非甾体抗炎药研究的最新进展

非甾体抗炎药(NSAIDs)是一类广泛用于抗炎、解热、镇痛的药物,但由于胃肠道毒副作用和肾毒性使它的应用受到很大限制。因此研制出能降低传统NSAIDs副作用且具良好活性的新型NSAIDs成为这类药物发展的主要方向,如选择性环氧化酶-2(COX-2)抑制剂、一氧化氮释放型NSAIDs、环氧化酶/脂氧合酶(COX/LOX)双重抑制剂、脂蛋白磷脂酶A2(LP-PLA2)抑制剂、前列腺素E2合成酶-1(mPGES-1)抑制剂以及肿瘤坏死因子-α(TNF-α)抑制剂等。本文从这几个方面对NSAIDs最新研究进行了简要介绍。     

2001～2003年上海地区镇痛及解热镇痛抗炎药用药分析

目的:探讨上海地区镇痛及解热镇痛抗炎药用药趋势。方法:按购药金额,对上海地区48家医院2001-2003年镇痛药及解热镇痛抗炎药的用药数据作统计,并进行分析。结果:(1)上海地区整个镇痛药用药呈上升趋势,每年增长率在23%以上。用药金额最高的是曲马朵、吗啡;增长率最高的是芬太尼,特别是其贴剂。(2)解热镇痛抗炎药用药水平总体较平稳。较新的品种特别是环氧化酶-2(COX-2)选择性抑制剂和特异性抑制剂有较大增长。传统的非甾体类抗炎药(NSAIDs)用量呈现下降趋势,但仍排名前列。结论:整个镇痛及解热镇痛抗炎药用药构成将会在现有的基础上有较小的改变,镇痛药用量还将继续上升,在NSAIDs类药物中COX-2选择性抑制剂会有进一步增长,而特异性抑制剂用量将减少。     

2016年度我院解热镇痛抗炎药使用分析

目的 促进解热镇痛抗炎药的合理应用;为临床安全、有效使用解热镇痛抗炎药提供分析依据;提高医药人员对合理使用解热镇痛抗炎药的认识.方法 通过分析各类解热镇痛抗炎药的DDD(限定日剂量)、DDDS(用药频度)、DUI(药物利用指数)以及DDC(限定日费用),评价药物临床应用的合理性.结果 所有解热镇痛抗炎药DUI均≤1;门诊所使用的所有解热镇痛抗炎药中,阿司匹林肠溶片DDDS最高;DDC最高的是艾瑞昔布片.结论 目前我院解热镇痛抗炎药的使用处于基本合理的水平.     

吡咯布洛芬(Pirprofen)

异名 Rangasil、Rengasil、C 21524 SU 化学名 2-[3-氯-4-(3-吡咯啉-1-基)苯基]丙酸药效分类解热镇痛抗炎药开发单位(瑞士)Ciba Geigy 上市厂商(法)Ciba-Geigy 1983年5月文献 Fed Proc 1973,32:803 AbsClin Pharmacol Ther 1974,16(1):69 药理本品为极强的非甾体抗炎药。动物实验中,在镇痛、解热和抗炎方面均有显著活性。它抑制前列腺素合成酶,对白细胞的趋化性具有抑制作用。大鼠脚爪水肿试验、棉球肉芽肿试验和佐剂关节炎等药理研究,均显示本品的抗炎     

解热镇痛药水杨酸镁研制成功

水杨酸镁化学名为双一(2-羟基苯甲酸-O~1,O~2)镁四水合物。美国化学文摘,化合物登记号(18917-89-0)是一非甾体抗炎药,具有解热、镇痛、抗炎和抗风湿作用。药效确实,其治疗作用类似于阿斯匹林和水杨酸钠,但水杨酸镁最大的特点是对肠     

高选择性非甾体抗炎药物的进展与合理应用

非甾体抗炎药 (ＮＳＡＩＤｓ)是指一类具有解热、镇痛、抗炎作用而非类固醇结构的药物。自 1899年德国化学家Ｈｏｆｆｍａｎｎ合成了第 1个非甾体抗炎药阿司匹林以来 ,ＮＳＡＩＤｓ的作用不断拓展。近年来 ,ＮＳＡＩＤｓ新品种陆续上市 (见表 1,表 2 ) ,确立了其在解热、镇痛、抗风湿和抗炎治疗中的主导地位。1　非甾体抗炎药的研究进展ＮＳＡＩＤｓ是一类广泛用于临床的抗炎药 ,迄今已发展到结构不同、种类繁多的一大类药物 ,传统的ＮＳＡＩＤｓ选择性不强 ,主要抑制环氧化酶 1(ＣＯＸ 1) ,导致不良反应较多。近年来 ,人们通过各种途径研制…     

昔布类药物的心血管风险评价

昔布类药物是一类新型非甾体解热镇痛抗炎药，能选择性抑制环氧酶-2（COX-2），而对环氧酸-1（COX-1）影响较小。因较COX-1抑制剂的胃肠道不良反应小，该类产品自1998年问世后的5年间拥有很高的商业价值，在非甾体解热镇痛抗炎药的市场中占有较大份额。但2004年9月，美国默沙东公司突然主动宣布从全球撤回罗非昔布（rofecoxib），引发了学术界对选择性COX-2抑制剂心血管安全性问题的关注。     

布托啡诺复合丙帕他莫在下肢术后自控静脉镇痛的应用

术后镇痛的最常见的药物配方是对乙酰氨基酚和非甾体解热镇痛抗炎药( NSAIDs)或选择性环氧合酶2( COX-2)抑制药以及阿片类药物、曲马多配合[1].布托啡诺(butorphanol)是阿片受体激动-拮抗镇痛药,主要激动k阿片肽受体,对μ受体则具有激动和拮抗双重作用,用于术后镇痛安全有效,镇痛效果可靠[2].     

某院2016年-2018年解热镇痛抗炎药品临床使用情况分析

目的:分析医院2016年—2018年解热镇痛抗炎药品的临床使用情况。方法:采用回顾性分析法,抽取医院2016年—2018年间临床使用解热镇痛抗炎药品的处方,比较和分析3年内不同年度内解热镇痛抗炎药品的年销售金额及其构成比和排序、处方中出现的频率及用药频度(DDDs)和日均费用(DDC)排序。结果:2016年—2018年间每年10种主要解热镇痛抗炎药品年销售金额相差不大,但其中塞来昔布胶囊、洛索洛芬钠分散片3年间的年销售金额均占据年销售榜首;注射用氯诺昔康、氟比洛芬酯注射液2016年后年销售额急剧下滑,而注射用精氨酸阿司匹林、氨酚双氢可待因片自2016年后年销售额显著增长;阿司匹林肠溶片在处方中出现的频率为最高,而注射用氯诺昔康、氟比洛芬酯注射液及注射用精氨酸阿司匹林出现的频率较低;阿司匹林肠溶片DDDs、DDC连续3年排序在第1、10位,而氟比洛芬酯注射液、盐酸氨基葡萄糖胶囊DDDs变化较大。结论:该院2016年—2018年间解热镇痛抗炎药品的使用情况较为合理。     

2015—2017年天津市津南区咸水沽医院解热镇痛抗炎药品的使用情况分析

目的 调查分析2015-2017年天津市津南区咸水沽医院解热镇痛抗炎药品的应用情况及趋势,为科学管理和合理应用提供参考。方法 采用数据回顾性方法,对天津市津南区咸水沽医院解热镇痛抗炎药品的用药金额、用药数量及构成比、限定日计量（DDD）值、用药频度（DDDs）及日均费用（DDC）等数据进行统计与分析。结果 共有28种解热镇痛抗炎药,涵盖口服、注射、外用3种剂型。口服剂型解热镇痛抗炎药的销售金额逐年上升,注射剂型解热镇痛抗炎药的销售金额逐年下降。洛索洛芬钠分散片的销售金额及构成比稳居首位。2015年注射用氯诺昔康的销售金额居第2位,但2016、2017年,注射用精氨酸阿司匹林跃居第2位。氨咖黄敏口服溶液的DDDs稳居首位。牛痘疫苗接种家兔炎症皮肤提取物片的DDC排名第1位,2017年加巴喷丁胶囊的DDC排名跃居第1位。结论 天津市津南区咸水沽医院解热镇痛抗炎药品的管理比较规范,药物使用大致合理。     

肿柄菊的化学成分及药理作用研究进展

肿柄菊来源于菊科肿柄菊属植物,主要化学成分是倍半萜内酯,还含有黄酮、色原烯以及二萜、蒽醌和神经酰胺等。肿柄菊的药理作用主要有抗炎、抗疟、抗肿瘤、降血糖以及其他一些活性。对近年来肿柄菊的倍半萜、色原烯等化学成分以及抗疟、抗炎、降血糖等药理活性做简要综述。     

Structure-based discovery of inhibitors of microsomal prostaglandin E2 synthase-1, 5-lipoxygenase and 5-lipoxygenase-activating protein: promising hits for the development of new anti-inflammatory agents

Microsomal prostaglandin E(2) synthase (mPGES)-1 catalyzes the transformation of PGH(2) to PGE(2) that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC(50) value of 3.2 μM, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC(50) = 0.4 μM).     

Microsomal prostaglandin E2 synthase-1 inhibitors: a patent review

Introduction: Microsomal prostaglandin E₂ synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E₂ (PGE₂) generation. It is strongly upregulated in inflamed tissues and overexpressed in tumors and it has been recognized as a key enzyme in inflammatory diseases such as arthritis, atherosclerosis, stroke and cancer. Thus, a great effort has been devoted in developing synthetic mPGES-1 inhibitors as novel anti-inflammatory agents.

Areas covered: This review article summarizes the mPGES-1 inhibitors presented in patent literature from 2000 to August 2016 and their biological evaluation, discussing their activities in vitro and in vivo.

Expert opinion: The side effects of NSAIDs and COX-2 inhibitors on the gastrointestinal tract and the cardiovascular system showcase the urgent need for the discovery of novel potent and safe anti-inflammatory drugs. mPGES-1 inhibitors may present superior safety in comparison to existing anti-inflammatory drugs. The first synthetic inhibitor of mPGES-1 was reported in 2001 and up to now a variety of structurally different inhibitors has been developed. However, only recently two inhibitors entered clinical trials and none has reached yet the market. More preclinical and clinical studies on mPGES-1 inhibitors are needed to realize if indeed they may become novel agents for the treatment of inflammation and cancer.     

Investigation into potent inflammation inhibitors from traditional Chinese medicine

Microsomal prostaglandin E synthase-1 (mPGES-1) is the key enzyme for prostaglandin E2 (PGE2) generation during inflammation and is a potential target for designing anti-inflammatory drugs. Potential inhibitors of m-PGES-1 were selected from traditional Chinese medicine (TCM Database@Taiwan) based on the pharmacophore map generated by the top HypoGen hypothesis and validated using structure- and ligand-based analysis. Key features for potential m-PGES-1 inhibitors include pi-interactions and H-bond donors. TCM compounds, shanciol B, shanciol A, castilliferol, and aurantiamide acetate, contoured to the quantitative structure-activity relationship pharmacophore and exhibited high docking scores and binding stability with m-PGES-1. Bioactivity models multiple linear regression (MLR) and support vector machine also supported activity predictions for the candidate compounds. Our results indicate that the investigated TCM compounds could be of use for development into mPGES-1 inhibitors.     

Pharmacophore modeling and virtual screening for novel acidic inhibitors of microsomal prostaglandin E₂ synthase-1 (mPGES-1)

Microsomal prostaglandin E(2) synthase-1 (mPGES-1) catalyzes prostaglandin E(2) formation and is considered as a potential anti-inflammatory pharmacological target. To identify novel chemical scaffolds active on this enzyme, two pharmacophore models for acidic mPGES-1 inhibitors were developed and theoretically validated using information on mPGES-1 inhibitors from literature. The models were used to screen chemical databases supplied from the National Cancer Institute (NCI) and the Specs. Out of 29 compounds selected for biological evaluation, nine chemically diverse compounds caused concentration-dependent inhibition of mPGES-1 activity in a cell-free assay with IC(50) values between 0.4 and 7.9 μM, respectively. Further pharmacological characterization revealed that also 5-lipoxygenase (5-LO) was inhibited by most of these active compounds in cell-free and cell-based assays with IC(50) values in the low micromolar range. Together, nine novel chemical scaffolds inhibiting mPGES-1 are presented that may possess anti-inflammatory properties based on the interference with eicosanoid biosynthesis.     

Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor

Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E₂ (PGE₂) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis and inflammatory pain, largely attributed to the inhibition of PGE₂ synthesis, provides a rationale for exploring mPGES-1 inhibition as a potential novel therapy for these diseases. Toward this aim, we identified PF-9184 as a novel mPGES-1 inhibitor. PF-9184 potently inhibited recombinant human (rh) mPGES-1 (IC₅₀ = 16.5 ± 3.8 nM), and had no effect against rhCOX-1 and rhCOX-2 (>6500-fold selectivity). In inflammation and clinically relevant biological systems, mPGES-1 expression, like COX-2 expression was induced in cell context- and time-dependent manner, consistent with the kinetics of PGE₂ synthesis. In rationally designed cell systems ideal for determining direct effects of the inhibitors on mPGES-1 function, but not its expression, PF-9184 inhibited PGE₂ synthesis (IC₅₀ in the range of 0.5-5 μM in serum-free cell and human whole blood cultures, respectively) while sparing the synthesis of 6-keto-PGF_1α (PGF_1α) and PGF_2α. In contrast, as expected, the selective COX-2 inhibitor, SC-236, inhibited PGE₂, PGF_1α and PGF_2α synthesis. This profile of mPGES-1 inhibition, distinct from COX-2 inhibition in cells, validates mPGES-1 as an attractive target for therapeutic intervention.     

Prostaglandin E synthase: a novel drug target for inflammation and cancer

Prostaglandin E synthase (PGES), which converts cyclooxygenase (COX)-derived prostaglandin (PG) H(2) to PGE(2), occurs in multiple forms with distinct enzymatic properties, modes of expression, cellular and subcellular localizations and intracellular functions. Two of them are membrane-bound enzymes and have been designated as mPGES-1 and mPGES-2. mPGES-1 is a perinuclear protein belonging to the MAPEG (for membrane-associated proteins involved in eicosanoid and GSH metabolism) family. This enzyme is markedly induced by proinflammatory stimuli, is down-regulated by anti-inflammatory glucocorticoids, and is functionally coupled with cyclooxygenase (COX)-2 in marked preference to COX-1. mPGES-2 is synthesized as a Golgi membrane-associated protein, and the proteolytic removal of the N-terminal hydrophobic domain leads to the formation of a mature cytosolic enzyme. This enzyme is rather constitutively expressed in various cells and tissues and is functionally coupled with both COX-1 and COX-2. Cytosolic PGES (cPGES) is constitutively expressed in a wide variety of cells and is functionally linked to COX-1 to promote immediate PGE(2) production. This review highlights the latest understanding of the expression, regulation and functions of these three PGES enzymes. In particular, recent gene targeting studies of mPGES-1 have revealed that this enzyme represents a novel target for anti-inflammatory and anti-cancer drugs.     

Prostaglandin E2 synthase inhibition as a therapeutic target

Background: Most NSAIDs function by inhibiting biosynthesis of PGE₂ by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I₂ (PGI₂) and thromboxane A₂ (TXA₂) with a bias towards TXA₂ may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. Methods: Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E₂ synthases. Microsomal prostaglandin E₂ synthase-1 (mPGES-1) specifically isomerizes PGH₂ to PGE₂, under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. Conclusion: mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.