[Show abstract][Hide abstract] ABSTRACT: Acute studies suggested a therapeutic benefit for fundus-relaxing drugs in functional dyspepsia (FD) with visceral hypersensitivity (VH) to gastric distention or impaired accommodation (IA), but long-term studies are lacking. R-137696 is a serotonin-1A (5-HT(1A)) receptor agonist which relaxes the proximal stomach in man. Our aim was to investigate the influence of R-137696 on symptoms in FD with VH or IA. Randomized, double-blind, placebo-controlled, parallel group study of 4 weeks R-137696 2 mg t.i.d. in FD with VH or IA. Symptoms were assessed using the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) total score and individual symptom subscales. Barostat studies were performed before and after 4 weeks of treatment. Fifty-three patients (33 VH and 20 IA), 18 men, mean age 40 +/- 13 years were recruited. Twenty-four received placebo and 29 received R-137696. In VH patients, both placebo and R-137696 improved total symptom scores, with a tendency for superiority of placebo (-1.12 vs-0.51, P = 0.07). Placebo was superior for the subscales of early satiety, bloating, fullness and discomfort (all P < 0.05). In IA, both placebo and R-137696 had no significant influence on total or individual symptom scores (-0.08 and -0.27). In VH, both placebo and R-137696 increased the discomfort volume, without a statistical difference between both arms (+120 and +164 mL). In IA, both placebo and R-137696 enhanced accommodation, without a statistical difference between both (+77 and +159 mL). Adverse events were similar for drug and placebo. A 4-week administration of the fundus-relaxing 5-HT(1A) agonist R-137696 failed to significantly improve symptoms, VH or gastric accommodation compared to placebo.
Neurogastroenterology and Motility 02/2009; 21(6):619-26, e23-4. · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gastro-oesophageal reflux disease (GERD) is associated with a variety of typical and atypical symptoms. Patients often present in the first instance to a pharmacist or primary care physician and are subsequently referred to secondary care if initial management fails. Guidelines usually do not provide a clear guidance for all healthcare professionals with whom the patient may consult.
To update a 2002-treatment algorithm for GERD, making it more applicable to pharmacists as well as doctors.
A panel of international experts met to discuss the principles and practice of treating GERD.
The updated algorithm for the management of GERD can be followed by pharmacists, for over-the-counter medications, primary care physicians, or secondary care gastroenterologists. The algorithm emphasizes the importance of life style changes to help control the triggers for heartburn and adjuvant therapies for rapid and adequate symptom relief. Proton pump inhibitors will remain a prominent treatment for GERD; however, the use of antacids and alginate-antacids (either alone or in combination with acid suppressants) is likely to increase.
The newly developed algorithm takes into account latest clinical practice experience, offering healthcare professionals clear and effective treatment options for the management of GERD.
[Show abstract][Hide abstract] ABSTRACT: The water drink test is a good tool to evoke dyspeptic symptoms. To what extent these symptoms are related to altered gastric distribution is not clear. Therefore, we determined gastric volumes after a drink test using SPECT. After a baseline scan 20 healthy volunteers (HV) and 18 patients with functional dyspepsia (FD) underwent a drink test (100 mL min(-1)) followed by five scans up to 2 h. Dyspeptic symptoms were scored before every scan. A Wilcoxon signed rank test (P < 0.05) and a mixed effects model were used for statistical analyses. Fasting volumes were significantly higher in FD compared to HV for total, proximal and distal stomach (P < 0.001). Functional dyspeptic patients ingested significantly less water (P < 0.001) and had an impaired filling of the distal part of the stomach (P = 0.001) after the drink test. In FD, bloating (prox. 80%, dist. 56%), pain (prox. 87%, dist. 62%) and fullness (prox. 80%, dist. 59%) were determined more by proximal stomach volume rather than distal stomach volume. These data suggest that drinking capacity is mainly determined by antral volume, with a reduced antral filling in FD compared to HV. The persisting symptoms of bloating, pain and fullness in FD are predominantly associated with proximal stomach volume.
Neurogastroenterology and Motility 12/2007; 19(12):968-76. · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to evaluate the axial and radial distribution of histological markers including hyperplasia of the basal cell layer, elongation of the papillae and dilatation of the intercellular spaces of the squamous epithelium in patients with nonerosive reflux disease compared to controls and to relate this to the macroscopic topography in erosive reflux disease. Two different study populations were included in this report. Endoscopic esophageal biopsies were taken from 21 healthy control subjects and 21 nonerosive reflux disease patients before and after 4 weeks of esomeprazole therapy. Endoscopic still images from 50 erosive reflux disease patients were reviewed for the radial orientation of LA grade A and/or B esophagitis (Los Angeles criteria for grading of reflux esophagitis). The 3 o'clock position of the squamocolumnar junction showed significantly thicker basal cell layer (P=0.011) and more intercellular space dilatation (P=0.01) in nonerosive reflux disease patients compared to the 9 o'clock position. Only a significant difference in dilatation of the intercellular spaces (P=0.018) between nonerosive reflux disease patients and controls were observed in the 3 o'clock region at the squamocolumnar junction, whereas 1-2 cm orally, all three histological criteria differed significantly (P<or=0.01). After treatment, on the contrary, papillary length was significantly less pronounced at the squamocolumnar junction (P<0.01). Endoscopically, erosions were predominantly visualized in the 3 o'clock region (P<0.05). Histological mucosal changes in nonerosive reflux disease patients and visible mucosal erosions in erosive reflux disease patients occur most frequently at the same position, namely in the 3 o'clock quadrant in the distal esophagus. The histological difference between nonerosive reflux disease patients and controls are more distinct 1-2 cm oral to rather than at the squamocolumnar junction. However the effect of therapy is most pronounced at the squamocolumnar junction.
Diseases of the Esophagus 06/2007; 20(3):232-8. · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study tested the diagnostic value of high-resolution endoscopy for the recognition of subtle diagnostic esophageal mucosal changes in nonerosive reflux disease.
Ten control subjects and eleven patients with nonerosive reflux disease confirmed by a validated questionnaire, standard endoscopy, and 24-hour pH-metry participated in the study. Still images were collected by high-resolution endoscopes from the distal esophagus in a standardized manner, incorporating iodine staining. Assessments were repeated in the patients with reflux disease after 4 weeks of esomeprazole therapy. Interobserver variability in the recognition of the proposed criteria was initially evaluated by 27 endoscopists using an Internet-based process. After optimisation of image quality the evaluation was repeated face-to-face with six expert endoscopists.
No criterion was identified in either assessment that was sufficiently sensitive and specific to patients with reflux disease to be clinically useful. The kappa value, used to assess interobserver variation, was acceptably high only for invisibility of palisade vessels (0.59). Triangular indentations, apical mucosal breaks, and pinpoint blood vessels at the squamocolumnar junction were identified more frequently in the patients with reflux disease ( P < 0.05). These changes and the invisibility of the palisade vessels were significantly less prevalent in reflux patients after therapy ( P < 0.01).
Though some distal esophageal mucosal appearances observed with the high-resolution endoscope appeared to be related to nonerosive esophageal mucosal injury, none of these changes proved to be sufficiently sensitive and specific to justify their use as a diagnostic criterion for nonerosive reflux disease.
[Show abstract][Hide abstract] ABSTRACT: As fundic dysaccommodation represents one of the pathophysiological mechanisms underlying functional dyspepsia, gastric relaxant agents may serve as a new treatment of this disorder. Previous studies have suggested the involvement of 5HT1 receptors in the control of gastric tone. Our aim was to study the effect of R137696, a novel 5HT1A agonist, on fundus sensorimotor function in healthy volunteers. The effect of single oral doses (1-2 mg) R137696 was evaluated in a double-blind, placebo-controlled manner on fasting fundic volume, visceral perception, distension-evoked symptoms and fundic compliance in 21 healthy male subjects. R137696 increased the proximal stomach volumes in a dose-dependent manner. Distention-evoked symptoms or distention and discomfort threshold were not altered by R137696. A logistic regression model, characterizing the relationships between the volume and the visual analogue scale score for dyspeptic symptoms (nausea, fullness, discomfort, pain and satiety) as a sigmoidal curve, revealed that R137696 had no effect on distension-induced discomfort, fullness, pain and satiety compared to placebo. R137696 relaxes the gastric fundus in fasting conditions but has no effect on distension-evoked dyspeptic symptoms in healthy volunteers.
Neurogastroenterology and Motility 11/2006; 18(10):919-26. · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Distal esophageal carcinomas can be resected using transthoracic esophagectomy or transhiatal esophagectomy. Accurate diagnosis of subcarinal and supracarinal lymph-node metastases is important for selecting the surgical strategy. The impact of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) on the preoperative diagnosis of subcarinal and supracarinal lymph-node metastases in patients with distal esophageal carcinoma was therefore investigated.
Patients with a resectable distal esophageal carcinoma and subcarinal and/or supracarinal lymph nodes visualized on preoperative EUS were prospectively included. The lymph nodes were sampled using EUS-FNA, and if they were found to have metastases, transthoracic resection was offered; by contrast, patients without metastases were offered a transhiatal resection.
Lymph-node metastases were found with EUS-FNA in 11 of the 48 patients included (23 %). Thirteen patients had suspicious nodes on EUS, in four of whom (31 %) the diagnosis was changed into nonmalignant nodes with FNA. Thirty-five patients had nonsuspicious nodes on EUS, in three of whom (9 %) the FNA procedure revealed malignant cells.
EUS with the addition of the FNA procedure has a significant impact on decision-making in patients with esophageal carcinoma in whom transhiatal esophagectomy would otherwise be planned.
[Show abstract][Hide abstract] ABSTRACT: Though functional gastrointestinal complaints are recognised as being common throughout the world, there have been few comparative studies of prevalence.
To compare the prevalence and management of abdominal cramping/pain in nine countries.
In a two-stage community survey, approximately 1000 subjects were interviewed in each of nine countries to establish the demographics of individuals with abdominal cramping/pain (stage 1) followed by market research-driven interviews with >or=200 sufferers per country (stage 2).
9042 subjects were interviewed in stage 1. Mexico (46%) and Brazil (43%) had the highest prevalence of abdominal cramping/pain; Japan the lowest (10%). Abdominal cramping/pain was more common in women (12-55%) than in men (7-38%). About 1717 subjects participated in stage 2; 65% were women and the average age at symptom onset was 29 years. The frequency of episodes differed between countries, being highest in the US (61% suffered at least once in a week). Sufferers in the US and Latin America reported a higher usage of medications (around 90%) than those in Europe (around 72%). In most countries over-the-counter drugs were principally used. Antispasmodic drugs were most popular in Latin America and Italy, antacids in Germany and the UK. Drug therapy decreased the duration of episodes (by up to 81% in Brazil).
The community prevalence, severity, healthcare seeking and medication usage related to abdominal cramping/pain are high overall, but vary considerably between countries.
[Show abstract][Hide abstract] ABSTRACT: To compare the efficacy and tolerability of oral hyoscine butylbromide (hereafter hyoscine) 10 mg t.d.s., paracetamol 500 mg t.d.s. and their fixed combination against placebo in patients with recurrent crampy abdominal pain.
A total of 1637 patients were entered into a four-arm double-blind study. After a 1 week placebo run-in, they were randomized to 3 weeks of treatment with one of the four therapies with assessments after 1, 2 and 3 weeks. Pain intensity (Visual Analogue Scale) and pain frequency (Verbal Rating Scale) were self-assessed daily.
Pain intensity on the Visual Analogue Scale decreased in all treatment groups; the adjusted mean changes from baseline were 2.3, 2.4 and 2.4 cm for the hyoscine, paracetamol and combination groups, respectively, compared with 1.9 cm for the placebo group (all P < 0.0001). The Verbal Rating Scale also showed a statistically significant decrease of 0.7, 0.7 and 0.7 in the hyoscine, paracetamol and combination groups compared with 0.5 in placebo (all P < 0.0001). All treatments were well tolerated: 16%, 14%, 17% and 11% of patients on hyoscine, paracetamol, combination and placebo reported at least one adverse event.
Hyoscine, paracetamol and their fixed combination are effective in the treatment of recurrent crampy abdominal pain and well tolerated if used three times daily continuously for 3 weeks.
[Show abstract][Hide abstract] ABSTRACT: To commemorate Edkins' discovery of gastrin in 1905, we review a century of progress in the physiology and pathobiology of gastrin and acid secretion especially as it pertains to clinical aspects of gastro-oesophageal reflux disease. Although initially ignored, Edkins' observations eventually led to the enthusiastic investigation of gastrin and acid regulation in peptic ulcer disease, culminating in important therapeutic advances in the management of acid peptic disease. Following the improved understanding of gastric secretory physiology, and the development of acid suppressants with increasing efficacy, the use of surgical intervention for peptic ulcer disease was almost eliminated. Surgery became obsolete with the discovery of Helicobacter pylori. Three other advances are also influencing modern practice: the gastrotoxicity of aspirin and non-steroidal anti-inflammatory drugs is now increasingly appreciated, the role of endoscopy in the diagnosis and therapy of upper gastrointestinal bleeding, and the use of intravenous acid-suppressive agents. The major issue for the future resides within the epidemic of gastro-oesophageal reflux disease. How to diagnose, categorize and treat this condition and how to identify and prevent neoplasia, are the challenges of the new century.
[Show abstract][Hide abstract] ABSTRACT: Acid pockets at the gastro-oesophageal junction escape buffering from meals in the stomach. Combining high-dose antacid with alginate may therefore be of benefit in gastro-oesophageal reflux disease.
To characterize the antacid and raft-forming properties of Rennie alginate suspension (containing high-dose antacid and alginate; Bayer Consumer Care, Bladel, the Netherlands).
The in vitro acid-neutralizing capacity of Rennie algniate was compared with Gaviscon (Reckitt Benckiser, Slough, UK) by pH-recorded HCl titration. Alginate raft weight formed in vitro at different pH was used to evaluate the pH dependency of raft formation with each product. A double-blind, placebo-controlled, randomized crossover study also compared the antacid activity of Rennie alginate vs. placebo in vivo using continuous intragastric pH monitoring in 12 healthy fasting volunteers.
Compared with Gaviscon, Rennie alginate had a higher acid-neutralizing capacity, greater maximum pH and longer duration of antacid activity in vitro. However, the two products produced comparable alginate rafts at each pH evaluated. In vivo, Rennie alginate provided rapid, effective and long-lasting acid neutralization, with an onset of action of <5 min, and duration of action of almost 90 min.
The dual mode of action of Rennie alginate offers an effective treatment option for mild symptomatic gastro-oesophageal reflux disease particularly considering recent findings regarding 'acid pockets'.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Visceral hypersensitivity is a consistent finding in a considerable proportion of patients with irritable bowel syndrome (IBS), and may provide a physiological basis for the development of IBS symptoms. In this study, we aimed to confirm the hypothesis that nitric oxide (NO) is involved in maintaining visceral hypersensitivity in IBS. Ten healthy volunteers (HV) and 12 IBS patients with documented hypersensitivity to rectal distension underwent a rectal barostat study. The effect of placebo and the specific NO synthase inhibitor NG -monomethyl-L-arginine (L-NMMA) on resting volume, rectal sensitivity to distension and rectal compliance was evaluated in a double-blind, randomized, cross-over fashion. NG -monomethyl-L-arginine did not alter resting volumes in HV or IBS patients. In HV, l-NMMA did not alter rectal sensory thresholds compared to placebo (45 +/- 3 and 46 +/- 3 mmHg, respectively). In contrast, L-NMMA significantly increased the threshold for discomfort/pain in IBS patients (placebo: 18 +/- 2, l-NMMA: 21 +/- 3 mmHg, P < 0.05). Rectal compliance was not affected by L-NMMA. Although NO does not seem to play a major role in normal rectal sensation or tone, we provide evidence that NO may be involved in the pathophysiology of visceral hypersensitivity in IBS.
Neurogastroenterology and Motility 02/2006; 18(2):115-22. · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Visceral hypersensitivity is considered an important pathophysiological mechanism in irritable bowel syndrome, yet its relationship to symptoms is unclear.
To detect possible associations between symptoms and the presence of hypersensitivity to rectal distension in patients with irritable bowel syndrome.
Ninety-two irritable bowel syndrome patients and 17 healthy volunteers underwent a rectal barostat study. The association between specific irritable bowel syndrome symptoms and the presence of hypersensitivity was examined using Area under the Receiver Operating Characteristic curves.
Irritable bowel syndrome patients had significantly lower thresholds for discomfort/pain than healthy volunteers: 24 (18-30) and 30 (27-45) mmHg above minimal distending pressure, respectively. Forty-one patients (45%) showed hypersensitivity to rectal distension. Proportions of patients with different predominant bowel habits were similar in hypersensitive and normosensitive subgroups (diarrhoea predominant: 39 and 41%, respectively; alternating type: 27 and 28%, respectively; constipation predominant: 34 and 31%, respectively). Severe abdominal pain was more frequent in hypersensitive, compared with normosensitive patients (88% vs. 67%, P = 0.02), but none of the individual irritable bowel syndrome symptoms could accurately predict the presence of hypersensitivity, as assessed by Area under the Receiver Operating Characteristic curve analysis.
Hypersensitive and normosensitive irritable bowel syndrome patients present with comparable, heterogeneous symptomatology. Therefore, selection based on clinical parameters is unlikely to discriminate individual irritable bowel syndrome patients with visceral hypersensitivity from those with normal visceral sensitivity.
[Show abstract][Hide abstract] ABSTRACT: At present, the concept of visceral hypersensitivity provides the leading hypothesis regarding the generation of symptoms in functional gastrointestinal disorders. This paper discusses the current clinical evidence for drugs that have been proposed to interfere with visceral sensitivity in functional gastrointestinal disorders. Several possible pharmacological targets have been identified to reduce visceral pain and to reverse the processes underlying the persistence of visceral hypersensitivity. However, most of the available evidence comes from experimental animal models and cannot simply be extrapolated to patients with functional gastrointestinal disorders. In this review, we selected five drug classes that have been shown to exhibit visceral analgesic properties in experimental studies, and of which data were available regarding their clinical efficacy. These included opioid substances, serotonergic agents, antidepressants, somatostatin analogues and alpha(2)-adrenergic agonists. Although clinical trials show a limited benefit, in particular for serotonergic agents, the evidence illustrating that these effects result from normalization of visceral sensation is currently lacking. Therefore, we conclude that the concept of targeting visceral hypersensitivity as a treatment for functional gastrointestinal disorders is still controversial. Future evaluations require patient selection based on the presence of visceral hypersensitivity and application of compounds that exhibit 'true' viscerosensory effects.
[Show abstract][Hide abstract] ABSTRACT: The major oesophageal complications associated with persistent gastro-oesophageal reflux disease (GERD) include erosive oesophagitis, ulceration, strictures and gastrointestinal (GI) bleeding. Although the causes of these complications are uncertain, studies indicate that erosive oesophagitis may progress to the development of ulcers, strictures and GI bleeding. Pharmacological treatment with proton pump inhibitors is favoured over that with H(2)-receptor antagonists for the treatment of strictures. The treatment of strictures is accomplished with dilation and many favour the concomitant use of proton pump inhibitors. Most gastroenterologists are seeing far fewer oesophageal strictures these days since the introduction of proton pump inhibitors. In addition, research has shown that oesophageal complications have a greater impact on patients suffering from night-time GERD than on those suffering from daytime GERD. Barrett's oesophagus is a significant complication associated with persistent GERD and those at risk generally experience a longer duration of symptoms, especially those with a high degree of severity. In addition, there is a strong relationship between Barrett's oesophagus and oesophageal adenocarcinoma. This is in part due to the association of obesity and the development of hiatal hernias. Furthermore, endoscopic screening is being used to detect Barrett's oesophagus and oesophageal adenocarcinoma in persons suffering from chronic GERD, even though screening may not have an impact on outcomes (Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett's esophagus: The AGA Chicago Workshop. Gastroenterology 2004; 127: 310-30.).
[Show abstract][Hide abstract] ABSTRACT: The management of patients with esophageal cancer with malignant celiac lymph nodes (CLNs) is controversial. In this study we evaluated the management and survival of patients with positive CLN findings on endoscopic ultrasonography (EUS) and compared the outcome in surgically treated patients with that of nonsurgically treated patients.
The EUS database of the Academic Medical Center was retrospectively searched for patients with esophageal carcinoma and EUS-positive CLN. Follow-up comprised the review of medical charts and contact with general practitioners.
From 1993 through 2000, 78 patients with esophageal carcinoma and suspicious CLN were eligible for inclusion in this study. The median survival of patients with CLN size < 2 cm was 13.5 months vs. 7.0 months for patients with CLN size >2 cm ( P = 0.01). In a multivariate model, CLN size was the only predictive factor for poor patient survival. Of the 78 study patients, 13 underwent a surgical resection and 65 received nonsurgical treatment. The surgical group was significantly younger and all patients in this group had CLN size < 2 cm. The median survival for the surgical group was 13.7 months vs. 13.5 months for the nonsurgical group with CLN size < 2 cm ( P = 0.63).
In this retrospective study, CLN size was a significant predictor for poor survival. The surgically treated patients had a medium-term survival similar to that of nonsurgically treated patients with a CLN size < 2 cm. These findings underline the prognostic value of CLN size in patients with esophageal carcinoma.
[Show abstract][Hide abstract] ABSTRACT: In a Barrett's oesophagus without dysplasia, endoscopic control every 3-5 years is sufficient. If low-grade dysplasia is encountered in the surveillance biopsies, then endoscopy should be repeated within 3-6 months and yearly thereafter if the low-grade dysplasia persists. Antacid medication must be prescribed in cases with extensive inflammation. The endoscopic treatment of patients with high-grade dysplasia and/or early cancer of the mucosa in a Barrett's oesophagus (tissue ablation and/or mucosa resection) seems a promising alternative to surgery in view of the combination of effectiveness, limited invasiveness compared to surgical resection, and the preservation of a functional oesophagus. Data from long-term follow-up are still limited. Strict endoscopic surveillance will probably detect metachronic abnormalities in an early and still curable stage, creating a new opportunity for endoscopic treatment.
Nederlands tijdschrift voor geneeskunde 12/2003; 147(46):2275-81.