人死亡，是美国1至44岁人口的主要死亡原因。由此造成的生产寿命年损失超过任何其他疾病，估计每年的社会损失为4500亿美元。大多数创伤死亡是由于失血过多导致的组织灌流不足造成的。目前对创伤受害者的临床治疗依赖于大量和快速的输液，而大量这类受害者往往对此没有反应。因此，迫切需要制定有效的战略来复苏严重创伤失血。仅在美国，出血治疗的市场潜力估计就达100亿美元/年。我们最近发现，大鼠失血后，血管对肾上腺髓质素(AM)的反应性降低，而其新的结合蛋白(即AMBP-1)可显著改善AM的反应性。大鼠AM联合AMBP-1治疗可减少失血和大容量复苏后的组织损伤和炎症反应，提示AM/AMBP-1可能是一种有益于人类创伤的治疗方法。阻碍AM/AMBP-1作为失血性休克治疗剂发展的一个障碍是大鼠蛋白在人类体内的潜在免疫原性。然而，目前尚不清楚人AM和人AMBP-1是否也是有益的，如果是的话，在减少复苏液量的情况下使用它们是否会降低出血后的死亡率。因此，我们假设，即使在低容量复苏的情况下，给予人AM/AMBP-1也能改善严重失血后的存活率。因此，该项目的主要目标是证明进一步开发人AM/AMBP-1作为一种新的治疗剂的可行性，以减少失血性大鼠模型中由失血引起的器官损伤、炎症和死亡率。本研究为进一步开发AM/AMBP-1作为治疗失血性休克的有效疗法提供了有价值的可行性信息。我们的最终目标(IISBIR阶段及以后)是开发人AM/AMBP-1的商业用途，作为一种安全有效的复苏方法，用于严重失血的创伤受害者，特别是用于前线战场的战斗伤员护理。