Treatment of Surgical Sepsis with AM/AMBP-1

描述(由申请人提供)： 败血症仍然是外科重症监护病房最常见的死亡原因。尽管创伤伤员的治疗取得了进步，但败血症和感染性休克的发生率仍显著增加。仅在美国，每年就有超过75万名患者发展为严重的脓毒症，总死亡率为28.6%。每个案件的平均成本为22,100美元，全国每年的总成本超过160亿美元。虽然活化蛋白C是FDA批准的唯一治疗脓毒症的药物，但由于其对凝血的不利影响，其使用仅限于非手术患者。因此，迫切需要一种有效的新疗法来治疗外科脓毒症。仅在美国，脓毒症治疗的市场潜力估计就达到每年100-250亿美元。我们最近发现，早期注射大鼠肾上腺髓质素(AM)及其新的特异性结合蛋白(即AMBP-1)可减少脓毒症的组织损伤和死亡率。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，延迟给药是否降低了脓毒症的死亡率。因此，我们假设，即使在脓毒症发病较晚的时候，给予人AM/AMBP-1也可以减轻炎症反应，降低死亡率。本项目的主要目标是通过确定人AM/AMBP-1在脓毒症中的剂量反应效应，证明进一步开发和商业化人AM/AMBP-1作为减少脓毒症所致死亡率的新型治疗药物的可行性。将采用大鼠盲肠结扎穿孔(CLP)脓毒症模型。在CLP后10小时(即严重脓毒症开始)给予不同剂量的AM/AMBP-1后，将采集血样以评估组织损伤指标(即肝酶、乳酸、肌酐)和促炎细胞因子(TNF-α、IL-1β、IL-6、HMGB-1)，并收集组织样本进行组织学检查。此外，在CLP和手术切除坏死性盲肠后，将进行为期10天的生存研究。建议的研究将提供有用的可行性信息，使我们能够进一步开发AM/AMBP-1作为治疗外科脓毒症的有效的新型治疗剂。我们的最终目标(第二阶段SBIR及以后)是开发人AM/AMBP-1的商业应用，作为一种安全有效的脓毒症患者治疗方法，特别是那些在创伤、出血或大手术后发生脓毒症的患者。

DESCRIPTION (provided by applicant): Sepsis continues to be the most common cause of death in surgical intensive care units. Despite advances in the management of trauma victims, the incidence of sepsis and septic shock has increased significantly. More than 750,000 patients develop severe sepsis each year with an overall mortality rate of 28.6% in the US alone. The average costs per case are $22,100, with annual total costs of more than $16 billion nationally. Although activated protein C is the only FDA-approved therapeutic agent for sepsis, its use is limited to non-surgical patients due to the adverse effects on coagulation. Thus, there is a great need for an effective novel treatment for surgical sepsis. The market potential for sepsis treatment is estimated at $10-25 billion/year in the US alone. We have recently shown that early injection of rat adrenomedullin (AM), a recently identified potent vasodilatory peptide, in combination with its novel specific binding protein (i.e., AMBP-1) reduced tissue injury and mortality in sepsis. However, it remains unknown if human AM plus human AMBP-1 is also beneficial and, if so, whether the delayed administration reduces mortality in sepsis. We therefore hypothesize that administration of human AM/AMBP-1 even late after the onset of sepsis attenuates inflammatory responses and reduces mortality. The primary goal of this project is to demonstrate the feasibility of further development and commercialization of human AM/AMBP-1 as a novel therapeutic agent in reducing sepsis-induced mortality by determining the beneficial effects of dose-response of human AM/AMBP-1 in sepsis. The rat cecal ligation and puncture (CLP) model of sepsis will be used. After administration of various doses of AM/AMBP-1 at 10 h after CLP (i.e., the beginning of severe sepsis), blood samples will be collected for assessment of tissue injury indicators (i.e., liver enzymes, lactate, creatinine) and proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, HMGB-1), and tissue samples harvested for histology. In addition, a 10-day survival study will be conducted following CLP and surgical removal of the necrotic cecum. The proposed studies should provide useful feasibility information that will allow us to further develop AM/AMBP-1 as an effective novel therapeutic agent for treatment of surgical sepsis. Our ultimate goal (Phase II SBIR and beyond) is to develop the commercial utilization of human AM/AMBP-1 as a safe and effective therapy of septic patients, especially those who develop sepsis following trauma, hemorrhage, or major surgery.