关节炎药物或增加卒中死亡风险

日前,Neurology杂志上的一篇研究报告称,一种用于治疗关节炎和疼痛的常用药物或许可以增加个体因卒中死亡的风险。来自奥胡斯大学的研究人员检测的药物都是具有抑制环氧化酶-2(COX-2)作用的非甾体类抗炎药(NSAIDs),如双氯芬酸、依托度酸、萘丁美酮和美洛昔康。同时,研究人员对昔布类的新药也进行了检测,如选择性NSAIDs(COX-2抑制剂)塞来考昔和罗非昔布;另外,也对非选择性的NSAIDs类药物进行了研究,包括常见的布洛芬和萘普生等止痛药。     

第二代环氧酶-2特异性抑制剂的研究进展

为降低NSAIDs类药物的典型胃肠道不良反应，人们开发了选择性更高的第二代环氧酶-2(COX-2)特异性抑制剂。已开发的代表性化合物有戊地昔布、帕瑞昔布、依地昔布和氯美昔布等。临床试验证实，这些药物具有可靠的抗炎和止痛作用，其中帕瑞昔布作为第一个注射用NSAIDs类药物，可用于治疗手术后疼痛。本文综述该领域的研究进展。     

新型非甾体抗炎药作用靶环氧酶—2研究进展

非甾体抗炎药（NSAIDs)具有解热、镇痛、抗炎和抗风湿等作用。长期服用NSAIDs的人群中约有20%出现胃肠道不良反应,研究表明,NSAIDs的抗炎、解热镇痛作用与抑制环氧酶-2（COX-2）的活性有关,而其主要不良反应与抑制COX-1的活性有关,因此,开发特异性COX-2抑制剂已成为研究新一代NSAIDs的热点,本文对COX-2的基因表达调控、抑制剂筛选模型及选择性抑制剂的研究进行了综述。     

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…     

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。     

帕瑞昔布对腹腔镜胆囊切除术患者术后镇痛效果的临床观察

帕瑞昔布钠是新一代解热镇俑抗炎药,与传统的非选择性非甾体类抗炎药不同,帕瑞昔布钠是高选择性的环氧化酶-2(COX-2)抑制剂,治疗剂量不抑制COX-1,静脉注射或肌肉注射后发挥较强镇痛作用的同时,对胃肠道、肾脏及血小板的不良反应极小.     

昔布类药物的临床安全性

昔布类药物即高选择性COX-2抑制剂,通过选择性抑制COX-2,阻断花生四烯酸合成前列腺素而发挥抗炎镇痛作用,可减少传统NSAID药物消化系统的不良反应,主要品种有罗非昔布、塞来昔布、伐地昔布、帕瑞昔布、依托昔布及卢米昔布等。其中罗非昔布(万络)在2004年9月由于心血管不良反     

选择性环氧合酶-2抑制剂体外筛选模型的建立

目的:建立选择性环氧合酶-2(COX-2)抑制剂筛选模型。方法:以脂多糖(LPS)为刺激剂刺激大鼠腹腔巨噬细胞产生前列腺素E2(PGE2),采用放免法确定最佳刺激浓度和时间,以选择性COX-2抑制剂戊地昔布和达布非隆(darbufelone)为阳性对照药验证实验模型。结果:达布非隆和戊地昔布对COX-2和COX-1的半数抑制浓度(IC50)的比值分别为3．175×10-4和3．576×10-3。结论:本实验建立的COX-2抑制剂筛选模型比较灵敏,可靠,可用于选择性COX-2抑制剂的筛选。     

万络事件及COX-2抑制剂心血管安全性的最新评估

万络(罗非昔布)为非甾体抗炎药,是环氧化酶-2(COX-2)选择性抑制剂,通过选择性地抑制COX-2阻断花生四烯酸合成前列腺素而发挥抗炎镇痛作用。自塞来昔布(西乐葆)和罗非昔布(万络)分别于1998年和1999年上市后,COX-2选择性抑制剂发展迅速,伐地昔布、依托昔布、帕瑞昔布等新产品相继上市。由于这类药物现已成为治疗风湿性关节炎的主要药物,且其胃肠道不良反应如穿孔、溃疡、出血的风险据称低于非选择性COX抑制剂,从而使万络等药物广泛应用于临床。然而,近年的新数据显示万络有严重心血管事件风险(包括心脏病发作和心肌梗死风险)。为此,默克…     

昔布类药物的临床安全性

昔布类药物即高选择性COX-2抑制剂,通过选择性抑制COX-2,阻断花生四烯酸合成前列腺素而发挥抗炎镇痛作用[1],可减少传统NSAID药物消化系统的不良反应,主要品种有罗非昔布、塞来昔布、伐地昔布、帕瑞昔布、依托昔布及卢米昔布等.其中罗非昔布（万络）在2004年9月由于心血管不良反应撤市,引起人们对昔布类药物安全性的争论,为客观评价昔布类药物的临床安全性,现综述近年来国内外关于该类药物的文献和报道,分别对以上几种昔布类药物总结如下.     

COX-2 and the kidney

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation. Nonselective NSAIDs inhibit both cyclooxygenase (COX)-1 and COX-2. Nephrotoxicity of nonselective NSAIDs has been well documented. The effects of selective COX-2 inhibitors on renal function and blood pressure are attracting increasing attention. In the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in the mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow. Similar to nonselective NSAIDs, inhibition of COX-2 may cause edema and modest elevations in blood pressure in a minority of subjects. COX-2 inhibitors may also exacerbate preexisting hypertension or interfere with other antihypertensive drugs. Occasional acute renal failure has also been reported. Caution should be taken when COX-2 inhibitors are prescribed, especially in high-risk patients (including elderly patients and patients with volume depletion).     

COX-2 and the kidneys

The kidney is the second most frequent target of serious adverse effects of non-steroidal antiinflammatory drugs (NSAIDs). The renal side effects of NSAIDs related to inhibition of cyclooxygenase (COX) comprise reduction in renal blood flow (RBF) and glomerular filtration rate (GFR), sodium/water retention, water intoxication and hyperkalemia. The discovery of two COX-isoenzymes, a constitutive COX-1, serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for proinflammatory prosta noid production, led to the development of new NSAIDs: Preferential and specific COX-2 inhibitors, promising minimal NSAID-typical toxicity with equivalent efficacy. However, we learned that there is no clear distinction in "physiologic" constitutive COX-1 and "inflammatory" inducible COX-2. This is particular true for the kidney of humans and other mammalians, where COX-2 was found constitutively in meaningful amounts. Animal experiments and clinical trials with preferential and specific COX-2 inhibitors revealed that COX-2 is the critical enzyme for sodium excretion, renin release and likely antagonism of antidiuretic hormone. Additionally, a significant role of COX-2 for nephro genesis is suggested. For renal hemodynamics the given evidence point to COX-1 as the predominant enzyme, but further investigations are required. In summary, the gain of renal safety by use of preferential or specific COX-2 inhibitors is small or negligible with respect to sodium retention, hyperkalemia and probably water intoxication. These drugs may be advantageous regarding renal perfusion, but presently the same precautions as for conventional NSAIDs must be used.     

Carbonic anhydrase inhibition: insight into non-COX-2 pharmacological effect of some coxibs

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described adverse drug reactions (ADRs) limit their use. These drugs act via the inhibition of cyclooxygenase (COX) enzyme of which at least two isoforms were described: COX-1 which plays important roles in homeostatic processes such as thrombogenesis and homeostasis of the gastrointestinal tract and kidneys and COX-2 expressed in pathological conditions such as inflammation or cancer proliferation. Selective COX-2 inhibitors or "coxibs" were initially developed as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of non specific NSAIDs. However, this class of drug did not fulfill all their promises. Indeed, numerous unexpected side effects have limited their use and some of them have been withdrawn or suspended from the market for different safety reasons including cardiovascular, hepatic and skin adverse reactions. For instance, cardiovascular warnings have been applied to the whole class of coxibs and more recently for all classical NSAIDs as well. However, differences in the chemical structures should be taken into consideration in order to discriminate between coxibs and the development of some ADRs of which renal events and hypertension. The aim of this paper is to focus on the differences in chemical structures of all marketed COX-2 inhibitors and their unexpected effects on carbonic anhydrase in order to provide non-COX-2 mechanistic insights into some of the differences observed between coxibs.     

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.     

Gastrointestinal sparing anti-inflammatory drugs--COX-2 selective inhibitors and NO-releasing NSAIDs

The use of NSAIDs is associated with a wide array of alterations in the gastrointestinal integrity and function. Various approaches have been taken to develop NSAIDs with reduced gastrointestinal toxicity, and few have successfully reduced the incidence of adverse reactions. These include COX-2 selective inhibitors and NO-releasing NSAIDs. Much has been written about the potential of COX-2 inhibitors as antiinflammatory agents that lack the gastrointestinal side effects of traditional NSAIDs. COX-2 expression is most evident at sites of inflammation, while COX-1 accounts for most of the PG synthesis in the normal gastrointestinal tract. However, there are distinct examples of circumstances in which COX-2-derived PGs play a role in the maintenance of the mucosal integrity, and the differentiation of COX-1 and COX-2 is not quite as clear as has been suggested. On the other hand, the rational behind the NO-releasing NSAIDs is that NO released from the derivatives exerts beneficial effects on the gastrointestinal mucosa. The present article overviews the roles of COX and NO in housekeeping functions of the gastrointestinal mucosa in various circumstances and the effects of gastrointestinal sparing NSAIDs, such as COX-2 selective inhibitors and NO-releasing NSAIDs, on the ulcerogenic and healing responses in the gastrointestinal mucosa.     

Efficacy of the newest COX-2 selective inhibitors in rheumatic disease

Non-steroidal antiinflammatory drugs (NSAIDs) are standard treatment for the pain and inflammation associated with arthritis. Traditional NSAIDs and cyclooxygenase-2 (COX-2) selective inhibitors exhibit comparable efficacy, with different safety profiles. Traditional NSAIDs are associated with an increased risk of serious gastrointestinal (GI) adverse events versus COX-2 selective inhibitors, and chronic use frequently necessitates adjunctive therapy with gastroprotective agents. COX-2 selective inhibitors are often used in preference to avoid these GI adverse events. Recent studies have raised the concern that COX-2 selective inhibitors and traditional NSAIDs appear to be associated with a higher incidence of thrombotic cardiovascular events versus placebo. The key in prescribing these agents is for the physician to take a proactive approach to patient management and evaluation of GI and cardiovascular risk factors. This review examines the role of the newest COX-2 selective inhibitors, etoricoxib and lumiracoxib, in treating rheumatic disease.     

COX-2 inhibitors vs. NSAIDs in gastrointestinal damage and prevention

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit production of protective gastric mucosal prostaglandins and also have a direct topical irritant effect. In some patients this results in dyspepsia and development of gastroduodenal erosions and ulceration. The risk of ulcer complications, such as bleeding, perforation and death is increased approximately 4-fold in NSAID users. Patients at high risk of ulcer complications include the elderly, those taking anticoagulants, steroids and aspirin, those with a previous history of peptic ulceration and patients with concomitant serious medical problems. The interaction of NSAIDs with Helicobacter pylori (the major cause of peptic ulceration in non-NSAID users) is controversial and some studies suggest that H. pylori infection may even protect against NSAID-induced ulceration. Selective inhibitors of the inducible cyclooxygenase-2 (COX-2) enzyme spare COX-1 in the gastric mucosa and, hence, do not inhibit production of mucosal prostaglandins. COX-2-selective inhibitors are associated with a significant reduction in gastroduodenal damage compared with traditional NSAIDs. Proton pump inhibitors (PPI) are probably the best agents for healing and prevention of NSAID-induced ulcers. Preliminary studies suggest that COX-2 selective inhibitors, like traditional NSAIDs, may prevent lower gastrointestinal cancer. Further studies are needed but they may be useful in individuals at high risk of certain types of lower gastrointestinal malignancy with increased gastrointestinal tolerability and safety.     

The role of COX-2 in acute pain and the use of selective COX-2 inhibitors for acute pain relief

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain. Cyclooxygenase (COX) enzyme is of particular interest because it is the major target of NSAIDs. Although NSAIDs are remarkably effective in the management of pain and inflammation, their use is limited by several adverse effects including gastrointestinal bleeding and ulceration, impaired renal function, and inhibition of platelet aggregation. Discovery of a second cyclooxygenase, COX-2, led to the hypothesis that NSAID side effects could be decreased, as the inhibition of COX-2 is more directly implicated in ameliorating inflammation while the inhibition of COX-1 is related to adverse effects in the GI tract. This stimulated the development of selective COX-2 inhibitors (coxibs) that are better tolerated than nonselective NSAIDs but comparable in analgesic efficacy. This article provides an overview on the therapeutic use of selective COX-2 inhibitors for relief of acute pain, largely based on clinical trials in patients undergoing the surgical removal of impacted third molars, with focus on analgesic efficacy and the potential safety associated with their use compared to dual COX-1/COX-2 inhibitors.     

The second generation of COX-2 inhibitors: what advantages do the newest offer?

The discovery of two cyclooxygenase (COX)-isoenzymes, a constitutive COX-1, serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for proinflammatory prostanoid production, led to the development of new non-steroidal anti-inflammatory drugs (NSAIDs), the selective COX-2 inhibitors, promising minimal NSAID-typical toxicity with full anti-inflammatory efficacy. So far, the strategy of selective COX-2 inhibition has been successful. Selective COX-2 inhibitors have significantly less gastrotoxicity and no effects on platelet aggregation. However, with regard to renal adverse events, selective COX-2 inhibitors do not offer a clinically relevant advantage over non-selective inhibitors. Moreover, concerns over the cardiovascular risk of selective COX-2 inhibitors have recently been raised. The second generation of COX-2 inhibitors with higher COX-2 selectivity was developed with the promise of further reduction of NSAID-typical adverse effects. The leading compounds are valdecoxib, parecoxib, etoricoxib and lumaricoxib. At the present time they have proven efficacy for the treatment of pain and inflammation. Parecoxib as a parenteral, highly selective COX-2 inhibitor has the potential to become the NSAID of choice for treatment of postoperative pain. In clinical trials, valdecoxib, parecoxib, etoricoxib and lumaricoxib have caused no more endoscopic ulcers than placebo. However, to date, no data on the clinically relevant endpoints perforation, symptomatic ulcer and bleeding are available. Furthermore, no definite conclusions on renal and cardiovascular safety are possible. Current evidence points to a marginal, if any, gain of safety compared with the first generation of COX-2 inhibitors. However, trials with the new COX-2 inhibitors offer the chance to address these open questions of highly selective COX-2 inhibition; that is, thrombogenic risk, sodium and water retention, and interference with tissue repair, in particular, healing of mucosal damage.     

Cyclooxygenase (COX)-2 selective inhibitors: aspirin, a dual COX-1/COX-2 inhibitor, to COX-2 selective inhibitors

Aspirin was developed as a non-steroidal anti-inflammatory drug (NSAID) in 1899. During the century after that, aspirin has been found to show its anti-inflammatory, analgesic and anti-pyretic activities by reducing prostaglandins biosynthesis through inhibition of cyclooxygenase (COX); and then COX was found to be constituted of two isoforms, constitutive COX-1 and inducible COX-2. Currently, novel NSAIDs, acting through selective inhibition of COX-2, that have efficacy as excellent as aspirin with significantly lower incidence of gastrointestinal adverse effects are available in America and some other countries, but not in Japan. Physiological and pathophysiological roles of COX-1 and COX-2 have been explained from studies in experimental animals, but there are many differences in species and diseases between animals and humans. Thus, physiological and pathophysiological roles of COX-2 were considered from the standpoint of clinical effects of the two latest COX-2 selective inhibitors, celecoxib and rofecoxib, on inflammation, pain, fever and colorectal cancer together with their adverse effects on gastrointestinal, renal and platelet functions; and the usefulness and limits of COX-2-selective inhibitors were discussed with the trends of new NSAIDs development.