Randomized clinical trial: effect of the 5-HT4 receptor agonist revexepride on reflux parameters in patients with persistent reflux symptoms despite PPI treatment.

BACKGROUND: Approximately, 20-30% of patients with gastro-esophageal reflux disease (GERD) experience persistent symptoms despite treatment with proton pump inhibitors (PPIs). These patients may have underlying dysmotility; therefore, targeting gastric motor dysfunction in addition to acid inhibition may represent a new therapeutic avenue. The aim of this study was to assess the pharmacodynamic effect of the prokinetic agent revexepride (a 5-HT4 receptor agonist) in patients with GERD who have persistent symptoms despite treatment with a PPI. METHODS: This was a phase II, exploratory, multicenter, randomized, placebo-controlled, double-blind, parallel-group study in patients with GERD who experienced persistent symptoms while taking a stable dose of PPIs (ClinicalTrials.gov identifier: NCT01370863). Patients were randomized to either revexepride (0.5 mg, three times daily) or matching placebo for 4 weeks. Reflux events and associated characteristics were assessed by pH/impedance monitoring and disease symptoms were assessed using electronic diaries and questionnaires. KEY RESULTS: In total, 67 patients were enrolled in the study. There were no significant differences between study arms in the number, the mean proximal extent or the bolus clearance times of liquid-containing reflux events. Changes from baseline in the number of heartburn, regurgitation, and other symptom events were minimal for each treatment group and no clear trends were observed. CONCLUSIONS & INFERENCES: No clear differences were seen in reflux parameters between the placebo and revexepride groups.

Effect of baclofen on the acid pocket at the gastroesophageal junction.

Previous studies established that a pocket of highly acidic gastric juice is present postprandially at the gastroesophageal junction in man. The GABA-B agonist baclofen inhibits postprandial reflux events through its effects on the lower esophageal sphincter (LES). The aim of the current study was to investigate whether baclofen would affect the location and the extent of the postprandial acid pocket in healthy volunteers. Twelve healthy volunteers underwent acid pocket studies on two different occasions, at least 1 week apart. LES position was determined preprandially with pull-through manometry. Dual pH electrode and manometry probe stepwise pull-through (1 cm/minute, LES-10 to +5 cm) was performed at 30-minute intervals for 150 minutes, with administration of placebo or baclofen 40 mg after the first and ingestion of a liquid meal after the second pull-through. After placebo, a significant drop in intragastric gastric pH was present at the gastroesophageal junction after the meal, reflecting the acid pocket, and this was associated with a drop in LES pressure. Baclofen did not affect the presence of the acid pocket, but prevented the postprandial drop in LES pressure, and the extent of the acid pocket above the upper margin of the manometrically located LES was significantly decreased by baclofen (1.6 ± 0.7 vs. 0.3 ± 0.4 cm at 60 minutes, 2.2 ± 0.6 vs. 0.2 ± 0.6 at 90 minutes, and 1.5 ± 0.5 vs. 0.7 ± 0.7 cm at 120 minutes, all P < 0.05). Baclofen does not alter the intragastric acid pocket, but limits its extension into the distal esophagus, probably through an increase in postprandial LES pressure.

Patients with esophageal motility disorders show distinct patterns based on axial force measurements.

BACKGROUND: Using manometry, the classification of motility-related disorders in the esophagus is vague and overlapping. We present a new method, which combines manometry and axial force measurements in a single catheter. AIM: The aim was to examine the manometric and axial force recordings during swallows. METHODS: Recordings from 20 patients suffering from diffuse esophageal spasms (DES) (8), achalasia (5) and other diseases including gastro-oesophageal reflux (7) were compared to recordings made in ten healthy subjects. The probe was capable of measuring axial force 6.5-cm proximal to the lower esophageal sphincter (LES) and pressures 8-, 10- and 12-cm proximal to the LES. After insertion, five dry and five wet swallows were made. Swallows were repeated with 0, 2, 4 and 6 ml of water in a bag mounted distal to the axial force recording site. Each contraction was analysed for duration and amplitude, and was categorised according to its configuration. RESULTS: The number of failed contractions measured with axial force was lower for the achalasia (P < 0.001) and DES groups (P < 0.001) compared to the healthy volunteers. The number of multi-peaked contractions was unchanged for the achalasia and DES groups while it increased for the group of healthy volunteers. On several occasions a negative traction force was encountered though the manometric pattern appeared normal. CONCLUSIONS: Measurements of axial force generated by primary peristalsis provide additional information about esophageal neuromuscular function in different diseases that is not demonstrable with manometry alone.

A double-blind sham-controlled study of the effect of radiofrequency energy on symptoms and distensibility of the gastro-esophageal junction in GERD.

OBJECTIVES: Several studies have reported symptom relief in gastro-esophageal reflux disease (GERD) patients treated with radiofrequency delivery (Stretta procedure) at the gastro-esophageal junction (GEJ), but the mechanism underlying this improvement is unclear. The objective of this study was to test the hypothesis that Stretta alters GEJ resistance. METHODS: We conducted a double-blind randomized cross-over study of Stretta and sham treatment. Consecutive GERD patients were included in the study. The study was conducted in a tertiary care center. Patients underwent two upper gastrointestinal endoscopies with 3 months interval, during which active or sham Stretta treatment was performed in a randomized double-blind manner. Symptom assessment, endoscopy, manometry, 24-h esophageal pH monitoring, and a distensibility test of the GEJ were done before the start of the study and after 3 months. RESULTS: Barostat distensibility test of the GEJ before and after administration of sildenafil was the main outcome measure. In all, 22 GERD patients (17 females, mean age 47±12 years) participated in the study; 11 in each group. Initial sham treatment did not affect any of the parameters studied. Three months after initial Stretta procedure, no changes were observed in esophageal acid exposure and lower esophageal sphincter (LES) pressure. In contrast, symptom score was significantly improved and GEJ compliance was significantly decreased. Administration of sildenafil, an esophageal smooth muscle relaxant, normalized GEJ compliance again to pre-Stretta level, arguing against GEJ fibrosis as the underlying mechanism. CONCLUSIONS: The limitation of this study was reflux evaluation did not include impedance monitoring. In this sham-controlled study, Stretta improved GERD symptoms and decreased GEJ compliance. Decreased GEJ compliance, which reflects altered LES neuromuscular function, may contribute to symptomatic benefit by decreasing refluxate volume.

Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers.

There are limited data concerning the effects of 5-HT(1A) receptor activation on esophageal motility. Sumatriptan, a 5-HT(1A) receptor agonist, was recently reported to enhance esophageal peristalsis after intravenous administration. Buspirone, an orally available 5-HT(1A) receptor agonist, was shown to modulate gastroduodenal motor function. Our aim was to evaluate the effect of buspirone on esophageal motility of healthy volunteers. On two separate visits, 20 healthy volunteers aged 21-29 years (nine women) underwent esophageal manometry before and 10, 30, and 60 minutes after the administration of buspirone 20-mg or placebo capsule, according to a double-blind crossover design. At each time point, we compared buspirone and placebo effects on: resting pressure of the lower esophageal sphincter (LES); residual pressure and duration of LES relaxation; amplitude, duration, and onset velocity of esophageal body contractions, during 10 swallows of 5 mL of water. Significant analysis of variance differences (P < 0.05) are presented as mean ± standard deviation. Buspirone significantly increased mean distal esophageal wave amplitude (151 vs. 87 mmHg, P < 0.05) and duration (6.1 vs. 4.2 seconds, P < 0.05). Similarly, buspirone significantly increased mean LES resting pressure (26 vs. 21 mmHg, P < 0.05) and mean residual LES pressure (7.9 vs. 2 mmHg, P < 0.05), whereas reduced mean LES relaxation duration (7.2 vs. 8.0 seconds, P < 0.05) and mean distal onset velocity (7.6 vs. 14.7 cm/second, P < 0.05). Buspirone enhances esophageal peristalsis and LES function in healthy volunteers. Further study is warranted on the effects of buspirone on esophageal function and symptoms in patients with ineffective esophageal motility.

Gastric emptying and different types of reflux in adult patients with cystic fibrosis.

BACKGROUND: Increased gastro-oesophageal reflux (GER) is common in patients with cystic fibrosis (CF). Previous studies showed delayed gastric emptying (GE) and a high prevalence of bile acids in saliva suggesting duodenogastro-oesophageal reflux (DGER). AIM: To assess different types of reflux (acid, weakly acidic and bile) and their relationship with rate of GE in adult CF patients. METHODS: Gastric emptying was assessed in 33 CF patients using breath tests, reflux was monitored in 42 patients using impedance-pH-metry and 14 CF patients underwent combined impedance-pH-Bilitec monitoring. RESULTS: Delayed GE was found in 33%, increased GER (predominantly acid) in 67% and pathological DGER in 35% of the CF patients. There was a significant correlation between oesophageal bile and acid exposure (P < 0.0001, r = 0.85). Patients with increased DGER had a higher proximal extent of reflux compared to those without DGER [17 (9-35) vs. 5 (1-12), P = 0.04]. There was no correlation between GE and reflux parameters, however, in a subgroup of 10 patients studied by impedance-pH-Bilitec and GE, there was a strong correlation between GE rate and bile exposure (P = 0.005, r = 0.83). CONCLUSIONS: Delayed gastric emptying is present in 1/3 of patients with cystic fibrosis. There is a subgroup of these patients with both delayed gastric emptying and increased acidic duodenogastro-oesophageal reflux with high proximal extent and risk of aspiration. Controlled studies should be performed to evaluate the effect of prokinetics or antireflux surgery on the clinical cystic fibrosis evolution in these patients.

Increasing body weight enhances prevalence and proximal extent of reflux in GERD patients 'on' and 'off' PPI therapy.

BACKGROUND: Increased body weight is associated with higher intragastric pressure. Proximal extent of reflux is a determinant of symptoms in patients with gastro-esophageal reflux disease (GERD). We aimed to investigate the association between body mass index (BMI) and abdominal circumference on the incidence and proximal extent of reflux. METHODS: A total of 95 patients [37 men, age 51(16-82) years] with typical and/or atypical GERD symptoms underwent 24 h impedance-pH monitoring. Forty-nine patients were studied 'off' and 46 'on' proton pump inhibitors (PPI) treatment. Reflux was classified as acid (pH < 4) or weakly acidic (pH 4-7). Proximal extent was defined as the number of reflux events reaching ≥15 cm above the lower esophageal sphincter. Body mass index and abdominal circumference (cm) were assessed. KEY RESULTS: In patients 'off' PPI, there was a correlation between BMI and esophageal acid exposure (ρ = 0.53, P < 0.001), volume exposure (ρ = 0.48, P < 0.001), total number of reflux events (ρ = 0.47, P < 0.001) and number of acid reflux events (ρ = 0.49, P < 0.001). In patients 'on' PPI there was a correlation between BMI and esophageal acid exposure (ρ = 0.32, P = 0.03), volume exposure (ρ = 0.46, P < 0.01) and total number of reflux events (ρ = 0.33, P = 0.03). Similar correlations were found between abdominal circumference and reflux. A correlation between BMI and proximal extent of reflux was present in patients 'off' PPI (ρ = 0.32, P = 0.03). In patients 'on' PPI, we found a correlation between abdominal circumference and proximal extent (ρ = 0.31, P = 0.03). CONCLUSIONS & INFERENCES: Body mass index and abdominal circumference may contribute to GER and its proximal extent, in patients 'on and 'off' PPI. Further studies investigating the role of weight reduction in the control of GERD symptoms are warranted.

Modulation of the postprandial acid and bile pockets at the gastro-oesophageal junction by drugs that affect gastric motility.

BACKGROUND: Previous studies have established the presence of a postprandial acid pocket at the gastro-oesophageal junction. AIMS: To investigate whether altering gastric motility would affect the location and the extent of postprandial acid pockets in healthy volunteers and also to study the presence of bile in this pocket. METHODS: A total of 16 healthy volunteers underwent pH and Bilitec probe stepwise pull-through to measure regional differences in pH and bile absorbance before and 10, 30 and 50 min after a liquid meal. At the start of the meal, saline, erythromycin or sumatriptan was administered. RESULTS: After saline, ingestion of a meal induced an acid pocket, with a mean pH drop of 2.26 (compared to 0.25 before the meal, P < 0.05) and a nadir pH of 2.71. The acid pocket persisted 30 and 50 min postprandially (pH drops 1.59 and 1.68 and nadir pH 3.17 and 2.52 respectively). Compared with saline, erythromycin significantly suppressed the pH drop and nadir pH (on average 0.66 and 3.4 at 10 min; comparable patterns at 30 and 50 min). After sumatriptan a significantly lower nadir pH was observed at 30 and 50 min (respectively 2.02 and 1.74, P < 0.05 compared with saline). A postprandial bile pocket was noted in 50% of pull-throughs after saline, compared to 78% after erythromycin and 31% after sumatriptan. CONCLUSIONS: The presence of a bile pocket in a subset of the subjects confirms the heterogeneity of postprandial intragastric contents. Erythromycin disrupts the acid pocket but increases the presence of bile, while sumatriptan has opposite effects.

Review article: the pathophysiology, differential diagnosis and management of rumination syndrome.

BACKGROUND: Rumination syndrome, characterised by the effortless, often repetitive, regurgitation of recently ingested food into the mouth, was originally described in children and in the developmentally disabled. It is now well-recognised that rumination syndrome occurs in patients of all ages and cognitive abilities. AIM: To review a scholarly review on our current understanding of the rumination syndrome. METHODS: The review was conducted on the basis of a medline search to identify relevant publications pertaining to the pathophysiology, clinical diagnosis and management of rumination syndrome. RESULTS: The Rome III consensus established diagnostic criteria for rumination syndrome in adults, children and infants. A typical history can be highly suggestive but oesophageal (high resolution) manometry/impedance with ingestion of a meal may help to distinguish rumination syndrome from other belching/regurgitation disorders. The pathophysiology is incompletely understood, but involves a rise in intra-gastric pressure, generated by a voluntary, but often unintentional, contraction of the abdominal wall musculature, at a time of low pressure in the lower oesophageal sphincter, causing retrograde movement of gastric contents into the oesophagus. To date, controlled trials in the treatment rumination syndrome are lacking. The mainstay of treatment for rumination syndrome is explanation and behavioural treatment which consists of habit reversal techniques that compete with the urge to regurgitate. Chewing gum, prokinetics, baclofen and even antireflux surgery have been proposed as adjunctive therapies, but high quality studies are generally lacking. CONCLUSIONS: Rumination is an under-recognised condition with incompletely understood pathophysiology. Behavioural therapy seems effective, but controlled treatment trials are lacking.

Bile acids aspiration reduces survival in lung transplant recipients with BOS despite azithromycin.

Azithromycin (AZM) improved bronchiolitis obliterans syndrome (BOS) and reduced aspiration in lung transplant (LTx) recipients. We hypothesize that AZM could improve graft and overall survival more efficiently in LTx patients with BOS who have bile acid (BA) aspiration by protecting against the aspiration-induced progression of BOS. The goal was to compare FEV(1) (% baseline), BOS progression and overall survival in LTx recipients treated with AZM for BOS, both with versus without BA aspiration. Therefore, LTx recipients treated with AZM for BOS were recruited and broncho-alveolar lavage (BAL) samples were analyzed for the presence of BA and neutrophilia before the start of AZM treatment. Short-term effect of AZM on FEV(1) and BAL neutrophilia was assessed, progression of BOS and survival were followed-up for 3 years and results were compared between patients with/without BA aspiration. 19/37 LTx patients had BA in BAL. BA aspiration predisposed to a significantly worse outcome, in terms of decline in FEV(1) , progression of BOS ≥ 1 and survival. AZM does not seem to protect against the long-term allograft dysfunction caused by gastroesophageal reflux (GER) and aspiration and an additional treatment targeting aspiration may be indicated in those LTx patients.

Effect of rimonabant on oesophageal motor function in man.

BACKGROUND: Cannabinoid type 1 (CB1) receptors are implicated in the control of transient lower oesophageal sphincter relaxations (TLESRs) in animals. In man, it is unclear whether CB1 receptors are involved in the control of oesophageal function. AIM: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. METHODS: Twelve healthy volunteers underwent two oesophageal manometry studies with administration of wet swallows and a meal after 3 days' premedication with placebo or rimonabant 20 mg. RESULTS: Rimonabant did not significantly alter preprandial LES pressure (21.1±4.0 vs. 17.3±3.0 mmHg, N.S.), but postprandial LES pressures were significantly enhanced (9.9±1.9 vs.17.1±2.7 mmHg in the first and 10.0±1.4 vs. 19.3±3.6 mmHg in the second postprandial hour, both P<0.05). Swallow-induced relaxations and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contractions at all time points (e.g. 5.0±0.3 vs. 8.0±0.3s preprandially and 5.0±0.2 vs. 8.2±0.3s at 60 min postprandially, both P<0.01). The number of postprandial TLESRs (3.1±0.5 vs. 1.2±0.5, P<0.05) and acid reflux episodes (1.4±0.2 vs. 0.3±0.1, P<0.05) were significantly lower after rimonabant. CONCLUSION: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and decreases TLESRs in healthy subjects.

The relationship between gastroesophageal reflux and cough in children with chronic unexplained cough using combined impedance-pH-manometry recordings.

INTRODUCTION: Assessment of the reflux-cough association in children is challenging. Esophageal (impedance) pH recording is sensitive to recognize reflux. However, cough recorded by an event marker, possibly lacks accuracy. We aimed to study the exact time relationship between reflux and cough in children with chronic cough. METHODS: Twenty-six children (12 boys; 1-10.5 years) with chronic unexplained cough underwent ambulatory impedance-pH-manometry recordings. Manometry was used for precise cough recognition. Reflux was assessed with impedance-pH monitoring and defined as acid (pH <4), weakly acidic (WA) (pH 4-7), weakly alkaline (WALK) (pH ≥7), or acid only (pH <4 for ≥4 sec without impedance pattern). Cough was considered "induced by" reflux, if it started ≤2 min after reflux. The Symptom Association Probability (SAP) was calculated and considered positive if >95%. Cough-induced reflux if it occurred 30 sec before the reflux event. RESULTS: Impedance-pH detected 30 (21-52) reflux episodes/patient (55.2% acid, 41.5% WA, and 3.3% WALK). Additionally 59 acid only events were identified [1 (0-21)/patient]. Manometry detected 47 (5-203) cough bursts/patient. Reflux-cough was found in 22/26 patients. Ten patients had a +SAP for reflux-cough (one acid, six WA, and three acid + WA gastroesophageal reflux [GER]), of which nine had a normal acid exposure. Six out of 10 patients with +SAP using manometry had a +SAP using the event marker. Cough-reflux was detected in 19 patients [3 (0-7)/patient]. Only a small fraction of the esophageal acid exposure [9.6 (0.4-31.8%)] was secondary to cough. CONCLUSION: Both acid and WA GER may precede cough in children with unexplained cough, but cough does not induce GER. Objective cough recording improves symptom association analysis.

The effects of itopride on oesophageal motility and lower oesophageal sphincter function in man.

BACKGROUND: Itopride is a new prokinetic agent that combines antidopaminergic and cholinesterase inhibitory actions. Previous studies suggested that itopride improves heartburn in functional dyspepsia, and decreases oesophageal acid exposure in gastro-oesophageal reflux disease. It remains unclear whether this effect is due to effects of itopride on the lower oesophageal sphincter (LES). AIMS: To study the effects of itopride on fasting and postprandial LES function in healthy subjects. METHODS: Twelve healthy volunteers (five men; 32.6 ± 2.0 years) underwent three oesophageal sleeve manometry studies after 3 days premedication with itopride 50 mg, itopride 100 mg or placebo t.d.s. Drug was administered after 30 min and a standardized meal was administered after 90 min, with measurements continuing to 120 min postprandially. Throughout the study, 10 wet swallows were administered at 30-min intervals, and gastrointestinal symptoms were scored on 100 mm visual analogue scales at 15-min intervals. RESULTS: Lower oesophageal sphincter resting pressures, swallow-induced relaxations and the amplitude or duration of peristaltic contractions were not altered by both doses of itopride, at all time points. Itopride pre-treatment inhibited the meal-induced rise of transient LES relaxations (TLESRs). CONCLUSIONS: Itopride inhibits TLESRs without significantly affecting oesophageal peristaltic function or LES pressure. These observations support further studies with itopride in gastro-oesophageal reflux disease.

Treatment of gastro-esophageal reflux disease: the new kids to block.

Refractory gastro-esophageal reflux disease (GERD), defined as persistent symptoms despite proton pump inhibitor (PPI) therapy, is an increasingly prevalent condition and is becoming a major challenge for the clinician. Since non-acidic reflux may be associated with symptoms persisting during PPI treatment, the lower esophageal sphincter (LES), the most important barrier protecting against reflux, has become an important target for the treatment of (refractory) GERD. Preclinical research has identified several receptors that are involved in the control of transient lower esophageal sphincter relaxations (TLESRs), the predominant mechanism of both acid and non-acidic reflux events, and several drugs have now been tested in humans. The GABA(B) agonist baclofen has demonstrated to effectively reduce the rate of TLESRs and the amount of reflux in both GERD patients and healthy volunteers. Nevertheless, the occurrence of central side effects limits its clinical use for the treatment of GERD. Several analogues are being developed to overcome this limitation and have shown promising results. Additionally, metabotropic glutamate receptor 5 (mGluR5) receptor antagonists have shown to reduce both acid and non-acidic reflux in GERD patients and several molecules are currently being evaluated. Although CB(1) antagonists have been shown to reduce TLESRs, they are also associated with central side effects, limiting their clinical applicability. Despite the identification of several potentially interesting drugs, the main challenge for the future remains the reduction of central side effects. Moreover, future studies will need to demonstrate the efficacy of these treatments in patients with refractory GERD.

Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis.

OBJECTIVES: Increased gastroesophageal reflux (GER) is common in children with cystic fibrosis (CF). We studied the occurrence of acid, weakly acidic (WA), and weakly alkaline (WALK) reflux in children with CF and evaluated a possible surrogate marker for risk of gastric content aspiration. PATIENTS AND METHODS: Twenty-four children with CF underwent impedance-pH monitoring for detection of acid (pH < 4), WA (pH 4-7), and WALK-GER (pH > or = 7). In 11 children, cough was objectively recorded with esophageal manometry and the symptom association probability was calculated to determine the reflux-cough relation. Presence of bile acids (BA) was measured in the saliva of 65 patients with CF and 23 healthy children, respectively. RESULTS: Sixteen of the 24 children had increased GER (esophageal acid exposure). The majority of reflux events were acidic in nature. WA reflux was less common and WALK reflux was rare. The sequence reflux-cough was found in 8 of the 11 children and 1 of 11 children had a positive symptom association probability for reflux-cough. The sequence cough-reflux was found in only 3 of the 11 children. Only a small fraction of the total esophageal acid and volume exposure was secondary to cough. Twenty-three of the 65 children with CF had BA in saliva compared with none of the healthy controls. CONCLUSIONS: Although WA-GER is uncommon, acid GER is prevalent in children with CF. It is a primary phenomenon and is not secondary to cough. One third of the children with CF have BA in saliva, which may indicate an increased risk for aspiration. However, the impact of salivary BA and potential aspiration on CF pulmonary disease needs further investigation.

Influence of intra-oesophageal capsaicin instillation on heartburn induction and oesophageal sensitivity in man.

Heartburn is the most typical gastro-oesophageal reflux disease (GERD) symptom. The transient receptor potential vanilloid receptor-1 (TRPV(1)) is a candidate mediator of heartburn. Exposure of TRPV(1) to capsaicin is characterized by activation, followed by desensitization. Our aim was to investigate the effect of intra-oesophageal capsaicin instillation on oesophageal symptom perception (activation) and on sensitivity to oesophageal acid perfusion and oesophageal balloon distention (desensitization). In a first protocol (n = 10), saline or capsaicin solution were instilled in the mid-oesophagus and symptoms were rated at 5-min intervals for 60 min. In a second study (n = 10), oesophageal 0.1 N hydrochloric acid perfusion was performed 60 min after pretreatment with saline, low or high dose capsaicin. In a third study (n = 10), sensitivity to oesophageal balloon distention was determined before and at 30-min intervals up to 90 min after pretreatment with saline, low or high dose capsaicin. Areas under the curve (AUC) for symptom intensities under different conditions were calculated and compared with Kruskal-Wallis test. Oesophageal capsaicin instillation induced transient symptoms of retrosternal and epigastric burning in a dose-dependent fashion. After oesophageal capsaicin or saline instillation, there was no difference in symptom pattern and intensities induced by oesophageal acid perfusion. After oesophageal capsaicin or saline instillation, sensitivity to oesophageal balloon distention and oesophageal compliance were not significantly altered. Oesophageal instillation of the TRPV(1) receptor agonist capsaicin induces symptoms of retrosternal and epigastric burning in a dose-dependent fashion. Pretreatment with capsaicin does not desensitize the oesophagus to acid perfusion or to balloon distention.

The spectrum of motor function abnormalities in gastroesophageal reflux disease and Barrett's esophagus.

Barrett's esophagus has traditionally been regarded as the most severe end of the spectrum of gastroesophageal reflux disease and is of great clinical importance in view of the association with esophageal adenocarcinoma. Studies have documented high levels of esophageal acid exposure in Barrett's esophagus. Various pathogenetic mechanisms underlie this phenomenon. These include abnormalities in esophageal peristalsis, defective lower esophageal sphincter pressures, gastric dysmotility and bile reflux. Whilst these factors provide evidence for an acquired cause of Barrett's esophagus, an underlying genetic predisposition cannot be ruled out. Although the past decade has brought about many new discoveries in the pathogenesis of Barrett's esophagus, it has also added further controversy to this complex disorder. A detailed analysis of the gastrointestinal motor abnormalities occurring in Barrett's esophagus follows, with a review of the currently available literature and an update on this condition that continues to be of interest to the gastroenterologist.

Azithromycin reduces gastroesophageal reflux and aspiration in lung transplant recipients.

Azithromycin (AZI) is a macrolide antibiotic that improves lung function in lung transplant recipients (LTx). Gastroesophageal reflux (GER) has been implicated in the pathogenesis of chronic rejection after LTx. Macrolide antibiotics may affect GER by modifying esophageal and gastric motility. The purpose of this study was to evaluate the effect of AZI on GER and gastric aspiration after LTx. Acid and weakly acidic GER was measured with 24-h pH-impedance monitoring in 47 LTx patients (12 patients "on" AZI). Gastric aspiration was assessed in a separate group of 30 LTx patients before and after AZI by measurements of pepsin and bile acid in bronchoalveolar lavage fluid (BALF). Patients "on" AZI had a significant lower total number of reflux events [41 (30-61) vs. 22.5 (7-37.5)], number of acid reflux events [24 (16-41) vs. 8 (4-18)], esophageal acid exposure [2.9% (0.7-7.3) vs. 0.2% (0.1-2.0)], bolus exposure [0.73% (0.5-1.4) vs. 0.21% (0.12-0.92)], and proximal extent of reflux [14 (9-24) vs. 5 (2-7)]. AZI reduced the concentration of bile acids in BALF without affecting levels of pepsin. LTx patients "on" AZI have less GER and bile acids aspiration. This effect might be due to enhanced esophageal motility and accelerated gastric emptying.

Regional oesophageal sensitivity to acid and weakly acidic reflux in patients with non-erosive reflux disease.

The mechanisms underlying symptoms in non-erosive reflux disease (NERD) remain to be elucidated. Non-erosive reflux disease patients appear to be more sensitive to intraluminal stimula than erosive patients, the proximal oesophagus being the most sensitive. In order to assess regional oesophageal changes in reflux acidity and sensitivity to reflux, according either to the acidity or the composition of the refluxate, combined multiple pH and multiple pH-impedance (pH-MII) was performed in 16 NERD patients. According to multiple pH-metry, 29% and 12% of reflux events reached the middle and proximal oesophagus respectively, and 35% and 19% according to conventional pH-MII (P < 0.05). The per-individual analysis confirmed the difference between the two techniques. According to combined distal and proximal pH-MII, approximately 30% of distal acid reflux became weakly acidic at the proximal oesophagus. In all patients, the frequency of symptomatic refluxes, both acid and weakly acidic, was significantly higher at the proximal, compared with distal oesophagus (25 +/- 8%vs 11 +/- 2% for acid reflux and 27 +/- 8%vs 8 +/- 2% for weakly acidic reflux; P < 0.05). Compared with multiple pH-metry, pH-MII shows a higher sensitivity in the detection of proximal reflux. As approximately 30% of acid reflux becomes weakly acidic along the oesophageal body, to better characterize proximal reflux, in clinical practice, combined proximal pH-impedance monitoring should be used. In NERD patients, the proximal oesophagus seems to be more sensitive to both acid and weakly acidic reflux.

Continuous distal oesophageal acidification decreases postprandial gastric acidity in healthy human subjects.

BACKGROUND: Previously, we hypothesized that exposing the distal oesophagus to acid signals the stomach to decrease gastric acidity. AIM: To test the hypothesis that exposing the distal oesophagus to acid signals the stomach to decrease gastric acidity. METHODS: Twenty-two healthy humans ingested a standard meal containing [(14)C]octanoic acid and [(13)C]glycine over 30 min on 2 separate occasions. Gastric pH was measured for 90 min before and 240 min after the meal. 10 mm HCl was infused continuously at 1 mL/min into either the distal oesophagus or stomach in a 2-way crossover fashion for 60 min before and 240 min after the meal. Gastric emptying of solid and liquid were determined with breath tests. RESULTS: Compared to gastric infusion, oesophageal infusion significantly decreased gastric acidity after the meal, but not before the meal and the magnitude of the decrease varied directly with gastric acidity. Gastric emptying of solid or liquid with oesophageal infusion was not significantly different from that with gastric infusion. CONCLUSIONS: These findings support the hypothesis of the existence of a physiological oesophago-gastric feedback mechanism that might contribute to regulation of postprandial gastric acidity. Oesophageal acidification might decode gastric information and signal the stomach to decrease gastric acidity. Further studies are needed to assess the characteristics of such feedback mechanism in-patients with gastro-oesophageal reflux disease (GERD).