Non-steroidal anti-inflammatory drugs,aspirin and newly diagnosed colitis: a case-control study

BACKGROUND: There have been a number of reports of colitis following exposure to non-steroidal anti-inflammatory drugs (NSAIDs) and salicylates. AIM: To conduct a case-control analysis of new cases of colitis, with particular reference to the usage of NSAIDs and salicylates prior to the development of the disease. METHODS: One hundred and five consecutive new cases of colitis presenting to a single gastroenterologist were questioned about their recent usage of NSAIDs and salicylates. For comparison, the frequency of usage of these compounds was studied in two groups of 105 age- and sex-matched controls taken from hospital in-patients and community cases attending the Accident and Emergency Department. RESULTS: Of the 105 cases of colitis studied, 78 patients (74%) had been taking NSAIDs or salicylates prior to or during the development of their disease. By comparison, 20% of community controls were using NSAIDs or salicylates (P < 0.001) and 30% of hospital in-patients were taking these compounds (P < 0.001). Comparison of these frequencies with those of the colitis group gave odds ratios of 9.1 (4.5, 21.9) with the community controls and 6.2 (3.2, 13.5) with the hospital controls. CONCLUSIONS: In new patients presenting with colitis, there is a significantly high frequency of antecedent exposure to NSAIDs or salicylates, supporting the concept that these agents may be important in the pathogenesis of colitis.     

Gastrointestinal side effects of drugs

Drugs can have adverse effects on any part of the gastrointestinal (GI) tract from mouth to colon. It is essential that a detailed and accurate drug history is taken in patients presenting with GI complaints. Many drug-induced effects will regress or heal on cessation of treatment. NSAIDs are usually associated with gastric and duodenal ulcers but are also recognised to cause lichen planus in the mouth, oesophageal inflammation and strictures, and small bowel and colonic ulcers and strictures. A newer class of anti-inflammatory drugs, the cyclooxygenase-2 (COX-2)-selective inhibitors, have been developed and have a more favourable GI safety profile than standard NSAIDs. Acute diarrhoea, relapse of inflammatory bowel disease (IBD), microscopic colitis and acute pancreatitis are also induced by ingestion of standard NSAIDs. The calcium antagonists, phenytoin and cyclosporin, induce gum hyperplasia, particularly in patients with poor oral hygiene. Alendronate, a bisphosphonate, has been associated with development of oesophageal ulcers, and specific recommendations are now given to reduce this complication. Of the many different forms of colitis associated with drug ingestion, the most frequent is pseudomembranous colitis. This is a complication of antibiotics and is caused by the toxin produced by Clostridium difficile. Many drugs have been associated with the development of acute pancreatitis, although a definite cause and effect relationship has been shown for only a few drugs. These include didanosine, furosomide, corticosteroids, azathioprine and sodium valproate.     

The role of nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors on experimental colitis

The nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in the management of pain and inflammation. Unfortunately, they are associated with dose-dependent gastrointestinal (GI) adverse events ranging from dyspepsia to symptomatic and complicated ulcers. The mechanism of NSAID action is attributed to the cyclooxygenase (COX) inhibition. New anti-inflammatory drugs have been synthesized, such as selective COX-2 inhibitors, however, these drugs may present side effects, such as modification of the epithelial barrier. Inflammatory bowel disease (IBD) is a common chronic gastrointestinal disorder characterized by alternating periods of remission and active intestinal inflammation. A possible association between the use of NSAIDs and the relapse of IBD has been repeatedly suggested. For this reason, many studies are conducted with the use of COX-2 in experimental models. The objective of this review is to describe the role of NSAIDs and COX-2 inhibitors in different experimental models of colitis. We reviewed controlled trials, original articles, case reports and reviews. The role of selective inhibition of COX-2 in the inflammatory process and the course of experimental and human colitis is controversially discussed. In conclusion, the relative role of COX-2 selective inhibitors on human and experimental colitis remains to be explored. Thus, the use of COX-2 inhibitors in IBD should be considered with caution.     

Chronic use of non-steroidal anti-inflammatory drugs does not alter colonic mucosa of patients without diarrhoea

BACKGROUND: Several types of colitis can be NSAID-induced, but whether chronic use of NSAIDs alters colonic mucosa in patients without diarrhoea is not known. PATIENTS AND METHODS: Biopsy specimens of rectal mucosa were taken in six patients with rheumatoid arthritis without diarrhoea receiving NSAIDs (group 1, n=6). Patients with rheumatoid arthritis without diarrhoea not receiving NSAIDs (group 2, n=9), and patients undergoing surveillance colonoscopy (group 3, n=23) served as controls. In all patients from the three study groups, intraepithelial lymphocyte count and apoptotic cell count were assessed, and sub-epithelial collagen band thickness was measured. Leucocyte population of lamina propria was evaluated semi-quantitatively. HLA-DR and CD25 expression of mucosal cells was appreciated by immunohistochemistry. RESULTS: Intraepithelial lymphocyte count was in the normal range in all three group patients, and not statistically different between groups. Apoptotic epithelial cell count was not different between groups. Sub-epithelial collagen band thickness was normal in all the patients. No patient had a marked infiltration of lamina propria by leucocytes, and HLA-DR and CD25 were normally expressed in all patients. CONCLUSION: These results from a small sample of patients suggest that patients without diarrhoea receiving NSAIDs on a long-term basis do not develop microscopic or inflammatory colitis.     

Side-effects of non-steroidal anti-inflammatory drugs: Studies from the tayside medicines monitoring unit

The Tayside Medicines Monitoring Unit (MEMO) database is a record-linkage system prospectively built for the purposes of carrying out pharmacoepidemiological research. MEMO links community dispensed prescribing data with hospitalization morbidity data. MEMO collects data on all dispensed drugs in Tayside. Data on all NSAIDs and ulcer healing drugs (UHDs) are available from 1989 onwards. Using this resource, studies that have been carried out have demonstrated the safety of topically applied NSAIDs, have shown that the risk of upper gastrointestinal complications associated with oral NSAIDs is constant with continuous exposure, and have quantified the attributable risk of NSAIDs for any given combination of risk factors. The rank order of NSAID toxicity in these studies has been similar to those from other recent studies using data from different sources. MEMO has also examined the associations between NSAID exposure and colorectal cancer, colitis, appendicectomy, cholecystectomy and acute renal failure. The MEMO record-linkage database is a powerful tool for quantifying the side-effects of NSAIDs. MEMO is currently exploring mechanisms for expanding its capability to the population of Scotland.     

Impact of COX-2 inhibitors in common clinical practice a gastroenterologist's perspective

Non-selective NSAIDs enhance the risk of serious ulcer complications (bleeding, perforation, obstruction), hospitalization and death about 3-10-fold. The gastrointestinal side effects of NSAIDs have a considerable economical burden, since they are responsible for 5-10 billion dollars in hospitalization charges and lost work time. NSAIDs cause gastrointestinal damage by both topical and systemic effects. COX-1-mediated inhibition of prostaglandin synthesis is probably the most relevant mechanism, but NSAIDs can cause gastrointestinal injury also by COX-independent pathways. COX-2-selective inhibitors (Coxibs) such as celecoxib, rofecoxib or valdecoxib have been developed to achieve an equal relief of pain and inflammation as classical NSAIDs but without their risk of gastrointestinal side effects. Within the first three months, celecoxib became the fastest selling drug in history. The gastrointestinal safety of classical NSAIDs and Coxibs has been compared in a variety of endoscopic investigations, meta-analyses and outcome studies. In conclusion, these studies have clearly shown, that Coxibs are associated with significantly less dyspeptic symptoms, erosions, ulcers and ulcer complications. In contrast, Coxibs seem to delay gastric ulcer healing to the same extent as traditional NSAIDs. Besides their effects on the upper gastrointestinal tract, NSAIDs can cause small intestinal inflammation, ulcers of the small and large intestine, ileal dysfunction, intestinal strictures, colitis and NSAID enteropathy. In addition, NSAIDs increase the risk of lower gastrointestinal complications including bleeding, perforation and obstruction. Current data suggest, that Coxibs are associated with a significantly lower risk of serious lower GI events than traditional NSAIDs. It is now under debate, who should receive COX-2-selective inhibitors instead of classical NSAIDs, since Coxibs are much more expensive. Data from cost-effectiveness studies suggest, that Coxibs should currently be used only in patients with high risks of GI complications.     

Pemetrexed disodium in ovarian cancer treatment

INTRODUCTION: Current therapies for recurrent ovarian cancer (OC) yield relatively modest improvements in survival. Many drugs are available but recently a renewed interest is addressed on antimetabolite drugs. Pemetrexed (PEM) is a multitargeted antifolate cytotoxic agent mainly used in lung cancer. AREAS COVERED: This review summarizes the available evidence on the use of PEM in the treatment of OC. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to November 2011. Currently available published data on mechanism of action, pharmacokinetics, safety and efficacy of PEM in the treatment of recurrent OC are described. EXPERT OPINION: Eight trials evaluated the use of PEM in OC patients. Studies using PEM in combination with carboplatin in platinum-sensitive OC suggested that the response rate is similar to other combination therapies. However, based on the absence of randomized trials comparing this doublet with currently used combination treatments, it is difficult to draw conclusions on the efficacy of PEM regimens in these patients. In platinum-resistant OC patients, two studies suggested that PEM alone might have equivalent activity to other single-agent treatment. Further pharmacogenomic and clinical data are warranted to better define the role of PEM in the treatment of recurrent OC.     

Nonsteroidal anti-inflammatory drugs and inflammatory bowel disease: current perspectives.

Mechanisms underlying the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) have been extensively investigated, whereas those leading to intestinal damage are not completely understood. Several hypotheses have been put forward on the pathophysiology of intestinal damage by NSAIDs: enhanced intestinal permeability, inhibition of cyclooxygenase (COX), enterohepatic recirculation, and formation of adducts. The effects of COX-2 selective inhibitors, which appear to have better gastric tolerability when compared to nonselective NSAIDs, on normal and inflamed intestinal mucosa (as in Crohn's disease or ulcerative colitis) are still largely unexplored. If COX-2 inhibition plays a key role in suppressing the inflammatory process, recent evidence suggests that COX-2 products are involved in maintaining the integrity of intestinal mucosa, in the healing of gastrointestinal ulcers and in the modulation of inflammatory bowel disease (IBD). Animal models of intestinal inflammation have so far yielded conflicting results on the effects of COX-2 selective inhibitors on the intestinal mucosa. It is now clear that NSAIDs do not act through cyclooxygenase inhibition, but also have different targets such as nuclear factor-kappaB and/or peroxisome proliferator-activated receptors gamma. The peculiar pharmacological profile of each compound may help to explain the different impact of each NSAID on the inflammatory process and on IBD. Notably, the salicylic acid derivative 5-ASA is widely used in the treatment of IBD and is believed to act through nuclear factor-kappaB inhibition. Although the use of COX-2 selective inhibitors remains contraindicated in patients with IBD, studying their effects on intestinal mucosa may offer new insights into their subcellulars mechanisms of action and open new avenues for the development of novel therapies for IBD.     

Pemetrexed disodium in ovarian cancer treatment

Introduction: Current therapies for recurrent ovarian cancer (OC) yield relatively modest improvements in survival. Many drugs are available but recently a renewed interest is addressed on antimetabolite drugs. Pemetrexed (PEM) is a multitargeted antifolate cytotoxic agent mainly used in lung cancer.

Areas covered: This review summarizes the available evidence on the use of PEM in the treatment of OC. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to November 2011. Currently available published data on mechanism of action, pharmacokinetics, safety and efficacy of PEM in the treatment of recurrent OC are described.

Expert opinion: Eight trials evaluated the use of PEM in OC patients. Studies using PEM in combination with carboplatin in platinum-sensitive OC suggested that the response rate is similar to other combination therapies. However, based on the absence of randomized trials comparing this doublet with currently used combination treatments, it is difficult to draw conclusions on the efficacy of PEM regimens in these patients. In platinum-resistant OC patients, two studies suggested that PEM alone might have equivalent activity to other single-agent treatment. Further pharmacogenomic and clinical data are warranted to better define the role of PEM in the treatment of recurrent OC.     

显微镜结肠炎21例临床分析

目的分析慢性腹泻患者的临床资料,以探讨显微镜结肠炎的临床特点。方法回顾性分析2009年4月～2012年4月本院门诊以水样腹泻为主诉的患者结肠镜及组织病理结果,对诊断为显微镜结肠炎患者的病史及临床资料进行分析。结果 168例水样腹泻患者中诊断为显微镜结肠炎21例,其中,淋巴细胞性结肠炎17例,胶原性结肠炎4例,男：女为1：1.3。9例患者既往有服用相关药物病史。诊断前水样腹泻持续1.0～8.5个月,排便次数为6～10次/d;除水样腹泻外相关症状有腹部不适、失禁、紧迫感、腹胀、体重减轻;结肠镜下病变部位：2例病变累计≥2节段,4例仅累计单个肠段,15例结肠镜下表现正常,无全结肠受累患者;结肠镜下表现：15例结肠黏膜正常,4例局部黏膜充血红肿,2例结肠黏膜糜烂,1例除结肠黏膜糜烂外回盲部见非特异性溃疡。结论显微镜结肠炎是慢性水样腹泻的重要原因,临床症状及结肠镜表现均无特异性,诊断需结合组织病理学结果,其发病可能与自身免疫及使用某些药物（如NSAIDs）有关。     

Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study

Aliment Pharmacol Ther 2010; 32: 1124–1128

Summary

Background Microscopic colitis causes chronic watery diarrhoea. Recent studies have suggested an aetiological role for various medications, including proton pump inhibitors, in the pathogenesis of microscopic colitis. Aim To determine whether an association exists between microscopic colitis and proton pump inhibitor use in patients with documented microscopic colitis vs. age‐ and gender‐matched controls. Methods In this retrospective case–control study, cases of microscopic colitis from a secondary and tertiary referral medical centre diagnosed in the last 5 years were reviewed. Demographic characteristics, clinical, histological and endoscopic records, as well as exposure to PPIs and NSAIDs were assessed. Controls from the population were matched to cases by gender and by age. Results During the investigated period, 136 cases were identified in both hospitals. Of these, 95 cases of microscopic colitis were retrieved for detailed analysis. Exposure to proton pump inhibitors at the time of the histological diagnosis was significantly higher in patients with collagenous colitis than in controls [38% vs. 13%, P < 0.001; adjusted OR of 4.5 (95% CI 2.0–9.5)]. Conclusions This observation confirms the presumed association between microscopic colitis and PPI use, and it supports the possible aetiological role of PPI exposure in the development of microscopic colitis.     

参麦注射液联合培美曲塞及奈达铂治疗晚期肺腺癌的临床观察

目的：观察参麦注射液联合培美曲塞（PEM）及奈达铂（NDP）治疗晚期肺腺癌的临床效果。方法将62例晚期肺腺癌患者随机分为治疗组和对照组,治疗组30例,接受PEM及NDP化疗方案治疗,化疗过程中配合参麦注射液静脉滴注;对照组32例,给予PEM及NDP方案化疗。 PEM 500 mg/m2静脉滴入,〉10 min,第1天;NDP 80 mg/m2静脉滴入,第1天,21 d为1个化疗周期。2个周期化疗后评价患者的生存质量、临床疗效及不良反应,随访1年。结果治疗组的生存质量评分改善73.3豫,明显高于对照组的46.9豫（P〈0.05）。治疗组的有效率为53.3豫,明显高于对照组的28.1豫（P〈0.05）。治疗组的1年生存率为63.3豫,明显高于对照组的37.5豫（P〈0.05）。治疗组患者出现贫血、白细胞下降、血小板减低的概率低于对照组（P〈0.05）。结论参麦注射液联合PEM及NDP方案治疗晚期肺腺癌安全、有效,对改善生存质量、提高近期疗效及保护骨髓功能具有重要作用。     

Lumiracoxib: the evidence of its clinical impact on the treatment of osteoarthritis

INTRODUCTION: The symptoms of osteoarthritis (OA) include joint pain, stiffness, and a reduced ability to perform normal daily activities, which result in decreased quality of life. There is currently no known cure or means of preventing the progression of joint damage due to OA. Therefore, treatment focuses on the control of symptoms, including the use of various agents [including nonselective and selective nonsteroidal antiinflammatory drugs (NSAIDs)] to provide pain relief and reduce inflammation. Lumiracoxib is a selective cyclooxygenase-2 (COX-2) inhibitor for the treatment of OA. AIMS: To review the evidence for the treatment of OA with lumiracoxib. EVIDENCE REVIEW: There is evidence that lumiracoxib reduces the pain and stiffness associated with OA, and is as effective as nonselective NSAIDs, and the COX-2 inhibitor celecoxib. There is some evidence that lumiracoxib treatment results in a lower incidence of upper gastrointestinal (GI) ulcer complications compared with nonselective NSAIDs. However, evidence suggests that there is no GI benefit in patients receiving concomitant aspirin medication. With the exception of GI ulcers, the evidence indicates that lumiracoxib has a tolerability profile similar to nonselective NSAIDs: low risk of cardiovascular (CV) events and a low incidence of edema. Changes in liver function occur in some patients, largely at doses >100 mg. The cost effectiveness of lumiracoxib compared with nonselective NSAIDs remains to be determined. CLINICAL VALUE: Lumiracoxib is an alternative treatment option for OA which provides effective pain relief without the GI complications associated with nonselective NSAIDs, and with a low risk of CV events. Lumiracoxib is contraindicated in patients with current, previous, or at risk of, hepatic impairment.     

The Impact of NSAID Treatment on Cardiovascular Risk – Insight from Danish Observational Data

This MiniReview describes the present evidence for the relationship between cardiovascular risk and use of non‐steroidal anti‐inflammatory drugs (NSAIDs) with special focus using Danish register‐based data. NSAIDs are among the most widely used drugs worldwide and mainly used for management of pain and inflammatory conditions. Through the past decade, much attention has been given to the cardiovascular safety of these drugs, and several studies have shown increased risk of adverse cardiovascular effects associated with NSAID use. Current guidelines discourage any use of NSAIDs in patients with cardiovascular disease, yet over a period of 8–10 years, 35–44% of patients with myocardial infarction or heart failure were exposed to NSAIDs in Denmark. Furthermore, NSAID use was associated with an increased risk of death or myocardial infarction by up to 5 times that of non‐users. There was also a clear indication for a dose‐related response in risk associated with NSAID therapy, supporting a causal association. Notably, the cardiovascular risk associated with NSAID treatment was prevalent at start of treatment, suggesting no safe treatment window for NSAIDs in patients with cardiovascular disease. Thus, evidence from observational studies is accumulating, suggesting that NSAIDs are a major public health concern due to the widespread use of these drugs. Although it seems unlikely that we can completely avoid use of NSAIDs, even among high‐risk patients, these results highlight the importance of balancing the benefit versus the risk of treatment before initiating NSAID treatment.     

Economic evaluation of etoricoxib versus non-selective NSAIDs in the treatment of osteoarthritis and rheumatoid arthritis patients in the UK

INTRODUCTION: The objective of this study was to evaluate the potential economic implications of using etoricoxib versus non-selective NSAID alternatives in the treatment of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in the UK. STUDY DESIGN: Decision-analytical modelling was used to calculate the expected costs and consequences of the use of etoricoxib compared with non-selective NSAIDs alone, NSAIDs plus proton pump inhibitors (PPIs), NSAIDs plus histamine H2 receptor antagonists and NSAIDs plus misoprostol over a continuous treatment period of 1 year. METHODS: The model considered direct medical costs from the perspective of the UK National Health Service (NHS) and used data from phase IIb and III clinical trials of etoricoxib to determine probabilities of gastrointestinal (GI) events. Model outcomes were defined as resource-consuming GI-related events, including clinically evident gastroduodenal perforations, symptomatic gastroduodenal ulcers, or upper GI bleeding (collectively, PUBs ['perforation, ulcers and/or bleeding']). Resource utilisation and costs (2002 values) for the treatment of OA and RA as well as GI events were based on published literature and information available from UK-specific sources. MAIN OUTCOME MEASURES AND RESULTS: The model suggests that etoricoxib is cost saving compared with non-selective NSAIDs plus PPIs or non-selective NSAIDs plus misoprostol. The model also suggests that etoricoxib is cost effective in terms of the incremental cost per QALY gained for non-selective NSAIDs alone (pound 19,766) and for non-selective NSAIDs plus H2 antagonists (pound 9350). The incremental cost of etoricoxib per PUB avoided was pound 12,446 versus non-selective NSAIDs alone and pound 6438 versus NSAIDs co-prescribed with H2 antagonists. For patients without the presence of specific GI risk factors (history of GI event, corticosteroid use or disability), etoricoxib may be cost effective for patients over age 56 years, assuming a cost-effectiveness threshold of pound 30,000 per QALY gained. Etoricoxib may also be cost effective in patients of all ages who had at least one specific GI risk factor. CONCLUSIONS: The model suggests, with its underlying assumptions and data, that etoricoxib is a cost-effective alternative to therapeutic regimens involving non-selective NSAIDs for OA or RA, from the UK NHS perspective. Etoricoxib may be cost saving and dominant over non-selective NSAIDs used together with a PPI or misoprostol. When compared with non-selective NSAIDs alone or non-selective NSAIDs co-prescribed with H2 antagonists, the incremental cost per QALY gained with use of etoricoxib was within the generally accepted threshold for cost effectiveness (less than pound 30,000 per QALY gained).     

Evolution of topical NSAIDs in the guidelines for treatment of osteoarthritis in elderly patients

Increasing age is the primary predictor of osteoarthritis, the most prevalent painful condition in the US. Because there are no disease-modifying therapies for osteoarthritis, relief of symptoms and maintenance of quality of life through improving joint function become the focus of management. Although highly effective for pain relief, oral nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with systemic adverse reactions that are sometimes treatment limiting, especially for older patients. Thus, osteoarthritis management in elderly populations is shifting away from traditional NSAIDs to therapies that provide comparable pain relief with improved safety. Since the approval by the US Food and Drug Administration of the use of topical NSAIDs to manage osteoarthritis pain, current treatment guidelines put forth by several professional societies have begun to recommend topical NSAIDs as an alternative therapy and, most recently, as first-line therapy for osteoarthritis management in the elderly. This review provides an overview of the various treatment guidelines that are available to assist prescribers in making safe and effective decisions in the treatment of osteoarthritis in this high-risk patient population.     

NSAIDs in the treatment and/or prevention of neurological disorders

Non-steroidal anti-inflammatory drugs (NSAIDs) have been used extensively in the treatment of inflammatory disorders and pain. In recent years, emerging data suggest that some NSAIDs possess pharmacological properties, in addition to cyclooxygenase inhibition, which may be beneficial in the treatment of several neurological conditions. For example, fenamate NSAIDs potentiate GABA-A receptor function, indomethacin scavenges nitric oxide free radicals, and acetylsalicylic acid inhibits the translocation of NF-κB, all of which may contribute to their neuroprotective actions in selected experimental models of stroke. The purpose of this review is to explore the diverse pharmacological properties of NSAIDs in relation to their potential value in the treatment of selected neurological diseases.     

2006～2008年我院非甾体抗炎药的应用分析

目的研究中山大学附属第二医院非甾体抗炎药的应用状况和发展趋势,并进行临床利用评价,为临床合理、有效、经济地选用药物提供科学依据。方法采用金额排序和用药频度（DDDs）、日治疗费用方法对中山大学附属第二医院2006～2008年非甾体抗炎药的使用情况进行统计分析。结果2006—2008年间非甾体抗炎药用药金额呈逐年上升趋势,临床的用药量相对稳定。结论非甾体抗炎药的使用数量和频率呈现上升状态。安全、有效、价格低廉且与其他药物相互作用小的非甾体抗炎将成为临床治疗的主要药物。