VSL#3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reduces inflammation.

BACKGROUND: Alkaline sphingomyelinase, an enzyme found exclusively in bile and the intestinal brush border, hydrolyzes sphingomyelin into ceramide, sphingosine and sphingosine-1-phosphate, thereby inducing epithelial apoptosis. Reduced levels of alkaline sphingomyelinase have been found in premalignant and malignant intestinal epithelia and in ulcerative colitis tissue. Probiotic bacteria can be a source of sphingomyelinase. OBJECTIVE: To determine the effect of VSL#3 probiotic therapy on mucosal levels of alkaline sphingomyelinase, both in a mouse model of colitis and in patients with ulcerative colitis. METHODS: Interleukin-10 gene-deficient (IL10KO) and wild type control mice were treated with VSL#3 (10(9) colony-forming units per day) for three weeks, after which alkaline sphingomyelinase activity was measured in ileal and colonic tissue. As well, 15 patients with ulcerative colitis were treated with VSL#3 (900 billion bacteria two times per day for five weeks). Alkaline sphingomyelinase activity was measured through biopsies and comparison of ulcerative colitis disease activity index scores obtained before and after treatment. RESULTS: Lowered alkaline sphingomyelinase levels were seen in the colon (P=0.02) and ileum (P=0.04) of IL10KO mice, as compared with controls. Treatment of these mice with VSL#3 resulted in upregulation of mucosal alkaline sphingomyelinase activity in both the colon (P=0.04) and the ileum (P=0.01). VSL#3 treatment of human patients who had ulcerative colitis decreased mean (+/- SEM) ulcerative colitis disease activity index scores from 5.3+/-1.8946 to 0.70+/-0.34 (P=0.02) and increased mucosal alkaline sphingomyelinase activity. CONCLUSION: Mucosal alkaline sphingomyelinase activity is reduced in the intestine of IL10KO mice with colitis and in humans with ulcerative colitis. VSL#3 probiotic therapy upregulates mucosal alkaline sphingomyelinase activity.

Conservative management of small adenomata in ulcerative colitis.

OBJECTIVE AND METHODS: Patients with chronic ulcerative colitis may develop colitis-related dysplasia and/or sporadic adenomata. Differentiating between these two processes is important because they may dictate different therapeutic approaches. Although distinguishing features of sporadic adenomata versus colitis-related dysplasia have been suggested previously on an a priori basis, they have never been verified by follow-up analysis. We have identified six chronic ulcerative colitis patients whose discrete adenomata were managed conservatively, with subsequent continuation in their surveillance programs. RESULTS: Mean patient age was 69 yr with a mean 21.3 yr of ulcerative colitis. Surveillance endoscopy of 63 patient-yr duration yielded 24 adenomata. A mean follow-up after the initial adenoma diagnosis was 7.2 yr with no carcinoma identified (including the examination of one prophylactic colectomy specimen). One patient, with a 34-yr history of ulcerative colitis and a single sporadic adenoma subsequently developed dysplasia of flat mucosa 14 months later. CONCLUSIONS: Our findings concur with previous reports and indicate that small, discrete adenomata with morphology identical to those seen in the general population occur in patients with ulcerative colitis. Such lesions in patients older than 45 yr, with tubular or tubulovillous architecture and low-grade dysplasia, are effectively treated by polypectomy only and are not necessarily an indication for colectomy. However, sporadic adenomata and colitis-related dysplasia can develop metachronously. It is suggested that subsequent to a diagnosis of sporadic adenoma in a patient with chronic ulcerative colitis, surveillance should increase to colonoscopic examination every 6 to 12 months.

Characterization of chromosomal DNA profiles from Helicobacter pylori strains isolated from sequential gastric biopsy specimens.

The restriction endonuclease profiles of DNAs from Helicobacter pylori strains isolated from 20 patients in two or more consecutive biopsy specimens over a period of up to 2 years were analyzed by pulsed-field gel electrophoresis with NotI and NruI. H. pylori strains possess a high degree of genomic diversity which was not observed to occur in vivo, and attempts to observe it in vitro were not successful.

Isolation and characterization of Campylobacter pyloridis from gastric biopsies.

Gastric biopsy specimens were examined microbiologically and histologically for the presence of Campylobacter pyloridis. Of 51 randomly selected patients, 22 (43%) were found to harbor C. pyloridis in the gastric mucosa. The histologic demonstration of spiral organisms observed by staining with hematoxylin and eosin correlated well with microbiologic isolation of the organisms. There was a strong association (95.5%) between C. pyloridis in the gastric mucosa and histologically defined gastritis. However, there was no obvious association between C. pyloridis and ulcers. All C. pyloridis strains isolated exhibited uniform biochemical characteristics and had almost identical protein profiles, which indicated that they belong to a relatively homogeneous group distinct from other Campylobacter species. All C. pyloridis isolates were uniformly susceptible to ampicillin, amoxicillin, cephalothin, gentamicin, kanamycin, tetracycline, coumermycin, ciprofloxacin, novobiocin, clorobiocin, and nitrofurantoin. They were moderately resistant to nalidixic acid.

Enprostil reduces G-cell hyperplasia and hypergastrinemia in duodenal ulcer.

A 42-year-old man with a 26-year history of duodenal ulcer volunteered for a 24-hour intragastric pH monitoring study, at which time his fasting gastrin concentration was found to be elevated. Secretin injection decreased the serum gastrin concentration. When not on treatment his total gastrin, gastrin-17 (G-17), and gastrin-34 (G-34) response to a protein-containing breakfast was marked. Immunocytochemical staining of antral biopsies showed hyperplasia of gastrin-containing cells, more pronounced for G-17 than for G-34. Cimetidine or cimetidine plus pirenzepine increased 24-hour intragastric pH, whereas pirenzepine alone rendered the gastric contents more acidic, particularly overnight. The total serum gastrin concentrations increased after meals and were unaffected by cimetidine or pirenzepine; enprostil, however, reduced the postprandial increase in total gastrin, G-34, and G-17. After six weeks of treatment with enprostil, the number of cells containing G-17 and G-34 was reduced. The findings show that G-cell hyperplasia may occur in the presence of a normal fasting serum gastrin concentration; fasting serum gastrin concentrations may fluctuate widely over time; the food-stimulated increase in G-17 was greater than that for G-34, and is associated with more pronounced antral hyperplasia for G-17 and G-34; and enprostil blunts the postprandial increase in G-17, G-34, and total gastrin. These observations suggest that enprostil may reduce G-cell hyperplasia and hypergastrinemia.

Synergistic interaction between an H2-receptor antagonist and enprostil on 24-hour intragastric pH, serum gastrin concentration, and tissue immunoperoxidase staining for gastrin, somatostatin, and serotonin in a patient with metastatic gastrinoma.

A 56-year-old woman newly diagnosed as having Zollinger-Ellison syndrome due to a metastatic gastrinoma underwent 24-hour intragastric pH monitoring, serum gastrin (total, G-17 and G-34) measurements, and immunoperoxidase staining of duodenal, antral, and gastric body biopsies for gastrin, somatostatin, and serotonin. Determinations were made while the patient was given different doses of ranitidine, enprostil (a synthetic orally administered prostaglandin E2), or ranitidine plus enprostil. Following are the findings from this single-patient study: Intragastric pH was persistently low but varied in response to food when the patient was given ranitidine. Immunocytochemical staining of antral biopsies obtained before the patient was treated revealed a reduced number of cells containing G-17 and G-34 but an increase in the antral somatostatin-containing D-cells. Treatment with 35 micrograms of enprostil BID plus 300 mg of ranitidine BID for two and 11 weeks was associated with an increased number of duodenal G-cells, a decrease in antral D-cells, and a decrease in the number of antral serotonin-containing cells. Enprostil in a dosage of 35 or 70 micrograms BID had no effect on intragastric pH, but when enprostil was given in combination with ranitidine, postprandial and nocturnal intragastric alkalinity was accentuated along with a return of duodenal and antral G-cells and a loss of the antral D-cell hyperplasia. Optimal pH control was achieved with 300 mg of ranitidine BID; more frequent dosing with ranitidine did not further increase intragastric pH. Both the total serum gastrin concentration and G-17 levels fluctuated in response to meals. The serum concentrations of total gastrin, G-17, and G-34 were reduced with enprostil and with ranitidine.

Nutritional status of gastroenterology outpatients: comparison of inflammatory bowel disease with functional disorders.

Dietary intakes of two groups of gastrointestinal patients, one group with inflammatory bowel disease (IBD)--Crohn's disease or chronic ulcerative colitis--and the other with functional disorders (FD)--irritable bowel syndrome, nonulcer dyspepsia, or gastroesophageal reflux disease, were assessed by means of 48-hour recalls. The relationships between dietary intake and anthropometric and biochemical measurements were examined. The IBD group had lower mean serum albumin and hemoglobin levels (p less than .05); however, FD patients had less adequate diets. The mean energy intake of women with FD was significantly lower than that of women with IBD (p less than .05) and was associated with inadequate or marginal intakes of many nutrients. Comparison of nutrient intakes between the IBD and FD groups revealed a significantly lower mean intake of folate, ascorbic acid, and vitamin A for women with FD than for women with IBD (p less than .05). In general, women had poorer diets and a higher prevalence of abnormal biochemical parameters than men. One notable feature of the dietary pattern of the women was that they consumed less meat than the general population consumed. Increasing meat consumption would improve the intake of many nutrients, including protein and iron. The results of this study suggest that more attention should be given to the adequacy of dietary intakes of gastrointestinal patients in general and of women in particular.

Protein-energy malnutrition in gastroenterology outpatients: increased risk in Crohn's disease.

A screening study was conducted to identify malnutrition in gastroenterology outpatients and to ascertain whether poor food intake is a contributing factor. A 48-hour recall method was used to collect dietary data from 154 patients (87 women and 67 men). Fourteen (16%) of the women and 8 (12%) of the men were classified as having protein-energy malnutrition (PEM) on the basis of abnormal anthropometric measurements or low serum albumin concentration. PEM was found in several diagnostic groups, but 9 of the 14 malnourished women had Crohn's disease. Protein undernutrition was more evident in women; calorie undernutrition was more evident in men. More women than men had low serum albumin levels. Low hemoglobin levels were particularly prevalent among patients with Crohn's disease. Many of the patients, especially women, had "inadequate" and "marginal" intakes of folate, vitamin A, thiamin, and calcium according to Nutrition Canada interpretive standards. The intake of iron was particularly poor among women: 59% of the intakes of female patients were classified as inadequate (less than 10 mg/day). Ten of the 14 female patients with PEM had inadequate iron intakes. Serum folates of less than 5 ng/ml were present in 72% of the women and 77% of the men. The data suggest that gastrointestinal outpatients are at high risk of malnutrition and that one of the factors contributing to the problem is inadequate food intake.

A comparative trial of ranitidine 300 mg at night with ranitidine 150 mg twice daily in the treatment of duodenal and gastric ulcer.

A multicenter double-blind comparative trial of oral ranitidine, 300 mg hs versus 150 mg bid, was conducted in 89 patients with duodenal ulcer (DU) and 54 with gastric ulcer (GU). Antacid tablets were prescribed prn. After 4 wk of treatment there were no statistically significant differences in the ulcer healing rates associated with the once daily (DU 86.4%, GU 62.5%) and the twice daily (DU 84.4%, GU 73.3%) regimens. Antacid consumption, by both DU and GU patients, was higher in the 150 mg bid group, but the differences did not achieve statistical significance. Further improvement in cumulative healing rates in response to both treatment regimens was observed following a second 4-wk treatment for those patients whose ulcers had failed to heal during the 1st month. Smoking adversely affected the rate of ulcer healing in DU patients, but had no significant effect on GU healing. No serious adverse effects or biochemical abnormalities were observed. Ranitidine 300 mg hs appears to be equally safe and effective as the standard regimen of 150 mg bid in the short-term treatment of uncomplicated gastroduodenal ulcer.

Comparative study of cimetidine and Mylanta II in the 6-week treatment of gastric ulcer.

The efficacy of antacid in the treatment of benign gastric ulcer is less well established than in the treatment of duodenal ulcer. The objective of this study was to monitor ulcer healing and symptom relief in 38 patients with gastric ulceration treated for 6 weeks with cimetidine (Tagamet) 300 mg q.i.d. or an aluminum-magnesium containing antacid (Mylanta II) 10 ml q.i.d. (acid neutralizing capacity 203.2 mEq/day). The study was single-blind; the study physicians and those providing endoscopic assessments were not aware of the patients' treatment. Entered into the study were 19 male and 19 female patients ranging in age from 17 to 70 years, with a mean age of 52 years. None of the patients had taken cimetidine in the previous month, and none abused alcohol or nonsteroidal anti-inflammatory agents, but two-thirds of the patients were smokers. Five patients in the antacid group withdrew for numerous reasons including continued pain, noncompliance, and side effects. All patients in the cimetidine group completed the study, and no side effects were noted. There was no difference between the antacid- and the cimetidine-treated patients in the relief of symptoms. There was a significant difference in the 6-week ulcer healing between the groups, with 14/19 (74%) healed in the cimetidine group compared with only 6/14 (43%) healed in the antacid group (p less than 0.025). Thus, Mylanta II, 10 ml four times daily, is comparable to cimetidine 300 mg q.i.d. in the symptomatic relief of benign gastric ulceration, but ulcer healing was superior using cimetidine.

Postprandial changes in serum concentrations of gastrin-17, gastrin-34, and total gastrin in patients with duodenal or gastric ulcers and in normal subjects.

The fasting concentrations of total gastrin and gastrin-17 (G-17) were similar in healthy volunteers and in asymptomatic patients with gastric ulcers or duodenal ulcers. However, the fasting serum concentration of gastrin-34 (G-34) was higher in patients with gastric ulcers than in normal subjects, in whom it was higher than in patients with duodenal ulcers. In response to food, the increases in G-17, G-34, and total gastrin were greater in ulcer patients than in healthy subjects. Cimetidine administration was associated with further increases in G-17, G-34, and total gastrin in normal subjects and gastric ulcer patients after meals. The ratio G-17/G-34 was similar in placebo-treated normal subjects and placebo-treated patients with gastric or duodenal ulcers. Cimetidine produced an increase in G-17/G-34 in placebo-treated normal subjects and placebo-treated patients with gastric or duodenal ulcers, but the ratio G-17/G-34 was greater in patients with gastric ulcers than in normal subjects. These results indicate that: differences in serum gastrin concentrations between patient groups, treatment regimens, and time of day are better detected by measuring G-17 and G-34 rather than total gastrin; there are differences in fasting and food-stimulated gastrin concentrations between normal subjects and patients with gastric or duodenal ulcers; the fasting concentration of G-34 is higher than G-17 in normal subjects and patients with gastric ulcers but not in patients with duodenal ulcers; food increases G-17 in all subjects but G-34 only in subjects with gastric ulcers; cimetidine increases the fasting concentration of total gastrin in normal subjects and patients with gastric ulcers and increases G-17 and G-34 in normal subjects; cimetidine increases the ratio G-17/G-34 in normal subjects and patients with gastric ulcers, but decreases G-17/G-34 in patients with duodenal ulcers. It is proposed: that measurements of total gastrin concentration should be replaced by measurements of G-17 and G-34 and that such measurements of G-17 and G-34 indicate differences in serum gastrin concentrations between normal subjects and those with peptic ulcers and between those with gastric versus duodenal ulcers. The role of altered gastrin metabolism in the pathogenesis of ulcers needs to be established.

Protein-energy intake and malnutrition in Crohn's disease.

A detailed nutrient assessment was made of 23 male and 24 female patients with Crohn's disease who entered sequentially into an outpatient clinic. Assessment included 48-hour dietary recall, anthropometric measurements, and biochemical and hematological tests appropriate to characterize protein-energy malnutrition. Approximately 40% of patients had energy intakes equal to only two-thirds of the Recommended Dietary Allowance (RDA). Three men and five women had relative body weights less than 85% of standard, but body weight was not correlated with energy intake. Relative body weight was correlated with arm muscle circumference in both male and female patients and with triceps skinfold and total lymphocyte count in women. Although the mean protein intake was greater than 150% of the RDA, evidence of protein malnutrition included low arm muscle circumference in 14% of the men and 15% of the women, low serum albumin concentration in 13% of the women, and low total lymphocyte count in one-half of the patients. The Crohn's disease activity index was correlated significantly with serum albumin, energy intake, and duration of disease in men and with serum ferritin and hemoglobin concentration in women. Thus, a reduced relative body weight or reduced serum albumin was not uncommon in patients with Crohn's disease but did not necessarily occur in those with reduced intakes of protein and energy. However, a low relative body weight may indicate need for further nutritional assessment.

Ranitidine versus cimetidine in the management of acute upper gastrointestinal tract bleeding.

Ranitidine and cimetidine were compared with respect to their effect on preventing the continuation or recurrence of acute upper gastrointestinal bleeding secondary to peptic ulcer disease. Fifty patients were randomly allocated to treatment with either ranitidine or with cimetidine. The two groups were comparable for age, sex, and severity of hemorrhage. There was no statistically significant difference in outcome between the groups when assessing need for surgery, total number of units in blood required, days in hospital, incidence of rebleeding, or deaths. However, there was a trend in favor of ranitidine: only one ranitidine-treated patient went to operation versus four of the cimetidine group. In addition, the number of rebleeds was higher in the cimetidine group (14) compared to the ranitidine group (1). Two patients in each group died. Therefore, ranitidine appears to be comparable to cimetidine in the management of patients with acute upper gastrointestinal tract bleeding. However, this study did not include a placebo group, and thus the generalized use of H2-receptor blockers in all patients with acute upper gastrointestinal tract bleeding has not been proven.

Ranitidine in the treatment of symptomatic gastroesophageal reflux disease.

We undertook a multicenter double-blind study comparing ranitidine to placebo in 73 patients with symptomatic gastroesophageal reflux ranging in age from 22 to 80 years (mean 49). Initially, all patients had moderate to severe symptoms associated with abnormal endoscopic and/or microscopic appearance of the mucosa. After six weeks, 46% of ranitidine-treated patients had a one-grade improvement in their symptom of regurgitation, as compared with 19% treated with placebo (p less than 0.01); ranitidine was no better than placebo in the improvement of pain or dysphagia. Endoscopic improvement occurred in 61% of ranitidine- and 48% of placebo-treated patients (p less than 0.05). Histological improvement occurred in a similar and small portion of patients treated with ranitidine and placebo; there was no correlation between clinical, endoscopic, and histological improvement. Antacid consumption was only half as great in the ranitidine as in the placebo group. Therapy with ranitidine was maintained for up to 12 months. The patients remained free of regurgitation or pain and there was a trend towards further improvement in the endoscopic or histopathologic appearance of the esophagus. Ranitidine 150 mg b.i.d. is recommended for the relief of symptoms and improvement in the endoscopic appearance of the esophagus. Treatment should be for a minimum of 6 weeks, but may be continued for up to a year if the patient's symptoms persist or return.

Gastrin, gastric emptying, and gastroesophageal reflux after ranitidine.

In a double-blind study comparing ranitidine to placebo in the treatment of symptomatic gastroesophageal reflux disease (GERD), we assessed gastric emptying time, gastroesophageal reflux, and gastrin response to food. Mean half-time for gastric emptying, measured using 99mTc-sulfur colloid, was 109 minutes in GERD and 102 minutes in nine healthy asymptomatic controls. This difference was not significant, but one-third of GERD had emptying times of 2 S.D.s beyond the mean for the normal controls. The patients with GERD refluxed an average of 2.3% (0.1-10%) of the isotope in 120 minutes compared with only 0.2% (0.0-0.5%) in control subjects. Reflux scans and gastric emptying times did not change with healing of esophagitis or with symptomatic improvement from ranitidine and antacids. There was no relationship between the percentage of the test dose refluxed into the esophagus and the rate of gastric emptying. The mean fasting gastrin concentration in GERD, 133 +/- 12 pg/ml, was higher than in healthy controls, 93 +/- 10 pg/ml (p less than 0.01). After stimulation with a standard meal, the integrated gastrin response (IGR) was similar in controls and GERD patients, but IGR was significantly higher after 6 weeks therapy with ranitidine. These results suggest that: 1) gastric emptying time may be prolonged in some patients with GERD, 2) basal but not food-stimulated gastrin concentrations may be abnormal in GERD, 3) reflux scans have limited use in the investigation of GERD, and 4) ranitidine therapy is associated with an increase in food-stimulated gastrin concentrations.

Cimetidine for recurrent ulcer after gastric surgery.

Seven of nine patients with ulcers recurring after a variety of gastric operations enjoyed loss of dyspeptic symptoms within 2 days of taking cimetidine, 1,200 mg/day for 6 weeks, and endoscopic confirmation of healing of the recurrent ulcer was established within 6 weeks of therapy. Once ulcer healing had been achieved in these seven patients, symptomatic remission persisted for over 19 months without maintenance therapy with cimetidine, and no complications suggestive of recurrent ulcerations occurred during this period in these seven patients. The eighth patient with a recurrent ulcer after vagotomy and pyloroplasty had symptoms suggestive of a gastric outlet obstruction in association with a bezoar and an elevated fasting serum gastrin concentration; cimetidine failed to heal the ulcer and a partial gastrectomy with Billroth I anastomosis was undertaken. The ninth patient lost his dyspeptic symptoms while on cimetidine, but 1 month after stopping therapy he succumbed to a massive hemorrhage; autopsy revealed a large pyloric channel ulcer. We suggest that cimetidine is helpful for the control of symptoms and the healing of recurrent ulcers after gastric surgery, but that endoscopy be repeated after an appropriate interval while such patients remain on cimetidine to assure that the disappearance of symptoms is truly associated with a lack of peptic ulceration. If the ulceration persists, we believe that cimetidine should be continued for a longer period.

Effect of ranitidine on healing of peptic ulcer: a 2-month study.

A multicenter trial of oral ranitidine 150 mg bid was conducted in 41 patients with duodenal and 30 with gastric ulcers. Patients were randomly allocated in double-blind fashion to 4 wk treatment with either ranitidine or placebo, after which all unhealed patients were given 4 wk on the active drug without breaking the original allocation code. After 4 wk of treatment the healing rate associated with ranitidine was significantly superior to that of placebo in both duodenal and gastric ulcer patients. Further improvement in cumulative healing rates was observed after the 2nd month of the study. After the allocation code was broken and all patients had had the opportunity of up to 8 wk on the active drug, there remained only a single unhealed pyloric ulcer. No serious adverse effects or biochemical abnormalities were observed. Ranitidine is a potent and well-tolerated H2 antagonist. Therapy for 4 or 8 wk is highly effective in the treatment of uncomplicated gastroduodenal ulcer.