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 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

SELECT is a large-scale, prospective, international, multicentre, double-blind, double-dummy, randomized, parallel-group trial. Patients with exacerbation of osteoarthritis were treated with the recommended dose of meloxicam (7.5 mg) or piroxicam (20 mg) once daily for 28 days; 4320 patients were administered meloxicam and 4336 piroxicam. The incidence of adverse events was significantly lower in the meloxicam group (22.5%) compared with the piroxicam group (27.9%; P < 0.001), mainly due to the significantly lower incidence of gastrointestinal (GI) adverse events in the meloxicam than in the piroxicam group (10.3% vs 15.4%,; P < 0.001), while the efficacy of both drugs was equivalent. Individual GI events occurred significantly less often with meloxicam than piroxicam: dyspepsia (3.4% vs 5.8%; P < 0.001), nausea/vomiting (2.5% vs 3.4%; P < 0.05) and abdominal pain (2.1% vs 3.6%; P < 0.001). There were 16 patients with perforations, ulcerations or bleeding (PUBs) of the upper GI tract in the piroxicam group compared with seven in the meloxicam group (relative risk piroxicam:meloxicam = 1.4). Four PUBs were complicated (perforations or bleedings); none of these occurred in the meloxicam group (relative risk piroxicam:meloxicam = 1.9). The outcome of SELECT is consistent with that of the large-scale clinical trial of similar design and size which compared 7.5 mg meloxicam with 100 mg diclofenac in patients with osteoarthritis, and with a previous global analysis of the safety of meloxicam. It adds further data to the proposed relationship between selective inhibition of cyclooxygenase-2 and improved GI tolerability of non-steroidal anti-inflammatory drugs.
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PMID:Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis. 978 58

Nonsteroidal anti-inflammatory drugs (NSAIDs) play a major role in the management of inflammation and pain caused by arthritis. A new class of NSAIDs that selectively inhibit the cyclooxygenase-2 (COX-2) enzyme has been developed. The first COX-2 inhibitors, celecoxib and rofecoxib, are said to provide therapeutic benefit with less toxicity than traditional NSAIDs. A third COX-2-selective inhibitor, meloxicam, has recently been introduced. COX-2 inhibitors and traditional NSAIDs do not appear to differ significantly in their effectiveness in alleviating pain or inflammation. They have similar gastrointestinal side effects, including abdominal pain, dyspepsia and diarrhea. However, short-term studies show fewer gastrointestinal ulcers in patients treated with COX-2 inhibitors compared with traditional NSAIDs.
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PMID:Cyclooxygenase-2 enzyme inhibitors: place in therapy. 1123 80

Prevention of gastrointestinal toxicity begins with the selection of an appropriate analgesic or anti-inflammatory agent. For conditions without inflammation, such as some cases of osteoarthritis, an analgesic with no risk for gastrointestinal toxicity is appropriate. Risk factors for nonsteroidal anti-inflammatory drug (NSAID)-related complications include advanced age; history of ulcer disease or gastrointestinal bleeding; concomitant corticosteroid or anticoagulant use; use of high-dose or multiple NSAIDs; and certain chronic diseases, such as cardiovascular disease. If an NSAID must be used in a patient with risk factors, the patient should receive the lowest-risk NSAID and, in most cases, co-therapy to reduce the risk for NSAID-associated ulcers and their complications. The PGE1 prostaglandin analogue misoprostol is highly efficacious for the prevention of both gastric and duodenal ulcers and has also been shown to reduce the incidence of NSAID-induced ulcer complications. Side effects, such as diarrhea, may limit patient acceptance of the drug. Acid suppression with traditional ulcer-healing doses of H2-blockers significantly reduces rates of duodenal ulcer but is ineffective in reducing gastric ulceration. More potent acid inhibition with double-dose H2-blockers reduces rates of both gastric and duodenal ulcers. Proton-pump inhibitors, such as omeprazole, have been shown to prevent gastric and duodenal ulcers with an efficacy equal to that of misoprostol. They also reduce NSAID-related dyspepsia. Specific cyclooxygenase-2 (COX-2) inhibitors are associated with a markedly reduced rate of endoscopic ulcers. Very high-risk patients who receive these agents may still require co-therapy to prevent complications or reduce dyspepsia. This protocol may be changed by the results of long-term gastrointestinal outcome studies now underway.
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PMID:Preventing NSAID Toxicity to the Upper Gastrointestinal Tract. 1109 21

The introduction of the highly selective cyclooxygenase-2 (COX-2) inhibitors (Coxibs) has resulted in the greatest new drug use ever. The hypothesis on which these drugs were developed was that COX-2-specific inhibitors would retain the advantageous aspects but restrict the deleterious effects of conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Current practice and evidence suggests that bleeding from the gastrointestinal tract is reduced to the level of placebo and that dyspepsia persists, and in other areas (particularly renal side effects), COX-2-specific inhibitors still have classic NSAID problems.
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PMID:Cyclooxygenase-2: a major therapeutic advance? 1116 96

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

The literature on peptic ulcer and gastritis in 2000 again focused on the topics of Helicobacter pylori, nonsteroidal anti-inflammatory drugs (NSAIDs), and gastric cancer. New diagnostic tests for H. pylori infection have been evaluated, and rescue therapies for failed H. pylori eradication have been tested. The causal relationship between H. pylori infection and nonulcer dyspepsia, gastric cancer, gastroesophageal reflux disease, and NSAID-related ulcers remained heated topics of debate. In 2000, landmark clinical trials and meta-analyses were published addressing these issues. The role of endoscopy in managing nonulcer dyspepsia was better defined. The role of H. pylori eradication in NSAID/aspirin users was reexamined in high-risk patients. Clinical benefit was finally confirmed for specific inhibitors of cyclooxygenase-2 (COX-2). The millennium year turned out to be a very important one in the advancement of knowledge in this field.
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PMID:Ulcer and gastritis. 1182 5

Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic conditions requiring long-term therapy for pain relief. Currently prescribed non-steroidal anti-inflammatory drugs (NSAIDs) provide symptomatic efficacy, but are frequently associated with gastrointestinal (GI) toxicities such as dyspepsia and ulcerations. In a small but significant number of cases, complications including perforations and massive bleeding develop and these may be fatal. A desirable therapeutic strategy would maintain efficacy while minimizing gastric intolerance. Two potential approaches have been suggested: (i) administration of NSAIDs in combination with gastroprotective compounds; or (ii) administration of potentially safer anti-inflammatory compounds which act via selective inhibition of cyclooxygenase-2 (COX-2). The selective COX-2 inhibitors rofecoxib and celecoxib consistently demonstrate efficacy comparable to conventional NSAIDs in patients with RA and OA, but have a significantly reduced propensity to cause GI toxicity. In many cases, the gastric effects of therapeutically active doses of COX-2 inhibitors are indistinguishable from placebo. The safety benefits of COX-2 inhibitors given alone appear similar to combined therapy with conventional NSAIDs and gastroprotective agents. Findings warrant the consideration of COX-2 inhibitors as first-line therapy in patients requiring long-term pain relief.
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PMID:Clinical experience with cyclooxygenase-2 inhibitors. 1217 76

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of medications in the USA, annually accounting for over 100 million prescriptions. Gastrointestinal complications associated with NSAIDs are common, and result in a substantial amount of morbidity and mortality, despite the advent of the cyclooxygenase-2 selective inhibitors or 'coxibs'. Emerging clinical and economic data suggest that, depending on the baseline risk to patients, the use of a traditional NSAID alone or in combination with a proton pump inhibitor are effective and well tolerated alternatives to coxibs. The optimal therapeutic strategy for NSAID selection and use of co-therapy should be guided by a consideration of each patient's risk of having an adverse event arising from the NSAID. Patients at the highest risk for gastrointestinal complications with traditional NSAIDs are those with a history of an ulcer or ulcer complication, those of advanced age (greater than 65 years), and those receiving concurrent aspirin, anticoagulants or corticosteroid therapy. Proton pump inhibitor co-therapy is highly effective in reducing NSAID-related dyspeptic symptoms, healing the injured mucosa even in those who continue to ingest NSAIDs, and preventing gastrointestinal complications. In addition to their selective use in patients who experience NSAID-related dyspepsia and other symptoms, proton pump inhibitor co-therapy should be considered in those at high risk (with coxib or traditional NSAID therapy) and is necessary in high-risk patients receiving aspirin, with or without NSAID therapy.
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PMID:Review article: appropriate use of proton pump inhibitors with traditional nonsteroidal anti-inflammatory drugs and COX-2 selective inhibitors. 1472 81

Gastric epithelial cells were incubated with a panel of clinical isolates of Helicobacter pylori, including nonulcer dyspepsia with gastritis (HS, n = 20), gastric ulcer (HU, n = 20), duodenal ulcer (HD, n = 21), and gastric cancer (HC, n = 20). HC strains induced a higher cyclooxygenase-2 (COX-2) expression than those from HS, HD, and HU. The bacterial virulence factors and the host cellular pathways were investigated. Virulence genes of iceA, vacA, babA2, cagA 3' repeat region, and hrgA failed to show any association with the disease status and COX-2 expression. Methylation-specific polymerase chain reaction revealed HC strains not affecting the methylation status of COX-2 promoter. Nuclear factor (NF)-kappaB, NF-interleukin 6, and cAMP response element were found to be involved in COX-2 induction. We explored a novel NF-kappaB activation pathway. The mutants of TLR2 and TLR9, but not TLR4, inhibited H. pylori-induced COX-2 promoter activity, and neutralizing antibodies for TLR2 and TLR9 abolished H. pylori-induced COX-2 expression. Phosphatidylinositol-specific phospholipase C (PI-PLC), protein kinase C (PKC), and Src inhibitors inhibited COX-2 induction. The dominant-negative mutants of NIK and various IkappaB kinase complexes, including IKKbeta (Y188F), IKKbeta (Y199F), and IKKbeta (FF), inhibited the COX-2 promoter activity. Phosphorylation of GST-IKKbeta (132-206) at Tyr188 and Tyr199 by c-Src was found after H. pylori infection. In summary, H. pylori induces COX-2 expression via activations of NF-kappaB, NF-interleukin 6, the cAMP response element. In NF-kappaB activation, H. pylori acts through TLR2/TLR9 to activate both the cascade of PI-PLCgamma/PKCalpha/c-Src/IKKalpha/beta and the cascade of NIK/IKKalpha/beta, resulting in the IkappaBalpha degradation and the expression of COX-2 gene. The COX-2 overexpression may contribute to the carcinogenesis in patients colonized with these strains.
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PMID:Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. 1545 96


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