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首页> 外文期刊>CNS drug reviews >DP-155, a lecithin derivative of indomethacin, is a novel nonsteroidal antiinflammatory drug for analgesia and Alzheimer's disease therapy.
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DP-155, a lecithin derivative of indomethacin, is a novel nonsteroidal antiinflammatory drug for analgesia and Alzheimer's disease therapy.

机译：DP-155是消炎痛的卵磷脂衍生物，是一种用于镇痛和阿尔茨海默氏病治疗的新型非甾体类抗炎药。

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DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A2 (PLA)(2) to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following indomethacin administration. The brain to serum ratio was 3.5 times higher for DP-155 than for indomethacin. In vitro studies demonstrated that DP-155 is a selective cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its indomethacin derivative nonselectively inhibits both COX-1 and -2. DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its indomethacin metabolite. DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while indomethacin caused gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with DP-155 compared to indomethacin. In addition to reduced toxicity, DP-155 had similar ameliorative effects to indomethacin in antipyretic and analgesia models. Moreover, DP-155 and indomethacin were equally efficacious in reducing levels of amyloid ss (Ass)42 in transgenic Alzheimer's disease mouse (Tg2576) brains as well as reducing Ass42 intracellular uptake, neurodegeneration, and inflammation in an in vitro AD model. The relatively high brain levels of indomethacin after DP-155 administration explain the equal efficacy of DP-155 despite its low systemic blood concentrations. Compared to indomethacin, the favored safety profile and equal efficacy of DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for analgesia.
机译：DP-155是吲哚美辛的脂质前药，其包含经由5-碳长度接头在sn-2位置与卵磷脂缀合的后者。它被磷脂酶A2（PLA）（2）裂解的程度比具有2、3和4个碳原子的类似化合物更大。吲哚美辛是大鼠血清中DP-155的主要代谢产物，口服DP-155后，该代谢产物在血清和脑中的半衰期分别为22和93 h，而吲哚美辛施用后分别为10和24 h。 DP-155的脑血比是消炎痛的3.5倍。体外研究表明，DP-155是一种选择性环氧合酶（COX）-2抑制剂。切割后，其消炎痛衍生物非选择性抑制COX-1和-2。 DP-155表现出较好的毒性，这可能是由于持续的低血清水平和消炎痛代谢物的最大浓度降低所致。在测试的最高急性剂量（0.28 mmol / kg）下，DP-155不会产生胃毒性，而消炎痛以较低的33倍剂量引起胃溃疡。此外，与吲哚美辛相比，重复口服后，胃肠道和肾脏的毒性较低（分别为10倍和5倍），而DP-155延迟。除了降低毒性外，DP-155在退烧和镇痛模型中的消炎作用与消炎痛相似。此外，DP-155和消炎痛在降低转基因阿尔茨海默病小鼠（Tg2576）脑中淀粉样蛋白（Ass）42的水平以及体外AD模型中减少Ass42细胞内摄取，神经退行性变和炎症方面同样有效。 DP-155给药后脑中消炎痛的相对较高水平解释了DP-155的全身血药浓度低，但疗效相同。与消炎痛相比，DP-155的安全性和同等疗效使该化合物成为长期用于治疗AD相关病理和镇痛的潜在候选药物。

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