COX-2特异性抑制剂的安全性与合理使用

COX-2(环氧合酶-2)特异性抑制剂是新一代解热镇痛抗炎药.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,可减轻传统非甾体抗炎药(NSAID)消化道系统的不良反应,又有抗炎镇痛作用。目前已在全球70多个国家上市,市场前景十分广阔。全球已上     

脂氧合酶和环氧合酶-2双重抑制剂dar-bufelone甲磺酸盐

非甾体抗炎药 ( NSAID)是临床上应用最广泛的一类治疗风湿病药物。目前已知环氧合酶 ( COX)存在 COX- 1和 COX- 2两种亚型。选择性 COX- 2抑制剂以其作用强、胃肠道刺激小等优良的药效学性质成为治疗风湿性炎症和疼痛的有效药物。目前已上市的 COX- 2抑制剂有尼美舒利 ( nimesulide)、美洛昔康 ( meloxicam)、rofecoxib和 celecoxib。在花生四烯酸 ( AA)代谢过程中由 5-脂氧合酶( 5- LOX)催化生成的白三烯类物质 ( LT)也是一类强的炎症介质。因此 ,寻找 COX和 5- LOX双重抑制剂成为抗风湿性药物研究的一个热点。darbufelone甲…     

5-脂氧合酶和结直肠癌关系的研究进展

结直肠癌是我国最常见的胃肠道恶性肿瘤之一,发病率仅次于食管癌和胃癌,且发病率和病死率呈逐年升高趋势.花生四烯酸代谢通路在肿瘤的发生发展中起着重要作用.环氧合酶(cyclooxygenase,COX)及脂氧合酶(lipoxygenase,LOX)是催化体内花生四烯酸代谢通路的两个关键酶,花生四烯酸可通过环氧合酶(COX)通路代谢,主要生成血栓素A2(TXA2)、前列环素(PGI2)、前列腺素E2(PGE2)、前列腺素D2(PGD2)、前列腺素F2α(PGF2α),参与多种疾病的发生;亦可通过脂氧合酶(LOX)途径生成具有生物活性的多种物质,如炎症介质HD4等.大量实验证明,脂氧合酶代谢途径中的代谢产物在肿瘤中表达升高,其表达水平与肿瘤的分期、分级、转移、预后生存相关,其代谢途径通过影响细胞的增殖、凋亡、血管生成、细胞的侵袭和迁移等机制参与肿瘤的发生发展.使用脂氧合酶抑制剂(lipoxygenase inhibitors)特别是5-脂氧合酶抑制剂(5-lipoxygenase inhibitors)可预防及抑制肿瘤的发生、发展.     

新型 非甾体抗炎药ML—3000

非甾体抗炎药(NASIDs)一般是通过抑制环氧合酶(COX)起作用,而COX为在花生四烯酸转变为可引起炎症的前列腺素和血栓素的代谢途径中的关键酶.     

抗类风湿性关节炎药Iguratimod

类风湿性关节炎药物的研发已有数10年历史,目前上市和尚处开发阶段的该类药物主要包括干扰花生四烯酸代谢的非甾体抗炎药（NSAIDs）、具抗炎和免疫调节活性的糖皮质激素、病症缓解性抗风湿药（DMARDs）及免疫调节剂。为了发现具更弱的胃肠道副作用和除抑制环氧合酶以外的新作用机制的抗炎药物,     

抗丙型肝炎病毒药物作用靶标和小分子抑制剂研究进展

针对发病率逐年增高的丙型肝炎,目前主要依靠利巴韦林和干扰素的联合用药加以控制症状,但在治疗同时伴有明显不良反应,而且至今仍无法治愈。因此,临床上迫切需要研发出新型抗丙型肝炎病毒(HCV)药物,并且随着HCV生物学研究的快速发展,对HCV的感染和复制有了更深入的了解,加速了新药研发进程。本文综述了抗HCV药物作用靶标和新型小分子抑制剂,重点对其抑制剂的化学结构、抗HCV活性和构效关系进行了相关总结。     

环氧合酶-2和5-脂氧化酶双重抑制剂的研究进展

传统的非甾体抗炎药和选择性环氧合酶-2(COX-2)抑制剂在治疗炎症过程中引发胃肠道及肾脏不良反应,制约了其临床应用。COX-2和5-脂氧化酶(5-LOX)双重抑制剂同时抑制前列腺素(PGs)和炎症介质白三烯类(LTs)的生物合成,比单一的抑制剂抗炎效果好、安全性高,是一类有发展前景的新型非甾体抗炎药。笔者简要介绍COX-2/5-LOX双重抑制剂的研究进展,并讨论其作用机制及构效关系     

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     

环氧合酶结合抑制剂的分子图形学研究

环氧合酶具有两种结构亚型,即环氧合酶－１和环氧合酶－２,环氧合酶－２选择性抑制剂的毒副作用低,是较好的非甾体抗炎药物。本文通过选择性抑制剂ＳＣ－５５８和非选择性抑制剂吲哚美辛分别与环氧合酶－１和２－进行对接,利用分子图形学,从定量和定性的角度阐明了抑制剂选择结合环氧合酶－１和２－的原因。     

以脂氧合酶为靶标的治疗前列腺癌的新方法

前列腺癌与其他癌症不同,它属于激素依赖性癌症,因而血管源性因子在其转移机制中有重要作用。无论是环氧合酶(COX)还是脂氧合酶(LOX)进行的花生四烯酸的代谢,在肿瘤的发展过程中都起着重要的作用。因而,使用COX抑制剂和LOX抑制剂不失为治疗前列腺癌的好办法。     

Recent development in the field of dual COX / 5-LOX inhibitors

Cyclooxygenases and lipoxygenase are key enzymes in the arachidonic acid metabolism. Dual inhibitors are drugs able to block both the COX and the 5-LOX metabolic pathways. Compared to COX or LOX pathways single inhibitors, dual inhibitors present at least two major advantages. First, dual inhibitors, by acting on the two major arachidonic acid metabolic pathways, possess a wide range of anti-inflammatory activities. Secondly, dual inhibitors appear to be almost exempt from gastric toxicity, which is the most troublesome side effect of non-selective COX inhibitors.     

Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways. Impact on inflammation and cancer

Eicosanoids are potent biologically active arachidonic acid-derived lipid mediators that are intimately involved in inflammation and cancer. Cyclooxygenase (COX), the key enzyme in prostaglandin (PG) biosynthesis, controls one of the major pathways of arachidonic acid metabolism and is the main target for non-steroidal anti-inflammatory drugs (NSAIDs). COX exists in two distinct isoforms, COX-1 and COX-2, the latter being primarily involved in inflammation and cell proliferation. For this reason, in recent years, selective COX-2 inhibitors, that achieve the same anti-inflammatory efficacy as traditional NSAIDs but minimize the risk of unwanted side-effects, have been developed. On the other hand, emerging information has appreciated the role of other arachidonic acid metabolic pathway (the 5-lipoxygenase (5-LO) pathway) in producing and maintaining inflammation. Moreover, it is now being perceived that COX-2 and 5-LO have converging functions not only in inflammation but also in cell proliferation and neo-angiogenesis. In this regard, there is evidence that COX-2 and 5-LO are co-expressed and up-regulated in a number of inflammatory and neoplastic disorders, and that COX-2 as well as 5-LO inhibitors have beneficial effects in inflammatory diseases and are being investigated as potential anticancer drugs. This review provides an overview and an update of the progress achieved in the knowledge of COX-2 and 5-LO pathways and their involvement in inflammation and cancer. It also proposes a model of integrated pharmacological intervention on these pathways and reviews the information available regarding the use of the novel dual COX-2/5-LO inhibitors that block both pathways equally well.     

PGE synthase inhibitors as an alternative to COX-2 inhibitors

NSAIDs and selective COX-2 inhibitors reduce the formation of prostanoids, particularly PGE2, to diminish inflammation. However, these drugs exhibit toxicities, including gastrointestinal bleeding and myocardial infarction. In cells, arachidonic acid is converted to PGE2 by the action of COX enzymes and terminal PGE synthase. This review discusses the problems associated with selective COX-2 inhibitors and describes the microsomal PGE synthase-1 enzyme, its regulation and role in inflammatory diseases, its known inhibitors, and its potential as an alternative target for the development of novel anti-inflammatory agents.     

Anti-inflammatory potential of 2-styrylchromones regarding their interference with arachidonic acid metabolic pathways

Cyclooxygenases (COXs) are the key enzymes in the biosynthesis of prostanoids. COX-1 is a constitutive enzyme while the expression of COX-2 is highly stimulated in the event of inflammatory processes, leading to the production of large amounts of prostaglandins (PGs), in particular PGE₂ and PGI₂, which are pro-inflammatory mediators.Lipoxygenases (LOXs) are enzymes that produce hydroxy acids and leukotrienes (LTs). 5-LOX metabolizes arachidonic acid to yield, among other products, LTB₄, a potent chemoattractant mediator of inflammation.The aim of the present work was to evaluate the anti-inflammatory potential of 2-styrylchromones (2-SC), a chemical family of oxygen heterocyclic compounds, vinylogues of flavones (2-phenylchromones), by studying their COX-1 and COX-2 inhibitory capacity as well as their effects on the LTB₄ production by stimulated human polymorphonuclear leukocytes (PMNL).Some of the tested 2-SC were able to inhibit both COX-1 activity and LTB₄ production which makes them dual inhibitors of the COX and 5-LOX pathways. The most effective compounds in this study were those having structural moieties with proved antioxidant activity (3′,4′-catechol and 4′-phenol substituted B-rings).This type of compounds may exhibit anti-inflammatory activity with a wider spectrum than that of classical non-steroidal anti-inflammatory drugs (NSAIDs) by inhibiting 5-LOX product-mediated inflammatory reactions, towards which NSAIDs are ineffective.     

Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality?

Background  

Nonsteroidal anti-inflammatory drugs (NSAIDs), conventional and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely used medications for the treatment of various inflammatory conditions. There is strong evidence of a possible association between the use of these drugs and the relapse of inflammatory bowel diseases (IBD).     

Anti-inflammatory drugs: new multitarget compounds to face an old problem. The dual inhibition concept.

In this short review we have tried to focus on some new relevant aspects of the pharmacological control of inflammation. The clinical availability of new drugs able to produce a selective inhibition of type 2 cyclooxygenase (COX-2), the enzyme thought to be mainly responsible for generating arachidonic-acid-derived inflammatory mediators, has been the origin of much hope. However, expectations of having an effective and completely safe non-steroidal anti-inflammatory drug (NSAID) have been only partially fulfilled. Emerging information has challenged some aspects of the original hypothesis indicating COX-2 as devoid of 'housekeeping' physiological functions. Moreover, the recently available clinical studies have indicated only a relatively small improvement in the tolerability of the newer 'selective' COX-2 inhibitors over the classical COX-1/COX-2 mixed type NSAIDs. The new appreciation of the role of other arachidonic acid derivatives, the leukotrienes (LTS), in producing and maintaining inflammation has generated considerable interest in drugs able to block LTS receptors or to produce a selective inhibition of 5-lipoxygenase (5-LO), the initial key enzyme of the leukotriene pathway. These drugs are now included among the effective therapies of asthma but appear, in the few clinical studies performed, to be an insufficient single therapeutic approach in other inflammatory diseases. Drugs able to block equally well both COX and 5-LO metabolic pathways (dual inhibitors) have been developed and experimentally evaluated in the last few years, but none are available on the market yet. The pharmacological rationale at the basis of their development is strong, and animal studies are indicative of a wide range of anti-inflammatory activity. What appears most impressive from the available studies on dual inhibitors is their almost complete lack of gastric toxicity, the most troublesome side effect of NSAIDs. The mechanism of the gastric-sparing properties of these drugs is not yet completely understood; however, it appears that leukotrienes significantly contribute to gastric epithelial injury particularly when these compounds represent the major arachidonic acid derivatives present in the gastric mucosa after inhibiton of prostanoid production.     

Molecular mechanisms involved in the regulation of prostaglandin biosynthesis by glucocorticoids

The anti-inflammatory properties of glucocorticoids are attributed in part, to their interference with prostaglandin synthesis. Phospholipases A₂ and cyclooxygenases, the key enzymes of prostaglandin biosynthesis, are targets of glucocorticoid action; the molecular mechanisms, however, are not yet understood in detail. Obviously, glucocorticoids can act at different levels of gene regulation depending on cell type and inducing stimulus. The current knowledge of glucocorticoid interference with phospholipase A₂ and cyclooxygenase expression is summarized. In comparison with other nonsteroidal anti-inflammatory drugs, glucocorticoids are unique inasmuch as they also inhibit cytokine synthesis and expression of other inflammation-related enzymes. Based on a more detailed understanding of glucocorticoid action, it may be possible to therapeutically exploit the anti-inflammatory effects and at the same time avoid the unwanted metabolic actions of these steroids.     

Interleukins in glioblastoma pathophysiology: implications for therapy

Despite considerable amount of research, the poor prognosis of patients diagnosed with glioblastoma multiforme (GBM) critically needs new drug development to improve clinical outcomes. The development of an inflammatory microenvironment has long been considered important in the initiation and progression of glioblastoma; however, the success of developing therapeutic approaches to target inflammation for GBM therapy has yet been limited. Here, we summarize the accumulating evidence supporting a role for inflammation in the pathogenesis of glioblastoma, discuss anti-inflammatory targets that could be relevant for GBM treatment and provide a perspective on the challenges faced in the development of drugs that target GBM inflammation. In particular, we will review the function of IL-1β, IL-6 and IL-8 as well as the potential of kinase inhibitors targeting key players in inflammatory cell signalling cascades such as JAK, JNK and p38 MAPK.     

New trends in dual 5-LOX/COX inhibition

Dual inhibitors are drugs able to block both the COX and the 5-LOX metabolic pathways. The interest of developing such compounds is supported by a large number of pharmacological studies. Compared to COX or LOX pathways single inhibitors, dual inhibitors present at least two major advantages. First, dual inhibitors, by acting on the two major arachidonic acid metabolic pathways, possess a wide range of anti-inflammatory activity. Secondly, dual inhibitors appear to be almost exempt from gastric toxicity, which is the most troublesome side effect of COX inhibitors. The mechanism of their gastric-sparing properties is not completely understood, although it has been demonstrated that leukotrienes significantly contribute to the gastric epithelial injury. Finally, both COX and LOX derivatives (prostanoids and leukotrienes, respectively) are involved in other diseases than inflammation such as cancer proliferation where the use of dual inhibitors could be an interesting approach.     

环氧合酶／5-脂氧合酶双重抑制剂的研究进展

非甾体类抗炎药(NSAID)广泛用于各种炎症的治疗。长期使用经典的NSAID会产生严重的副作用,尤其是胃肠道副作用。为避免经典的NSAID的副作用,开发出了选择性COX-2抑制剂,但长期使用选择性COX-2抑制剂对心血管系统有副作用。COX/5-LOX双重抑制剂通过同时阻断炎症介质前列腺素和白三烯的形成,产生协同的抗炎作用,有望提高疗效,同时避免COX抑制剂引发的副作用。本文对COX/5-LOX双重抑制剂的抗炎镇痛作用机制,以及研究现状进行综述。