A2A AR Agonists as Adjunct Therapy Against S. aureus Sepsis

描述（由申请人提供）：这是一项I期STTR申请，旨在研究腺苷治疗学（ATL）实验室开发的选择性腺苷A2 A受体（A2 AR）激动剂在革兰氏阳性细菌败血症模型中的疗效，该模型将在弗吉尼亚大学（UVA）实验室由感染性疾病领域专家Michael Scheld博士进行。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210，000例死亡，其中50%的脓毒症病例是由革兰氏阴性病原体如S。金黄色。虽然已经尝试了许多针对炎症级联反应方面的新疗法，但结果普遍令人失望。我们假设，在脓毒症综合征开始后，选择性腺苷A2 A受体（A2 AR）激动剂通过灭活炎性造血细胞（中性粒细胞、单核细胞、巨噬细胞和T细胞）来保护组织免受损伤和炎症的有害影响。这导致嗜中性粒细胞-内皮细胞相互作用减少，从而消除促炎细胞因子释放的早期级联反应，并加重抗炎性趋化因子-趋化因子反应。我们将具体评价1）3种新的、高选择性和有效的A2 AR激动剂的药代动力学和制剂稳定性; 2）使用S.金黄色;和3）评价对照和药物治疗的动物的细胞因子谱，以获得对脓毒症中的潜在机制和信号分子的更好理解。这些目标直接关系到国家过敏和传染病研究所的使命，即开展和支持基础和应用研究，通过针对革兰氏阳性脓毒症的药物开发，更好地了解，治疗和最终预防传染性，免疫性和过敏性疾病，目前的治疗方法对于患者护理和生存并不理想。

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.