Transient Lower Esophageal Sphincter Relaxations Research Articles

Reflux symptoms and obesity.

In the paper titled “Assessment of the relationship between reflux and body mass index with different regression models” Pourhoseingholi et al (1), report the results of a population based cross sectional case controlled study (1). The study investigates the relationship between body mass index (BMI) and reflux symptoms. The authors report that they found no correlation between BMI and reflux symptoms using 3 different statistical tools. On initial reflection this study appears to be contradicting the widely accepted belief that reflux is more prevalent in people with high BMI (2). Western population are aging and facing a relentless increase in the prevalence of obesity. Population studies from the United States suggest 15% of adults aged between 20 and 75 years are obese. Furthermore the incidence of obesity increased at an amazing 5 % per year between the early 1992 and 2005. It is anticipated that by 2020, as a result of increased food intake and reduced physical activity, approximately 40% of adults will be obese. Coinciding with this temporal increase in obesity there has been an increase in the prevalence of gastro-oesophageal reflux disease (GORD) and oesophageal cancer (3). It is only natural that investigators would wonder if the increasing prevalence of obesity is contributing to the increasing prevalence of these two conditions. The pathophysiology of GORD has been extensively studies. Any condition that compromises integrity of the lower oesophageal sphincter will predispose to the reflux of gastric contents into the oesophagus and the development of GORD. GORD is associated with the presence of a hiatus hernia, increased frequency of transient lower oesophageal sphincter relaxation and a weak lower oesophageal sphincter basal tone. GORD can be diagnosed by questionnaires, endoscopy and oesophageal manometry and pH studies. Oesophageal manometry and pH studies have shown that obesity is associated with increased exposure of the oesophagus to gastric acid reflux (4). Studies have also shown that obese patients have an increased frequency of transient lower oesophageal relaxations and a weaker lower oesophageal sphincter compared to non-obese individuals. It thus seems very plausible that obesity predisposes to GORD. These clinical studies have been supported by epidemiological studies. These have confirmed an association between obesity and GORD in a white population, with a progressive increase in the proportion of subjects reporting GORD symptoms as BMI increased (5). GORD symptoms are associated with the presence of Barrett’s oesophagus (BO) and the development of oesophageal adenocarcinoma (OA). The incidence of oesophageal adenocarcinoma has been progressively increasing in Western populations. Studies have investigated obesity as a risk factor for both BO and OA. Studies have suggested that obesity predisposes to both BO and OA in North American populations but the results of similar studies investigating adenocarcinoma of the gastric cardia have been conflicting (3). Before we consider the conclusions from this study, we must first look at the differences between this study and many of the studies that have previously been reported from Western populations. The study used a survey in the general population - subjects were not recruited from hospital clinics. The population surveyed was also young. Lastly we know that obesity is less prevalent in Iranian populations than in many Western populations. We may conclude that in a young population, with a low prevalence of obesity, as reported in this study, obesity is not a major risk factor for reflux symptoms. Had the authors surveyed an older population, with reflux symptoms and predisposing factors, such as a hiatus hernia, there findings may well have been different. The reader can conclude that there are many risk factors for GORD and that as populations become ‘Westernised’ that the aetiology of GORD in their aging society will change. In 10 years time we may predict that the Iranian population will be older and, perhaps, suffering from the Western obesity epidemic. It will then be interesting to compare the results of this study, current studies in Western populations and Iranian studies performed in an older society.

High‐resolution esophageal pressure topography is superior to conventional sleeve manometry for the detection of transient lower esophageal sphincter relaxations associated with a reflux event

Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-esophageal reflux and are detected during manometric studies using well defined criteria. Recently, high-resolution esophageal pressure topography (HREPT) has been introduced and is now considered as the new standard to study esophageal and lower esophageal sphincter (LES) function. In this study we performed a head-to-head comparison between HREPT and conventional sleeve manometry for the detection of TLESRs. A setup with two synchronized MMS-solar systems was used. A solid state HREPT catheter, a water-perfused sleeve catheter, and a multi intraluminal impedance pH (MII-pH) catheter were introduced in 10 healthy volunteers (M6F4, age 19-56). Subjects were studied 0.5 h before and 3 h after ingestion of a standardized meal. Tracings were blinded and analyzed by the three authors according to the TLESR criteria. In the HREPT mode 156 TLESRs were scored, vs 143 during sleeve manometry (P = 0.10). Hundred and twenty-three TLESRs were scored by both techniques. Of all TLESRs (177), 138 were associated with reflux (78%). High-resolution esophageal pressure topography detected significantly more TLESRs associated with a reflux event (132 vs 119, P = 0.015) resulting in a sensitivity for detection of TLESRs with reflux of 96% compared to 86% respectively. Analysis of the discordant TLESRs associated with reflux showed that TLESRs were missed by sleeve manometry due to low basal LES pressure (N = 5), unstable pharyngeal signal (N = 4), and residual sleeve pressure >2 mmHg (N = 10). The HREPT is superior to sleeve manometry for the detection of TLESRs associated with reflux. However, rigid HREPT criteria are awaited.

Herbs for Gastroesophageal Reflux Disease

Herbal medicines offer many potential ways to help people with gastroesophageal reflux disease (GERD), including by treating the underlying transient lower esophageal sphincter relaxations (TLESR), helping relieve symptoms, and reducing inflammation. Fumaria officinalis (fumitory-of-the-wall) and Chelidonium majus (celandine) are two among many cholagogues that empirically seem to be helpful. Another cholagogue, Artemisia asiatica (Asian wormwood), has been shown experimentally to reduce GERDrelated symptoms. Atropa belladonna (belladonna, deadly nightshade) and other anticholinergics may also correct TLESR. Demulcents, such as alginic acid, Ceratonia siliqua (carob), Ulmus rubra (slippery elm), Althaea officinalis (marshmallow), and Aloe vera (aloe) leaf gel can reduce acute symptoms and heal acid-damaged tissues. Inflammation modulators, such as deglycyrrhizinated licorice, Calendula off icinalis (calendula), Curcuma longa (turmeric), Zingiber off icinale (ginger), Rosmarinus off icinalis (rosemary), and Symphytum off icinale (comfrey) may also help with tissue repair and symptom control. Herbal medicine has much to offer patients with GERD but more clinical research is needed.

Alterations confined to the gastro-oesophageal junction: the relationship between low LOSP, TLOSRs, hiatus hernia and acid pocket

The gastro-oesophageal junction is a specialised segment of the gut designed to prevent reflux of gastric contents into the oesophagus. This task is fulfilled by two structures, i.e. the lower oesophageal sphincter and the crural diaphragm, which generate a high pressure zone. Especially during low pressure at the junction, as in case of long-lasting transient lower oesophageal sphincter relaxations, reflux can occur but mainly if a positive pressure gradient exists between stomach and the oesphagogastric junction. Although patients with gastro-oesophageal reflux disease have increased oesophageal acid exposure compared to controls, the number of transient relaxations is not increased compared to healthy controls. Instead, the risk to have acid reflux is at least doubled in patients, especially in those with a hiatal hernia, most likely as a result of the supradiaphragmatic position of the acid pocket. In hiatal hernia patients, the acid pocket is indeed often trapped in the hernia above the diaphragm. Which factors exactly determine the physical composition (liquid or gas) and the proximal extent of the refluxate however requires further research.

Medical treatment of GORD. Emerging therapeutic targets and concepts

Approximately 20-30% of patients with gastro-oesophageal reflux symptoms report inadequate symptom relief while on PPI therapy. Persisting acid or non-acid reflux can be demonstrated in 40-50% of them suggesting that there is room for anti-reflux therapy in these patients. New anti-reflux compounds aim at decreasing the occurrence of transient lower oesophageal sphincter relaxations (TLOSRs) which represent the main mechanism of all types of reflux. The most promising classes of compounds are GABA(B) agonists and mGluR5 antagonists which have been shown to reduce both reflux episodes and symptoms and are currently under evaluation in phase II and III clinical trials. Compounds that target TLOSR activity represent a promising new therapeutic option for patients who suffer from GORD symptoms. These drugs will probably be developed as add-on therapy in combination with PPIs provided the tolerability and safety issues are resolved.

An algorithm for diagnosis and treatment of refractory GERD

Patients with gastro-esophageal reflux disease (GERD) who are not responding to proton pump inhibitors (PPIs) given once daily are very common. These therapy-resistant patients have become the new face of GERD in clinical practice in the last decade. Upper endoscopy appears to have a limited diagnostic value. In contrast, esophageal impedance with pH testing on therapy appears to provide the most insightful information about the subsequent management of these patients. Commonly, doubling the PPI dose or switching to another PPI will be offered to patients who failed PPI once daily. Failure of such therapeutic strategies is commonly followed by assessment for weakly or residual acidic reflux. There is growing information about the potential value of compounds that can reduce transient lower esophageal sphincter relaxation rate. Esophageal pain modulators are commonly offered to patients with functional heartburn although supportive clinical studies are still missing.

Environmental – Lifestyle related factors

The prevalence of gastro-oesophageal reflux disease (GORD) has been increasing worldwide. This increase is likely associated with the increased prevalence of obesity, the ageing of the population and the decreased prevalence of Helicobacter pylori (Hp) infection. These different environmental factors interact with GORD pathogenesis in a potentially negative way. Oesophago-gastric junction (OGJ) competence, oesophageal clearance mechanisms and reflux causticity are involved in GORD pathophysiology. Obesity alters GORD pathogenesis by disrupting the OGJ and increasing intragastric pressure. Additionally, the number of transient lower oesophageal sphincter relaxations is potentially increased in obese patients. The potential effect of obesity on oesophageal peristalsis and the implication of impaired oesophageal clearance in GORD pathogenesis are still to establish. Ageing also plays an important role in GORD pathogenesis by decreasing lower oesophageal sphincter pressure and impairing oesophageal clearance. However a link between these abnormalities and an increased acid oesophageal exposure has not yet been demonstrated in the elderly. The role of H. pylori and its eradication remain controversial. The type of Hp gastritis may explain the controversial effect. Hp with antral predominant gastritis is responsible for an increased gastric acid secretion and thus promotes GORD. On the opposite spectrum, Hp with diffuse gastritis induces a gastric atrophy and in this particular case, the Hp eradication may restore acid secretion and lead to a more caustic refluxate in patients with predisposing conditions for GORD. The association of GORD and the type of Hp gastritis remains to be confirmed.

Evaluation of the Pharmacokinetic Interaction between Lesogaberan (AZD3355) and Esomeprazole in Healthy Subjects

Background: Transient lower esophageal sphincter relaxations (TLESRs) have been identified as a primary cause of reflux events in patients with gastroesophageal reflux disease (GERD). GABAB receptor agonists such as lesogaberan (AZD3355) have been shown to inhibit TLESRs in healthy subjects and patients with GERD, and, therefore, offer a novel therapeutic add-on strategy to acid suppression for the management of GERD. As lesogaberan is being developed as an add-on treatment for the management of patients with GERD who have a partial response to proton pump inhibitor (PPI) therapy, it is important to rule out any clinically important pharmacokinetic drug-drug interaction between lesogaberan and PPIs.Objective: To evaluate the effect of esomeprazole on the pharmacokinetics and safety of lesogaberan and vice versa.Study Design: This was an open-label, randomized, three-way crossover study. The study was open to healthy adult male and female subjects. The study subjects received treatment with, in random order, lesogaberan (150mg twice daily [dose interval 12 hours]), esomeprazole (40 mg once daily), and a combination of both, during 7-day treatment periods.Main Outcome: The presence or absence of pharmacokinetic interactions between lesogaberan and esomeprazole was assessed by measuring the steady-state area under the plasma concentration-time curves during the dosing interval (AUCτ) and the maximum observed plasma concentration (Cmax) for lesogaberan and esomeprazole.Results: Thirty male subjects (mean age 23.2 years, 97% Caucasian) were randomized to treatment and 28 subjects completed the study (one subject was lost to follow-up, and one subject discontinued due to an adverse event). The 95% confidence intervals of the geometric mean ratios for AUCτ and Cmax of lesogaberan and esomeprazole administered alone and concomitantly were within the recognized boundaries of bioequivalence (0.8–1.25). No new safety concerns were raised during this study. The number of patients with adverse events during treatment with lesogaberan alone (n = 17) and concomitantly with esomeprazole (n = 18) were comparable but higher than with esomeprazole alone (n = 10). Paresthesia (episodic, mild, and transient), pharyngitis, and flatulence were the most frequently reported adverse events.Conclusions: There was no observed pharmacokinetic interaction between lesogaberan and esomeprazole when concomitantly administered to healthy subjects, and concomitant therapy was well tolerated.Trial registration number (clinicaltrials.gov): NCT00684190

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

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). To study the effects of itopride on fasting and postprandial LES function in healthy subjects. 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. 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). Itopride inhibits TLESRs without significantly affecting oesophageal peristaltic function or LES pressure. These observations support further studies with itopride in gastro-oesophageal reflux disease.

Mechanisms of nocturnal gastroesophageal reflux events in obstructive sleep apnea

Obstructive sleep apnea (OSA) is associated with increased nocturnal gastroesophageal reflux (nocturnal GER) events and symptoms. Treatment of OSA with continuous positive airway pressure (CPAP) reduces nocturnal GER in patients with OSA. This study sought to determine the: (1) relationship of nocturnal GER events with apnea/hypopnea and arousal, (2) effect of upper airway obstruction on the barrier function of the lower esophageal sphincter (LES), (3) mechanism of LES failure for each nocturnal GER event and (4) effect of CPAP on LES function during sleep. Eight patients with OSA and nocturnal GER underwent polysomnography with esophageal manometry and pH monitoring. The first half of the night was spent without CPAP and the second half with 10 cmH(2)O CPAP. Baseline LES barrier pressure (P (b)) was low in these patients. When patients were off CPAP, there were 2.7 ± 1.8 nocturnal GER events per hour and 70 ± 39 obstructive respiratory events per hour. There was no direct relationship between the occurrence of GER and obstructive events. While upper airway obstruction did not alter P (b), CPAP tended to increase the nadir P (b) during LES relaxation (LESR) and decreased the duration of LESR. Upper airway obstructive and nocturnal GER events are not directly related. The relatively low P (b) in these OSA patients raises the possibility of weakening of the gastroesophageal junction from repetitive strain associated with obstructed breathing events. The favourable effect of CPAP on nocturnal GER is possibly due to an increase in nadir P (b) and decrease in the duration for which the LES relaxes during swallow-induced and transient LESR.

The Role of Weakly Acidic Reflux in Proton Pump Inhibitor Failure, Has Dust Settled?

Patients that do not respond satisfactorily to standard proton pump inhibitor (PPI) treatment have become the most common presentation of gastro-esophageal reflux disease (GERD) in third referral gastrointestinal practices. The causes of refractory GERD include lack of compliance with treatment, residual acid reflux and weakly acidic reflux, esophageal hypersensitivity and persistent symptoms not associated with reflux. A role for weakly acidic reflux in symptom generation has been proposed since the availability of impedance-pH monitoring. The possible mechanisms by which persistent weakly acidic reflux might contribute to persistent symptoms in patients under PPI treatment may include esophageal distension by increased reflux volume, persistent impaired mucosal integrity (ie, dilation of intercellular spaces) and/or esophageal hypersensitivity to weakly acidic reflux events. To establish a definite role of weakly acidic reflux in refractory GERD, outcome studies targeting this type of reflux are still lacking. Treatment strategies to reduce the number or effect of weakly acidic reflux could involve drugs that decrease transient lower esophageal sphincter relaxations (ie, baclofen or similar), improve oesophageal mucosa resistance or visceral pain modulators. Finally, anti-reflux surgery can be considered, only if a clear symptom-weakly acidic reflux association was demonstrated.

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.

Efficacy, tolerability and pharmacokinetics of a modified release formulation of ADX10059, a negative allosteric modulator of metabotropic glutamate receptor 5: an esophageal pH‐impedance study in healthy subjects

Animal studies show metabotropic glutamate receptor 5 inhibition reduces transient lower esophageal sphincter relaxations and increases lower esophageal sphincter tone. A preliminary, single-day study, demonstrated oral ADX10059 reduced 24-h esophageal acid exposure and clinical symptoms in gastro-esophageal reflux disease (GERD) patients, but had suboptimal tolerability, ascribable to the compound's rapid absorption. This study evaluated ADX10059 modified-release (MR) formulation pharmacokinetics, tolerability, and pharmacodynamics. Randomized, double-blind placebo-controlled study. Three groups of eight healthy, male subjects received placebo (n = 2) or ADX10059 (n = 6) 50, 125 or 250 mg b.i.d. for 6 days. Esophageal pH-impedance was performed on day 1 and day 6 of treatment, for 1-h fasting and for 4 h post refluxogenic meal. Treatment effect was determined by Kruskall-Wallis test and placebo comparison by Wilcoxon rank sum. Following placebo, reflux episodes increased from day 1 to day 6. Significant treatment effect was seen for total esophageal acid exposure (P = 0.048) and postprandial number of weakly acidic reflux episodes (P = 0.041). Significant differences from placebo were seen for 125 mg b.i.d.; 250 mg b.i.d. was not more effective than 125 mg b.i.d. Twice daily ADX10059 MR gave satisfactory 24-h exposure and good tolerability. ADX10059 decreased reflux episodes in healthy subjects. The MR formulation is suitable for longer-term treatment to evaluate symptom control in GERD patients.

Management of gastroesophageal reflux disease that does not respond well to proton pump inhibitors

Patients with gastroesophageal reflux disease (GERD) who are not responding to proton pump inhibitors (PPIs) given once daily are very common. These therapy-resistant patients have become the new face of GERD in clinical practice in the last decade and presently pose a significant therapeutic challenge to the practicing physician. We reviewed newly accumulated information about the management of PPI failure that has been published over the past 2 years. There are diverse mechanisms that contribute to the failure of PPI treatment in GERD patients and they are not limited to residual reflux. Some of the causes of PPI failure may coincide in the same patient. Upper endoscopy appears to have limited diagnostic value. In contrast, esophageal impedance with pH testing on therapy appears to provide the most insightful information about the subsequent management of these patients. Commonly, doubling the PPI dose or switching to another PPI will be offered to patients who failed PPI once daily. Failure of such therapeutic strategies is commonly followed by assessment for residual reflux. There is growing information about the potential value of compounds that can reduce transient lower esophageal sphincter relaxations. Esophageal pain modulators are commonly offered to patients with functional heartburn, although supportive clinical studies are still missing. Management of refractory GERD patients remains an important clinical challenge. Recent studies have cemented the value of impedance-pH testing in pursuing proper treatment. Presently, the most promising therapeutic development for this patient population is transient lower esophageal sphincter relaxation reducers.

Persistent Reflux Symptoms in the Proton Pump Inhibitor Era: The Changing Face of Gastroesophageal Reflux Disease

Given the widespread use of potent acid suppressive therapies and primary caregivers’ increasing comfort with prescribing these medications at high doses, the patient population presenting to gastroenterologists for symptoms of gastroesophageal reflux disease (GERD) has changed. Whereas previous consultation often revolved around the control of erosive disease and other mucosal manifestations of GERD, and terminated with the prescription of proton pump inhibitor (PPI) therapy, gastroenterologists often now only enter the scene after failure of PPI therapy, for symptoms either resistant or only partially responsive to these medications. Because of the high proportion of subjects with esophagitis who are healed with PPI, 1,2 upper endoscopy of such individuals is low yield, 3 with only a small minority demonstrating erosive disease. The care of such patients is challenging. High-quality evidence supporting useful diagnostic testing or alternative effective therapies is largely lacking. However, the number of subjects with GERD symptoms incompletely or nonresponsive to PPI therapies is high, and their utilization of healthcare resources is substantial. The purpose of this mini-review is to examine the definition and epidemiology of esophageal GERD symptoms incompletely responsive to PPI therapy, the potential pathophysiologic mechanisms behind these symptoms, the differential diagnosis and evaluation of such patients, and current and developing therapeutic options.

Evolving drugs in gastroesophageal reflux disease: pharmacologic treatment beyond proton pump inhibitors

Importance of the field: Despite the clinical success of proton pump inhibitors to treat gastroesophageal reflux disease (GERD), for the majority of patients in both gastroenterology and primary care clinics there is still a substantial group of patients (up to 40% in some studies) who do not completely respond symptomatically to a standard dose of proton pump inhibitors (PPIs). Specific explanations for these PPI noncomplete responders included transient lower esophageal sphincter relaxations (TLESRs), sensitivity to weakly acidic and/or alkaline reflux, large volume of reflux and esophageal hypersensitivity. There is a clear need for GERD therapies beyond the PPIs.Areas covered in this review: These drug classes include the GABAB receptor agonists (including lesogaberan and arbaclofen placarbil), mGluR5 receptor antagonists, P-CABs, cholecystokinin2 antagonists and add-on therapies to PPIs including mosapride and rikkunshito.What the reader will gain: Both physicians and patients are eagerly awaiting the development and FDA approval of a new class of anti-GERD medications targeting distinct mechanisms. This article provides information on pharmacologic strategies, clinical trials and side-effect profiles on several of the most promising and heavily researched compounds being developed today for the treatment of GERD symptoms and inflammation. Hopefully, this important research will help a large group of PPI noncomplete responding patients receive symptomatic relief and reduce esophageal inflammation through a unique pharmacologic mechanism in the near future.Take home message: The treatment of GERD has greatly improved with the PPI class of therapy. Despite excellent success, there is a sizeable population of patients who do not have adequate response to therapies directed only at acid suppression. Emerging new pharmacologic treatment options show promise in further advancing the treatment success of GERD.

Effects of Lesogaberan on Reflux and Lower Esophageal Sphincter Function in Patients With Gastroesophageal Reflux Disease

Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind reflux. This study assessed the effects of lesogaberan (AZD3355), a novel gamma-aminobutyric acid type B receptor agonist, on reflux and lower esophageal sphincter (LES) function when used as add-on treatment in patients with reflux symptoms despite proton pump inhibitor (PPI) treatment. In this randomized, double-blind, placebo-controlled, crossover study, patients received lesogaberan (65 mg) or placebo twice on day 1 (morning/evening) and once on day 2 (morning), in addition to existing PPI treatment. Patients consumed a standardized meal 45-60 minutes after morning doses. Ambulatory impedance-pH monitoring was conducted for 24 hours after the first dose on day 1. Stationary manometry and impedance-pH monitoring was conducted for 4 hours after the third dose on day 2. Of 27 randomized patients, 21 were included in the per-protocol efficacy analysis. During the 24 hours after treatment start, lesogaberan reduced the mean number of reflux events by approximately 35% compared with placebo. During the 3 postprandial hours on day 2, lesogaberan reduced the geometric mean number of TLESRs by 25% and increased geometric mean LES pressure by 28% compared with placebo. The most common adverse events were headache (placebo: 11/27 patients; lesogaberan: 8/25 patients) and paresthesia (transient; placebo: 3/27 patients; lesogaberan: 5/25 patients). In patients with reflux symptoms despite PPI treatment, lesogaberan decreased the number of TLESRs and reflux episodes, and increased LES pressure compared with placebo. These findings support further evaluation of lesogaberan as an add-on treatment in patients partially responding to PPIs.

Effect of lesogaberan, a novel GABAB‐receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects

Transient lower oesophageal sphincter relaxations (TLESRs) are a major mechanism behind gastro-oesophageal reflux disease (GERD). To assess the effect of lesogaberan (AZD3355) - a novel peripherally active GABA(B) receptor agonist - on TLESRs. Twenty-four healthy men were enrolled in this single-blind, placebo-controlled, randomized, single-centre, three-period crossover phase 1 study. Subjects were randomized to receive single oral doses of lesogaberan (0.8 mg/kg), baclofen (40 mg) and placebo, separated by washout periods of < or = 7 days. Subjects finished a meal 1 h after the dose. Oesophageal manometry and pH-metry measurements were taken during the 3 h after the meal. Twenty-one subjects completed the study. Compared with placebo, lesogaberan 0.8 mg/kg significantly reduced the number of TLESRs by 36% [geometric mean ratio (GMR): 0.64; 95% confidence interval (CI): 0.51-0.82] and significantly reduced the number of acid reflux episodes (mean reduction: 1.6; 95% CI: 0.34-2.9). Lesogaberan also significantly increased lower oesophageal sphincter (LES) pressure by 39% compared with placebo (GMR: 1.39; 95% CI: 1.18-1.64). Comparable results were observed with baclofen. Similar numbers of adverse events were reported by subjects taking lesogaberan and placebo. Compared with placebo, lesogaberan significantly reduced TLESRs and acid reflux episodes and increased LES pressure.

T1893 Effects of Red Chili, a Natural Capsaicin Receptor Agonist, on Gastroesophageal Reflux (GER) Symptoms and Transient Lower Esophageal Sphincter Relaxations (TLESRs) in Healthy Humans

Capsaicin or TRPV1 receptors have been reported to be increased in the esophagus of patients with non-erosive reflux disease. The effects of red chili, a natural capsaicin agonist, on TLESRs have not been reported. Aim: To investigate the effects of red chili on gastroesophageal reflux symptoms and TLESRs in healthy humans. Methods: After an overnight fast, 8 healthy volunteers (5 males, mean age 31±3 years) underwent high resolution esophageal manometry with ingestion of 2 gm red chili (capsaicin = 1.46 mg) or placebo in capsules, in a randomized double blind cross-over fashion with a one-week washout period. Lower esophageal sphincter pressure monitoring began at 15 minutes before chili or placebo ingestion. All subjects ingested standard liquid meals (250 ml of Ensure®) at 15 minutes after the ingestion of chili or placebo capsules. Lower esophageal sphincter monitoring was continued for 2 hours after the meal ingestion. The TLESRs were defined as the relaxations which fulfilled the 4 following criteria: 1) absent of swallowing between 4 seconds before and 2 seconds after the onset of LES relaxations, 2) relaxation rate of >1 mmHg/second, 3) time from onset to complete relaxation of 10 seconds and fulfilled the last 3 criteria. The number of TLESRs and other esophageal manometry parameters were compared between after placebo and chili ingestion. GER and dyspeptic symptoms were evaluated using 10 cm long visual analog scales. Results: (data were expressed as mean±SEM or median and interquartile range) All subjects completed the studies. After ingestion of red chili, heartburn, acid regurgitation, food regurgitation and abdominal burning symptom scores were significantly increased compared to placebo (2.5±0.9, 1.6±0.4, 2.1±0.4, and 5.9±0.7 vs 0.3±0.3, 0.9±0.2, 0.9±0.2, and 0.5±0.2, respectively, p 0.05). The resting LES pressure (19.8±0.9 vs 19.8±0.7 mmHg) was not significantly different between after chili and placebo ingestions (p>0.05). There was no significant correlation between the number of TLESRs and heartburn, acid regurgitation, or food regurgitation scores (p>0.05). Conclusions: Ingestion of red chili increases GER symptoms and epigastrium burning symptoms in healthy volunteers. However, red chili has no significant effect on TLESRs. This suggests that, in healthy volunteers, red chili modulates GER symptoms by its effect on esophageal sensation rather than on the TLESRs.

551 Effect of Gastric Emptying on Pressure-Flow Dynamics of Oesophago-Gastric Junction

Introduction Oesophago-gastric junction (OGJ) incompetence is a primary determinant of gastrooesophageal reflux disease (GORD) severity. Especially, the pressure-flow gradients across the OGJ during lower oesophageal sphincter (LOS) relaxation have important implications in GORD pathogenesis and subsequent planning of its treatment. Our aim was to evaluate the pressure-flow dynamic changes occurring at GOJ barrier during transient lower oesophageal sphincter relaxation (TLOSRs) and study the impact of gastric emptying after a meal on those events using combined high-resolution manometery and high-resolution impedance monitoring (HRMZ, ManoScan Z™). Methods HRMZ was performed in eight healthy subjects (6M and 2F, 27±7 years) for 4 h after a refluxogenic meal (1000 kcal). Pressure–flow dynamics of OGJ during TLOSR events including their frequency, duration, gastro-oesophageal pressure gradient (GO pressure gradient) and proximal extent of migration of the reflux episodes were computed. Gastric emptying of the meal was assessed by 13C-labelled octanoic acid breath test and gastric emptying lag time, half emptying time and gastric retention time were calculated. Results All subjects completed the study. During TLOSR events there was reciprocal relationship between GE pressure grad. and retrograde flow of gastric contents, the gradient was greatest at the onset of retrograde flow, decreasing progressively as the flow continued and became lowest by the end of flow across the OGJ (GO pressure gradient start of flow=9.5±2.6, peak flow=6.05±2.5 (p= Conclusion Our results suggest HRMZ is effective in elucidating the pressure-flow dynamics of OGJ. The proximal extent of the reflux episode correlates with gastric retention time of the meal; however other gastric emptying parameters did not show significant correlation despite promising trends. Further studies involving GORD patients might give us important insights into the role of OGJ pressure flow dynamics in the pathophysiology of GORD.