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Biomedical subjects

C J Hawkey

Publications and source records attributed to C J Hawkey.

At least 181 records · Page 10Linked to original sources
PubMed1993

Effect of Helicobacter pylori colonisation on gastric mucosal eicosanoid synthesis in patients taking non-steroidal anti-inflammatory drugs.

Colonisation with Helicobacter pylori may influence susceptibility to gastroduodenal injury and ulceration in patients taking non-steroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to determine if Helicobacter pylori colonisation altered eicosanoid synthesis by gastric mucosa in these patients. Sixty five patients with long-standing NSAID intake and 23 control subjects underwent endoscopy. In vitro gastric antral biopsies were stimulated by vortex mixing and eicosanoid measurements determined by radioimmunoassay. Helicobacter pylori colonisation was determined by a CLO test (a gel based rapid urease test) and histological assessment. Median prostaglandin E2 synthesis by gastric mucosa was 61.0 (interquartile range: 19.2-73.1) pg/mg in control subjects colonised with Helicobacter pylori compared with 46.5 (23.3-65.5) pg/mg in Helicobacter pylori negative subjects. This was not significantly different. Treatment with NSAIDs was associated with a significant difference (p < 0.001) in prostaglandin E2 (PGE2) synthesis between those colonised with Helicobacter pylori (37.5(22.0-77.3) pg/mg) compared with patients not infected (12.6(7.0-19.3) pg/mg). Values in patients taking NSAIDs who were colonised were not different from control subjects. Synthesis of PGE2 was strongly associated with type B (chronic active), but not type C (chemical) gastritis. Dyspeptic symptoms were more common in subject colonised with Helicobacter pylori (p < 0.002) and were associated with higher PGE2 synthesis. In patients taking NSAIDs Helicobacter pylori colonisation removes rather then enhances depression of PGE2 synthesis associated with NSAIDs and may promote dyspepsia associated with ulcers and prevent superficial mucosal injury.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

In vivo rectal inflammatory mediator changes with radiotherapy to the pelvis.

In vivo changes in the rectal values of eicosanoid inflammatory mediators induced by pelvic radiotherapy were measured to study the pathophysiology of the early radiation bowel reaction. Ten patients having pelvic radiotherapy, aged 57 to 78, had rectal dialysis. Values of the eicosanoids leukotriene B4 (LTB4), thromboxane B2 (TXB2), and prostaglandin E2 (PGE2) were measured before radiotherapy, at the end of radiotherapy, and at least four weeks after radiotherapy. Values of LTB4 rose with radiotherapy from 0.21 ng.ml-1 (median) to 1.14 ng.ml-1 (p = 0.012); PGE2 rose from 0.60 ng.ml-1 to 1.58 ng.ml-1 (p = 0.038), and TXB2 rose from 0.365 ng.ml-1 to 1.6 ng.ml-1 (p = 0.005). The rise in eicosanoid inflammatory mediators may have an important role in the pathophysiology of the early radiation bowel reaction.

Aged↗
PubMed1993

Gastroduodenal problems associated with non-steroidal, anti-inflammatory drugs (NSAIDs).

Non-steroidal, anti-inflammatory drugs (NSAIDs) inhibit gastric mucosal prostaglandins (PG) synthesis and thereby induce mucosal injury and ulceration, and possibly impair pain perception and ulcer healing. Dyspepsia is a poor guide to ulceration so a life threatening complication may be the first presentation and vigilance is important. Impaired healing can be overcome with more potent or prolonged ulcer healing therapy. For prophylaxis of high-risk patients (elderly women, past history, taking high doses, steroid co-therapy, first three months of treatment) the prescriber has to choose between the side effects of misoprostol or the more limited efficacy against gastric ulcers of ranitidine. Both drugs are highly effective in preventing duodenal ulcers.

Aged↗
PubMed1992

Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.

OBJECTIVE: To determine whether azathioprine can prevent relapse in ulcerative colitis. DESIGN: One year placebo controlled double blind trial of withdrawal or continuation of azathioprine. SETTING: Outpatient clinics of five hospitals. SUBJECTS: 79 patients with ulcerative colitis who had been taking azathioprine for six months or more. Patients in full remission for two months or more (67), and patients with chronic low grade or corticosteroid dependent disease (12) were randomised separately. 33 patients in remission received azathioprine and 34 placebo; five patients with chronic stable disease received azathioprine and seven placebo. MAIN OUTCOME MEASURE: Rate of relapse. Relapse was defined as worsening of symptoms or sigmoidoscopic appearance. RESULTS: For the remission group the one year rate of relapse was 36% (12/33) for patients continuing azathioprine and 59% (20/34) for those taking placebo (hazard rate ratio 0.5, 95% confidence interval 0.25 to 1.0). For the subgroup of 54 patients in long term remission (greater than six months before entry to trial) benefit was still evident, with a 31% (8/26) rate of relapse with azathioprine and 61% (17/28) with placebo (p less than 0.01). For the small group of patients with chronic stable colitis (six were corticosteroid dependent and six had low grade symptoms) no benefit was found from continued azathioprine therapy. Adverse events were minimal. CONCLUSIONS: Azathioprine maintenance treatment in ulcerative colitis is beneficial for at least two years if patients have achieved remission while taking the drug. Demonstration of the relapse preventing properties of azathioprine has implications for a large number of patients with troublesome ulcerative colitis, who may benefit from treatment with azathioprine.

Azathioprine↗
PubMed1992

Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial.

OBJECTIVE: To investigate the possible therapeutic role of omeprazole, a powerful proton pump inhibitor, in unselected patients presenting with upper gastrointestinal bleeding. DESIGN: Double blind placebo controlled parallel group study. Active treatment was omeprazole 80 mg intravenously immediately, then three doses of 40 mg intravenously at eight hourly intervals, then 40 mg orally at 12 hourly intervals. Treatment was started within 12 hours of admission and given for four days or until surgery, discharge, or death. SETTING: The medical wards of University and City Hospitals, Nottingham. SUBJECTS: 1147 consecutive patients aged 18 years or more admitted over 40 months with acute upper gastrointestinal bleeding. MAIN OUTCOME MEASURES: Mortality from all causes; rate of rebleeding, transfusion requirements, and operation rate; effect of treatment on endoscopic appearances at initial endoscopy. RESULTS: Of 1147 patients included in the intention to treat analysis, 569 received placebo and 578 omeprazole. No significant differences were found between the placebo and omeprazole groups for rates of transfusion (302 (53%) placebo v 298 (52%) omeprazole), rebleeding (100 (18%) v 85 (15%)), operation (63 (11%) v 62 (11%)), and death (30 (5.3%) v 40 (6.9%)). However, there was an unexpected but significant reduction in endoscopic signs of upper gastrointestinal bleeding in patients treated with omeprazole compared with those treated with placebo (236 (45%) placebo v 176 (33%) omeprazole; p less than 0.0001). CONCLUSIONS: Omeprazole failed to reduce mortality, rebleeding, or transfusion requirements, although the reduction in endoscopic signs of bleeding suggests that inhibition of acid may be capable of influencing intragastric bleeding. Our data do not justify the routine use of acid inhibiting drugs in the management of haematemesis and melaena.

Age Factors↗
PubMed1992

Effect of indomethacin and misoprostol on fasted gallbladder volume and meal-induced gallbladder contractility in humans.

Impaired gallbladder contractility is a prerequisite for gallstone formation in animal models. Prostaglandins are important mediators of gallstone formation and may affect gallbladder contractility in animals. The aim of this study was to evaluate the effect of indomethacin, an inhibitor of prostaglandin synthesis, and misoprostol, a synthetic prostaglandin, on gallbladder contractility in man. Seven male volunteers (18-33 years old, mean age 23 years) were studied under blinded conditions after an overnight fast, during control periods and following ingestion of indomethacin 125 mg (75 mg at 10 PM, 50 mg at 6:30 AM) or misoprostol 800 micrograms (400 micrograms at 10 PM, 400 micrograms at 6:30 AM) orally. Gallbladder residual volume was determined by real-time ultrasonography before and 10, 20, 30, 40, and 50 min after ingestion of a standard liquid fatty meal stimulus. Fasting gallbladder volume (milliliters) was similar in all three periods [control 20.8 (1.6); indomethacin 20.8 (2.9); misoprostol 18.3 (1.6)]. The fatty meal stimulus caused prompt contraction, resulting in minimum residual volume of 7.5 (1.4) ml in the control period. Pretreatment with misoprostol or indomethacin did not affect the minimum volume obtained compared with control period [misoprostol: 5.8 (1.4) ml; indomethacin 5.9 (1.3) ml)]. Thus administration of indomethacin and misoprostol had no effect on fasting gallbladder volume or gallbladder contractility in humans as assessed by ultrasonography.

Adolescent↗
PubMed1992

Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators.

Whatever initiates inflammation, the final message mediating cellular invasion is chemical. This consideration allows rational development of anti-inflammatory treatments. Two main classes of chemotactic mediator are recognised. Water-soluble peptides, e.g. cytokines derived from macrophages and other cells, play an important integrating part in the early recruitment of neutrophils and mononuclear cells, and in the amplification of immune responses. Lipid-soluble mediators, of which leukotriene B4 is the most highly chemotactic for neutrophils, are important in secondary amplification. In inflammatory bowel disease, we have shown evidence of increased synthesis of cytokines interleukin 1, 6 and 8. These are associated with activation of circulating monocytes in active Crohn's disease, of lamina propria macrophages in relapse of both ulcerative colitis and Crohn's disease, and development of adhesion molecules on vascular endothelium. Our studies show that interleukin 6 is selectively increased in Crohn's disease, whilst preliminary findings suggest that enhanced synthesis of interleukin 8 is particularly characteristic of ulcerative colitis. Patterns of cytokine synthesis may, therefore, be of diagnostic value. They also offer the potential for therapeutic strategies since cytokine antagonists are becoming available. We have also demonstrated increased synthesis of leukotrienes in active inflammatory bowel disease. Since leukotriene B4 is quantitatively the main chemotactic signal in the mucosa in inflammatory bowel disease during relapse, we investigated the therapeutic effect of suppressing leukotriene B4 synthesis by treating patients with fish oil (as Hi-EPA), giving 4.5 g daily of eicosapentaenoic acid. This competes for the 5-lipoxygenase enzymes, inhibiting leukotriene B4 and promoting synthesis of the less chemotactic product, LTB5.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminosalicylic Acids↗
PubMed1992

Therapeutic approaches to the problem of biliary sludge and gallstone formation during total parenteral nutrition.

Prolonged total parenteral nutrition is associated with the development of biliary sludge, which consists of super-saturated bile containing cholesterol crystals, bilirubin granules and a very high concentration of mucin glycoprotein. Reduced gallbladder contractility in TPN patients appears to be essential for the pathogenesis of sludge, which represents an important stage in the formation of gallstones, a common and well recognised complication of TPN. Possible approaches to the prevention of these biliary complications of TPN include: 1) inhibition of prostaglandin mediated mucin hypersecretion with aspirin, NSAIDs or possibly by n-3 essential fatty acids; 2) stimulation of gallbladder contractility by early oral feeding or the use of CCK; and 3) reduction of cholesterol saturation and mucin secretion by ursodeoxycholic acid.

Journal Article↗
PubMed1992

Enhanced synthesis of neutrophil-activating peptide-1/interleukin-8 in active ulcerative colitis.

1. We studied neutrophil-activating peptide-1/interleukin-8 in inflammatory bowel disease. 2. Mucosal levels of neutrophil-activating peptide-1/interleukin-8 were significantly higher in patients with active ulcerative colitis [median 74.5 (range 17.7-450.8) pg/mg] than in patients with active Crohn's disease [10.4 (4-46.9) pg/mg; P less than 0.002] or in normal control subjects [10.4 (4-16.6) pg/mg; P less than 0.002]. 3. Circulating neutrophil-activating peptide-1/interleukin-8 was generally undetectable but there were higher levels of anti-neutrophil-activating peptide-1/interleukin-8 antibodies in patients with active ulcerative colitis [62.9 (3.4-239) ng/ml] than in patients with active Crohn's disease [5.9 (2.1-18.10) ng/ml; P less than 0.001] or in control subjects [6.1 (3.2-15.8) ng/ml; P less than 0.001]. 4. Neutrophil-activating peptide-1/interleukin-8 may be of specific functional importance in mediating inflammation in ulcerative colitis.

Antibodies↗
PubMed1992

Monoclonal antigranulocyte antibody imaging in inflammatory bowel disease: a preliminary report.

The 99Tcm-labelled antigranulocyte antibody BW250/183 has been used in the detection of intestinal inflammation in patients with active ulcerative colitis and Crohn's disease. Planar images were obtained up to 24 h after intravenous injection of the antibody. Eight out of nine patients with ulcerative colitis and six out of seven patients with Crohn's disease gave positive images. In 11 patients distribution of the inflammation was confirmed by barium studies, colonoscopy or surgery, whilst in two the antibody scan suggested more extensive disease than barium enema. None of the patients had any adverse reactions. Imaging with BW250/183 appears to give an accurate indication of the extent of inflammation in inflammatory bowel disease.

Colitis, Ulcerative↗
PubMed1992

Ranitidine: differential effects on gastric bleeding and mucosal damage induced by aspirin.

This study investigated the influence of ranitidine on mucosal injury and gastric bleeding in 20 normal volunteers taking 600 mg aspirin q.d.s. This study was a double-blind placebo controlled crossover study comparing ranitidine, as 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. with placebo. Gastric mucosal injury was assessed at unsedated endoscopy by counting haemorrhagic and non-haemorrhagic erosions; bleeding was measured in gastric washings. Aspirin alone increased mucosal injury from 0 to 11.4 erosions (mean, P < 0.01) and bleeding from 1.77 to 9.11 microliters blood/10 min (mean P < 0.001). Ranitidine prophylaxis reduced bleeding to 5.34, 3.18 and 3.47 microliters/10 min with 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. respectively (overall effect of ranitidine P < 0.001) and also reduced haemorrhagic erosions though it had no effect on the total number of erosions. Ranitidine is effective at reducing aspirin-induced gastric bleeding and whilst not reducing aspirin-induced gastric erosions, it does reduce the number that appear haemorrhagic. Ranitidine may have a role in the prophylaxis of aspirin-induced gastric bleeding.

Adult↗
PubMed1992

Colorectal leukotriene B4 synthesis in vitro in inflammatory bowel disease: inhibition by the selective 5-lipoxygenase inhibitor BWA4C.

The in vitro synthesis of leukotriene B4 (LTB4) was evaluated in colorectal biopsy specimens and resection tissue from patients with inflammatory bowel disease. The in vitro formation of LTB4 from biopsy tissues stimulated with calcium ionophore A23187 correlated with the degree of mucosal inflammation assessed at sigmoidoscopy, and with neutrophil infiltration measured as myeloperoxidase activity. Biopsy specimens from patients taking prednisolone formed less LTB4 than those from patients not on prednisolone, with comparable levels of inflammation seen at sigmoidoscopy. The formation of LTB4 was reduced dose-dependently by the acetohydroxamic acid 5-lipoxygenase inhibitor BWA4C, with no significant inhibition of prostaglandin E2 or thromboxane B2 synthesis. In inflamed colonic resection tissue from colitic patients, the IC50 for inhibition of LTB4 formation by BWA4C was 0.03 mumol/l, compared with an IC50 of 0.8 mumol/l for NDGA. Thus, BWA4C is a potent and selective inhibitor of LTB4 synthesis in colonic tissue from patients with ulcerative colitis. Acetohydroxamic acid 5-lipoxygenase inhibitors, exemplified by BWA4C, may be useful to evaluate the clinical importance of LTB4 in ulcerative colitis, and offer a novel therapy for the disease.

Benzeneacetamides↗
PubMed1992

Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised controlled trial.

The effect of fish oil on the course of ulcerative colitis was investigated in a randomised blinded controlled study. Eighty seven patients received supplements of 20 ml HiEPA fish oil as triglyceride (4.5 g of eicosapentaenoic acid) or olive oil placebo daily for one year. The oils were given in addition to standard drug therapy and trial entry was stratified for disease activity. Fish oil significantly increased the eicosapentaenoic acid content of rectal mucosa to 3.2% of total fatty acids at six months, compared with 0.63% for patients on olive oil. This was associated with increased synthesis of leukotriene B5, and 53% suppression of leukotriene B4 synthesis by ionophore--stimulated neutrophils. Leukotriene B4 suppression persisted for at least two months after treatment was stopped. Treatment with fish oil resulted in measurable, but only limited clinical benefit. For patients entering the trial in relapse (n = 53), there was a significant reduction in corticosteroid requirement after one and two months treatment. There was a trend towards achieving remission (off corticosteroids) faster in the patients on fish oil, although differences were not significant. For patients in remission at trial entry or during the trial (n = 69), there was no significant difference in the rate of relapse by log rank analysis. We conclude that fish oil supplementation produces a modest corticosteroid sparing effect in active disease, but there is no benefit in maintenance therapy.

Adolescent↗