Search PubMed⌕ Search

Biomedical subjects

C J Hawkey

Publications and source records attributed to C J Hawkey.

At least 73 records · Page 4Linked to original sources
PubMed2000

Management of gastroduodenal ulcers caused by non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a major cause of morbidity and mortality, probably resulting in the death of 1200 patients per annum in the UK. The main mechanism of toxicity involves an inhibition of prostaglandin synthesis that results in mucosal erosion as a result of the abrogation of defence mechanisms. However, acid peptic attack can deepen this initial injury. Thus, logical treatments include prostaglandin analogues as 'replacement therapy', acid suppression, enteric coating to avoid topical effects and the use of safer NSAIDs, including those that have little or no effect on gastric mucosal prostaglandin synthesis. There is less logic to the strategy of Helicobacter pylori (H. pylori) eradication, and the status of this approach is controversial. Overall, proton pump inhibitors have the best profile of efficacy and side-effects for the healing and prevention of NSAID-associated ulcers. Misoprostol is also effective and appears to be superior to proton pump inhibitors for superficial erosive injury. Early indications are that selective inhibitors of the inducible cyclooxygenase-2 enzyme have little or no effect in causing ulcers. Growing experience with these agents will probably revolutionize the management of patients with arthritic conditions. However, the increasing use of low-dose aspirin for cardiovascular prophylaxis means that gastroenterologists will have to continue to grapple with the problems of NSAID-associated ulcers for some time to come.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Nonsteroidal anti-inflammatory drug gastropathy.

By inhibiting prostaglandin synthesis, nonsteroidal anti-inflammatory drugs (NSAIDs) compromise gastroduodenal defense mechanism including blood flow and mucus/bicarbonate secretion. This has led to NSAIDs being the most widely reported drug cause of adverse events. While NSAIDs also cause dyspepsia, inhibition of prostaglandin synthesis may reduce this from even higher levels that would otherwise prevail and mask ulcer-related dyspepsia, making anticipatory management difficult. On average, the risk of ulcer complications increases 4-fold, resulting in 1.25 additional hospitalizations per 100 patient-years according to one estimate. Older patients, those with a past history, and those taking anticoagulants or corticosteroids are at higher risk. Risk is dose dependent and is lower with ibuprofen at low doses than with other NSAIDs. It is unlikely that Helicobacter pylori increases the risk, and under some circumstances it may be protective. Selective inhibitors of the inducible cyclooxygenase 2 spare gastric mucosal prostaglandin synthesis and do not damage the gastric mucosa. Their place in therapy, compared with use of misoprostol or proton pump inhibitors, is currently emerging. Future competitors may include nitric oxide-donating, zwitterionic, or R-enantiomer NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

What consideration should be given to Helicobacter pylori in treating nonsteroidal anti-inflammatory drug ulcers?

Although Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) both cause peptic ulcers, they do so by different mechanisms so any interaction is not necessarily harmful. H. pylori has been shown to enhance gastric mucosal prostaglandin synthesis, while NSAIDs suppress it Pragmatically, there is no compelling evidence in favour of H. pylori eradication in all patients who take NSAIDs. As a broad generalisation, in therapeutic studies of NSAID users, those who have no ulcer at trial entry are more prone to ulcer development if they are H. pylori-positive. By contrast, in those who have ulcers at baseline, H. pylori-positive individuals are less likely to develop ulcers, particularly if taking acid-suppressive therapy. Trials of H. pylori eradication therapy tend to replicate this dichotomy. In one study of patients starting NSAIDs for the first time, with no ulcer history and no baseline ulcer, use of bismuth-based eradication therapy was associated with a lower incidence of gastric ulcer at 2 months. Conversely, in a study of patients with endoscopically proven ulcers and/or troublesome dyspepsia, proton pump inhibitor based eradication treatment had no effect on outcome (of acid suppression) over 6 months. H. pylori eradication has been associated with significantly slower healing of gastric ulcers compared with patients who did not undergo eradication. However, the effect of H. pylori eradication on healing of NSAID-associated duodenal ulcers does not appear to be so dramatic, and limited evidence suggests that it may be possible to prevent H. pylori-associated duodenal ulcer by eradicating the infection. An evidence-based approach to treatment would suggest that NSAID users should undergo H. pylori eradication therapy if they have a duodenal ulcer, whether or not they continue NSAIDs. Because COX-2 inhibitors appear not to be ulcerogenic, management of H. pylori in patients taking these drugs can be based upon the same risk assessment as in patients not taking anti-arthritis drugs. H. pylori eradication should not be used universally or in high-risk gastric ulcer patients who require management with acid suppression.

Anti-Bacterial Agents↗
PubMed2000

Risk of ulcer bleeding in patients infected with Helicobacter pylori taking non-steroidal anti-inflammatory drugs.

OBJECTIVE: To determine whether Helicobacter pylori is an independent risk factor for bleeding peptic ulcer in users of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. DESIGN: A prospective matched case-control study. SETTING: Odense University Hospital, Denmark. SUBJECTS: 132 patients with a bleeding peptic ulcer (n=124) or haemorrhagic gastritis (n=8) at endoscopy who had taken an NSAID in the previous week and 136 controls who had taken NSAIDs without gastrointestinal complications. The controls were recruited from rheumatology and geriatric outpatient clinics. MEASUREMENTS: H pylori status assessed by serology and 13C-urea breath test and regarded as positive if either test was positive. Data on potential confounding factors including smoking and alcohol were collected by interview. MAIN RESULT: H pylori was present in 57% of cases and 43% of controls. The adjusted odds ratio of bleeding from a peptic ulcer owing to H pylori infection in NSAID users was 1.81 (95% CI 1.02 to 3.21) and was similar in aspirin and non-aspirin NSAID users. Peptic ulcer bleeding was also statistically significantly associated with a history of previous ulcer bleeding, dyspepsia within the previous 3 months, drinking alcohol but not with smoking. About 16% of bleeding peptic ulcers in NSAID users could be attributed to H pylori infection. CONCLUSION: NSAID users infected with H pylori have an almost doubled risk of bleeding peptic ulcer compared with uninfected NSAID users.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa.

BACKGROUND AND AIMS: Constitutive cyclooxygenase (COX) 1 is believed to mediate prostaglandin dependent gastric protection. However, gastric mucosa contains cells capable of expressing inducible COX-2. We therefore investigated COX-1 and COX-2 expression, localisation, and activity in normal and abnormal human gastric mucosa. METHODS: COX-1 and COX-2 distribution was investigated by light and electron microscopic immunohistochemistry and by western blot analysis, and their contribution to prostaglandin (PG)E(2) synthesis using selective enzyme inhibitors. RESULTS: There was strong parietal cell COX-1 and COX-2 immunoreactivity in all sections and isolated cells, with macrophage and myofibroblast reactivity in some sections. Immunostaining was specifically abolished by antigen absorption. Western blot analysis confirmed COX-1 and 2 expression. COX-1 and COX-2 immunostaining was increased in Helicobacter pylori gastritis, particularly the mid glandular zone and lamina propria inflammatory cells. This was associated with increased ex vivo PGE(2) synthesis (62.4 (13.5) pg/mg v 36.3 (15.5) pg/mg in uninflamed mucosa; p=0. 017) which was significantly inhibited by COX-1 but not COX-2 inhibition. Increased COX-2 immunostaining in macrophages, endothelial cells, and myofibroblasts (with reduced epithelial expression) was seen at the rim of ulcers. CONCLUSION: COX-2, as well as COX-1, is expressed by normal human gastric mucosa and is increased at the rim of ulcers. Although both are increased with H pylori, COX-1 contributes more than COX-2 to gastric PGE(2) production.

Biopsy↗
PubMed2000

COX-2 selective nonsteroidal anti-Inflammatory drugs: do they really offer any advantages?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for substantial morbidity and mortality as a result of the complications associated with gastroduodenal ulcers, such as perforation and bleeding. The central mechanism leading to the gastroduodenal toxicity of NSAIDs is their ability to inhibit mucosal prostaglandin synthesis. Recent recognition that there are 2 isoforms of the enzyme cyclooxygenase (COX) responsible for prostaglandin synthesis has enabled the development of drugs capable of sparing the gastric mucosa. The inducible COX-2 enzyme is responsible for some aspects of pain and inflammation in arthritis while the constitutive COX-1 enzyme appears responsible for most of the gastro-protective prostaglandin synthesis in the stomach and duodenum. Drugs selective for COX-2 probably act by binding to a pocket in the enzyme that is present in COX-2 but not in COX-1. As a result, drugs that have little or no COX-1 activity across their therapeutic dosage range have been developed. Two drugs that are claimed to be highly selective or specific in their ability to inhibit COX-2, rofecoxib and celecoxib, are now available on prescription in the US and rofecoxib is available in Europe. Short term volunteer studies of 7 days' duration and patient studies of 6 months' duration have shown these drugs to have a level of gastroduodenal injury that is similar or equivalent to that seen with placebo, whereas high rates of damage and ulceration are seen with nonselective NSAIDs. In addition, there appear to have been fewer perforations, clinical ulcers and bleeds in the phase III clinical trials of these agents, compared with nonselective NSAIDS. However, more experience will be needed before this promise can be confirmed. In addition, COX-2 inhibitors share the adverse effects of NSAIDs outside the gastrointestinal tract that are dependent on COX-2 inhibition.

Animals↗
PubMed1999

Irritable bowel syndrome clinical trial design: future needs.

This article addresses a series of points that should be considered in the design of future clinical trials in irritable bowel syndrome (IBS). A precise, uncontroversial definition of the disorder and the affected patient is required that accurately describes the condition that practitioners recognize intuitively exists. Regarding patient source and selection, the principle should be applied that patients be recruited to trials from all sources to which an indication is intended. Because abdominal pain is the most central symptom of IBS, it should be used as the primary trial endpoint. Because there are currently no effective treatments, placebo-controlled trials pose no ethical problems. High placebo responses may equally well be the temporary spontaneous improvements that are characteristic of the condition. Clinical trials should be designed to meet specific aims of treatments: when taken as single doses to terminate an attack of pain; when taken over a brief period of time to speed resolution of a period of exacerbation of IBS; when taken after termination of a period of activity to prevent relapse; when taken regularly on a long-term basis to reduce the days on which a number of symptoms are experienced; when taken in form of discrete courses of treatment designed to achieve a pivotal change in the natural history of the condition.

Clinical Trials as Topic↗
PubMed1999

COX-2 inhibitors.

In the past 100 years aspirin has demonstrated its value as an analgesic, anti-inflammatory, and antithrombotic agent. However, by 1938, it was clear that aspirin was gastrotoxic. Non-steroidal anti-inflammatory drugs (NSAIDs), developed since the 1960s, failed to achieve the goal of "a safer aspirin". The demonstration that inhibition of prostaglandin synthesis via a cyclo-oxygenase (COX) enzyme was central to both the therapeutic and toxic effects of aspirin and non-aspirin NSAIDs appeared to establish the principle of no gain without pain. This link may have been broken by drugs that selectively inhibit the inducible COX-2 enzyme. The COX enzyme is now a target of drug interventions against the inflammatory process. Might the "safe aspirin" be here at last?

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Vacuolating cytotoxin (vacA) alleles of Helicobacter pylori comprise two geographically widespread types, m1 and m2, and have evolved through limited recombination.

Vacuolating cytotoxin (vacA) alleles of Helicobacter pylori vary, particularly in their mid region (which may be type m1 or m2) and their signal peptide coding region (type s1 or s2). We investigated nucleotide diversity among vacA alleles in strains from several locales in Asia, South America, and the USA. Phylogenetic analysis of vacA mid region sequences from 18 strains validated the division into two main groups (m1 and m2) and showed further significant divisions within these groups. Informative site analysis demonstrated one example of recombination between m1 and m2 alleles, and several examples of recombination among alleles within these groups. Recombination was not sufficiently extensive to destroy phylogenetic structure entirely. Synonymous nucleotide substitution rates were markedly different between regions of vacA, suggesting different evolutionary divergence times and implying horizontal transfer of genetic elements within vacA. Non-synonymous/synonymous rate ratios were greater between m1 and m2 sequences than among m1 sequences, consistent with m1 and m2 alleles encoding functions fitting strains for slightly different ecological niches.

Alleles↗
PubMed1999

Neutrophils, Helicobacter pylori, and nonsteroidal anti-inflammatory drug ulcers.

BACKGROUND & AIMS: Gastric injury by nonsteroidal anti-inflammatory drugs (NSAIDs) is minimal in neutropenic animals. This study examined peptic ulcer development in the presence or absence of gastric neutrophils in patients requiring long-term use of NSAIDs. METHODS: Gastric histology, neutrophils, and Helicobacter pylori were assessed in 120 patients randomized to receive placebo or 20 or 40 mg famotidine twice daily as prophylaxis against NSAID-related ulcers and who underwent endoscopy at 0, 4, 12, and 24 weeks. RESULTS: In 43 patients without gastric neutrophils, ulcers developed in 1 of 14 (7.7%) taking placebo, 2 of 16 (12.5%) taking 20 mg famotidine, and none of 13 taking 40 mg famotidine. However, in 77 patients with neutrophils, ulcers developed in 13 of 28 (47. 4%) taking placebo (P < 0.001), 3 of 26 (12.6%) taking 20 mg famotidine, and 3 of 23 (13%) taking 40 mg famotidine. Eight of 46 patients (17%) without H. pylori had neutrophils compared with 69 of 74 (93%) with both H. pylori and neutrophils (P < 0.001). CONCLUSIONS: Gastric neutrophils increase the incidence of ulceration in long-term NSAID users. Because neutrophils exist with H. pylori, eradicating this infection might prevent NSAID-related peptic ulcers.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

NSAIDs and the GI tract-potential hazards and benefits.

Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) have a substantial impact upon the gastrointestinal tract with both toxicity and benefit. The major toxicity relates to gastroduodenal ulceration and injury to the small and large intestine. The major benefits relate to evidence that the drugs may prevent, delay or cause regression of progress towards malignancy in the colon, and almost certainly also the stomach. The mechanism of toxicity has been thought to relate to inhibition of the synthesis of prostaglandins, since these are protective to the gastrointestinal mucosa as a result of effects on blood flow and mucus and bicarbonate secretion. It is difficult to attribute any anti-cancer effect to these actions. Promotion of apoptosis, which appears to be independent of prostaglandin synthesis, may better account for both therapeutic benefits and possibly some of the toxicity.

Journal Article↗
PubMed1999

Amphiregulin acts as an autocrine growth factor in two human polarizing colon cancer lines that exhibit domain selective EGF receptor mitogenesis.

Colonic enterocytes, like many epithelial cells in vivo, are polarized with functionally distinct apical and basolateral membrane domains. The aims of this study were to characterize the endogenous epidermal growth factor (EGF)-like ligands expressed in two polarizing colon cancer cell lines, HCA-7 Colony 29 (HCA-7) and Caco-2, and to examine the effects of cell polarity on EGF receptor-mediated mitogenesis. HCA-7 and Caco-2 cells were grown on plastic, or as a polarized monolayer on Transwell filters. Cell proliferation was measured by 3H-thymidine incorporation and EGF receptor (EGFR) binding was assessed by Scatchard analysis. EGFR ligand expression was determined by Northern blot analysis, reverse transcription polymerase chain reaction, metabolic labelling and confocal microscopy. We found that amphiregulin (AR) was the most abundant EGFR ligand expressed in HCA-7 and Caco-2 cells. AR was localized to the basolateral surface and detected in basolateral-conditioned medium. Basolateral administration of neutralizing AR antibodies significantly reduced basal DNA replication. A single class of high-affinity EGFRs was detected in the basolateral compartment, whereas the apical compartment of polarized cells, and cells cultured on plastic, displayed two classes of receptor affinity. Basolateral administration of transforming growth factor alpha (TGF-alpha) or an EGFR neutralizing antibody also resulted in a dose-dependent stimulation or attenuation, respectively, of DNA replication. However, no mitogenic response was observed when these agents were added to the apical compartment or to confluent cells cultured on plastic. We conclude that amphiregulin acts as an autocrine growth factor in HCA-7 and Caco-2 cells, and EGFR ligand-induced proliferation is influenced by cellular polarity.

Amphiregulin↗
PubMed1999

Protection of human gastric mucosa against aspirin-enteric coating or dose reduction?

BACKGROUND: Aspirin is widely used for cardiovascular prophylaxis. AIM: To compare the effectiveness of two widely-used strategies-dose reduction and enteric coating-for the minimization of gastric mucosal injury or toxicity. METHODS: Twelve healthy volunteers were studied. On four separate occasions each received, under blinded conditions, five daily doses of plain aspirin 300 mg, plain aspirin 75 mg, enteric-coated aspirin 300 mg or placebo. Ex vivo prostaglandin E2 synthesis was stimulated by the vortex mixing of gastric mucosal biopsies in Tris saline and measured by radioimmunoassay. Mucosal injury was quantified both by counting erosions and with a visual analogue scale. RESULTS: All three preparations reduced prostaglandin E2 synthesis by day five, by (median) 84% for plain aspirin 300 mg, by 80% for enteric coated aspirin 300 mg and by 63% for plain aspirin 75 mg. There was little mucosal injury prior to the start of each dose and period and no significant change with placebo. Plain aspirin caused a dose-dependent mucosal injury, with two (median, IQR 0-7) gastric erosions after five days of plain aspirin 75 mg, and 18 (2-26) after five days of plain aspirin 300 mg. With enteric-coated aspirin 300 mg there were 0 (0-1) gastric erosions (P = 0.003 compared to plain aspirin 300 mg P = 0.11, compared to plain aspirin 75 mg). CONCLUSION: Enteric coated aspirin reduces acute gastric mucosal injury to placebo levels, despite its inhibition of prostaglandin synthesis. Enteric coating is an appropriate strategy for the prevention of gastric mucosal damage induced by low-dose aspirin, which warrants systematic clinical evaluation.

Adult↗
PubMed1999

Protection against aspirin-induced human gastric mucosal injury by bosentan, a new endothelin-1 receptor antagonist.

BACKGROUND: Gastric ulceration induced by aspirin and by non-steroidal anti-inflammatory drugs (NSAIDs) is a major clinical problem. The mechanism of injury is unclear. There is evidence that NSAID-induced injury may cause endothelin activation. Endothelin-induced vasoconstriction has been shown to be capable of causing gastric ulceration. AIM: To investigate whether acute gastroduodenal injury induced in humans by aspirin can be prevented by the endothelin-1 antagonist, bosentan. METHODS: Eighteen healthy volunteers each received 5 x 900 mg aspirin every 12 h on three separate occasions (with either placebo, bosentan 700 mg or misoprostol 400 mg). Treatment order was randomized by Latin square design. Subjects were endoscoped and erosions counted before and 90 min after the first and last dose of aspirin. Plasma concentrations of bosentan were measured up to 5 h post-dose. RESULTS: There was a significant reduction in the mean number of erosions in the aspirin plus bosentan and aspirin plus misoprostol groups after the first dose of aspirin, compared with controls (aspirin plus placebo) (P<0.05). This was not sustained after the fifth dose of aspirin in the aspirin plus placebo and aspirin plus bosentan groups, but was still present in the aspirin plus misoprostol group. The mean plasma concentration of bosentan measured 3.5 h post-dose fell from 4510 (95% CI: 2791-6230) ng/mL after the 1st dose to 2508 (95% CI: 1733-3283) ng/mL after the 5th dose (P = 0.02). CONCLUSION: Endothelin receptor antagonism by bosentan can protect the gastric mucosa against aspirin damage. After five doses, bosentan levels fell, possibly because of enzyme induction, and protection was no longer evident. Further investigation is needed to assess whether higher doses would be effective.

Adult↗
PubMed1999

Personal review: Helicobacter pylori, NSAIDs and cognitive dissonance.

Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs) each cause peptic ulcers but by different mechanisms. As a result, the effect of both of these risk factors together is not a synergistic enhancement of injury, ulceration or rates of complications. Indeed, there are circumstances under which patients infected with H. pylori are less prone to NSAID-induced ulcers than those who are not infected or who have undergone eradication treatment. This may be because of opposite effects on gastric mucosal prostaglandin synthesis or for other reasons. Reluctance to accept that there may be specific circumstances where H. pylori is beneficial may arise because of the psychological process of cognitive dissonance.

Animals↗
PubMed1999

Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The International Consensus Meeting on the Mode of Action of COX-2 Inhibition (ICMMAC) brought together 17 international experts in arthritis, gastroenterology and pharmacology on 5 6 December 1997. The meeting was convened to provide a definition of COX-2 specificity and to consider the clinical relevance of COX-2-specific agents. These compounds are a new class of drugs that specifically inhibit the enzyme COX-2 while having no effect on COX-1 across the whole therapeutic dose range. The objectives of the meeting were to review the currently available data regarding the roles and biology of COX-1 and COX-2, and to foster a consensus definition on COX-2 specificity. At the present time, no guidelines exist for the in vitro and in vivo assessment of COX specificity, and it was felt that consensus discussion might clarify some of these issues. The meeting also reviewed recent clinical data on COX-2-specific inhibitors. The following article reflects discussion at this meeting and provides a consensus definition of COX-2-specific inhibitors.

Anti-Inflammatory Agents, Non-Steroidal↗