Development of PEG Hemoglobin blood substitute to treat hemorrhagic shock

描述（由申请人提供）：出血是战斗创伤死亡的主要原因，也是平民死亡的第二大原因。创伤主要用静脉内液体治疗，例如等渗晶体溶液。尽管需要体积扩张，但这些解决方案都不能克服组织缺氧（缺血）。正确使用输血可以帮助复苏;然而，其使用存在重大问题，包括储存限制，可用性，分型，疾病传播和免疫抑制的风险。这些问题使得常规使用储存的人血在医院外使用是不切实际的。为了克服这些问题中的许多问题，已经努力开发基于血红蛋白的氧载体（HBOC）血液替代品，其具有诸如降低疾病传播的机会、不需要分型以及最重要的是在降低储存需求的情况下提高可用性的优点。Prolong Pharmaceuticals开发了一种独特的HBOC产品，用于治疗严重失血性休克，该产品由聚乙二醇化牛血红蛋白（PEG-Hb）和高渗盐水（HS）组成。其专门设计用于增加血液的携氧能力，并通过其高渗-膨胀作用保持血管系统开放，从而增强向组织输送氧气。我们已经发现该产品能够在严重创伤性休克的动物模型中快速恢复组织氧合并偿还氧债。在这项快速通道SBIR资助中，我们将进行支持IND所需的临床前研究，以进行产品的临床试验。在I期部分，我们将进行PEG-Hb/HS的药代动力学分析，以确定随访疗效和毒理学评估的最佳剂量，并为未来的临床研究建立给药参数。在II期SBIR部分中，我们将进行额外的疗效研究，以确定PEG-Hb/HS在我们的创伤动物模型中诱导的生存程度，并将进行毒理学评估，以支持该产品在创伤治疗中的未来用途。公共卫生相关性：本研究旨在进一步开发PEG-Hb/HS作为血红蛋白氧载体治疗创伤性休克。我们已经证明，该产品可以逆转严重失血性休克动物模型中的氧债，本授权中提出的研究将推进该产品的临床前开发，包括额外的疗效研究和IND支持药代动力学和毒理学研究。

DESCRIPTION (provided by applicant): Hemorrhage is the leading cause of death from combat trauma and the second leading cause of civilian death. Trauma is mainly treated with intravenous liquids, such as isotonic crystalloid solutions. Although volume expansion is desirable, none of these solutions is capable of overcoming tissue oxygen deficits (ischemia). Proper use of transfused blood can assist in resuscitation; however there are significant problems with its use, including storage restraints, availability, typing, risk of disease transmission and immune suppression. These issues make the routine use of stored human blood for use outside the hospital impractical. In an attempt to overcome many of these issues, efforts have been made to develop hemoglobin based oxygen carrier (HBOCs) blood substitutes which have advantages such as decreased chance of disease transmission, lack of a need for typing, and most importantly improved availability with decreased storage demands. Prolong Pharmaceuticals has developed a unique HBOC product for the treatment of severe hemorrhagic shock consisting of a combination of PEGylated bovine hemoglobin (PEG-Hb) and hypertonic saline (HS). It is specifically designed to increase the oxygen carrying capacity of blood as well as to enhance the delivery of oxygen to tissues by keeping the vasculature open through its hypertonic-oncotic actions. We have found this product to be capable of rapidly restoring tissue oxygenation and repaying oxygen debt in an animal model of severe traumatic shock. In this Fast- Track SBIR grant, we will conduct the preclinical studies needed to support an IND to conduct clinical testing of the product. In the phase I component, we will conduct pharmacokinetic analysis of PEG-Hb/HS to define optimal dosing for follow up efficacy and toxicology assessment and to establish dosing parameters for future clinical studies. In the phase II SBIR component we will conduct additional efficacy studies to determine the extent of survival that PEG-Hb/HS induces in our animal model of trauma and will also perform toxicology assessment to support the future use of this product in the treatment of trauma. PUBLIC HEALTH RELEVANCE: The studies proposed in this grant are designed to further the development of PEG- Hb/HS as a hemoglobin based oxygen carrier to treat traumatic shock. We have shown that this product can reverse oxygen debt in an animal model of severe hemorrhagic shock and studies proposed in this grant will move forward the preclinical development of this product including additional efficacy studies and IND supporting pharmacokinetic and toxicology studies.