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

描述(由申请人提供)：这项SBIR第二阶段提案是一项计划，旨在进一步开发一种新的治疗方法，以挽救脓毒症患者的生命。尽管对脓毒症复杂的病理生理机制的认识日益加深，但严重的脓毒症仍会导致显著的发病率和死亡率。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。脓毒症治疗的全球市场潜力估计每年超过300亿美元。因此，成功开发一种新的抗感染疗法不仅将对医疗保健产生积极影响，而且将具有显著的商业效益。平衡的炎症反应是创伤后成功的宿主防御的基本要素。然而，过度产生促炎细胞因子可能会导致进一步的组织损伤。巨噬细胞/枯否细胞在脓毒症的促炎细胞因子产生中起重要作用。神经系统反射性地实时调节炎症反应。我们已经证明，败血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(2-肾上腺素受体，即(2A-AR))增强内毒素诱导的肿瘤坏死因子-α的上调。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，用特异性(2A-AR拮抗剂，2-[(4，5-二氢-1H-咪唑-2-基)甲基]-2，3-二氢-1-甲基-1H-异吲哚马来酸(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，我们已完成的第一阶段项目的主要目标是确定延迟给药BRL-44408对脓毒症引起的炎症、器官损伤和死亡率的影响。我们已经清楚地表明，在CLP后5小时(即脓毒症早期)给药BRL-44408对实验动物具有保护作用。这些结果证实了拟议二期工程的技术优势和可行性。因此，我们继续假设，在已建立的脓毒症中给予小分子候选药物BRL-44408马来酸酯可以减轻组织损伤并提高存活率。在这份第二阶段的提案中，我们将进行详细的毒理学评估和药代动力学表征，并确定顺丁烯二酸丁酯-44408在大鼠脓毒症中的最佳保护剂量(S)和时程。为了将这项技术推向临床试验，将在兔脓毒症模型上测试BRL-44408马来酸酯的疗效。这些拟议的研究将提供重要的临床前数据，帮助我们向美国食品和药物管理局提交IND申请，启动临床试验，以便将BRL-44408马来酸酯作为安全有效的脓毒症治疗药物进行商业应用。 公共卫生相关性：败血症是重症监护病房的主要死亡原因之一。在美国，每年有超过21万人死于这种压倒性的感染。最近的一项流行病学研究估计，每年有超过75万人患上败血症，在全国范围内造成167亿美元的损失。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。因此，脓毒症患者迫切需要一种有效的新疗法，但尚未得到满足。

DESCRIPTION (provided by applicant): This SBIR Phase II proposal is a plan to further develop a novel therapeutic approach that will save the lives of patients with sepsis. Despite the increased understanding of the complex pathophysiology of sepsis, severe sepsis still results in significant morbidity and mortality. As such, there is an urgent unmet medical need for an effective novel therapy for septic patients. The global market potential for sepsis treatment is estimated at over $30 billion annually. Thus, successful development of a new anti-sepsis therapy will not only have a positive impact on health care, but also will 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 may cause further tissue injury. Macrophages/Kupffer cells play important roles in producing proinflammatory cytokines in sepsis. The nervous system reflexively regulates the inflammatory response in real time. We have demonstrated 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 (2-adrenoceptors (i.e., (2A-AR) expressed on the surface of Kupffer cells. Pre-treatment with a specific (2A-AR antagonist, 2-[(4,5-dihydro-1H-imidazol-2-yl) methyl]-2,3-dihydro-1-methyl-1H-isoindole 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 remained unknown whether the delayed administration of BRL-44408 maleate (which is more clinically relevant) reduces sepsis-induced mortality as well. Accordingly, the primary objective of our completed Phase I project was to determine the effect of delayed administration of BRL-44408 maleate on sepsis-induced inflammation, organ injury, and mortality. We have clearly shown that administration of BRL-44408 maleate at 5 h after CLP (i.e., at the early stage of sepsis) is protective in experimental animals. These results have established the technical merit and feasibility of the proposed Phase II project. We therefore continue to hypothesize that the administration of the small molecule drug candidate BRL-44408 maleate in established sepsis attenuates tissue injury and improves survival. In this Phase II proposal, we will perform detailed toxicological evaluation and pharmacokinetic characterization, and determine the optimal protective dose(s) and time- course of BRL-44408 maleate in sepsis in the rat. In order to advance the technology to clinical trials, the efficacy of BRL-44408 maleate will be tested in a rabbit model of sepsis. These proposed studies should provide important preclinical data that will help us filing an IND application to the FDA to initiate clinical trials in order to obtain commercial utilization of BRL-44408 maleate as a safe and effective therapy for sepsis. PUBLIC HEALTH RELEVANCE: Sepsis is one of the leading causes of death in intensive care units. Over 210,000 people succumb to this overwhelming infection in the United States annually. A recent epidemiologic study estimated that more than 750,000 people develop sepsis each year at a cost of $16.7 billion nationally. Given the intensive and prolonged care necessary to treat patients with sepsis, the economic burden is profound. Thus, there is an urgent unmet medical need for an effective novel therapy for patients with sepsis.