Objective Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are chronic conditions caused by backflow of gastric and duodenal contents into the esophagus and proximal aerodigestive tract, respectively. Mucosal barrier dysfunction resultant from the synergistic actions of chemical injury and the mucosal inflammatory response during reflux contributes to symptom perception. Alginates effectively treat symptoms of mild to moderate GERD and have recently shown benefit for LPR. In addition to forming a “raft” over gastric contents to reduce acidic reflux episodes, alginates have been found to bind the esophageal mucosa thereby preserving functional barrier integrity measured by transepithelial electrical resistance. The aim of this study was to further examine the topical protective capacity of alginate‐based Gaviscon Advance (GA) and Double Action (GDA) against pepsin‐acid mediated aerodigestive epithelial barrier dysfunction in vitro. Study Design Translational. Methods Immortalized human esophageal and vocal cord epithelial cells cultured in transwells were pretreated with liquid formula GA, GDA, matched viscous placebo solution, or saline (control), then treated for 1 h with saline, acid (pH 3–6) or pepsin (0.1–1 mg/ml) at pH 3–6. Endpoint measure was taken of horseradish peroxidase (HRP) allowed to diffuse across monolayers for 2 h. Results Pepsin (0.1‐1 mg/ml) at pH 3‐6 increased HRP flux through cultures pretreated with saline or placebo (p < 0.05); acid alone did not. GA and GDA prevented barrier dysfunction. Conclusions GA and GDA preserved epithelial barrier function during pepsin‐acid insult better than placebo suggesting that protection was due to alginate. These data support topical protection as a therapeutic approach to GERD and LPR. Laryngoscope, 132:2327–2334, 2022
Background/aimsInvestigation of gastro-oesophageal reflux disease is usually performed off proton pump inhibitors (PPIs). This can exacerbate symptoms, potentially impacting investigation accuracy if patients circumvent the preinvestigation instructions. There are no standard recommendations on how to manage PPI withdrawal. We aimed to assess the impact of structured alginate use on symptom burden.MethodsParticipants were already established on ≥4 weeks of PPI therapy and being referred for manometry and 24-hour pH/impedance testing. Preinvestigation instructions involved stopping PPIs and H2 receptor antagonists for 1 week, but antacids and alginates were allowed until the night before. Participants were randomised to follow these standard instructions (control group), or the same instructions with the provision of Gaviscon Advance to be taken four times daily (treatment group). The primary outcome assessed change in Gastro-Oesophageal Reflux Disease Health-Related Quality of Life Score.Key resultsData for 48 patients were available for primary outcome assessment. While patients in the control group had a significant increase in symptoms (median difference 6.5, 95% CI (1 to 7), p=0.04), no change occurred in the treatment arm (median difference -1.5, 95% CI (-2, 3.5), p=0.54). There were no serious adverse events.ConclusionsStructured alginate use prevents symptom exacerbation during preinvestigation PPI wash-out. These findings are limited to the 1-week wash-out period but can benefit thousands of patients undergoing investigation for gastro-oesophageal reflux each year. Further research is required to assess this effect in other settings, such as sustained PPI deprescription. The trial was funded by Reckitt Benckiser.Trial registration numberEudraCT registration 2019-004561-41
Introduction: Proton pump inhibitors (PPIs) used in the management of gastro-esophageal reflux disease (GORD) are among the most frequently prescribed classes of drug worldwide. Currently, however, physicians are prescribing PPIs for extended periods, often without an indication, which is not in line with current guidance and therefore preventing appropriate reflux management. Inappropriate or excessive PPI prescribing is becoming increasingly visible, yet there is currently little research available on the impact such current practice has on the patient experience. This study aims to understand patient attitudes toward their PPI treatment and the impact current PPI prescribing patterns have on the patient experience. Methods: An online survey of current and previous users of PPI for GORD was conducted in the UK and Germany. Topics covered included prior steps taken before first consultation with a physician, initial recommendations, PPI treatment initiation and duration, use of PPI, management of reflux whilst taking a PPI, stopping PPI treatment, and patient attitudes. Results: Among 566 patient participants (UK, n = 372; Germany, n = 194) 69% to 79% reported being prescribed medication at their first visit to a physician, of which 61% to 68% were prescribed a PPI either alone or combined with another treatment. 41% to 48% of patients answered “don’t know” when asked how long they expected to continue taking their PPI. 49% to 50% of patients currently on PPIs also reported having concerns with regards to long-term treatment. 70% of patients recalled being well informed on dosage and treatment regimens. However, other safety and usage information was reported as being less frequently discussed. Conclusions: Although patients reported concerns regarding ongoing long-term PPI treatment, this was not reflected in the prescribing pattern from physicians. More can be done to ensure patients are fully informed about their PPI treatment at consultation. Findings also suggest a disconnect exists between standard treatment guidelines and prescribing patterns, as experienced by patients.
Epithelial barrier dysfunction is a hallmark of gastroesophageal reflux disease (GERD) related to symptom origination, inflammatory remodeling and carcinogenesis. Alginate-based antireflux medications were previously shown to topically protect against peptic barrier disruption, yet the molecular mechanisms of injury and protection were unclear. Herein, Barrett’s esophageal (BAR-T) cells were pretreated with buffered saline (HBSS; control), dilute alginate medications (Gaviscon Advance or Gaviscon Double Action, Reckitt Benckiser), a viscosity-matched placebo, or ADAM10 and matrix metalloproteinase (MMP) inhibitors before exposure to HBSS pH7.4 or pH4 ± 1 mg/mL pepsin for 10–60 min. Cell viability was assessed by ATP assay; mediators of epithelial integrity, E-cadherin, ADAM10, and MMPs were examined by Western blot and qPCR. Alginate rescued peptic reduction of cell viability (p < 0.0001). Pepsin-pH4 yielded E-cadherin fragments indicative of regulated intramembrane proteolysis (RIP) which was not rescued by inhibitors of known E-cadherin sheddases. Transcriptional targets of E-cadherin RIP fragments were elevated at 24 h (MMP-1,2,9,14; p < 0.01). Alginate rescued E-cadherin cleavage, ADAM10 maturation, and MMP induction (p < 0.01). Results support RIP as a novel mechanism of peptic injury during GERD. Alginate residue after wash-out to mimic physiologic esophageal clearance conferred lasting protection against pepsin-induced molecular mechanisms that may exacerbate GERD severity and promote carcinogenesis in the context of weakly acidic reflux.
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