Safety of A2A Adenosine Agonist for Treatment of Sepsis

A2A 腺苷激动剂治疗脓毒症的安全性

• 批准号: 7108075
• 负责人: Shannon P Williams
• 金额: $ 86.17万
• 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: 2006-07-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108075
• 关键词: adenosine; cytokine; model; pharmacokinetics; septicemia

DESCRIPTION (provided by applicant): ATL146e is a synthetic small molecule developed by Adenosine Therapeutics, LLC (ATL) that acts as a selective agonist of the adenosine A2A receptor. ATL146e, sterile solution for intravenous (i.v.) bolus injection, is currently in Phase III of clinical development for use as a coronary vasodilator in pharmacodynamic stress imaging. ATL146e, when administered parenterally (intravenously, i.v.; intraperitoneally, i.p.; or subcutaneously s.c.) at much lower levels of systemic exposure (below those that elicit cardiovascular effects) exerts potent anti-inflammatory/tissue protective effects in sepsis and multiple other models of acute inflammation. Based upon its established nonclinical and clinical safety, ATL is rapidly advancing development of ATL146e for the treatment of sepsis. Accordingly, we are applying for an SBIR advanced technology grant to complete the following specific aims: 1) complete required toxicity testing for ATL146e in a second animal species to demonstrate that ATL146e is equally safe when administered as a continuous i.v. infusion compared to its administration as an i.v. bolus and 2) conduct additional pharmacodynamic testing with both ATL146e and ATL's identified lead backup compound, ATL313, in clinically-relevant mouse and rabbit models of sepsis: cecal ligation-puncture model (CLP) of polymicrobial bacteremia in mice and rabbits; and fungemia model (Candida albicans) in mice. The rationale for conduct of the additionally proposed pharmacological studies include: 1) establishment of benefit of ATL146e and ATL313 in clinically-relevant, polymicrobial models of septicemia 2) demonstrate that protective effects are not species specific (i.e. demonstrable protective effects in second nonrodent species (rabbit CLP moldel); 3) expansion of potential for use in septicemia induced by fungal infections; 4) identification of relevant cytokines that could serve as surrogate markers for monitoring clinical benefit of treatment. Since research shows that mechanisms for protection against sepsis-induced mortality by ATL146e and ATL313 relate to their broad-spectrum anti-inflammatory properties, the research proposed in this grant has direct relevance to the Small Business Bio-defense program of the National Institute for Allergy and Infectious Diseases (NIAID).

描述（由申请人提供）：ATL146e 是由 Adenosine Therapeutics, LLC (ATL) 开发的合成小分子，充当腺苷 A2A 受体的选择性激动剂。 ATL146e 是用于静脉（i.v.）推注的无菌溶液，目前正处于临床开发的 III 期，用作药效应激成像中的冠状血管扩张剂。 ATL146e，当以低得多的全身暴露水平（低于引起心血管效应的水平）肠胃外（静脉内，i.v.；腹膜内，i.p.；或皮下皮下）给药时，在脓毒症和多种其他急性模型中发挥有效的抗炎/组织保护作用炎。基于其已确立的非临床和临床安全性，ATL 正在快速推进 ATL146e 用于治疗脓毒症的开发。因此，我们正在申请 SBIR 先进技术拨款，以完成以下具体目标：1）在第二种动物物种中完成 ATL146e 所需的毒性测试，以证明 ATL146e 在连续静脉注射给药时同样安全。输注与静脉注射相比2) 在临床相关小鼠和兔脓毒症模型中，使用 ATL146e 和 ATL 确定的先导备用化合物 ATL313 进行额外的药效学测试：小鼠和兔多种微生物菌血症的盲肠结扎穿刺模型 (CLP)；和小鼠真菌血症模型（白色念珠菌）。进行额外提议的药理学研究的基本原理包括：1) 在临床相关的败血症多微生物模型中确立 ATL146e 和 ATL313 的益处 2) 证明保护作用不是物种特异性的（即在第二种非啮齿动物物种中可证明的保护作用）兔 CLP 模型）；3）扩大用于治疗真菌感染引起的败血症的潜力； 4) 鉴定可作为监测治疗临床获益的替代标记的相关细胞因子。由于研究表明 ATL146e 和 ATL313 预防脓毒症引起的死亡的机制与其广谱抗炎特性有关，因此本次资助中提出的研究与国家过敏研究所的小型企业生物防御计划直接相关和传染病 (NIAID)。