Safety of Adenosine A2a Agonist for Treatment of Sepsis

腺苷 A2a 激动剂治疗脓毒症的安全性

• 批准号: 7247106
• 负责人: Shannon P Williams
• 金额: $ 41.5万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247106
• 关键词: Acute; Adenosine; Adenosine A2A Receptor; Advanced Development; Agonist; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Bacteremia; Bioavailable; Bolus Infusion; Businesses; Candida albicans; Canis familiaris; Cardiac; Cardiovascular system; Clinical; Communicable Diseases; Development; Disease model; Doctor of Philosophy; Dose; Drug Kinetics; Evaluation; Foundations; Funding; Fungemia; Generations; Goals; Grant; Half-Life; Human; Image; Inflammation; Infusion procedures; Injection of therapeutic agent; Intervention; Intravenous; Laboratories; Lead; Life; Ligation; Miniature Swine; Modeling; Monitor; Mus; Mycoses; National Institute of Allergy and Infectious Disease; Oral Administration; Oryctolagus cuniculus; Pharmacodynamics; Pharmacology; Phase; Plasma; Property; Puncture procedure; Relative (related person); Reporting; Research; Research Contracts; Safety; Sepsis; Septicemia; Severities; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solid; Solutions; Sterility; Stress; Surrogate Markers; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Toxicity Tests; Week; Work; antimicrobial; base; chemokine; clinically relevant; coronary vasodilator; cytokine; esterase; in vivo Model; mortality; mouse model; prevent; programs; protective effect; receptor; research clinical testing; small molecule

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）：ATL 146 e是由腺苷治疗有限责任公司（ATL）开发的合成小分子，作为腺苷A2 A受体的选择性激动剂。ATL 146 e，用于静脉内（i. v.）推注，目前处于临床开发的III期，用作药效学负荷成像中的冠状血管扩张剂。ATL 146 e，当肠胃外（静脉内，i. v.;腹膜内，i. p.;或皮下注射）在低得多的全身暴露水平（低于引起心血管效应的水平）下，在脓毒症和多种其他急性炎症模型中发挥有效的抗炎/组织保护作用。基于其已确立的非临床和临床安全性，ATL正在快速推进ATL 146 e治疗脓毒症的开发。因此，我们正在申请SBIR先进技术补助金，以完成以下具体目标：1）在第二种动物物种中完成ATL 146 e的所需毒性测试，以证明ATL 146 e作为连续静脉内输注施用时与作为静脉内推注施用时同样安全，以及2）在临床相关的脓毒症小鼠和兔模型中，用ATL 146 e和ATL的已鉴定的先导备用化合物ATL 313进行额外的药效学测试：小鼠和兔中的多微生物菌血症的盲肠结扎-穿刺模型（CLP）;和真菌血症模型（白色念珠菌）。进行额外拟定药理学研究的依据包括：1）确定ATL 146 e和ATL 313在临床相关的多微生物败血症模型中的获益2）证明保护作用不具有种属特异性（即在第二种非啮齿动物物种（兔CLP模型）中具有可证实的保护作用; 3）扩大用于真菌感染诱导的败血症的潜力; 4）鉴定可用作监测治疗的临床益处的替代标志物的相关细胞因子。由于研究表明，ATL 146 e和ATL 313对脓毒症诱导的死亡率的保护机制与其广谱抗炎特性有关，因此该研究经费中提出的研究与国家过敏和传染病研究所（NIAID）的小企业生物防御计划直接相关。