A2A AR Agonists as Adjunct Therapy Against S. aureus Sepsis

A2A AR 激动剂作为金黄色葡萄球菌败血症的辅助治疗

• 批准号: 7155473
• 负责人: JAYSON MICHAEL RIEGER
• 金额: $ 13.28万
• 依托单位: ADENOSINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155473
• 关键词: cytokine; model; neutrophil; septicemia; syndrome

DESCRIPTION (provided by applicant): This is a phase I STTR application to study the efficacy of selective adenosine A2A receptor (A2AR) agonists developed in the laboratories of Adenosine Therapeutics (ATL) in models of Gram-positive bacterial sepsis which will be conducted in the University of Virginia (UVA) laboratories of Dr. Michael Scheld, an expert in the field of infectious disease. Sepsis syndrome is the 11th leading cause of death in the United States. Nearly 900,000 cases occur annually, resulting in 210,000 deaths, with 50% of sepsis cases due to Gram-negative pathogens such as S. aureus. While many new therapies targeting aspects of the inflammatory cascade have been tried, the results have been generally disappointing. We hypothesize that following the initiation of sepsis syndrome, selective adenosine A2A receptor (A2AR) agonists afford protection from tissue injury and the deleterious effects of inflammation by inactivating inflammatory hematopoeitic cells (neutrophils, monocytes, macrophages and T cells). This results in reduced neutrophil-endothelial cell interactions, thus abrogating the early cascade of pro-inflammatory cytokine release with an accentuation of an anti-inflammatory cytokine-chemokine response. We will specifically evaluate 1) the pharmacokinetics and formulation stability of 3 new, highly selective and potent A2AR agonists; 2) evaluate these compounds in a lethal murine model of sepsis using S. aureus; and 3) evaluate the cytokine profile of control and drug-treated animals to gain greater understanding of underlying mechanisms and signaling molecules in sepsis. These objectives directly relate to the mission of the National Institute of Allergy and Infectious Diseases, which is to conduct and support basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases, by targeting drug development for gram-positive sepsis, for which current therapies are not ideal for patient care and survival.

描述（由申请人提供）：这是I期STTR的应用，用于研究选择性腺苷A2A受体（A2AR）激动剂在腺苷疗法实验室（ATL）中开发的革兰氏阳性细菌脓毒症模型中的功效，该模型将在弗吉尼亚大学（UVA）（UVA）实验室的迈克尔·塞尔德（Michael Scheld Scheld）的专业人士（UVA）实验室中进行。败血症综合征是美国第11大死亡原因。每年发生近900,000例病例，导致21万例死亡，其中50％由于革兰氏阴性病原体（如金黄色葡萄球菌）引起的败血症病例。尽管已经尝试了许多针对炎症性级联反应方面的新疗法，但结果通常令人失望。我们假设在开始败血症综合征，选择性腺苷A2A受体（A2AR）激动剂后，可以保护组织损伤和通过失活的炎症血肿细胞（中性粒细胞，单细胞，单细胞，巨噬细胞和T细胞）的炎症影响。这导致嗜中性粒细胞 - 内皮细胞相互作用减少，从而消除了促炎性细胞因子释放的早期级联反应，并加剧了抗炎细胞因子 - 化学化学反应。我们将特别评估1）3种新的，高度选择性和有效的A2AR激动剂的药代动力学和配方稳定性； 2）使用金黄色葡萄球菌在败血症的致命鼠模型中评估这些化合物； 3）评估对照和药物处理的动物的细胞因子谱，以对败血症中的潜在机制和信号分子有更深入的了解。这些目标直接与国家过敏和传染病研究所的使命有关，该疾病是通过针对革兰氏阳性脓毒症的药物开发来进行基础和应用研究，以更好地理解，治疗，治疗，最终预防传染性，免疫学和过敏性疾病。