[Assessment of the efficacy and safety of the phytopharmacon STW 5 versus metoclopramide in functional dyspepsia--a retrolective cohort study]. / Wirksamkeit und Unbedenklichkeit des Phytopharmakons STW 5 versus Metoclopramid bei funktioneller Dyspepsie unter Praxisbedingungen--eine retrolektive Kohortenstudie.

AIM: The objective of this study was to assess the efficacy and safety of the phytopharmacon STW 5 versus metoclopramide in functional dyspepsia. METHODS: A retrolective, epidemiological cohort study with parallel groups in 23 randomised centres where both drugs were used routinely was performed. The main outcome variable was improvement of 10 dyspepsia-specific symptoms of a valid gastrointestinal symptom score (GIS) during therapy. For inclusion, patients had to suffer from at least three of these symptoms before therapy. Secondary outcome variables were change of single symptoms, time till complete symptom relief, investigators' judgement of efficacy and tolerability, duration of inability to work and occurrence of adverse events. RESULTS: The per protocol collective comprised 490 STW 5 and 471 MCP patients. Anamnestic data were comparable. 439 of patients had taken MCP as drops. There was no relevant difference in median treatment duration. Significantly more patients were symptom-free after STW 5 treatment (71.6 vs. 62.8% p = 0,012). Additionally, the extent of symptom improvement (excluding nausea and vomiting) and median duration of inability to work (1 vs. 3 days) were significantly different in favour of STW 5. More physicians assessed STW 5 as effective (71.6 vs. 63.1% p<0.01) and very well tolerated (90 vs. 70.6% p<0.001). Adverse drug reactions were documented only under MCP. CONCLUSION: The present study illustrates a comparable to higher efficacy of STW 5 vs. MCP with better tolerability in treating functional dyspepsia under practice conditions, especially regarding complete symptom improvement, symptom duration and quality of life. The study confirms the results of prospective trials for STW 5 as being an appropriate alternative to the frequently administered antacids and prokinetics.

Mechanisms of cisapride affecting gallbladder motility.

Regulation of gallbladder motility is complex. Mechanisms via which cisapride may interact with gallbladder function are being reviewed. These are multiple and include direct effects on gallbladder and the sphincter of oddi, as well as indirect effects involving gastro-intestinal hormone levels, gastric emptying, gallbladder refilling, interdigestive migrating motor cycle (IMMC) and small intestinal transit. Effects, moreover, may vary according to dose, route and duration of cisapride administration, which may explain conflicting data so far with cisapride.

Biliary excretion of benzbromarone and its hydroxilated main metabolites in humans.

Hepatic metabolism of the uricosuric drug benzbromarone results in the formation of two hydroxilated main metabolites M1 (1'-hydroxybenzbromarone) and M2 (6-hydroxybenzbromarone). As urinary excretion of benzbromarone and its metabolites is very low, we investigated biliary and plasma concentrations of the parent drug and the metabolites after oral administration of a single 100 mg dose of benzbromarone in 6 patients requiring diagnostic gastroduodenoscopy. Benzbromarone, M1 and M2 were detectable in bile samples 12 hours after drug application. No dehalogenated derivatives (bromobenzarone, benzarone) were present in the bile. 12h, 24h, and 36h plasma concentrations of the parent drug and the main metabolites varied substantially. Our data provide direct evidence of biliary excretion of benzbromarone and its hydroxilated main metabolites 1'-OH-bzbr (M1) and 6-OH-bzbr (M2) and demonstrate the lack of excretion of debrominated products.

Treatment of active and postactive ileal and colonic Crohn's disease with oral pH-modified-release budesonide. German Budesonide Study Group.

BACKGROUND/AIMS: Budesonide is a glucocorticoid with a high topical anti-inflammatory but low systemic activity due to its rapid hepatic inactivation. The aim of this open, multicenter study was to investigate efficacy and safety of oral pH-modified-release budesonide in patients with active Crohn's disease of the ileum and colon and in maintaining budesonide-induced remission in postactive Crohn's disease. MATERIALS AND METHODS: 81 patients (intention-to-treat) received 3 x 3 mg budesonide/day for 6 weeks, followed by 3 x 2 mg budesonide for another 6 weeks in case of response to initial treatment. Clinical and laboratory parameters were assessed at study entry as well as after 2, 4, 6 and 12 weeks of treatment. RESULTS: On an intention-to-treat basis remission was induced in 54.3% of 81 patients with active Crohn's disease, 71.4% of 35 patients stayed in remission after the acute-phase treatment until the end of the trial. Typical steroid-related side effects were observed during the acute-phase treatment in only 18% of the patients. Duration, severity and extent of disease at study entry played no significant role in the outcome of the trial, but there was a tendency towards better results during the acute-phase treatment in patients with moderate disease activity and affection of the terminal ileum and proximal colon. CONCLUSIONS: Budesonide could be an alternative to conventional steroid treatment in patients with active Crohn's disease.

Risk of infection with Helicobacter pylori and hepatitis A virus in different groups of hospital workers.

OBJECTIVES: The purpose of this study was to determine whether different staff groups in an acute care hospital are at increased risk of acquiring Helicobacter pylori and hepatitis A virus infection. METHODS: We examined staff members of an acute care hospital for serum antibodies to H. pylori IgG (n = 457) and to hepatitis A virus (n = 434). The staff members were assigned to three groups: 1) nonmedical staff (n = 110), 2) medical and nursing staff (n = 272), and 3) medical and nursing staff working in a gastroenterology and endoscopy unit (n = 75). Serum antibodies were measured by validated enzyme immunoassays. A questionnaire inquiring about medical and professional history, history of upper GI pain and ulcer, as well as about the use of nonsteroidal anti-inflammatory drugs or medication for GI complaints and smoking habits was completed by each person. RESULTS: The seroprevalence of H. pylori was 35.5% in group I, 34.6% in group II, and 24.0% in group III (not significant). The seroprevalence of H. pylori antibodies increased with age (p < 0.001), and antibodies were present more frequently in women than in men (36.2 vs 25.4%, p < 0.05). After adjustment for age, duration of experience and the number of years working in the gastroenterology or endoscopy unit did not increase H. pylori seropositivity. No significant association was found between H. pylori seropositivity and history of upper GI pain, ulcers, use of nonsteroidal anti-inflammatory drugs or medication for GI complaints, or tobacco use. The prevalence of hepatitis A antibodies was similar in the three groups (group I, 26.4%; II, 26.5% III, 21.7%; not significant). Cross-tabulation showed that 67 subjects (15.4%) were seropositive for both H. pylori and hepatitis A (p < 0.001) and that 245 (56.5%) were negative for both. Seventy-seven (17.7.%) and 45 (10.4%) were seropositive for only H. pylori and for only hepatitis A, respectively. CONCLUSION: Occupational exposure to patients in an acute care hospital as well as to patients and to endoscopic procedures of a gastroenterology and endoscopy unit does not increase the rate of infection with H. pylori. The significant correlation between the seroprevalences of H. pylori and hepatitis A antibodies suggests fecal-oral transmission of H. pylori.

Effect of longterm placebo controlled calcium supplementation on sigmoidal cell proliferation in patients with sporadic adenomatous polyps.

A longterm, double blind intervention trial was undertaken in patients with sporadic adenoma treated by polypectomy to investigate the putative role of calcium as a protective factor in colon carcinogenesis. The aim of the study was to assess the effect of a daily dietary supplementation of 2 g calcium over nine months on cell proliferation measured as proliferation index in colonic mucosa. A total of 48 patients were entered into the study of which 30 were fully compliant. After intervention proliferation index % (mean (SEM) in colonic epithelium was decreased in both the calcium (13.5 (1.5) to 11.4 (1.2)) and the placebo group (13.7 (0.9) to 10.8 (1.1)). The difference in the change between the two groups was not significant (p = 0.7). Changes in proliferation index % of crypt compartments were also not significantly different between the two groups. A significantly positive correlation between soluble calcium in faeces and the total proliferation index % in colonic epithelium at baseline and after intervention (r = 0.54, p < 0.01, r = 0.50, p < 0.01 respectively) suggests that an increase of free luminal calcium alone is insufficient for inhibition of cellular proliferation.

Serum hepatocyte growth factor levels in primary biliary cirrhosis.

BACKGROUND: Recent studies have shown that serum levels of hepatocyte growth factor, a potent mitogen for hepatocytes, are increased in patients with fulminant liver failure and with advanced stages of liver cirrhosis. DESIGN: Retrospective study. METHODS: Serum levels of hepatocyte growth factor (HGF) were determined in 26 patients with advanced stages of liver cirrhosis by means of an enzyme-linked immunosorbent assay. In 23 of these patients, liver biopsies were obtained before treatment with ursodeoxycholic acid and investigated for hepatocyte expression of the proliferating cell nuclear antigen (PCNA) and the Ki-67 antigen by immunocytochemical methods. RESULTS: In 25 of the 26 patients, serum HGF levels did not differ from those of patients with histologically normal livers. Levels did not vary between the different stages of primary biliary cirrhosis but increased moderately when re-evaluated after a period of 24 +/- 4.9 months or 54 +/- 10.7 months. An abnormally increased serum HGF level was observed in only one patient, who had end-stage liver cirrhosis before liver transplantation. Both PCNA and Ki-67 antigen labelling indices were significantly higher at all stages of primary biliary cirrhosis than in normal liver, indicating increased hepatocyte proliferation, but the labelling indices did not correlate with the HGF concentrations in serum. CONCLUSION: Serum HGF levels in almost all patients with primary biliary cirrhosis were within normal limits despite increased hepatocyte proliferation. The results support the hypothesis that HGF serum levels may reflect liver dysfunction rather than active hepatocyte proliferation.

Lack of association of Helicobacter pylori seroprevalence and gastric cancer in a population with low gastric cancer incidence.

BACKGROUND: Previous studies have suggested that infection with Helicobacter pylori is associated with an increased risk of gastric adenocarcinoma. METHODS: We examined the sera of 111 Caucasian patients with histologically confirmed gastric cancer (36 with cancer of the cardia, 70 with cancer of the body or antrum, and 5 with stump carcinomas after Billroth-II procedures) and 111 age-matched controls with colorectal carcinomas for the presence of H. pylori IgG antibodies by enzyme-linked immunoassay. RESULTS: The overall prevalence of H. pylori infection was 58.6% (65 of 111) in gastric cancer patients as compared with 50.5% (56 of 111) in matched control subjects (odds ratio, 1.39; 95% confidence interval, 0.82 to 2.36). Carcinomas of the cardia were not linked to H. pylori infection (odds ratio, 1.25; 95% confidence interval, 0.65 to 2.46), nor diffuse or intestinal-type carcinomas (odds ratios, 1.79 and 1.0; 95% confidence intervals, 0.69 to 4.67 and 0.34 to 2.91, respectively). Age, sex, and height of the IgG immune response did not affect risk. CONCLUSIONS: In contrast to previous results, these data do not provide evidence that the contribution of H. pylori infection to the carcinogenesis of gastric cancer is of major significance in a population with low gastric cancer rates and with high socioeconomic status.

Biotransformation and uric acid lowering effect of benzbromarone in patients with liver cirrhosis - evidence for active benzbromarone metabolites?

The disposition of benzbromarone and its uric acid lowering effect were investigated in 8 patients with compensated liver cirrhosis in order to obtain evidence whether dose requirements differ from subjects with normal liver function. Following a single oral dose of 100 mg benzbromarone, the plasma concentrations of the parent drug and the two hydroxylated main metabolites M1 and M2 as well as uric acid were determined up to at least 72 h. All patients were found to be rapid benzbromarone eliminators. In patients 2-8 the extent of systemic availability of benzbromarone, as estimated by the average AUC(0-infinite), was similar to previous observations in healthy individuals, whereas the values of both metabolites M1 and M2 tended to be lower in patients with liver cirrhosis. Cmax of benzbromarone and M1 also were lower in patients, M2 was equivalent to the data in subjects with normal liver function. tmax and the plasma elimination half-life t(1/2) varied within the same range as previously observed in healthy individuals. One patient exhibited much higher values in AUC(0-infinite); and Cmax of benzbromarone and both metabolites, and in addition of the elimination half-life of M1 and M2, whereas the plasma elimination of benzbromarone itself was not delayed. An effect of altered liver function cannot be excluded in this patient. Ten hours after benzbromarone administration the mean plasma uric acid in patients 2-8 was reduced by 31.5% and in patient 1 by 44.2% as compared to pretreatment values. Baseline levels were not regained until 72 h. These data are compatible with a prolonged uric acid lowering effect of an active benzbromarone metabolite. Altogether, the present observations do not suggest dose adjustment to be necessary in patients with compensated liver cirrhosis Child A and B.

Biliary excretion of mezlocillin in patients with hepatic disease.

In three patients with liver disease (2 patients with alcoholic liver cirrhosis and 1 patient with chronic cholangitis) total, renal, biliary and metabolic clearance of the acylureidopenicillin mezlocillin was examined under steady state conditions. Mezlocillin was infused for 6 hours at a constant infusion rate of 10 mg/min. Renal clearance was calculated based on urinary excretion rates. Duodenal perfusion and marker dilution technique was applied to determine biliary excretion rates of the drug. Clearances were estimated by dividing the excretion rate by the respective plasma concentration. Total clearance was calculated by dividing the infusion rate by the plasma concentration. Biliary clearance was markedly reduced in the patients compared to the data of 8 healthy controls (0.65 +/- 0.33 ml/min vs 98.6 +/- 42.5 ml/min). Total and renal clearance were diminished (total clearance: 121.4 +/- 21.6 ml/min vs 286.5 +/- 54.6 ml/min, renal clearance, 65.4 +/- 1.0 ml/min vs 137.6 +/- 32.6 ml/min). In contrast, metabolic clearance was not changed (53.3 23.1 ml/min vs 50.3 +/ 24.2 ml/min). As mezlocillin is well tolerated and has a wide margin of safety we do not recommend reduced dosage. On the contrary, it might even be necessary to increase the dose when treating biliary tract infections in patients with cholestasis in order to assure effective drug concentrations in the bile.

Treatment of active Crohn's ileocolitis with oral pH-modified budesonide. Germany Budesonide Study Group.

Budesonide is a topical steroid which after intestinal absorption is rapidly degraded into inactive metabolites in the liver. Its systemic bioavailability is only 10-15%. In the present open trial the efficiency and safety of oral pH-modified release budesonide were assessed in patients with active Crohn's ileocolitis. This report describes the results of the first 30 of 78 patients. After 6 weeks of treatment with 3 x 3 mg budesonide/day 67% of the patients were in clinical remission. Typical steroid-related side effects were observed in only one patient. Budesonide therefore seems to be suited as an alternative for classical steroids in patients with Crohn's ileocolitis. Its clinical efficacy is comparable with classical steroids but it's rate of steroid-related side effects is lower.

Biliary lipids, lithogenic index and biliary drug concentrations during etofibrate and bezafibrate treatment.

Hypolipidemic drugs like etofibrate and bezafibrate may induce lithogenic bile and increase the risk of gallstone formation. In this study, biliary lipids, lithogenic index and biliary drug concentrations were investigated in 6 hyperlipidemic patients after cholecystectomy. Patients were treated once daily for 5 days with either 500 mg/day etofibrate or 400 mg/day bezafibrate. Hepatic bile was collected for 6 days via T-drainage in 4 hourly aliquots. In the patients treated with etofibrate, the range of the lithogenic index remained stable with 0.89-1.69 before and 0.78-1.51 after 5 day drug therapy. In the bezafibrate group, the range of the lithogenic index rose from 0.81-1.40 to 1.26-1.66 mainly as a result of an increase of biliary cholesterol concentrations. Biliary drug concentrations were substantially higher under bezafibrate treatment than under etofibrate treatment. In conclusion, the fibrate drugs, etofibrate and bezafibrate, are different with regard to lithogenicity of bile and extent of biliary excretion. The safety profile of etofibrate may be preferably compared to other fibrate drugs.

Prevalence of Helicobacter pylori infection and gastritis among young adults in China.

To investigate the prevalence of gastritis and H. pylori infection among young Chinese in Henan Province, a high incidence area for oesophageal cancer in China, the gastric mucosa was examined in 194 asymptomatic subjects, aged 15-26 years, in the course of an epidemiological study of precursor lesions of oesophageal cancer. Histopathological grading of gastritis and determination of H. pylori infection were performed on haematoxylineosin and Warthin-Starry stained section. An enzyme-linked immunosorbent assay was used to detect the presence of serum IgG antibodies to H. pylori. A very high prevalence of gastritis (93.8%) was found: 71 subjects (36.6%) presented with superficial gastritis (14 active), 94 (48.5%) with diffuse gastritis (92 active) and in 17 cases (8.8%) diffuse gastritis (16 active) was accompanied by focal atrophy. Silver staining detected H. pylori in 166 (85.6%) of the study participants. However, serological techniques identified H. pylori in only 109 (56.2%). H. pylori was seen in all the 119 cases showing histological signs of active gastritis, in 41 of the 63 cases (65%) without activity, and also in 50% (6/12) of histologically normal subjects. H. pylori infection was found to be associated with a 2.5-fold higher prevalence of chronic atrophic gastritis compared with non-atrophic gastritis. A family history of stomach cancer, consumption of pickled vegetables more than twice a month, and a high monthly salt consumption (> 500 g/month) also showed a positive association.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatocyte proliferation in primary biliary cirrhosis as assessed by proliferating cell nuclear antigen and Ki-67 antigen labelling.

Expression of the proliferating cell nuclear antigen and Ki-67 antigen by hepatocytes was investigated in liver tissue specimens of 29 patients with primary biliary cirrhosis (stage I 13, stage II 6, stage III 5 and stage IV 5 patients) prior to treatment with ursodeoxycholic acid and of five control subjects using immunocytochemical methods. Proliferating cell nuclear antigen and Ki-67 expression were reevaluated in seven patients after 3 years of treatment with ursodeoxycholic acid. Proliferating cell nuclear antigen labelling indices were significantly higher in primary biliary cirrhosis (stage I, 6.4% to 32.4%, median, 10.9%; stage II, 9.6% to 21.6%, median 11.4%; stage III, 5.2% to 12.5%, median, 7.6%; stage IV, 3.8% to 8.9%, median, 5.6%) than in controls (0% to 0.5%, median, 0.1%; p < 0.005). Ki-67 antigen labelling counts were lower than proliferating cell nuclear antigen indices but elevated in all stages of primary biliary cirrhosis (stage I, 0.5% to 3.5%, median 2.0%; stage II, 1.8% to 3.6%, median 2.6%; stage III, 1.3% to 2.5%, median 1.9%; stage IV, 0.4% to 1.7%, median 1.0%) compared with controls (0% to 0.5%, median 0.3%; p < 0.005). After ursodeoxycholic acid treatment, mean proliferating cell nuclear antigen and Ki-67 labelling indices decreased from a median of 9.0% (range, 3.8% to 32.4%) to a median of 7.8% (range, 4.5% to 17.2%; p = 0.045) for proliferating cell nuclear antigen and from a median of 2.5% (range, 0.8% to 3.6%) to a median of 2.1% (range, 0.9% to 3.1%; p = 0.031) for Ki-67 antigen. It is concluded that hepatocyte proliferation is markedly increased in primary biliary cirrhosis, particularly in the early stages of the disease, and that ursodeoxycholic acid treatment reduces proliferative activity in primary biliary cirrhosis.

Effect of ursodeoxycholic acid on biochemical parameters, hepatocyte proliferation and liver histology in galactosamine hepatitis in the rat.

The effect of oral administration of ursodeoxycholic acid (UDCA) on biochemical parameters, liver histology and liver cell proliferation was investigated in rats with galactosamine hepatitis. Treatment with UDCA led to a decrease of aminotransferases, but did not show any significant changes in liver histology or liver cell proliferation. The improvement of liver enzymes without change of histology in this animal model of hepatitis following treatment with UDCA is in agreement with results obtained from clinical trials with UDCA in patients with chronic viral hepatitis.

Plasma kinetics and biliary excretion of colchicine in patients with chronic liver disease after oral administration of a single dose and after long-term treatment.

Plasma kinetics and biliary excretion of colchicine in patients with chronic liver disease were evaluated after oral administration of a single dose and after long-term treatment. A single oral dose of 1 mg colchicine led to a mean peak concentration of 3.60 +/- 1.04 ng/ml at a peak time of 2.16 +/- 0.34 h and a mean area under the plasma concentration time curve, extrapolated from time 0 to infinity, of 24.90 +/- 8.47 ng.h/ml. Comparable values were obtained after repeated administration. Distribution half-life was 2.83 +/- 0.74 h, and terminal plasma half-life was 9.81 +/- 2.08 h; the mean apparent volume of distribution and the mean apparent plasma clearance were 1448 +/- 4061 and 175.3 +/- 47.6 1/h, respectively. Colchicine concentrations in bile (2025 +/- 1368 ng/ml) were clearly higher than in plasma. Long-term treatment with colchicine (1 mg/day) in patients with various stages of primary biliary cirrhosis (PBC) was associated with colchicine concentrations varying from < 0.15 to 2.0 ng/ml, with a slight tendency to higher concentrations in PBC stages III-IV than I-II. Although about 20% of colchicine is excreted in bile within 24 h, accumulation of colchicine may appear only in patients with advanced liver disease and cholestasis.

Bone mineral density and calcium regulating hormones in patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis).

Inflammatory bowel disease (Crohn's disease and ulcerative colitis) is associated with decreased bone mineral density and increased risk of osteoporosis. However, the pathogenesis of this bone loss is not yet fully understood. In the present study we measured lumbar bone mineral density (by dual photon absorptiometry), serum levels of parathyroid hormone (PTH) and vitamin D metabolites, and serum markers of bone turnover (alkaline phosphatase and osteocalcin) in 15 patients with Crohn's disease and in 4 patients with ulcerative colitis. The median duration of the disease was 4 years and the median lifetime steroid dose was 10g of prednisone. We compared our results to a control group of 19 normal persons, who were matched for age and sex to the patients. We found that lumbar bone density was reduced by 11% in patients compared with control persons (Z-score -0.6 +/- 0.6 versus -0.1 +/- 0.8; p < 0.05). In patients, the serum levels of PTH, 25-hydroxyvitamin D3, and calcitriol (1,25(OH)2D3) were significantly reduced compared with control persons. Serum alkaline phosphatase activity (AP) was significantly higher in the patients and was inversely related to lumbar bone density. Osteocalcin values were not different between patients and control persons. There was also no difference in serum levels of calcium between the two groups, whereas phosphorus levels were higher in patients. We conclude that malabsorption of calcium was not a primary cause of bone loss in our patients, because we did not find secondary hyperparathyroidism. Accordingly, we did not find a severe vitamin D deficiency, since 25-hydroxyvitamin D3 levels were within the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Proliferation cell nuclear antigen (clone 19A2) correlates with 5-bromo-2-deoxyuridine labelling in human colonic epithelium.

Measurements of cell proliferation can be used as biomarkers of preneoplastic change. In this study, two immunocytochemical methods that measure different components of the cell cycle were compared to assess cell proliferation on biopsy samples from human colonic mucosa. These methods are based on a monoclonal antibody against 5-bromo-2-deoxyuridine (BrdU), which is confined to S phase cells, and a more broad assessment of proliferation based on an antibody against proliferating cell nuclear antigen (PCNA, clone 19A2). In the PCNA assay, only strongly immunostained nuclei were included. The proliferation index was assessed in colonic mucosa from patients with no colonic disorders. Correlation between individual total proliferation indices determined by either method was significant with rs = 0.6 (p < 0.05). The mean proliferation index in the study group was 7.79% using BrdU and 7.64% using PCNA immunocytochemistry. Distribution of labelled cells within crypts was similar with respect to the two methods with a peak at the 18th and the 24th percentile in the case of BrdU and at the 23rd percentile for PCNA. Variance component analysis showed that at least two biopsy specimens should be evaluated per subject to allow a precise individual characterisation. It is concluded that PCNA (19A2) immunocytochemistry may be used as an operational marker of cell proliferation in normal colonic mucosa. A significant correlation and an agreement in the mean proliferation index between PCNA (19A2) and BrdU can only be achieved by a strictly standardised enumeration of labelled cells limited to strongly stained nuclei in the PCNA evaluation.