Novel A2A Adenosine Agonists in Vascular Protection

新型 A2A 腺苷激动剂的血管保护作用

• 批准号: 6950277
• 负责人: JAYSON MICHAEL RIEGER
• 金额: $ 81.16万
• 依托单位: ADENOSINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950277
• 关键词: adenosine; antiinflammatory agents; biotechnology; blood vessel prosthesis; cardiovascular disorder prevention; chemoprevention; combination chemotherapy; cytoprotection; drug delivery systems; drug screening /evaluation; histopathology; immunocytochemistry; liquid chromatography mass spectrometry; neurotransmitter agonist; pharmacokinetics; phosphodiesterase inhibitors; purinergic receptor; restenosis; surface coating; swine

DESCRIPTION (provided by applicant): This is a phase II SBIR proposal to develop a new drug eluting stent to prevent restenosis. It is a 3-way collaboration between Adenosine Therapeutics, LLC, Setagon, Inc., and the University of Virginia. The work described here will be done at Adenosine Therapeutics (compound synthesis and pharmacokinetics) and the University of Virginia (Stent studies in pigs). The nanoporous stent coating will be refined for optimal delivery of two drugs and provided by Setagon, Inc. The goal of this proposal is to demonstrate that the combined used of two synergistic anti-inflammatory compounds, ATL146e, an agonist of A2A adenosine receptors, and rolipram, a type IV phosphodiesterase (PDE) inhibitor, loaded into a proprietary nanoporous stent coating, inhibits stent restenosis in pigs more effectively than current state-of-the-art polymeric stent coatings. If these experiments are successful our plan is to develop the ATL146e/rolipram stent as a new product. ATL146e and rolipram are both approved for use in man and Adenosine Therapeutics has issued patents for the combined use of these compounds to prevent restenosis. Aim 1 proposes to investigate the elution kinetics of ATL146e and rolipram from stents into blood in vitro. In this aim we also will determine the terminal disposition half-life of ATL146e and rolipram in pigs using liquid chromatography/ mass spectroscopy of compounds extracted from pig blood after intravenous administration. Based on these data we will load stents with compounds sufficient to achieve free blood concentrations of only 1 ng/kg, that are unlikely to produce side effects. Aim 2 proposes to examine restenosis in pigs of stents loaded with ATL146e+/- rolipram. The results will be compared to commercially available stents containing sirolimus as a gold standard. Since ATL146e and rolipram have both been approved for human use, we anticipate that if the results of this study show that ATL146e +/- rolipram is more effective that sirolimus, it will be possible to initiate phase II clinical trials to test ATL146e/rolipram stents in man.

描述（由申请人提供）：这是一项II期SBIR提案，用于开发一种新的药物洗脱支架以防止再狭窄。这是腺苷Therapeutics，LLC，Setagon，Inc。和弗吉尼亚大学之间的三通合作。此处描述的工作将在腺苷治疗剂（化合物合成和药代动力学）和弗吉尼亚大学（猪的支架研究）上完成。纳米孔支架涂层将被完善，以最佳递送两种药物，并由Setagon，Inc.提供。该提案的目的是证明，两种协同抗炎化合物的合并使用ATL146E，ATL146E，A2A腺苷受体的激动剂，A2A腺苷受体和Rololipram，typerie iv iiv positeSedeSpase（prosie iniv postosepase）（plosepodiereSter）（postosepodiereSter）（postosepodiereSter）（postosepodiereSter）（prosectase）（PDECHODODIESERSER）。纳米孔支架涂层比当前最新的聚合支架涂料更有效地抑制猪的支架再狭窄。如果这些实验成功，我们的计划是开发ATL146E/ROLIPRAM支架作为新产品。 ATL146E和ROLIPRAM都被批准用于人类，腺苷治疗药已为这些化合物的联合使用以预防再狭窄。 AIM 1提议研究ATL146E和Rolipram的洗脱动力学，并从支架上进行体外血液。在此目标中，我们还将使用静脉内给药后从猪血中提取的化合物的液相色谱/质谱来确定猪ATL146E和Rolipram的末端处置半衰期。基于这些数据，我们将使用足以实现仅1 ng/kg的自由血液浓度的化合物加载支架，这不太可能产生副作用。 AIM 2建议检查装有ATL146E +/- rolipram的支架猪的再狭窄。结果将与包含Sirolimus作为黄金标准的市售支架进行比较。由于ATL146E和ROLIPRAM均已批准用于人类使用，我们预计如果这项研究的结果表明ATL146E +/- rolipram比Sirolimus更有效，那么可以启动II期临床试验以测试MAN中的ATL146E/Rolipram Stents。