Reduction of gastrointestinal toxicity of NSAIDs via molecular modifications leading to antioxidant anti-inflammatory drugs
Reduction of gastrointestinal toxicity of NSAIDs via molecular modifications leading to antioxidant anti-inflammatory drugs
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DOI：
10.1016/s0300-483x(99)00208-5
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发表时间：
2000-04-03
期刊：
影响因子：
4.5
通讯作者：
Galanakis, D
中科院分区：
文献类型：
--
作者：
Kourounakis, PN;Tsiakitzis, K;Galanakis, D
活性氧和自由基反应与多种病理条件有关，包括炎症和胃溃疡。后者是几乎所有非类固醇抗炎药的主要不良副作用。由于NSAIDs的这种作用不仅受到被抑制的环氧合酶的类型的极大影响，而且还受到分子的酸性性质的影响，我们认为通过改变其结构以产生抗氧化剂、中性分子或酸性大大降低的分子是很有趣的。因此，我们合成了四种广为人知的非甾体抗炎药的酰胺类化合物。即双氯芬酸、托芬那酸、布洛芬和消炎痛，以及众所周知的抗氧化剂半胱胺。合成的衍生物具有良好的抗炎和抗氧化活性，在胃肠道(GI)毒性研究中显示出非常显著的降低溃疡形成的作用。以死亡率(%)、胃溃疡发生率(%)、体重减轻(g/100gbw)和黑色素沉着(Melena)作为大鼠溃疡毒性的指标。所有含有半胱胺的非甾体抗炎药的酰胺类化合物在胃肠道几乎都是无毒的。在我们的实验条件下，与其父母的非类固醇抗炎药相比。这些结果归因于获得的抗氧化活性以及与母体化合物相比酸性的降低。因此，可以得出结论，将抗炎和抗氧化活性这两种性质结合起来，同时大幅降低酸性，可能会导致开发出新的、有用的抗炎和细胞保护药物分子。具有潜在的重要治疗应用。(C)2000爱思唯尔爱尔兰科学有限公司。保留所有权利。
Reactive oxygen species and free radical reactions are related to several pathologic conditions including inflammation and gastric ulceration. The latter is the major undesired side-effect of almost all NSAIDs. Since this effect of NSAIDs is greatly influenced not only by the type of cyclooxygenase which is inhibited but also by the acidic nature of the molecule, we considered it interesting to modify their structure in such a way that it would lead to an antioxidant, neutral molecule or a molecule with greatly reduced acidic character. Thus, we synthesized amide derivatives of four well-known NSAIDs. i.e. diclofenac acid, tolfenamic acid, ibuprofen and indomethacin, with cysteamine, a well-known antioxidant. The synthesized derivatives, with demonstrated good anti-inflammatory and antioxidant activities, showed very significant reduction of ulcerogenicity in the investigation of gastrointestinal (GI) toxicity. As indices of ulcerogenic toxicity in rats, we used the mortality (%), the incidence of GI ulcers (%), body weight reduction (g/100 g BW) and the incidence of melena. All amide derivatives of the NSAIDs with cysteamine were almost non-toxic in the GI tract. under our experimental conditions, in contrast to their parent NSAIDs. These results are attributed to the acquired antioxidant activity as well as to the reduction of acidic character compared with the parent compounds. Therefore, it call be concluded that the combination of these two properties, anti-inflammatory and antioxidant activity, with a simultaneous drastic reduction of acidic character, may lead to the development of novel, useful anti-inflammatory and cytoprotective pharmacomolecules. with potentially important therapeutic applications. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.