Excessive Supragastric Belching Research Articles

Prevalence of behavioral disorders in patients with vonoprazan-refractory reflux symptoms.

Behavioral disorders, such as supragastric belching (SGB) and rumination syndrome (RS), which may be treated by cognitive behavioral therapy, are common in patients with reflux symptoms refractory to proton pump inhibitors (PPI). Vonoprazan (VPZ) has been used as a new type of acid inhibitor in Japan since 2015. We herein investigated the prevalence of behavioral disorders in patients with VPZ-refractory reflux symptoms and attempted to identify predictive factors. We retrospectively analyzed esophagogastroduodenograms, high-resolution manometry, and 24-h multiluminal impedance pH-metry (MIIpH) in patients with VPZ-refractory reflux symptoms (heartburn or regurgitation) receiving 20mg VPZ who underwent these tests at our hospital between January 2015 and April 2020. Patients were divided as follows: non-erosive reflux disease with pathological esophageal acid exposure (NERD), functional heartburn (FH), reflux hypersensitivity (RH), excessive (> 13 per day) SGB, and possible RS based on MIIpH parameters. Among 49 patients, 6 (12.2%) had SGB, 4 (8.2%) possible RS, 29 (59.2%) FH, 9 (18.4%) RH, and 1 (2%) NERD. Possible RS patients had more postprandial non-acid reflux events than FH patients (p < 0.05). The multivariate logistic regression analysis did not identify any predictive factors with statistical significance. More than 20% patients with VPZ-refractory reflux symptoms had behavioral disorders. The use of HRM and MIIpH may be clinically relevant for a better diagnosis and more specific treatment.

Belching in Gastroesophageal Reflux Disease: Literature Review.

Belching is a common phenomenon. However, it becomes bothersome if excessive. Impedance–pH monitoring can classify the belching into two types: gastric belching and supragastric belching (SGB). The former is a physiological mechanism to vent swallowed air from the stomach, whereas the latter is a behavioral disorder. Gastroesophageal reflux disease (GERD) is the most relevant condition in both types of belching. Recent findings have raised awareness that excessive SGB possibly sheds light on the pathogenesis of a part of proton pump inhibitor (PPI) refractoriness in GERD. SGB could cause typical reflux symptoms such as heartburn, regurgitation or chest pain in two ways: SGB-induced gastroesophageal reflux or SGB-induced esophageal distension. In PPI-refractory GERD, it is important to detect hidden SGB as a cause of reflux symptoms since SGB requires psychological treatment instead of high dose PPIs or pain modulators. In the case of PPI-refractory GERD with excessive SGB, recent studies imply that the combination of a psychological approach and conventional treatment can improve treatment outcome.

Identification of Different Phenotypes of Esophageal Reflux Hypersensitivity and Implications for Treatment

Reflux hypersensitivity (RH), a functional esophageal disorder, is detected in 14%-20% of patients who present with typical esophageal symptoms. As many as 40% of patients with RH do not respond to treatment with pain modulators or proton pump inhibitors (PPIs); behavior disorders might contribute to lack of treatment efficacy. We aimed to assess the prevalence of behavioral disorders and their effects on typical reflux symptoms in patients with RH. We performed a retrospective study of 542 patients with PPI-refractory esophageal symptoms (heartburn, regurgitation, or chest pain) or with symptoms that responded to PPI therapy, evaluated for anti-reflux surgery from January 2016 through August 2019 at a single center in London, United Kingdom. We collected data on symptoms, motility, and impedance-pH monitoring and assigned patients to categories of RH (n = 116), functional heartburn (n = 126), or non-erosive reflux disease (n = 300). Of the 116 patients with a diagnosis of RH, 59 had only hypersensitivity, whereas 57 patients (49.2%) had either excessive supragastric belching (SGB, 39.7%), based on 24-hour impedance-pH monitoring, or rumination (9.5%), based on postprandial manometry combined with impedance. The prevalence of SGB and rumination in patients with RH was significantly higher than in patients with functional heartburn (22%; P < .001). Patients with RH and rumination were significantly younger (P = .005) and had the largest number of non-acid reflux episodes (P = .023). In patients with RH with SGB, SGB episodes were associated with 40.6% of marked reflux symptoms (heartburn, regurgitation, or chest pain), based on impedance-pH monitoring. In patients with RH and rumination, 40% of reflux-related symptoms (mostly regurgitation) were due to possible rumination episodes. Almost half of patients with a diagnosis of RH have behavior disorders, including excessive SGB or rumination. Episodes of SGB or rumination are associated with typical reflux symptoms. Segregation of patients with diagnosis of RH into those with vs without behavioral disorders might have important therapeutic implications.

Tu1248 – The Efficacy of Fluoxetine for Treatment of Excessive Supragastric Belching (ESGB)

Tu1248 – The Efficacy of Fluoxetine for Treatment of Excessive Supragastric Belching (ESGB)

Su1081 - Repetitive Belching is Predictive of Supragastric Belching Diagnosis

Introduction Belching is common in gastro-oesophageal reflux disease (GORD). Diaphragmatic breathing can reduce belching and GORD symptoms, but only patients with excessive supra-gastric belching (SGB) responded to this treatment. 24 hour pH-impedance study is the gold standard to diagnose SGB but is expensive and invasive. Our study aimed to identify clinical factors that can predict excessive SGB (>13/day) in GORD patients. Methods We prospectively analysed patients with a belching visual analogue scale (VAS) score ≥6 and a clinical or endoscopic diagnosis of GORD. All patients underwent 24 hour pH-impedance studies off medications. Patients were given questionnaire on belching symptoms, including belching VAS, belching frequency, repetitive nature of belching and ability to control belching. GORD symptoms were evaluated via Reflux Disease Questionnaire (RDQ), somatization scores via PHQ15 and mood disorders via Hospital Anxiety and Depression Scales (HADS). Statistical analysis via independent t-test and Chi2 test were done for univariate analysis, while logistic regression analysis was used for multivariate analysis of clinical factors most predictive of excessive SGB. Results We recruited 36 patients between April 2015 and October 2016 (25 women; mean age 45.5±12.7). 32 patients had excessive SGB, while 4 had predominantly gastric belching on pH-impedance studies. Repetitive belching and RDQ regurgitation score ≥2 were significantly more likely in patients with excessive SGB, but only repetitive belching was significant on multivariate analysis. Repetitive belching on questioning has a sensitivity of 93.4% and specificity of 75% for SGB diagnosis, positive predictive value 96.8% and negative predictive value 60.0%. Conclusions We identified that a simple questioning on the repetitive nature of belching can be used as a screening tool to predict SGB in belching patients, and hence predict response to diaphragmatic breathing exercises.

Treatment of supragastric belching with cognitive behavioral therapy improves quality of life and reduces acid gastroesophageal reflux.

Excessive supragastric belching (SGB) manifests as troublesome belching, and can be associated with reflux and significant impact on quality of life (QOL). In some GERD patients, SGB-associated reflux contributes to up to 1/3 of the total esophageal acid exposure. We hypothesized that a cognitive-behavioral intervention (CBT) might reduce SGB, improve QOL, and reduce acid gastroesophageal reflux (GOR). We aimed to assess the effectiveness of CBT in patients with pathological SGB. Patients with SGB were recruited at the Royal London Hospital. Patients attended CBT sessions focused on recognition of warning signals and preventative exercises. Objective outcomes were the number of SGBs, esophageal acid exposure time (AET), and proportion of AET related to SGBs. Subjective evaluation was by patient-reported questionnaires. Of 51 patients who started treatment, 39 completed the protocol, of whom 31 had a follow-up MII-pH study. The mean number of SGBs decreased significantly after CBT (before: 116 (47-323) vs. after 45 (22-139), P<0.0003). Sixteen of 31 patients were shown to have a reduction in SGB by >50%. In patients with increased AET at baseline, AET after CBT was decreased: 9.0-6.1% (P=0.005). Mean visual analog scale severity scores decreased after CBT (before: 260 (210-320) mm vs. after: 140 (80-210) mm, P<0.0001). Cognitive behavioral therapy reduced the number of SGB and improved social and daily activities. Careful analysis of MII-pH allows identification of a subgroup of GERD patients with acid reflux predominantly driven by SGB. In these patients, CBT can reduce esophageal acid exposure.

Diaphragmatic Breathing Reduces Belching and Proton Pump Inhibitor Refractory Gastroesophageal Reflux Symptoms

In patients with gastroesophageal reflux disease (GERD) and excessive belching, most belches are supragastric, and can induce reflux episodes and worsen GERD. Supragastric belching (SGB) might be reduced with diaphragmatic breathing exercises. We investigated whether diaphragmatic breathing therapy is effective in reducing belching and proton pump inhibitor (PPI)-refractory gastroesophageal reflux symptoms. We performed a prospective study of 36 consecutive patients with GERD refractory to PPI therapy and a belching visual analogue scale (VAS) score of 6 or more, seen at a gastroenterology clinic at a tertiary hospital in Singapore from April 2015 through October 2016. Patients underwent high-resolution manometry and 24-hour pH-impedance studies while they were off PPIs. Fifteen patients were placed on a standardized diaphragmatic breathing exercise protocol (treatment group) and completed questionnaires at baseline, after diaphragmatic breathing therapy, and 4 months after the therapy ended. Twenty-one patients were placed on a waitlist (control subjects), completed the same questionnaires with an additional questionnaire after their waitlist period, and eventually received diaphragmatic breathing therapy. The primary outcome was reduction in belching VAS by 50% or more after treatment. Secondary outcomes included GERD symptoms (evaluated using the reflux disease questionnaire) and quality of life (QoL) scores, determined from the Reflux-Qual Short Form and EuroQoL-VAS. Nine of the 15 patients in the treatment group (60%) and none of the 21 control subjects achieved the primary outcome (P < .001). In the treatment group, the mean belching VAS score decreased from 7.1 ± 1.5 at baseline to 3.5 ± 2.0 after diaphragmatic breathing therapy; in the control group, the mean VAS score was 7.6 ± 1.1 at baseline and 7.4 ± 1.3 after the waitlist period. Eighty percent of patients in the treatment group significantly reduced belching frequency compared with 19% in control subjects (P= .001). Treatment significantly reduced symptoms of GERD (the mean reflux disease questionnaire score decreased by 12.2 in the treatment group and 3.1 in the control group; P= .01). The treatment significantly increased QoL scores (the mean Reflux-Qual Short Form score increased by 15.4 in the treatment group and 5.2 in the control group; P= .04) and mean EuroQoL-VAS scores (15.7 increase in treatment group and 2.4 decrease in the control group). These changes were sustained at 4 months after treatment. In the end, 20 of the 36 patients who received diaphragmatic breathing therapy (55.6%), all with excessive SGB, achieved the primary outcome. In a prospective study, we found a standardized protocol for diaphragmatic breathing to reduce belching and PPI-refractory gastroesophageal reflux symptoms, and increase QoL in patients with PPI-refractory GERD with belching-especially those with excessive SGB.

49 Supra gastric belching symptoms, prevalence and associated disease

Background Supragastric belching (SGB) is considered a behavioural disorder where air is ingested in to eosophagus and immediately expelled again; it can result in symptoms of excessive belching and has a significant impact on quality of life. With the advent of the intraluminal impedance recording technique, it has become possible to monitor the passage of air through the oesophagus, either in ab-oral or ad-oral directions. Aim Determine the prevalence of excessive SGB within our tertiary referral gastrointestinal physiology unit and evaluate the predominant presenting symptoms and examine its association with gastro-esophageal reflux disease and motility disorders. Method Data was collected retrospectively from our data base system, we reviewed 442 reports of 24 hours PH-Impedance and high resolution oesophageal manometry from January 2015 to December 2016. Symptoms were reviewed from patients’ charts. These included the predominant presenting symptom, symptoms of acid reflux and heartburn, regurgitation and dysphagia. Results A total of 98 (22%) patients were found to have excessive SGB. predominant presenting symptom was heartburn (55%), only 18% had pathological acid exposure. Dysphagia was reported in 23% and regurgitation in 7%. only 7% presented with isolated symptom of belching,Esophageal hypomotility was seen in 48%. Conclusions Excessive SGB was common finding in 24 hours PH-impedance manometry studies, the main predominant symptom was heartburn, and there appears to be an association with oesophageal hypomotility and to a lesser extent with gastroeosphageal reflux disease.

Paroxysmal belching: Epileptic or nonepileptic?

The prevalence and localizing value of ictal belching are yet unknown. We present the case of a patient with medically refractory focal epilepsy with simple and complex partial seizures, as well as generalized seizures. One presumed seizure type comprised frequent episodes of repetitive belching. Video-EEG monitoring during these attacks showed no ictal changes. The belching episodes were inducible and terminable through suggestion. The diagnosis of excessive supragastric belching, a previously described psychogenic condition, was made.

Mechanisms of gastric and supragastric belching: a study using concurrent high‐resolution manometry and impedance monitoring

Esophageal impedance monitoring has made it possible to distinguish two types of belches, designated gastric and supragastric. We aimed to compare the esophageal pressure characteristics during supragastric belches and gastric belches using combined high-resolution manometry and impedance monitoring. We included 10 patients with severe and frequent belching. Combined high-resolution manometry and impedance monitoring was performed. Whereas gastric belching was relatively rare in all patients (median incidence 2 per 90-min period), nine of the 10 patients exhibited excessive supragastric belching (36 in 90 min). Supragastric belches were characterized by: (i) movement of the diaphragm in aboral direction and increased esophagogastric junction (EGJ) pressure, (ii) decrease in esophageal pressure, (iii) upper esophageal sphincter (UES) relaxation, (iv) antegrade airflow into the esophagus, and (v) increase in esophageal and gastric pressure leading to expulsion of air out of the esophagus in retrograde direction. In contrast, gastric belches were characterized by: (i) decreased or unchanged EGJ pressure, which was significantly lower than during supragastric belches, (ii) absence of decreased esophageal pressure preceding entrance of air into the esophagus (iii) retrograde airflow into the esophagus, (iv) common cavity phenomenon, and (v) upper esophageal sphincter relaxation after the onset of the retrograde airflow. In gastric belching UES relaxation is a late event, allowing efflux of air that entered the esophagus from the stomach. In most patients with supragastric belching air is brought into the esophagus by movement of the diaphragm in aboral direction, creation of negative esophageal pressure, and UES relaxation.

Impaired health-related quality of life in patients with excessive supragastric belching

Excessive supragastric belching, sometimes called aerophagia, is a rare behavioural disorder in which patients belch frequently, up to 20 times a minute. This is perceived by the patients as disturbing and interferes with social functioning and is likely to affect quality of life. Twenty-one patients [11 male, aged 49 (28-78) years] with supragastric belching were asked to fill in questionnaires regarding the presence and severity of their symptoms, quality of life (short form-36) and the hospital anxiety and depression scale. The most frequently reported symptoms were belching, epigastric discomfort and fullness whereas heartburn, epigastric burning, retrosternal pain, early satiety, nausea and vomiting were hardly mentioned. Compared with normative values, patients showed a decreased health-related quality of life for the domains social functioning (64.3 ± 17.8), mental health (67.4 ± 16.5), vitality (47.6 ± 20.3), bodily pain (58.9 ± 21.7) and general health (44.8 ± 19.8) but not for physical functioning (75.5 ± 21.5) and physical (63.1 ± 40.0) and emotional role (81.0 ± 35.9). The hospital anxiety and depression scale for anxiety (3 iqr 2-4) and/or depression (2 iqr 1-4) were not elevated. In patients with excessive supragastric belching, health-related quality of life is significantly impaired, in particular because of impairment of social function and vitality. Furthermore, the symptom pattern observed in these patients does not resemble that of patients with gastro-oesophageal reflux disease or functional dyspepsia and anxiety disorders and depression are not prevalent in these patients.

M1143 Quality of Life in Patients With Excessive Supragastric Belching

Excessive supragastric belching, sometimes called aerophagia, is a rare behavioural disorder in which patients belch frequently, up to twenty times a minute. This is perceived by the patients as disturbing and interferes with social functioning and is likely to affect quality of life. Psychiatric disorders such as anxiety and depression are suggested to play a role. Methods: 21 patients (11 males, age 49 (28-78)) whose presenting symptom was excessive belching underwent impedance monitoring to confirm the diagnosis of supragastric belching. They were asked to fill in questionnaires regarding the presence and severity of their symptoms, quality of life (SF-36), reflux and dyspepsia related quality of life (QoLRaD) and the hospital anxiety and depression scale (HADS). Results: Impedance monitoring showed supragastric belching in all patients, concurrent with audible belches. On a scale 0-4 patients scored the frequency of the following symptoms: epigastric discomfort (4 iqr 3-4), heartburn (1 iqr 0-1), retrosternal pain (0 iqr 0-2), early satiety (0 iqr 0-2), bloating (0 iqr 0-3), nausea (0 iqr 0-2), belching (4 iqr 4-4) and vomiting (0 iqr 0-0). On a scale 0-5 patients scored the severity of the following symptoms: epigastric discomfort (3 iqr 2-4), heartburn (0 iqr 0-1), retrosternal pain (0 iqr 0-3), early satiety (0 iqr 0-3), bloating (0 iqr 0-3), nausea (0 iqr 0-2), belching (4 iqr 3-4) and vomiting (0 iqr 0-0). Compared to normative values, patients showed a decreased quality of life for the domains social functioning (64.3 ± 17.8), mental health (67.4 ± 16.5), vitality (47.6 ± 20.3), bodily pain (58.9 ± 21.7) and general health (44.8 ± 19.8) but not for physical functioning (75.5 ± 21.5) and physical (63.1 ± 40.0) and emotional role (81.0 ± 35.9). The QoLRaD scores were not decreased for any factor (emotional distress (4.7 iqr 4.2-6.2), sleep disturbance (5.0 iqr 3.8-6.3), food and drink problems (4.8 iqr 3.2-6.4), physical and social function (5.0 iqr 4.3-5.9), vitality (5.0 iqr 3.8-6.0)). The median HADS for anxiety (3 iqr 2-4) and/or depression (2 iqr 1-4) were not elevated and only 1 patient showed a score higher than 8 for anxiety (9) and another one for depression (10). Conclusions: In patients with excessive supragastric belching, quality of life is significantly decreased, in particular due to impairment of social function and vitality. Patients with excessive belching present a distinct symptom pattern which does not resemble reflux disease or functional dyspepsia, furthermore reflux symptoms and dyspepsia do not play a role in the observed reduction of quality of life. Depression and anxiety disorders are absent.

M1144 Dysphagia in the Community With Over 50,000 Person-Years of Follow-up: Comorbidity and Survival

Excessive supragastric belching, sometimes called aerophagia, is a rare behavioural disorder in which patients belch frequently, up to twenty times a minute. This is perceived by the patients as disturbing and interferes with social functioning and is likely to affect quality of life. Psychiatric disorders such as anxiety and depression are suggested to play a role. Methods: 21 patients (11 males, age 49 (28-78)) whose presenting symptom was excessive belching underwent impedance monitoring to confirm the diagnosis of supragastric belching. They were asked to fill in questionnaires regarding the presence and severity of their symptoms, quality of life (SF-36), reflux and dyspepsia related quality of life (QoLRaD) and the hospital anxiety and depression scale (HADS). Results: Impedance monitoring showed supragastric belching in all patients, concurrent with audible belches. On a scale 0-4 patients scored the frequency of the following symptoms: epigastric discomfort (4 iqr 3-4), heartburn (1 iqr 0-1), retrosternal pain (0 iqr 0-2), early satiety (0 iqr 0-2), bloating (0 iqr 0-3), nausea (0 iqr 0-2), belching (4 iqr 4-4) and vomiting (0 iqr 0-0). On a scale 0-5 patients scored the severity of the following symptoms: epigastric discomfort (3 iqr 2-4), heartburn (0 iqr 0-1), retrosternal pain (0 iqr 0-3), early satiety (0 iqr 0-3), bloating (0 iqr 0-3), nausea (0 iqr 0-2), belching (4 iqr 3-4) and vomiting (0 iqr 0-0). Compared to normative values, patients showed a decreased quality of life for the domains social functioning (64.3 ± 17.8), mental health (67.4 ± 16.5), vitality (47.6 ± 20.3), bodily pain (58.9 ± 21.7) and general health (44.8 ± 19.8) but not for physical functioning (75.5 ± 21.5) and physical (63.1 ± 40.0) and emotional role (81.0 ± 35.9). The QoLRaD scores were not decreased for any factor (emotional distress (4.7 iqr 4.2-6.2), sleep disturbance (5.0 iqr 3.8-6.3), food and drink problems (4.8 iqr 3.2-6.4), physical and social function (5.0 iqr 4.3-5.9), vitality (5.0 iqr 3.8-6.0)). The median HADS for anxiety (3 iqr 2-4) and/or depression (2 iqr 1-4) were not elevated and only 1 patient showed a score higher than 8 for anxiety (9) and another one for depression (10). Conclusions: In patients with excessive supragastric belching, quality of life is significantly decreased, in particular due to impairment of social function and vitality. Patients with excessive belching present a distinct symptom pattern which does not resemble reflux disease or functional dyspepsia, furthermore reflux symptoms and dyspepsia do not play a role in the observed reduction of quality of life. Depression and anxiety disorders are absent.

Excessive belching and aerophagia: two different disorders

Belching is physiological venting of excessive gastric air. Excessive and bothersome belching is a common symptom, which is often seen in patients with functional dyspepsia and gastroesophageal reflux disease. Other symptoms are usually predominant. However, a small group of patients complain of isolated excessive belching, with a frequency of several belches per minute. In these patients, the eructated air does not originate from the stomach but is sucked or injected in the esophagus from the pharynx and expelled immediately afterward in oral direction. This behavior is called supragastric belching because the air does not originate from the stomach and does not reach the stomach either. Excessive belching can be treated by speech therapy or behavior therapy. The term aerophagia should be reserved for those patients where there is evidence that they swallow air too frequently and in too large quantities. These patients have excessive amounts of intestinal gas visualized on a plain abdominal radiogram and their primary symptoms are bloating and abdominal distension and they belch only to a lesser degree. Aerophagia and excessive supragastric belching are thus two distinct disorders.

Speech therapy in patients with excessive supragastric belching – a pilot study

In patients whose main symptom is excessive belching, supragastric belching appears to be the predominant mechanism. This belch pattern is characterized by a rapid influx of air into the oesophagus, immediately followed by rapid air expulsion. The rate at which supragastric belching occurs is influenced by attention and distraction, suggesting a behavioural disorder and speech therapy may be of benefit to these patients. In 17 consecutive patients with excessive belching, concurrent impedance monitoring and high-resolution manometry were performed to ascertain the mechanism of belching. Patients with supragastric belches were referred to a speech therapist, who was familiar with the concept of supragastric belching. Before and after treatment by the speech therapist, patients filled out a VAS scale regarding the severity of their symptoms. In all patients, supragastric belches were identified with impedance monitoring. Eleven patients were referred to a speech therapist, six patients were not able or willing to undergo repetitive treatments. Eleven patients completed treatment by the speech therapist consisting of 10 (8-10) sessions. Overall, the VAS scales showed a significant improvement of the severity of symptoms (P < 0.05). Six of the 11 patients reported a large decrease (>30%) in their symptoms and four patients reported a modest decrease (<30%). In one patient, the VAS scores indicated an increase in symptoms. Speech therapy performed by a well-informed speech pathologist leads to a significant symptom reduction in patients with excessive supragastric belching. This is the first study indicating benefit of a treatment for excessive belching.

T1221 Speech Therapy in Patients with Excessive Supragastric Belching

The circular muscle fibers at the end of the esophagus are traditionally considered the lower esophageal sphincter. However, the first barrier to gastric reflux is actually the clasp/sling fiber complex of the stomach. Relaxation mediates transient lower esophageal sphincter relaxation underlying the pathophysiology of gastroesophageal reflux disease (GERD). This study determined the pharmacologic specificity of the nicotinic receptor mediated relaxation of pre-contracted strips of human and porcine clasp muscle fibers. Human specimens were obtained from organ transplant donors. Clasp fiber muscle strips were exposed to increasing carbachol concentrations (human) or acetylcholine with physostigmine to block cholinesterase (pig). At concentrations higher than 30 uM, abrupt relaxations were produced. After 60 minutes of repeated washing, strips were exposed to various ganglionic and neuromuscular nicotinic receptor antagonists for 30 minutes then rechallenged with cholinergic agonists. Results, as a percentage of relaxation in time control strips are shown in the figure below. The neuromuscular blockers d-tubocurarine, decamethonium (human) and pancuronium (pig) inhibited relaxation whereas the ganglionic blocker hexamethonium (human) and the alpha7 selective antagonist methyllycaconitine did not. Other ganglionic blockers such as MG624, NDNI and TMPH blocked these relaxations whereas mecamylamine was only partially effective in human tissue. These results indicate that the pharmacology of the nicotinic receptor mediating relaxation of the gastric clasp fibers may be unique and a potential target for development of selective agents for treatment of GERD.