A2a Adenosine Agonist Cardiac Reperfusion Injury

A2a 腺苷激动剂心脏再灌注损伤

• 批准号: 6937332
• 负责人: Shannon P Williams
• 金额: $ 28.83万
• 依托单位: ADENOSINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6937332
• 关键词: acute disease /disorder; antiinflammatory agents; blood chemistry; blood vessel prosthesis; clinical research; clinical trial phase I; disease /disorder prevention /control; drug administration rate /duration; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; echocardiography; heart disorder; heart disorder chemotherapy; heart revascularization; human subject; medical complication; myocardial infarction; neurotransmitter agonist; pharmacokinetics; purinergic receptor; reperfusion; urinalysis

DESCRIPTION (provided by applicant): Founded in 1999, Adenosine Therapeutics LLC (ATL) is a drug discovery and development company that has developed a family of potent and selective adenosine A2A receptor agonists. With the help of STTR funding, ATL has developed a lead adenosine A2A receptor agonist, ATL-146e, that is currently in late Phase II of clinical development for use as a coronary vasodilator in cardiac stress imaging. The central goal of this project is to further the clinical development of ATL-146e for prevention of cardiac reperfusion injury that occurs in patients with evolving acute myocardial infarction (AMI) who undergo revascularization with primary coronary stenting. AMI is the leading single cause of death in the US, accounting for 500,000- 700,000 coronary-artery disease-related deaths annually and for which only one therapeutic intervention is approved. We have demonstrated that ATL-146e protects against ischemia-reperfusion injury in liver and kidney, as well as in mouse, rabbit and canine models of coronary ischemia-reperfusion injury. The safety of ATL146e in man has been established during bolus administration that is used for pharmacological stress imaging. Its administration as a continuous IV infusion, which produces optimal cardioprotection from reperfusion injury, has not been studied clinically. Thus the current proposal provides for the conduct of a safety, pharmacokinetic, and pharmacodynamic study of ATL-146e when given as a continuous infusion in healthy volunteers. Specifically we will study ATL-146e given as a continuous IV infusion to human volunteers also treated with a low IV bolus of endotoxin to establish the following: 1) safety and tolerability; 2) pharmacokinetics of ATL-146e and its primary metabolite including steady state levels and time to steady state; and 3) pharmacodynamic effects, (based on its ability to inhibit transient production of proinflammatory cytokines that occur in response to endotoxin). Collectively, the data derived from this study will provide the foundation for the conduct of a subsequent pilot Phase II clinical trial supported by the Phase 2 portion of this SBIR Fast-Track application that will be conducted in patients with AMI. This pilot Phase II study will then be used as a basis for a definitive Phase II clinical trial, followed by a definitive Phase III clinical trial and eventual market approval.

描述（由申请人提供）：Adenosine Therapeutics LLC (ATL) 成立于 1999 年，是一家药物发现和开发公司，开发了一系列有效的选择性腺苷 A2A 受体激动剂。在 STTR 资金的帮助下，ATL 开发了一种主要腺苷 A2A 受体激动剂 ATL-146e，目前处于临床开发的后期阶段，用作心脏负荷成像中的冠状血管扩张剂。该项目的中心目标是进一步推进 ATL-146e 的临床开发，用于预防接受初次冠状动脉支架置入术进行血运重建的进展型急性心肌梗死 (AMI) 患者发生的心脏再灌注损伤。 AMI 是美国主要的单一死因，每年导致 500,000-700,000 例与冠状动脉疾病相关的死亡，并且针对该疾病仅批准一种治疗干预措施。我们已经证明，ATL-146e 可以保护肝脏和肾脏以及小鼠、兔和犬冠状动脉缺血再灌注损伤模型中的缺血再灌注损伤。 ATL146e 在人体中的安全性已在用于药理应激成像的推注给药过程中得到确定。其作为连续静脉输注的给药方式可以产生最佳的心脏保护作用，防止再灌注损伤，但尚未进行临床研究。因此，当前的提案规定对健康志愿者连续输注 ATL-146e 进行安全性、药代动力学和药效学研究。具体来说，我们将研究 ATL-146e 作为连续静脉输注给同样接受低静脉推注内毒素治疗的人类志愿者，以确定以下几点：1）安全性和耐受性； 2) ATL-146e及其主要代谢物的药代动力学，包括稳态水平和达到稳态的时间； 3) 药效学效应（基于其抑制内毒素反应中促炎细胞因子瞬时产生的能力）。总的来说，从这项研究中获得的数据将为随后开展 II 期试点临床试验奠定基础，该试验由 SBIR 快速通道应用程序的 2 期部分支持，该试验将在 AMI 患者中进行。这项 II 期试验研究将作为最终的 II 期临床试验的基础，随后是最终的 III 期临床试验和最终的市场批准。