Intracavitary Hemostatic Agent for Non-compressible Hemorrhage

不可压缩性出血的腔内止血剂

• 批准号: 7221106
• 负责人: Martin H Bluth
• 金额: $ 10.31万
• 依托单位: BIOMEDICA MANAGEMENT CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221106
• 关键词: Intracavitary; Hemostatic; Agent; Non; compressible

DESCRIPTION (provided by applicant): Hemorrhage resulting from traumatic injuries is a major cause of death in accidents, and the primary cause of death on the battlefield. Early and effective hemorrhage control can save more lives than any other measure. Tissue adhesives and sealants have been developed to control bleeding; but, currently, all existing haemostatic agents for abdominal intracavitary bleeding are designed to be used in the operating room--not in an emergency at the site of accident or in the battlefield. The goal of the proposed project is to develop an intracavitary hemostatic agent --Hemostatic Adhesive Foam (HAF) --that promotes hemostasis in cases of severe bleeding that would otherwise lead to exsanguination. This approach is based on the physical and coagulation properties of a mixture of Teleostan Gelatin type A, Polyvinylpyrrolidone, Sucrose and Fibrinogen, with a water-soluble foam inducer; the addition of thrombin and P-selectin inmunoglobin chimera, and on its form of application. The cross- linked compound forms an adhesive matrix over damaged, lacerated tissue following abdominal or other intracavitary trauma. In preliminary studies, it was demonstrated that HAF can generate adaptable foam that is distributed uniformly, and adheres to the abdominal cavity, even under profuse bleeding, when it is injected intraperitoneally through a Verres disposable needle. Our hypothesis is that once HAF is injected in the peritoneal cavity, it distributes and adheres evenly to the walls, improving the adhesiveness between lacerated tissues and potentiating clot formation through the up-regulation of P-selectin. Our specific aims are to demonstrate in two ex vivo models: a) that the upregulation of P-selectin enhances the adhesive, physical, and coagulation properties of HAF, and to determine the extent to which this agent promotes adhesiveness between tissue and damaged surfaces in the presence of profuse bleeding; b) its effects on clot formation; c) to determine if the addition of other thrombin and fibrin like agents and P-selectin-immunoglobulin chimera -that specifically stimulate P-selectin, will enhance clot formation and clot strength effects of this agent, and; d) evaluate restoration of vital functions and survival. Phase I proposed studies could provide the "proof of concept" for the use HAF as an intracavitary hemostatic agent in cases of non-compressible hemorrhage. Phase II studies will define the adhesive and coagulation properties of the compound in an intracavitary hemorrhage military-relevant animal model (pig), study tissue distribution, pharmacokinetics, reabsorption and toxicity of HAF. Upon completion of the phase II effort, phase III studies will involve extended pharmacokinetic studies for filing an Investigative New Drug (IND) application to start studies in human volunteers. In an age of speed, civil violence and armed conflicts, the incidence of penetrating and blunt injuries to the abdomen has been on the increase. On average, nationwide 41.8% of the trauma cases admitted at hospitals are due to road traffic accidents. Also, hemorrhage remains the primary cause of death on the battlefield in conventional warfare. Although, the morbidity and mortality from these injuries are gradually decreasing, abdominal injuries still pose a formidable problem, especially in young adults, Early and effective hemorrhage control could theoretically save more lives than any other measure; however, the best strategy to achieve this goal outside of the operating room and particularly in austere and hostile field situations is not clear. Currently, all existing haemostatic agents for abdominal intracavitary bleeding are designed to be used in the OPERATING ROOM not at the site of injury (i.e. battlefield, car accident, shot wound). A novel form of application through a Verres needle and the utilization of novel procoagulants compounds such as P-selectin immunoglobulin chimera incorporated to gelatin sealants could provide the adhesion strength and coagulatory properties necessary to stop bleeding in the site of injury We propose to develop an intracavitary hemostatic agent --Hemostatic Adhesive Foam (HAF)--that forms an adhesive matrix over damaged, lacerated tissue following abdominal or other intracavitary trauma to promote hemostasis in cases of severe bleeding which, if not treated immediately, would lead to exsanguinations. The proposed study provides an opportunity to demonstrate HAF efficacy as an intracavity hemostatic agent. This therapeutic approach will reduce killed in action (KIA) rate, increased life saving capability for the medic, and reduce need for surgery and transfusion.

描述（申请人提供）：跌打损伤出血是事故死亡的主要原因，也是战场上死亡的首要原因。早期有效的出血控制比任何其他措施都可以挽救更多的生命。组织粘合剂和密封剂已被开发用于控制出血；但目前，所有现有的用于腹部腔内出血的止血剂均设计用于手术室，而不是在事故现场或战场的紧急情况下使用。该项目的目标是开发一种腔内止血剂——止血粘合剂泡沫（HAF）——在严重出血的情况下促进止血，否则会导致失血。该方法基于 Teleostan A 型明胶、聚乙烯吡咯烷酮、蔗糖和纤维蛋白原与水溶性泡沫诱导剂的混合物的物理和凝固特性；添加凝血酶和P-选择素免疫球蛋白嵌合体，及其应用形式。交联化合物在腹部或其他腔内创伤后在受损、撕裂的组织上形成粘合基质。初步研究表明，当HAF通过Verres一次性针头腹腔注射时，即使在大量出血的情况下，HAF也能产生均匀分布的适应性泡沫，并粘附在腹腔上。我们的假设是，一旦将 HAF 注射到腹膜腔中，它就会均匀分布并粘附在壁上，从而改善撕裂组织之间的粘附性，并通过上调 P-选择素来增强凝块形成。我们的具体目标是在两个离体模型中证明：a) P-选择素的上调增强了 HAF 的粘附、物理和凝血特性，并确定该试剂促进组织和受损表面之间粘附的程度。存在大量出血； b) 对血凝块形成的影响； c)确定添加其他凝血酶和纤维蛋白样试剂以及特异性刺激P-选择素的P-选择素-免疫球蛋白嵌合体是否会增强该试剂的凝块形成和凝块强度作用，并且； d) 评估生命功能和生存的恢复情况。第一阶段拟议的研究可以为在不可压缩性出血的情况下使用 HAF 作为腔内止血剂提供“概念证明”。 II 期研究将确定该化合物在军事相关动物模型（猪）的腔内出血中的粘附和凝血特性，研究 HAF 的组织分布、药代动力学、重吸收和毒性。 II 期工作完成后，III 期研究将涉及扩展药代动力学研究，以提交新药研究 (IND) 申请，以在人类志愿者中开始研究。在速度、国内暴力和武装冲突的时代，腹部穿透伤和钝器伤的发生率不断增加。全国平均41.8%的医院收治的创伤病例是由道路交通事故造成的。此外，失血仍然是常规战争战场上死亡的主要原因。尽管这些损伤的发病率和死亡率正在逐渐下降，但腹部损伤仍然是一个严峻的问题，特别是对年轻人来说。理论上，早期有效的出血控制比任何其他措施都可以挽救更多的生命；然而，在手术室外，特别是在严峻和敌对的现场情况下，实现这一目标的最佳策略尚不清楚。目前，所有现有的用于腹部腔内出血的止血剂均被设计为在手术室中使用，而不是在受伤部位（即战场、车祸、枪伤）。通过 Verres 针的新型应用形式以及使用新型促凝血化合物（例如掺入明胶密封剂的 P-选择素免疫球蛋白嵌合体）可以提供受伤部位止血所需的粘附强度和凝血特性。我们建议开发一种腔内止血剂。止血剂——止血粘合剂泡沫（HAF）——在腹部或其他腔内创伤后在受损、撕裂的组织上形成粘合基质，以促进止血严重出血的情况，如果不立即治疗，会导致失血。拟议的研究提供了一个机会来证明 HAF 作为腔内止血剂的功效。这种治疗方法将降低阵亡（KIA）率，提高医务人员的救生能力，并减少手术和输血的需要。