NSAID-Phosphatidylcholine Association: Insight in GI Ulcer Pathogenesis/Therapy

NSAID-磷脂酰胆碱协会：胃肠道溃疡发病机制/治疗的见解

• 批准号: 7817520
• 负责人: LENARD M LICHTENBERGER
• 金额: $ 49.31万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7817520
• 关键词: Accounting; Address; Adverse effects; Affect; Alzheimer' s Disease; American; Anti Inflammatory Analgesics; Applications Grants; Area; Award; Bile Acids; Bile fluid; Biological; Biological Preservation; Cell Culture System; Cell Line; Cell Membrane Permeability; Cellular Membrane; Cessation of life; Characteristics; Chronic; Collaborations; Consumption; Coxibs; Development; Disease; Drug Formulations; Drug usage; Drug user; Dyes; Endoscopy; Energy Transfer; Equilibrium; Exclusion; Family; Fever; Fluorescent Probes; Gastrointestinal tract structure; Grant; Health; Hemorrhage; Ibuprofen; Inflammation; Injury; Institution; Intestines; Lecithin; Liposomes; Malignant Neoplasms; Membrane; Membrane Fluidity; Membrane Microdomains; Micelles; Modality; Mucous Membrane; NMR Spectroscopy; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Steroidal Anti-Inflammatory Agents; Nuclear Magnetic Resonance; Occupations; Pathogenesis; Pathway interactions; Permeability; Pharmaceutical Preparations; Phospholipids; Play; Property; Prostaglandin-Endoperoxide Synthase; Regulatory Pathway; Rodent Model; Rofecoxib; Role; Series; Small Intestines; Soybeans; Stomach; Stroke; Surface; Surface Plasmon Resonance; System; Techniques; Therapeutic; Thrombosis; Tissues; Translating; Translational Research; Treatment Efficacy; Ulcer; Universities; Withdrawal; base; capsule; cellular imaging; chemical association; clinically significant; cost; cytotoxic; extracellular; insight; light scattering; meetings; molecular dynamics; nanoparticle; novel; novel strategies; novel therapeutics; pain inhibition; pre-clinical; prevent; public health relevance; research study; soy; trend

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DK-103: "Translate discovery of new molecules/pathways in pathogenesis of NIDDK diseases in potential therapies." We have assembled a team of experts to characterize the mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) chemically associate with and destabilize phosphatidylcholine(PC) that plays an important role in the surface barrier property of the GI mucosa . This mechanism is independent of the ability of the drugs' to inhibit cyclooxygenase (COX) and is exacerbated by bile acids, that are present in high concentration to the lumen of the small intestine, by forming toxic mixed micelles due to their common amphipathic properties. The latter is consistent with recent capsule endoscopy evidence suggesting that NSAID-induced injury to the lower gut is much more prevalent than was once thought, affecting as much as 40% of chronic NSAID users. To elucidate the chemical associations between NSAIDs, PC and bile acids we propose to use: molecular dynamic (MD) simulation; surface plasmon resonance (SPR); and nuclear magnetic resonance (NMR) spectroscopy. To study the nanoparticles formed by these associations we propose a series of experiments with synthetic liposomal/micellar systems using: dynamic light scattering for size determination, and fluorescent probes such as, fluorescent resonance energy transfer (FRET) and dye exclusion analysis to assess the effects of NSAID bile acid interactions on membrane fluidity, microdomain formation and permeability. Studies on gastric and intestinal cell lines are proposed to evaluate the effects of our treatment on biological membranes as assessed by cellular - imaging (using fluorescent probes) - permeability and replication. These studies will then be translated to rodent models of NSAID-induced GI ulceration bleeding/ulceration and therapeutics, that are readily available in the PI's lab. Lastly, Challenge grant support will be used to partially defray the expense of performing the required formulation optimization, manufacturing and stability analyses of our first PC-NSAID under development (Ibuprofen-PC) by a university-based start-up company, PLx Pharma founded by the PI, to meet FDA requirements to obtain an New Drug Application, so that this novel class of GI-safer NSAIDs can be made available to the public. PUBLIC HEALTH RELEVANCE: Due to their remarkable efficacy to inhibit pain, inflammation and fever and their preventative efficacy for diseases such as cancer, stroke, thrombosis and Alzheimer's disease, it has been estimated that NSAIDs are consumed by ~70 million Americans on a chronic basis. The major health concern with this trend, is that the consumption of NSAIDs is well known to be associated with side-effects, with GI ulceration and bleeding being most common, accounting for 400,000 people being hospitalized at an estimated cost of $ 124.8 billion/yr and 16,000-20,000 deaths annually. With the withdrawal of selective COX-2 inhibitors, such as Vioxx, there is a great "unmet need" for novel strategies to understand and prevent NSAID-induced GI side-effects. This Translational Science Challenge grant is focused on understanding how NSAIDs chemically associate with and destabilize phosphatidylcholine(PC) that plays an important role in the surface barrier property of the GI mucosa. Furthermore, by pre-associating soy PC with NSAIDs we have developed a novel family GI-safer, therapeutically effective PC-NSAIDs that can be made available to the public using an accelerated FDA regulatory pathway.

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15-DK-103：“在潜在治疗中发现NIDDK疾病发病机制中的新分子/途径。“我们已经组建了一个专家团队，以表征非甾体抗炎药（NSAID）与磷脂酰胆碱（PC）化学结合并使其不稳定的机制，PC在GI粘膜的表面屏障特性中起着重要作用。该机制不依赖于药物抑制环加氧酶（考克斯）的能力，并且由于胆汁酸的共同两亲性质，胆汁酸通过形成毒性混合胶束而加剧，胆汁酸以高浓度存在于小肠腔中。后者与最近的胶囊式内窥镜证据一致，表明NSAID诱导的下肠道损伤比以前认为的要普遍得多，影响多达40%的慢性NSAID使用者。为了阐明NSAID、PC和胆汁酸之间的化学关联，我们建议使用：用途：分子动力学（MD）模拟、表面等离子体共振（SPR）和核磁共振（NMR）光谱。为了研究这些协会形成的纳米粒子，我们提出了一系列的实验与合成脂质体/胶束系统使用：动态光散射的大小测定，和荧光探针，如荧光共振能量转移（FRET）和染料排斥分析，以评估非甾体抗炎药胆汁酸相互作用对膜流动性，微区形成和渗透性的影响。对胃和肠细胞系的研究被提出来评估我们的治疗对生物膜的影响，如通过细胞成像（使用荧光探针）-渗透性和复制所评估的。然后将这些研究转化为NSAID诱导的GI溃疡出血/溃疡和治疗的啮齿动物模型，这些模型在PI实验室中随时可用。最后，挑战补助金支持将用于部分支付由PI创立的大学初创公司PLx Pharma对我们正在开发的第一种PC-NSAID（布洛芬-PC）进行所需配方优化、生产和稳定性分析的费用，以满足FDA获得新药申请的要求，从而使这种新型GI-更安全的NSAID可以向公众提供。 公共卫生关系：由于其在抑制疼痛、炎症和发烧方面的显着功效以及对癌症、中风、血栓形成和阿尔茨海默病等疾病的预防功效，据估计，约有7000万美国人长期服用非甾体抗炎药。这种趋势的主要健康问题是，众所周知，NSAID的消费与副作用有关，GI溃疡和出血是最常见的，每年有400，000人住院，估计费用为1248亿美元，每年有16，000 - 20，000人死亡。随着选择性考克斯-2抑制剂如万络的停用，对于了解和预防NSAID诱导的GI副作用的新策略存在巨大的“未满足的需求”。这项转化科学挑战资助的重点是了解NSAID如何与磷脂酰胆碱（PC）化学结合并使其不稳定，而PC在GI粘膜的表面屏障特性中起着重要作用。此外，通过将大豆PC与NSAID预结合，我们开发了一种新的家族GI-更安全，治疗有效的PC-NSAID，可以使用加速的FDA监管途径向公众提供。