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

Meloxicam is a new preferential cyclooxygenase-2 (COX-2) inhibitor for the treatment of rheumatic disease. This paper presents a global safety analysis of data from meloxicam clinical studies, focusing on gastrointestinal (GI) adverse events. Meloxicam 7.5 and 15 mg (n = 893 and 3282) were compared with piroxicam 20 mg (n = 906), diclofenac 100 mg slow release (n = 324) and naproxen 750-1000 mg (n = 243). With respect to all GI adverse events, meloxicam 7.5 and 15 mg were significantly better than all comparators in a pooled analysis of double-blind studies in rheumatoid arthritis (RA) and osteoarthritis (OA). When examining non-serious GI events, severe GI events, discontinuous due to GI events, dyspepsia, abdominal pain and upper GI events, both meloxicam doses were significantly better than comparator non-steroidal anti-inflammatory drugs (NSAIDs) in most cases. Where statistical significance was not demonstrated, there was generally a trend in favour of meloxicam. With respect to upper GI perforations, ulcerations and bleedings, the most serious of NSAID-associated side-effects, meloxicam was better tolerated than the comparators, reaching statistical significance for piroxicam and naproxen. Meloxicam's improved GI safety profile is likely to be due to its preferential inhibition of inducible COX-2 relative to constitutive COX-1.
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PMID:Safety of meloxicam: a global analysis of clinical trials. 863 Jun 41

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

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

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

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit production of protective gastric mucosal prostaglandins and also have a direct topical irritant effect. In some patients this results in dyspepsia and development of gastroduodenal erosions and ulceration. The risk of ulcer complications, such as bleeding, perforation and death is increased approximately 4-fold in NSAID users. Patients at high risk of ulcer complications include the elderly, those taking anticoagulants, steroids and aspirin, those with a previous history of peptic ulceration and patients with concomitant serious medical problems. The interaction of NSAIDs with Helicobacter pylori (the major cause of peptic ulceration in non-NSAID users) is controversial and some studies suggest that H. pylori infection may even protect against NSAID-induced ulceration. Selective inhibitors of the inducible cyclooxygenase-2 (COX-2) enzyme spare COX-1 in the gastric mucosa and, hence, do not inhibit production of mucosal prostaglandins. COX-2-selective inhibitors are associated with a significant reduction in gastroduodenal damage compared with traditional NSAIDs. Proton pump inhibitors (PPI) are probably the best agents for healing and prevention of NSAID-induced ulcers. Preliminary studies suggest that COX-2 selective inhibitors, like traditional NSAIDs, may prevent lower gastrointestinal cancer. Further studies are needed but they may be useful in individuals at high risk of certain types of lower gastrointestinal malignancy with increased gastrointestinal tolerability and safety.
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PMID:COX-2 inhibitors vs. NSAIDs in gastrointestinal damage and prevention. 1133 66

Nabumetone is a nonsteroidal anti-inflammatory prodrug, which exerts its pharmacological effects via the metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). Nabumetone itself is non-acidic and, following absorption, it undergoes extensive first-pass metabolism to form the main circulating active metabolite (6-MNA) which is a much more potent inhibitor of preferentially cyclo-oxygenase (COX)-2. The three major metabolic pathways of nabumetone are O-demethylation, reduction of the ketone to an alcohol, and an oxidative cleavage of the side-chain occurs to yield acetic acid derivatives. Essentially no unchanged nabumetone and < 1% of the major 6-MNA metabolite are excreted unchanged in the urine from which 80% of the dose can be recovered and another 10% in faeces. Nabumetone is clinically used mainly for the management of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) to reduce pain and inflammation. The clinical efficacy of nabumetone has also been evaluated in patients with ankylosing spondylitis, soft tissue injuries and juvenile RA. The optimum oral dosage of nabumetone for OA patients is 1 g once daily, which is well tolerated. The therapeutic response is superior to placebo and similar to nonselective COX inhibitors. In RA patients, nabumetone 1 g at bedtime is optimal, but an additional 0.5-1 g can be administered in the morning for patients with persistent symptoms. In RA, nabumetone has shown a comparable clinical efficacy to aspirin (acetylsalicylic acid), diclofenac, piroxicam, ibuprofen and naproxen. Clinical trials and a decade of worldwide safety data and long-term postmarketing surveillance studies show that nabumetone is generally well tolerated. The most frequent adverse effects are those commonly seen with COX inhibitors, which include diarrhoea, dyspepsia, headache, abdominal pain and nausea. In common with other COX inhibitors, nabumetone may increase the risk of GI perforations, ulcerations and bleedings (PUBs). However, several studies show a low incidence of PUBs, and on a par with the numbers reported from studies with COX-2 selective inhibitors and considerably lower than for nonselective COX inhibitors. This has been attributed mainly to the non-acidic chemical properties of nabumetone but also to its COX-1/COX-2 inhibitor profile. Through its metabolite 6-MNA, nabumetone has a dose-related effect on platelet aggregation, but no effect on bleeding time in clinical studies. Furthermore, several short-term studies have shown little to no effect on renal function. Compared with COX-2 selective inhibitors, nabumetone exhibits similar anti-inflammatory and analgesic properties in patients with arthritis and there is no evidence of excess GI or other forms of complications to date.
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PMID:Nabumetone: therapeutic use and safety profile in the management of osteoarthritis and rheumatoid arthritis. 1545 29

Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H. pylori) are major factors in gastritis and peptic ulcer However, the role of NSAIDs and H. pylori infection in dyspepsia remains unclear. Gastric adaptive relaxation may be related to the pathogenesis of functional dyspepsia because the response is often disturbed in dyspeptic patients. In this study, we investigated the effects of indomethacin or H. pylori water extracts on gastric adaptive relaxation. This experiment was performed using the modified method of Desai et al. Isolated guinea-pig stomach in an organ bath was monitored for intragastric pressure and volume. Adaptive relaxation was induced by gastric luminal distention. The effects of indomethacin and H. pylori on gastric relaxation were tested in this system. Indomethacin (> 1 x 10(-5) M) significantly inhibited adaptive relaxation. Indomethacin (> 3 x 10(-6) M) induced gastric relaxation in a dose-dependent fashion. However, aspirin at a concentration sufficient for cyclooxygenase (COX)-1 inhibition did not induce gastric relaxation. Preincubation with N-nitro-L-arginine methyl ester, a nitric oxide (NO)-synthase inhibitor, inhibited indomethacin-induced gastric relaxation. Adaptive relaxation was not affected by H. pylori water extracts. In conclusion, indomethacin inhibited adaptive relaxation via prior gastric relaxation. NO production, but not COX-1 inhibition, may be involved in this effect of indomethacin. H. pylori water extracts may not have direct effects on adaptive relaxation. Inhibition of adaptive relaxation may be one of the major mechanisms underlying NSAID-induced dyspepsia.
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PMID:Indomethacin, but not Helicobacter pylori, inhibits adaptive relaxation in isolated guinea-pig stomach. 1570 Jul 51

NSAIDs are used extensively worldwide at a cost of billions of dollars annu-ally. Adverse side effects, especially in the gastrointestinal (GI) tract, are uncommon but cause a substantial burden of illness because of the volume of use. Important upper GI complications include dyspepsia, gastric erosions and peptic ulcers and complications such as bleeding, perforation or gastric outlet obstruction. Dyspeptic symptoms may occur without correlation to endoscopic findings. Topical injury and COX-1 inhibition resulting in gastric prostaglandin suppression are two commonly postulated mechanisms of gastroduodenal damage. Advanced age, previous peptic ulcers or ulcer complications, concomitant use of glucocorticoids or anticoagulants, and high-dose or prolonged NSAID administration are known risk factors. Prevention of adverse GI events involves use of safer NSAIDs including COX-2 inhibitors, and co-prescription of gastroprotective agents. NSAID-induced ulcers heal with proton pump inhibitors or misoprostol. The role of Helicobacter pylori eradication in NSAID ulcer prophylaxis and management is controversial. Choice of NSAIDs and gastroprotective agents should be guided by risk/benefit and cost-effectiveness assessment.
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PMID:Gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs. 1579 10


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