bluuebunny/crossref_metadata_2025 huggingface dataset:
αa‐Adrenoceptor activation induces rhythmic contractile activity in carotid arteries from young, not adult, rats
Authors: EDDINGER T. J. , RATZ P. H.
Published: October 2003

Rhythmic contractions are produced by small arteries, arterioles and veins in several vascular beds, but they are often absent in large arteries. However, under certain conditions, and in certain disease states, large arteries may produce rhythmic contractions. For this reason, the present study was undertaken to test the hypothesis that rhythmic contractions may be a ‘normal’ response in large arteries at some stage in development. We investigated this hypothesis by examining contractions of carotid arteries in male and female rats aged 15, 25 and 30 days, and in adult rats. Rhythmic contractions were produced by exposure to, or during washout of, α‐adrenoceptor agonists in young, but not adult, rats. In particular, rhythmic activity was identified in 40, 95 and 50% of the arteries from, respectively, 15, 25 and 30‐day‐old rats. No differences were found in rhythmic activity between female and male rats. Furthermore, the rhythmic activity was not inhibited by the K+ channel blocker TEA (20 mm), or the Na+/K+‐ATPase inhibitor, ouabain (32 μm). Nor was it inhibited by endothelial denudation. However, the Ca2+ channel blocker, nifedipine (0.1 μm), completely eliminated rhythmic contractions. These results suggest that receptor‐induced rhythmic contractile activity is a ‘normal’ characteristic at ∼25 days of development in carotid arteries of rats, but that this activity declines with age until it is completely absent by adulthood. We proposed that this difference was due to unfused and fused Ca2+ channel activities in, respectively, young and adult rat arteries, to differential expression of Ca2+ channel isotypes, or to differences in receptor‐mediated signal transduction mechanisms ‘upstream’ from Ca2+ channels.
Influence of sympathetic stimulation on the mechanical properties of the aorta in humans
Authors: SONESSON B. , VERNERSSON E. , HANSEN F. , LÄNNE T.
Published: October 2003

The mechanical properties of the aorta play a major role in the regulation of blood pressure and cardiac performance. The effect of sympathetic stimulation on the mechanical properties of the human abdominal aorta was studied in 19 healthy volunteers, divided into young (25±2 years) and elderly individuals (69±2 years) of both sexes. A non‐invasive ultrasonic echo‐tracking system for measurement of systolic/diastolic variation of aortic diameter in combination with intra‐aortic pressure measurements was used to determine wall mechanics. The pressure–diameter (P–D) relationship and the distensibility indices, stiffness (β) and pressure strain elastic modulus (Ep) of the abdominal aorta were obtained. Measurements were made at rest and during sympathetic stimulation induced by lower body negative pressure (LBNP).

As a sign of sympathetic activation, the peripheral resistance increased by 74–96% (P<0.001) during LBNP. However, the mechanical properties of the abdominal aorta remained unaltered, as estimated either from the P–D relationship or from the indices Ep and β, both in the young (rest: Ep=0.53±0.18, β=4.5±1.5; LBNP: Ep=0.51±0.15, β=4.5 ±1.2, NS) and in the elderly (rest: Ep=2.17±0.70, β=17.6 ±5.8; LBNP: Ep=2.11±0.60, β=16.9±3.9, NS).

In conclusion, this investigation shows that LBNP‐induced sympathetic activation does not change aortic wall mechanics. Thus, sympathetic modulation of the aortic smooth muscle contractile activity seems to be unimportant in the blood pressure regulation.
Altered basal and adenosine‐mediated protein flux from coronary arterioles isolated from exercise‐trained pigs
Authors: HUXLEY V. H. , WILLIAMS D. A. , MEYER JR. D. J. , LAUGHLIN M. H.
Published: October 2003

Solute flux per unit surface area and concentration gradient, (JS/SΔC), was quantified in arterioles isolated from hearts of sedentary (SED) and exercise‐trained (EX) female Yucatan Miniature Swine. Apparent permeability (PS) was assessed from measures of JS/SΔC for two proteins, α‐lactalbumin (α‐lact) and porcine serum albumin (PSA), under basal conditions and following 5 min suffusion with 10−5M adenosine (ADO). Both proteins were labelled with the fluorescent dye tetramethyl rhodamine isothiocyanate. Basal Ps to α‐lact differed with exercise training ((Pα‐lacts)SED=5.2±1.8 (median±median absolute deviation (MAD), n=9 pigs) versus (Pα‐lacts)EX=7.4±1.1×10−7 cm s−1, n=9, P<0.05). For the larger protein PSA, basal Ps did not change with training ((PPSAs)SED=5.0±1.6, N=11 vs. (PPSAs)EX=4.1±1.2×10−7 cm s−1, N=11). Suffusion of the arterioles (33±4 μm diameter, n=18 vessels) from SED hearts (n=14) with 10−5M ADO decreased Pα‐lacts 15±8% relative to control and was without effect on PPSAs. By contrast, in arterioles (39±4 μm diameter, n=22 vessels) from EX hearts (n=14), ADO increased Pα‐lacts and PPSAs by 32 and 65% respectively, indicating that receptor‐mediated changes in permeability were also sensitive to exercise training. These data demonstrate that, for coronary arterioles, permeability to macromolecules adapts to exercise training. The adaptive mechanisms may involve more than one structural component of the vessel wall as the changes in permeability were size‐dependent.
Gender and age differences in transthoracic bioimpedance
Authors: METRY G. , WIKSTRÖM B. , LINDE T. , DANIELSON B. G.
Published: October 2003

Thoracic impedance consists of a constant baseline component Z0 and a time‐variable component ΔZ which represents the impedance change related to the cardiac cycle. The maximum part of ΔZ [
(dZ/dt)max] represents the peak of the ascending aortic blood flow. Measurements of basal thoracic impedance are affected by structural and anatomical differences in the thorax related to sex and ageing. This component is a variable in the denominator of Sramek's formula which is used for calculating stroke volume. The aim of this study was to elucidate the question as to whether the age‐ and sex‐related variation in basal impedance may affect bioimpedance measurements of stroke volume.

The study comprised 111 healthy subjects (55 males and 56 females) of ages between 20 and 69 years, divided according to age decades into five groups each of males and females. Stroke volume index (SI), Z0 and (dZ/dt)max were measured in every subject, using transthoracic bioimpedance cardiography. Z0 and (dZ/dt)max had significantly higher values in females than in males in every age group except the oldest one in the case of Z0 and the oldest two groups in the case of (dZ/dt)max. Stroke index showed no significant sex difference, although the higher Z0 in females may underestimate the values of stroke index. Elevation of (dZ/dt)max in females may therefore reflect a positive relation to Z0 rather than higher flow rates. Since Z0 and (dZ/dt)max are variants in opposite positions in Sramek's formula (denominator and numerator, respectively), this functional relationship may keep the bioimpedance measurements from being affected by the sex‐ and age‐related changes in Z0.
Manganese and the heart: acute cardiodepression and myocardial accumulation of manganese
Authors: BRUROK H. , SCHJØ/snm> J. , BERG K. , KARLSSON J. O. G. , JYNGE P.
Published: October 2003

The aim of study was to assess acute effects of the divalent manganese ion (Mn2+) in an intact but isolated heart preparation. Rat hearts were perfused in the Langendorff mode at constant flow rate. Left ventricular (LV) developed pressure (LVDP), LV pressure first derivatives (LVdp/dt max and min), heart rate (HR) and aortic pressure (AoP) were recorded. Ventricular contents of high energy phosphate compounds (HEP) and Mn metal were measured at the end of experiment. Infusion of MnCl2 for 5 min with perfusate concentrations 1–3000 μM induced an immediate depression of contractile function at and above 30 μM and negative chronotropy at and above 300 μM. These EC50 values were found (μM): LVDP 250; LVdp/dt max 160; LVdp/dp min 120; HR 1000; and increase in AoP 80. Recovery of function during a 14 min washout period was rapid and extensive, except for Mn2+ 3000 μM. Somewhat unexpected, Mn2+ 30–1000 μM raised coronary vascular resistance up to about twice the control level, whereas the vasoconstrictory response was overcome at 3000 μM. Mn2+ 3000 μM reduced tissue HEP. Ventricular Mn content rose stepwise for perfusate Mn2+ above 1 μM up to about 55 times the control level for perfusate Mn2+ 3000 μM. It is concluded that: acute effects of Mn2+ like depression of contractility and rate is rapidly reversible; and rat hearts accumulate and buffer large amounts of Mn2+ without affecting cardiac function or energy metabolism in the acute stage.
Gastric MALT‐lymphoma and Helicobacter pylori infection
Authors: BAYERDÖRFFER E. , MIEHLKE S. , NEUBAUER A. , STOLTE M.
Published: October 2003

The presence of lymphoid tissue in the gastric mucosa is virtually pathognomonic of Helicobacter pylori infection. This lymphoid tissue has mucosa–associated lymphoid tissue (MALT) characteristics suggesting that H. pylori infection may represent a stimulus for the growth of gastric MALT lymphoma. H. pylori can be detected in more than 90% of patients with low–grade gastric MALT lymphoma supporting the aetiological role of the organism. The strongest evidence for the significance of H. pylori in the pathogenesis of low aetological–grade gastric MALT lymphoma is provided by clinical studies showing that cure of H. pylori infection is followed by a complete regression of these tumours in most patients. This paper reviews the current knowledge about antibacterial treatment of low–grade gastric MALT lymphoma, and immunological and molecular aspects in the pathogenesis of the disease.
Long‐term treatment with lansoprazole for patients with Zollinger–Ellison syndrome
Authors: HIRSCHOWITZ B. I. , MOHNEN J. , SHAW S.
Published: October 2003

Background: Normalization of gastric secretion and cure of associated upper gastrointestinal lesions by resection of gastrinoma is possible in ≈20% of patients with Zollinger–Ellison syndrome, leaving ≈80% dependent on medical treatment with proton pump inhibitors for acid suppression.

Methods: Lansoprazole was given for 3–48 months (median 28 months) to 26 Zollinger–Ellison syndrome patients with peptic ulcer manifestations in all and oesophagitis in 13. Starting with 60 mg/day, the dose was individualized to lower basal acid output to less than 5 mmol/h for those with intact stomachs and less than 1 mmol/h in those who had prior gastrectomy or with oesophagitis. The patients were studied every 3 months for 1 year and then every 6 months with gastric analysis (basal and maximal acid and pepsin output) and endoscopy with biopsy for enterochromaffin‐like (ECL) cells.

Results: Lansoprazole inhibited basal acid output by 95%, pepsin output by 65% and remained effective at the initial mean (66±4.3 mg/day) or smaller doses (56±12 mg/day) at 48 months. Mucosal lesions healed and symptoms (ulcer‐type pain, diarrhoea, heartburn, weight loss) resolved rapidly, usually within a few weeks. Serum gastrin and ECL cell populations, which were elevated before treatment, remained statistically unchanged but one of the three multiple endocrine neoplasia I (MEN‐I) patients developed a small carcinoid. Of the three patients with metastatic gastrinoma at diagnosis one has died and one has progressed, while the third has had stable liver metastases for 26 years. Ulcer‐type relapses occurred in three of the five post‐gastrectomy patients, one with fatal jejunal ulcer perforation despite adequate acid suppression. No biochemical or clinical adverse events due to lansoprazole were encountered.

Conclusion: Lansoprazole effectively inhibits acid and pepsin secretion in Zollinger–Ellison syndrome patients without any demonstrated side‐effects. Despite strict acid control, post‐gastrectomy Zollinger–Ellison syndrome patients were more liable to ulcer relapse, while oesophagitis was not a marker for therapeutic difficulty.
Effects of rebamipide on bile acid‐induced inhibition of gastric epithelial repair in a rabbit cell culture model
Authors: WATANABE S. , WANG X.‐E. , HIROSE M. , YOSHIZAWA T. , IWAZAKI R. , OIDE H. , KITAMURA T. , MIWA H. , A.  , SATO N.
Published: October 2003

Background: Anti‐ulcer agents exert various functional effects on gastric epithelial cells.

Aim: The effects of a novel gastro‐cytoprotective agent (rebamipide) on epithelial restoration following bile acid damage were assessed using primary cultured rabbit gastric epithelial cells.

Methods: Rebamipide was added to complete confluent cell sheets with deoxycholic acid just after creating a cell‐free wound (2 mm2). The restoration was monitored and analysed by phase contrast microscopy and an image analyser for 48 h. The migration speed was measured during the initial 3 h after wounding. Cell proliferation was detected by staining for bromodeoxyuridine (BrdU) at 12‐h intervals. The labelling index was calculated per unit area. The major cytoskeletal protein actin was detected by immunohistochemical staining.

Results: In the controls, restoration was completed 48 h following wounding. Deoxycholic acid retarded this process. The addition of rebamipide to deoxycholic acid abolished the bile acid‐induced retardation. The migration speed was 26 μm/h in the controls, 15 μm/h in the deoxycholic acid group and 27 μm/h in the deoxycholic acid plus rebamipide group. In the controls, BrdU‐positive cells, which were rarely detected in the initial 24 h, were maximal at 36 h (labelling index 1.7%). In the deoxycholic acid group, proliferation was inhibited (peak labeling index; 0.5% at 48 h). Actin‐containing stress fibres were detected throughout the cells and the periphery of the lamellipodia in the controls, and were disrupted in the deoxycholic acid‐treated group. Rebamipide prevented these effects.

Conclusions: Deoxycholic acid significantly retarded restoration by the inhibition of both cell migration and proliferation, potentially through an effect on the cytoskeleton. Rebamipide protected the mucosal cells from bile acid mediated injury.
Prescribing patterns for dyspepsia in primary care: a prospective study of selected general practitioners
Authors: BODGER K. , DALY M. J. , HEATLEY R. V.
Published: October 2003

Aim: To define prescribing patterns for symptomatic dyspeptic patients in a cross‐section of general practitioners in Leeds, United Kingdom.

Methods: Nine general practitioners from a range of practices took part in a prospective observational study of prescribing patterns for dyspepsia. All consultations with symptomatic dyspeptic patients were recorded over a 4‐month period. Symptoms were recorded as ulcer‐like, reflux‐like, or nonspecific, and details of recent therapy, previous investigations and any prescription issued were noted.

Results: 257 consecutive consultations were recorded (new patients 23%, consulted before but not investigated 33%, previously investigated 44%). 93% of consultations resulted in a prescription (antacids 24%, prokinetic/motility agent 8%, H2‐receptor antagonist 36%, proton pump inhibitor 24%, Helicobacter pylori eradication therapy 8%). 42.5% of new patients received an acid‐suppressing drug as first‐line therapy, of which only 32% had tried over‐the‐counter remedies. Symptom‐type (ulcer‐like, reflux‐like or nonspecific) significantly influenced choice of empiric therapy (P<0.001), though prescribing was still variable. Although around 60% of patients with previously negative investigations or only minor disease received acid‐suppressing drugs, such patients were six times more likely to receive ‘less potent’ treatments (no prescription, antacid or motility agent) than those with known acid‐peptic disease (odds ratio 6.23, P<0.01). Only 30% of patients with previously documented peptic ulcer received H. pylori eradication therapy, yet patients with a wide range of other diagnoses received this form of treatment.

Conclusions: Management guidelines may help to promote a more consistent and selective use of newer treatments, and promote more cost‐effective patient care.
Implication of nitric oxide synthase activity in the genesis of water immersion stress‐induced gastric lesions in rats: the protective effects of FK506
Authors: HISANAGA Y. , GOTO H. , TACHI K. , HAYAKAWA T. , SUGIYAMA S.
Published: October 2003

Background: Nitric oxide (NO) is a potent cytoprotective substance of gastric mucosa. FK506, an immunosuppressive drug, shows anti‐gastric ulcer effects equivalent to famotidine, an H2 blocker, in rats. This study was designed to evaluate the cytoprotective mechanism of FK506 on gastric mucosa in relation to the changes in NO synthase activity.

Methods: Gastric lesions were induced in rats by water immersion stress. Changes in NO synthase activity during water immersion stress treatment, and effects of FK506 on NO synthase activity were determined enzymatically. Gastric mucosal interleukin (IL)‐1β and IL‐2 were measured by immunoradiometric assay. Gastric mucosal blood flow was measured by hydrogen gas clearance technique.

Results: FK506 mitigated gastric lesions developed by water immersion stress. Stress‐induced lesions were exacerbated by NG‐monomethyl‐L‐arginine (L‐NMMA), a specific inhibitor of NO synthase, while sodium nitroprusside, a NO donor, mitigated the lesions. Water immersion stress increased NO synthase activity in the early phase (0.5 h after stress treatment) and decreased it in the late phase (6 h after). Decrease in NO synthase activity in the late phase was significantly mitigated by FK506, though it did not affect changes in NO synthase activity in the early phase. Water immersion stress increased gastric mucosal IL‐1β and IL‐2 contents 6 h after stress treatment, and these increases were prevented by FK506. FK506 itself did not affect gastric mucosal blood flow. L‐NMMA treatment significantly decreased gastric mucosal blood flow. In contrast, gastric mucosal blood flow was significantly increased by sodium nitroprusside.

Conclusions: Increase in NO synthase activity might contribute to cytoprotection, and a decrease in activity might be a harmful factor for the gastric mucosa. Preservation of NO synthase activity by FK506 might be involved in FK506's protective effects on the gastric mucosa.
safety of bismuth in the treatment of gastrointestinal diseases
Authors: TILLMAN L. A. , DRAKE F. M. , DIXON J. S. , WOOD J. R.
Published: October 2003

Bismuth preparations are commonly used to treat a variety of gastrointestinal disorders, including peptic ulcers and dyspepsia. The safety profile of currently approved bismuth preparations, such as tripotassium dicitrato bismuthate (De‐Nol), bismuth subsalicylate (Pepto‐Bismol) and ranitidine bismuth citrate (Pylorid, Tritec), is excellent. Adverse reactions to these agents are mild, transient and infrequent, and reports of serious adverse reactions are rare. This, in part, reflects the low systemic bioavailability of bismuth from these medicines: less than 1% of the bismuth dose administered is absorbed.

During repeated dosing with ranitidine bismuth citrate 200, 400 or 800 mg b.d. trough plasma bismuth concentrations remain well below 50 μg/L. After 4 weeks of treatment median concentrations of 3.4 μg/L or less were reported amongst 1210 duodenal ulcer patients receiving this new chemical entity, while mean concentrations of 5.1 μg/L (plasma) and 12.3 μg/L (blood) have been reported in two studies of patients receiving tripotassium dicitrato bismuthate 120 mg q.d.s. for 4 weeks. Transient peak plasma bismuth concentrations greater than 50 μg/L are observed 30–60 min after dosing with tripotassium dicitrato bismuthate in some patients, but are not associated with any toxic effects. After discontinuation of treatment with bismuth preparations its excretion in urine may continue for up to 3 months, by which time blood bismuth concentrations have declined to pre‐treatment values.
Megestrol acetate therapy for anorexia and weight loss in children with malignant solid tumours
Authors: AZCONA C. , CASTRO L. , CRESPO E. , JIMÉNEZ M. , SIERRASESÚMAGA L.
Published: October 2003

Background: Malnutrition is very frequent in childhood cancer. Its main cause is inadequate intake for energy demands owing to lack of appetite. Megestrol acetate is a synthetic progestin that has been used for reversing anorexia in adult cancer.

Objectives: To assess megestrol acetate efficacy and side‐effects in treating anorexia in childhood cancer.

Methods: Thirty‐five children with solid tumours were receiving antitumour therapy. Nutritional assessment was by anthropometry. Megestrol acetate efficacy was assessed by evaluating grade of appetite, energy intake and well‐being. Side‐effects were evaluated by means of clinical history, physical examination, lipid profile, coagulation tests and cortisol rhythm.

Results: When compared to baseline all the anthropometric measurements increased (P<0.05) from the first month of megestrol acetate therapy, as well as appetite and energy intake. No significant side‐effects were found.

Conclusion: Megestrol acetate therapy is a powerful appetite stimulant which led to weight gain, composed of both fat mass and fat‐free mass. Megestrol acetate is well tolerated, with few and mild side‐effects. If megestrol acetate therapy is started at the onset of anorexia, the use of more expensive, invasive and complicated techniques of nutritional support may be avoided.
Omeprazole prevents indomethacin‐induced gastric ulcers in rabbits
Authors: LEE M. , KALLAL S. M. , FELDMAN M.
Published: October 2003

Background: The role of gastric acid in the development of non‐steroidal anti‐inflammatory drug (NSAID)‐induced gastric ulcers is unclear. The aim of this study was to determine the effect of the proton pump inhibitor omeprazole on the formation of indomethacin‐induced gastric ulcers in a rabbit model.

Methods: Twenty‐four rabbits were randomly divided into four groups and treated as follows: vehicle for indomethacin; vehicle for omeprazole; indomethacin (20 mg/kg b.d. subcutaneously for seven doses); and indomethacin plus omeprazole (both at 20 mg/kg b.d. subcutaneously for seven doses). On day 4 (after the seventh injection), rabbits were sacrificed, and gastric mucosal injury and prostaglandin formation were assessed.

Results: Subcutaneous administration of 20 mg/kg omeprazole b.d. caused a profound suppression of gastric acidity (i.e. pH above 5.0 continuously). This same dose of omeprazole significantly reduced gastric ulcer formation induced by indomethacin despite significant (>80%) inhibition of gastric mucosal prostaglandin E2 (PGE2) formation.

Conclusion: We conclude from these observations that gastric acid plays a critical role in the formation of indomethacin‐induced gastric ulcers in rabbits.
Symptomatic and endoscopic duodenal ulcer relapse rates 12 months following Helicobacter pylori eradication treatment with omeprazole and amoxycillin with or without metronidazole
Authors: BELL G. D. , BATE C. M. , AXON A. T. R. , TILDESLEY G. , MARTIN J. L. , TAYLOR M. D. , RICHARDSON P. D. I.
Published: October 2003

Aim: To determine the effect of Helicobacter pylori eradication with omeprazole and amoxycillin, with or without metronidazole, on the 12‐month course of duodenal ulcer disease.

Methods: In a randomized, double‐blind study, conducted in 19 hospitals, 105 H. pylori positive duodenal ulcer patients were healed and symptom‐free following either omeprazole dual therapy (omeprazole 40 mg o.m.+amoxycillin 500 mg t.d.s., OA, eradication rate 46%, n=52) or omeprazole triple therapy (omeprazole 40 mg o.m.+amoxycillin 500 mg t.d.s.+metronidazole 400 mg t.d.s., OAM, eradication rate 92%, n=53) for 2 weeks, followed by 2 weeks of omeprazole 20 mg o.m. and a 12‐month untreated follow‐up period, after which time all patients were endoscoped. Endoscopic and symptomatic relapse rates, and effect on H. pylori status measured using 13C‐urea breath test, were determined.

Results: During the 12‐month untreated follow‐up period, the life‐table endoscopic relapse rates were 12% (95% CI: 2–22%) and 2% (95% CI: 0–6%) for OA and OAM patients, respectively. By 12 months, life‐table symptomatic relapse rates were 22% (95% CI: 13–37%) and 19% (95% CI: 8–30%) for OA and OAM, respectively. In the 12 months untreated follow‐up period, 2/69 (3%, 95% CI: 0–7%) patients rendered H. pylori negative had an endoscopic relapse at the end of the 12‐month follow‐up period, compared with 5/31 (16%, 95% CI: 3–29%) patients remaining H. pylori positive (P=0.03 between H. pylori positive and negative groups). Twelve of 69 (17%, 95% CI: 8–26%) patients rendered H. pylori negative relapsed symptomatically, compared with 9/31 (29%, 95% CI: 13–45%) patients remaining H. pylori positive (P= N.S. between groups). There was a significant improvement in epigastric pain (P=0.0001), nausea and vomiting (P<0.05) between entry to the study and 1, 6 and 12 months post‐treatment for both treatment groups.

Conclusions: OAM eradicates H. pylori in significantly more patients than OA, but successful H. pylori eradication with either OAM or OA predisposes to low endoscopic and symptomatic relapse rates for duodenal ulcer patients when followed up for 12 months.
older systemic and newer topical glucocorticosteroids and the gastrointestinal tract
Authors: THIESEN A. , THOMSON A. B. R.
Published: October 2003

Systemic steroids have been used in gastrointestinal disorders, such as ulcerative colitis and Crohn's disease. However, glucocorticosteroids are associated with potentially serious adverse effects. For that reason there is a search for a steroid which would have rapid first‐pass metabolism in the intestine and liver, low systemic bioavailability, high topical activity and rapid excretion. This review will consider the absorption, transport, metabolism, mechanisms of action, general effects and effects of steroids on the intestine, and the new steroids in particular.
The safety and efficacy of ranitidine bismuth citrate in combination with antibiotics for the eradication of Helicobacter pylori
Authors: WYETH J. W. , POUNDER R. E. , DUGGAN A. E. , O'MORAIN C. A. , SCHAUFELBERGER H. D. , DE KOSTER E. H. , RAUWS E. A. J. , BARDHAN K. D. , GILVARRY J. , BUCKLEY M. J. M. , GUMMETT P. A. , LOGAN R. P. H.
Published: October 2003

Background: Ranitidine bismuth citrate is a novel salt of ranitidine and a bismuth citrate complex. It has intrinsic antisecretory and anti‐Helicobacter pylori activity, but monotherapy rarely eradicates H. pylori infection in man.

Aim: A pilot study to investigate rates of H. pylori eradication achieved by co‐prescription of ranitidine bismuth citrate with antibiotics, and to identify several regimens which would merit further investigation.

Method: One hundred dyspeptic patients infected with H. pylori were randomly allocated to treatment with ranitidine bismuth citrate 800 mg b.d. plus either amoxycillin, metronidazole, clarithromycin, cefuroxime axetil, tetracycline, tetracycline plus metronidazole or clarithromycin plus tetracycline for 14 days. Eradication of infection was assessed using the 13C‐urea breath test 4 weeks after the end of treatment.

Results: In a per protocol analysis eradication of H. pylori ranged between 22 and 100%; the intention‐to‐treat eradication rates ranged between 15 and 92%. No adverse events were specifically attributed to ranitidine bismuth citrate.

Conclusion: Co‐prescription therapy, using ranitidine bismuth citrate and one or more antibiotics, is suitable for further investigation in large‐scale clinical trials in patients infected with H. pylori.
Low‐dose famotidine and ranitidine as single post‐prandial doses: a three‐period placebo‐controlled comparative trial
Authors: REILLY T. G. , SINGH S. , COTTRELL J. , MANN S. G. , STAUFFER L. , WALT R. P.
Published: October 2003

Background: Low‐dose H2‐receptor antagonists are available without prescription for the self‐medication of dyspepsia.

Methods: To investigate the relative abilities of low doses of famotidine and ranitidine to raise intragastric pH after a single post‐prandial evening dose, 25 healthy volunteers completed a three‐period cross‐over trial of famotidine 10 mg, ranitidine elixir 75 mg and placebo. A standard meal was given at 18.30 h and drug or placebo at 19.30 h to subjects fasted for 5.5 h. Intragastric pH was recorded with nasogastric electrodes from 18.00 to 07.30 h by GastrograpH II recorder.

Results: The geometric mean area under the pH–time curve for the 5–9 h post‐dose period was 1.49 pH units/h following placebo, 3.43 pH units/h following famotidine 10 mg (agent/placebo ratio 2.3; P< 0.001, ANOVA) and 2.6 pH units/h following ranitidine 75 mg (1.75; P<0.001). The geometric mean area under the pH–time curve ratio of famotidine 10 mg to ranitidine 75 mg was 1.32 (P<0.016). Median pH over the 5–9 h period was 1.1 following placebo, 2.7 following famotidine 10 mg (P<0.05 by comparison with placebo) and 1.9 following ranitidine 75 mg (P<0.05); comparison of median pH showed no significant difference between the active drugs. The percentage of pH values greater than 3.0 for the period 0–12 h post‐dose was 9.7% following placebo, 30.0% following famotidine 10 mg (P<0.05) and 24.9% following ranitidine 75 mg (P<0.05); there was no significant difference between the active drugs.

Conclusions: We conclude that both famotidine 10 mg and ranitidine 75 mg significantly raise intragastric pH when given as single post‐prandial doses. Famotidine 10 mg may have a greater effect than ranitidine elixir 75 mg over the 5–9‐h period after dosing.
The palatability of five colonic lavage solutions
Authors: DIAB F. H. , MARSHALL J. B.
Published: October 2003

Background: Many patients dislike the taste and saltiness of polyethylene glycol–electrolyte colonic lavage solutions. Several commercially available lavage solutions have been introduced with reduced salt content or flavouring added in an attempt to improve palatability and to encourage patient compliance.

Aim: To determine which of the commercially available lavage solutions are the most palatable.

Methods: A taste test of the five commercially available lavage solutions was performed by two groups of subjects: (a) adult patients scheduled to undergo colonoscopy (n=50) and (b) adult family members of patients scheduled to undergo colonoscopy and hospital volunteers (n=50). Subjects sampled all five products and were asked to grade the taste and saltiness, and to rank them in their overall order of preference.

Results: Similar findings were observed in the two groups of subjects. Colyte‐Flavored, Cherry‐NuLytely, NuLytely and GoLytely had similar median taste scores and a similar frequency of taste scores labelled as ‘unacceptable’ (8–11%); these four products ranked ahead of plain Colyte (which had a 25% frequency of taste scores labelled as ‘unacceptable’). However, in the ranking phase of the study, about three‐quarters of the subjects preferred a flavoured lavage solution to an unflavoured one. Colyte‐Flavored and Cherry‐NuLytely rated almost equal. Twenty‐two per cent of subjects rated an unflavoured lavage solution (generally NuLytely or GoLytely) as their first choice. This included a subset of subjects who disliked the flavoured solutions and greatly preferred an unflavoured product.

Conclusions: Four of the five commercially available products studied received similar taste scores. However, in the direct comparison phase of the study, a majority of subjects expressed a preference for a flavoured lavage solution. On the other hand, about one in five subjects expressed a dislike for the available flavoured solutions and preferred an unflavoured one.
Xanthine oxidase activity is not increased in the colonic mucosa of ulcerative colitis
Authors: REYNOLDS P. D. , RHENIUS S. T. , HUNTER J. O.
Published: October 2003

Aim: To measure urate and xanthine by high‐performance liquid chromatography in mucosal biopsies from patients with ulcerative colitis and controls.

Results: Reactive oxygen metabolite activity was demonstrated by a cystine to cysteine ratio of 0.24±0.08 in the control biopsies compared with 1.79±0.25 in ulcerative colitis. The product to substrate ratio (urate to xanthine) for xanthine oxidase and mucosal urate concentrations were not different between ulcerative colitis patients and controls. Xanthine oxidase activity after incubation of homogenized biopsies was 0.451 (±0.175) nmol.min/mg protein in ulcerative colitis patients compared with 2.585 (±0.823) nmol.min/mg protein in controls (P<0.01).

Conclusion: These results suggest that xanthine oxidase may not be the major source of superoxide formation in ulcerative colitis.
Clinical response after transjugular intrahepatic portosystemic stent shunt insertion for refractory ascites in cirrhosis
Authors: FORREST E. H. , STANLEY A. J. , REDHEAD D. N. , McGILCHRIST A. J. , HAYES P. C.
Published: October 2003

Background: Transjugular intrahepatic portosystemic stent shunts (TIPSS) have been used successfully to reduce portal pressure in the context of variceal haemorrhage. Recent interest has focused on the possible use of TIPSS to manage refractory ascites.

Aim: To study the effect of TIPSS insertion in 18 patients with refractory ascites.

Results: Response rates were 33.3%, 50%, 33.3% and 26.7% at 1 week, 4 weeks, 3 months and 6 months, respectively. Overall mortality was 50% with a new or worsening encephalopathy rate also of 50%. Patients with lower serum bilirubin and serum creatinine prior to TIPSS insertion had greater response at 1 and 4 weeks, respectively. There was no improvement in either liver or renal function after TIPSS insertion by standard laboratory tests, although serum sodium increased in the responders after 1 month.

Conclusion: TIPSS improves refractory ascites in only a minority of patients, and is associated with high encephalopathy and mortality rates.
management of patients with non‐responsive coeliac disease
Authors: O'MAHONY S. , HOWDLE P. D. , LOSOWSKY M. S.
Published: October 2003

A substantial minority of patients with coeliac disease (estimated at anything between 7 and 30%) fail to respond to treatment with a gluten‐free diet. Non‐responsiveness may be primary, that is when the patient fails to respond to treatment following initial diagnosis, or secondary, when a patient who has previously had a documented response to gluten exclusion becomes non‐responsive to therapy. The commonest cause of non‐responsiveness is continued gluten ingestion, either voluntary or inadvertent. Other causes to be considered include intolerances to dietary constituents other than gluten (e.g. milk, soya), pancreatic insufficiency, enteropathy‐associated T‐cell lymphoma and ulcerative jejunitis. There is some evidence that ulcerative jejunitis is, in fact, a manifestation of lymphoma.

The most important steps in the management of the non‐responsive coeliac patient are (a) to determine whether the patient is indeed coeliac, (b) to exclude lymphoma and (c) to establish the cause of the non‐responsiveness. In those coeliac patients with no demonstrable cause for non‐responsiveness, a variety of therapeutic stratagems (mostly based on small, uncontrolled studies) have been described; these include elimination diets, dietary supplementation with zinc and copper, and pharmacological therapy in the form of steroids, azathioprine and cyclosporin. In a minority of non‐responsive patients, the clinical course is characterized by a rapid decline, and total parenteral nutrition is required.

None of the therapies described above has been subjected to rigorous controlled studies. The precise mechanisms of non‐responsiveness in coeliac patients need to be unravelled before rational therapeutic approaches can be established.
The effect of a non‐absorbable fat substitute, sucrose polyester, on gastrointestinal function
Authors: KELLY S. M. , HUNTER J. O.
Published: October 2003

Objectives: To assess the effects of a single dose of a non‐absorbable fat substitute, sucrose polyester, on gastrointestinal function.

Methods: The effects of 50 g of sucrose polyester taken as a single drink on gastric emptying, small bowel transit time (SBTT), whole gut transit time (WGTT) and faecal weight compared with a control fat were examined in double‐blind studies. The effect of sucrose polyester on gallbladder ejection fraction and gastrointestinal hormones was also assessed.

Results: Sucrose polyester was found to accelerate gastric emptying significantly (98.33±71.0 vs. 112.92±82.0 min, P=0.042) but to slow SBTT (153.75±36.25 vs. 128.75±47.39 min, P=0.006). A trend to faster WGTT (37.47±15.61 vs. 46.63±20.65 h) and increased faecal weight was observed (453.33±122.05 vs. 395.0±107.85 g/48 h), but this did not reach statistical significance. There was a striking reduction in gallbladder ejection fraction with sucrose polyester (21.69±25.32 vs. 45.27±27.67%), P=0.039) and a corresponding significant decrease in the release of cholecystokinin. Lower levels of motilin and enteroglucagon were also observed.

Conclusions: Sucrose polyester has significant effects on gastrointestinal transit, gallbladder contraction and gastrointestinal hormones. These effects can be explained on the basis of decreased luminal products of digestion and may have implications for the widespread use of sucrose polyester as a fat substitute.
Effervescent and standard formulations of ranitidine—a comparison of their pharmacokinetics and pharmacology
Authors: WATSON R. G. P. , JOHNSTON B. T. , THAM T. C. K. , KERSEY K.
Published: October 2003

Background: An effervescent formulation of ranitidine may be absorbed faster and achieve a faster onset of action than conventional tablet form. The aim of this study was to compare the effects of effervescent formulations of ranitidine with equivalent dose standard tablets, in terms of intragastric pH and plasma pharmacokinetics in the initial 6 h following dosing.

Methods: Fifteen fasting healthy males, aged 18–31 (mean 29) years, were each randomly given, at weekly intervals, 150 mg standard and effervescent ranitidine and 300 mg standard and effervescent ranitidine. Ambulatory gastric pH was performed and plasma drug levels measured at regular intervals.

Results: Plasma ranitidine levels increased more rapidly with both effervescent formulations compared with standard tablets as indicated by mean area under curve (AUC) at 1 h (P<0.001). However, the pH profiles produced by all four treatments were similar with a steep rise in pH at 40–60 min to give a sustained level of pH 7 for the following 5 h. The effervescent formulations produced a transient rise in pH immediately following dosing, and for 300 mg this rise was significantly different at 10–20 min compared with the standard tablet (median pH 4.75 vs. 2.3, P<0.05).

Conclusions: Plasma drug levels increase more rapidly following effervescent ranitidine. Effervescent and standard formulations of 150 and 300 mg are all equally effective in producing gastric pH 7 after 1 h. However, effervescent formulations produce an early transient rise in pH which may be of clinical benefit.
Review article: methotrexate in gastroenterology—dangerous villain or simply misunderstood?
Authors: TANG H. , NEUBERGER J.
Published: October 2003

Methotrexate has a place in the treatment of an increasing number of diseases. Its emerging role in the treatment of primary biliary cirrhosis and inflammatory bowel disease still requires further evaluation.

Its toxicity profile is wide and is affected by a variety of factors. Hepatotoxicity from long‐term use in patients with psoriasis and rheumatoid arthritis holds particular concern for the physician. Appropriate monitoring guidelines for hepatotoxicity can only be made after careful evaluation of available data and consideration of cost‐to‐benefit models.
Review article: β3‐adrenoceptor agonists—future anti‐inflammatory drugs for the gastrointestinal tract?
Authors: ANTHONY A.
Published: October 2003

The β3‐adrenoceptor is now a recognized sub‐type of β‐adrenoceptor and is the principle adrenoceptor responsible for lipolysis in rat adipocytes. The receptor is also found in the gastrointestinal tract where β3‐adrenoceptor agonists are both spasmolytic and potent inhibitors of experimental non‐steroidal anti‐inflammatory drug (NSAID)‐induced gastric and small intestinal ulcers. There is evidence to suggest that the underlying mechanism of protection involves enhancement of mucosal blood flow, possibly as a result of relaxation of vascular and non‐vascular smooth muscle.

This review examines some possible therapeutic applications for β3‐adrenoceptor agonists in ulcero‐inflammatory disorders of the gastrointestinal tract where an altered blood flow state is a component of the underlying pathogenic process.
Review article: antibiotic‐induced Clostridium difficile infection
Authors: SETTLE C. D. , WILCOX M. H.
Published: October 2003

The great majority of cases of Clostridium difficile infection are hospital‐acquired, and the reported incidence in England and Wales has increased sixfold between 1990 and 1993, with at least 17 patients dying in a recent large nosocomial outbreak. C. difficile infection accounts for an average 3‐week increased length of stay in hospital. Acquisition of a toxigenic strain of Clostridium difficile may be followed by asymptomatic carriage, diarrhoea, colitis or pseudomembranous colitis. Antibiotic treatment and older age are major risk factors for the development of symptomatic disease, but less well‐defined differences in strain virulence and host susceptibility are also probably important. Accurate data on the relative risks of different antibiotics to induce symptomatic C. difficile infection are scarce, but third‐generation cephalosporins are frequently implicated. New kits are becoming available for the laboratory diagnosis of C. difficile infection but many of these lack sensitivity. Oral metronidazole or vancomycin are the main treatment options but avoidance of further antibiotics should also be encouraged where possible. The role of environmental C. difficile spores, which are highly resistant to conventional disinfectants, needs to be defined. Proven strategies for the prevention of C. difficile infection are required, in particular protocols to ensure that cross‐infection does not occur.
5‐amino salicylic acid absorption and metabolism in ulcerative colitis patients receiving maintenance sulphasalazine, olsalazine or mesalazine
Authors: STRETCH G. L. , CAMPBELL B. J. , DWARAKANATH A. D. , YAQOOB M. , STEVENSON A. , MORRIS A. I. , RHODES J. M.
Published: October 2003

Background: All 5‐aminosalicylic acid (5‐ASA) preparations are potentially nephrotoxic, but there has been concern that newer delivery systems may increase this risk, either because of altered absorption or altered metabolism. Previous studies of 5‐ASA absorption and excretion have usually either been performed in healthy controls or have only examined short‐term therapy. 5‐ASA and N‐acetyl‐5‐ASA have therefore been measured in blood samples, and N‐acetyl‐5‐ASA in urine samples, from patients with ulcerative colitis on long‐term maintenance with different 5‐ASA preparations and compared with sensitive markers of renal damage.

Methods: Patients receiving mesalazine (Asacol) (n=13), sulphasalazine (n=12) or olsalazine (Dipentum) (n=8), all at doses within the recommended range were studied. Six‐hour and trough serum concentrations of 5‐ASA and N‐acetyl‐5‐ASA and 24‐h urinary excretion of N‐acetyl‐5‐ASA were measured by high‐performance liquid chromatography.

Results: Absorption of 5‐ASA, assessed as 24‐h excretion of N‐acetyl‐5‐ASA expressed as molar % of ingested dose, was greater in patients receiving mesalazine, 23.25±10.65% (mean±s.d.; n=13), than those receiving sulphasalazine (11.16±10.52%, n=12; P=0.003) or olsalazine (9.70±3.89%, n=8; P<0.002). The ratio of 5‐ASA:N‐acetyl‐5‐ASA in the serum 6 h after dose was also greater with mesalazine (1.02±0.44, mean±s.d.) than sulphasalazine (0.54±0.44, P<0.02) or olsalazine (0.38±0.44, P<0.005). Urinary markers of tubular damage were increased in four of 33 patients, but showed no correlation with concentration of 5‐ASA or N‐acetyl‐5‐ASA in serum and N‐acetyl‐5‐ASA in urine, nor with lifetime dose or average daily dose of 5‐ASA.

Conclusions: In patients with ulcerative colitis receiving maintenance 5‐ASA therapy there was greater absorption and less acetylation of 5‐ASA from mesalazine (Asacol) compared with sulphasalazine or olsalazine, but no evidence from this study that this resulted in increased nephrotoxicity.
Treatment of reflux oesophagitis of moderate and severe grade with ranitidine or pantoprazole—comparison of 24‐hour intragastric and oesophageal pH
Authors: ARMBRECHT U. , ABUCAR A. , HAMEETEMAN W. , SCHNEIDER A. , STOCKBRÜGGER R. W.
Published: October 2003

Background:

Proton pump inhibiting drugs strongly decrease gastric acid secretion and have proven more effective in the treatment of reflux oesophagitis than H2‐receptor antagonists.

Methods:

In a double‐blind randomized trial, 24 patients with oesophagitis grade II (n=15) and III (n=9) were treated for 4 weeks with either ranitidine 150 mg b.d. (n=13) or pantoprazole 40 mg o.m. (n=11). Before the trial and on the last day of medication, 24‐h intra‐, gastric pH and oesophageal pH profiles were performed. Healing was assessed by endoscopy.

Results:

Pantoprazole increased median gastric pH from 1.7 to 3.9. Virtually no change in gastric pH was seen in the ranitidine group. Pantoprazole reduced the fraction time of pH < 4 in the oesophagus from 21% to 3% (P=0.0005), and the median number of refluxes from 206 to 56 (P=0.022). Oesophageal acid exposure was not decreased by ranitidine. Healing of the oesophagitis was seen in 6/11 cases after pantoprazole and in 3/13 cases after ranitidine (N.S.)

Conclusion:

In patients with oesophagitis of moderate and severe grade, pantoprazole 40 mg o.m. decreases intragastric acidity and gastro‐oesophageal acid reflux more effectively than ranitidine 150 mg b.d.
Controlled trial of oral 5‐aminosalicylic acid for the prevention of early relapse in Crohn's disease
Authors: FRANCHIS R. DE , OMODEI P. , RANZI T. , BRIGNOLA C. , ROCCA R. , PRADA A. , PERA A. , VECCHI M. , PIANO M. DEL , FERRARA A. , BELLOLI C. , PIODI L. , FRAMARIN L. , ASTEGIANO M. , RICCIOLI F. A. , MEUCCI G.
Published: October 2003

Background

Recent data indicate that 5‐aminosalicylic acid (5‐ASA) is most effective in preventing relapse of Crohn's disease in patients with a short duration of remission before enrolment.

Aim

To evaluate the efficacy of oral 5‐ASA treatment, started immediately after achieving steroid‐induced remission, in preventing clinical relapses of Crohn's disease.

Methods

Patients with active Crohn's disease, achieving remission on steroids, were randomized to oral 5‐ASA 3 g/day or placebo, while steroids were tapered over 6 weeks. The trial was terminated after interim analysis showed a slightly higher relapse rate in the 5‐ASA group, and the calculated probability of seeing a statistically significant difference by completing the study was minimal.

Results

Final analysis included 117 patients (58 taking 5‐ASA and 59 taking placebo; follow‐up 9.2 ± 6.5 months). Cumulative relapse rates at 6 and 12 months were 34% and 58% in 5‐ASA patients and 31% and 52% in placebo patients, respectively (rate difference + 0.095; 95% CI = −0.085– + 0.274). Subgroups analysis showed that 5‐ASA was equally ineffective in patients with ileal, colonic or ileocolonic disease.

Conclusions

Contrary to previous results, in our study early introduction of treatment with oral 5‐ASA did not prevent relapse in Crohn's disease patients treated with steroids to induce remission.