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Biomedical subjects

C J Hawkey

Publications and source records attributed to C J Hawkey.

At least 37 records · Page 2Linked to original sources
PubMed2003

Dual COX inhibition and upper gastrointestinal damage.

Aspirin and non-aspirin NSAIDs injure the gastrointestinal tract principally as a result of their inhibition of prostaglandin synthesis. This is mediated via abrogation of the secretion of mucus and bicarbonate and by reduction in mucosal blood flow. Topical injury and inhibition of platelet thromboxane may also contribute respectively to damage and ulcer bleeding. Recognition of a second cyclooxygenase, COX-2, enabled drugs to be developed that selectively target this enzyme which is expressed in inflamed joints. These have proved to be effective treatments whilst causing little or no acute gastroduodenal injury and reduced ulcers and their complications. Future strategies may capitalise upon the phenomenon of substrate diversion of lipoxygenase products. Balanced cyclooxygenase/lipoxygenase inhibition maybe less harmful than cyclooxygenase inhibition. Also, nitric oxide can subserve many of the protective effects of prostaglandins and NO-donating NSAIDs are under evaluation.

Cyclooxygenase 1↗
PubMed2003

COX-LOX inhibition: current evidence for an emerging new therapy.

Safe and effective drug treatment is an important objective of all doctors. In the treatment of arthritis, non-steroidal anti-inflammatory drugs offer effective treatment but safety is significantly limited, largely due to gastrointestinal toxicity. Attention has recently focused on exploiting increased knowledge of metabolism of arachidonic acid to allow the development of safer anti-inflammatory drugs. Dual inhibitors of cyclo-oxygenase and lipoxygenase are planned. These drugs may inhibit formation of both prostaglandins and leukotrienes. This review outlines the salient features of cyclo-oxygenase and lipoxygenase metabolism of arachidonic acid. The role of the eicosanoids in mediating inflammation and gastrointestinal integrity is delineated. Evidence is presented regarding action of licofelone, one COX/LOX inhibitor that is currently in advanced stages of clinical trials. This review examines the hypothesis that licofelone is an effective anti-inflammatory agent that does not cause peptic damage.

Acetates↗
PubMed2002

Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding.

AIM: To investigate the role of Helicobacter pylori, expressing the virulence marker CAGA (cytotoxin associated gene product A) in ulcer complications and its interaction with nonsteroidal anti-inflammatory drugs (NSAIDs) and other risk factors. DESIGN: Case control study using conditional logistic regression analysis. SETTING: University and City Hospitals, Nottingham. SUBJECTS: 203 consecutive patients with ulcer bleeding and 203 age- and sex-matched controls. RESULTS: Ulcer bleeding was more likely with positive H. pylori serology (odds ratio = 3.3, 95% CI: 1.7--6.6 for CagA positive, but only OR = 1.6, 95% CI: 0.7-3.7 for CagA negative serology), current smoking (OR 2.2, 95% CI: 1.04-4.7), aspirin < or = 300 mg daily (OR 7.7, 95% CI: 2.8-20.6), all other nonsteroidal anti-inflammatory drugs (NSAIDs: OR 10.6, 95% CI: 3.1-35.7 for < or = 1 defined daily dose lower and OR 22.6, 95% CI: 6.2-82.0 for higher doses) and past ulcer history (OR 5.6, 95% CI: 2.3-14.1). Aspirin < or = 300 mg daily was used by 25.1% of patients vs. 7.4% of controls. Smoking only enhanced risk in the presence of H. pylori, with a synergistic interaction (interaction odds ratio = 4.9, 2.4-9.9, P=0.002). Conversely, risks with non-aspirin NSAIDs were reduced in the presence of H. pylori, particularly if CagA-positive (interaction odds ratio=0.21, 0.05-0.9, P=0.03). CONCLUSIONS: CagA positive H. pylori infection is associated with an increased risk of ulcer bleeding. The risk from non-aspirin NSAIDs is even higher, but is less in H. pylori infected people. Low-dose aspirin is now commonly associated with ulcer bleeding.

Adult↗
PubMed2002

Cyclooxygenase inhibition: between the devil and the deep blue sea.

Non-steroidal anti-inflammatory drugs (NSAIDs) account for more reports of drug related toxicity than any other class of drugs. Their most widely recognised adverse effects are on the gastrointestinal tract. They cause acute erosions and chronic ulcers that result in hospitalisation and death because of ulcer bleeding and perforation. Between them, aspirin and non-aspirin NSAIDs may account for more than half of all episodes of ulcer bleeding and perforation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Relative contribution of mucosal injury and Helicobacter pylori in the development of gastroduodenal lesions in patients taking non-steroidal anti-inflammatory drugs.

BACKGROUND AND AIMS: A past history of peptic ulceration increases the risk of an ulcer developing during non-steroidal anti-inflammatory drug (NSAID) use. Whether this is due to Helicobacter pylori infection or to reactivation of the original lesion is unclear. METHODS: We used multivariate regression analyses of three large similar trials to identify factors that placed patients at high risk of ulcer development or relapse. We compared the efficacy of omeprazole 20 mg daily, misoprostol 200 micro g twice daily, and ranitidine 150 mg twice daily in preventing ulcers and erosions at different sites and in patients who were H pylori positive and negative. RESULTS: Patients with endoscopic lesions (which healed) initially were significantly more likely than those without to develop further erosions or ulcers during treatment (rate ratio 2.12, 1.07-4.17). Risk mounted further with ulcers versus erosions, particularly those that had been slow to heal. There was a highly significant tendency for the relapse lesion to replicate the site and type of the original lesion (mean odds ratios ranging from 3 to 14). Treatment failure was significantly less likely with omeprazole than with placebo, misoprostol, or ranitidine. This advantage was especially evident in H pylori positive patients receiving acid suppression (5.7% v 16.6% for gastric ulcer with omeprazole). CONCLUSIONS: Relapse of lesions in patients taking NSAIDs was highly site and type specific and not adversely affected by H pylori status. This strongly implies that local mucosal factors predispose to ulcer development in patients taking NSAIDs. Identification of the responsible mucosal changes would aid understanding and could promote better treatment.

Adult↗
PubMed2002

Influence of sex and Helicobacter pylori on development and healing of gastroduodenal lesions in non-steroidal anti-inflammatory drug users.

BACKGROUND AND AIMS: Factors predisposing to endoscopic ulcer formation or healing with non-steroidal anti-inflammatory drugs (NSAIDs) have not been well defined. METHODS: We used multivariate analysis of data from three large similar trials to identify factors associated with endoscopic lesions and healing. We compared the effectiveness of omeprazole 20 mg and 40 mg daily, misoprostol 200 micro g four times daily, and ranitidine 150 mg twice daily in healing ulcers and erosions at different sites and in patients who were Helicobacter pylori positive and negative. RESULTS: Older age, past ulcer history, rheumatoid arthritis, and H pylori infection were significantly associated with ulcers. Duodenal ulcer was significantly more likely than gastric ulcer with a past ulcer history (odds ratio 1.59, 1.16-2.17), H pylori infection (1.4, 1.04-1.92), and male sex (2.35, 1.75-3.16) while female sex, older age (> or = 60 years: 1.39, 1.03-1.88), and higher NSAID dose (>1 defined daily dose: 1.57, 1.16-2.14) were associated with gastric ulceration. Sex differences were seen in both H pylori positive and negative patients. Gastric and duodenal ulcer healing was significantly faster with omeprazole 20 mg than with misoprostol 200 micro g four times daily or ranitidine 150 mg twice daily although misoprostol was more effective at healing erosions. Gastric ulcer healing was slower with large ulcers (0.37, 0.25-0.54 for >10 mm v 5-10 mm) or a past ulcer history (0.51, 0.34-0.76), and faster with H pylori infection (1.55, 1.06-2.29), especially with acid suppression (72% v 37% at four weeks with ranitidine). CONCLUSIONS: Among NSAID users, H pylori and male sex independently increase the likelihood of duodenal ulceration. H pylori infection does not affect duodenal ulcer healing and enhances gastric ulcer healing by ranitidine and possibly other acid suppressing treatments.

Adult↗
PubMed2002

Gastrointestinal safety of selective COX-2 inhibitors.

It appears that selective Cox-2 inhibitors do not affect the gastro duodenal mucosa whilst having anti-inflammatory and analgesic efficacy similar to non-selective NSAIDs. Two broad categories of drugs are Cox-2 selective: coxibs and a number of pre-existing NSAIDs retrospectively found to have selectivity. Cox-2 inhibitors cause less dyspepsia than NSAIDs. They spare gastrointestinal mucosal generation of prostaglandins (PGs) and PG-dependent bicarbonate secretion. Coxibs cause no acute mucosal injury in endoscopic ulcers compared to NSAID comparators. In the VIGOR study all upper GI events were reduced from 4.5 per 100 patient years to 2.1 per 100 patient years with supra-therapeutic doses of rofecoxib compared with naproxen. In the CLASS study, over a period of 3 days to 6 months, incidence of ulcer complications was 0.76% with celecoxib and 1.45% for ibuprofen or diclofenac. The less substantial reduction in events in the CLASS study compared with the VIGOR may be due, at least in part, to the fact that 21% of the patients were also on low dose aspirin. However it is premature to say that the benefit of Cox-2 inhibitors is lost in patients taking aspirin. There is continuing debate on the role of Cox-2 inhibitors in patients who have other risk factors for complicated ulcer disease e.g. patients who are elderly, on aspirin or corticosteroids, have a previous ulcer or have H. pylori infection.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Prescribing in the UK.

Explore the source record for details and available documents.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Questions regarding future research on aspirin and the gastrointestinal tract.

Despite great proven and potential benefits, aspirin also has adverse side effects on all parts of the gastrointestinal tract including ulceration, bleeding, perforation, and stenosis. Because of widespread and growing use, there is a need to understand and, if possible, prevent the adverse effects of aspirin while maintaining its benefits. This article is part of a report from a consensus meeting in 1999 on nonsteroidal anti-inflammatory drugs, and examines possible mechanisms of each of the risks of normal and low-dose aspirin use including areas of uncertainty. Based on these issues, we recommend studies that would further clarify the actions of aspirin. We also examine various strategies that might be used to prevent or mitigate adverse effects. Finally, we propose future research prospects in the search for a safer aspirin.

Animals↗
PubMed2001

Gastrointestinal safety of COX-2 specific inhibitors.

Coxibs are a major advance in the therapy of patients with painful and inflammatory conditions. At present, the theoretical harm that derives from inhibiting vascular COX-2 has not emerged as a significant risk, although more research is needed. What has emerged is that some NSAIDs, particularly naproxen, may have an aspirin-like effect in reducing the risk of vascular disease, although more research is needed. Whether this finding is sufficient to recommend naproxen for the management of patients with arthritis who also require vascular protection is intriguing and worth further evaluation. It is widely believed and maintained that coxibs have the greatest potential value in patients with other risk factors for ulcer disease, and this seems likely to be the case for patients taking corticosteroids or anticoagulants and probably those who are elderly. Dosing should be [figure: see text] cautious in old patients, however, because of the ability of NSAIDs and coxibs to cause fluid retention, heart failure, and hypertension. It is less clear that coxibs reduce risk sufficiently in patients with previous ulceration (particularly recent) to make them a better strategy than acid co-therapy. This possibility requires further evaluation, as does the competing value of the 2 strategies for patients infected with H. pylori. If coxibs are used in patients with H. pylori-associated risks, there are grounds to recommend eradication. For patients taking aspirin or drugs [figure: see text] with an aspirin-like effect, the intrinsic risk of these drugs may mandate use of acid suppression and obviate the use of coxibs (Fig. 8). Available data suggest that the risk reduction in patients with no risk factors who use coxibs may be almost as great as in patients with risk factors, with the added advantage that patients may be taken to a state that is virtually free of any risk of ulcer complications that otherwise might require additional therapy. Contrary to current popular truisms, the greatest value of coxibs may be in patients without risk factors because it is in this unconfounded group that the ability of coxibs to free patients of ulcer risk appears to be delivered in full.

Adrenal Cortex Hormones↗
PubMed2001

Review article: the gastrointestinal safety profile of rofecoxib, a highly selective inhibitor of cyclooxygenase-2, in humans.

Highly selective inhibitors of cyclooxygenase-2, such as rofecoxib, are hypothesized to have an improved gastrointestinal tolerability and safety profile compared with non-selective NSAIDs, which inhibit cyclooxygenase-1 and cyclooxygenase-2 non-selectively. This paper reviews data from randomized, double-blind, placebo-controlled studies which investigated the effects of rofecoxib and NSAIDs on the human gastrointestinal tract. In healthy subjects, rofecoxib 25 mg and 50 mg daily had no effect on gastric mucosal prostaglandin synthesis, whilst naproxen 1000 mg daily caused a 70% reduction. Therapeutic doses of rofecoxib 25 mg and 50 mg daily did not increase intestinal permeability or faecal blood loss in healthy subjects, whereas increases in both measures were seen with indometacin 150 mg or ibuprofen 2400 mg. A supra-therapeutic dose of rofecoxib (250 mg) given daily for 7 days did not induce an increase in gastroduodenal erosions in healthy subjects, whilst increased numbers of erosions were found in subjects given ibuprofen 2400 mg or aspirin 2600 mg. The endoscopic findings in healthy subjects were confirmed in two 6-month clinical studies involving 1516 patients with osteoarthritis; the incidences of ulcers following rofecoxib 25 mg or 50 mg daily were similar to placebo and less than ibuprofen 2400 mg. The advantage of rofecoxib over NSAIDs in these studies appears to translate into clinically relevant benefits; an analysis of 5435 patients with osteoarthritis found a significantly lower incidence of gastrointestinal perforations, ulcers and bleeds in patients taking rofecoxib compared with patients taking NSAIDs. Overall, the findings from these studies suggest that, as a result of cyclooxygenase-1 sparing, rofecoxib is significantly less gastrotoxic than non-selective NSAIDs, and may not differ from placebo.

Anti-Inflammatory Agents, Non-Steroidal↗