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

描述（由申请人提供）：该SBIR II期提案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学的了解有所增加，但严重的脓毒症仍然会导致显著的发病率和死亡率。因此，对于脓毒症患者来说，迫切需要一种有效的新疗法。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败血症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。平衡的炎症反应是损伤后宿主防御成功的基本要素。然而，过度产生促炎细胞因子可能导致进一步的组织损伤。巨噬细胞/库普弗细胞在脓毒症中产生促炎细胞因子中发挥重要作用。神经系统反射性地实时调节炎症反应。我们已经证明，从肠道释放的交感神经递质去甲肾上腺素（NE）在败血症中增加，并且NE通过Kupffer细胞表面表达的2-肾上腺素受体(即（2A-AR）的A亚型增强内毒素诱导的TNF-（上调）。在盲肠结扎穿刺（CLP）诱导的多微生物脓毒症大鼠模型中，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 -异吲哚马来酸盐（BRL- 44408马来酸盐）预处理可下调TNF-(，减轻组织损伤，提高生存率。然而，延迟给药BRL-44408马来酸盐（这与临床更相关）是否也能降低败血症引起的死亡率，目前尚不清楚。因此，我们完成的I期项目的主要目的是确定延迟给药BRL-44408马来酸盐对败血症引起的炎症、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）给予马来酸BRL-44408对实验动物具有保护作用。这些结果确定了建议的第二期工程的技术优点和可行性。因此，我们继续假设小分子候选药物BRL-44408马来酸盐在确定的败血症中可以减轻组织损伤并提高生存率。在这个II期项目中，我们将进行详细的毒理学评估和药代动力学表征，并确定BRL-44408对脓毒症大鼠的最佳保护剂量和时间过程。为了将该技术推向临床试验，我们将在兔脓毒症模型中测试马来酸BRL-44408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FDA提交IND申请，启动临床试验，以获得BRL-44408马来酸盐作为一种安全有效的败血症治疗药物的商业利用。

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.