非甾体抗炎药物研究进展

非甾体抗炎药(NSAIDs)包括传统的非甾体类抗炎药(COX-1抑制剂)和非传统的非甾体类抗炎药(COX-2抑制剂).论文分析了国内外市场状况,并指出临床应用所存在的问题.介绍了常用非甾体抗炎药的作用机制,总结了常用抗炎药不良反应,提出了应用时应注意的事项.     

解热镇痛药的发展概况

解热镇痛类药物包括传统的非甾体类抗炎药(COX-1抑制剂)、非传统的非甾体类抗炎药(COX-2抑制剂和一氧化氮释放型NSAIDs)。文章分析其国内外市场状况,并指出临床应用所存在的问题。总结了常用解热镇痛药的不良反应,提出了应用时应注意的事项。预计在今后的一段时期内,研究COX-2选择性抑制剂,发现新结构类型的高活性化合物仍是主攻方向,而且开发NO-NSAIDs也会成为降低NSAIDs的不良反应,增加其疗效的途径之一。     

抗炎药物及作用机理最新研究进展

抗炎药主要包括非甾体类抗炎药、甾体类抗炎药和中药。由于传统的抗炎药选择性较差,副作用明显,临床应用受到很大限制。近年来,随着人们对炎症机制认识的不断深入及分子生物学技术的广泛应用,一些疗效好、副作用小的新型抗炎药相继问世,应用于临床。作者主要对上述3种抗炎药物及其作用机理在近几年来的研究进展作一探讨分析。     

蒲公英提取物对急性肺损伤小鼠iNOS、COX-2mRNA及NF-kB(p65)蛋白表达的影响

研究蒲公英提取物对急性肺损伤(ALI)小鼠炎症介质NO和PGE2的限速酶iNOS和COX-2 mRNA及核转录因子NF-kB (p65)蛋白表达的影响,初步探讨其对ALI小鼠的保护作用机制.采用逆转录聚合酶链式反应(RT-PCR)法检测iNOS和COX-2的mRNA表达,Western-blot检测NF-kB (p65)的表达.结果表明蒲公英提取物抑制了ALI小鼠肺组织中iNOS、COX-2 mRNA及NF-kB蛋白的表达,分析其对ALI小鼠的保护作用可能通过此途径完成.     

美洛昔康在猪场临床上的应用

非甾体抗炎药（Nonsteroidal anti-inflammatory drugs,NSAIDs）是一类具有抗炎与镇痛作用的药物,作为改善炎性症状和缓解疼痛的理想药物,在临床上已广泛应用。中国现有兽用NSAIDs品种单一、副作用明显,迫切需要开发引进有更好疗效和较小副作用的新药。     

非甾体抗炎药在猫临床疼痛管理中的应用

疼痛是猫常见且多发的问题,诱发原因很多。近几年,随着国内外兽医对宠物猫的慢性疼痛问题以及临床中疼痛管理日益重视,疼痛管理已成为临床兽医必须面对的重要课题之一。非甾体抗炎药因其解热、抗炎和镇痛的特性而逐渐被广泛应用于动物医学。国内有关非甾体类抗炎药在猫临床疼痛管理中的应用少见报道。主要就国外发表的一些关于猫长期使用非甾体抗炎药的相关文献进行综述,以期为非甾体抗炎药在猫临床疼痛管理中的进一步应用提供参考。     

氟尼辛葡甲铵——动物专用的解热镇痛消炎药

介绍了动物专用非甾体类抗炎药———氟尼辛葡甲铵的研究应用现状,包括其结构性状、药效学、药动学、毒副作用、临床应用及与其他非甾体类抗炎药比较等内容。     

蒲公英提取物对急性肺损伤小鼠iNOS、COX-2 mRNA及NF-κB(p65)蛋白表达的影响

研究蒲公英提取物对急性肺损伤(ALI)小鼠炎症介质NO和PGE2的限速酶iNOS和COX-2 mRNA及核转录因子NF-κB(p65)蛋白表达的影响,初步探讨其对ALI小鼠的保护作用机制。采用逆转录聚合酶链式反应(RT-PCR)法检测iNOS和COX-2的mRNA表达,Western-blot检测NF-κB(p65)的表达。结果表明蒲公英提取物抑制了ALI小鼠肺组织中iNOS、COX-2 mRNA及NF-κB蛋白的表达,分析其对ALI小鼠的保护作用可能通过此途径完成。     

兽用非甾体抗炎药的应用现状

动物疼痛和炎症可影响其健康状况、养殖场经济效益等,预防和治疗动物疼痛、炎症具有重要意义。非甾体抗炎药可以减少动物疼痛和炎症的发生。近几年对非甾体抗炎药在动物中的应用研究越来越多,同时非甾体抗炎药的一些新功能被发现。论文对兽医常用非甾体抗炎药物的应用研究进展做一综述,以期为非甾体抗炎药在动物中的合理使用以及进一步研究提供参考。     

抗炎中药作用机制新靶点研究－对cAMP-磷酸二酯酶活性的影响

抗炎药是目前临床上应用仅次于抗感染药的第二大类药物,除肾上腺皮质激素类和非甾体类抗炎药外,传统中药尤其是清热解毒类中药也是应用很广泛的抗炎药.合理使用抗炎中药具有抗炎效果好、毒副作用小等优点,且资源丰富,因此,用现代科学方法研究传统中药的抗炎机制与临床应用一直是新型抗炎药开发的热点.     

Ex vivo COX-1 and COX-2 inhibition in equine blood by phenylbutazone,flunixin meglumine,meloxicam and firocoxib: Informing clinical NSAID selection

Newer cyclo-oxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs), such as firocoxib, are proposed to reduce inhibition of cyclo-oxygenase-1 (COX-1) and avoid undesirable side effects, while continuing to inhibit inflammation associated with COX-2. However, COX selectivity is typically based on in vitro testing, which may not provide sufficient information critical for treatment selection. This study investigated the pharmacokinetics and ex vivo COX-1 and COX-2 inhibition of phenylbutazone, flunixin meglumine, meloxicam and firocoxib. Horses (n = 3) were administered one of the four drugs, in a randomised cross-over design, with 3-week washout periods. For each drug, three doses were given and sampling performed. Drug plasma concentrations, thromboxane B₂ (TXB₂) and prostaglandin E₂ (PGE₂) were determined. After one dose, TXB₂ and PGE₂ levels were significantly higher in horses administered firocoxib compared to flunixin meglumine. Following the third dose, TXB₂ levels in horses administered firocoxib and meloxicam were significantly higher compared to flunixin meglumine or phenylbutazone; all drugs reduced PGE₂ to a similar degree. The mean plasma half-lives were 5.97 ± 0.47, 4.74 ± 0.14, 8.24 ± 3.74 and 47.42 ± 7.41 h for phenylbutazone, flunixin meglumine, meloxicam and firocoxib, respectively. Firocoxib and meloxicam exhibited significantly less COX-1 inhibition compared to flunixin meglumine and phenylbutazone; all drugs inhibited COX-2. The plasma half-life of firocoxib was longer than the other NSAIDs, including meloxicam. Data from this study have important clinical relevance and should be used to inform practitioners’ drug selection of a COX-1 sparing or traditional NSAID and dose selection and to provide knowledge of the duration for the four NSAIDs studied.     

Development of in vitro assays for the evaluation of cyclooxygenase inhibitors and predicting selectivity of nonsteroidal anti-inflammatory drugs in cats

OBJECTIVE: To develop and validate in cats suitable in vitro assays for screening and ranking nonsteroidal antiinflammatory drugs (NSAIDs) on the basis of their inhibitory potencies for cyclooxygenase (COX)-1 and COX-2. ANIMALS: 10 cats. PROCEDURE: COX-1 and COX-2 activities in heparinized whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. For the COX-2 assay, blood was pretreated with aspirin. The COX-1 and COX-2 assays were standardized, such that time courses of incubation with the test compounds and conditions of COX expression were as similar as possible in the 2 assays. Inhibition of thromboxane B2 production, measured by use of a radioimmunoassay, was taken as a marker of COX-1 and COX-2 activities. These assays were used to test 10 to 12 concentrations of a COX-1 selective drug (SC-560) and of 2 NSAIDs currently used in feline practice, meloxicam and carprofen. Selectivities of these drugs were compared by use of classic 50% and 80% inhibitory concentration (ie, IC50 and IC80) ratios but also with alternative indices that are more clinically relevant. RESULTS: These assay conditions provide a convenient and robust method for the determination of NSAID selectivity. The S(+) enantiomeric form of carprofen was found to be COX-2 selective in cats, but meloxicam was only slightly preferential for this isoenzyme. CONCLUSIONS AND CLINICAL RELEVANCE: In vitro pharmacodynamic and in vivo pharmacokinetic data predict that the COX-2 selectivity of both drugs for cats will be limited when used at the recommended doses. This study provides new approaches to the selection of COX inhibitors for subsequent clinical testing.     

Cyclooxygenase (COX) inhibitors and the intestine

Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used for the treatment of pain and inflammation because of their inhibitory effects on cyclooxygenase (COX). For almost as long as NSAIDs have been in use, multiple adverse effects have been noted. Assessment of many of these adverse effects have been complicated because of the discovery of multiple splice variants of the cox gene, and a greater array of COX inhibitors, especially the COX-2 selective inhibitors have become available. Some of these adverse effects cannot be readily explained by the effect of these drugs on COX. This has sparked a new field of investigation into the COX-independent effects of the COX inhibitors. The major noncyclooxygenase targets of the COX inhibitors of particular relevance to inflammation and the gastrointestinal tract are phosphatidylinositol 3'-kinase Akt signaling, uncoupling of oxidative phosphorylation, PPARgamma, nuclear factor KB, mitogen activated protein kinases, and heat shock proteins.     

Preferential and non-selective cyclooxygenase inhibitors reduce inflammation during lipopolysaccharide-induced synovitis

Synovitis in horses is frequently treated by administration of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase isoforms (COX-1 and COX-2). Constitutively expressed COX-1 is involved in physiologic functions such as maintenance of gastric mucosal integrity, whereas COX-2 is up-regulated at sites of inflammation. Thus, COX-2 inhibitors reduce inflammation with reduced gastrointestinal side effects as compared to non-selective COX inhibitors. The objective of the present study was to compare the anti-inflammatory effects of the preferential COX-2 inhibitor etodolac with the non-selective COX inhibitor phenylbutazone in horses with lipopolysaccharide (LPS)-induced synovitis. Three groups of horses (n=6) received no treatment, phenylbutazone (4.4 mg/kg, IV, q12h), or etodolac (23 mg/kg, IV, q12h), respectively, 2-h following injection of LPS into one middle carpal joint. Synovial fluid was analyzed for white blood cell (WBC) count, and TXB2 and PGE2 levels. Phenylbutazone and etodolac significantly reduced WBC count 6 and 24-h following injection of LPS compared to untreated horses. In addition, both drugs significantly reduced PGE2 levels (P<0.05) 6-h following LPS injection, whereas the probable COX-1 prostanoid TXB2 was significantly reduced by phenylbutazone (P<0.05), but not etodolac. Etodolac may serve as a more selective anti-inflammatory agent than phenylbutazone for treatment of equine synovitis.     

The effects of cyclo-oxygenase inhibitors on bile-injured and normal equine colon

A potential adverse effect of cyclo-oxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) in horses is colitis. In addition, we have previously shown an important role for COX-produced prostanoids in recovery of ischaemic-injured equine jejunum. It was hypothesised that the nonselective COX inhibitor flunixin would retard repair of bile-injured colon by preventing production of reparative prostaglandins, whereas the selective COX-2 inhibitor, etodolac would not inhibit repair as a result of continued COX-1 activity. Segments of the pelvic flexure were exposed to 1.5 mmol/l deoxycholate for 30 min, after which they were recovered for 4 h in Ussing chambers. Contrary to the proposed hypothesis, recovery of bile-injured colonic mucosa was not affected by flunixin or etodolac, despite significantly depressed prostanoid production. However, treatment of control tissue with flunixin led to increases in mucosal permeability, whereas treatment with etodolac had no significant effect. Therefore, although recovery from bile-induced colonic injury maybe independent of COX-elaborated prostanoids, treatment of control tissues with nonselective COX inhibitors may lead to marked increases in permeability. Alternatively, selective inhibition of COX-2 may reduce the incidence of adverse effects in horses requiring NSAID therapy.     

Sparing the gut: COX-2 inhibitors herald a new era for treatment of horses with surgical colic

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage a wide variety of conditions in horses, including management of colic. Flunixin meglumine is by far the most commonly used drug in the control of colic pain and inflammation and has become a go-to for not only veterinarians but also horse-owners and nonmedical equine professionals. NSAID use, however, has always been controversial in critical cases due to a high risk of adverse effects associated with their potent cyclo-oxygenase (COX) inhibition. There are two important COX isoenzymes: COX-1 is generally beneficial for normal renal and gastrointestinal functions and COX-2 is associated with the pain and inflammation of disease. Newer selective NSAIDs can target COX-2-driven pathology while sparing important COX-1-driven physiology, which is of critical importance in horses with severe gastrointestinal disease. Emerging research suggests that firocoxib, a COX-2-selective NSAID labelled for use in horses, may be preferable for use in colic cases in spite of the decades-long dogma that flunixin saves lives.     

Histopathology and oxidative stress analysis of concomitant misoprostol and celecoxib administration

Nonsteroidal anti-inflammatory drugs (NSAIDs), non-selective or selective inhibitors of cyclooxygenase (COX-1 and -2), reduce pain and inflammation associated with arthritic diseases. Celecoxib, a COX-2-selective inhibitor providing decreased gastric injury relative to non-selective NSAIDs, is commonly prescribed. Misoprostol, a prostaglandin analog, supplements NSAID-inhibited prostaglandin levels. As concomitant celecoxib and misoprostol administration has been shown to intensify renal adverse effects, this article examined the influence of concomitant administration on hepatic histopathology, oxidative stress, and celecoxib concentration. On days 1 and 2, rat groups (n = 6) were gavaged twice daily (two groups with vehicle and two groups with 100 μg/kg misoprostol). From day 3 to day 9, one celecoxib dose (40 mg/kg) replaced a vehicle dose of one group and one group received celecoxib in addition to misoprostol. Livers were harvested on day 10. No hepatic abnormalities were observed denoting a lack of influence by either drug. Also no change in mean biomarker levels was detected. The changes in hepatic celecoxib concentration in the misoprostol-receiving group compared to control were not significant. Thus misoprostol does not influence hepatic celecoxib effects in terms of histopathology, oxidative stress, or celecoxib concentration level at the dosage and duration examined.