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Biomedical subjects

C J Hawkey

Publications and source records attributed to C J Hawkey.

At least 55 records · Page 3Linked to original sources
PubMed2001

Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trials.

BACKGROUND: Highly selective inhibitors of the inducible cyclooxygenase-2 enzyme (coxibs) have been associated with less gastrotoxicity than nonselective NSAIDs in clinical studies. AIM: To evaluate the influence of risk factors for NSAID-induced gastrotoxicity on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen. METHODS: We analysed pooled data from two identical double-blind, randomized, 12-week endoscopy studies which compared the gastroduodenal toxicity of placebo (n=371), rofecoxib 25 mg (n=390), rofecoxib 50 mg (n=379), and ibuprofen 2400 mg daily (n=376) in patients with osteoarthritis. The potential risk factors evaluated were: age (< 65, > or = 65 years), sex, race (white, nonwhite), Helicobacter pylori status, presence of gastroduodenal erosions at baseline, a history of upper gastrointestinal disease, prior NSAID use within 30 days of study entry, and smoking. We also evaluated these factors for possible association with the development of clinically-evident gastrointestinal perforations, ulcers or bleeds over 12 weeks. RESULTS: Across all treatment groups, the likelihood of detecting endoscopic ulcers, or of clinical presentation with a bleed, over 12 weeks was increased approximately 4-5-fold in patients with previous upper gastrointestinal disease (relative risk [95% confidence interval] of 4.2 [2.5, 7.1] for endoscopic ulcers; 3.8 [1.4, 10.6] for bleeds), or those with gastroduodenal erosions at baseline endoscopy (relative risk of 4.4 [2.6, 7.5] for endoscopic ulcers; 5.0 [1.9, 13.5] for bleeds). H. pylori infection did not increase the risk of endoscopic ulcers or bleeds (relative risk of 1.1 [0.8, 1.6] for endoscopic ulcers; 0.3 [0.1, 0.9] for bleeds). The risk factor sub-group effects were constant across all treatment groups, and the significantly higher incidence of ulcers with ibuprofen as compared to rofecoxib and placebo was maintained in all risk factor subgroups. CONCLUSIONS: Gastroduodenal erosions at baseline and a clinical history of upper gastrointestinal disease, but not H. pylori colonization, increased the risk for endoscopically-detected ulcers and clinical bleeds. Rofecoxib did not magnify the risk in any of the patient subgroups studied.

Aged↗
PubMed2001

Characteristics of patients with irritable bowel syndrome recruited from three sources: implications for clinical trials.

BACKGROUND: Variation in the characteristics of irritable bowel syndrome patients recruited for clinical trials from different sources could affect their response and the generalizability of trial results. AIM: To describe and compare the characteristics of three different groups of irritable bowel syndrome patients recruited into a 'mock clinical trial.' METHODS: We enrolled 245 irritable bowel syndrome patients from three sources: (i) 121 from British primary practitioners; (ii) 72 from California newspaper advertisements; and (iii) 52 from a California gastroenterologist's practice. We obtained demographic, clinical, and Hospital Anxiety and Depression (HAD) Scale data. RESULTS: Most patients were young to middle-aged women; the majority reported symptoms for > 5 years in all three groups. Subject characteristics varied among the groups. Typically, primary care patients were anxious, smokers and daily alcohol drinkers who had sought care recently for irritable bowel syndrome and tried antispasmodic drugs. Their symptoms were intermediate in severity between those of the other two groups. Advertisement subjects were the oldest, most highly educated, most often depressed, and were least likely to have sought care recently for symptoms, which were almost uniformly only moderate in severity. Gastroenterologist patients tended to be anxious and had nearly all sought care recently for symptoms, which were the most severe and most likely to include all three pain-related Rome I criteria. CONCLUSION: Recruitment methodology affects important characteristics of an irritable bowel syndrome study group.

Adolescent↗
PubMed2001

Eradicating Helicobacter pylori in patients with a past history of peptic ulcer: is the juice worth the squeeze?

The efficacy of Helicobacter pylori eradication for H. pylori associated duodenal ulcer disease is beyond dispute. However, little attention has been paid to how feasible it is in primary care to undertake H. pylori eradication for patients with a past history of peptic ulcer disease. Patients identified by computer search of three general practices with a documented history of peptic ulcer disease were invited to attend for H. pylori testing and eradication therapy if H. pylori positive. A total of 101 patients were identified from a combined practice size of 24,780 of whom 34 were eligible for testing. Twenty-one per cent (seven patients) declined testing, 3% (one patient) refused therapy and another 21% (seven patients) were H. pylori negative. Helicobacter pylori eradication was highly successful (95%) and had an effect on prescription and reconsultation rates at 12 months. Eradicating H. pylori in patients with a past history of peptic ulcer disease not associated with non-steroidal anti-inflammatory drug ingestion is a challenging goal in general practice.

Adult↗
PubMed2001

COX-1 and COX-2 inhibitors.

By inhibiting prostaglandin synthesis, non-steroidal anti-inflammatory drugs (NSAIDs) cause mucosal damage, ulceration and ulcer complication throughout the gastrointestinal tract. The recognition that there are two cyclo-oxygenase enzymes, one predominating at sites of inflammation (COX-2) and one constitutively expressed in the gastrointestinal tract (COX-1), has led to the important therapeutic development of COX-2 inhibitors. COX-2 is phylogenetically more primitive that COX-1 and, while very similar, has critical differences, particularly the existence of a small pocket half way down the active enzyme site. A number of drugs achieve selectivity by binding to this pocket, including presumptively rofecoxib and celecoxib. Others, such as meloxicam, may inhibit COX-2 by different mechanisms. Truly selective COX-2 inhibitors have been shown to have no effect on gastric mucosal prostaglandin synthesis, to cause no acute injury, and no chronic ulceration compared to placebo. Rofecoxib has, in a prospective systematic evaluation involving 8076 patients, been shown to reduce clinically significant ulcers, ulcer complications and gastrointestinal bleeding significantly compared to naproxen. Outcomes data for celecoxib have also been published although differences from the combined comparator agents (diclofenac and ibuprofen) did not reach statistical significance. Use of aspirin in the class study has shown that the benefits of COX-2 inhibitors may be reduced by aspirin use. The VIGOR study has raised the possibility that some NSAIDs, particularly naproxen, may protect against vascular disease compared to COX-2 inhibitors (or placebo).

Celecoxib↗
PubMed2001

Physiology and organ-related pathology of the elderly: stomach ulcers.

Peptic ulcer disease, particularly as a result of its complications, is a burden that is focused on the elderly through their higher Helicobacter pylori prevalence and use of non-steroidal anti-inflammatory drugs (NSAIDs). In these patients, senescence may further increase ulcer susceptibility, particularly in the stomach, by the loss of mucosal protection and repair mechanisms. Age is mainly a marker for the increased prevalence of other complicated ulcer risk factors such as previous ulcer history and use of anti-coagulants, steroids and aspirin. The development of selective cyclo-oxygenase inhibitors (coxibs) has reduced the specific risk of NSAID ulceration, but the residual incidence in high risk patients remains substantially higher than that in young patients without other risk factors. The argument for early surgery versus endoscopic therapy in high risk patients with bleeding ulcers has not been resolved, both having a high mortality. There is still potential for the development of new strategies to prevent primary and secondary ulcers, either by new drug development or by expanding existing co-prescription strategies.

Aged↗
PubMed2001

Rofecoxib, a COX-2 inhibitor, does not inhibit human gastric mucosal prostaglandin production.

BACKGROUND & AIMS: Rofecoxib, an inhibitor of the inducible cyclooxygenase (COX)-2 enzyme, appears not to cause acute gastroduodenal injury or chronic ulceration. To attribute this to COX-2 selectivity with sparing of gastric mucosal prostaglandin synthesis requires direct proof. METHODS: Twenty-four healthy, nonsmoking Helicobacter pylori-negative volunteers were randomized to 1 of 2 separate concurrent blinded crossover studies. Sixteen volunteers received rofecoxib, 50 mg once daily, for 5 days in one treatment period and placebo in the other. Eight volunteers similarly received naproxen, 500 mg twice daily, and placebo. On day 5 of each period, antral mucosal prostaglandin E2 (PGE2) synthesis was measured by radioimmunoassay after vortexing for 3 minutes. Whole blood COX-1 activity was measured as serum thromboxane (TXB)2- and COX-2 activity as lipopolysaccharide (LPS)-induced PGE2. RESULTS: Naproxen decreased gastric mucosal PGE2 synthesis by 65% (90% confidence interval [CI], 53%-74%; P = 0.001 vs. placebo) in contrast to an 18% increase after rofecoxib (90% CI, -11% to 57%; P = 0.313 vs. placebo). Naproxen also significantly inhibited both serum TXB2 by 94% and LPS-induced PGE2 production by 77% (both P < or = 0.002 vs. placebo), but rofecoxib only inhibited COX-2-dependent LPS-induced PGE(2) (by 79%; P < 0.001 vs. placebo). CONCLUSIONS: Rofecoxib (50 mg) lacked naproxen's ability to reduce the availability of gastroprotective prostaglandins.

Adult↗
PubMed2001

Nocardia asteroides lung abscess in acute ulcerative colitis treated with cyclosporine.

Cyclosporine is a potent suppresser of cell-mediated immunity that is mainly used in organ transplantation to prevent rejection. It is also being used increasingly outside of transplantation and probably is the only new treatment to have made an impact in acute ulcerative colitis (UC) resistant to steroid therapy. We describe a case of Nocardia asteroides lung abscess in a patient treated with cyclosporine for acute steroid resistant UC that was successfully managed with antibiotics and by discontinuing cyclosporine. With increasing use of cyclosporine for acute UC it is to be anticipated that opportunistic infections such as Nocardia will be more frequently encountered in the future.

Acute Disease↗
PubMed2001

Drug treatments in upper gastrointestinal bleeding: value of endoscopic findings as surrogate end points.

INTRODUCTION: Pharmacotherapy for upper gastrointestinal bleeding has been difficult to evaluate because clinical end points are infrequent and affected by other factors. AIMS: To evaluate whether blood in the stomach at endoscopy reflected severity of bleeding, predicted clinical outcomes, and could be altered by therapeutic agents. METHODS: We studied 414 consecutive admissions with suspected upper gastrointestinal bleeding. Patients were randomised to receive lansoprazole 60 mg followed by 30 mg four times daily, tranexamic acid 2 g followed by 1 g four times daily, both drugs, or placebo for four days, until discharge or a clinical end point occurred. Logistic regression analysis was used to determine predictors of endoscopic changes and clinical outcomes, and to investigate the effects of drug treatments on blood in the stomach. RESULTS: Of 414 patients with suspected upper gastrointestinal bleeding, 379 were endoscoped. Upper gastrointestinal bleeding was confirmed in 316. Sixteen required surgery within 30 days and 16 died on the index admission. Trial treatments were evaluable on a per protocol basis in 228 patients. The amount of blood in the stomach was found to reflect initial risk, with significant associations with high risk categorisation (odds ratio 3.7 (95% confidence interval 1.5-9.4) for more than a trace v none/trace), age (1.5 (1.1-1.9) per decade), and initial pulse (1.02 (1.00-1.04) per beat), and to predict rebleeding (9.2 (4.6-18.7)) and surgery (8.2 (2.9-22.9)). Other stigmata were less significant in these respects. The amount of blood in the stomach at endoscopy was reduced significantly by both lansoprazole (0.22 (0.07-0.63)) and tranexamic acid (0.27 (0.09-0.81)), although there was no evidence of synergy. CONCLUSIONS: Blood in the stomach reflects clinical features in patients with acute upper gastrointestinal bleeding and is reduced by treatment with lansoprazole and tranexamic acid.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2001

Update in the pharmacological management of peptic ulcer haemorrhage.

The management of peptic ulcer haemorrhage still poses questions and controversies and this applies to the pharmacological mode. This review suggests that high-dose acid suppression is beneficial in reducing rebleeding and surgery rates. The choice of acid suppressant is far from conclusive, but emerging evidence suggests that proton pump inhibitors may be more effective than H2-antagonists. The only other drug which may be useful in selected patients is octreotide, but its universal use cannot be recommended.

Anti-Ulcer Agents↗
PubMed2000

Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.

BACKGROUND: Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. METHODS: We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). RESULTS: Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. CONCLUSIONS: In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.

Adult↗
PubMed2000

Differential levels of granzyme B, regulatory cytokines, and apoptosis in Crohn's disease and ulcerative colitis at first presentation.

The mechanisms of tissue damage in ulcerative colitis and Crohn's disease may reflect disordered humoral or cell-mediated effector mechanisms, respectively. Mucosal biopsies from untreated inflammatory bowel disease patients and normal controls were analysed for the expression of granzyme B, a cytotoxic effector molecule specifically associated with cell-mediated immunity, and for regulatory cytokines. Messenger RNA (mRNA) was analysed by reverse transcription-polymerase chain reaction and enzyme-linked oligonucleotide chemiluminescence assay. Mucosal biopsies were analysed by immunohistochemistry for granzyme B protein and lymphocyte markers and for the presence of apoptotic cells by terminal deoxynucleotidyl transferase end labelling. Granzyme B mRNA was elevated in Crohn's disease, but not in ulcerative colitis or control mucosal biopsies. Granzyme B mRNA levels correlated with interferon gamma mRNA levels in Crohn's disease. Granzyme B was expressed in CD3+, CD8+ T cells in the lamina propria of Crohn's disease mucosa and there were significantly more apoptotic cells in the lamina propria in Crohn's disease. In conclusion, granzyme B-expressing T lymphocytes are present in the focal mucosal lesions of Crohn's disease, together with spatially related apoptotic cell death. These results support the hypothesis that T-cell-mediated cytotoxic effector mechanisms may play a role in Crohn's disease.

Adolescent↗
PubMed2000

The nonsteroidal anti-inflammatory drugs controversy.

The relationship between NSAIDs and H. pylori as risk factors for the development of peptic ulcer is complex and controversial. In the case of duodenal ulcers in NSAID users, there now is enough information to suggest that eradication of H. pylori usually is worthwhile. In the stomach, however, there is some evidence that ulcers heal faster and are no more likely to reappear if the infection is left alone, provided that patients continue to take an NSAID. Why this situation should be so is unclear. Possibilities include greater efficacy of antisecretory agents, a smaller inhibition of prostaglandin production, and a blunted apoptotic response in patients who are infected with H. pylori and take NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Ibuprofen versus other non-steroidal anti-inflammatory drugs: use in general practice and patient perception.

OBJECTIVE: To investigate whether ibuprofen was as well-regarded by patients as other non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN: Questionnaire sent to 1137 consecutive recipients of an NSAID prescription from 21 doctors in six general practices with computerized records. Patient responses were subsequently linked to data held on the practice records. SETTING: General practices in and around Nottingham, selected to reflect local variations in number of partners, list size, geographical location, deprivation, prescribing burden and prescribing rate. SUBJECTS: Unselected patients receiving NSAIDs prescribed for all indications for use. MAIN OUTCOME MEASURES: Effectiveness of ibuprofen and other NSAIDs, possible drug related adverse events, patients' overall satisfaction with ibuprofen and other NSAIDs, factors associated with choice of ibuprofen, drug costs of ibuprofen and other NSAIDs. RESULTS: The main NSAIDs used were ibuprofen, diclofenac and naproxen. Ibuprofen use ranged from 1.0% of prescriptions in one practice to 69.1% in another. Although ibuprofen was generally prescribed in low doses, it was perceived by patients as being as effective as the other NSAIDs used, even after allowing for severity of the pre-treatment condition. Overall, 50.5% of patients rated their NSAID the best treatment they had received for their condition with no differences between individual drugs. CONCLUSIONS: Ibuprofen is as highly regarded as other NSAIDs when used in similar circumstances. Switching patients to ibuprofen may be a realistic way of reducing financial and medical costs associated with NSAIDs.

Adolescent↗
PubMed2000

Pharmacoepidemiology of non-steroidal anti-inflammatory drug use in Nottingham general practices.

AIM: To investigate the pharmacoepidemiology of NSAID usage in Nottingham general practices. DESIGN: Questionnaire sent to 1137 consecutive recipients of an NSAID prescription from 21 doctors in six general practices with computerized records. Patient responses were subsequently linked to data held on the practice records. SETTING: General practices in and around Nottingham, selected to reflect local variations in number of partners, list size, geographical location, deprivation, prescribing burden and prescribing rate. SUBJECTS: Unselected patients receiving NSAIDs prescribed for all indications. MAIN OUTCOME MEASURES: Indication for treatment, differences in prescribing to different age groups, compliance and overall scheme drug exposure, drug effectiveness and tolerability, possible drug-related adverse events, patients' overall satisfaction with treatment and estimated costs of care. RESULTS: NSAIDs were used for a wide range of conditions and only a small number of patients had rheumatoid arthritis. The main drugs used were ibuprofen, diclofenac and naproxen. Patients making short-term use of NSAIDs had low compliance if they experienced adverse drug effects, whilst conversely in long-term users, those with high compliance reported more adverse drug effects. Calculated compliance did not vary with age although older patients (over 65 years) claimed in their questionnaires to be more compliant than younger patients. Half the patients reported good or complete symptom relief. Half of those questions (and two thirds of those with good or complete symptom relief) rated their NSAID as the best treatment they had received for their current condition. The frequency of gastrointestinal adverse events was higher in the young and the old, which correlated with the use of anti-ulcer drugs, and increased with the total number of medications used. CONCLUSIONS: NSAIDs are used for a wide-range of conditions. They give symptom relief to, and are perceived as effective by, most patients taking them.

Adolescent↗
PubMed2000

Low-dose misoprostol for the prevention of low-dose aspirin-induced gastroduodenal injury.

INTRODUCTION: The harmful effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastric mucosa and the prophylactic effects of misoprostol are both dose-dependent. AIM: To investigate whether a low-dose of misoprostol is sufficient to prevent gastric mucosal injury caused by low-dose aspirin. METHODS: We conducted a double-blind placebo controlled parallel group endoscopic study in 32 evaluable volunteers. The main outcome measure was erosive injury (ulcers and superficial erosions) in the gastric mucosa over 28 days. RESULTS: Most subjects developed erosions on aspirin 300 mg daily. This was significantly reduced by misoprostol 100 microg daily. (Odds ratio 0.18, 95% CI: 0.07-0.48). There were no drug-related or gastrointestinal adverse events in subjects receiving misoprostol. CONCLUSION: Misoprostol 100 microg daily can prevent low-dose aspirin induced gastric mucosal injury without causing identifiable adverse effects.

Adult↗
PubMed2000

Dose-dependent effects of ketoprofen on the human gastric mucosa in comparison with ibuprofen.

BACKGROUND: As non-steroidal anti-inflammatory drugs (NSAIDs) become available for over-the-counter use, it is important to define doses that would not cause undue gastroduodenal damage during the short periods for which self-medication with NSAIDs is licensed. AIM: To establish what dose of ketoprofen most closely resembles the maximum dose of ibuprofen (400 mg t.d.s.) licensed for self-medication. METHODS: We studied healthy volunteers in a double-blind double-dummy randomized crossover study. Each subject took, over four separate 10-day dosing periods, ibuprofen 400 mg t.d.s., ketoprofen 12.5 mg t.d.s., ketoprofen 25 mg t.d.s. or ketoprofen 50 mg t.d.s. Mucosal injury was assessed by endoscopy at baseline and on the 3rd and 10th day of each dosing period. Ex vivo gastric mucosal prostaglandin (PG) E2 evoked by vortex mixing was measured by radioimmunoassay. Serum thromboxane was also measured by radioimmunoassay. RESULTS: Ketoprofen 50 mg t.d.s. suppressed prostaglandin synthesis to a significantly greater extent than ibuprofen and caused significantly more gastroduodenal injury. The profile of prostaglandin synthesis and injury on ketoprofen 12.5 mg t.d.s. most closely resembled that of ibuprofen 400 mg t.d.s. CONCLUSIONS: Ketoprofen 12.5 mg t.d.s. is an appropriate dose for self-medication, which is likely to be similar to ibuprofen 400 mg t. d.s. in its effects on the stomach and duodenum.

Administration, Oral↗
PubMed2000

Acid suppression in peptic ulcer haemorrhage: a 'meta-analysis'.

BACKGROUND: The use of acid-decreasing agents in the management of peptic ulcer haemorrhage continues to be controversial. Most clinical trials examining the efficacy of these drugs contain small numbers of patients, making it difficult to draw conclusions about their efficacy. METHODS: We report a meta-analysis that examined the effect of these drugs in the management of peptic ulcer haemorrhage. Included studies were located using a search of the Medline database between 1980 and 1999. Studies were published in English, randomized and controlled by a placebo group. Mantel-Haenszel and blinded random models were used in conducting the statistical processing of this meta-analysis. RESULTS: Twenty-one randomized placebo-controlled trials were included. The total number of patients was 3566 and the mean study size was 170 (range 20-1005). Seventeen of the papers assessed the efficacy of H2-antagonists, three assessed proton pump inhibitors and one was concerned with antacid therapy. The meta-analysis showed a significant reduction in re-bleeding rates (odds ratio, OR 0.727, 0.618-0.855, P < 0.001) and surgery rates (OR 0.707, 0.582-0.859, P < 0.001) when acid decreasing agents are used for acute peptic ulcer haemorrhage. Mortality rates appear to be unaffected (OR 1.140, 0.818-1.588, P=0. 49). CONCLUSIONS: This meta-analysis demonstrates a significant beneficial effect of acid-decreasing agents in lowering re-bleeding and surgery rates, but demonstrated no effect upon mortality.

Antacids↗