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Biomedical subjects

C J Hawkey

Publications and source records attributed to C J Hawkey.

At least 145 records · Page 8Linked to original sources
PubMed1996

Mucosal factors inducing neutrophil movement in ulcerative colitis: the role of interleukin 8 and leukotriene B4.

BACKGROUND: The movement of neutrophils into the colonic mucosa in ulcerative colitis is induced by chemokines including interleukin 8 (IL8) and leukotriene B4 (LTB4). AIMS: To compare the ability of mucosa from ulcerative colitis patients and controls to stimulate neutrophil movement, to define the contribution of LTB4 to this, and to define the relative biological importance of LTB4 and IL8. PATIENTS: Resected mucosa was obtained from seven control patients and 10 patients with ulcerative colitis. METHODS: Mucosal homogenate supernatants were used to stimulate isolated neutrophils and the effect assessed by the neutrophil shape change response. Responses were inhibited with either the LTB4 receptor antagonist SC41930- or neutralising anti-IL8 antibody. LTB4 was extracted and assayed by RIA. RESULTS: Homogenate supernatants from inflamed mucosa were more bioactive (median 1.2 mg/ml-1 induced 50% response) than those from uninflamed mucosa (4.25 mg/ml-1 induced 50% response; difference 2.8 mg/ml-1 (96.5% CI 0.5 to 6.1, p < 0.05). Maximal inhibition by SC41930 of the response was significantly greater in inflamed mucosa (54% median) than in uninflamed mucosa (34%). This inhibition correlated with the level of immunoreactive LTB4 (r = 0.78). Anti-IL8 reduced bioactivity of homogenate supernatants from inflamed mucosa (at 1:10 dilution) by 11.4% (IQR 1.2 to 51.8, p = 0.021) whereas SC41930 reduced it by 54.8% (35.6 to 77.5, p = 0.008). CONCLUSIONS: Inflamed colonic mucosa releases more neutrophil movement inducing bioactivity than uninflamed mucosa, and has greater LTB4 dependent activity. It yields both IL8 and LTB4 dependent activity but greater LTB4 dependent activity.

Adult↗
PubMed1996

Non-steroidal anti-inflammatory drug gastropathy: causes and treatment.

Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) almost invariably cause acute gastroduodenal injury and probably account for approximately 12,000 ulcer bleeding episodes and 1200 deaths per annum in the United Kingdom. Clinically significant intestinal toxicity is also recognized but less clearly defined. The main risk factors for NSAID-related peptic ulcer complications are age, past history, use of higher risk individual NSAIDs, drug dose, concurrent use of warfarin or corticosteroids. The underlying reason for NSAID use and Helicobacter pylori status is not clearly associated with increased risk. Whether NSAIDs cause drug-induced non-ulcer dyspepsia is also controversial. Acute injury occurs more readily with aspirin than with non-aspirin NSAIDs, and the spectrum of acute injury is of little value in predicting clinically significant end points in comparison with different NSAIDs. However, acute studies of co-prescribed protective agents are highly predictive of performance in clinical practice. Gastric mucosal integrity is maintained by the interplay of three protective networks: prostaglandin synthesis, nitric oxide synthesis and the activity of the enteric nervous system. Aspirin and NSAIDs act by inhibiting prostaglandin synthesis catalysed by two cyclooxygenase enzymes. Most existing NSAIDs are unselective and inhibit the activity of the constitutive cyclooxygenase (COX) 1 enzyme in the stomach as much as the cyclooxygenase (COX) 2 enzyme which is induced at sites of inflammation such as joint disease. There are, however, prospects for selective cyclooxygenase 2 inhibitors. Some NSAIDs, particularly aspirin, have additional topical toxicity, which may in part reflect mucosal trapping. Some data favor an effect of NSAIDs in inhibiting mitochondrial oxidative phosphorylation. The principal physiological mechanisms which are compromised by NSAID use are mucosal blood flow, secretion of mucus and bicarbonate and maintenance of a hydrophobic mucosal surface. Animal data suggest that polymorphonuclear leukocytes (PMNs) are important for acute damage though the relevance to humans has yet to be established. As well as damaging the mucosa, NSAIDs impair ulcer healing and are associated with reduced epithelial proliferation and evidence of diminished angiogenesis. An interaction between prostaglandins and growth factors, as well as the synthesis of antiproliferative products of arachidonic acid metabolism may be involved. Healing of NSAID ulcers by conventional doses of H2 antagonists is slow and H2 antagonists are poor at preventing gastric ulcer development or recurrence. These problems can be overcome by the use of more potent acid suppression. Misoprostol heals NSAID-associated ulcers, though whether healing is as fast as with non-NSAID ulcers has not been formally established. Misoprostol is effective prophylactic treatment but has a significant incidence of adverse events, particularly diarrhoea. Misoprostol has been reported to prevent ulcer complications, and in endoscopic studies has been superior as prophylaxis to standard dose ranitidine. Results of its efficacy compared to proton-pump inhibitors are awaited. For many patients appropriate management is avoidance of NSAIDs or use of less potent/toxic alternatives such as ibuprofen. Reductions in prescribing arising from a prior authorization scheme show that this can be achieved. For high-risk patients requiring continuing NSAID use co-prescription of omeprazole or misoprostol should be considered.

Acute Disease↗
PubMed1996

Quality of life in users of non-steroidal anti-inflammatory drugs.

In clinical practice, non-steroidal anti-inflammatory drugs are used for a wide variety of painful conditions, in many of which inflammation is not a fundamental feature. Despite this they are favourably perceived by patients and limited data suggest that when used for relatively 'minor' conditions they are probably more effective than paracetamol. However, some patients develop life-threatening complications from these drugs. Assessment of Quality of Life (QOL) in NSAID users represents a balance between the adverse effects of the underlying condition, the QOL disturbance from side effects from NSAID use and the benefits and side effects of drugs used as prophylaxis against NSAID complications. The Health Assessment Questionnaire (HAQ) is a well-established scale measuring QOL in patients with rheumatoid arthritis, but there are fewer established instruments for use in patients using NSAIDs for other conditions.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Personality, smoking and inflammatory bowel disease.

OBJECTIVE: To assess whether psychological factors distinguished patients with Crohn's disease (CD) from those with ulcerative colitis (UC). DESIGN: Survey of prevalent inflammatory bowel disease patients (n = 82) attending a gastroenterology clinic. METHODS: Administration of three self-report rating scales, the Eysenck Personality Questionnaire, the General Health Questionnaire and the Hospital Anxiety and Depression scale. RESULTS: CD patients were significantly more extroverted (P = 0.04) than UC patients, tended to have higher psychoticism scores (P = 0.06) but similar neuroticism scores. Extroversion and psychoticism scores were weakly associated with smoking status. In logistic regression models that adjusted for age, sex and smoking the associations with extroversion and psychoticism scores persisted but were no longer significant at the 5% level. In the final model the psychoticism score was more important than the extroversion score. CONCLUSION: These results suggest that there are substantial personality differences between patients with CD and UC. Although some of the differences in this study were associated with smoking, adjusting for smoking reduced, but did not abolish, the associations with personality scores.

Colitis, Ulcerative↗
PubMed1995

Safety of acid-suppressing drugs.

There is an extensive literature on the adverse effects of drugs that inhibit gastric acid secretion. This study presents a critical examination of interactions between antisecretory drugs and other compounds, the frequency of serious adverse effects relating to various body systems, the safety of antisecretory drugs in pregnancy, and longer-term safety data from postmarketing surveillance studies. While interactions with some other drugs, alcohol, and certain carcinogens are of potential concern, in practice clinically significant reactions appear to be rare if they occur at all. A small number of major side-effects have been documented, but they occur rarely, and postmarketing surveillance has not detected other longer-term sequelae. Safety of these drugs in pregnancy is not established, as data are so few. It is concluded that antisecretory agents, by comparison with most other classes of drugs, are remarkably well tolerated.

Female↗
PubMed1995

A flow cytometric method to measure shape change of human neutrophils.

1. We report a flow cytometric method in which changes in forward angle light scatter are shown to correlate with microscopically evaluated shape change in stimulated human neutrophils. Neutrophil movement and chemotaxis is conventionally measured using Boyden chambers, which is a laborious and exacting technique. Microscopic scoring of neutrophil shape change has been shown to correlate well with Boyden chamber measurements, and although less laborious, still requires manual counting. 2. We now show that measurement of forward angle light scatter in a benchtop flow cytometer correlates closely with microscopic evaluation of neutrophil shape change in dose-response stimulation experiments with leukotriene B4, N-formyl-methionine-leucine-phenylalanine or interleukin-8. The relationship between shape change and increased forward angle light scatter was confirmed using the fluorescence-activated cell sorter to separate partially stimulated neutrophils, followed by reanalysis by flow cytometry and microscopic examination. 3. This flow cytometric method provides a convenient, rapid and objective measure of neutrophil responses to external stimuli.

Cell Size↗
PubMed1995

Lansoprazole versus ranitidine for the treatment of reflux oesophagitis. UK Lansoprazole Clinical Research Group.

BACKGROUND: Lansoprazole is a H+.K(+)-ATPase (proton pump) inhibitor with an anti-secretory action and is therefore potentially useful in the treatment of gastro-oesophageal reflux. METHODS: This study was conducted to determine the efficacy and short-term safety of lansoprazole at doses of 30 mg or 60 mg once daily, compared with ranitidine 150 mg twice daily, in the treatment of patients with reflux oesophagitis. This was a double-blind, stratified, randomized, comparative, parallel group study conducted in five centres in the UK. A total of 229 patients (155 men) aged 18-79 years with endoscopically-confirmed oesophagitis were randomized to receive lansoprazole 30 mg p.o. daily, lansoprazole 60 mg p.o. daily, or ranitidine 150 mg p.o. b.d. Efficacy was assessed by endoscopic examination at 4 weeks and 8 weeks, together with symptom relief and antacid usage. RESULTS: Lansoprazole 30 mg and 60 mg were superior at 4 and 8 weeks (P < 0.01) to ranitidine in healing reflux oesophagitis: respective healing rates being 84%, 72% and 39% after 4 weeks and 92%, 91% and 53% after 8 weeks. Relief of heartburn with lansoprazole 30 mg and 60 mg was superior to that achieved with ranitidine at both week 4 (P < 0.01) and week 8 (P < 0.02). Sixty-four patients experienced a total of 85 adverse events, one-third of which were considered drug-related. The incidence and severity were similar in the three groups. CONCLUSION: Lansoprazole 30 mg and 60 mg once daily are more effective than ranitidine 150 mg twice daily in the short-term treatment of reflux oesophagitis.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

Gastric microbleeding following single and repeated dosing with naproxen.

BACKGROUND: Adaptation to gastric damage from nonsteroidal anti-inflammatory drugs (NSAID) has been observed during ongoing dosage in rats and humans. However, this does not always occur, and our previous data suggest that NSAID half-life may be a determining factor. AIM: To investigate whether adaptation occurs during 1 week of naproxen administration in humans. SUBJECTS: Thirteen healthy volunteers were studied at baseline, and after one or seven daily doses of naproxen 750 mg. Gastric microbleeding was measured 4 h after naproxen in gastric washings collected during a 30-min period. Serum thromboxane B concentrations were also assayed, as a marker of cyclo-oxygenase inhibition. RESULTS: Mean blood loss after placebo was 0.60 microL/10 min (95% CI: 0.21-0.98). This rose to 2.15 (0.73-3.57) and 1.75 (0.74-2.76) microL/10 min after one and seven daily doses of naproxen, respectively (P < 0.05 vs. baseline; day 1 vs. 7 not significant). Thromboxane B concentrations were < 10% of control at both day 1 and 7 of dosing. CONCLUSION: In accord with our findings in rats, adaptation to this moderately long acting NSAID in humans was not apparent. We conclude that any adaptation to naproxen is unlikely to be clinically important.

Adaptation, Physiological↗
PubMed1995

Effect of a test meal on the intragastric distribution of urea in the 13C-urea breath test for Helicobacter pylori.

Test meals are invariably used in the 13C-urea breath test (UBT) but their effect on the intragastric distribution and gastric residence time of urea given in the test is unknown. The site of Helicobacter pylori urease measured in the test is unknown and whether the test measures total or regional gastric urease is uncertain. This study reports the results of paired UBTs with simultaneous gastric distribution studies, one with and one without a fatty test meal, two weeks apart on seven H pylori infected subjects. The test meal did not affect UBT results at 10 minutes, but increased values at 30 minutes and thereafter. The amount of scintigraphic label in the antrum at 10 minutes was also unaffected by the meal but increased at 30 minutes and thereafter, whereas the amount in the body/fundus was greatly increased both at 10 minutes and throughout the test. There was considerable variation in intragastric distribution of urea between subjects, both with and without the test meal. This study shows that a test meal profoundly affects intragastric distribution of urea solution in the UBT, and increases UBT values at 30 minutes and later. Variability between subjects, however, means that accurate measurement of total or regional gastric urease is probably unrealistic.

Adult↗
PubMed1995

Detection of the intragastric sites at which Helicobacter pylori evades treatment with amoxycillin and cimetidine.

Treatment of Helicobacter pylori infection with amoxycillin is known to reduce the bacterial load to undetectable levels, while not eradicating the infection. It seems, therefore, that bacteria escape treatment at a 'sanctuary site'. This study examined whether such a site existed in the gastric antrum, body, or fundus. Twenty two patients with H pylori infection and duodenal ulcer disease were treated for one week with amoxycillin (500 mg three times a day) and cimetidine (800 mg at night). Before treatment, H pylori was detected throughout all stomachs, and 13C-urea breath testing at least 28 days after treatment confirmed that eradication of H pylori had occurred in no patients. While under treatment, H pylori was sought by conventional methods and by polymerase chain reaction assay and was found in the gastric fundus in 13 of 22 subjects, in the body in 10 of 22, and the antrum in three of 22: the difference between fundus and antrum was significant (p < 0.01). The continued antral infection in three subjects may have resulted from generalised treatment failure as two of three had H pylori detected throughout the stomach, and these two had compiled relatively poorly with treatment. This study suggests that amoxycillin and cimetidine are relatively effective at clearing H pylori from the gastric antrum, but that escape from treatment may occur in the gastric body, and especially the fundus.

Adult↗
PubMed1995

Late mortality in elderly patients surviving acute peptic ulcer bleeding.

Acute peptic ulcer bleeding is associated with a substantial short term mortality but it is generally assumed that in the modern era of effective medical treatment the longer term prognosis is good. This study evaluated 487 patients aged over 60 years who were discharged from Nottingham University and City Hospitals after admission for acute peptic ulcer bleeding during 1986-91 and 480 age and sex matched community controls. Follow up information was obtained from hospital and general practitioner records and from the National Health Service central register. Mortality was compared with control mortality and with rates expected for England and Wales. During a mean follow up of 34 months 142 (29%) of 487 patients died compared with 58 (12%) of 480 community controls and with 81.5 deaths expected (observed/expected (O/E) = 1.74, 95% confidence limits (CL) 1.5 to 2.1). Six years after admission the actuarial survival estimate was only 50% for ulcer patients compared with 76% for community controls and 69% expected. The increased mortality was similar in men and women and was greatest in the 60-74 year age group. Much of the excess mortality was accounted for by deaths from cancer (O/E 34/19.7 = 1.73; CL 1.2 to 2.4), from respiratory disease (O/E 28/10.9 = 2.57; CL 1.7 to 3.7), and in men from vascular disease (O/E 31/22.4 = 1.38; CL 0.9 to 2.0). Eight deaths resulted from recurrent ulcer complications and four deaths from gastric cancers undetected at the index admission. In conclusion, patients discharged after peptic ulcer bleeding had a substantially reduced life expectancy. The increased mortality was predominantly due to a variety of smoking related diseases rather than recurrent peptic ulcer complications. Deaths from recurrent peptic ulcer complications were infrequent and were less than reported in earlier years possibly reflecting prolonged and widespread used of H2 receptor antagonists.

Acute Disease↗
PubMed1995

Morbidity and treatment in elderly patients surviving hospital admission with bleeding peptic ulcer.

Bleeding peptic ulcer in the elderly is associated with use of non-steroidal, anti-inflammatory drugs (NSAIDs) and aspirin, presenting a therapeutic dilemma for the treatment of survivors. To determine the longterm morbidity of patients surviving bleeding peptic ulcer and their treatment, with particular reference to NSAID use, this study followed up 487 patients aged over 60 years, who survived an episode of bleeding peptic ulcer in Nottingham during 1986 to 1991. Information was gathered by evaluation of general practitioner and hospital records, scrutiny of death certificates, and postal questionnaire to surviving patients. Of 487 patients surviving a bleeding peptic ulcer, 345 were alive at the follow up, a mean 34.2 months after discharge. Of these 201 (58%) had taken NSAIDs before their ulcer bleed (104 non-aspirin NSAIDs, 77 aspirin, 20 both). Compared with non-users, the patients using NSAIDs at the time of presentation were significantly more likely subsequently to consult their general practitioner with locomotor symptoms (56% v 35%, p < 0.001) and receive further NSAIDs (34% v 13%, p < 0.001), but significantly less likely to consult their general practitioner for dyspepsia (31% v 54%, p < 0.001). Antiulcer drug use was widespread in both groups, with an overall point prevalence of 44%. Seventy five patients received NSAIDs during the follow up period (69% with coprescription of antiulcer drugs, usually H2 antagonists). Recurrent peptic ulcer, ulcer complications, and ulcer related deaths were uncommon. Antiulcer drug use was lower in those with ulcer recurrence compared with the point prevalence in those without (17% v 44%, p < 0.05). Patient questionnaire responses confirmed a high level of locomotor symptoms especially in patients previously admitted with NSAID associated ulcer bleeding. In conclusion, in patients surviving peptic ulcer bleeding, recurrent ulcer complications and death seem to be lower than reported by studies that preceded the advent of antiulcer drugs. It is suggested that this low incidence may be a consequence of their use. Granted the low level of recurrent ulceration and the high level of locomotor symptoms in patients studied, current treatment may unduly emphasise the importance of stopping NSAIDs in this group of patients.

Aged↗
PubMed1995

Angiogenesis in gastric ulcers: impaired in patients taking non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drug (NSAID) therapy is associated with delayed gastroduodenal ulcer healing. In rats the degree of angiogenesis (new vessel formation) within the ulcer bed correlates strongly with the extent and speed of ulcer healing and may be inhibited by NSAIDs. This study therefore assessed the vascularity of 38 antral gastric ulcers immunohistochemically, using CD31 a vascular endothelial cell marker, in 17 patients taking NSAIDs and 19 control patients. In the superficial granulation tissue NSAID therapy was associated with a significant reduction in the median number of capillaries (13.5 (IQR: 9.5-18) v 23.5 (14-31) (p < 0.005)), number of vessel buds (6 (4-12.5) v 17 (12-23) (p < 0.05)), and maximum vessel diameter (29 (20.75-30.75) v 33.75 (24-45) (p < 0.05)) when compared with controls. In deep granulation tissue NSAID therapy was similarly associated with a significant reduction in the number of capillaries (9 (6.5-12) v 14 (9-19.25) (p < 0.04)), number of vessel buds (5 (3.5-8.5) v 13 (7-16.5) (p < 0.01)), and maximum vessel diameter (23 (18-20.5) v 33 (21.5-45) (p < 0.02)). There were no differences in vascularity in the adjacent glandular mucosa. Impairment of angiogenesis may be an important mechanism of NSAID related delayed ulcer healing.

Aged↗
PubMed1995

Basic fibroblast growth factor treatment for non-steroidal anti-inflammatory drug associated gastric ulceration.

An open, pilot study tested the safety and efficacy of an acid stable form of the angiogenic protein basic fibroblast growth factor (bFGF) for healing of non-steroidal anti-inflammatory drug (NSAID) associated gastric ulcers in five patients with nine gastric ulcers that were resistant to conventional treatment (4) or had relapsed (5). Oral bFGF treatment for four weeks was safe and well tolerated. There was no evidence of systemic absorption. After four weeks, four ulcers had healed and there was a 89 (3)% mean (SEM) reduction in the area of the others. A controlled, comparative trial of this novel growth factor treatment is warranted.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Critical issues in the pathophysiology and management of peptic ulcer disease.

OBJECTIVE: To discuss some of the critical issues in the pathophysiology and management of peptic ulcer disease. OPINION: Peptic ulcer disease has multiple causes, although gastric acid has traditionally been considered the primary aggressive factor. Helicobacter pylori infection is established as a major causative factor, but some aspects of the mechanisms by which H. pylori causes peptic ulceration remain unclear. Treatment with proton pump inhibitors (PPIs) is the most effective means of healing peptic ulcers. In addition to healing a higher proportion of ulcers than H2-receptor antagonists, PPIs provide faster healing and relief of symptoms. The ability of PPIs to produce effective and sustained inhibition of gastric acid secretion suggests that they may also become the treatment of choice for gastric ulcers caused by non-steroidal anti-inflammatory drugs. However, eradication of H. pylori infection is more effective than maintenance therapy with antisecretory agents in reducing the rate of recurrence of peptic ulcers initially healed using antisecretory therapy. H. pylori eradication is therefore the optimal, and almost certainly the most cost-effective, approach to the long-term management of patients with peptic ulcer disease. Despite the fact that 90-95% of patients with demonstrable duodenal ulceration are probably infected with H. pylori, it is recommended that, in routine clinical practice, infection is diagnosed before eradication therapy is instituted. H. pylori testing 4-6 weeks after the completion of eradication therapy is also recommended to check that the infection has been successfully cured. For routine clinical practice, the highly sensitive and specific rapid urease test is probably the most useful diagnostic approach. The most appropriate H. pylori eradication regimen remains to be defined. However, 1-2 weeks of treatment with a combination of a PPI and two antimicrobial agents achieves eradication rates in excess of 90%, which are similar to those attained using standard triple therapy, but with the advantage of better patient compliance and greater tolerability. Preliminary evidence also suggests that H. pylori eradication prevents the recurrence of peptic ulcer bleeding, although further studies are required. CONCLUSION: H. pylori eradication by 1-2 weeks' treatment with a combination of a PPI and two antimicrobial agents appears to be the optimal (and probably the most cost-effective) approach to the long-term management of patients with peptic ulcer disease, and represents a major advance in the management of such patients.

Antacids↗