Development of PEG Hemoglobin blood substitute to treat hemorrhagic shock

描述（由申请人提供）：出血是战斗创伤导致死亡的主要原因，也是平民死亡的第二大原因。创伤的治疗主要是静脉输液，如等渗晶体溶液。虽然体积扩张是可取的，但这些解决方案都不能克服组织缺氧（缺血）。正确使用输血有助于复苏；然而，它的使用存在重大问题，包括储存限制、可得性、分型、疾病传播风险和免疫抑制。这些问题使得常规使用储存的人体血液供医院外使用变得不切实际。为了克服许多这些问题，已经努力开发基于血红蛋白的氧载体（HBOCs）血液替代品，其优点包括降低疾病传播的机会，不需要分型，最重要的是提高了可用性，减少了存储需求。延长制药公司开发了一种独特的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）的组合组成。它是专门设计来增加血液的携氧能力，并通过其高渗-肿瘤作用，保持血管的开放，加强向组织的氧气输送。我们发现该产品能够在严重创伤性休克动物模型中迅速恢复组织氧合并偿还氧债。在这个快速通道SBIR拨款中，我们将进行临床前研究，以支持IND进行产品的临床试验。在I期组分中，我们将对PEG-Hb/HS进行药代动力学分析，确定最佳给药剂量，用于后续疗效和毒理学评估，并为未来的临床研究建立给药参数。在II期SBIR组件中，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使用。

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.