GI safety and therapeutics of oil-based PC-NSAIDs

油基 PC-NSAID 的胃肠道安全性和治疗

• 批准号: 6897137
• 负责人: LENARD M LICHTENBERGER
• 金额: $ 38.36万
• 依托单位: PLX OPCO, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897137
• 关键词: antiatherogenic agent; aspirin; chemical stability; drug adverse effect; drug interactions; drug screening /evaluation; enzyme activity; gastrointestinal hemorrhage; gastrointestinal pharmacology; hepatotoxin; ibuprofen; infrared spectrometry; intermolecular interaction; laboratory rat; membrane permeability; nephelometry; nonsteroidal antiinflammatory agent; pharmacokinetics; phosphatidylcholines; prostaglandin endoperoxide synthase; renal toxin; ulcer; vegetable oils

DESCRIPTION (provided by applicant): In this Phase II application we propose to continue and expand the very promising line of experiments, performed during Phase I, to confirm the GI safety and therapeutic activity of a new family of phosphatidylcholine (PC) - associated nonsteroidal anti-inflammatory drugs (NSAIDs). In Phase I, we established the feasibility of modifying the formulae of PC-NSAIDs from an aqueous suspension to an oil-based formulation containing the NSAID (aspirin or ibuprofen) and equal parts of triple strength lecithin, which has benefits with regards to drug stability, cost of goods, and reduction in manufacturing steps. The data presented in the Phase I final report show that oil-based PC-ibuprofen and PC-aspirin reduced acute and chronic GI ulceration, promoted ulcer healing and had superior analgesic activity in comparison to the unmodified NSAID. In the outlined Phase II studies we propose to continue with these studies in more comprehensive chronic animal model systems, to compare PC-ibuprofen and PC-aspirin, our two lead compounds, on GI ulceration/bleeding and ulcer healing vs unmodified ibuprofen and aspirin, respectively. A similar series of experiments are also planned to compare the analgesic/anti-inflammatory activity of our test PC-NSAID formulations in acute and chronic models of hind paw inflammation. Further, we also propose a number of in vitro studies using Infrared and light scattering spectroscopy, and selective extrusion filtration techniques to demonstrate the molecular association of PC with either ibuprofen or aspirin and how this affects macromolecular structure of the lipidic particles. We also describe a number of experiments to define the molecular, cellular and physiological basis for the increased therapeutic activity of PC-NSAIDs, with a focus on membrane permeability, cyclooxygenase (COX)-inhibitory activity and bioavailability of the drugs. In the latter studies, we will investigate whether PC promotes the uptake and distribution of the NSAIDs into chylomicrons that enter the lymphatic system. Lastly, we include a series of experiments to confirm that any modification in the formulation of either oil-based PC-ibuprofen or PC-aspirin that are necessitated in response to manufacturing and stability issues, maintains the superior GI safety and therapeutic activity of this new family of NSAIDs.

描述（由申请人提供）：在本II阶段申请中，我们建议继续并扩大在第一阶段进行的非常有前途的实验线，以确认新的磷脂酰胆碱（PC）的新家族的GI安全性和治疗活性 - 相关的非甾体类药物抗炎药（NSAIDS）。在第一阶段，我们确定了将PC-NSAID的公式从水性悬浮液中修改为含有NSAID（阿司匹林或布洛芬）的油性配方的可行性和三重强度卵磷脂的相等部分，这在药物稳定性方面具有益处，商品成本和制造步骤的降低。第一阶段最终报告中提供的数据表明，与未修饰的NSAID相比，油性的PC-勃正环蛋白和PC-阿素蛋白降低了急性和慢性胃肠道溃疡，促进溃疡愈合，并具有优越的镇痛活性。在概述的第二阶段研究中，我们建议在更全面的慢性动物模型系统中继续进行这些研究，以比较我们的两种铅化合物PC-勃正环和PC-垫素化合物，即有关GI溃疡/出血和溃疡愈合与未修饰的Ibuprofen和Asproferin和Asproferin和Asprofin，Gi Clerceration/Blecer healing and avereding and Groce愈合分别。还计划进行类似的一系列实验，以比较我们测试PC-NSAID制剂在后爪炎症的急性和慢性模型中的镇痛/抗炎活性。此外，我们还提出了许多使用红外和光散射光谱的体外研究，以及选择性挤出过滤技术，以证明PC与布洛芬或阿司匹林的分子缔合，以及这如何影响脂质颗粒的大分子结构。我们还描述了许多实验，以定义PC-NSAIDS增加的分子，细胞和生理基础，重点是膜通透性，环氧酶（COX） - 抑制性 - 抑制性活性和药物的生物可获取性。在后一项研究中，我们将研究PC是否促进了NSAID在进入淋巴系统的乳糜微粒中的摄取和分布。最后，我们包括一系列实验，以确认在制定油基PC-纤维面包或PC-呼吸素方面的任何修改都需要响应制造和稳定性问题，都保持了这种新的GI安全性和治疗性的优越性NSAID家族。