An Alginate-Antacid Formulation Localizes to the Acid Pocket to Reduce Acid Reflux in Patients With Gastroesophageal Reflux Disease

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11:1585 1591 ALIMENTARY TRACT An Alginate-Antacid Formulation Localizes to the Acid Pocket to Reduce Acid Reflux in Patients With Gastroesophageal Reflux Disease WOUT O. ROHOF,* ROEL J. BENNINK, ANDRE J. P. M. SMOUT,* EDWARD THOMAS, and GUY E. BOECKXSTAENS k *Department of Gastroenterology and Hepatology, and Department of Nuclear Medicine, Academic Medical Centre, Amsterdam, the Netherlands; Reckitt Benckiser, Slough, Berkshire, United Kingdom; and k Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium This article has an accompanying continuing medical education activity on page e90. Learning Objectives At the end of this activity, the successful learner will understand the significance of the acid pocket as an important player in the pathogenesis of gastroesophageal reflux disease and will recognize its potential as a therapeutic target. BACKGROUND & AIMS: METHODS: RESULTS: CONCLUSIONS: Alginate rafts (polysaccharide polymers that precipitate into a low-density viscous gel when they contact gastric acid) have been reported to form at the acid pocket, an unbuffered pool of acid that floats on top of ingested food and causes postprandial acid reflux. We studied the location of an alginate formulation in relation to the acid pocket and the corresponding effects on reflux parameters and acid pocket positioning in patients with gastroesophageal reflux disease (GERD). We randomly assigned patients with symptomatic GERD and large hiatal hernias to groups who were given either 111 In-labeled alginate-antacid (n [ 8, Gaviscon Double Action Liquid) or antacid (n [ 8, Antagel) after a standard meal. The relative positions of labeled alginate and acid pocket were analyzed for 2 hours by using scintigraphy; reflux episodes were detected by using high-resolution manometry and ph-impedance monitoring. The alginate-antacid label localized to the acid pocket. The number of acid reflux episodes was significantly reduced in patients receiving alginate-antacid (3.5; range, 0L6.5; P [.03) compared with those receiving antacid (15; range, 5L20), whereas time to acid reflux was significantly increased in patients receiving alginate-antacid (63 minutes; range, 23L92) vs those receiving antacid (14 minutes; range, 9L23; P [.01). The acid pocket was located below the diaphragm in 71% of patients given alginate-antacid vs 21% of those given antacid (P [.08). There was an inverse correlation between a subdiaphragm position of the acid pocket and acid reflux (r [ L0.76, P <.001). In a study of 16 patients with GERD, we observed that the alginate-antacid raft localizes to the postprandial acid pocket and displaces it below the diaphragm to reduce postprandial acid reflux. These findings indicate the importance of the acid pocket in GERD pathogenesis and establish alginate-antacid as an appropriate therapy for postprandial acid reflux. www. trialregister.nl, Number: NTR3602 Keywords: Clinical Trial; Esophagus; Heartburn; EGJ. See editorial on page 1592. Gastroesophageal reflux disease (GERD) is a common condition where backflow of gastric contents into the esophagus causes symptoms and/or esophageal damage. 1 3 The majority of acidic gastroesophageal reflux episodes and symptoms occur after eating, which is somewhat paradoxical because the buffering effect of food causes a reduction in intragastric acidity. An explanation for this paradox was provided by Fletcher et al, 4 who were the first to detect an unbuffered pool of acid that floats on top of ingested food, referred to as the gastric acid pocket. The acid pocket develops as a result of poor mixing of newly secreted acid and food in the proximal stomach, which remains relatively quiescent after a meal compared with the distal stomach. 5 Abbreviations used in this paper: EGJ, esophagogastric junction; GERD, gastroesophageal reflux disease; HRM, high-resolution manometry; LES, lower esophageal sphincter; PPI, proton pump inhibitor. 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.04.046

1586 ROHOF ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 12 We recently reported that the position of the acid pocket relative to the crural diaphragm is an important determinant of the acidity of the refluxate. 6 In GERD, proximal extension of the acid pocket above the diaphragm increases the risk for acid reflux. 6,7 The acid pocket is therefore an important source of postprandial acid in GERD and, as such, represents a unique therapeutic target. 8 Emerging evidence suggests that alginates may act through direct targeting of the acid pocket. Alginates are natural polysaccharide polymers that, on contact with gastric acid, precipitate into a low-density viscous gel of near-neutral ph within minutes. 9,10 The change in ph triggers the sodium bicarbonate in the formulation to release carbon dioxide, which becomes trapped in the alginate gel, causing it to float to the top of the gastric contents like a raft. 9,10 Magnetic resonance imaging shows that alginate rafts form in the proximal stomach close to the esophagogastric junction (EGJ), precisely where the acid pocket develops. 11 Furthermore, a commercial alginate-antacid formulation, Gaviscon Double Action Liquid (Reckitt Benckiser Healthcare, Hull, UK), has been shown to shift the postprandial acidified segment in the proximal stomach away from the EGJ in GERD patients. 12 The raft of Gaviscon Double Action is reported to remain in the stomach, on top of the meal, for more than 4 hours, 13 while the acid pocket is reported to remain for up to 120 minutes. 6,8 It is attractive to hypothesize that the mode of action of alginates allows direct capping and displacement of the acid pocket, isolating it from the EGJ and reducing postprandial acid reflux events. 12 However, the position of the alginate raft in relation to the acid pocket has never been visualized in vivo. The aim of this study was to visualize the position of the alginate raft after administration of Gaviscon Double Action in GERD patients and to concurrently assess the effect on reflux parameters and position of the acid pocket compared with a commonly used antacid control. Materials and Methods Subjects The study was performed in 16 patients with proven GERD, which was defined by the presence of esophagitis observed during upper endoscopy and/or 24-hour ph-metry with an acid (ph <4) exposure time >4.5%, in combination with typical GERD symptoms. 14 Hiatal hernia size was measured by high-resolution manometry (HRM), and patients with small or no hiatal hernia (<3 cm) were excluded. Patients with confirmed long segment Barrett s epithelium who were unable to stop the use of proton pump inhibitors (PPIs) for 1 week or who had participated in another study that used radioactivity within the last year were also excluded. The study was approved by the Medical Ethics Committee of the Academic Medical Center. Written informed consent was obtained from all subjects before enrollment in the study. All authors had access to the study data and reviewed and approved the final manuscript. Study Medication Sodium alginate-bicarbonate (Gaviscon Double Action Liquid) is an oral liquid suspension, directly acting without absorption into the systemic circulation. The medication is a combination of 2 antacids (calcium carbonate and sodium bicarbonate) and sodium alginate. Each half-maximal 10-mL dose contains 500 mg sodium alginate, 213 mg sodium bicarbonate, and 325 mg calcium carbonate, with a neutralizing capacity of approximately 10 meq H þ. Gaviscon was labeled with 1 MBq indium-111 ( 111 In)-chloride according to the established labeling procedure. 15,16 Antagel (Pharmachemie, Haarlem, the Netherlands) is a common antacid drug with a neutralizing capacity of 30 meq H þ. Each 10-mL dose contains 200 mg magnesium hydroxide and 400 mg aluminum oxide. Study Design In this parallel designed study, 16 GERD patients were randomized to 111 In-labeled alginate-antacid (n ¼ 8) or antacid (n ¼ 8). Reflux episodes were detected by using concurrent HRM and ph impedance monitoring, and scintigraphy was performed to localize the alginate-antacid raft and the acid pocket relative to the crural diaphragm (Figure 1). Acid-suppressive medication was stopped at least 7 days before the study day. Patients were allowed to use antacids except for on the study day. Subjects fasted overnight for at least 12 hours. On the day of study, 350 MBq technetium-99m ( 99m Tc)-pertechnetate was injected intravenously. Tcpertechnetate behaves as a chloride ion and is secreted by the parietal cells of the stomach. 17 When this technique is used, acid distribution in the stomach can be visualized scintigraphically, as validated previously. 6 Figure 1. Study design.

December 2013 GAVISCON TARGETS THE ACID POCKET IN GERD PATIENTS 1587 Before introduction of the HRM catheter, 2 sealed markers impregnated with 99m Tc-pertechnetate were attached to the catheter to visualize the exact location of the catheter during scintigraphy. This makes it possible to integrate the distances from the manometry and the scintigraphy to relate the acid pocket to the crural diaphragm. 8 The HRM catheter and the ph impedance catheter were inserted transnasally into the stomach. The ph sensors of the ph impedance catheter were placed 5 cm above and 5 cm below the upper border of the lower esophageal sphincter (LES). Subsequently, the patients were positioned in an upright position in front of the scintigraphy camera. After positioning of the catheters, 5 minutes of baseline fasting measurements were obtained. Subjects then consumed a standardized meal within 10 minutes, consisting of 200 ml orange juice and 2 pancakes with jam (510 kcal). Thirty minutes after starting the measurement, patients drank 10 ml Gaviscon Double Action or 10 ml Antagel. After 2 hours of measurement the catheters were removed (Figure 1). Recording Methods HRM was performed by using a 21 lumen waterperfused HRM catheter (MMS, Enschede, the Netherlands). Eleven distal side-holes were positioned at 1-cm intervals, and the 10 proximal side-holes were spaced at 3-cm intervals. The side-holes were perfused with distilled water at 0.15 ml/min by using a pneumohydraulic capillary perfusion pump (MMS) and hydraulic flow restrictors. For ph impedance measurement, a Unisensor ph impedance catheter (Unisensor, Attikon, Switzerland) containing 2 ISFET ph sensors and 8 impedance electrodes was used, allowing ph recordings at 5 cm above and 5 cm below the upper border of the LES and impedance recordings at 3, 5, 7, 9, 15, and 17 cm above the upper border of the LES. Dynamic scintigraphic images were acquired on a gamma camera system (Diacam; Siemens Medical Solutions, Hoffman, IL), equipped with a medium-energy collimator. Dynamic recordings were made in posterior view for 2 hours (720 views, 10 s/view, 120 minutes total acquisition time). Gamma radiation of 99m Tc-pertechnetate and 111 In has different energy levels and can therefore be detected separately. Every acquisition was processed on a Hermes processing station (Hermes Medical Solutions, Stockholm, Sweden) for further analysis. Data Analysis Reflux episodes were detected by ph impedance monitoring, and each liquid or mixed reflux event was defined as acidic reflux when ph <4 and as weakly acidic when ph 4. The time from the intake of medication to the first acid reflux event was determined. A second ph sensor was positioned in the acid pocket to allow comparison of buffering time after administration of alginate-antacid and antacid. The amount of time that the acid pocket ph was >4 after medication intake was determined. HRM recordings were used to determine the exact distance from the crural diaphragm to the markers on the catheter for the position of the acid pocket. The lower and upper borders of the crural diaphragm and the middle of the LES zone were determined. Subsequently, calibrated Hermes software was used to measure the distance from the proximal end of the gastric acid pocket to the markers on the catheters on one image to calculate the distance between the acid pocket and the crural diaphragm. The position of the acid pocket was classified in 3 categories relative to the crural diaphragm: below the diaphragm, at the level of the diaphragm, or above the diaphragm. Measurements of the distances between the acid pocket and the diaphragm were made through a straight line in a planar posterior view of the stomach. Statistical Analysis On the basis of the mean numbers of acid reflux episodes reported previously, 18 a sample size of 7 per group in a parallel design was calculated to have 80% power to detect a difference in means of 5.8 (eg, a first condition mean of 8.4 and a second condition mean of 2.6), assuming a standard deviation of differences of 3.5, by using a Student t test with a 0.05 twosided significance level. To compensate for potential dropouts, 16 patients with GERD were included. Statistical analysis was performed by using SPSS 19.0 software for Windows (IBM, Armonk, NY). Results are presented as mean standard error of the mean in the case of a normal distribution or as median [interquartile range] for variables with a skewed distribution. For statistical analysis, the Mann Whitney test was used. Correlations were determined by using the Spearman correlation coefficient. Results Baseline Reflux Characteristics To determine whether patients were randomized well, we compared reflux variables obtained during the diagnostic 24-hour ph impedance recording before study inclusion. No significant difference in esophageal acid exposure was observed between antacid-treated and alginate-antacid treated patients (11% [2.2% 12%] vs 10% [6.7% 20%], P ¼.78), the number of reflux episodes (96 [64 146] vs 113 [69 201], P ¼ 1.0), or the number of acid reflux episodes (41 [24 65] vs 35 [25 126], P ¼.73). In addition, there was no difference in the rate of reflux episodes in the first 30 minutes of measurement, thus before medication intake, for antacid-treated and alginate-antacid treated patients (4.5 1.1 vs 3.6 0.9 episodes, P ¼.55). Relative Localization of the Alginate-Antacid Raft and the Acid Pocket In Vivo Scintigraphy allowed independent visualization of the 99m Tc-pertechnetate acid pocket and 111 In-labeled alginate raft (Figure 2A and B). The radiolabeled acid pocket was scintigraphically visible in all patients within 15 minutes of meal ingestion. The indium-labeled alginate-antacid was directly visible after administration. When the 2 simultaneous scintigraphic recordings were superimposed, the alginate raft colocalized precisely with the acid pocket (Figure 2C). The acid pocket and raft were visible for the entire length of the study. Reflux Episodes and Esophageal Acid Exposure The 16 GERD patients included in the study had a large hiatal hernia (3 cm as seen on endoscopy or HRM),

1588 ROHOF ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 12 Figure 2. Scintigraphic images of 99m Tc-pertechnetate labeled acid pocket (A) and 111m In-labeled alginate-antacid (B) and the 2 scintigraphic recordings superimposed (C). After a meal, 99m Tc-pertechnetate is excreted by the parietal cells of the stomach, and this visualizes the acid pocket near the EGJ (A). After intake, 111m In-labeled alginate-antacid (B) is present in the proximal stomach. Superimposed, it is demonstrated that the 111m In-labeled alginate-antacid is present on top and co-localizes with the acid pocket in the proximal stomach. In the Supplementary Video, the superimposed dynamic images demonstrate that the alginate-antacid remains in this position during the entire study period. resulting in a high rate of acid reflux episodes. A total of 266 reflux episodes were detected, of which 138 episodes (52%) were acidic. Compared with the antacid, the total number of reflux episodes was reduced with alginate-antacid ingestion (median, 21 [15 27] vs 14 [8.5 17], respectively; P ¼.05) (Figure 3). The number of acid reflux episodes and the rate of acid reflux were also significantly lower after treatment with alginateantacid, compared with antacid (15 [5.5 20] vs 3.5 [0-6.5], P ¼.03 and 68% [40% 79%] vs 21% [0% 44%], P ¼.02), and there was a trend toward reduced esophageal acid exposure (7.4 [2.1 22] vs 0.2 [0 4.1], P ¼.08) (Figure 3). Conversely, the number of weakly acid reflux episodes was not significantly different between alginate-antacid treated and antacid-treated patients (antacid 6 [6.0 7.5] vs alginate-antacid 8 [6.0 13.0], P ¼.38) (Figure 3). Figure 3. The mean numbers of reflux events (A), acid reflux episodes (B), and esophageal acid exposure (C) were reduced by alginate-antacid compared with antacid, but the mean number of weakly acid reflux episodes was higher with alginate-antacid (D).

December 2013 GAVISCON TARGETS THE ACID POCKET IN GERD PATIENTS 1589 Figure 4. Buffering capacity (A) was similar for antacid and alginate-antacid. However, mean time to acid reflux (B) and mean ph of reflux episodes (C) were significantly increased with alginate-antacid compared with antacid. Buffering Time and Time to Acid Reflux A ph sensor was continuously positioned in the acid pocket to allow comparison of buffering time after administration of alginate-antacid and antacid. The buffer time (amount of time that the acid pocket ph was >4) was not significantly different after antacid and alginate-antacid ingestion (3.5 minutes [0.3 4.5] vs 6 minutes [3 12], respectively; P ¼.13), and the mean ph measurements of the acid pockets were similar (2.1 [2.0 2.4) vs 2.5 [1.7 2.8], respectively; P ¼.71).However,comparedwithantacid,the time to acid reflux (antacid 14 minutes [9 23] vs alginateantacid 63 minutes [23 92], P ¼.01) and the mean ph of reflux episodes were significantly increased with alginateantacid (antacid 3.5 [2.0 5.0] vs alginate-antacid 5.0 [4.1 6.2], P <.05) (Figure 4). Acid Pocket Position and Acid Reflux Events Acid reflux occurred mainly when the acid pocket was located above (78 of 95 reflux episodes, 82%) or at the level of (47 of 78, 60%) the diaphragm, but seldom when the pocket was located below the diaphragm (13 of 88, 15%). There was a trend toward a higher rate of subdiaphragmatic positioning of the acid pocket with alginate-antacid, compared with antacid (71% [27% 78%] vs 21% (10% 51%), respectively; P ¼.08) (Figure 5A). The rate of subdiaphragmatic positioning of the acid pocket had a significant negative correlation with the rate of acid reflux (r ¼ 0.76, P <.001); that is, acid pocket positioning below the diaphragm corresponded to a lower rate of acid reflux (Figure 5B). Discussion Increased acid reflux after meals is a hallmark of GERD, with the amount of acid exposure determining the severity of symptoms and complications. The acid pocket, which is the most immediate source of postprandial refluxate in GERD, represents an important therapeutic target. Among current therapies, alginates, with their raft-forming mode of action in the proximal stomach, are interesting candidates for direct targeting of the acid pocket. Gaviscon Double Action has been shown previously to neutralize the acid pocket in GERD patients, significantly shifting the ph transition point away from the EGJ. 12 The raft-forming mode of action of alginates has been demonstrated repeatedly in vitro. 10 It was hypothesized that the alginate raft may cap and displace the acid pocket to a more distal position, but the localization of alginate in relation to the acid pocket had never been visualized in vivo. Here we demonstrate that the alginate raft targets the acid pocket. The scintigraphic recordings clearly showed the alginate raft forming within minutes of ingestion and co-localizing with the acid pocket. The alginate-antacid labeling persisted in the proximal stomach for the entire 2-hour study. Acid reflux episodes were reduced by more than 75% compared with antacid, and reflux was delayed for more than an hour after the meal, compared with 15 minutes with antacid. The buffering capacity of the 2 agents was similar during the 2-hour study, which confirmed that the difference in acid reflux rates was not a ph effect. Rather, these findings suggest that the alginate acts to suppress reflux in the proximal stomach by effectively capping the acid pocket. Because of the properties of the buoyant Figure 5. There was a trend for the acid pocket to be located below the diaphragm at an increased rate with alginate-antacid compared with antacid treatment (A). Subdiaphragmatic positioning negatively correlated with acid reflux (B). ***r ¼ 0.76, P <.001.

1590 ROHOF ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 12 alginate raft, it is likely that the raft is able to adapt to the acid pocket as it develops, continuously reacting with and floating above newly secreted acid close to the EGJ. Consistent with previous findings, non-acid reflux events were not reduced. 18 Despite a similar buffering capacity and acid pocket ph, the acidity of the refluxate was significantly reduced with alginate-antacid compared with antacid. This discrepancy between acid pocket ph and refluxate ph is most likely due to additional effects exerted by the alginate that make the acid of the pocket less available for reflux by either removing acid through chemical interaction and/or physically displacing the acid pocket distally. In healthy volunteers the pocket is highly acidic, but gastroesophageal reflux is usually weakly acidic. 19 In GERD patients there are proximal migration of the acid pocket and increased acidity of reflux. 6 Therefore, displacement of the acid pocket distally in GERD patients would be expected to create a situation similar to healthy volunteers, a shift from acidic to weakly acidic events, owing to the fact that the acid pocket is no longer the most immediate source of refluxate. Our previous observations in GERD patients with large hiatal hernia show that the acid pocket frequently extends into the hiatal sac above the diaphragm and that this significantly increases the risk for acid reflux. 6 This may explain why hiatal hernia size correlates closely with esophageal acid exposure and esophageal damage. 20 22 In a previous study we found that the prokinetic agent azithromycin is able to alter the acid pocket position from supradiaphragmatic to subdiaphragmatic in patients with a small hiatal hernia, but that this effect was eliminated by a large hiatal hernia. 8 The data presented here confirm that the raftforming mode of action of alginates is still present in patients with a large hiatal hernia (3 cm). Furthermore, the rate at which the acid pocket was located below the diaphragm was more than 3 times greater with alginate-antacid compared with antacid (although not reaching statistical significance, P ¼.08). This confirms that the alginate-antacid raft can displace the acid pocket distally out of the hiatal sac and builds on the previous data of Kwiatek et al, 12 who showed significant distal shifting of the ph transition point. Subdiaphragmatic positioning of the acid pocket had a significant negative correlation with acid reflux, confirming that the effect of alginate-antacid on acid pocket position contributes to the observed reduction in acid reflux. A potential weakness of the study is the parallel design in a relatively small patient population, although patient groups were well matched. Further experiments that use a larger population of patients and/or a maximal dose of Gaviscon are needed to establish the outcomes that were approaching significance, such as esophageal acid exposure and acid pocket positioning below the diaphragm (P ¼.08 for both). It would also be interesting to determine whether distal displacement of the acid pocket plays a role in the reduction of acid reflux seen in patients with no hiatal hernia 18 and to confirm whether the observed reduction in acid reflux suppression translates to a reduction in GERD symptoms. This seems likely because a previous systematic review of randomized, placebo-controlled trials demonstrated a benefit in symptomatic improvement over placebo of 60% with alginate-antacid compared with 11% improvement for anatacid. 23 In summary, Gaviscon Double Action forms a robust and persistent alginate raft that interacts with and caps the acid pocket, displacing it distally and reducing acid reflux events. These findings demonstrate the value of directly targeting the acid pocket with a nonsystemic, alginate-antacid formulation for the treatment of postprandial acid reflux in GERD. This may have clinical implications for patients who suffer primarily from postprandial reflux, who may be able to adequately control their symptoms with optimized use of alginate-antacid. Alginates may also benefit patients with insufficient response to PPIs. We have observed that the acid pocket persists after PPI treatment in GERD patients 24 and thus may play a role in the residual symptoms that can occur despite PPI therapy. If this is the case, direct capping of the acid pocket would be expected to benefit these patients. In supportofthis,arecentstudyin patients with nonerosive reflux disease demonstrated that supplementing PPI therapy with alginate more than doubled the number of patients who experienced complete reflux symptom relief. 25 Supplementary Material Note: To access the supplementary materials accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi. org/10.1016/j.cgh.2013.04.046. References 1. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidencebased consensus. Am J Gastroenterol 2006;101:1900 1920, quiz 1943. 2. Kahrilas PJ. GERD pathogenesis, pathophysiology, and clinical manifestations. Cleve Clin J Med 2003;70(Suppl 5):S4 S19. 3. Boeckxstaens GE. Alterations confined to the gastro-oesophageal junction: the relationship between low LOSP, TLOSRs, hiatus hernia and acid pocket. Best Pract Res Clin Gastroenterol 2010; 24:821 829. 4. Fletcher J, Wirz A, Young J, et al. Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal. Gastroenterology 2001;121:775 783. 5. Sauter M, Curcic J, Menne D, et al. Measuring the interaction of meal and gastric secretion: a combined quantitative magnetic resonance imaging and pharmacokinetic modeling approach. Neurogastroenterol Motil 2012;24:632 638. 6. Beaumont H, Bennink RJ, de Jong J, et al. The position of the acid pocket as a major risk factor for acidic reflux in healthy subjects and patients with GORD. Gut 2010;59:441 451. 7. Clarke AT, Wirz AA, Manning JJ, et al. Severe reflux disease is associated with an enlarged unbuffered proximal gastric acid pocket. Gut 2008;57:292 297. 8. Rohof WO, Bennink RJ, de Ruigh AA, et al. Effect of azithromycin on acid reflux, hiatus hernia and proximal acid pocket in the postprandial period. Gut 2012;61:1670 1677. 9. Tytgat GN, Simoneau G. Clinical and laboratory studies of the antacid and raft-forming properties of Rennie alginate suspension. Aliment Pharmacol Ther 2006;23:759 765. 10. Mandel KG, Daggy BP, Brodie DA, et al. Review article: alginate-raft formulations in the treatment of heartburn and acid reflux. Aliment Pharmacol Ther 2000;14:669 690. 11. Fox M, Kant R, Kaufman E, et al. The mechanism of reflux suppression by alginates visualized by magnetic resonance imaging and manometry. Poster presentation. Digestive Disease Week, May 2011. 12. Kwiatek MA, Roman S, Fareeduddin A, et al. An alginateantacid formulation (Gaviscon Double Action Liquid) can

December 2013 GAVISCON TARGETS THE ACID POCKET IN GERD PATIENTS 1591 eliminate or displace the postprandial acid pocket in symptomatic GERD patients. Aliment Pharmacol Ther 2011; 34:59 66. 13. Hampson FC, Jolliffe IG, Bakhtyari A, et al. Alginate-antacid combinations: raft formation and gastric retention studies. Drug Dev Ind Pharm 2010;36:614 623. 14. Kahrilas PJ, Quigley EM. Clinical esophageal ph recording: a technical review for practice guideline development. Gastroenterology 1996;110:1982 1996. 15. Taylor G, Warren S, Kellaway I, et al. Gastric residence of Gaviscon Advance and Liquid Gaviscon in healthy volunteers. J Pharm Pharmacol 1997;49(Suppl 4):73. 16. Davies N, Farr S, Kellaway I, et al. A comparison of the gastric retention of alginate containing tablet formulations with and without the inclusion of excipient calcium ions. Int J Pharmaceut 1994; 105:97 101. 17. Kuiken S, Van Den Elzen B, Tytgat G, et al. Evidence for pooling of gastric secretions in the proximal stomach in humans using single photon computed tomography. Gastroenterology 2002; 123:2157 2158. 18. Zentilin P, Dulbecco P, Savarino E, et al. An evaluation of the antireflux properties of sodium alginate by means of combined multichannel intraluminal impedance and ph-metry. Aliment Pharmacol Ther 2005;21:29 34. 19. Trudgill NJ, Riley SA. Transient lower esophageal sphincter relaxations are no more frequent in patients with gastroesophageal reflux disease than in asymptomatic volunteers. Am J Gastroenterol 2001;96:2569 2574. 20. van Herwaarden MA, Samsom M, Smout AJ. Excess gastroesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology 2000; 119:1439 1446. 21. van Herwaarden MA, Samsom M, Smout AJ. The role of hiatus hernia in gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 2004;16:831 835. 22. Jones MP, Sloan SS, Rabine JC, et al. Hiatal hernia size is the dominant determinant of esophagitis presence and severity in gastroesophageal reflux disease. Am J Gastroenterol 2001;96:1711 1717. 23. Tran T, Lowry AM, El-Serag HB. Meta-analysis: the efficacy of overthe-counter gastro-oesophageal reflux disease therapies. Aliment Pharmacol Ther 2007;25:143 153. 24. Rohof W, Bennink R, Boeckxstaens G. Effect of PPIs on the size, position and acidity of the postprandial acid pocket. Gastroenterology 2012;142:S-92. 25. Manabe N, Haruma K, Ito M, et al. Efficacy of adding sodium alginate to omeprazole in patients with nonerosive reflux disease: a randomized clinical trial. Dis Esophagus 2012;25:373 380. Reprint requests Address requests for reprints to: Guy E. Boeckxstaens, MD, PhD, Department of Gastroenterology, University Hospital of Leuven, University of Leuven, Herestraat 49, 3000 Leuven, Belgium. e-mail: guy.boeckxstaens@med.kuleuven; fax: 31-20-6917033. Conflicts of interest These authors disclose the following: A.J.P.M. Smout has acted as an invited speaker for Reckitt Benckiser; E.C.M. Thomas is an employee of Reckitt Benckiser; and G.E. Boeckxstaens is a consultant of Reckitt Benckiser. The remaining authors disclose no conflicts. Funding Reckitt Benckiser provided an educational grant to support this study but had no role in the study design, running of the study, or the decision to publish.