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

描述（由申请人提供）：本SBIR II期提案是一项进一步开发新型治疗方法的计划，该方法将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理解有所增加，但严重脓毒症仍然导致显著的发病率和死亡率。因此，对于脓毒症患者的有效新型疗法存在迫切的未满足的医疗需求。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菌治疗方法不仅对医疗保健产生积极影响，而且还将具有显著的商业效益。平衡的炎症反应是损伤后宿主成功防御的基本要素。然而，促炎性细胞因子的过度产生可引起进一步的组织损伤。巨噬细胞/枯否细胞在脓毒症产生促炎细胞因子中起重要作用。神经系统反射性地调节真实的炎症反应。我们已经证明，在脓毒症中，交感神经递质去甲肾上腺素（NE）从肠道的释放增加，并且NE通过β 2-肾上腺素受体的A亚型（即， （2A-AR）在枯否细胞表面表达。在盲肠结扎和穿孔（CLP）诱导的多微生物脓毒症大鼠模型中，用特异性β 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-α，减轻组织损伤，并提高存活率。然而，尚不清楚延迟给予BRL-44408马来酸盐（更具有临床相关性）是否也会降低脓毒症诱导的死亡率。因此，我们已完成的I期项目的主要目的是确定BRL-44408马来酸盐延迟给药对脓毒症诱导的炎症、器官损伤和死亡率的影响。我们已经清楚地表明，在CLP后5小时给予BRL-44408马来酸盐（即，在败血症的早期阶段）在实验动物中具有保护作用。这些结果确定了拟议第二期项目的技术优点和可行性。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马来酸盐可减轻组织损伤并改善存活率。在本II期研究提案中，我们将进行详细的毒理学评价和药代动力学表征，并确定BRL-44408马来酸盐在大鼠脓毒症中的最佳保护剂量和时程。为了将该技术推进临床试验，将在脓毒症家兔模型中测试BRL-44408马来酸盐的疗效。这些拟议的研究应提供重要的临床前数据，这将有助于我们向FDA提交IND申请，以启动临床试验，从而获得BRL-44408马来酸盐作为败血症安全有效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.