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Biomedical subjects

C J Hawkey

Publications and source records attributed to C J Hawkey.

At least 19 recordsLinked to original sources
PubMed2003

Safety and efficacy of 7-day rabeprazole- and omeprazole-based triple therapy regimens for the eradication of Helicobacter pylori in patients with documented peptic ulcer disease.

AIM: A double-blind, randomized study was designed to determine whether rabeprazole- and omeprazole-based triple therapy regimens are therapeutically equivalent in the eradication of Helicobacter pylori. METHODS: Three hundred and forty-five patients with current or previously active peptic ulcer and a positive H. pylori urease test were randomly assigned to receive RCA, OCA, RCM or OCM twice daily for 7 days (R, rabeprazole 20 mg; O, omeprazole 20 mg; C, clarithromycin 500 mg; A, amoxicillin 1000 mg; M, metronidazole 400 mg). H. pylori eradication was documented by negative 13C-urea breath tests at 4 and 12 weeks, and was evaluated using a 2 x 2 factorial design with proton pump inhibitor and antibiotic as factors. RESULTS: Overall eradication rates (per protocol/intention-to-treat) were 87%/77% and 85%/75% with rabeprazole and omeprazole, respectively (not significant). However, a statistical interaction between proton pump inhibitor and antibiotic was identified. RCA produced a somewhat higher eradication rate than OCA (94% vs. 84%; difference, 9.8%; 95% confidence interval, - 0.7% to + 20.4%), whereas RCM produced a lower eradication rate than OCM (79% vs. 86%; difference, 8.1%; 95% confidence interval, - 21.4% to + 5.1%). Ulcer healing rates were > 90% with H. pylori eradication. Each regimen was well tolerated. CONCLUSIONS: Rabeprazole- and omeprazole-based triple therapy regimens are therapeutically equivalent in the eradication of H. pylori and well tolerated. The statistical interaction observed between the proton pump inhibitor and supplementary antibiotic may be due to chance.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2003

Non-steroidal anti-inflammatory drugs: overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well recognised as causing peptic ulceration and ulcer complications. However, several critical issues, including the amount of both gastrointestinal and non-gastrointestinal disease affected by NSAIDs, their interaction with ancillary risk factors, and how to optimise management in subgroups, remain poorly understood. In this article, strategies for subgroups that take account of non-specific gastrointestinal risks, minimisation of residual risk, and the importance of non-gastrointestinal toxicity are suggested, and areas for research identified.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study.

BACKGROUND: Previous studies in patients with osteoarthritis have suggested that the selective cyclooxygenase (COX)-2 inhibitor rofecoxib results in less gastrointestinal damage than non-selective non-steroidal antiinflammatory drugs (NSAIDs). This study compared the incidence of endoscopically detected gastroduodenal ulcers in rheumatoid arthritis patients treated with rofecoxib or a non-selective NSAID. METHODS: In this multicentre, randomised, double blind, 12 week study, patients with rheumatoid arthritis were allocated to rofecoxib 50 mg once daily (n=219), naproxen 500 mg twice daily (n=220), or placebo (n=221). Endoscopy was performed at baseline and at six and 12 weeks. Lifetable analysis and log rank tests were used to analyse the incidence of gastroduodenal ulcers > or =3 mm. Gastric or duodenal ulcers > or =5 mm and erosions were also evaluated as secondary end points. Tolerability was assessed by adverse events. RESULTS: The cumulative incidence of ulcers > or =3 mm at 12 weeks was significantly higher in patients on naproxen (25.5%) than in patients receiving rofecoxib (6.8%; difference 18.7% (95% confidence interval (CI) 11.7%, 25.7%); p<0.001) or placebo (2.9%; difference 22.6% (95% CI 16.1%, 29.1%); p<0.001). The difference between rofecoxib (6.8%) and placebo (2.9%) did not reach statistical significance (p=0.066). Results were similar for ulcers > or =5 mm and for mean changes from baseline in the number of gastroduodenal erosions. The overall incidence of clinical adverse events was similar among treatment groups (61% of patients on placebo, 62% in patients on rofecoxib, and 66% in patients on naproxen). CONCLUSIONS: Rofecoxib 50 mg daily (twice the dose recommended for this patient population) resulted in a lower incidence of endoscopically detected gastroduodenal ulcers and erosions than treatment with naproxen 500 mg twice daily.

Adult↗
PubMed2003

Potential role for peroxisome proliferator activated receptor (PPAR) in preventing colon cancer.

BACKGROUND: Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors involved in genetic control of many cellular processes. PPAR and PPAR have been implicated in colonic malignancy. Here we provide three lines of evidence suggesting an inhibitory role for PPAR in colorectal cancer development. METHODS: Levels of PPAR mRNA and protein in human colorectal cancers were compared with matched non-malignant mucosa using RNAse protection and western blotting. APC(Min)/+ mice were randomised to receive the PPAR activator methylclofenapate 25 mg/kg or vehicle for up to 16 weeks, and small and large intestinal polyps were quantified by image analysis. The effect of methylclofenapate on serum stimulated mitogenesis (thymidine incorporation), linear cell growth, and annexin V and propidium iodide staining were assessed in human colonic epithelial cells. RESULTS: PPAR (mRNA and protein) expression levels were significantly depressed in colorectal cancer compared with matched non-malignant tissue. Methylclofenapate reduced polyp area in the small intestine from 18.7 mm(2) (median (interquartile range 11.1, 26.8)) to 9.90 (4.88, 13.21) mm(2) (p=0.003) and in the colon from 9.15 (6.31, 10.5) mm(2) to 3.71 (2.71, 5.99) mm(2) (p=0.009). Methylclofenapate significantly reduced thymidine incorporation and linear cell growth with no effect on annexin V or propidium iodide staining. CONCLUSIONS: PPAR may inhibit colorectal tumour progression, possibly via inhibition of proliferation, and may be an important therapeutic target.

Animals↗
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.

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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↗