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Biomedical subjects

C J Hawkey

Publications and source records attributed to C J Hawkey.

At least 127 records · Page 7Linked to original sources
PubMed1997

The gastroenterologist's caseload: contribution of the rheumatologist.

Rheumatological conditions often give rise to gastrointestinal (GI) symptoms and vice versa, but the greatest point of contact between rheumatologists and gastroenterologists arises through gastrointestinal toxicity resulting from the use of nonsteroidal antiinflammatory drugs (NSAIDs). Standard NSAIDs are toxic to the entire GI tract. The point prevalence of ulcers in patients on long-term NSAID treatment is about 20% and the annual incidence of complications in these patients is 1% to 4%; 1,200 patients in the United Kingdom die each year as a result. Withdrawing NSAID treatment, or reducing the dose, is not always possible, and approximately 25% of patients require continued long-term antiinflammatory treatment. Misoprostol and acid-suppressing drugs such as ranitidine and omeprazole are helpful as prophylactic treatment in high risk patients, and in healing established ulcers, especially in patients carrying Helicobacter pylori, but there is a pressing need for new, safer antiinflammatory drugs toease the burden of NSAID gastropathy. Selective inhibition of the COX-2 isoform of cyclooxygenase has been proposed as a new and safer therapeutic option. Clinical studies with meloxican, a selective COX-2 inhibitor, support this view. Meloxicam has been extensively studied in arthritis patients and combines antiinflammatory efficacy with a lower incidence of GI toxicity than currently available NSAIDs.

Animals↗
PubMed1997

Prescribing of nonsteroidal anti-inflammatory drugs in general practice: determinants and consequences.

AIM: To use Prescribing Analysis and Costs data to investigate factors associated with differences in rates of nonsteroidal anti-inflammatory drug prescribing in Nottingham general practices. RESULTS: Poisson regression analysis revealed that the Age. Sex and Temporary Resident Prescribing Unit Index was the largest identifiable influence; larger practice size and a higher index of deprivation were also significantly associated with lower prescribing, whilst the number of partners was associated with higher levels of prescribing. However, even after correcting for the influence of age, sex and temporary residents, there was an 5.9-fold variation in rates of prescribing. A similar Poisson regression analysis to identify factors associated with admission to hospital with ulcer bleeding in the elderly over the preceding 57 months identified the rate of nonsteroidal anti-inflammatory drug (NSAID) prescribing as the only significant influence. CONCLUSION: The data are compatible with 1 hospital admission per 2823 NSAID prescriptions (95% confidence intervals 2098-8110) and they emphasize the need for strategies to reduce levels of NSAID prescribing.

Aged↗
PubMed1997

Review article: COX-II inhibitors--a new generation of safer NSAIDs?

A hundred years after the introduction of aspirin as the first effective anti-inflammatory drug, problems of tolerability still beset this class of drugs, in particular, gastrointestinal toxicity. Despite this, NSAIDs are among the most widely used and prescribed drugs world-wide. Many agents have been used to counteract these side-effects with varying degrees of success and acceptance. Although the central mechanism of NSAID action, reduced prostaglandin production by cyclooxygenase (COX) inhibition, was first described 25 years ago, the recent discovery of a second, inducible form of cyclooxygenase, COX-2, has stimulated research and interest in producing NSAIDs that are inherently safer whilst maintaining efficacy. Specific COX-2 inhibitors, the first of which has recently been marketed in the UK, offer real hope as safer NSAIDs and this may be realised when drugs with even greater specificity become available. However, long-term safety and efficacy need to be demonstrated in clinical practice, and questions remain unanswered about possible physiological roles for COX-2. Other approaches to improving the safety of NSAIDs, including profound acid suppression and nitric oxide donation, may prove to be as successful in this rapidly changing field.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

A trial of zileuton versus mesalazine or placebo in the maintenance of remission of ulcerative colitis. The European Zileuton Study Group For Ulcerative Colitis.

BACKGROUND & AIMS: Leukotriene B4 is a major neutrophil chemoattractant detected during relapse of inflammatory bowel disease and represents a potentional therapeutic target. The aim of this study was to compare the efficacy of zileuton, an active 5-lipoxygenase inhibitor, with mesalazine and placebo in the maintenance of remission in ulcerative colitis. METHODS: A double-blind, parallel-group, multicenter, and multinational trial was conducted during a 6-month period in hospital-based patients with inflammatory bowel disease. Three hundred five evaluable patients with ulcerative colitis in remission at the start of the trial were randomized into groups to undergo oral treatment with zileuton (600 mg qid; n = 113), mesalazine (400 mg qid; n = 99), or placebo (n = 111). The primary efficacy outcome was maintenance of remission for 6 months. A multivariate analysis was used to investigate determinants of relapse. Safety was assessed by treatment discontinuation, adverse events, vital signs, and laboratory parameters. RESULTS: After 6 months, 54% of patients receiving zileuton remained in remission compared with 43% receiving placebo (P = 0.094) and 63% on mesalazine (P = 0.266). Relapse rates on mesalazine were significantly lower than those for placebo (P = 0.017). All treatments were well tolerated. CONCLUSIONS: Zileuton (600 mg qid) was not significantly better than placebo in the maintenance of remission of ulcerative colitis in this trial and may have limited potential in the treatment of this condition.

Adult↗
PubMed1997

Famotidine for healing and maintenance in nonsteroidal anti-inflammatory drug-associated gastroduodenal ulceration.

BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs) are strongly associated with gastroduodenal ulceration. How to manage patients with NSAID-associated ulcers is a common clinical dilemma. High-dose famotidine in the healing and maintenance of NSAID-associated gastroduodenal ulceration was therefore evaluated. METHODS: One hundred four patients with rheumatoid or osteoarthritis who had gastroduodenal ulceration received famotidine, 40 mg twice daily. Sixteen patients stopped and 88 continued their NSAID treatment. Ulcer healing was assessed endoscopically at 4 and 12 weeks. Seventy-eight NSAID users with healed ulcers were then randomized to receive 40 mg twice daily famotidine or placebo and underwent endoscopy at 4, 12, and 24 weeks. RESULTS: Cumulative ulcer healing rates at 12 weeks were 89.0% (95% confidence interval [CI], 82.3%-95.7%) for patients who continued NSAID treatment and 100% (95% CI, 82.9%-100.0%) for those who stopped. The subsequent estimated cumulative gastroduodenal ulcer relapse over 6 months for NSAID users who took placebo was 53.5% (95% CI, 36.6%-70.3%). This was reduced to 26.0% (12.1%-39.9%) in patients taking famotidine (P = 0.011). CONCLUSIONS: High-dose famotidine is effective ulcer healing therapy in patients who stop or continue NSAID treatment and significantly reduced the cumulative incidence of gastroduodenal ulcer recurrence compared with placebo when given as maintenance therapy.

Adult↗
PubMed1997

Clarification of the link between polyunsaturated fatty acids and Helicobacter pylori-associated duodenal ulcer disease: a dietary intervention study.

Epidemiological evidence has suggested that the declining prevalence of duodenal ulcer disease may be attributable to rising consumption of polyunsaturated fatty acids, a hypothesis supported by in vitro evidence of toxicity of such substances to Helicobacter pylori. The objective of the present study was to establish whether this association is causal. Forty patients with proven infection with H. pylori and endoscopic evidence of past or present duodenal ulcer disease were randomized to receive either polyunsaturated fatty acids (PUFA group), in the form of capsules and margarine, or a placebo (control). Both groups received concurrent H2 antagonist therapy. Efficacy of therapy was determined endoscopically by assessment of ulcer healing while H. pylori status was determined by antral biopsy, urease (EC 3.5.1.5) culture and histological assessment of the severity of H. pylori infection. Antral levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were quantified. Compliance was monitored. Before treatment, both groups were comparable for severity of H. pylori infection, smoking status and levels of LTB4 and PGE2. Despite a significant difference in consumption of linoleic acid (19.9 (SE 1.6) g for PUFA group v. 6.7 (SE 0.8) g for controls (P < 0.01) and linolenic acid (2.6 (SE 0.2) g v. 0.6 (SE 0.03) g (P < 0.01) there was no significant change in either the severity of H. pylori infection or prostaglandin levels in either group at 6 weeks. Consumption of a considerable amount of PUFA does not inhibit the colonization of the stomach by H. pylori nor does this alter the inflammatory changes characteristic of H. pylori gastritis. We conclude that the association between duodenal ulceration and a low level of dietary PUFA is likely to be spurious, probably reflecting the effect of confounding factors such as affluence, social class or smoking.

Combined Modality Therapy↗
PubMed1997

Specific mediator-directed therapy for gastrointestinal diseases.

A number of inflammatory mediators--such as proinflammatory cytokines, lipid derived eicosanoids and reactive oxygen metabolites--are elevated in chronic bowel inflammation. Existing drugs for Crohn's disease and ulcerative colitis, for example aminosalicylates and corticosteroids, work at many sites in the inflammatory cascade to control disease activity. These drugs may be associated with significant side-effects and do not always control the disease. Therefore there is an impetus to develop treatments which are safer and more specific for bowel inflammation. Specific inhibitors of inflammatory mediators have recently become available and some have been shown to be effective in animal models of bowel inflammation. Although far fewer data are currently available on specific mediator-directed therapy of intestinal inflammation in humans, early clinical trials in inflammatory bowel disease have given mixed results. It remains to be determined whether or not this strategy of specific mediator inhibition is an alternative to current therapy for chronic bowel inflammation in humans.

Animals↗
PubMed1997

Healing with basic fibroblast growth factor is associated with reduced indomethacin induced relapse in a human model of gastric ulceration.

BACKGROUND: Acid stable basic fibroblast growth factor (bFGF) promotes angiogenesis and healing of gastric ulcers in rats and reduces subsequent non-steroidal anti-inflammatory drug (NSAID) induced relapse. AIMS: To test in a double blind, placebo controlled, three way crossover study whether bFGF promotes healing and reduces subsequent relapse in a human model of gastric ulceration. SUBJECTS: Twelve healthy volunteers. METHODS: Subjects took aspirin 900 mg twice daily (days 1-3) with bFGF 0.1 mg twice daily or cimetidine 400 mg twice daily or placebo (days 1-14) and then indomethacin 50 mg thrice daily (days 15-21). Endoscopy was performed on days 1, 4, 8, 15, and 22 during each treatment period. Eight antral biopsy specimens were taken on day 1 and the number of unhealed biopsy induced mini-ulcers and NSAID induced erosions counted during subsequent endoscopies. RESULTS: Basic FGF and cimetidine were protective against aspirin and indomethacin induced duodenal (but not gastric) injury compared with placebo. There was significant relapse of biopsy induced mini-ulcers after indomethacin only in the placebo group (0 (0-0) before v 1 (0-4.5) after; p > 0.05). TGP-580 was detected in serum of one volunteer. CONCLUSIONS: Healing with bFGF (and cimetidine) was associated with reduced NSAID induced ulcer relapse in this model of gastric ulceration.

Adult↗
PubMed1997

Effect of sucralfate on aspirin induced mucosal injury and impaired haemostasis in humans.

BACKGROUND: Sucralfate does not have potent anti-ulcerogenic actions in users of non-steroidal anti-inflammatory drugs (NSAIDs). However, sucralfate may influence intragastric haemostasis favourably. AIM: To investigate separately the effects of sucralfate on acute gastric and duodenal injury and on changes in intragastric bleeding induced by aspirin. METHOD: On three occasions, 24 healthy volunteers received three days' treatment with aspirin 900 mg twice daily together with placebo, sucralfate 2 g twice daily or sucralfate 1 g four times daily. Injury was assessed endoscopically and bleeding by spontaneous and biopsy induced bleeding intragastric washings. Ex vivo prostaglandin E2 (PGE2) synthesis and serum thromboxane were measured by using radioimmunoassay. RESULTS: Aspirin significantly inhibited ex vivo gastric mucosal PGE2 synthesis, reduced serum thromboxane, caused gastric erosions, and increased spontaneous and biopsy induced bleeding. Sucralfate had no significant effects on endoscopic injury but sucralfate 1 g four times daily significantly reduced spontaneous and biopsy induced bleeding. Similar trends were seen with sucralfate 2 g twice daily but the results were less consistent. CONCLUSION: Sucralfate does not affect aspirin induced acute gastric mucosal injury but reduces aspirin associated intragastric bleeding.

Acute Disease↗
PubMed1997

Peptic ulcer bleeding in the elderly: relative roles of Helicobacter pylori and non-steroidal anti-inflammatory drugs.

BACKGROUND: Most ulcers are caused, one can deduce, by Helicobacter pylori or by use of non-steroidal anti-inflammatory drugs (NSAIDs). Whether both together are worse than one alone is something that is quite unknown. AIM: To study both factors in order to see wither they interact together positively. METHOD: A case control study of ulcer bleeding in elderly patients chosen without weeding. RESULTS: NSAID usage increased risk substantially. So did H pylori infection (but relative risk less than three). Neither seemed to interact. Their actions were discretely intact. CONCLUSION: H pylori effects ulcer bleeding in an adverse manner but does not make the risk of NSAIDs worse.

Aged↗
PubMed1997

Adult human colonic subepithelial myofibroblasts express extracellular matrix proteins and cyclooxygenase-1 and -2.

Interactions between epithelial cells and subepithelial myofibroblasts are increasingly recognized as important in the regulation of epithelial cell function. We have established primary cultures of subepithelial myofibroblasts from adult human colonic mucosal samples denuded of epithelial cells and maintained in culture. During culture of mucosal tissue, subepithelial myofibroblasts migrated out via basement membrane pores before establishment in culture. Despite prolonged culture and passage, the myofibroblasts maintained their phenotype, as demonstrated by expression of alpha-smooth muscle actin and vimentin. The cells expressed transcripts and protein for cyclooxygenase (COX)-1 and -2 enzymes, and their release of prostaglandin E2 (PGE2) was inhibited by selective COX-1 and -2 inhibitors. The myofibroblasts also expressed the extracellular matrix (ECM) proteins collagen type IV, laminin-beta 1 and -gamma 1, and fibronectin. Adult human colonic subepithelial myofibroblasts may influence epithelial cell function via products of COX-1 and -2 enzymes, such as PGE2 and secreted ECM proteins.

Actins↗
PubMed1996

Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs.

BACKGROUND: Acid suppression with famotidine, a histamine H2-receptor antagonist, provides protection against gastric injury in normal subjects receiving short courses of aspirin or naproxen. The efficacy of famotidine in preventing peptic ulcers in patients receiving long-term therapy with nonsteroidal antiinflammatory drugs (NSAIDs) is not known. METHODS: We studied the efficacy of two doses of famotidine (20 mg and 40 mg, each given orally twice daily), as compared with placebo, in preventing peptic ulcers in 285 patients without peptic ulcers who were receiving long-term NSAID therapy for rheumatoid arthritis (82 percent) or osteoarthritis (18 percent). The patients were evaluated clinically and by endoscopy at base line and after 4, 12, and 24 weeks of treatment. The evaluators were unaware of the treatment assignment. The primary end point was the cumulative incidence of gastric or duodenal ulceration at 24 weeks. RESULTS: The cumulative incidence of gastric ulcers was 20 percent in the placebo group, 13 percent in the group of patients receiving 20 mg of famotidine twice daily (P = 0.24 for the comparison with placebo), and 8 percent in the group receiving 40 mg of famotidine twice daily (P = 0.03 for the comparison with placebo). The proportion of patients in whom duodenal ulcers developed was significantly lower with both doses of famotidine than with placebo (13 percent in the placebo group, 4 percent in the low-dose famotidine group [P = 0.04], and 2 percent in the high-dose famotidine group [P = 0.01]). Both doses of famotidine were well tolerated. CONCLUSIONS: Treatment with high-dose famotidine significantly reduces the cumulative incidence of both gastric and duodenal ulcers in patients with arthritis receiving long-term NSAID therapy.

Adult↗
PubMed1996

Enhanced eradication of Helicobacter pylori by pre- versus post-prandial amoxycillin suspension with omeprazole: implications for antibiotic delivery.

BACKGROUND: Strategies to improve antibiotic treatment of Helicobacter pylori infection are hampered by lack of knowledge about the route of antibiotic delivery. Post-prandial dosing with antibiotics prolongs their gastric residence time and improves their intragastric distribution, leading to improved local delivery compared with pre-prandial dosing. We aimed to assess whether pre- or post-prandial dosing. with amoxycillin suspension was more effective for H. pylori eradication in an amoxycillin/omeprazole regimen. METHODS: Seventy-nine patients with H. pylori infection were treated with omeprazole 40 mg o.m. for 28 days and amoxycillin suspension 500 mg q.d.s. for days 15-28, the amoxycillin being randomized to either 1 h before or immediately after food. RESULTS: The H. pylori eradication rate, for those completing the trial, was 67% (22/33) when amoxycillin suspension was given pre-prandially, compared with 39% (15/38) when it was given post-prandially (P < 0.05). Good compliance was achieved, with H. pylori eradication in 59% (28/46) of good compliers compared with 36% (9/25) of others completing the protocol (P < 0.05). CONCLUSION: When given with omeprazole, pre-prandial dosing with amoxycillin suspension is more effective for H. pylori eradication than post-prandial dosing. This is consistent with the hypothesis that systemic rather than local delivery of amoxycillin is important for H. pylori eradication.

Adult↗
PubMed1996

Isolation and culture of human gastric endothelial cells.

BACKGROUND & AIMS: Angiogenesis plays an important role in gastric ulcer healing. Considerable heterogeneity exists between endothelial cells from different blood vessels in vitro. Hitherto, it has not been possible to study gastric angiogenesis using relevant endothelial cells. The aim of this study was to isolate and culture human gastric endothelial (HuGE) cells to allow investigation of gastric ulcer angiogenesis. METHODS: Gastric mucosa underwent mechanical and enzymatic disruption. Microvessel fragments and endothelial cells were selected using superparamagnetic beads (Dynabeads; Dynal, Wirral, England) coated with a murine monoclonal anti-human platelet-endothelial cell adhesion molecule 1 antibody. Contaminating nonendothelial cells were removed by mechanical weeding and further Dynabead separation of endothelial cells. RESULTS: HuGE cells have been cultured up to passage 19. HuGE cells formed contact-inhibited monolayers on gelatin coated surfaces and tube-like structures on basement membrane matrices. Indirect immunofluorescence studies confirmed the endothelial nature of these cells. Basic and acidic fibroblast growth factors and vascular endothelial growth factor promoted proliferation (but not epidermal growth factor). HuGE cells synthesized less prostaglandin I2 and E2 compared with human umbilical vein endothelial cells. CONCLUSIONS: Pure cultures of HuGE cells can be obtained. Physiologically important differences from large vessel endothelial cells require further investigation.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Comparison of effects of calcium carbasalate and aspirin on gastroduodenal mucosal damage in human volunteers.

Calcium carbasalate is a therapeutically active salicylate which seems to cause less gastroduodenal mucosal damage than aspirin in laboratory animals. This endoscopist-blinded, randomised, cross over trial aimed to compare acute gastric mucosal damage in 20 healthy volunteers treated with acetyl salicylic acid (ASA) (650 mg three times daily) and effervescent calcium carbasalate (ECC) (826.8 mg three times daily) bioequivalent to 650 mg ASA over a five day period. Endoscopy was performed immediately before treatment and on day 5 of each treatment. Serum salicylate, thromboxane B2, and gastric mucosal prostaglandin E2 (PGE2) concentrations were measured after endoscopy. ECC caused fewer gastric mucosal erosions than ASA. The total number of gastric erosions was 23.8 (16.1) in the ASA treated subjects compared with 9.1 (8.7) in ECC treated subjects (p = 0.004). Differences between ASA and ECC were significant for both the gastric antrum and body, and for both haemorrhagic and non-haemorrhagic erosions. The mean gastric body Lanza score for mucosal damage was lower after ECC than ASA (p = 0.003). The visual analogue score for gastric body damage was lower for ECC (16.9 mm (15.9)) than for ASA (32.7 mm (20.8)), p = 0.008. Serum salicylate concentrations were similar after both preparations (ASA: 66 (23) mg/l, versus ECC: 58 (17) mg/l, NS). Serum thromboxane B2 was similarly reduced using both preparations-97.2 (3.5)% inhibition with ASA, 95.2 (5.5)% inhibition with calcium carbasalate (NS). Suppression of gastric mucosal PGE2 synthesis was similar with both preparations (ASA: 83.4 (17.1)%; ECC 84.3 (12.9)%; NS). It is concluded that ECC causes significantly less gastroduodenal mucosal damage than ASA administered at bioequivalent doses as judged by serum salicylate, serum thromboxane, and mucosal PGE2 values. ECC may therefore be a less harmful alternative treatment to plain ASA.

Adolescent↗
PubMed1996

Effect of allopurinol, sulphasalazine, and vitamin C on aspirin induced gastroduodenal injury in human volunteers.

BACKGROUND: The mechanisms of aspirin induced gastroduodenal injury are not fully understood. Aspirin induces the release of reactive oxygen metabolites in animal models, which may contribute to mucosal injury. AIMS: To investigate the effects of aspirin administered with placebo or antioxidants on gastric mucosal reactive oxygen metabolite release and gastroduodenal injury in human volunteers. SUBJECTS: Fourteen healthy volunteers participated in the study (seven male; mean age 27 years, range 20-40). METHODS: In a double blind, randomised, crossover study, volunteers received aspirin 900 mg twice daily and either placebo, allopurinol 100 mg twice daily, sulphasalazine 1 g twice daily or vitamin C 1 g twice daily for three days. Injury was assessed endoscopically and by quantifying mucosal reactive oxygen metabolite release by measuring chemiluminescence before and after each treatment. The effect on prostanoids was determined by measuring ex vivo antral prostaglandin E2 (PGE2) synthesis and serum thromboxane B2 (TXB2). RESULTS: No drug reduced any parameter of gastric injury but vitamin C reduced duodenal injury assessed by Lanza score (p < 0.005). Chemiluminescence increased after aspirin both with placebo (p < 0.05) and vitamin C (p < 0.05). Post-treatment chemiluminescence was lower in subjects taking allopurinol (p < 0.05) or sulphasalazine (p < 0.005) than in those taking placebo with aspirin. CONCLUSIONS: In this study, aspirin induced gastric injury was associated with reactive oxygen metabolite release. This was reduced by sulphasalazine and allopurinol, although macroscopic injury was not affected. Vitamin C, however, was shown to have a previously unrecognised protective effect against aspirin induced duodenal injury.

Adult↗
PubMed1996

Nitric oxide donating compounds stimulate human colonic ion transport in vitro.

BACKGROUND: Nitric oxide (NO) has been recently implicated as a possible mediator of bowel inflammation and has also been shown to stimulate electrogenic chloride secretion in rat and guinea pig intestine. This study therefore investigated the effect on two NO donors, sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) on human colonic ion transport. METHODS: Changes in short circuit current (delta SCC) in response to nitric oxide donating compounds were measured in muscle stripped normal human colon mounted in Ussing chambers. The ion species and intracellular mechanisms responsible for delta SCC evoked by SNP were investigated. RESULTS: Basolateral SNP caused a progressive rise in delta SCC over the range 10(-7) to 10(-4)M (ED50 = 2.5 x 10(-5)M). SNAP 10(-4)M also evoked a qualitatively similar delta SCC compared with SNP 10(-4)M. Basolateral SNP evoked a greater delta SCC than apical and this was significantly attenuated by bumetanide 10(-4)M (52.9 +/- 10.1%) and in chloride free media (68.3 +/- 7.3%). delta SCC response to SNP was not significantly changed by basolateral 4-acetamido-4'-isothio-cyano-2,2'disulphonic acid stillbene (SITS 10(-3)M) an inhibitor of sodium/bicarbonate exchange, or apical amiloride 10(-5)M an inhibitor of sodium absorption. SNP induced delta SCC was also significantly reduced by piroxicam (mean (SEM)) 10(-5)M (57.9 (11.9)%), nordihydroguaretic acid 10(-4)M (48.0 (12.9)%), tetrodotoxin (TTX 10(-6)M, 52.3 (9.1)%), and practically abolished by TTX and piroxicam together (96.8 (3.3)%). CONCLUSION: NO donors stimulate human colonic ion transport in vitro. For SNP, increased delta SCC is at least due in part to chloride secretion, and the response seems to be transduced through enteric nerves and by local prostanoid synthesis. This study provides evidence that NO may be another important mediator of ion transport in human colon.

Colon↗