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Nonsteroidal anti-inflammatory drugs (NSAIDs) are capable of damaging the whole gastrointestinal tract. Small and large intestinal injuries manifest as acute changes in permeability with endoscopic erosions, chronic erosions and ulcers, diaphragms in the small bowel, and an increase in small and large bowel complications including perforation and diverticular bleeding. It is quite likely, though not proven, that such lesions contribute to anemia in patients taking them. A growing body of data shows that selective inhibitors of the cyclooxygenase-2 enzyme have much reduced toxicity in this respect. In addition, NSAID use has also been associated with development or relapse of ulcerative colitis. Whether the same is true of Crohn's disease, particularly of the small bowel, is less clear. An important point is that there are data that suggest that paracetamol may also not be devoid of toxicity. This makes use of selective cyclooxygenase-2 inhibitors attractive. There have been a number of reports of their use in inflammatory bowel disease. However, many of these have principally involved Crohn's disease and there have not been enough to be clear whether they affect the influence of relapse of ulcerative colitis.

Aspirin and non-aspirin NSAIDs injure the gastrointestinal tract principally as a result of their inhibition of prostaglandin synthesis. This is mediated via abrogation of the secretion of mucus and bicarbonate and by reduction in mucosal blood flow. Topical injury and inhibition of platelet thromboxane may also contribute respectively to damage and ulcer bleeding. Recognition of a second cyclooxygenase, COX-2, enabled drugs to be developed that selectively target this enzyme which is expressed in inflamed joints. These have proved to be effective treatments whilst causing little or no acute gastroduodenal injury and reduced ulcers and their complications. Future strategies may capitalise upon the phenomenon of substrate diversion of lipoxygenase products. Balanced cyclooxygenase / lipoxygenase inhibition maybe less harmful than cyclooxygenase inhibition. Also, nitric oxide can subserve many of the protective effects of prostaglandins and NO-donating NSAIDs are under evaluation.

Non-steroidal anti-inflammatory drugs (NSAIDs) account for more reports of drug related toxicity than any other class of drugs. Their most widely recognised adverse effects are on the gastrointestinal tract. They cause acute erosions and chronic ulcers that result in hospitalisation and death because of ulcer bleeding and perforation. Between them, aspirin and non-aspirin NSAIDs may account for more than half of all episodes of ulcer bleeding and perforation.

INTRODUCTION: Pharmacotherapy for upper gastrointestinal bleeding has been difficult to evaluate because clinical end points are infrequent and affected by other factors. AIMS: To evaluate whether blood in the stomach at endoscopy reflected severity of bleeding, predicted clinical outcomes, and could be altered by therapeutic agents. METHODS: We studied 414 consecutive admissions with suspected upper gastrointestinal bleeding. Patients were randomised to receive lansoprazole 60 mg followed by 30 mg four times daily, tranexamic acid 2 g followed by 1 g four times daily, both drugs, or placebo for four days, until discharge or a clinical end point occurred. Logistic regression analysis was used to determine predictors of endoscopic changes and clinical outcomes, and to investigate the effects of drug treatments on blood in the stomach. RESULTS: Of 414 patients with suspected upper gastrointestinal bleeding, 379 were endoscoped. Upper gastrointestinal bleeding was confirmed in 316. Sixteen required surgery within 30 days and 16 died on the index admission. Trial treatments were evaluable on a per protocol basis in 228 patients. The amount of blood in the stomach was found to reflect initial risk, with significant associations with high risk categorisation (odds ratio 3.7 (95% confidence interval 1.5-9.4) for more than a trace v none/trace), age (1.5 (1.1-1.9) per decade), and initial pulse (1.02 (1.00-1.04) per beat), and to predict rebleeding (9.2 (4.6-18.7)) and surgery (8.2 (2.9-22.9)). Other stigmata were less significant in these respects. The amount of blood in the stomach at endoscopy was reduced significantly by both lansoprazole (0.22 (0.07-0.63)) and tranexamic acid (0.27 (0.09-0.81)), although there was no evidence of synergy. CONCLUSIONS: Blood in the stomach reflects clinical features in patients with acute upper gastrointestinal bleeding and is reduced by treatment with lansoprazole and tranexamic acid.

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.

ABSTRACTAlleles of the vacuolating cytotoxin gene (vacA) ofHelicobacter pylorivary between strains, particularly in the region encoding the signal sequence (which may be type s1 or s2) and the midregion (which may be type m1 or m2). Using a PCR-based typing system developed in the United States, we showed that 36 strains from Asia and South America were all vacAsignal sequence type s1; 3 were midregion type m1 and 11 were m2, but 22 could not be typed for the vacAmidregion. All strains possessedcagA(cytotoxin-associated gene A), another virulence marker. vacAnucleotide sequence analysis showed that midregion typing failure was due to base substitutions at the primer annealing sites. Using the new sequence data, we developed two new PCR-based vacAmidregion typing systems, both of which correctly typed 41 U.S. strains previously typed by the old system and successfully typed all 36 of the non-U.S. strains. All previously untypeable strains were vacAm1, other than one m1/m2 hybrid. In summary, we describe and validate a simple PCR-based system for typing vacuolating cytotoxin (vacA) alleles of H. pyloriand show that this system correctly identifies the signal and midregion types of vacAin 77 strains from Asia and North and South America.

BACKGROUND: The basement membrane of human colonic mucosa contains numerous discrete pores. We have recently shown that following loss of the surface epithelium, many cells migrate out of the colonic lamina propria via basement membrane pores. AIMS: To characterise cells migrating out via basement membrane pores of the human gastric lamina propria, following loss of the surface epithelium. METHODS: Fresh human gastric mucosal samples were completely denuded of epithelial cells and placed in culture. Tissue samples were studied by electron microscopy (EM) and cells by EM, FACS analysis, immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: EM showed numerous discrete pores (0. 65-8.29 microm in diameter) in the subepithelial basement membrane. During culture of mucosal samples denuded of epithelial cells, lymphocytes, macrophages, and myofibroblasts migrated out of the lamina propria via the basement membrane pores. The lymphocytes were predominantly CD45RO+ and CD69+ T cells. Macrophages were shown to express cyclooxygenase (COX) 1 and 2 enzymes. Myofibroblasts were established in culture and, despite prolonged culture and passage, retained their phenotype. They expressed mRNA and protein for COX 1 and 2 enzymes and their release of prostaglandin E2 was inhibited by selective COX 1 and 2 inhibitors. CONCLUSIONS: Lamina propria cells migrating out of cultured denuded gastric mucosal samples have been characterised phenotypically and functionally. Such cells would be suitable for studies of their interactions with epithelial cells and also with Helicobacter pylori and its products.

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.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) and cause gastric ulceration. NSAIDs also impair granulation tissue angiogenesis and healing of established gastric ulcers in humans. The mechanism whereby NSAIDs inhibit granulation tissue angiogenesis is unknown but may involve inhibition of either or both COX isoforms (COX-1 and COX-2). AIMS: To investigate COX expression by human gastric endothelial (HuGE) cells during angiogenesis in vitro. METHODS: COX-1 and COX-2 expression by HuGE cells was investigated by western blot analysis, indirect immunofluorescence, reverse transcriptase polymerase chain reaction, and measurement of prostaglandin E(2) synthesis. Plating onto basement membrane matrix and stimulation by phorbol ester were used as in vitro models of angiogenesis. RESULTS: Under normal culture conditions (30% serum), HuGE cells expressed COX-1 and low levels of COX-2. COX-2 expression was induced in HuGE cells in both angiogenesis models. Prostaglandin E(2) production and tubular structure formation by HuGE cells on basement membrane matrix was significantly inhibited by a selective COX-2 inhibitor (NS-398). CONCLUSION: Angiogenesis by HuGE cells in vitro was associated with induction of functional COX-2 expression. A selective COX-2 inhibitor significantly decreased HuGE cell angiogenesis on basement membrane matrix. Extrapolation of these data to human gastric ulcer angiogenesis in vivo suggests that selective COX-2 inhibitors could delay gastric ulcer healing to the same extent as traditional NSAIDs which are non-selective COX inhibitors.

A rotating disc apparatus was used to study the dissolution of cholesterol in sodium cholate solutions and ox bile. Drugs with structures that render them capable of lowering interfacial resistance were tested and shown to increase cholesterol dissolution rates in both systems. In sodium cholate solutions, loperamide (3 times 10−4M) increased the rate of dissolution by over six times, and a similar effect was observed with amitriptyline (3 times 10−3M), diphenhydramine (3 times 10−3M), dicyclomine (3 times 10−3M) and propantheline (3 times 10−3M). These drugs are as effective as benzalkonium chloride at these concentrations. Amitriptyline, propantheline, dicyclomine and diphenhydramine also increased cholesterol dissolution rates into ox bile. If these drugs are excreted into human bile in sufficient quantities and in an active form they may be able to enhance the speed of cholesterol gallstone dissolution therapy.

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.

Haematological values were determined in 50 Rockhopper (Eudyptes crestatus), 19 Gentoo (Pygoscelis papua) and 12 Magellanic (Spheniscus magellanicus) penguins from various sites on the Falkland Islands. Adult Magellanic penguins had significantly lower haemoglobin (Hb) levels, packed cell volumes (PCV) and red cell counts (RBC) than adults of the other two species. Hb, PCV and RBC values were also lower in juvenile birds than in adults and lower in post-moult than in pre-moult adults. Comparison of findings in wild Rockhopper and Gentoo penguins with values obtained from captive birds showed slight but significant differences in Hb and mean cell haemoglobin concentration, and in the relative numbers of heterophils, lymphocytes, monocytes and eosinophils present.

Reference values for a variety of haematological parameters in 18 Mediterranean tortoises of two species (Testudo graecaand Testudo hermanni) were determined on six occasions during the year. Statistically significant seasonal variations were demonstrated in all parameters.

The effects of sulfasalazine and its moieties on synthesis of individual products of arachidonic acid metabolism by human colonic mucosa have been investigated. Sulfasalazine inhibited synthesis of the lipoxygenase products. Sulfasalazine and sulfapyridine also inhibited synthesis of thromboxane B2 while enhancing synthesis of prostaglandin (PG) F2a or PGE2, respectively. Inhibition of synthesis of lipoxygenase products and modulation of the profile of cyclooxygenase products could reduce inflammation and enhance mucosal resistance to damage in ulcerative colitis.

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 10PM, 50 mg at 6:30AM) or misoprostol 800 µg (400 µg at 10 PM, 400 µg 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.

OBJECTIVE: To determine how small differences in the efficacy and cost of two antibiotic regimens to eradicate Helicobacter pylori can affect the overall cost effectiveness of H pylori eradication in duodenal ulcer disease. DESIGN: A decision analysis to examine the cost effectiveness of eight H pylori eradication strategies for duodenal ulcer disease with and without 13C-urea breath testing to confirm eradication. MAIN OUTCOME MEASURES: Cumulative direct treatment costs per 100 patients with duodenal ulcer disease who were positive for H pylori. RESULTS: In model 1 the strategy of omeprazole, clarithromycin, and metronidazole alone was the most cost effective of the four strategies assessed. The addition of the 13C-urea breath test and a second course of omeprazole, clarithromycin, and metronidazole achieved the highest eradication rate (97%) but was the most expensive (62.63 pounds per patient). The cost of each additional effective eradication was 589.00 pounds (incremental cost per case) when compared with the cost of treating once only with omeprazole, clarithromycin, and metronidazole; equivalent to the cost of a patient receiving ranitidine for duodenal ulcer relapse for more than 15 years. Eradication strategies of omeprazole, amoxycillin, and metronidazole were less cost effective than omeprazole, clarithromycin, and metronidazole alone. In model 2 the addition of the 13C-urea breath test after treatment, and maintenance treatment, increased the cost of all the strategies and reduced the cost advantage of omeprazole, clarithromycin, and metronidazole alone. CONCLUSION: Small differences in efficacy can influence the comparative cost effectiveness of strategies for eradicating H pylori. Of the strategies tested the most cost effective (omeprazole, clarithromycin, and metronidazole alone) was neither the least expensive (omeprazole, amoxycillin, and metronidazole alone) nor the most effective (omeprazole, clarithromycin, and metronidazole with further treatment for patients found positive for H pylori on 13C-urea breath testing). Cost effectiveness should be an important part of choosing an eradication strategy for H pylori.

1. An increasing body of data suggests that the anti-haemostatic as well as the ulcerogenic actions of aspirin and other non-steroidal anti-inflammatory drugs may be operative when patients present with haematemesis and melaena. 2. We therefore developed methods to allow separate evaluation of the erosive and anti-haemostatic actions of aspirin in the human gastric mucosa. Volunteer subjects took 300 mg of aspirin daily in the morning or 600 mg of aspirin four times a day for 5 days under blinded randomized conditions. Changes in spontaneous gastric microbleeding, endoscopic signs of injury, spontaneous bleeding per gastric erosion, biopsy-induced bleeding and eicosanoids were studied. 3. Both doses of aspirin significantly inhibited gastric mucosal synthesis of prostaglandin E2 and reduced the serum thromboxane concentration. Erosions developed and regressed rapidly; compared with baseline 300 mg of aspirin daily in the morning caused substantial numbers of gastric erosions to develop (mean 5.3, 95% confidence limits 2.7–10.2) but this was significantly less than that caused by 600 mg of aspirin four times a day (10.9, 7.2–16.5, P < 0.05). The presence of erosions was associated with enhanced spontaneous bleeding, but only during aspirin administration. 4. Aspirin significantly increased bleeding induced by mucosal biopsy and was associated with significant enhancements in the rate of bleeding per gastric erosion. Bleeding rate per erosion but not biopsy-induced bleeding showed a significant dose-related increase with 600 mg of aspirin four times a day. Enteric coating reduced endoscopic signs of injury, but did not affect the impaired haemostasis caused by aspirin. 5. We conclude that aspirin can be shown to have both erosive and anti-haemostatic effects in the human stomach. Each can be evaluated separately in our model system. Both are potential therapeutic targets for the prevention of major upper-gastrointestinal bleeding caused by aspirin and probably other non-steroidal antiinflammatory drugs.

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 intraveous 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.

Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) almost invariably cause acute gastroduodenal injury and probably account for approximately 12000 ulcer bleeding episodes and 1200 deaths per annum in the United Kingdom. Clinically significant intestinal toxicity is also recognized but less clearly defined. The main risk factors for NSAID-related peptic ulcer complications are age, past history, use of higher risk individual NSAIDs, drug dose, concurrent use of warfarin or corticosteroids. The underlying reason for NSAID use and Helicobacter pylori status is not clearly associated with increased risk. Whether NSAIDs cause drug-induced non-ulcer dyspepsia is also controversial. Acute injury occurs more readily with aspirin than with non-aspirin NSAIDs, and the spectrum of acute injury is of little value in predicting clinically significant end points in comparison with different NSAIDs. However, acute studies of co-prescribed protective agents are highly predictive of performance in clinical practice. Gastric mucosal integrity is maintained by the interplay of three protective networks: prostaglandin synthesis, nitric oxide synthesis and the activity of the enteric nervous system. Aspirin and NSAIDs act by inhibiting prostaglandin synthesis catalysed by two cyclooxygenase enzymes. Most existing NSAIDs are unselective and inhibit the activity of the constitutive cyclooxygenase (COX) 1 enzyme in the stomach as much as the cyclooxygenase (COX) 2 enzyme which is induced at sites of inflammation such as joint disease. There are, however, prospects for selective cyclooxygenase 2 inhibitors. Some NSAIDs, particularly aspirin, have additional topical toxicity, which may in part reflect mucosal trapping. Some data favour an effect of NSAIDs in inhibiting mitochondrial oxidative phosphorylation. The principal physiological mechanisms which are compromised by NSAID use are mucosal Wood flow, secretion of mucus and bicarbonate and maintenance of a hydrophobic mucosal surface. Animal data suggest that polymorphonuclear leukocytes (PMNs) are important for acute damage though the relevance to humans has yet to be established. As well as damaging the mucosa, NSAIDs impair ulcer healing and are associated with reduced epithelial proliferation and evidence of diminished angiogenesis. An interaction between prostaglandins and growth factors, as well as the synthesis of antiproliferative products of arachidonic acid metabolism may be involved. Healing of NSAID ulcers by conventional doses of H2 antagonists is slow and H2 antagonists are poor at preventing gastric ulcer development or recurrence. These problems can be overcome by the use of more potent acid suppression. Misoprostol heals NSAID-associated ulcers, though whether healing is as fast as with non-NSAID ulcers has not been formally established. Misoprostol is effective prophylactic treatment but has a significant incidence of adverse events, particularly diarrhoea. Misoprostol has been reported to prevent ulcer complications, and in endoscopic studies has been superior as prophylaxis to standard dose ranitidine. Results of its efficacy compared to proton-pump inhibitors are awaited. For many patients appropriate management is avoidance of NSAIDs or use of less potent/toxic alternatives such as ibuprofen. Reductions in prescribing arising from a prior authorization scheme show that this can be achieved. For high-risk patients requiring continuing NSAID use co-prescription of omeprazole or misoprostol should be considered.

Prostaglandins protect the gastric mucosa in animals, but the evidence of an effect independent of pH changes in man is not overwhelming. Gastrointestinal bleeding because of non-steroidal anti-inflammatory drugs is a major clinical problem, which we have investigated in a model system measuring bleeding rates caused by short-term administration of aspirin. Of the various strategies tested, only those that elevated intra-gastric pH reduced aspirin-induced bleeding.

Captive Callitrichids frequently suffer a fatal wasting disease, wasting marmoset syndrome (WMS), of unexplained cause. This paper describes studies on the erythrocytes from animals in a breeding colony of tamarins (Saguinus labiatus), in which deaths from anaemia and wasting were occurring, to seek evidence for biochemical changes which could lead to oxidative damage and premature cell lysis. In only one animal of 33 studied did the red blood cell lipids show an increased susceptibility to oxidative damage. This animal, with some degree of certainty, could be diagnosed as having WMS. It was concluded that evidence for a primary deficiency of antioxidants as a cause of unexplained deaths, or WMS, in the colony could not at present be substantiated.

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.

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.

S&ELECT is a large-scale, prospective, international, multicentre, double-blind, double-dummy, randomized, parallel-group trial. Patients with exacerbation of osteoarthritis were treated with the recommended dose of meloxicam (7.5 mg) or piroxicam (20 mg) once daily for 28 days; 4320 patients were administered meloxicam and 4336 piroxicam. The incidence of adverse events was significantly lower in the meloxicam group (22.5%) compared with the piroxicam group (27.9%; P<0.001), mainly due to the significantly lower incidence of gastrointestinal (GI) adverse events in the meloxicam than in the piroxicam group (10.3% vs 15.4%; P<0.001), while the efficacy of both drugs was equivalent. Individual GI events occurred significantly less often with meloxicam than piroxicam: dyspepsia (3.4% vs 5.8%; P<0.001), nausea/vomiting (2.5% vs 3.4%; P<0.05) and abdominal pain (2.1% vs 3.6; P<0.001). There were 16 patients with perforations, ulcerations or bleeding (PUBs) of the upper GI tract in the piroxicam group compared with seven in the meloxicam group (relative risk piroxicam:meloxicam = 1.4). Four PUBs were complicated (perforations or bleedings); none of these occurred in the meloxicam group (relative risk piroxicam:meloxicam = 1.9). the outcome of SELECT is consistent with that of the large-scale clinical trial of similar design and size which compared 7.5 mg meloxicam with 100 mg diclofenac in patients with osteoarthritis, and with a previous global analysis of the safety of meloxicam. It adds further data to the proposed relationship between selective inhibition of cyclooxygenase-2 and improved GI tolerability of non-steroidal anti-inflammatory drugs.Keywords:Meloxicam, Piroxicam, Osteoarthritis, Gastrointestinal tolerability, Cyclooxygenase, Perforations, ulcerations or bleedings

Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19% P<0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P<0.001), nausea and vomiting (P<0.05), abdominal pain (P<0.01) and diarrhoea (P<0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P<0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P<0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.0% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P<0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy.Keywords:Meloxicam, NSAID, COX-2, Osteoarthritis, Large-scale clinical trial

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.

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.

Normal haematological reference values were obtained for Greater and Lesser flamingos (Phoenicopterus roseus, Phoeniconaias minor). Statistically significant differences in the total white cell count and the absolute heterophil count were found in the two species. The reference values were used to identify abnormalities in the blood of five sick birds. Three of these were anaemic, all showed red cell hypochromia and four had heterophilia. The findings suggested that haematological testing is of potential diagnostic value in the species.

As little comprehensive baseline data are available on age-related haematological changes in genetically-defined rat strains, the haematology of female F344 rats is described in animals sampled at 2, 4, 8, 20, 66 and 121 weeks of age. Values for Hb, RBC and PCV increased from 2 weeks of age to reach adult levels at 8 weeks, whereas MCV, MCH and reticulocyte counts were high initially but decreased to reach the adult range at 8 weeks. Between 66 and 121 weeks, reticulocyte counts were significantly increased and values for MCHC significantly decreased. Lymphocytes were the predominant white cell type in each age group. The absolute numbers of neutrophils and lymphocytes showed slight variations between 2 and 66 weeks and both cell types increased significantly between 66 and121 weeks. Platelet counts showed no overall age-related trends. Fibrinogen values increased from 2 weeks of age to reach the adult level at 8 weeks. One animal of the 14 sampled at 121 weeks showed changes in the blood, liver and spleen consistent with a diagnosis of lymphoid leukaemia.

Sucralfate does not have potent anti-ulcerogenic actions in users of non-steroidal anti-inflammatory drugs (NSAIDs). However, sucralfate may influence intragastric haemostasis favourably.

Reactivity of the monoclonal antibody 791T/36 with secondary malignant deposits has been investigated in frozen sections of 74 human liver biopsy specimens. There was no reactivity with hepatocytes but in some instances binding to fibrous tissues and in one case to portal tract lymphocytes was observed. Sections from 9 biopsy specimens contained malignant deposits. In seven of these 791T/36 bound either to malignant cells or to pseudoacinar contents (3 colorectal adenocarcinomas; 1 probable pancreatic adenocarcinoma; 1 medullary cell carcinoma of thyroid; 1 oat cell carcinoma of bronchus and 1 deposit of nodular sclerosing Hodgkins Disease). Two undifferentiated tumours (1 gastric adenocarcinoma and 1 oat cell bronchial carcinoma) showed no antibody binding. The histological pattern of reactivity previously reported with primary tumours appears to be similar in secondary deposits. A wider range of tumours than recognised hitherto binds 791T/36. Whether the binding to fibrous tissue seen in some instances is sufficient to cause diagnostic uncertainty when 791T/36 is used for scanning requires further investigation.

The effects of phencyclidine, ketamine and an alphaxalone-alphadolone mixture on the haematology of the patas monkey have been compared. In animals sedated with phencyclidine or ketamine the only significant difference detected was in the mean cell volume. Statistically significant differences in white-cell count and blood coagulation and fibrinolytic activity were found in monkeys which had received alphaxalone-alphadolone. It is suggested that ketamine is a suitable alternative to phencyclidine for haematological studies in these monkeys.

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 &lt; 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.

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.

Immune effector mechanisms are central to the disease process in inflammatory bowel disease, but it is not clear whether the mucosal or systemic immunological abnormalities are primary phenomena, or are secondary to disease activity. Corticosteroid drugs remain the most effective treatment for active disease, but there is no evidence that they are useful for maintenance therapy. Some patients, however, are dependent on low-dose corticosteroids, and relapse when the drug is withdrawn. These drugs have widespread actions on the immune response, and monocytes are particularly sensitive to corticosteroids. In contrast, sulphasalazine and 5-aminosalicylic acid are effective in maintenance therapy, but do not act primarily by immunosuppressive mechanisms. They are effective in maintenance therapy of ulcerative colitis, and mild relapses of ulcerative colitis and colonic Crohn’s disease. New preparations of 5-aminosalicylic acid have reduced side effects, many of which are due to sulphapyridine. Azathioprine and 6-mercaptopurine are used less widely: in Crohn’s disease there is reasonable evidence for benefit in chronic active disease unresponsive to corticosteroids, and maintenance of remission. In ulcerative colitis, the position is less clearcut. Overall, trials favour an effect in chronic active disease, and there are pointers to an effect in maintenance of remission. Because of their side effects, in particular marrow suppression, these drugs should be reserved for second-line therapy. Similarly, other cytotoxic drugs are not used because of their side effects. More recently, cyclosporin A, with its selective action on interleukin-2 release and/or synthesis, and inhibition of helper T cell function, has been shown to be helpful in Crohn’s disease. At present it should only be used in controlled trials, for patients with unresponsive disease in whom surgery is contraindicated. Renal toxicity may limit long term use. There is little data for cyclosporin A in ulcerative colitis. On the basis that there may be an underlying immune defect in Crohn’s disease leading to mucosal inflammation, immunostimulant therapy has been used, but there is no evidence for benefit from treatment with BCG or levamisole in active disease or in maintenance therapy. 7S-Immunoglobulin, plasmapheresis or T-lymphocyte apheresis have been used in acute relapse, but evidence is anecdotal, and does not support their use except as a desperate measure to avoid surgery. Further well-designed controlled trials are needed to define the role of all these drugs, and further research into the mechanism of action on the immune response may shed light on the pathogenesis of inflammatory bowel disease.

Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19% P&lt;0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P&lt;0.001), nausea and vomiting (P&lt;0.05), abdominal pain (P&lt;0.01) and diarrhoea (P&lt;0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P&lt;0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P&lt;0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.0% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P&lt;0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy.
Keywords:Meloxicam, NSAID, COX-2, Osteoarthritis, Large-scale clinical trial

S&ELECT is a large-scale, prospective, international, multicentre, double-blind, double-dummy, randomized, parallel-group trial. Patients with exacerbation of osteoarthritis were treated with the recommended dose of meloxicam (7.5 mg) or piroxicam (20 mg) once daily for 28 days; 4320 patients were administered meloxicam and 4336 piroxicam. The incidence of adverse events was significantly lower in the meloxicam group (22.5%) compared with the piroxicam group (27.9%; P&lt;0.001), mainly due to the significantly lower incidence of gastrointestinal (GI) adverse events in the meloxicam than in the piroxicam group (10.3% vs 15.4%; P&lt;0.001), while the efficacy of both drugs was equivalent. Individual GI events occurred significantly less often with meloxicam than piroxicam: dyspepsia (3.4% vs 5.8%; P&lt;0.001), nausea/vomiting (2.5% vs 3.4%; P&lt;0.05) and abdominal pain (2.1% vs 3.6; P&lt;0.001). There were 16 patients with perforations, ulcerations or bleeding (PUBs) of the upper GI tract in the piroxicam group compared with seven in the meloxicam group (relative risk piroxicam:meloxicam = 1.4). Four PUBs were complicated (perforations or bleedings); none of these occurred in the meloxicam group (relative risk piroxicam:meloxicam = 1.9). the outcome of SELECT is consistent with that of the large-scale clinical trial of similar design and size which compared 7.5 mg meloxicam with 100 mg diclofenac in patients with osteoarthritis, and with a previous global analysis of the safety of meloxicam. It adds further data to the proposed relationship between selective inhibition of cyclooxygenase-2 and improved GI tolerability of non-steroidal anti-inflammatory drugs.
Keywords:Meloxicam, Piroxicam, Osteoarthritis, Gastrointestinal tolerability, Cyclooxygenase, Perforations, ulcerations or bleedings

The possibility was examined that the membrane function of erythrocytes obtained from healthy common marmosets (Callithrix jacchus) was modified by the presence in the cells of Heinz bodies. No significant differences were found in erythrocyte endogenous free malonyl dialdehyde (MDA) or reduced glutathione (GSH) between normal human erythrocytes and marmoset erythrocytes containing Heinz bodies. Membrane fluorescent chromolipids, surface charge and thiol levels were similar in both species but average membrane bulk lipid fluidity was slightly elevated in the marmosets. It was concluded that, in contrast to the situation in human erythrocytes, the presence of Heinz bodies in red cells of marmosets does not adversely affect the properties of the membrane.

A monospecific antiserum against human corticosteroid binding globulin (hCBG) has been used to identify structural similarities between hCBG and CBG in the blood of other primates and representative species of different vertebrate classes. Double immunodiffusion analysis indicated that only CBG in Old World monkeys and apes cross-react with the hCBG antiserum. This was confirmed by a solid-phase radioimmunoassay for hCBG which also demonstrated that CBG in apes is immunologically identical to hCBG and that Old World monkey CBG comprises most, but not all, of the hCBG epitopes. The electrophoretic mobilities of human, gorilla and gibbon CBG were similar (RF0·50–0·51), but differed from Old World monkey CBG (RF0·44–0·49) and chimpanzee CBG (RF0·47). Although serum/plasma cortisol binding capacities were similar in Old World primates, the dissociation half-times (t½) of cortisol were higher from human and ape CBG (18–25 min) than from Old World monkey CBG (14–18 min). The steroid binding specificities of human and ape (CBG corticosterone > cortisol > progesterone ≥ testosterone) were also different from those of Old World monkey CBG (corticosterone >> cortisol ≃ progesterone > testosterone). Lemur plasma cortisol binding capacity and CBG dissociation t½of cortisol were similar to hCBG, but its steroid binding specificity was different (cortisol > corticosterone > progesterone ≥ testosterone) and it did not cross-react with the hCBG antiserum. We could not detect high affinity cortisol binding activity in blood samples from New World monkeys, and they did not cross-react with the hCBG antiserum. These results suggest that considerable modification in the steroid binding activity and structure of CBG has occurred since the evolutionary appearance of the primates, but that the rate of change decreased after the cladogenesis of Catarrhine primates.J. Endocr.(1985) 104, 251–257

A study has been made of the viscosity characteristics of the blood of a wide variety of mammals, and of related factors, ie haematocrit, plasma viscosity, plasma fibrinogen and MCV. Good correlations have been found between blood viscosity and both haematocrit and plasma viscosity across the various species studied. No such correlations were found with fibrinogen level or MCV.

In order to obtain haematological reference values for health assessment in captivity, blood samples were obtained from 143 feral Geochelone gigantea in a natural environment on Curieuse Island, Republic of the Seychelles. Tests were carried out by specially adapted field techniques. Because difficulty was experienced with obtaining a suitable blood sample, a method involving in vivo mixing was developed. Using this method it was found that values for haemoglobin (Hb), packed cell volume (PCV) and red (RBC) and white cell count (WBC) of healthy adult G. gigantea were low and the red cells were hypochromic and macrocytic compared with those of mammals and birds. Females had significantly lower Hb, RBC, PCV values and smaller red cells than males. Blood parasites were not found.