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: 7943076
• 负责人: LENARD M LICHTENBERGER
• 金额: $ 49.99万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943076
• 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）：此申请涉及广泛的挑战领域（15）转化科学和特定挑战主题，15-DK-103：“在潜在疗法中，在NIDDK疾病的发病机理中翻译新分子/途径。”我们组装了一支专家团队，以表征非甾体类抗炎药（NSAIDS）化学结合并破坏磷脂酰胆碱（PC）在Gi Mucosa的表面屏障特性中起重要作用的机制。该机制与药物抑制环氧合酶（COX）的能力无关，并因胆汁酸而加剧，胆汁酸会通过高浓度到小肠的腔内形成有毒的混合胶束，这些胶质因其共同的载体特性而形成有毒的混合胶束。后者与最近的胶囊内窥镜证据一致，表明NSAID诱导的较低肠道受伤比以前认为的更为普遍，影响了多达40％的慢性NSAID使用者。为了阐明我们建议使用的NSAID，PC和胆汁酸之间的化学关联：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。 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.提出了胃细胞系和肠细胞系的研究，以评估我们的治疗对通过细胞成像（使用荧光探针）评估的生物膜的影响 - 渗透性和复制。然后，这些研究将转化为NSAID诱导的胃肠道出血/溃疡和治疗剂的啮齿动物模型，这些模型在PI实验室中很容易获得。最后，挑战赠款支持将用于部分支付我们在开发的第一个PC-NSAID（Ibuprofen-PC）进行所需的公式优化，制造和稳定性分析的费用，该公司由PI The University Pharma建立的PLX Pharma，PI，PLX Pharma，以获得FDA要求，以满足这一新小说的应用程序，以获取这一新小说类别的Gi-Safer Nssa，可以为您提供Gi-Safer Nsaids的公开范围。 公共卫生相关性：由于它们出色地抑制疼痛，炎症和发烧的功效及其对诸如癌症，中风，血栓形成和阿尔茨海默氏病等疾病的预防功效，因此据估计，NSAID在长期以来消耗了约7000万美国人。这一趋势的主要健康问题是，众所周知，NSAID的消费与副作用有关，胃肠道溃疡和出血最为普遍，占40万人的住院，估计为1248亿美元/年/年，每年16,000-20,000人死亡。随着选择性COX-2抑制剂（例如Vioxx）的撤回，对于了解和预防NSAID诱导的GI副作用的新型策略有一个非常“未满足的需求”。这项转化科学挑战赠款的重点是理解NSAID如何将化学与磷脂酰胆碱（PC）的稳定性相关联，该磷脂酰胆碱（PC）在GI Mucosa的表面屏障特性中起着重要作用。此外，通过将大豆PC与NSAID进行预先关联，我们开发了一种新型的家庭gi-safer，具有治疗有效的PC-NSAID，可以使用加速的FDA调节途径向公众提供。