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.     

COX-2 inhibitors

These three applications claim 4-fluoroalkyl-6-(4-alkylsulfonyl)phenylpyrimidine derivatives that are selective COX-2 inhibitors. The presence of an additional 5-alkyl substituent markedly attenuates their potency but both 4-alkylamino and 4-alkoxy substituted compounds are potent and selective COX-2 inhibitors in the absence of the 5-substituent.     

Potential utility of COX-2 inhibitors in chemoprevention and chemotherapy

Increased prostaglandin (PG) production is associated with many inflammatory pathophysiological conditions; it is derived from arachidonic acid by either of two enzymes: cyclooxygenase-1 or -2 (COX-1 or COX-2). In addition to its role in inflammation, recent work suggests COX-2 derived prostaglandins may play a pivotal part in the maintenance of tumour viability, growth and metastasis. In this review, we summarise the non-steroidal anti-inflammatory drug (NSAID) epidemiological evidence, studies demonstrating overexpression of COX-2 in multiple human tumours and the pharmacological evidence in animal models which also support this hypothesis. We also discuss the potential functional roles of COX-2 activity during tumourigenesis, and speculate on the mechanism by which COX-2 inhibitors may exert their anticancer effects.     

Profiles of COX-2 inhibitors: present and future

Cyclooxygenases are responsible for the biosynthesis of prostanoids, the overt presence of which is often associated with inflammation and pain. Since the discovery of COX-2 in the last decade, a myriad of selective COX-2 inhibitors and their pharmacological profiles have been witnessed. Pharmacological observations of selective inhibition of COX-2 often go beyond initial expectations. This review is an overview of issues on selective COX-2 inhibitors, which include gastrointestinal and cardiovascular safety, emerging therapeutic areas and differentiation in drug profiles expected to be addressed by future generation COX-2 inhibitors. This article also covers recent patents and papers on new COX-2 inhibitors published since 2002. Future generation COX-2 inhibitors are sure to be safer and meet better medical needs than the COX-2 inhibitors currently available for the treatment or prevention of broadly ranged COX-2-mediated disorders.     

COX-2 selective inhibitors: analysis of the renal effects

COX-2 selective inhibitors provide analgesia and blunt inflammation while also sparing the gastrointestinal tract from classic NSAID toxicity. Therapeutic effects are thought to result from inhibition of the inflammatory COX-2 isoform. Organ sparing is considered the result of preservation of homeostatic COX-1 enzyme function. Similar roles of the COX isoforms in the kidney would reduce NSAID-associated nephrotoxicity. However, human kidney tissue expresses COX-2 enzyme, suggesting a role for this isoform in maintenance of physiological renal processes. Available clinical data on the renal effects of COX-2 selective inhibitors in humans also demonstrate nephrotoxic potential.     

Characterization of eltenac and novel COX-2 selective thiopheneacetic acid analogues in vitro and in vivo

We assessed the effect of novel selective thiopheneacetic acids on cyclooxygenase isoenzymes in vitro and in vivo. Thiopheneacetic acid Eltenac and derivatives were investigated in this study. In human whole blood experiments these derivatives were potent inhibitors of COX-2 (IC(50)=0.02-0.4 microM) with less pronounced effect on COX-1 (IC(50)=0.15-5.6 microM). With COX-1/COX-2 ratios between 7.5- and 16-fold they are in the range of Celecoxib (13-fold). The parent drug Eltenac demonstrated no selectivity for COX-2. In a rat paw edema model, these compounds showed reduction of edema volume in the range of 36-45% at 10 mg/kg (Eltenac 52%, Diclofenac 51%). However, the compounds were superior to Diclofenac and Eltenac with respect to their ulcerogenic and gastrointestinal properties. Introduction of a nitrate-ester moiety to either Eltenac or a derivative did neither improve selectivity or potency in vitro, nor ulcerogenicity in vivo. Molecular modeling of selective thiopheneacetic acid derivatives to the active site of human COX-2 suggested similar binding properties as Lumiracoxib and Diclofenac. In summary, modification of Eltenac generates moderately selective COX-2 drugs in the range of Celecoxib with respect to potency and selectivity. The drugs showed potent anti-inflammatory properties and significant improvement of animal survival in a sub-chronical experimental set up. Thiopheneacetic derivatives are characterized by low pK(a) values, short microsomal half-lives and binding mode to COX-2 similar to Diclofenac and Lumiracoxib. These properties may also have an impact on the transient inhibition of COX-2-dependent prostacyclin, thereby being less associated with vascular complications.     

环氧合酶-2及其抑制剂在胰腺癌血管靶向治疗中的作用

胰腺癌的诊治目前仍是医学界的难题,血管生成是胰腺癌生长和转移的必要因素。环氧合酶(cyclooxygenase,COX)为花生四烯酸代谢过程中的关键酶,存在COX-1及COX-2两种同工酶,其中COX-2在胰腺癌的发生发展及胰腺癌血管生成中发挥重要作用。COX-2抑制剂可分为非选择性及选择性两种,两种COX-2抑制剂都对胰腺癌及其血管形成的发生与进展存在抑制作用,COX-2抑制剂抗肿瘤血管形成的机制可能是抑制血管内皮生长因子(VEGF)、缺氧诱导因子-1及基质金属蛋白酶(MMP)的表达、降低前列腺素(PGs)及其他血管生成因子的表达、促进内皮细胞凋亡、抑制内皮细胞侵袭力和影响一氧化氮合酶(NOS)的表达。     

Adverse drug reactions to nonsteroidal anti-inflammatory drugs, COX-2 inhibitors and paracetamol in a paediatric hospital

AIMS: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in children has rapidly escalated over the last 5 years in Australia. This is primarily as a result of the availability of ibuprofen as an over-the-counter preparation. Several recent, significant adverse drug reactions (ADRs) to NSAIDs, at the Royal Children's Hospital (RCH) in Melbourne, Australia prompted review of all of the RCH reactions reported to these agents over 5 years. METHODS: The ADR programme documents both spontaneously reported ADRs and ADRs identified by discharge coding. For this study, reported reactions to aspirin, celecoxib, ibuprofen, indomethacin, naproxen, paracetamol and rofecoxib, for the previous 5-year period, were retrieved from the hospital ADR database. RESULTS: Nineteen reports of ADRs to NSAIDs and six to paracetamol, in patients aged from 4 months to 22 years (median 10 years) were identified. Reactions were predominantly rash (n = 10), gastrointestinal (n = 5) and respiratory (n = 4) side-effects. These included reports of haematemesis with both celecoxib and ibuprofen. One patient died of severe acute exacerbation of asthma following initiation of rofecoxib. CONCLUSION: NSAID exposures are a significant cause of morbidity in children. Both nonselective NSAIDs and the newer COX-2 inhibitors were associated with significant drug reactions. The overall severity of these ADRs highlights the need for vigilant surveillance of ADRs in paediatrics, including both established and newer agents.     

COX-2抑制剂的临床应用

非甾体类抗炎药(NSAIDs)是当今世界各国广泛应用的一类药物,每天全世界约有3千万人使用,主要应用于类风湿关节炎、骨关节炎及其他类型的关节炎。目前选择性COX-2抑制剂除用于镇痛、抗炎、解热,还用于治疗帕金森病、口腔癌、结肠肿瘤、前列腺癌等。     

Synthesis and biological evaluation of novel imidazolone derivatives as potential COX-2 inhibitors

Three novel series of 2-(substituted phenyl)-4-(substituted arylidene)-imidazolone-5-(4H)-ones were derived from the corresponding oxazolones by condensation with different arylamines. Eleven of the synthesized compounds were selected and evaluated for their effect on carrageenan-induced rat paw edema. Compound 4b had the same efficacy as the reference standard (indomethacin), and compounds 3b, 3c, 4a, 4d and 9a showed good to excellent activities, with other compounds only weakly active. The potent compounds were evaluated for their inhibitory activities against COX-2-catalyzed PGE(2) production, with 4a, 4b and 3c showing strong inhibitory activity.     

选择性COX-2抑制剂的用药风险与新功用

综述近年来国内外有关选择性COX-2抑制剂的潜在用药风险及新功用的报道，为探讨该类药物的发展方向提供参考。选择性COX-2抑制剂是一类新型非甾体抗炎药，由于其胃肠毒性低而倍受关注，但潜在的心血管风险限制了其临床上的应用，此类药物的去留引起了极大争议。     

选择性 COX-2抑制剂引发心血管事件研究进展

通过对国内外选择性环氧化酶-2(COX-2)抑制剂致心血管事件的相关文献检索.分析和总结了此类药物引发心血管事件的毒理学、相关研究和药害事件.提示在使用 COX-2抑制剂时,应关注其心血管等方面存在的潜在风险,采用短期低剂量治疗方法,同时对患者心血管方面的生命体征进行定期监测.     

Synthesis and biological activity of annulated pyrazoles as selective COX-2 inhibitors. I.

A series of disubstituted 4,5-polymethylenepyrazoles were synthesized and evaluated their inhibitory activities against COX-2. Some compounds showed strong (0.3 nM) inhibitory activity on COX-2 and were found somewhat selective (up to 16) on COX-2 over COX-1.     

Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors

A new class of selective cyclooxygenase-2 (COX-2) inhibitors has been identified by high throughput screening. Structurally distinct from previously described selective COX-2 inhibitors, these benzopyrans contain a carboxylic acid function and CF3 functionality. The compound SC-75,416 is a representative of this class. A range if in vitro and in vivo tests were employed to characterize its potency and selectivity. Using human recombinant enzymes, this compound displays a concentration that provides 50% inhibition (IC50) of 0.25 microM for COX-2 and 49.6 microM for COX-1. A mutation of the side pocket residues in COX-2 to COX-1 had little effect on potency suggesting that these inhibitors bind in a unique manner in COX-2 distinct from COX-2 inhibiting diaryl heterocycles. Using rheumatoid arthritic synovial cells stimulated with interleukin-1beta (IL-1beta) and washed platelets the compound displayed IC50 of 3 nM and 400 nM respectively. Potency and selectivity was maintained but predictably right shifted in whole blood with IC50 of 1.4 microM for lipopolysaccharide (LPS) stimulated induction of COX-2 and >200 microM for inhibition of platelet thromboxane production. SC-75,416 is 89% bioavailable and its in vivo half life is sufficient for once a day dosing. In the rat air pouch model of inflammation, the compound inhibited PGE2 production with an effective dose that provides 50% inhibition (ED50) of 0.4 mg/kg, while sparing gastric prostaglandin E2 (PGE2) production with an ED50 of 26.5 mg/kg. In a model of acute inflammation and pain caused by carrageenan injection into the rat paw, the compound reduced edema and hyperalgesia with ED50s of 2.7 and 4 mg/kg respectively. In a chronic model of arthritis the compound demonstrated an ED50 of 0.081 mg/kg and an ED(80) of 0.38 mg/kg. In a model of neuropathic pain, SC-75,416 had good efficacy. This compound's unique chemical structure and effect on COX enzyme binding and activity as well as its potency and selectivity may prove useful in treating pain and inflammation.     

Intrathecally administered COX-2 but not COX-1 or COX-3 inhibitors attenuate streptozotocin-induced mechanical hyperalgesia in rats

Members of the cyclooxygenase (COX) family are known to catalyze the rate-limiting steps of prostaglandins synthesis and reported to be involved in neuropathic pain. Diabetic neuropathy is a type of neuropathic pain, though it is not clear if COX is relevant to the condition. Recently, spinal COX-2 protein was found to be increasing in streptozotocin-induced rats as compared to the constitutive expression. We attempted to determine which cyclooxygenase isoforms are involved in streptozotocin-induced mechanical hyperalgesia, which was induced by a single intraperitoneal injection of 75 mg/kg of streptozotocin. Intrathecal administrations of the COX-2 inhibitors SC-58125 (7-100 microg) and NS-398 (7-60 microg), as well as a high dose (100 microg) of the COX-1 inhibitor SC-560 attenuated hyperalgesia, whereas intrathecal administrations of a low dose (10 microg) of SC-560 and the COX-3 inhibitor acetaminophen (1-7 mg) did not. Further, intrathecal administration of SC-58125 (100 microg) did not produce an analgesic effect in normal rats. These results indicate that intrathecal administration of COX-2 inhibitors has an anti-hyperalgesic effect on streptozotocin-induced mechanical hyperalgesia and we concluded that spinal COX-2 is pivotal in streptozotocin-induced hyperalgesia.     

An analysis from clinico-epidemiological data of the principal adverse events from the COX-2 selective NSAID, nimesulide, with particular reference to hepatic injury

The safety of the cyclo-oxygenase-2 (COX-2) selective NSAID, nimesulide, has been evaluated from information (a) in clinical trials in osteoarthritis that have been performed in Europe as well as in earlier pilot studies that were performed in patients with rheumatoid arthritis in the USA, and (b) in post-marketing studies (PMS) that have been performed by the manufacturer since the introduction of the drug in Europe and some South American countries. Upon analysis there have been clear indications of elevation of liver enzymes being related to the drug in 3/753 patients who were investigated in clinical trials in osteoarthritis. The results of the analysis of adverse drug reactions (ADRs) in patients with osteoarthritis (which is the principal indication for the drug) in PMS showed that the greatest number of these were in the skin and appendages, digestive system and organs wherein metabolic effects were manifest. There was a relatively low number of reports of gastrointestinal ulceration and haemorrhage, and these observations are in agreement with published experimental studies in humans and laboratory animals. Recent reports of ADRs in the liver in 25 patients were analysed in detail. In many of the cases there was evidence of confounding disease (e.g. cancer, prior liver damage) or prior or concurrent intake of known hepatotoxic NSAIDs (diclofenac, aspirin). Often elevations of liver enzymes above the laboratory norms are the only indication of liver injury and this in many cases is variable. The major cases of elevated liver enzymes and other liver changes have been in elderly patients. This first extensive analysis of ADRs from a COX-2 selective NSAID, nimesulide, indicates that there is a relatively low incidence of ADRs especially in the gastrointestinal tract, while those in the liver are within or below the general incidence with other NSAIDs.     

Selectivity of NSAIDs for COX-2 and cardiovascular outcome

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) with increased selectivity for the cyclooxygenase-2 (COX-2) isoform reduce gastrotoxicity but may increase adverse cardiovascular events. METHODS: We searched the literature for studies that reported the odds ratio (OR) for such events following exposure to NSAIDs. RESULTS: For studies comparing NSAID use with no use, increased COX-2 selectivity was significantly related to cardiovascular risk (log OR) amongst observational studies (R = -0.34, P < 0.001) and randomized controlled trials (RCTs) (R = -0.56, P < 0.001). For studies comparing NSAIDs, difference in selectivity was related to risk for observational studies (R = -0.28, P = 0.005) but not for RCTs (R = -0.23, P = 0.15). CONCLUSIONS: Although increased COX-2 selectivity may reduce gastrotoxicity, this may be at the cost of increasing cardiovascular risk.     

选择性环氧合酶-2抑制剂的研究现状及进展

非甾体抗炎药（NSAIDs）是临床上应用非常广泛的一类药物，但严重的不良反应使其应用受到很大限制。研究已经发现，NSAIDs对炎症的有效治疗源干其对环氧合酶-2（COX-2）的抑制作用。综述了选择性COX-2抑制剂作用的分子基础、构效关系及其目前研究开发的现状和最新进展。     

COX-2 inhibitors with a methylsulfoxide pharmacophore

Novel methylsulfoxide analogues, of known selective cyclooxygenase-2 (COX-2) inhibitors, with a methylsulfone moiety are claimed as COX-2 inhibitors. The inhibitors are useful for the treatment of COX-2-mediated disorders comprising inflammation and inflammation-associated disorders. The clinical applicability for development of the claimed sulfoxide analogues as COX-2 inhibitors is eval-uated against the car-diovascular and gastrointestinal safety.