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Biomedical subjects

C J Hawkey

Publications and source records attributed to C J Hawkey.

At least 109 records · Page 6Linked to original sources
PubMed1998

A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group.

BACKGROUND: Suppressing acid secretion is thought o reduce the risk of ulcers associated with regular use of nonsteroidal antiinflammatory drugs (NSAIDs), but the best means of accomplishing this is uncertain. METHODS: We studied 541 patients who required continuous treatment with NSAIDs and who had ulcers or more than 10 erosions in either the stomach or duodenum. Patients were randomly assigned to double-blind treatment with omeprazole, 20 mg or 40 mg orally per day, or ranitidine, 150 mg orally twice a day, for four or eight weeks, depending on when treatment was successful (defined as the resolution of ulcer and the presence of fewer than five erosions in the stomach, and fewer than five erosions in the duodenum, and not more than mild dyspepsia). We randomly assigned 432 patients in whom treatment was successful to maintenance treatment with either 20 mg of omeprazole per day or 150 mg of ranitidine twice a day for six months. RESULTS: At eight weeks, treatment was successful in 80 percent (140 of 174) of the patients in the group given 20 mg of omeprazole per day, 79 percent (148 of 187) of those given 40 mg of omeprazole per day, and 63 percent (110 of 174) of those given ranitidine (P<0.001 for the comparison with 20 mg of omeprazole and P=0.001 for the comparison with 40 mg of omeprazole). The rates of healing of all types of lesions were higher with omeprazole than with ranitidine. During maintenance therapy, the estimated proportion of patients in remission at the end of six months was 72 percent in the omeprazole group and 59 percent in the ranitidine group. The rates of adverse events were similar between groups during both phases. Both medications were well tolerated. CONCLUSIONS: In patients with regular use of NSAIDs, omeprazole healed and prevented ulcers more effectively than did ranitidine.

Adult↗
PubMed1998

Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group.

BACKGROUND: Misoprostol is effective for ulcers associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs) but is often poorly tolerated because of diarrhea and abdominal pain. We compared the efficacy of omeprazole and misoprostol in healing and preventing ulcers associated with NSAIDs. METHODS: In a double-blind study, we randomly assigned 935 patients who required continuous NSAID therapy and who had ulcers or more than 10 erosions in the stomach or duodenum (or both) to receive 20 mg or 40 mg of omeprazole orally in the morning or 200 microg of misoprostol orally four times daily. Patients were treated for four weeks or, in the absence of healing, eight weeks. Treatment success was defined as the absence of ulcers and the presence of fewer than five erosions at each site and not more than mild dyspepsia. We then randomly reassigned 732 patients in whom treatment was successful to maintenance therapy with 20 mg of omeprazole daily, 200 microg of misoprostol twice daily, or placebo for six months. RESULTS: At eight weeks, treatment was successful in 76 percent of the patients given 20 mg of omeprazole (233 of 308), 75 percent of those given 40 mg of omeprazole (237 of 315), and 71 percent of those given misoprostol (212 of 298). The rates of gastric-ulcer healing were significantly higher with 20 mg of omeprazole (but not 40 mg of omeprazole) than with misoprostol. Healing rates among patients with duodenal ulcers were higher with either dose of omeprazole than with misoprostol, whereas healing rates among patients with erosions alone were higher with misoprostol. More patients remained in remission during maintenance treatment with omeprazole (61 percent) than with misoprostol (48 percent, P=0.001) and with either drug than with placebo (27 percent, P<0.001). There were more adverse events during the healing phase in the misoprostol group than in the groups given 20 mg and 40 mg of omeprazole (59 percent, 48 percent, and 46 percent, respectively). CONCLUSIONS: The overall rates of successful treatment of ulcers, erosions, and symptoms associated with NSAIDs were similar for the two doses of omeprazole and misoprostol. Maintenance therapy with omeprazole was associated with a lower rate of relapse than misoprostol. Omeprazole was better tolerated than misoprostol.

Adult↗
PubMed1998

Lack of effectiveness of the platelet-activating factor antagonist SR27417A in patients with active ulcerative colitis: a randomized controlled trial. The Platelet Activating Factor Antagonist Study Group in Ulcerative Colitis.

BACKGROUND & AIMS: Platelet-activating factor (PAF) is increased during relapse of ulcerative colitis. In animal models of experimental colitis, specific inhibition of PAF has reduced inflammation. The aim of this study was to evaluate the efficacy and safety of the PAF antagonist SR27417A in moderately active UC. METHODS: A double-blind multicenter trial was conducted during a 28-day period in hospital outpatients with an exacerbation of ulcerative colitis. Patients were randomized to receive 10 mg/day SR27417A or placebo, and both groups were also given 2.4 g mesalazine. Patient classification at the end of the treatment period was based on sigmoidoscopy and clinical scores. RESULTS: One hundred fifty-one subjects entered the study (75 placebo and 76 SR27417A). The remission rate between placebo- and SR27417A-treated patients at 28 days was not significantly different (29.0% and 35.6% respectively; P = 0.44). Similarly, 49.2% treated with SR27417A had a definite or possible improvement of their symptom score compared with 48.3% of those treated with placebo (P = 0.43). Four subjects in the placebo group and 5 subjects in the SR27417A group discontinued the drug treatment because of adverse events. No significant adverse events were thought to be caused by SR27417A. CONCLUSIONS: Although the specific PAF antagonist SR27417A is safe in humans, there is no evidence of efficacy in the treatment of acute ulcerative colitis.

Adult↗
PubMed1998

Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drug users.

AIM: To investigate the efficacy of omeprazole 20 mg o.m. as primary prophylaxis against non-steroidal anti-inflammatory drug (NSAID)-associated ulcer disease or dyspeptic symptoms. METHODS: A parallel group study compared patients randomized to receive omeprazole 20 mg o.m. or placebo as co-therapy with on-going NSAID treatment, over 6 months, in 19 specialist centres in Ireland, Hungary, France, the UK and the USA. One hundred and sixty-nine patients taking NSAIDs regularly, chronically and above defined minimum doses entered the trial. The main outcome measure was the development of gastric or duodenal ulcers detected endoscopically, the development of multiple erosions in the stomach or duodenum, or the onset of moderate or severe dyspeptic symptoms. RESULTS: The estimated probability of remaining free of these end-points for 6 months for patients taking omeprazole was 0.78 compared to 0.53 for placebo (P = 0.004). Fourteen patients receiving placebo (16.5%) developed 15 ulcers, comprising nine gastric and six duodenal ulcers, compared to three patients (3.6%) receiving omeprazole (all gastric ulcers). Logistic regression analysis showed that older patients were less likely, whilst those with rheumatoid arthritis were more likely, to remain free of NSAID-associated problems. CONCLUSIONS: Omeprazole is an effective agent for gastroduodenal prophylaxis in patients taking NSAIDs. Its main effect is to reduce the rate of development of gastric and duodenal ulcers.

Adolescent↗
PubMed1998

Short- and long-term outcome of patients treated with cyclosporin for severe acute ulcerative colitis.

BACKGROUND: Recent evidence suggests that the immunosuppressive drug cyclosporin may be of benefit in treating patients with severe colitis who are steroid resistant. Although cyclosporin appears to be effective in reducing colectomy rates in the short term, few data are available on the long-term follow-up of such patients. AIM: To investigate the short- and long-term outcome of patients with severe steroid-resistant ulcerative colitis treated with cyclosporin who were otherwise being considered for colectomy. METHODS: Twenty-two patients with severe steroid-resistant exacerbations of ulcerative colitis who were being considered for colectomy were treated with cyclosporin (4 mg/kg i.v.) daily for 7 days followed by oral treatment (6 mg/kg/day) if colectomy was avoided. RESULTS: Twenty of 22 patients (91%) avoided colectomy during their initial hospital admission. With a mean follow-up period of 39 months (range 31-59), eight of these patients have subsequently relapsed and required colectomy and 12 patients have avoided colectomy (53%). Of the 12 patients avoiding colectomy, seven have successfully been weaned on to azathioprine while five are maintained on an aminosalicylate alone. None of these long-term responders require maintenance corticosteroids. The main side-effects during treatment with cyclosporin were headaches (six patients, 27%), paraesthesia and tremors (four patients, 18%) and hypertension (four patients, 18%). Two patients developed renal impairment on cyclosporin which resolved on lowering the dose. In no case was cyclosporin discontinued because of an adverse reaction. No clinical or laboratory features could be identified that predicted which patients treated with cyclosporin would later require colectomy. CONCLUSION: This study shows that cyclosporin is a viable alternative to emergency colectomy in severe ulcerative colitis in the short term. Although these benefits are not maintained in all patients, more than half were found to avoid colectomy in the longer term.

Colitis, Ulcerative↗
PubMed1998

Evaluation of a new Near Patient Test for the detection of Helicobacter pylori.

OBJECTIVE: Peptic ulcer disease is rare in the absence of Helicobacter pylori. Testing for H. pylori has recently become easier with the development of Near Patient Tests. However, the validity of many of these tests is unknown. The aim of this study was to assess the validity of the QuickVue one-step Near Patient Test for H. pylori in a group of patients attending for endoscopy at a tertiary referral hospital. METHODS: In a retrospective study the QuickVue one-step serum test (Quidel) was performed on the stored serum from 193 patients whose H. pylori status had been determined by a 'gold standard' using urease testing, histology, culture and 14C-urea breath testing. Twenty four other patients presenting to endoscopy were studied prospectively. For these patients QuickVue was performed on capillary and venous samples and the results were compared to a similar 'gold standard'. Enzyme immunoassay (Premier, H. pylori, Meridian Diagnostics, OH, USA) was used to define H. pylori status of patients with indeterminate H. pylori status by the above criteria. RESULTS: In the retrospective study the QuickVue one-step H. pylori test had a sensitivity (CI) of 82% (75-89) and specificity of 83% (74-92). In the prospective study on capillary blood its sensitivity (CI) was 89% (52-100) and its specificity 93% (68-100); and on venous blood, 78% (40-97) and 93% (68-100). Premier has previously been shown to have a sensitivity and specificity of 100%. CONCLUSION: In this group of patients the QuickVue one-step H. pylori Near Patient Test was less accurate than the Premier ELISA test, but its ease of use and availability in primary care make it useful for patient screening.

Adult↗
PubMed1998

Safety and efficacy of rabeprazole in combination with four antibiotic regimens for the eradication of Helicobacter pylori in patients with chronic gastritis with or without peptic ulceration.

OBJECTIVES: Rabeprazole is a new fast acting proton pump inhibitor that has recently been proven to be effective in the treatment of peptic ulceration and reflux esophagitis. The aim of this study was to evaluate rabeprazole in combination with antibiotics for the eradication of Helicobacter pylori (H. pylori) in patients with chronic active gastritis with or without peptic ulcer disease. METHODS: Seventy-five H. pylori-infected patients were randomized in a double-blind fashion to receive a 7-day treatment regimen consisting of: RAC, RAM, RCM, or RC (R=rabeprazole 20 mg b.d., A=amoxycillin 1 g b.d., C=clarithromycin 500 mg b.d., M=metronidazole 400 mg b.d.). Randomized patients were H. pylori-positive by gastric biopsy urease test, histology and 13C urea breath test (13C-UBT). H. pylori eradication was assessed by 13C-UBT, 4 and 8 wk after finishing treatment. Endoscopy with histology and culture for antibiotic sensitivity testing was performed pretreatment and if treatment failed. RESULTS: On an intention-to-treat analysis, treatment success was: RCM 100%, RAC 95%, RAM 90%, and RC 63%. The most common side effects were loose stools, headache, and taste disturbance, but there were no serious adverse events related to the study medication. The two patients failing RAM treatment had metronidazole-resistant strains before and after treatment. None of the pretreatment H. pylori isolates from six patients failing RC were clarithromycin resistant, but three of five successfully cultured posttreatment had developed clarithromycin resistance. CONCLUSION: Rabeprazole-based triple therapy with two antibiotics for 1 wk is safe and effective in eradicating H. pylori. Dual therapy with clarithromycin is less successful, and the majority of treatment failures develop clarithromycin resistance.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

Expression of interleukin 1 beta and interleukin 1 beta converting enzyme by intestinal macrophages in health and inflammatory bowel disease.

BACKGROUND: In the lipopolysaccharide (LPS) stimulated peripheral blood monocyte, the precursor form of interleukin 1 beta (IL-1 beta, 31 kD) is processed by IL-1 beta converting enzyme (ICE) to the mature, bioactive form (17 kD). IL-1 beta is a proinflammatory cytokine which is likely to have a role in the pathogenesis of inflammatory bowel disease (IBD). AIMS: To investigate the expression and processing of IL-1 beta and ICE by tissue macrophages from normal and IBD colonic mucosa. METHODS: Mucosal biopsy specimens and lamina propria cells from normal and IBD colons were studied by reverse transcription polymerase chain reaction (RT-PCR), western blot analysis, and ELISA (enzyme linked immunosorbent assay). RESULTS: Normal colonic macrophages synthesised only the precursor form of IL-1 beta whereas in IBD the mature form was also produced. Similarly, cells from normal colonic mucosa synthesised ICE as the precursor (p45) only, whereas macrophages from IBD colons produced active (p20) ICE. Ac-Tyr-Val-Ala-Asp-CHO, a specific peptide aldehyde inhibitor of ICE, significantly reduced the amount of mature IL-1 beta released by isolated IBD macrophages (from a median of 1.2 (range 0.78-4.42) ng/ml to 0.43 (0.21-1.6) ng/ml; p < 0.01). CONCLUSIONS: Exposure of normal colonic macrophages to LPS only induces the production of the precursor form of IL-1 beta, because the cells fail to activate ICE. In contrast, IBD colonic macrophages are able to activate ICE and hence release mature IL-1 beta in a manner similar to circulating monocytes. This is consistent with IBD macrophages being recently recruited from the circulating monocyte population. Targeted inhibition of ICE may represent a novel form of therapy in IBD.

Adult↗
PubMed1998

Expression of basic fibroblast growth factor in intact and ulcerated human gastric mucosa.

BACKGROUND: Basic fibroblast growth factor (bFGF) promotes angiogenesis and healing of gastric ulcers in rats, and bFGF expression is up regulated in such ulcers. However, little is known about expression of bFGF in human gastric mucosa. AIMS: To investigate bFGF expression in intact human gastric mucosa and gastric ulcers and to determine whether low bFGF content or altered binding by mucosa is associated with ulceration. SUBJECTS: Endoscopy outpatients, gastrectomy patients, and organ donors. METHODS: bFGF was isolated by heparin affinity chromatography and characterised by western blotting and endothelial cell bioassay. bFGF was measured by immunoassay and its distribution defined by immunohistochemistry and in situ hybridisation. Binding of bFGF by heparan sulphate proteoglycans was investigated by sodium chloride and heparin extraction. RESULTS: Bioactive bFGF (19 kDa) was detected in normal mucosa but bFGF mRNA was not found. bFGF expression was up regulated in granulation tissue endothelial cells, mononuclear cells, and epithelial cells at the ulcer rim. Gastric ulcer patients had constitutively low bFGF concentrations in intact antral mucosa which were not explained by changes in binding to heparan sulphate proteoglycans. CONCLUSIONS: bFGF expression is up regulated in human gastric ulcers. Low intact mucosal bFGF content is associated with gastric ulceration.

Blotting, Northern↗
PubMed1998

Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders.

Proton pump inhibitors (PPIs) are drugs which irreversibly inhibit proton pump (H+/K+ ATPase) function and are the most potent gastric acid-suppressing agents in clinical use. There is now a substantial body of evidence showing improved efficacy of PPIs over the histamine H2 receptor antagonists and other drugs in acid-related disorders. Omeprazole 20 mg/day, lansoprazole 30 mg/day, pantoprazole 40 mg/day or rabeprazole 20 mg/day for 2 to 4 weeks are more effective than standard doses of H2-receptor antagonists in healing duodenal and gastric ulcers. Patients with gastric ulcers should receive standard doses of PPIs as for duodenal ulcers but for a longer time period (4 to 8 weeks). There is no conclusive evidence to support the use of a particular PPI over another for either duodenal or gastric ulcer healing. For Helicobacter pylori-positive duodenal ulceration, a combination of a PPI and 2 antibacterials will eradicate H. pylori in over 90% of cases and significantly reduce ulcer recurrence. Patients with H. pylori-positive gastric ulcers should be managed similarly. PPIs also have efficacy advantages over ranitidine and misoprostol and are better tolerated than misoprostol in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In endoscopically proven gastro-oesophageal reflux disease, standard daily doses of the PPIs are more effective than H2-receptor antagonists for healing, and patients should receive a 4 to 8 week course of treatment. For severe reflux, with ulceration and/or stricture formation, a higher dose regimen (omeprazole 40 mg, lansoprazole 60 mg, pantoprazole 80 mg or rabeprazole 40 mg daily) appears to yield better healing rates. There is little evidence that PPIs lead to resolution of Barrett's oesophagus or a reduction of subsequent adenocarcinoma development, but PPIs are indicated in healing of any associated ulceration. In Zollinger-Ellison syndrome, PPIs have become the treatment of choice for the management of gastric acid hypersecretion.

Animals↗
PubMed1997

Platelet responses to several agonists and combinations of agonists in whole blood: a placebo controlled comparison of the effects of a once daily dose of plain aspirin 300 mg, plain aspirin 75 mg and enteric coated aspirin 300 mg, in man.

Platelet responses to several agonists and combinations of agonists have been measured in whole blood from healthy volunteers. We have determined the effects of once daily treatment for five days with plain aspirin 300 mg, plain aspirin 75 mg, enteric coated aspirin 300 mg or placebo. Measurements were made of platelet aggregation (using a platelet counting technique) and the release reaction (14C-5HT release from pre-labelled platelets). The extents of these responses before aspirin administration depended on the agonist used. ADP, adrenaline and PAF failed to induce any 14C-5HT release in most subjects, but combinations of these agonists acted synergistically to produce extensive 14C-5HT release. All three aspirin preparations reduced the extent of the platelet responses to most agonists: platelet aggregation induced by collagen, ristocetin and arachidonate and 14C-5HT release induced by collagen, streptokinase, and various combinations of ADP, adrenaline and PAF. None of the preparations had any effect on the aggregation that occurred in the absence of an agonist (spontaneous aggregation), but they all reduced streptokinase-induced aggregation to control (spontaneous) levels, and abolished the 14C-5HT release induced by arachidonate and by ristocetin. All three aspirin preparations were equally effective after two daily doses. No further inhibition of platelet responses was obtained after five daily doses. Plain aspirin 300 mg achieved its maximal effect after only a single dose, but enteric coated aspirin 300 mg (and sometimes plain aspirin 75 mg) produced sub-maximal inhibition after only a single dose. Parallel investigations on the effects of these aspirin regimes on gastric mucosal prostaglandin E2 synthesis and gastroduodenal mucosal injury were performed. These results will be reported separately.

Adenosine Diphosphate↗
PubMed1997

Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells.

Nonsteroidal antiinflammatory drugs reduce the risk of colon cancer, possibly via cyclooxygenase (COX) inhibition. The growth factor-inducible COX-2, which is overexpressed in neoplastic colonic tissue, is an attractive target to mediate this effect. Herein we have exploited the ability of a human colon cancer cell line, HCA-7 Colony 29, to polarize when cultured on Transwell (Costar) filters to study COX-2 production and the vectorial release of prostaglandins (PGs). Administration of type alpha transforming growth factor to the basolateral compartment, in which the epidermal growth factor receptor (EGFR) resides, results in a marked induction of COX-2 immunoreactivity at the base of the cells and the unexpected appearance of COX-2 in the nucleus. The increase in COX-2 protein is associated with a dose- and time-dependent increase in PG levels in the basolateral, but not apical, medium. Amphiregulin is the most abundantly expressed EGFR ligand in these cells, and the protein is present at the basolateral surface. EGFR blockade reduces baseline COX-2 immunoreactivity, PG levels, and mitogenesis in a concentration-dependent manner. Two specific COX-2 inhibitors, SC-58125 and NS 398, also, in a dose-dependent manner, attenuate baseline and type alpha transforming growth factor-stimulated mitogenesis, although PG levels are decreased > 90% at all concentrations of inhibitor tested. These findings show that activation of the EGFR stimulates COX-2 production and its translocation to the nucleus, vectorial release of PGs, and mitogenesis in polarized HCA-7 Colony 29 cells.

Amphiregulin↗
PubMed1997

Interleukin-8 and inducible nitric oxide synthase mRNA levels in inflammatory bowel disease at first presentation.

Interleukin-8 (IL-8) and nitric oxide (NO) may be important mediators in the pathogenesis of chronic idiopathic inflammatory bowel disease (CIIBD), but their roles in disease activity in ulcerative colitis (UC) and Crohn's disease (CD) are uncertain. The aim of this study was to measure mRNA for IL-8 and inducible NO synthase (iNOS) in small mucosal biopsies from untreated patients at first presentation and to relate these measurements to the histological levels of polymorph infiltration graded on a ten-point scale. For this purpose, a sensitive enzyme-linked oligonucleotide chemiluminescent assay (ELOCA) was developed to quantitate reverse transcription-polymerase chain reaction (RT-PCR) products amplified from RNA from paired biopsy samples. The levels of IL-8 and iNOS mRNAs were calculated as ratios of the RT-PCR products to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) RT-PCR product. In UC patients, median values of IL-8/GAPDH and iNOS/GAPDH were significantly elevated compared with controls and CD. However, in both UC and CD, the IL-8/GAPDH and iNOS/GAPDH ratios correlated significantly with polymorph infiltration. ELOCA enabled quantitation of multiple mRNAs in small mucosal biopsies from untreated patients with CIIBD and supported a role for IL-8 and iNOS in acute inflammation in both UC and CD.

Adult↗