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

Alpha2A-肾上腺素受体的拮抗作用：一种新型抗脓毒疗法

• 批准号: 7537019
• 负责人: Xiaoling Qiang
• 金额: $ 19.75万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537019
• 关键词: Adrenergic Receptor; Animals; Attenuated; Autopsy; BRL 44408; Blood Coagulation Disorders; Body Weight; C-reactive protein; Cardiac; Caring; Cause of Death; Cecum; Clinical Trials; Coagulation Process; Continuous Infusion; Coronary Care Units; Creatinine; Development; Dose; Economic Burden; Elements; Endotoxins; Enzymes; Equilibrium; Future; Goals; HMGB Proteins; HMGB1 Protein; Healthcare; Heart; Host Defense; Imidazole; Incidence; Inflammatory Response; Injury; Intensive Care Units; Interleukin-1; Interleukin-6; Kidney; Kupffer Cells; Ligation; Liver; Lung; Maleates; Marketing; Measurement; Measures; Medical; Modeling; Monitor; Multiple Organ Failure; Necrosis; Nervous system structure; Neurotransmitters; Norepinephrine; Numbers; Patients; Phase; Phase II Clinical Trials; Plasma; Play; Production; Protein C; Public Health; Puncture procedure; Rate; Rattus; Reporting; Research; Risk; Role; Sepsis; Septic Shock; Serum; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Small Intestines; Spleen; Staging; Staining method; Stains; Surface; TNF gene; Testing; Therapeutic Agents; Time; Tissues; Trauma; Up-Regulation; chemokine; clinically relevant; commercialization; cost; cytokine; day; dosage; improved; keratinocyte; macrophage; macrophage inflammatory protein 2; mortality; novel; novel therapeutics; preclinical study; response; septic

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.

描述（由申请方提供）：本SBIR I期提案旨在证明通过调节细胞因子产生进一步开发脓毒症患者新型治疗的可行性。败血症是非心脏重症监护病房的主要死亡原因。尽管在创伤患者的管理方面取得了进展，但脓毒症的发病率显著增加。仅在美国，每年就有超过75万患者发生败血症，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，成功开发一种新型有效的抗菌治疗方法不仅对医疗保健产生积极影响，而且还将产生重大的商业效益。平衡的炎症反应是损伤后成功的宿主防御的基本要素。然而，促炎细胞因子的过度产生[例如，TNF-1、IL-1（、IL-6和高迁移率族蛋白-1（HMGB-1））可能导致进一步的组织损伤。巨噬细胞/枯否细胞在脓毒症中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。我们的初步研究表明，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 2A-肾上腺素受体的A亚型（即，（2A-AR）在枯否细胞表面表达。在盲肠结扎穿孔（CLP）诱导的多微生物脓毒症大鼠模型中，用特异性β 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，延迟给予BRL-44408马来酸盐（更具有临床相关性）是否也能降低脓毒症诱导的死亡率仍不清楚。因此，我们假设在脓毒症发作后晚期给予BRL-44408马来酸盐可减轻组织损伤并提高生存率。该项目的主要目的是证明BRL-44408马来酸盐作为降低脓毒症死亡率的新型治疗药物的进一步开发和商业化的可行性。BRL-44408马来酸盐（延迟治疗）的最佳剂量将通过评估1）BRL-44408马来酸盐对脓毒症中促炎细胞因子和组织损伤的剂量反应效应来确定;和2）BRL-44408马来酸盐对脓毒症诱导的死亡率的剂量反应效应。我们的最终目标（SBIR II期及以后）是获得BRL-44408马来酸盐的商业利用，作为脓毒症或脓毒性休克患者的安全有效治疗。 公共卫生相关性：脓毒症是非冠状动脉重症监护病房（ICU）患者的第二大死亡原因，也是美国第十大死亡原因。有证据表明，仅在美国，每年就有超过75万人患败血症，总死亡率为28.6%。鉴于治疗脓毒症患者所需的密集和长期护理，经济负担是深刻的。最近的一份报告表明，每位败血症患者的平均费用至少为22，100美元，目前全国每年的总费用超过160亿美元。因此，对于脓毒症患者的有效新疗法存在迫切的未满足的医疗需求。