美洛昔康和尼美舒利治疗类风湿关节炎疗效和安全性的比较

非甾体抗炎药 (NSAIDs)是治疗类风湿关节炎 (RA)等关节炎性疾病最常用的药物 ,可以缓解和减轻关节炎疼痛与炎症 ,NSAIDs的抗炎作用和不良反应是因为环氧化酶(COX)受到抑制[1] 。COX有COX - 1和COX - 2两种同工酶。COX - 2是炎症和疾病相关的酶 ,而COX - 1则与胃肠保护性和血小板聚集有关 ,抑制COX - 1可导致NSAIDs毒性发生 ,所以更多抑制COX - 2而相对较少抑制COX - 1的药物应该是较为安全的[2 ] ,美洛昔康和尼美舒利均为选择性抑制COX - 2的NSAIDs。很多临床试验都证明了尼美舒利的疗效好 ,不良反应轻。本文旨在比较…     

环氧化酶（COX）-2选择性抑制剂

非甾体抗炎药(NSAIDs)是一类用途十分广泛的处方药，但由于胃肠道副作用和肾毒性使它的应用受到很大限制。自1971年Vane等揭示了NSAIDs是通过抑制COX而阻断花生四烯酸合成炎症介质PGS而发挥抗炎止痛的机制后，1991年Xie等发现了COX的两种同工酶即COX-1和COX-2其生理功能从而解释了NSAIDs在发挥治疗作用时产生胃及肾的不良反应的原因。为了保持其抗炎作用同时尽量减少对胃肠道和肾脏的毒性，相继合成了环氧化酶(COX)-2选择性抑制剂塞来昔布和罗非昔布。     

COX-2抑制剂的药理研究进展

环氧合酶 - 2 (COX - 2 )抑制剂是NSAIDs中最近问世的一个新类型 ,COX - 2抑制剂能特异性地抑制COX - 2 ,抑制与炎症相关的PG产生 ,不良反应比传统NSAIDs轻得多 ,因而受到广泛的关注。其中塞来昔布 (celecoxib ,西乐葆 )和罗非昔布 (rofecoxib ,万洛 )等新一代COX - 2抑制剂已在临床广泛应用于镇痛、关节炎和类风湿关节炎等治疗。本文对COX - 2抑制剂的药理等研究进展作一介绍。1　对胃肠道的作用与传统NSAIDs相比 ,COX - 2抑制剂不影响胃血流量 ,不影响胃粘膜中COX - 1mRNA的表达 ,不阻断COX- 1产生PG而维持正常的胃肠…     

新型COX-2抑制剂塞来昔布

塞来昔布(celecoxib)是美国 Searle 公司开发的第一个特异性环氧酶—2(COX—2)抑制剂,已于99年1月由美国FDA 批准上市,目前世界范围内已有37个国家批准上市。用于骨关节炎和类风湿性关节炎的症状治疗。此类药物是为避免胃肠道毒性和其他副作用而专门设计的,同时保留了抗炎药的有效作用。专家预测,在未来五年,COX—2抑制剂有望获得非甾体抗炎药一半以上的市场份额。1 药床药理在 Vane 提出 NSAIDs 通过抑制 COX 发挥抗炎作用理论近20年后,人们发现 COX 有2种异构酶,COX 可以催化花生四烯酸转变成前列腺素,是关节炎炎症反应的重要介质。NSAIDs 的治疗作用是由于它们能抑制 COX—2,后者     

尼美舒利的药物不良反应

尼美舒利(Nimesulide)化学名为4-硝基-2-苯氧基甲磺酰苯胺，是磺酰苯胺的衍生物，对环氧化酶(COX)有选择性的抑制作用。是前列腺素(PG)生物合成的关键酶。本品高度选择性抑制COX2的活性，对COX1抑制作用不明显，在发挥有效抗炎作用的同时，减少了其它NSAIDs常见的消化性溃疡和出血的副作用。该药最早由德国-家公司研制，1985年在意大利上市。随后在美国、德国上市，     

几种新的胃肠道低毒性非甾体抗炎药物简介

包括水杨酸类、杂芳基烷酸类、oxicam类及其他类非甾体抗炎药(NSAIDs)已有数十种,仅近几年上市的NSAIDs就达23种。NSAIDs主要是通过抑制花生四烯酸转化为前列腺素(PG)的环氧化酶(COX),减少PG生成而发挥镇痛和抗炎作用的。因PG具有保护胃粘膜,维持肾血流量和影响血小板功能的生理作用,故NSAIDs的药物不良反应(ADR)突出表现为对胃肠道的毒性作用,所致胃肠道出     

非甾体消炎镇痛药对肿瘤有预防作用

流行病学研究和实验室研究以及进入人体临床试验研究都强有力地支持非甾体消炎镇痛药(NSAIDs)在预防肿瘤发展方面具有保护作用．例如NSAIDs能降低家族性肠息肉肿瘤病人病情发展和在几种直肠癌动物模型减轻肿瘤的体积负重。多项研究证实，环氧合酶(COX)，特别是COX-2通过对前列腺素和其它类二十碳烯酸的合成调节与癌症的产生以及对细胞的增殖作用、血管瘤的产生、肿瘤的生长、免疫反应和炎症反应都有很大的关系。因此，有理由断定．作为(20X-2抑制剂的NSAIDs将是肿瘤预防和治疗很好的候选药物。动物研究和细胞培育生物学鉴定进一步表明，NSAIDs独自的环氧合酶作用也具有抗肿瘤的活性。研究表明。NSAIDs能够影响与肿瘤生成有关的许多转录因子表达，包括诱发的低氧因子-1(HIF-1)、GATA-6、NF-кB，β-catenin/TCF-4、早期生长反应-1(Egr-1)和雄激素受体。     

环氧化酶-2在恶性肿瘤细胞凋亡与增殖中的作用

流行病学研究表明 ,长期服用非甾体类抗炎药 (non -steroidanti-inflammatorydrugs,NSAIDs)可减少结直肠癌、食管癌、胃癌和胰腺癌等消化道肿瘤的危险性[1 ,2]。环氧化酶(cyclooxygenase ,COX) ,尤其是COX -2 ,有望成为抗癌药物的新靶点。COX -2参与肿瘤的发生发展 ,包括抑制凋     

环氧化酶-2(COX-2)抑制剂与肿瘤预防及治疗

环氧化酶－2（COX－2）抑制剂是选择性NSAIDs，因发现其在抑制大肠肿瘤发生、发展过程中具有一定作用而受到关注。近年来的研究发现，COX－2抑制剂不仅对大肠肿瘤而且对其他肿瘤亦有抑制作用。本文对COX－2抑制剂的预防和抗肿瘤作用及机制进行综述。     

环氧酶选择性抑制剂筛选模型的建立

目的　建立COX1和COX2活性检测模型,为COX2选择性抑制剂的筛选及抗炎作用机制研究提供可靠方法。方法　COX1抑制剂筛选模型用新生小公牛主动脉内皮细胞为酶源,6-keto-PGF_1α的含量变化评价化合物对COX1的抑制作用。COX2抑制剂筛选模型用激活的小鼠腹腔巨噬细胞,PGE₂含量变化评价化合物对COX2的抑制作用。结果　Indomethacin可显著地抑制COX1的活性, Meloxicam可显著地抑制COX2的活性, 其对COX2的选择性抑制作用高于前者。结论　COX1和COX2抑制剂筛选模型可用于COX2选择性抑制剂的筛选和机制研究。     

Cyclo-oxygenase-2 inhibitors: rationale and therapeutic potential for Alzheimer's disease

The newly introduced cyclo-oxygenase-2 (COX-2) inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs) have been established as effective agents in treating arthritic conditions, while greatly reducing the gastrointestinal adverse effects of traditional NSAIDs. There are expectations that NSAIDs will be useful in the treatment of Alzheimer's disease (AD), and that COX-2 inhibitors might have a role. However, a recently reported clinical trial of a COX-2 inhibitor in AD indicated that it was neither protective nor did it accelerate the decline. The expectations were based on pathological evidence of inflammatory changes associated with AD lesions and epidemiological evidence of a reduced prevalence of AD in populations taking NSAIDs. They were supported by preliminary evidence showing efficacy of NSAIDs in treating patients with AD. These data are based on the use of traditional NSAIDs. Whether COX-2 inhibitors would be similarly effective was uncertain since COX-2 is constitutively expressed in neurons. Animal experiments suggest that COX-2 may be performing adaptive functions associated with normal neurons and protective functions associated with stressed neurons. These results emphasise that the appropriate target for NSAID trials in AD is COX-1, but they also indicate that there would be no contraindication to the use of those traditional NSAIDs which have mixed COX-1/COX-2 inhibiting activity.     

COX-2 and Alzheimer's disease: potential roles in inflammation and neurodegeneration

Epidemiological and clinical data suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are beneficial in the treatment and prevention of Alzheimer's disease (AD). NSAIDs act by inhibiting cyclooxygenase, an enzyme that occurs in constitutive and inducible isoforms, known respectively as COX-1 and COX-2. Recognition that COX-2 plays a key role in inflammation led to the hypothesis that COX-2 might represent the primary target for NSAIDs in AD, consistent with inflammatory processes occurring in AD brain. This review highlights recently gathered evidence leading to a more complex view of the role of COX-2 in AD, including evidence that COX-2 directly contributes to neuronal vulnerability. Consideration of these roles is critical for the rational implementation of NSAID therapy in AD.     

COX-2 and Alzheimer’s disease: potential roles in inflammation and neurodegeneration

Epidemiological and clinical data suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are beneficial in the treatment and prevention of Alzheimer’s disease (AD). NSAIDs act by inhibiting cyclooxygenase, an enzyme that occurs in constitutive and inducible isoforms, known respectively as COX-1 and COX-2. Recognition that COX-2 plays a key role in inflammation led to the hypothesis that COX-2 might represent the primary target for NSAIDs in AD, consistent with inflammatory processes occurring in AD brain. This review highlights recently gathered evidence leading to a more complex view of the role of COX-2 in AD, including evidence that COX-2 directly contributes to neuronal vulnerability. Consideration of these roles is critical for the rational implementation of NSAID therapy in AD.     

Are rofecoxib and celecoxib safer NSAIDS?

NSAIDs work by inhibiting the enzyme cyclo-oxygenase (COX), responsible for prostaglandin synthesis. This enzyme exists in two isoforms, COX-1 and COX-2. Inhibition of COX-1 is thought to be the main cause of the gastrointestinal unwanted effects of NSAIDs, whilst inhibition of COX-2 results in anti-inflammatory effects. [symbol: see text]Rofecoxib (Vioxx--MSD) and [symbol: see text]celecoxib (Celebrex--Searle) have been developed as selective inhibitors of COX-2. Rofecoxib is licensed for the symptomatic treatment of osteoarthritis, but not for rheumatoid arthritis. The manufacturer claims that "in clinical studies rofecoxib inhibits COX-2 but not COX-1", has "the power of high-dose NSAIDs--diclofenac and ibuprofen" and "superior GI safety profile compared to conventional NSAIDs". Celecoxib is licensed for symptom relief in osteoarthritis and rheumatoid arthritis. The manufacturer claims that celecoxib has "comparable efficacy and superior GI tolerability when compared to diclofenac or naproxen". Here, we review rofecoxib and celecoxib and consider whether they are safer than conventional NSAIDs.     

Dual COX-inhibitors: the answer is NO?

Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) are a new class of anti-inflammatory agents obtained by adding an NO releasing moiety to existing NSAIDs. They have also christened as COX inhibiting NO-donating drugs (CINOD). Preclinical and clinical studies suggest that CINOD inhibit COX-1 and COX-2 activities while cause less adverse effects on gastrointestinal tract in comparison to conventional NSAIDs and coxibs and reduce systemic blood pressure. A different class of NO-donating drugs has been obtained by coupling NO to aspirin. These NO-releasing aspirins are new chemical entities that maintain and possibly expands the pharmacological properties of aspirin, but spare the gastrointestinal mucosa. Animal studies have shown that CINOD and NO-aspirins maintain gastric mucosal blood flow and reduce leukocyte-endothelial cell adherence.     

Gastrointestinal effects of COX-2 inhibitors

The developing popularity of non-steroidal anti-inflammatory drugs (NSAIDs) over the last 100 years has been paralleled by an increase in associated complications, particularly affecting the gastrointestinal (GI) tract [1]. Over this period, there have been several attempts to develop less toxic NSAIDs, most of which have been unsuccessful. Since the discovery that the enzyme cyclooxygenase (COX) exists as two isoforms, the largely constitutive COX-1 and the mainly inducible COX-2, much interest has centred on the development of drugs capable of selectively inhibiting COX-2. Early studies that investigated specific COX-2 inhibitors (with no effect on the COX-1 isoform over the whole range of concentrations achieved in clinical usage) are encouraging, as they demonstrate that these drugs have fewer effects on gastroduodenal mucosa than standard NSAIDs given at equivalent doses. Further clinical experience with these agents outside trial settings and additional studies to assess the role of COX-2 when induced in the GI tract are needed, before such agents can be safely recommended for widespread prescribing.     

Gastrointestinal effects of COX-2 inhibitors

The developing popularity of non-steroidal anti-inflammatory drugs (NSAIDs) over the last 100 years has been paralleled by an increase in associated complications, particularly affecting the gastrointestinal (GI) tract [1]. Over this period, there have been several attempts to develop less toxic NSAIDs, most of which have been unsuccessful. Since the discovery that the enzyme cyclooxygenase (COX) exists as two isoforms, the largely constitutive COX-1 and the mainly inducible COX-2, much interest has centred on the development of drugs capable of selectively inhibiting COX-2. Early studies that investigated specific COX-2 inhibitors (with no effect on the COX-1 isoform over the whole range of concentrations achieved in clinical usage) are encouraging, as they demonstrate that these drugs have fewer effects on gastroduodenal mucosa than standard NSAIDs given at equivalent doses. Further clinical experience with these agents outside trial settings and additional studies to assess the role of COX-2 when induced in the GI tract are needed, before such agents can be safely recommended for widespread prescribing.     

Cyclooxygenase-2 selective inhibitors

The identification of two cyclooxygenase (COX) enzymes has been a tremendous advance in understanding the role of prostaglandins in inflammation and the actions of nonsteroidal antiinflammatory drugs (NSAIDs). COX-1 activity appears to be related to "constitutive" or "housekeeping" functions in the gastric mucosa, kidney and platelets. COX-2 activity is "inducible" and generally occurs in response to a specific stimulus to enhance inflammatory actions. Current NSAIDs inhibit both COX-1 and COX-2, although the clinical benefit of NSAIDs appears to be associated with inhibition of COX-2 activity. The inhibition of COX-1 activity by NSAIDs is related to adverse side effects in general, particularly gastrointestinal toxicity. Recently, COX-2 selective inhibitors have been developed. Current data would suggest that by inhibiting COX-2 action, these agents may have efficacy similar to that of standard NSAIDs and that by not inhibiting COX-1 activity, they may have less toxicity than standard NSAIDs. Thus, these actions indicate that COX-2 selective inhibitors will have similar clinical efficacy to the traditional NSAIDs with fewer adverse side effects.     

Toxicity of human THP-1 monocytic cells towards neuron-like cells is reduced by non-steroidal anti-inflammatory drugs (NSAIDs).

There is mounting evidence that inflammatory processes, including activation of microglia, are upregulated in Alzheimer's disease. The importance of this phenomenon is indicated by multiple epidemiological studies showing that patients taking non-steroidal anti-inflammatory drugs (NSAIDs) have a substantially reduced prevalence of Alzheimer's disease. The pharmacological actions of anti-inflammatory drugs in brain are still uncertain. As a step towards identifying key pharmacological targets, we developed a neurotoxicity assay based on the property of supernatant media from stimulated human monocytic THP-1 cells to cause human neuroblastoma cell death. Similar neurotoxicity was observed when postmortem human microglia were substituted for THP-1 cells, establishing the validity of the assay for simulating neurotoxicity in human brain. A combination of lipopolysaccharide and interferon-gamma was used to activate the THP-1 cells. NSAIDs were effective in inhibiting neurotoxicity by this assay, while steroidal anti-inflammatories and propentofylline had no effect. The neuroprotective potency of NSAIDs appeared to be unrelated to their selective ability to inhibit cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2). It is suggested that inhibition of monocyte cytotoxicity might be responsible for the apparent beneficial effects of NSAIDs in Alzheimer's disease.     

Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.