Development of novel adenosine polymers for coating medical devices

开发用于涂覆医疗器械的新型腺苷聚合物

基本信息

  • 批准号:
    8057469
  • 负责人:
  • 金额:
    $ 18.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-09-01 至 2013-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Percutaneous coronary intervention (PCI) is the most frequently employed strategy to revascularize atherosclerotic stenosis of native coronary arteries and saphenous vein grafts. Tissue perfusion is frequently impaired following PCI, particularly in patients with ST segment elevation myocardial infarction (STEMI). This results in the "no-reflow" phenomenon which is an important predictor of mortality. Adenosine is an endogenous nucleoside that attenuates many of the mechanisms responsible for the "no-reflow" phenomenon. Experimental and clinical studies have confirmed adenosine's efficacy in enhancing myocardial salvage and improving microvascular blood flow. Adensoine's full therapeutic potential is compromised due to its ultra short half life requiring large doses to obtain adequate blood levels at the target organ. Since the guidewire is the first PCI device that perturbs the vascular bed, we have developed the concept of elution of adenosine continuously via an adenosine-polymer-coated guidewire. We have developed a number of unique physiologic polymers in which adenosine can be covalently incorporated and placed on a guidewire. We tested out first generation polymers (LDI-glycerol and LDI-adenosine) in a small animal model and verified that it resulted in a substantial increase in blood flow. However in a large animal model the kinetic profile was too rapid for a typical interventional procedure (~45 mins). We have subsequently developed two new polymers, LDI- cysteine and LDI-PEG. Prior to initiating large animal studies in a Phase 2 study it is imperative we optimize the polymer structure, guidewire-coating methodology and kinetic release profile. We therefore propose the following studies with the new polymers to identify an ideal product. First we will develop and characterize the structure of the polymers and permutations thereof and evaluate numerous coating methodologies to optimize release kinetic profile. Second we will evaluate adenosine elution utilizing a temperature controlled recirculating water bath system and measure adenosine release serially with HPLC. Third we will determine if the selected polymer is safe for clinical use by employing NAMSA- based screening tests for cytotoxicity, pyrogenicity, hemolysis, and sensitization. Finally we will evaluate the stability and durability of the polymer with glass transition temperature experiments and by passing coated wires through simulated lesions. If the "anti-no-reflow" wire is shown to be effective in improving outcomes after interventional procedures it will represent a major advance in the treatment of patients with coronary artery disease undergoing PCI. This will have important societal benefits due to the large number of interventional procedures performed in the US each year for coronary artery disease. PUBLIC HEALTH RELEVANCE: The improved outcomes that may potentially occur with the device would have important societal benefits due to the large number of interventional procedures performed in the US each year for atherosclerotic disease.
描述(由申请人提供):经皮冠状动脉介入治疗(PCI)是自体冠状动脉和隐静脉移植物动脉粥样硬化性狭窄血运重建的最常用策略。PCI术后组织灌注经常受损,尤其是ST段抬高型心肌梗死(STEMI)患者。这导致“无复流”现象,这是死亡率的重要预测因素。腺苷是一种内源性核苷,可减弱许多导致“无复流”现象的机制。实验和临床研究证实了腺苷在增强心肌挽救和改善微血管血流方面的功效。腺苷的全部治疗潜力由于其极短的半衰期而受到损害,需要大剂量才能在靶器官获得足够的血液水平。由于导丝是第一个干扰血管床的PCI器械,我们开发了通过腺苷聚合物涂层导丝连续洗脱腺苷的概念。我们已经开发了许多独特的生理聚合物,其中腺苷可以共价结合并放置在导丝上。我们在小动物模型中测试了第一代聚合物(LDI-glycerol和LDI-adenosine),并验证了其导致血流量的大幅增加。然而,在大型动物模型中,动力学曲线对于典型的介入手术来说太快(约45分钟)。我们随后开发了两种新的聚合物,LDI-cysteine和LDI-PEG。在II期研究中启动大型动物研究之前,我们必须优化聚合物结构、导丝涂层方法和动力学释放曲线。因此,我们建议使用新聚合物进行以下研究,以确定理想的产品。首先,我们将开发和表征聚合物及其排列的结构,并评估多种包衣方法以优化释放动力学曲线。其次,我们将评估腺苷洗脱利用温度控制的循环水浴系统和测量腺苷释放连续HPLC。第三,我们将通过采用基于NAMSA的细胞毒性、致热原性、溶血性和致敏性筛选试验,确定所选聚合物在临床使用中是否安全。最后,我们将评估聚合物的稳定性和耐久性与玻璃化转变温度实验,并通过涂层电线通过模拟病变。如果“抗无复流”导丝被证明能有效改善介入手术后的结局,则它将代表接受PCI的冠状动脉疾病患者治疗的重大进展。这将具有重要的社会效益,因为每年在美国进行大量的冠状动脉疾病介入手术。 公共卫生相关性:由于每年在美国进行的动脉粥样硬化疾病的大量介入手术,使用该器械可能发生的结局改善将具有重要的社会效益。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Development of a novel adenosine-eluting guidewire (Adenowire) for coronary vasodilation during percutaneous coronary intervention.
开发一种新型腺苷洗脱导丝(Adenowire),用于经皮冠状动脉介入治疗期间的冠状血管舒张。
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Mervyn B. Forman其他文献

Percutaneous transluminal coronary angioplasty in hemophilia.
血友病经皮腔内冠状动脉成形术。
  • DOI:
    10.1016/0002-8703(86)90569-7
  • 发表时间:
    1986
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Mervyn B. Forman;Harry A. Kopelman;John H. Gleaton;Robert L. Janco;James M. Perry
  • 通讯作者:
    James M. Perry
Coronary angioplasty at the time of initial catheterization using small diagnostic catheters
  • DOI:
    10.1016/s0002-8703(05)80107-3
  • 发表时间:
    1990-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Hercules Panayiotou;John W. Norris;Mervyn B. Forman
  • 通讯作者:
    Mervyn B. Forman
Safety and success of the beginning percutaneous transluminal coronary angioplasty program using the steerable guidewire system.
使用可操纵导丝系统开始经皮腔内冠状动脉成形术计划的安全性和成功。
  • DOI:
  • 发表时间:
    1986
  • 期刊:
  • 影响因子:
    2.8
  • 作者:
    W. Harston;Spencer Tilley;Richard Rodeheffer;Mervyn B. Forman;James M. Perry
  • 通讯作者:
    James M. Perry
923-3 Fluosol Reduces Myocardial Reperfusion Injury by Prolonged Suppression of Neutrophils by its Detergent Component (RheothRx) and not by Enhancing O<sub>2</sub>Delivery
  • DOI:
    10.1016/0735-1097(95)91880-7
  • 发表时间:
    1995-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    João V. Vitola;David A. Ingram;John P. Holsinger;James B. Atkinson;Mervyn B. Forman;John J. Murray
  • 通讯作者:
    John J. Murray
Percutaneous transluminal angioplasty of an internal mammary graft in homozygous familial hypercholesterolemia
  • DOI:
    10.1016/0002-8703(86)90649-6
  • 发表时间:
    1986-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Mervyn B. Forman;Robert M. Campbell;Murray Mazer;James M. Perry
  • 通讯作者:
    James M. Perry

Mervyn B. Forman的其他文献

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{{ truncateString('Mervyn B. Forman', 18)}}的其他基金

Development of Novel Adenosine Polymers for Coating Medical Devices
用于医疗器械涂层的新型腺苷聚合物的开发
  • 批准号:
    9407582
  • 财政年份:
    2017
  • 资助金额:
    $ 18.3万
  • 项目类别:
Novel Guidewire Design and Coating for Adenosine Delivery
用于腺苷输送的新型导丝设计和涂层
  • 批准号:
    10699444
  • 财政年份:
    2017
  • 资助金额:
    $ 18.3万
  • 项目类别:

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细胞外腺苷(Adenosine)作为干细胞旁分泌因子的生物学鉴定和功能分析
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靶向 A2B 腺苷受体用于胰腺癌的免疫预防
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