Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013395 (dyspepsia)
 4,879 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Meloxicam is a new once daily non-steroidal anti-inflammatory drug (NSAID). Double-blind trials in over 5000 patients with osteoarthritis and rheumatoid arthritis have shown that meloxicam 7.5 mg and 15 mg are significantly more effective than placebo and comparable in efficacy to standard NSAIDs such as naproxen 750-1000 mg, piroxicam 20 mg and diclofenac 100 mg slow release. In a global safety analysis, both meloxicam doses produced significantly fewer gastrointestinal (GI) side effects than the comparators (p < 0/05). Severe GI side effects, discontinuations due to GI side effects and less serious events such as dyspepsia and abdominal pain were also significantly less frequent with meloxicam. Perforations, ulcerations and bleedings occurred in 0.1%, 0.2%, 1.2%, 0.6% and 2.1% of meloxicam 7.5 mg, 15 mg, piroxicam, diclofenac and naproxen patients respectively (p < 0.05 for piroxicam and naproxen compared with meloxicam). This improved safety profile is likely to be due to meloxicam's selective inhibition of COX-2 relative to COX-1.
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PMID:Review of clinical trials and benefit/risk ratio of meloxicam. 862 79

Nonsteroidal antiinflammatory drugs (NSAIDs) exert their actions by inhibiting cyclooxygenase (COX). It has recently been postulated that NSAIDs' antiinflammatory efficacy arises from inhibition of the COX-2 isoform of cyclooxygenase, whereas inhibition of the COX-1 isoform produces the troublesome and sometimes serious gastric and renal side effects of NSAIDs. A relatively selective COX-2 inhibitor, such as meloxicam, may combine antiinflammatory efficacy with improved tolerability. In volunteers, indomethacin 75 mg, but not meloxicam 7.5 mg, inhibited renal prostaglandin E2 excretion and platelet aggregation (COX-1 mediated effects). Double-blind, randomized trials in osteoarthritis and rheumatoid arthritis patients have shown equivalent antiinflammatory efficacy among meloxicam 7.5 mg or 15 mg and diclofenac 100 mg, naproxen 750 mg, and piroxicam 20 mg. In a double-blind, placebo-controlled trial, meloxicam (7.5 or 15 mg) caused less endoscopically detected gastrointestinal (GI) damage (Lanza scale) than piroxicam 20 mg. The MELISSA study, a double-blind, randomized, 28-day trial in over 9,000 patients showed that meloxicam 7.5 mg caused statistically less total GI toxicity, dyspepsia, abdominal pain, nausea and vomiting, and diarrhea than diclofenac 100 mg, despite equivalent reductions in pain on movement for each treatment. A global safety analysis of clinical trials, representing over 5,600 patients and comprising 170 and 1,100 patient-years of exposure for meloxicam 7.5 mg and 15 mg, respectively, showed that meloxicam caused less GI toxicity and fewer peptic ulcers and GI bleeds than naproxen, diclofenac, or piroxicam. The renal safety profile and incidence of liver function abnormalities with meloxicam is equivalent to other NSAIDs available for clinical use. In conclusion, relatively selective COX-2 inhibition exemplified by meloxicam may offer effective symptom relief with an improved GI tolerability profile.
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PMID:Meloxicam: selective COX-2 inhibition in clinical practice. 921 16

1. Non-steroidal antiinflammatory drugs (NSAIDs) are among the most frequently prescribed medications and are used primarily to control pain, stiffness, and reduce inflammation. 2. One of the most common adverse effects of NSAID therapy is gastrointestinal (GI) problems, specifically indigestion, nausea, dyspepsia, diarrhea, constipation, and gastritis. 3. Considerations in chronic pain management include non-pharmacologic treatment options (i.e., physical therapy, behavioral therapy, etc.), use of misoprostol for clients at high risk for NSAID induced GI problems, and monitoring blood and urine every 3 months to 1 year with chronic NSAID therapy to detect liver, kidney, and hematologic problems. 4. Current research is focused on development of a prostaglandin H synthetase (PGHS-2) inhibitor which should offer efficacy equal to the most potent NSAIDs with minimal side effects, including gastric safety.
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PMID:Non-steroidal antiinflammatory drugs. A review. 965 39

Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19%; P < 0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P < 0.001), nausea and vomiting (P < 0.05), abdominal pain (P < 0.001) and diarrhoea (P < 0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P < 0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P < 0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.01% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P < 0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may in part reflect the preferential COX-2 selectivity of meloxicam, although the dose and other aspects of tolerability may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy.
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PMID:Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment. 1050 39

This article provides a systematic review of the frequency and severity of adverse gastrointestinal (GI) events among patients using meloxicam, a cyclooxygenase (COX)-2-selective nonsteroidal anti-inflammatory drug (NSAID). A MEDLINE search of English language articles from 1990-1998, a manual search of citations from primary trials and review articles, and a manual search of proceedings from international gastroenterology meetings were conducted. Randomized clinical trials comparing the frequency of GI adverse events for meloxicam versus non-COX-2-selective NSAIDs were selected. Specific data about the frequency of dyspepsia; perforations, ulcers, and bleeds (PUBs); and withdrawal of medication because of adverse GI events was also extracted. From a pool of 62 potentially relevant citations, 12 randomized trials were identified. All trials concerning symptomatic GI adverse events used the World Health Organization's Adverse Reaction Terminology List (WHO-ARTL) to code adverse events. Patients using meloxicam had fewer GI adverse events compared with non-COX-2-selective NSAIDs (odds ratio = 0.64; 95% confidence interval [CI], 0.59-0.69). Patients using meloxicam experienced less dyspepsia (odds ratio = 0.73; 95% CI, 0.64-0.84), fewer PUBs (odds ratio = 0.52; 95% CI, 0.28-0.96), and less frequent discontinuation of NSAID because of adverse GI events (odds ratio = 0.59; 95% CI, 0.52-0.67) compared with non-COX-2 selective NSAIDs. Meloxicam, a COX-2-selective NSAID, appears to cause fewer adverse GI events than standard, non-COX-2-selective NSAIDs. However, the generalizability of these data may be limited by the low dose of meloxicam used in most trials and the use of the WHO-ARTL to code adverse events.
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PMID:Gastrointestinal safety profile of meloxicam: a meta-analysis and systematic review of randomized controlled trials. 1062 93

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective antipyretic, analgesic and anti-inflammatory agents. One of the major concerns regarding the use of these compounds is the incidence of gastrointestinal (GI) adverse effects, ranging from dyspepsia to the serious and potentially life threatening complications of ulcers, haemorrhages, and perforations. Thus, the prevention and/or treatment of upper GI damage is estimated to increase the overall cost of NSAID therapy by at least 40%. The pathogenesis of NSAID-induced gastroduodenal mucosal injury appears to involve both topical and systemic mechanisms. The former is related to the acidic nature of most NSAIDs, which promotes the accumulation of ionised molecules (ion trapping) within the mucosal cells. Topical mucosal injury may also occur as a result of biliary excretion of active NSAID metabolites. The systemic effect has, however, the predominant role. It is mediated through cyclo-oxygenase (COX) inhibition and a subsequent decrease in gastroprotective prostaglandins. Fortunately, 2 forms of COX enzymes, designated COX-1 and COX-2, have been recognised. COX-1 appears to function as a house-keeping enzyme, whereas COX-2 is primarily induced by inflammatory stimuli and mitogens in various cells, including macrophages and synovial cells. Accordingly, the inhibition of COX-2 would result in anti-inflammatory effects, whereas gastroduodenal ulceration is thought to be related to the inhibition of COX-1. Animal data have suggested that nabumetone has a low ulcerogenic potential in comparison with other available NSAIDs. This feature was further supported by controlled clinical trials as well as epidemiological studies. The relative GI safety of nabumetone may be attributed to its lack of direct and indirect topical effects because of its nonacidic nature and absence of enterohepatic recirculation. Furthermore, the active metabolite [6-methoxy-2-naphthylacetic acid (6-MNA)] may be gastro-sparing as a result of its property of COX-2 preferential inhibition.
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PMID:[Gastrointestinal tolerance of nonsteroidal anti-inflammatory agents]. 1084 Oct 69

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used successfully by many patients for the treatment of the signs and symptoms of arthritis, and other painful and inflammatory disorders. However, traditional nonselective NSAIDs that inhibit COX-1 and COX-2 lead to a state of propensity for gastric and duodenal ulcer disease and ulcer complications. The point prevalence of endoscopic ulcers ranges from 14 to 44% of patients using NSAIDs. Moreover, it is estimated that 1.46-1.90% of chronic NSAID users develop serious upper gastrointestinal (UGI) toxicity annually, most notably UGI bleeding, gastric/duodenal obstruction or ulcer perforation. In the USA, it has been estimated that 107,000 hospitalisations and 16,500 deaths occur annually related to the use of nonselective NSAIDs. Because these ulcer complications are often not heralded by chronic symptoms of dyspepsia, symptoms alone are not sufficient to guide long-term management of NSAID-related toxicity. Instead, prophylactic and preventive therapies are recommended in patients at above-average and high risk. Epidemiological data have identified that patients with a past history of ulcer disease, past history of UGI bleeding, greater age, concomitant corticosteroid use, and those who use higher doses and multiple NSAIDs fall into this category. Other risk factors of lesser importance have also been identified. A controversial issue remains regarding the possible increased risk of NSAID-associated ulcers and ulcer complications in patients who are infected with Helicobacter pylori. Prophylactic therapies have been evaluated primarily in randomised clinical trials, with the rate of endoscopic ulcers as the primary endpoint. It is assumed, but not proven, that these endoscopic ulcer rates are surrogate markers for gastrointestinal toxicity and are predictive of the rate of significant UGI adverse events. In the only outcomes trial to date, it was reported that misoprostol (200 microg 4 times daily) caused an approximately 50% reduction in serious UGI adverse events in a large 6-month trial involving rheumatoid arthritis patients. In parallel, this approximates the 50% reduction of endoscopic ulcers seen in randomised controlled trials using misoprostol. While H2 receptor antagonists are ineffective agents at traditional doses, proton pump inhibitors have been clearly shown to reduce the rate of endoscopic ulcers in several trials. In fact, the efficacy approximates to the efficacy seen with misoprostol. Beyond efficacy and in practical terms, the choice of optimal prophylaxis should take into consideration patient compliance, patient satisfaction, side-effects and cost.
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PMID:Who needs prophylaxis of nonsteroidal anti-inflammatory drug-induced ulcers and what is optimal prophylaxis? 1092 93

Although Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) both cause peptic ulcers, they do so by different mechanisms so any interaction is not necessarily harmful. H. pylori has been shown to enhance gastric mucosal prostaglandin synthesis, while NSAIDs suppress it Pragmatically, there is no compelling evidence in favour of H. pylori eradication in all patients who take NSAIDs. As a broad generalisation, in therapeutic studies of NSAID users, those who have no ulcer at trial entry are more prone to ulcer development if they are H. pylori-positive. By contrast, in those who have ulcers at baseline, H. pylori-positive individuals are less likely to develop ulcers, particularly if taking acid-suppressive therapy. Trials of H. pylori eradication therapy tend to replicate this dichotomy. In one study of patients starting NSAIDs for the first time, with no ulcer history and no baseline ulcer, use of bismuth-based eradication therapy was associated with a lower incidence of gastric ulcer at 2 months. Conversely, in a study of patients with endoscopically proven ulcers and/or troublesome dyspepsia, proton pump inhibitor based eradication treatment had no effect on outcome (of acid suppression) over 6 months. H. pylori eradication has been associated with significantly slower healing of gastric ulcers compared with patients who did not undergo eradication. However, the effect of H. pylori eradication on healing of NSAID-associated duodenal ulcers does not appear to be so dramatic, and limited evidence suggests that it may be possible to prevent H. pylori-associated duodenal ulcer by eradicating the infection. An evidence-based approach to treatment would suggest that NSAID users should undergo H. pylori eradication therapy if they have a duodenal ulcer, whether or not they continue NSAIDs. Because COX-2 inhibitors appear not to be ulcerogenic, management of H. pylori in patients taking these drugs can be based upon the same risk assessment as in patients not taking anti-arthritis drugs. H. pylori eradication should not be used universally or in high-risk gastric ulcer patients who require management with acid suppression.
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PMID:What consideration should be given to Helicobacter pylori in treating nonsteroidal anti-inflammatory drug ulcers? 1092 94

Rheumatoid arthritis and osteoarthritis are prevalent and costly conditions. A large proportion of the direct costs associated with these conditions relates to management of iatrogenic side effects. The cyclooxygenase (COX)-2-specific inhibitors lead to equivalent control of pain and disability compared with traditional NSAIDs. However, the COX-2-specific inhibitors have significant potential to reduce health-care costs, principally through the reduction of side effects. These cost savings are most likely to be realized through reductions in costs associated with dyspepsia and upper gastrointestinal ulcers and bleeding. Reduced indirect costs through improved disability scores and improved health-related quality of life are also predictable with the use of COX-2-specific inhibitors. This is accomplished without the attendant increase in risk to the gastrointestinal tract associated with traditional NSAIDs.
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PMID:The economic implications of cyclooxygenase-2-specific inhibitors. 1117 51

The mechanisms by which aspirin(ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal symptoms are poorly understood. They probably arise from several causes, including direct and indirect mucosal injury, exacerbation of underlying peptic ulcer disease or non-ulcer dyspepsia, exacerbation of Helicobacter pylori gastritis, and possibly motility disorders. No single form of therapy has been generally successful. Because, in most cases, symptoms abate fairly rapidly with continued treatment, there is little evidence that benefit associated with any symptom-directed drug therapy is superior to placebo beyond 4 weeks. Exceptions may be the subsets of patients with pre-existing ulcer disease or heartburn, exacerbated by the NSAID therapy, who usually benefit from acid-suppressive drug treatment. Different NSAIDs vary in the frequency with which their use leads to gastrointestinal(GI) complications such as haemorrhage, perforation, obstruction, or the symptomatic ulcers from which about 40% of the complications arise. Most gastroduodenal ulcers heal over time, albeit more slowly, with conventional doses of any of the available anti-ulcer drugs. Maintenance therapy may be needed in many patients who continue NSAID therapy. Anti-ulcer drugs have not, thus far, been shown to be more effective than placebo in preventing ulcer complications or their recurrence. The use of COX-2-selective inhibitors appears, in outcome studies, to reduce gastrointestinal bleeding, including bleeding from ulcers, but it is not established that the ulcers protected were caused by NSAIDs, as distinct from ulcers exacerbating or recurring from antecedent peptic ulcer disease. To-date, perforation or obstruction have not been shown to be affected by selective COX-2 inhibitor drugs. If the major problem giving rise to severe NSAID complications is pre-existing peptic ulcer disease, it may yet emerge that the most effective approach will be the use of proton pump inhibitor drugs, for the duration of NSAID therapy, in a small subset of high-risk patients. Most other low-risk patients may not need any special care. Co-morbid conditions have a major impact on outcome of NSAID therapy. Morbidity or even death attributable solely to NSAIDs is probably small in normal patients, and requires little in the way of prophylaxis.
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PMID:Prevention and treatment of gastrointestinal symptoms and complications due to NSAIDs. 1156 39


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