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(申请人提供)：本申请涉及广泛的挑战领域(15)翻译科学和特殊挑战主题，15-DK-103：“在潜在疗法中翻译NIDDK疾病发病机制中的新分子/途径的发现。”我们组织了一个专家小组来研究非类固醇抗炎药物(NSAIDs)与磷脂酰胆碱(PC)化学结合并破坏其稳定性的机制，磷脂酰胆碱在胃肠道粘膜的表面屏障特性中起着重要作用。这一机制与药物抑制环氧合酶(COX)的能力无关，并因胆汁酸的共同两亲性而形成有毒的混合胶束，从而加剧了胆汁酸的作用。胆汁酸存在于小肠的腔内，浓度较高。后者与最近胶囊内窥镜检查的证据一致，该证据表明NSAID对下肠道的损伤比人们原先认为的要普遍得多，影响多达40%的慢性NSAID使用者。为了阐明NSAIDs、PC和胆汁酸之间的化学联系，我们建议使用：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。为了研究由这些缔合形成的纳米粒子，我们提出了一系列使用合成脂质体/胶束系统的实验：使用动态光散射来确定大小，以及荧光探针，如荧光共振能量转移(FRET)和染料排斥分析，以评估非类固醇胆汁酸相互作用对膜流动性、微区形成和通透性的影响。建议对胃和肠细胞系进行研究，以评估我们的治疗对生物膜的影响，通过细胞成像(使用荧光探针)-渗透性和复制来评估。然后，这些研究将被转化为非甾体抗炎药诱导的胃肠道溃疡出血/溃疡的啮齿动物模型和治疗方法，这些模型可以在PI的实验室中随时获得。最后，挑战资助将用于支付由PI创建的大学初创公司PLx Pharma对我们正在开发的第一个PC-NSAID(布洛芬-PC)进行所需配方优化、制造和稳定性分析的部分费用，以满足FDA获得新药申请的要求，从而使这种新型的GI-SAFER非类固醇抗炎药能够向公众提供。 与公共卫生相关：由于非类固醇抗炎药在抑制疼痛、炎症和发烧方面的显著效果，以及对癌症、中风、血栓形成和阿尔茨海默病等疾病的预防效果，据估计，约有7000万美国人长期服用非类固醇抗炎药。这一趋势的主要健康问题是，众所周知，非类固醇抗炎药的消费与副作用有关，胃肠道溃疡和出血是最常见的，有40万人住院，估计每年的费用为1248亿美元，每年有16,000-20,000人死亡。随着选择性COX-2抑制剂的停用，如万络，对了解和预防NSAID引起的胃肠道副作用的新策略有很大的“未得到满足的需求”。这项翻译科学挑战基金的重点是了解非类固醇抗炎药如何与磷脂酰胆碱(PC)化学结合并使其不稳定，磷脂酰胆碱在胃肠道粘膜的表面屏障特性中扮演着重要角色。此外，通过将大豆PC与NSAIDs预先关联，我们开发了一种新的GI家族-更安全、治疗有效的PC-NSAIDs，可以通过加快FDA的监管途径向公众提供。