Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity.
Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity.
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DOI：
10.1358/dot.2009.45.12.1441075
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发表时间：
2009-12
期刊：
影响因子：
1.8
通讯作者：
L. Lichtenberger;M. Barron;U. Marathi
中科院分区：
文献类型：
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作者：
L. Lichtenberger;M. Barron;U. Marathi
非甾体类抗炎药 (NSAID) 是抑制疼痛和炎症的高效药物，也许由于炎症在潜在病因中的作用，NSAID 也被证明可以有效降低患者患多种癌症和神经系统疾病（例如阿尔茨海默病）的风险。这些强效药物的效用因其胃肠道 (GI) 副作用而受到限制，特别是消化性溃疡和胃肠道出血，本文对此进行了简要回顾。我们还描述了胃肠道粘膜的屏障特性以及它如何受到 NSAID 的影响，因为我们的立场是，除了选择性抑制 COX-2 之外，表面屏障的破坏也是药物发病机制的一个重要组成部分，而 COX-2 已被证明是有问题的。我们还讨论了目前正在采取的减轻 NSAID 胃肠道副作用的替代方法，包括开发组合药物，其中 NSAID 与 HCl 分泌抑制剂（例如质子泵抑制剂或 H2 受体拮抗剂）包装在一起。然后，我们介绍了开发与 PC 相关的 NSAID 技术的基本原理，该技术源于我们的观察，即哺乳动物胃粘膜具有疏水性、不可润湿的特性，为腔酸提供了屏障，以及磷脂，特别是磷脂酰胆碱 (PC) 在这种屏障特性中的作用。在最后一节中，我们回顾了当前基于脂质的 PC-NSAID 制剂的开发，以及验证其胃肠道安全性和治疗功效的令人鼓舞的临床前和临床观察。
Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective drugs that inhibit pain and inflammation, and perhaps due to the role of inflammation in the underlying etiology, NSAIDs have also demonstrated efficacy in reducing a patient's risk of developing a number of cancers and neurological diseases (e.g. Alzheimer's disease). The utility of these powerful drugs is limited due to their gastrointestinal (GI) side-effects, notably peptic ulceration and GI bleeding which is briefly reviewed here. We also describe the barrier property of the GI mucosa and how it is affected by NSAIDs, as it is our position that disruption of the surface barrier is an important component in the drugs' pathogenesis, in addition to selective inhibition of COX-2, which has proven to be problematic. We also discuss current alternative approaches being taken to mitigate the GI side-effects of NSAIDs, including developing combination drugs where NSAIDs are packaged with inhibitors of HCl secretion such as proton pump inhibitors or H2-receptor antagonists. We then present the rationale for the development of the PC associated NSAID technology which came out of our observation that the mammalian gastric mucosa has hydrophobic, nonwettable properties that provides a barrier to luminal acid, and the role of phospholipids and specifically phosphatidylcholine (PC) in this barrier property. In the last section we review the development of our current lipid-based PC-NSAID formulations and our encouraging preclinical and clinical observations validating their GI safety and therapeutic efficacy.