Clinical trial: protective effect of a commercial fish protein hydrolysate against indomethacin (NSAID)-induced small intestinal injury.

BACKGROUND: A partially hydrolysed and dried product of pacific whiting fish is marketed as a health food supplement supporting 'intestinal health'. AIM: To examine whether the partially hydrolysed and dried product of pacific whiting fish influenced the small intestinal damaging side effects of the nonsteroidal anti-inflammatory drug, indomethacin. METHODS: Eight human volunteers completed a double-blind, placebo-controlled, crossover protocol of clinically relevant dose of indomethacin (50 mg t.d.s. p.o. for 5 days) with 7 days of fish hydrolysate or placebo starting 2 days prior to indomethacin. Changes in gut permeability were assessed using 5 h urinary lactulose:rhamnose (L/R) ratios. RESULTS: Fish hydrolysate given alone did not affect permeability. In the main study (n = 8), baseline values were similar for both arms (0.28 +/- 0.05 and 0.35 +/- 0.07). Administration of indomethacin (+placebo) caused a fivefold rise in L/R ratios (increasing to 1.54 +/- 0.35), whereas L/R ratios in the same subjects ingesting indomethacin + fish hydrolysate was only 0.59 +/- 0.14 (P < 0.01 vs. indomethacin alone). Dyspeptic symptoms occurred in four of eight subjects taking indomethacin alone, but zero of eight when hydrolysate was co-administered. CONCLUSION: Natural bioactive products (nutriceuticals), such as fish hydrolysates, may provide a novel approach to the prevention and treatment of NSAID-induced and other gastrointestinal injurious conditions.

Trial of trefoil factor 3 enemas, in combination with oral 5-aminosalicylic acid, for the treatment of mild-to-moderate left-sided ulcerative colitis.

BACKGROUND: Current treatment of ulcerative colitis is imperfect. Trefoil peptides are known to stimulate repair in many models of injury, including animal models of colitis. AIM: To assess the efficacy of trefoil factor family-3 enema treatment in a clinical trial. METHODS: A total of 16 patients with mild-to-moderate left sided ulcerative colitis were recruited into a double-blind randomized placebo-controlled study. Patients taking steroids or with proctitis only were excluded. Patients received 75 mL enemas containing either human recombinant trefoil factor family-3 (10 mg/mL) or saline alone once a day for 14 days. All patients also received an oral dose-increment of 1.2 g of mesalazine daily above their normal usage. Patients were assessed at 0, 2, 4 and 12 weeks. Remission was defined as Ulcerative Colitis Disease Activity Index of 0 or 1 with no blood in stool. Individual clinical improvement was defined as a Ulcerative Colitis Disease Activity Index reduction of >3. Data was analysed using chi-square test and anova. RESULTS: Median Ulcerative Colitis Disease Activity Index at entry were 8.5 (trefoil factor family-3 group) and 8 (placebo group). Analysed on an intention-to-treat basis, only one patient went into remission (in trefoil factor family-3 group at day 28). Clinical improvement was seen in two trefoil factor family-3 and three placebo patients on day 14 and two patients in each group on day 28. CONCLUSION: Increasing the dose of 5-aminosalicylic acid was moderately effective in reducing the Ulcerative Colitis Disease Activity Index but was insufficient to induce remission. Trefoil factor family-3 enemas were well-tolerated but did not provide additional benefit above that of adding additional 5-aminosalicylic acid alone.

Colostrum and milk-derived peptide growth factors for the treatment of gastrointestinal disorders.

Colostrum is the specific first diet of mammalian neonates and is rich in immunoglobulins, antimicrobial peptides, and growth factors. In this article we review some of these constituents of human and bovine colostrum in comparison with those of mature milk. Recent studies suggest that colostral fractions, or individual peptides present in colostrum, might be useful for the treatment of a wide variety of gastrointestinal conditions, including inflammatory bowel disease, nonsteroidal antiinflammatory drug-induced gut injury, and chemotherapy-induced mucositis. We therefore discuss the therapeutic possibilities of using whole colostrum, or individual peptides present in colostrum, for the treatment of various gastrointestinal diseases and the relative merits of the 2 approaches.

Current practice in surveillance strategy for patients with Barrett's oesophagus in the UK.

BACKGROUND: Many guidelines exist regarding the surveillance of patients with Barrett's oesophagus. There are limited data, however, with regard to whether practitioners follow these guidelines. METHODS: We assessed current surveillance practice amongst members of the British Society of Gastroenterology using a simple 11-question anonymous survey, mailed to 300 randomly selected members from the British Society of Gastroenterology Handbook. RESULTS: Two hundred and three of the 300 (68%) responded, 76% considering that surveillance was worthwhile. In those who considered surveillance to be worthwhile, 83% used sub-selection based on age, the length of Barrett's oesophagus or the presence of ulcer or stricture. Patients with Barrett's oesophagus of < 3 cm (short-segment) were considered to be inappropriate for surveillance by 62%. Forty-one per cent reported following the 'advised' recommendations of four-quadrant biopsies every 2 cm, whereas 44% followed a 'random and suspicious areas only' protocol. Marked variation was reported in the re-endoscope interval for both low- and high-grade dysplasia. Only 55% reported that two experienced pathologists reviewed all biopsies showing high-grade dysplasia. CONCLUSIONS: Despite the existence of multiple guidelines for Barrett's surveillance, clinical practice varies widely in the UK. This may be due to a lack of knowledge or because gastroenterologists remain unconvinced by the quality of the current evidence of its value. These results have implications for studies attempting to collate data from multiple centres.

Use of the 'nutriceutical', bovine colostrum, for the treatment of distal colitis: results from an initial study.

BACKGROUND: Bovine colostrum is a rich source of nutrients, antibodies and growth factors. AIM: To examine the efficacy of colostrum enemas in the treatment of distal colitis using a randomized, double-blind, controlled protocol. METHODS: Fourteen patients (eight female), with a mean age of 45 years (range, 16-75 years) and mild to moderately severe distal colitis (Powell-Tuck scoring system), received colostrum enema (100 mL of 10% solution) or placebo (albumin solution) b.d. for 4 weeks. Both groups also received mesalazine (1.6 g/day) or, if already taking it, had a dose increment of 1.6 g/day. Disease activity was documented at 0, 2 and 4 weeks. RESULTS: After 4 weeks, the colostrum group showed a mean reduction in symptom score of - 2.9 (95% confidence interval (CI), - 5.4 to - 0.3), whereas the placebo group showed a mean response of + 0.5 (95% CI, - 2.4 to +3.4). The histological score improved in five of the eight patients in the colostrum group (mean response, - 0.9; 95% CI, - 1.69 to - 0.03), whereas the histological scores only improved in two of the six patients in the placebo group (mean response, 0.2; 95% CI, - 2.4 to +2.6). CONCLUSIONS: Bovine colostrum enema shows potential as a novel therapy for left-sided colitis with additional benefits over using mesalazine alone. Further studies appear to be warranted.

Development of a two-site ELISA assay for the dimeric form of human TFF1.

TFF1 is one of three human trefoil proteins expressed principally in the gastrointestinal tract in normal tissues. TFF1 protects the gastric mucosa against damage as a result of its ability to facilitate reconstitution of damaged gastric mucosa and its involvement in the secretion and structure of gastric mucus. The most biologically active molecular form in cell culture and animal models tested is a dimer formed by a disulfide bond between two cysteine residues close to the C terminus of the protein. We have therefore developed an assay for this form of TFF1 which should facilitate its measurement in biological samples.

Synergistic effects of systemic trefoil factor family 1 (TFF1) peptide and epidermal growth factor in a rat model of colitis.

Novel therapies for the treatment of colitis are required. We therefore examined the potential value of the trefoil factor family 1 (TFF1) peptide and epidermal growth factor (EGF) alone and in combination. Effects of TFF1- Cys58 +/- EGF on an in vitro HT29 cell wounding model of restitution showed synergistic activity when used in combination. In addition, animals had colitis induced by adding 4% dextran sulphate sodium (DSS) to the drinking water for 7 days and they also received twice daily subcutaneous injections of test peptides. Treatment with TFF1-Cys58 alone (100 microg/kg) reduced histological colitis score by 22%, but the TFF1-Ser58 variant was ineffective. In a second study, TFF1-Cys58 reduced histological colitis score by 15%, EGF (600 microg/kg) by 26%, and an additive response (42% reduction) was demonstrated when used together (P < 0.01 versus either peptide given alone). Similar results were found using tissue myeloperoxidase (MPO) activity as a marker of inflammation. Where clinical risk/benefit seems justified, these initial studies suggest that combination therapy of systemic EGF and TFF peptides may prove useful for treatment of colitis in patients with disease extending beyond the reach of topical (enema) therapy.

Effect of chymotrypsin on human cholecystokinin release: use of clostripain in the validation of a new radioimmunoassay.

We have developed and validated a new radioimmunoassay for cholecystokinin. In order to establish that the antiserum binds large and small forms of CCK to an equal extent, we used the microbial enzyme clostripain, which cleaves large forms of CCK yielding CCK 8. Cleavage by clostripain of synthetic and purified forms of CCK, and CCK extracted at from human jejunum and CCK in human plasma was found not to affect immunoactivity, indicating that the antiserum reacts similarly with all forms of CCK. There is controversy over whether intraduodenal trypsin inhibits release of CCK in man. We used our radioimmunoassay to investigate whether chymotrypsin, rather than trypsin, could be the major mediator of negative feedback control of CCK release. Six normal subjects received an intraduodenal infusion of L-phenylalanine and L-tryptophan on two occasions, with the addition of either 1 g/l bovine chymotrypsin or 1 g/l albumin. Plasma CCK concentrations rose in response to the amino acid infusion, but were not affected by the addition of chymotrypsin, indicating that this enzyme is not a mediator of CCK feedback regulation in man.

Does the response of the intestinal epithelium to keratinocyte growth factor vary according to the method of administration?

BACKGROUND: Keratinocyte growth factor (KGF) is a potent mitogen and may be of value for the treatment of conditions such as short bowel syndrome and chemotherapy-induced mucositis. However the most efficacious route and method of administration is unclear. METHODS: Rats maintained by total parenteral nutrition (TPN) were given KGF (1 mg/kg/rat/day, i.v.) infused continuously or as a once-daily injection. The same dose was also given s.c. to chow-fed rats. Changes in gut growth were assessed by measurement of wet weight, proliferation (vincristine induced metaphase arrest) and crypt branching index. Changes in gut hormone profile were also determined to examine if any trophic effects were mediated via this mechanism. RESULTS: KGF caused a 70-100% increase in wet weight of the stomach, small and large intestine of TPN-fed rats (P < 0.01) with no significant differences seen between the two methods of administration. The increase in metaphase counts was greatest in the stomach (about seven-fold P < 0.01), but was less pronounced in the distal small intestine and colon (about 50% increase). The trophic effect of KGF was much less prominent in orally-fed rats. Crypt branching index was significantly reduced by KGF in the proximal small intestine of TPN, but not orally-fed rats. Plasma gastrin, PYY, total glucagon, enteroglucagon and GLP-1 all increased by two-three-fold (all P < 0.01) in response to KGF whereas insulin levels fell by about 25% in the TPN group. CONCLUSIONS: The mitogenic action of KGF occurred predominantly in the stomach and proximal small intestine. Its efficacy was less pronounced in orally-fed animals, suggesting KGF may be of greatest benefit in conditions associated with lowered intestinal proliferation. Clinical trials of KGF can probably use single daily i.v. injections without reduction in efficacy.

Endogenous peptides and peptide therapy in gut defense and repair.

The gastrointestinal tract shows a remarkable ability to withstand injury. Factors important in maintaining integrity include rapid proliferation, an excellent blood supply and, in the stomach and colon, the presence of a protective mucus layer. When an injury occurs, the healing process consists of an initial phase of cell migration (restitution), followed by an increase in proliferation and remodeling. There is now a large body of evidence suggesting that at least 30 different peptides are involved in maintaining mucosal integrity and in stimulating the repair process. Insights into the pathophysiological function of these peptides can be gained from considering them as belonging to broad groups based on their overall role in maintaining gut growth or in stimulating repair. Considered in this way, they can be usefully compartmentalized into: 1) mucosal integrity peptides, which are predominantly involved in maintaining normal mucosal integrity; 2) luminal surveillance peptides, which are constantly present in the lumen but which only stimulate proliferation and repair at sites of injury; and 3) rapid response peptides, whose production is rapidly regulated at sites of injury and the function of which is to stimulate the repair process. If peptide therapy for gastrointestinal conditions is to be used, potential methods of delivery include oral, systemic and gene therapy; however, orally delivered peptides may be digested in the gut lumen, systemic administration may result in side effects at sites distant to the gut and methodological problems remain when considering gene therapy. Peptides play a key role in maintaining mucosal homeostasis in the gut. Over the next five years, recombinant peptides are likely to be increasingly used to treat a wide variety of gastrointestinal disorders such as inflammatory bowel disease and necrotizing enterocolitis.

The development of a fluoroimmunoassay for beta-2-microglobulin in serum.

A liquid-phase fluoroimmunoassay has been developed for the measurement of beta-2-microglobulin in undiluted serum or plasma. Protein labelled with fluorescein-isothiocyanate at a molar ratio of 1:2 respectively is employed as a tracer together with an antiserum to beta-2-microglobulin raised in a sheep. Separation is achieved by means of rabbit anti-sheep immunoglobulin G and, following precipitation of the bound fraction by centrifugation, the free fraction together with any potentially interfering factors is removed in the supernatant. Finally the precipitate is dissolved and the fluorescence measured. The assay is simple and rapid in that all reactants, including the second antibody, can be added at the start of the assay and equilibrium is attained within 60 min. The assay is reproducible and sufficiently sensitive to allow measurement of normal serum levels and has a wide range avoiding the need for sample dilution. Results correlated well with those of an established radioimmunoassay.

Right ventricular pacing wire thrombus presenting as pyrexia of unknown origin.

Pacing wire thrombosis may be invisible echocardiographically while producing severe symptoms. We report a patient whose pacing wire thrombosis presented as a pyrexial illness 5 months after its insertion. Treatment with tissue plasminogen activator provoked cardiovascular collapse; therefore, we recommend that such thrombosis be treated surgically.

Surveillance for Barrett's oesophagus: is there light the end of the metaplastic tunnel?

Metaplastic change of the oesophageal epithelium from normal stratified squamous to columnar-lined with intestinal metaplasia results in an increased risk of development of adenocarcinoma. As a result, endoscopic surveillance has been recommended for the surgically-fit patient. The evidence that these programmes are altering clinical outcome to any major degree, however, is weak. This review highlights some of the areas of controversy and outstanding points that need to be clarified to allow establishment of evidence-based medicine for this condition.

Final results from 10 year cohort of patients undergoing surveillance for Barrett's oesophagus: observational study.

OBJECTIVES: To review the benefit of an endoscopic surveillance programme for patients with Barrett's oesophagus. DESIGN: Observational study. SETTING: University teaching hospital. PARTICIPANTS: 409 patients in whom Barrett's oesophagus was identified during 1984-94; 143 were entered into the annual surveillance programme. MAIN OUTCOME MEASURES: Development of dysplasia and cancer and mortality. RESULTS: The average period of surveillance was 4.4 years; 55 patients were reassessed in 1994 but only eight remained in the programme in 1999, withdrawal being due to death (not from carcinoma of the oesophagus), illness, or frailty. Five of the patients who entered surveillance developed carcinoma of the oesophagus. Only one cancer was identified as a result of a surveillance endoscopy, the others being detected during endoscopy to investigate altered symptoms. Of the 266 patients who were not suitable for surveillance, one died from oesophageal cancer and 103 from other causes. Surveillance has resulted in 745 endoscopies and about 3000 biopsy specimens. CONCLUSION: The current surveillance strategy has limited value, and it may be appropriate to restrict surveillance to patients with additional risk factors such as stricture, ulcer, or long segment (>80 mm) Barrett's oesophagus.

Pantoprazole, Prout and the proton pump.

Pantoprazole is a proton pump inhibitor which has recently had its clinical license extended to include maintenance therapy for the treatment of reflux oesophagitis, Helicobacter pylori eradication and short-term intravenous administration. This article reviews the history of gastric acid secretion and examines the role of proton pump inhibitors, particularly pantoprazole, in the treatment of acid-related disorders.