Antagonism of Alpha2A-Adrenoceptor: A Novel Anti-Sepsis Therapy

描述(由申请人提供)：这项SBIR第一阶段提案旨在证明通过调节细胞因子的产生进一步开发一种新的脓毒症治疗方法的可行性。败血症是非心脏重症监护病房的主要死亡原因。尽管创伤受害者的治疗取得了进步，但脓毒症的发生率显著增加。仅在美国，每年就有超过75万患者患上脓毒症，总死亡率为28.6%。脓毒症治疗的全球市场潜力估计每年超过300亿美元。因此，成功开发一种新颖有效的抗感染疗法不仅将对医疗保健产生积极影响，而且还将具有显著的商业效益。平衡的炎症反应是成功的(宿主受伤后的)防御的基本要素。然而，过度产生促炎细胞因子[例如，肿瘤坏死因子-1、白介素1(IL-6)和高迁移率族蛋白-1(HMGB-1)]可能会导致进一步的组织损伤。巨噬细胞/枯否细胞在脓毒症过程中发挥重要的促炎细胞因子的作用。神经系统反射性地实时调节炎症反应。我们的初步研究表明，脓毒症时肠道交感神经递质去甲肾上腺素(NE)的释放增加，NE通过库普弗细胞表面表达的A亚型(2A-肾上腺素受体，即(2A-AR))增强内毒素诱导的肿瘤坏死因子-α上调。在盲肠结扎和穿孔(盲肠结扎和穿孔)诱导的多菌脓毒症大鼠模型中，用特定的(2A拮抗剂，2-[(4，5-二氢-1H-咪唑-2-基)甲基]-2，3-二氢-1-甲基-1H-异吲哚-2A马来酸酯(BRL-44408))预治疗，可下调肿瘤坏死因子-α，减轻组织损伤，并提高存活率。然而，目前尚不清楚延迟给予BRL-44408马来酸酯(临床意义更大)是否也能降低败血症引起的死亡率。因此，我们假设，在脓毒症发病后期给予顺丁烯二酸BRL-44408可以减轻组织损伤并提高存活率。该项目的主要目标是证明BRL-44408马来酸酯作为一种降低脓毒症死亡率的新型治疗剂的进一步开发和商业化的可行性。确定BRL-44408马来酸酯(延迟治疗)的最佳剂量(S)将通过评估1)BRL-44408对脓毒症促炎细胞因子和组织损伤的剂量反应效应；2)BRL-44408马来酸BRL-44408对脓毒症所致死亡率的剂量反应效应。我们的最终目标(SBIR第二阶段及以后)是将BRL-44408马来酸酯作为一种安全有效的治疗败血症或感染性休克患者的药物获得商业应用。 公共卫生相关性：脓毒症是非冠脉重症监护病房(ICU)患者的第二大死亡原因，也是美国总的第十大死亡原因。有证据表明，仅在美国，每年就有超过75万人患上脓毒症，总死亡率为28.6%。考虑到治疗脓毒症患者所需的密集和长期护理，经济负担是沉重的。最近的一份报告表明，每个败血症患者的平均成本至少为22,100美元，目前全国每年的总成本超过160亿美元。因此，迫切需要一种有效的新疗法来治疗败血症患者，这种需求尚未得到满足。

DESCRIPTION (provided by applicant): This SBIR Phase I proposal is intended to demonstrate the feasibility of further development of a novel therapy for patients with sepsis through the modulation of cytokine production. Sepsis is a leading cause of death in non-cardiac intensive care units. Despite advances in the management of trauma victims, the incidence of sepsis has significantly increased. More than three quarters of a million patients develop sepsis each year in the US alone with an overall mortality rate of 28.6%. The global market potential for sepsis treatment is estimated at over $30 billion annually. Thus, successful development of a novel and effective anti-sepsis therapy will not only have a positive impact on health care, but will also have significant commercial benefits. A balanced inflammatory response is an essential element of a successful( host defense after injury. However, excessive production of proinflammatory cytokines [e.g., TNF-1, IL-1(, IL-6, and high mobility group box-1 (HMGB-1)] may cause further tissue injury. Macrophages/Kupffer cells play important roles in producing proinflammatory cytokines during sepsis. The nervous system reflexively regulates the inflammatory response in real time. Our preliminary studies indicate that the release of the sympathetic neurotransmitter, norepinephrine (NE), from the gut is increased in sepsis, and that NE potentiates endotoxin-induced TNF-( upregulation via the A subtype of (2A-adrenoceptors (i.e., (2A-AR) expressed on the surface of Kupffer cells. Pre-treatment with a specific (2A antagonist, 2-[(4,5-dihydro-1H-imidazol-2-yl) methyl]-2,3-dihydro-1-methyl-1H-isoindole 2A maleate (BRL-44408 maleate), downregulates TNF-(, attenuates tissue injury, and improves survival in a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). However, it remains unknown whether the delayed administration of BRL-44408 maleate (which is more clinically relevant) reduces sepsis-induced mortality as well. We, therefore, hypothesize that the administration of BRL-44408 maleate late after the onset of sepsis attenuates tissue injury and improves survival. The primary objective of this project is targeted towards demonstrating the feasibility of the further development and commercialization of BRL-44408 maleate as a novel therapeutic agent in reducing mortality in sepsis. The optimal dosage(s) of BRL-44408 maleate (delayed treatment) will be determined by assessing 1) the dose- response effect of BRL-44408 maleate on proinflammatory cytokines and tissue injury in sepsis; and 2) the dose-response effect of BRL-44408 maleate on sepsis-induced mortality. Our ultimate goal (SBIR Phase II and beyond) is to obtain commercial utilization of BRL-44408 maleate as a safe and effective treatment for patients with sepsis or septic shock. PUBLIC HEALTH RELEVANCE: Sepsis is the second leading cause of death among patients in non-coronary intensive care units (ICU) and the 10th leading cause of death overall in this nation. Evidence indicates that in the US alone, more than 750,000 people develop sepsis each year with an overall mortality rate of 28.6%. Given the intensive and prolonged care necessary to treat patients with sepsis, the economic burden is profound. A recent report indicates that the average cost per septic patient is at least $22,100, with current annual total costs of more than $16 billion nationally. Thus, there is an urgent unmet medical need for an effective novel therapy for septic patients.