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（由申请人提供）：创伤伤害引起的出血是事故死亡的主要原因，也是战场上死亡的主要原因。早期有效的出血控制可以挽救比其他任何措施更多的生命。已经开发了组织粘合剂和密封剂来控制出血。但是，目前，所有现有的腹腔内出血的止血剂被设计用于手术室，而不是在事故现场或战场上的紧急情况下使用。拟议项目的目的是开发腔内止血剂 - 紧急粘合剂泡沫（HAF） - 在严重出血的情况下促进止血，否则会导致解血。这种方法基于定蛋白明胶A型，聚乙烯基吡咯烷酮，蔗糖和纤维蛋白原的混合物的物理和凝结特性，以及水溶性泡沫诱导剂；添加凝血酶和P-选择蛋白的非果蛋白嵌合体以及其应用形式。交叉连接的化合物形成了粘合剂基质，而腹部或其他腔内创伤后受损，裂伤的组织。在初步研究中，有证明HAF可以产生均匀分布的适应性泡沫，并在通过Verres partosoposable的针头注入腹膜内注射时，即使在大量的出血下也粘附在腹腔。我们的假设是，一旦将HAF注射到腹膜腔中，它就会均匀地分布并粘附在墙壁上，从而通过上调P-链染料的上调来提高裂缝组织之间的粘附性并增强凝块形成。我们的具体目的是在两个离体模型中证明：a）P-选择蛋白的上调增强了HAF的粘合性，物理和凝结性能，并确定该药物在存在PROFUSE PLEEDED的情况下组织和在多大程度上促进组织和受损表面之间的粘附性； b）它对凝块形成的影响； c）确定添加其他凝血酶和纤维蛋白（例如剂）以及P-选择蛋白 - 免疫球蛋白嵌合蛋白是否会特别刺激P-蛋白，会增强该药物的凝块形成和凝块强度效应，并且d）评估重要功能和生存的恢复。第一阶段提出的研究可以为在不可压缩出血的情况下使用HAF用作时期内止血剂的“概念证明”。第二阶段的研究将定义化合物在腔内出血与军事相关的动物模型（PIG），研究组织分布，药代动力学，重吸收和HAF毒性中的粘合性和凝结特性。 II期努力完成后，第三阶段的研究将涉及扩展的药代动力学研究，以提交调查性新药（IND）应用以开始在人类志愿者中进行研究。在速度，民事暴力和武装冲突的时代，腹部穿透和钝伤的发生率一直在增加。平均而言，全国41.8％的医院的创伤案件是由于道路交通事故。同样，出血仍然是传统战场战场上死亡的主要原因。尽管这些伤害的发病率和死亡率正在逐渐减少，但腹部受伤仍然构成一个巨大的问题，尤其是在年轻人中，从理论上讲，早期和有效的出血控制可以比任何其他措施挽救更多的生命。但是，在手术室之外，尤其是在严峻和敌对的野外情况下实现这一目标的最佳策略尚不清楚。目前，所有现有的腹中室内出血的止血剂均设计为在手术室中使用，而不是在受伤部位（即战场，车祸，射击伤口）。 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在严重出血的情况下，腹部或其他卫生部创伤后受损的，裂缝的组织可促进止血，如果不立即治疗，则会导致外动性。拟议的研究提供了证明HAF功效为腔内止血剂的机会。这种治疗方法将降低行动案（KIA）的速度（KIA）速度，提高医疗救生能力，并减少对手术和输血的需求。