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Biomedical subjects

G Holtmann

Publications and source records attributed to G Holtmann.

At least 19 recordsLinked to original sources
PubMed2003

Clinical trial guidelines for pharmacological treatment of irritable bowel syndrome.

Appropriate guidelines for clinical trials in irritable bowel syndrome are needed because of the inadequacy of previously performed trials, the use of new and more adequate patient definition, new emerging pathophysiological models and the unique requirements related to the assessment of treatment outcome that, in the absence of a biological marker, can rely only on the evaluation of clinical manifestations. This consensus report highlights the following points. (a) A 4-week period is considered to be adequate to assess drug efficacy for the control of symptoms. (b) For the cyclic and non-life-threatening nature of the disease, a long-term study of 4-6 months or more of active treatment to establish efficacy is considered to be inappropriate in the large majority of patients. (c) In the initial assessment phase of drug efficacy, the withdrawal effect of treatment can be ascertained during a follow-up period prolonged for a sufficient time (4-8 weeks) after stopping treatment. Subsequent trials with proper withdrawal phase design and duration can then ascertain the drug post-treatment benefit. (d) Considering the intermittent clinical manifestations of irritable bowel syndrome, designing trials with on-demand or repeated cycles of treatment could be envisaged. However, the lack of a definition of what constitutes an exacerbation is a major obstacle to the design of such trials. In the absence of an established gold standard, appropriately justified novel trial designs are welcome. (e) Patients eligible for inclusion should comply with the Rome II diagnostic criteria for irritable bowel syndrome. (f) The main efficacy outcome of the treatment should be based on one primary end-point. (g) The primary efficacy end-point could combine, in a global assessment, the key symptoms (abdominal pain, abdominal discomfort, bowel alterations) of irritable bowel syndrome or rate any single symptom for drugs considered to target specific symptoms. (h) A 50% improvement in the primary efficacy end-point seems to be a reasonable definition of a responder.

Clinical Trials as Topic↗
PubMed2003

Reflux disease and Barrett's esophagus.

Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal disorders. The key feature of GERD is reflux of gastric contents into the esophagus. Medical treatment with proton-pump inhibitors (PPIs) is well established and is considered the standard treatment. Given the high prevalence of the condition and the excellent response to medical therapy, antireflux surgery is an option for patients with volume reflux that is not properly controlled by medical therapy. Adenocarcinoma is a rare but life-threatening complication of GERD. The only known precursor lesion for esophageal adenocarcinoma is Barrett's esophagus. In recent years, a clearer understanding of the development of Barrett's and of its progression toward invasive cancer has developed. Genetic factors almost certainly determine the individual risk. The length of the Barrett's esophagus segment and the size of a hiatal hernia are associated with the risk of developing high-grade dysplasia and esophageal adenocarcinoma.With regard to the clinical management of GERD patients with Barrett's, endoscopic surveillance at 3-year intervals is now considered appropriate in the absence of dysplasia. In patients with high-grade dyspepsia, the situation is more difficult. While a considerable proportion of these patients may already have invasive cancers, there is also the possibility that there is only focal dysplasia. For this reason, it is justifiable to carry out curative endoscopic resection. Mucosal ablation procedures may also be appropriate, but these still need to be properly investigated in clinical trials.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2003

Persistently altered visceral perception after resection of an esophageal granular cell myoblastoma: a therapeutic concept revisited.

Granular cell tumors (GCTs) are rare and usually benign gastrointestinal tumors. Their most frequent symptoms are dysphagia and epigastric or retrosternal discomfort. We here report a case of esophageal GCT with continued symptoms of retrosternal discomfort, postprandial feeling of fullness, and early satiety despite complete thoracoscopic resection of the tumor. In contrast, all functional tests were in the normal range. We thus suggest that, due to their neuroectodermal origin, GCTs may affect neuronal alterations leading to a persistently disturbed visceral mechanosensory perception. Consequently, this case also cautions the therapeutic concept to solely relieve GCT symptoms by resection if the tumor is less than 20 mm in diameter.

Adult↗
PubMed2002

[Epidemiology and clinical phenomenology of visceral pain].

Visceral pain is characterized by a subjectively painful perception located in the abdominal area. Distinct structural lesions or biochemical abnormalities which could serve as explanation for these painful sensations can be only detected in a proportion of patients. In the absence of precise causes for visceral pain, the symptoms are attributed to functional disorders. The two major single entities among functional disorders of the gut are functional dyspepsia and irritable bowel syndrome. Patients with functional dyspepsia characteristically localize the symptoms in the upper abdomen. Functional gastrointestinal disturbances which are localized in the lower abdomen are summarized as irritable bowel syndrome. Interestingly,both functional dyspepsia and irritable bowel syndrome may overlap.

Dyspepsia↗
PubMed2002

[Diagnostic criteria and therapeutic strategies of abdominal pain syndromes].

Abdominal pain syndromes can be categorised into acute or chronic manifestations. In general, diagnostic work-up is targeted upon identification of structural lesions that cause the symptoms and allows therapeutic measures that permanently cure the cause of symptoms. If no structural or biochemical abnormality can be identified upon utilising the necessary diagnostic measures, a functional disorder as the cause of symptoms is assumed. For these disorders no cure is currently available and treatment is targeted towards relief of symptoms only.

Abdominal Pain↗
PubMed2002

A randomized, double-blind, comparative study of standard-dose rabeprazole and high-dose omeprazole in gastro-oesophageal reflux disease.

BACKGROUND: Rabeprazole has a faster onset of antisecretory action than omeprazole, and it is of interest to determine whether this translates into faster symptom relief in patients with gastro-oesophageal reflux disease. AIMS: To assess the relief from heartburn after 3 days of treatment with standard-dose rabeprazole or high-dose omeprazole (primary end-point). Secondary end-points included the decrease in score for other symptoms of gastro-oesophageal reflux disease, healing rates and quantification of antacid use. METHODS: Patients with endoscopically confirmed erosive oesophagitis were randomized to receive 4 weeks of double-blind treatment with rabeprazole (20 mg) or omeprazole (40 mg). Patients who were not healed after 4 weeks received a further 4 weeks of treatment. RESULTS: Two hundred and seventy-four patients were screened, 251 patients were randomized and 230 patients completed the trial. The numbers of patients with relief from heartburn on day 4 were similar in the two groups (84% for rabeprazole; 95% confidence interval, 76-90%; 83% for omeprazole; 95% confidence interval, 75-89%). There were no significant differences between the treatments in the relief from other gastro-oesophageal reflux disease symptoms or in healing rates. The number of reports of severe heartburn during the first 3 days was higher in the omeprazole group (daytime heartburn: 4.7% for rabeprazole vs. 10.3% for omeprazole, P=0.005; night-time heartburn: 4.7% for rabeprazole vs. 9.8% for omeprazole, P=0.01; statistical comparisons defined post hoc). CONCLUSIONS: Standard-dose rabeprazole was as effective as high-dose omeprazole in relieving symptoms by day 4 of treatment and in healing oesophageal lesions, but had a faster onset of action in patients with severe heartburn. This suggests that the improved pharmacological properties of rabeprazole translate into a clinically relevant advantage.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2002

A randomized placebo-controlled trial of simethicone and cisapride for the treatment of patients with functional dyspepsia.

AIM: To compare the efficacy of simethicone with placebo and the prokinetic cisapride in patients with functional dyspepsia. METHODS: One hundred and eighty-five patients with functional dyspepsia were randomized and treated in a double-dummy technique with simethicone (105 mg t.d.s.), cisapride (10 mg t.d.s.) or placebo (t.d.s.). The primary outcome measure was the O'Brien global measure of the patients' rating of 10 upper gastrointestinal symptoms (graded as absent = 0, moderate = 1, severe = 2 or very severe = 3). Outcome measures were assessed at baseline and after 2, 4 and 8 weeks of treatment (intention-to-treat). RESULTS: At 2, 4 and 8 weeks, treatment with simethicone and cisapride yielded significantly (all P values < 0.0001) better improvement of symptoms compared to placebo. Simethicone was significantly better than cisapride after 2 weeks (P = 0.0007), but the differences were not statistically significant after 4 and 8 weeks. Patients treated with simethicone judged the efficacy of their treatment as very good in 46% of cases, compared to 15% and 16% receiving cisapride and placebo, respectively. CONCLUSIONS: Simethicone and cisapride were significantly better than placebo for symptom control in patients with functional dyspepsia after 2, 4 and 8 weeks of treatment. Simethicone was also superior to the prokinetic cisapride in the first 2 weeks of treatment.

Adult↗
PubMed2002

[Gastrocolic fistula - a rare cause of cachexia and polyneuropathy].

Gastrocolic fistula is a rare clinical disorder which in the past most often occurred after gastric surgery or carcinoma of the gastrointestinal tract. However, during the last decade an increasing number of cases after benign gastric ulcers have been described. Most common symptoms have been weight loss, abdominal pain, diarrhea and copremesis. A 49-year-old cachectic patient presented with a 2-year history of abdominal discomfort and diarrhea. He reported a weight loss of 32 kg during this period and was finally unable to move because of exhaustion. Furthermore, he suffered of burning paresthesia of the legs and the abdomen. His medical history included a Billroth II operation because of recurrent ulcer disease in 1987. Barium enema revealed a gastrocolic fistula which caused small bowel bacterial overgrowth with villous atrophy and malabsorption and development of polyneuropathy. The fistula was surgically resected, and postoperatively, the patient improved and regained his weight. Gastrocolic fistula is a rare cause of diarrhea and should be considered in clinical practice. Barium enema is superior to endoscopy in detecting gastrocolic fistula.

Cachexia↗
PubMed2002

Capsaicin-sensitive nerve fibres induce epithelial cell proliferation, inflammatory cell immigration and transforming growth factor-alpha expression in the rat colonic mucosa in vivo.

BACKGROUND: Capsaicin-sensitive nerve fibres protect gastrointestinal mucosa in animal models of mucosal injury by modulation of mucosal blood flow and mucus secretion. The aim of our study was to evaluate the effects of capsaicin-sensitive nerve fibres in rat colonic mucosa on epithelial cell proliferation and transforming growth factor-alpha (TGFalpha) expression, which is important in mucosal defence, protection and repair. METHODS: Male Wistar rats received either a capsaicin enema with or without giving antagonists to calcitonin-gene-related-peptide (CGRP) or substance P (SP) i.v. immediately prior to the capsaicin enemas; a capsaicin enema after sensory desensitization as described previously; or a vehicle enema. In all experiments, animals received 50 mg/kg BrdU i.v. and were killed at 2, 4, 8, 12, 24 and 48 h after the various treatments. Colonic mucosal specimens were evaluated microscopically for mucosal damage, changes in the numbers of inflammatory cells and BrdU-immunoreactive epithelial cell nuclei. In the same specimens, TGFalpha-mRNA and -protein expression were evaluated by RT-PCR and Western blot analysis using standardized procedures. RESULTS: A significant increase in the number of mucosal inflammatory cells and an increase in BrdU-immunoreactive nuclei were detected following mucosal exposure to capsaicin. A 2-fold increase of TGFalpha mRNA and a 10-fold increase of TGFalpha protein expression were obtained 2-12 h after capsaicin enemas. The effects on the invading number of inflammatory cells and on the increase in BrdU immunoreactive epithelial cell nuclei were significantly reduced by both CGRP and SP antagonists and were abolished in rats previously sensory-desensitized. CONCLUSION: Capsaicin-sensitive nerve fibres modulate epithelial cell proliferation and TGFalpha expression in colonic mucosa as well as a migration of inflammatory cells into the colonic mucosa. These effects are mediated by the neurotransmitters CGRP and SP.

Animals↗
PubMed2001

[Chronic intestinal pseudo-obstruction. Clinical symptomatology and course].

BACKGROUND AND OBJECTIVE: Chronic intestinal pseudoobstruction (CIP) is a motility disorder clinically characterized by recurrent symptoms of small intestinal or large bowel obstruction without organic stenosis. The aim of the present study was to assess the clinical presentation and course of the disease. PATIENTS AND METHODS: During a four year period all available data including the symptoms as assessed by the bowel disease questionnaire (BDQ) of all patients with newly established diagnosis of CIP were analyzed including duration of symptoms and previous surgical interventions due to the abdominal symptoms. RESULTS: Data of nine patients (five females, four males, age 20 - 64 years) with newly diagnosed CIP were available for analysis. Median age at initial onset of symptoms were 24 years. The final diagnosis of CIP was established after a median of 7 years (range 1 - 20). Initially, the majority of patients suffered from uncharacteristic symptoms such as abdominal fullness and abdominal pain. All patients had undergone repeated abdominal surgical interventions for suspected mechanical bowel obstruction. On average, the first surgical intervention was performed 5 years after the onset of symptoms and there was a median number of 10 treatments as in-patients. Suspected acute bowel obstruction occurred between 1 and 14 times and laparotomies were performed in 50 % of these events. CONCLUSION: The diagnosis of CIP is usually preceded by several years with uncharacteristic abdominal symptoms. During this time, most patients undergo multiple surgical interventions. Thus, in patients with repeated suspected acute bowel obstruction without definite proof of mechanical obstruction, CIP has to be taken into consideration as differential diagnosis. In this context, small bowel manometry is an important diagnostic tool.

Adult↗
PubMed2001

H. pylori and functional dyspepsia: increased serum antibodies as an independent risk factor?

The relationship between H. pylori and functional dyspepsia is controversial. Hypothesizing that subjects with a more intense immune response to H. pylori (and hence higher antibody titers) would be at greater risk of dyspepsia, we aimed to identify risk factors for the development of dyspeptic symptoms. In all, 491 healthy blood donors with no history of peptic ulceration and 74 consecutive patients with a confirmed diagnosis of functional dyspepsia were studied. Symptoms and potential risk factors [nonsteroidal antiinflammatory drugs (NSAIDs), alcohol, and smoking] were measured by a validated questionnaire. H. pylori status was determined by IgG antibodies using a validated ELISA test with a cutoff titer for a positive serology of 10 units/ml. Logistic regression analysis assessed the association between risk factors and dyspepsia. Among blood donors, 21% (95% CI 17.6-24.8) reported dyspepsia (pain localized to the upper abdomen); 7.7% (95% CI 5.5-10.4) had frequent dyspepsia (>6 times in the prior year). The age-adjusted prevalence of H. pylori was not significantly different in blood donors with (39.5%, 95% CI 24.0-56.6) and without frequent dyspepsia (34.2%, 95% CI 29.8-38.36), but was significantly greater in patients with functional dyspepsia (68.8%, 95% CI 57.3-77.9). In the combined study population of blood donors and patients with functional dyspepsia, logistic regression adjusting for age identified the following independent risk factors for frequent dyspepsia: high serum antibody levels against H. pylori (OR for IgG titer >50 units/ml vs H. pylori titers 11-50 units/ml 4.6, 95% CI 2.7-7.8) and consumption of standard NSAIDs (OR 2.4,95% CI 1.3-4.5). In contrast, alcohol (OR 0.6, 95% CI 0.3-1.0), smoking (OR 1.5, 95% CI 1.0-2.3) or positive H. pylori serology with titers < or = 50 units/ml (OR 1.6, 95% CI 0.8-2.9) were not associated with frequent dyspepsia. In conclusion, in a subgroup of H. pylori-infected subjects who have high antibody titers, H. pylori appears to be associated with functional dyspepsia.

Adolescent↗
PubMed2001

Diurnal variation of abdominal motor responses to colorectal distension and plasma cortisol levels in rats.

Most patients with functional bowel disorders complain of daytime symptoms while they remain asymptomatic at night. As symptoms are associated with heightened visceral sensitivity, we hypothesized that circadian fluctuations of the visceral sensory function occur. At four different timepoints (06.00, 12.00, 18.00 and 24.00 h), colorectal distensions (CRD) were performed in fasting conscious male Lewis rats using a balloon catheter and a barostat device. The abdominal wall contractions (behavioural pain response) were assessed during colorectal distension by abdominal wall electromyography (EMG). Plasma levels for endogenous cortisol were determined simultaneously at these timepoints. EMG responses to CRD were significantly (P < 0.05) higher at midnight and in the early morning. Plasma cortisol levels peaked in the evening. In night-active Lewis rats, the behavioural pain response to noxious visceral stimulation is augmented at night and fluctuations of visceral sensitivity are accompanied by circadian changes of plasma concentrations of endogenous cortisol. We conclude that there are marked circadian fluctuations in visceral sensory functions. Thresholds are low during time periods of normal behavioural activity. These findings suggest that fluctuation of the sensory functions may be linked to the circadian variability of symptoms in patients with functional GI disorders.

Abdomen↗
PubMed2001

The management of irritable bowel syndrome: a European, primary and secondary care collaboration.

OBJECTIVE: To develop recommendations for the diagnosis and management of irritable bowel syndrome for European doctors delivering primary care. These recommendations can be adapted by local medical groups according to their language, custom and health-care systems. METHODS: Twenty-one general practitioners and gastroenterologists from Europe attended a workshop planned by a steering committee. After a state-of-the-art symposium, four working groups considered the following aspects of irritable bowel syndrome management: what to tell the patient, diagnosis, non-medical treatment and psychosocial management. Current and future drug management was reviewed by the steering committee. The resulting recommendations were considered at two plenary sessions during the meeting, and by circulation of the material during development of the manuscript. RESULTS: The process permitted a unique dialogue between general practitioners and gastroenterologists, in which it was necessary to reconcile the specialists' emphasis on thoroughness with the practical, epidemiological and economic realities of primary care. Despite this dichotomy, consensus was achieved. CONCLUSIONS: European general practitioners and gastroenterologists have produced recommendations that emphasize education of the patient, a positive symptom-based diagnosis, diet and lifestyle advice, psychological support and a critical analysis of current specific psychological and pharmacological treatments.

Colonic Diseases, Functional↗
PubMed2001

Epithelial cell-derived components induce transforming growth factor-alpha mRNA expression and epithelial cell proliferation in vitro.

BACKGROUND: Epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha protect the gastrointestinal mucosa against injury. In response to mucosal injury TGF-alpha, but not EGF, is locally increasingly expressed in the mucosa of the rat colon and stomach 4-8 h after injury. The aim of our present study was to characterize the possible signal for the induction of TGF-alpha expression. METHODS: Monolayers of the non-transformed intestinal epithelial cell (IEC)-6 and IEC-18 lines were harvested, homogenized and shock-frozen at -80 degrees C for 1 h. Cell cultures of intact IEC-6 or IEC-18 cells were exposed to these cell homogenates and modulation of epithelial cell migration and proliferation was evaluated using standardized procedures as described previously. TGF-alpha mRNA expression in the exposed epithelial cell monolayers was assessed using reverse transcriptase-polymerase chain reaction (RT-PCR) and normalized to the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RESULTS: The proliferation of IEC-6 and IEC-18 epithelial cell monolayers was significantly inhibited if epithelial cell homogenates of 2000 cells/ml or more, and significantly induced if homogenates of less than 2000 cells/ml, were applied to the medium of the monolayers in vitro. In proliferating epithelial cells, a significant two-fold increase in TGF-alpha mRNA expression was obtained at 48 h and 72 h after application of the cell homogenates. The homogenate-induced epithelial cell proliferation was completely abolished after preincubation of the epithelial cell homogenates with neutralizing monoclonal anti-TGF-alpha antibodies. No effect on epithelial cell migration was noticed after application of epithelial-cell homogenates to the cell cultures. CONCLUSIONS: Epithelial cell-derived components induce TGF-alpha mRNA expression and TGF-alpha-dependent cell proliferation of intact epithelial cells. We hypothesize that epithelial cell interaction bears one of the possible signals for the increased TGF-alpha mRNA expression after mucosal injury.

Animals↗