Effects of Antidepressants on Gastric Function in Patients with Functional Dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is a highly prevalent functional bowel disorder. The effects of antidepressant therapy (ADTx) on gastric sensorimotor function in FD patients are poorly understood. AIMS: Determine whether FD and subtypes with abnormalities in gastric function respond differently to ADTx compared to those with normal physiology. METHODS: This multicenter, prospective trial randomized FD patients to 12 weeks of amitriptyline (AMI; 50 mg), escitalopram (ESC; 10 mg), or matching placebo. Demographics, symptoms, psychological distress, gastric emptying, and satiation were measured. Gastric accommodation (GA) using single-photon emission computed tomography imaging was performed in a subset of patients. An intent to treat analysis included all randomized subjects. The effect of treatment on gastric emptying was assessed using ANCOVA. A post hoc appraisal of the data was performed categorizing patients according to the Rome III subgrouping (PDS and EPS). RESULTS: In total, 292 subjects were randomized; mean age=44 yrs. 21% had delayed gastric emptying. Neither antidepressant altered gastric emptying, even in those with baseline delayed gastric emptying. GA increased with ADTx (P=0.02). Neither antidepressant affected the maximal-tolerated volume (MTV) of the nutrient drink test although aggregate symptom scores improved compared to placebo (P=0.04). Patients with the combined EPS-PDS subtype (48%) had a lower MTV on the nutrient drink test compared to the EPS group at baseline (P=0.02). Postprandial bloating improved with both AMI (P=0.03) and ESC (P=0.02). CONCLUSIONS: Amitriptyline (50 mg) improves FD symptoms but does not delay gastric emptying, even in patients with baseline delayed gastric emptying. GA improved with low-dose ADTx; the precise mechanism of action is unknown warranting further study.

Review article: current treatment options and management of functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD), a common functional gastrointestinal disorder, is defined by the Rome III criteria as symptoms of epigastric pain or discomfort (prevalence in FD of 89-90%), postprandial fullness (75-88%), and early satiety (50-82%) within the last 3 months with symptom onset at least 6 months earlier. Patients cannot have any evidence of structural disease to explain symptoms and predominant symptoms of gastroesophageal reflux are exclusionary. Symptoms of FD are non-specific and the pathophysiology is diverse, which explains in part why a universally effective treatment for FD remains elusive. AIM: To present current management options for the treatment of FD (therapeutic gain/response rate noted when available). RESULTS: The utility of Helicobacter pylori eradication for the treatment of FD is modest (6-14% therapeutic gain), while the therapeutic efficacy of proton pump inhibitors (PPI) (7-10% therapeutic gain), histamine-type-2-receptor antagonists (8-35% therapeutic gain), prokinetic agents (18-45%), tricyclic antidepressants (TCA) (response rates of 64-70%), serotonin reuptake inhibitors (no better than placebo) is limited and hampered by inadequate data. This review discusses dietary interventions and analyses studies involving complementary and alternative medications, and psychological therapies. CONCLUSIONS: A reasonable treatment approach based on current evidence is to initiate therapy with a daily PPI in H. pylori-negative FD patients. If symptoms persist, a therapeutic trial with a tricyclic antidepressant may be initiated. If symptoms continue, the clinician can possibly initiate therapy with an anti-nociceptive agent, a prokinetic agent, or some form of complementary and alternative medications, although evidence from prospective studies to support this approach is limited.

Esophageal spasm: demographic, clinical, radiographic, and manometric features in 108 patients.

Diffuse esophageal spasm (DES) remains insufficiently understood. Here we aimed to summarize the demographic, clinical, radiographic, and manometric features in a large cohort of patients with DES. We identified all consecutive patients diagnosed with DES from 2000 to 2006 at Mayo Clinic Florida. The computerized records of these patients were reviewed to extract relevant information. We performed 2654 esophageal motilities during that period. There were 108 patients with esophageal spasm, and 55% were female. Median age was 71 years. The most common leading symptom was dysphagia in 55, followed by chest pain in 31. Weight loss occurred in 28 patients. The median of time from onset of symptoms to diagnosis was 48 months (range 0-480), with a median of time from the first medical consultation to diagnosis of 8 months (range 0-300). The most frequent comorbidities were hypertension and psychiatric problems. At presentation, 81 patients were taking acid-reducing medications, and 49 patients were taking psychotropic drugs. An abnormal esophagogram was noted in 46 of 76 patients with this test available, but most radiographic findings were nonspecific with the typical 'corkscrew' appearance seen in only three patients. Gastroesophageal reflux disease (GERD) was diagnosed by pH testing or endoscopy in 41 patients. We did not find any difference between the rate of simultaneous contractions or esophageal amplitude between patients with a leading symptom of dysphagia and those with chest pain. DES is an uncommon motility disorder that often goes unrecognized for years. Physicians should be aware of the clinical heterogeneity of DES and consider motility testing early in the course of unexplained esophageal symptoms. Given the high prevalence of GERD in DES, the role of GERD and the impact of acid-reducing therapy in DES deserve further study.

Inter-observer agreement for multichannel intraluminal impedance-pH testing.

Twenty-four-hour ambulatory multichannel intraluminal impedance (MII)-pH detects both acid and nonacid reflux (NAR). A computer-based program (Autoscan™, Sandhill Scientific, Highlands Ranch, CO, USA) automates the detection of reflux episodes, increasing the ease of study interpretation. Inter-observer agreement between multiple reviewers and with Autoscan™ for the evaluation of significant NAR with MII-pH has not been studied in the adult population. Twenty MII-pH studies on patients taking a proton pump inhibitor twice daily were randomly selected. Autoscan™ analyzed all studies using the same pre-programmed parameters. Four reviewers interpreted the MII-pH studies, adding or deleting reflux episodes detected by Autoscan™. Positive studies for NAR and total reflux episodes were based on published criteria. Cohen's kappa statistic (κ) evaluated inter-observer agreement between reviewers and Autoscan™ analysis. The average κ for pathologic NAR between reviewers was 0.57 (0.47-0.70), and between reviewers and Autoscan™ was 0.56 (0.4-0.8). When using the total reflux episode number as a marker for pathologic reflux (acid and NAR), the κ score was 0.72 (0.61-0.89) between reviewers, and 0.74 (0.53-0.9) when evaluating total reflux episodes. Two reviewers agreed more often with each other and with Autoscan™ on the number of NAR episodes, while the other two reviewers agreed with each other, but did not agree with either Autoscan™ or the first two reviewers. Inter-observer agreement between reviewers and Autoscan™ for detecting pathologic NAR is moderate, with reviewers either excluding more of the Autoscan™-defined events or excluding fewer events and therefore agreeing with Autoscan™.

Effect of cyclooxygenase-2 inhibitors on gastric emptying and small intestinal transit in humans.

Endogenous prostaglandins regulate smooth muscle activity; prostaglandins and cyclooxygenase (COX) inhibitors influence gastrointestinal motility in inflammatory states such as postoperative ileus in animal models. The objective of this study was to evaluate the effects of two COX-2 inhibitors on gastric emptying and intestinal transit in healthy humans. In a double-blind, placebo-controlled, parallel-group study, 66 healthy volunteers were randomized to one of two commercially available oral COX-2 inhibitors (celecoxib and rofecoxib), cisapride (positive control), or placebo. Following 7 days on therapy, study participants underwent a test of gastric emptying and small bowel transit of liquids and solids using scintigraphy. Data were analysed using Kruskal-Wallis (ANOVA on ranks)and Mann-Whitney rank sum tests. There were significant group effects on transit of solids: gastric emptying (ANOVA, P = 0.005) and small bowel transit (ANOVA, P = 0.056). However, neither COX-2 inhibitor significantly accelerated the liquid or solid gastric emptying or small bowel transit compared with placebo. The positive control, cisapride, accelerated gastric emptying of solids (post-lag slope of gastric emptying, P < 0.05), and small bowel transit of solids (t10%, P = 0.016). At maximum clinically approved dosages, celecoxib and rofecoxib have no significant effects on gastric emptying or small intestinal transit in healthy humans. Cisapride accelerates gastric emptying and small bowel transit in healthy humans.

Successful oesophageal pH monitoring with a catheter-free system.

BACKGROUND: Traditional catheter-based oesophageal pH testing is limited by patient discomfort and the tendency for patients to alter their diet and activities during the study. A catheter-free pH monitoring system (Bravo) designed to avoid these problems has recently become available, but the advantages and limitations of this device have not been fully explored. AIM: To report our initial experience with this new technology. METHODS: The records of consecutive patients undergoing Bravo pH monitoring were reviewed. The squamo-columnar junction was localized endoscopically and the pH capsule was placed 6 cm above this junction. All patients were re-endoscoped immediately following placement to document mucosal attachment. Patients were monitored for 24-48 h and then returned the radiotelemetry recording device. Data were subsequently downloaded to a personal computer. RESULTS: Sixty studies were performed over an 11-month period. In seven of the 60 (12%), the probe did not attach properly, but in six of these a replacement probe was prepared and deployed without difficulty. In one case, the probe could not be attached after two attempts and the procedure was abandoned. During one procedure, the probe was attached to the mucosa at a point 9 cm from the squamo-columnar junction, but a positive test result was obtained. In two cases, the data were not initially retrievable from the recorder, but in one case the manufacturer was able to retrieve the data overnight. Finally, two patients were away from the data recorder for extended periods, resulting in a loss of data, in two cases, but there was sufficient information for interpretation in both studies. Therefore, adequate diagnostic data were obtained in 58 of the 60 (97%) studies. CONCLUSIONS: Catheter-free pH testing is a major advance in patient convenience and comfort. The technical difficulties associated with this new technology are minimal and appear to be no more frequent than those seen with catheter-based systems.

SPECT imaging of the stomach: comparison with barostat, and effects of sex, age, body mass index, and fundoplication. Single photon emission computed tomography.

BACKGROUND: Impaired gastric accommodation may lead to dyspeptic symptoms. A non-invasive method using single photon emission computed tomography (SPECT) has been developed to measure gastric volumes. AIMS AND METHODS: Our aims were: to assess the accuracy of SPECT with three dimensional image analysis to measure balloon volumes in vitro; to compare gastric barostat balloon volumes measured post-meal and post-distension with total gastric volumes measured simultaneously with SPECT; to present normal gastric volume data for healthy adults; and to compare SPECT data in health with symptomatic post-fundoplication patients. RESULTS: In vitro balloon volumes measured by SPECT were highly accurate (R(2)=0.99). When measured simultaneously by gastric barostat and SPECT, postprandial/fasting volume ratios (2.2 (0.12) (mean (SEM)) v 2.3 (0.15), respectively; p=0.6) and post-distension volume ratios (1.4 (0.1) v1.3 (0.1); p=0.2) were highly comparable. In females, postprandial gastric volumes (675 (14) v 744 (20) ml for males; p=0.004) and changes in gastric volumes (464 (14) ml v 521 (20) ml for males; p=0.01) measured by SPECT were significantly lower than in males. No effects of age or body mass index were noted. The postprandial/fasting gastric volume ratio by SPECT was lower in post-fundoplication patients (2.7 (0.2)) than in healthy controls (3.4 (0.1); p=0.003). CONCLUSIONS: SPECT provides a non-invasive estimate of the effect of a meal on total gastric volume that is comparable to changes in balloon volume observed with the gastric barostat. The SPECT technique is promising for investigation of gastric volumes in health and disease and the effects of pharmacological agents.

Rational approach to patients with unintentional weight loss.

Unintentional weight loss is a problem encountered frequently in clinical practice. Weight loss and low body weight have potentially serious clinical implications. Although a nonspecific observation, weight loss is often of concern to both patients and physicians. There are multiple potential etiologies and special factors to consider in selected groups, such as older adults. A rational approach to these patients is based on an understanding of the relevant biologic, psychological, and social factors identified during a thorough history and physical examination. The goal of this article is to discuss the clinical importance, review potential pathophysiology, and discuss specific etiologies of unintentional weight loss that will enable the clinician to formulate a practical stepwise approach to patient evaluation and management.

Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder.

BACKGROUND & AIMS: Prucalopride (PRU) is a selective benzofuran 5-hydroxytryptamine(4)-receptor agonist with gastrointestinal and colonic prokinetic activities. We evaluated the effects of PRU on gastrointestinal and colonic transit in patients with constipation. METHODS: Gastrointestinal and colonic transit were measured over 48 hours in 40 patients who fulfilled modified Rome I criteria for functional constipation. Patients had no evidence of a rectal evacuation disorder. Subjects were randomized to receive a daily dose of 2 or 4 mg PRU or placebo in a double-blind, parallel-group design. Each treatment lasted 7 days. The transit test was performed over the last 48 hours of the study. Effects on gastric emptying, small bowel transit, and colonic transit were analyzed using Kruskal-Wallis and Wilcoxon rank sum tests. RESULTS: Of 61 patients screened, 40 were eligible and randomized. Two patients withdrew because of adverse events. PRU accelerated overall gastric emptying and small bowel transit. PRU tended to accelerate overall colonic transit with significantly faster overall colonic transit and ascending colon emptying with the 4-mg dose. CONCLUSIONS: PRU accelerates transit through the stomach, small bowel, and colon in patients with constipation unassociated with a rectal evacuation disorder.

Cerebral topography of rectal stimulation using single photon emission computed tomography.

Central processing of visceral information in humans is incompletely understood. We aimed to demonstrate the feasibility of single photon emission computed tomography (SPECT) and to quantitate the changes in regional cerebral blood flow during rectal distension. Ten healthy volunteers underwent randomized sham and active rectal distensions on separate days, during which cerebral blood flow was assessed by intravenous technetium-99m ethyl cysteinate dimer ((99m)Tc-ECD) SPECT. Three-dimensional coregistration of brain images was used to quantitate activation in four preselected cerebral foci and two control regions. Paired analysis compared blood flow during sham and active distensions. There was increased right anterior cingulate gyrus activity (6.5 +/- 2.9%, P = 0.03) with active rectal distension. A 5.4 +/- 2.4% reduction in blood flow in the superior parieto-occipital control region (P = 0.04) suggested blood "redistribution" during stimulation. Marked variability in activation of the frontal cortex, thalamus/basal ganglia complex, and mesiotemporal lobe was noted. Thus rectal distension increases activity in the right anterior cingulate gyrus on average; other foci of cerebral activation are quite variable, suggesting a lack of specific cerebral projections during rectal stimulation.

Nutritional management of chronic intestinal pseudo-obstruction.

Chronic intestinal pseudo-obstruction (CIP) is a gastrointestinal motility disturbance characterized by recurrent episodes of postprandial nausea and bloating in the absence of mechanical obstruction of the small bowel or colon. Weight loss and severe malnutrition are often seen in advanced stages of the disorder. This article discusses the nutritional management of patients with CIP, focusing on general dietary as well as enternal and parenternal nutritional support. Enteral access methods and various enteral formulas used in CIP are also discussed.

Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans.

BACKGROUND: Prucalopride (R093877) is a selective and specific 5HT4 agonist, the first of a new chemical class of benzofurans, with gastrointestinal prokinetic activities in vitro. AIMS: To evaluate the effects of prucalopride on gastrointestinal and colonic transit. METHODS: A validated scintigraphic technique was used to measure gastrointestinal and colonic transit over 48 hours in 50 healthy volunteers. For seven days, each subject received a daily dose of 0. 5, 1, 2, or 4 mg prucalopride, or placebo in a double blind, randomised fashion. The transit test was performed over the last 48 hours. RESULTS: There were significant accelerations of overall colonic transit at 4, 8, 24, and 48 hours (p<0.05) and proximal colonic emptying t1/2 (p<0.05). The 0.5, 2, and 4 mg doses of prucalopride were almost equally effective and accelerated colonic transit compared with placebo. Prucalopride did not significantly alter gastric emptying (p>0.5) or small bowel transit (overall p=0. 12). The medication appeared to be well tolerated during the seven day treatment of healthy subjects. CONCLUSION: Prucalopride accelerates colonic transit, partly by stimulating proximal colonic emptying, but does not alter gastric or small bowel transit in healthy human subjects. Prucalopride deserves further study in patients with constipation.

Predicting the presence of choledocholithiasis in patients with symptomatic cholelithiasis.

OBJECTIVES: Accurate preoperative prediction of choledocholithiasis is essential in order to minimize patient risk and curtail health care expenditures. This study was designed to identify independent risk factors for choledocholithiasis in patients who had undergone cholecystectomy for symptomatic cholelithiasis and to develop a predictive model based on those factors. METHODS: The charts of 1264 consecutive patients who had undergone cholecystectomy at one of three North Carolina hospitals between January 1, 1989 and December 31, 1991 were reviewed; 465 of these patients had confirmed presence or absence of choledocholithiasis by cholangiography and/or common bile duct exploration and were eligible for analysis. Candidate predictor variables included age and maximum preoperative values for each of the following: temperature, alkaline phosphatase, bilirubin, AST, amylase, white blood cell count, and common bile duct diameter. Model development and validation were conducted using standard data-splitting (60% "training," 40% "test") and logistic regression techniques. RESULTS: Choledocholithiasis was confirmed in 115 (25%) of the 465 eligible patients. Univariate analysis identified bilirubin, common bile duct diameter, AST, temperature, alkaline phosphatase, and age as predictors. Multivariable analysis subsequently identified bilirubin, common bile duct diameter, AST, alkaline phosphatase, and age as independent predictors of choledocholithiasis. A final model containing these variables (except age, whose contribution to the model was small) accurately predicted choledocholithiasis (c-index = 0.76). CONCLUSIONS: Accurate estimates of choledocholithiasis risk can be made using maximum preoperative bilirubin, common bile duct diameter, AST, and alkaline phosphatase values. Use of the model may help physicians select those patients with symptomatic cholelithiasis who would most likely benefit from further investigation to exclude choledocholithiasis.

Evidence for indirect dietary regulation of cholecystokinin release in rats.

Food ingestion stimulates cholecystokinin (CCK) release from the proximal intestine, but the mechanisms involved are not well understood. To investigate this effect in vivo in intact rats, plasma CCK was measured after orogastric feeding of proteins, protein hydrolysates, amino acids, glucose, and starch. Intact proteins were the only nutrients to stimulate CCK release. The possibility of direct interaction between different dietary constituents and intestinal CCK-secreting endocrine cells was then examined using a perfusion system containing isolated mucosal cells from the rat duodenojejunum. The functional validity of this system was established by demonstrating that monitor peptide and bombesin both stimulated CCK release in a dose-dependent manner. The stimulatory effect of bombesin required extracellular calcium and was not inhibited by addition of tetrodotoxin. Perifusion of proteins, protein digests, and carbohydrates did not stimulate CCK release. These results indicate that proteins stimulate CCK release postprandially via an indirect mechanism, most likely related to inhibition of intraluminal trypsin. Perifusion of dispersed mucosal cells constitutes a reproducible model to investigate hormonal and peptidergic regulation of CCK release in vitro.

Role of calcium in monitor peptide-stimulated cholecystokinin release from perifused intestinal cells.

Monitor peptide stimulates cholecystokinin (CCK) release from the intestine, but the cellular mechanisms responsible for this effect are uncertain. In the present study, the roles of membrane potential difference and calcium influx in monitor peptide-mediated CCK release were examined in a perifusion system containing isolated mucosal cells from the rat duodenum. This method represents an in vitro system in which CCK-releasing cells can be challenged with secretagogues or other maneuvers to study the dynamics of hormone secretion. High concentrations of KCl (50 mM), which reduce electrical potential difference across the cell membrane, caused the release of CCK. This effect was inhibited by the calcium channel blocker MnCl2. Monitor peptide stimulated CCK release in a dose-dependent manner at concentrations from 3 x 10(-12) to 3 x 10(-8) M. The requirement for extracellular calcium in secretagogue-stimulated release of CCK was investigated using ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), a calcium chelator, and MnCl2. A calcium-free environment supplemented with 2 mM EGTA completely inhibited CCK secretion in response to stimulatory doses of monitor peptide. CCK secretion was restored when calcium was reintroduced into the system. Similarly, MnCl2 completely blocked monitor peptide-stimulated CCK release. These data indicate that membrane depolarization and monitor peptide stimulate the release of CCK through calcium-dependent mechanisms, suggesting that increases in intracellular calcium within CCK cells are likely to be important in CCK release.