Prolonged Acid Suppression Research Articles

Potassium-competitive acid blockers, a new therapeutic class, and their role in acid-related diseases: a narrative review.

A new therapeutic class, potassium-competitive acid blockers (P-CABs), has emerged in Brazil to promote a superior antisecretory effect addressing the unmet needs related to acid-related disease management. Vonoprazan fumarate showed a good safety profile and was approved by the Brazilian regulatory agency - ANVISA. This narrative review was conducted to review the general concepts regarding P-CABs, focussing on vonoprazan fumarate. A literature search was conducted through April-May 2021 using official databases with a combination of MeSH controlled vocabulary and text words. The authors selected articles that described pivotal and novel insights about P-CABs and vonoprazan fumarate. Vonoprazan is a drug of the P-CABs class newly approved for the management of acid-related diseases in Brazil. P-CABs achieve rapid, potent, and prolonged acid suppression (including night-time) and promise to address some unmet clinical needs in GERD. Furthermore, considering the difficulties encountered in attaining effective symptomatic control - particularly at night - using currently available PPIs, this new drug class is promising. This review brings important information about vonoprazan, a new therapeutic option in Brazil, which may be considered as a valuable tool for managing acid-related diseases.

Gut Microbiota Characteristics in Children After the Use of Proton Pump Inhibitors.

Prolonged acid suppression from proton pump inhibitor (PPI) has been shown to cause gut microbiota alteration which may increase risk of various infections in adults. We aimed to characterize gut microbiota profiles in children after a short-term use of PPI. Children aged 1-18 years who underwent PPI therapy were included during April-December 2017. We excluded children who previously used antibiotics or acid suppressants, had a history of acute gastroenteritis or specific food avoidance one month prior to the enrolment. The stool samples before and after the PPI use were collected for gut microbiota composition. The 16S ribosomal RNA gene sequencing was performed by using Illumina MiSeq. The differences in gut microbiota profile after the use of PPI were compared to pre-PPI period. We completed stool collection in 20 children (median age of 5.8 years and 60% were female). No significant changes in the overall number of species-level taxonomy categories or predominant bacteria phylum (Bacteroidetes) were noted. We found a trend increase in the proportion of phylum Firmicutes among children living in the metropolitan/suburban area (P=.07) and among males (P=.11). In four children with infection-related adverse effects, we noted a non-significant increase in the proportion of phylum Firmicutes after the PPI use (from 35 to 52%, P = .14). Even the total number and predominant gut microbiota did not significantly change after a four- to eight-week course of PPI therapy; we found a trend of increased proportion of phylum Firmicutes in certain groups of children.

Pathophysiology and treatment options for gastroesophageal reflux disease: looking beyond acid.

Gastroesophageal reflux disease (GERD) is a disorder due to the retrograde flow of refluxate into the esophagus. Although GERD is a common clinical diagnosis, its pathogenesis is quite complex. As a result of its multifactorial development, many patients continue to experience adverse symptoms due to GERD despite prolonged acid suppression with proton pump inhibitor therapy. The pathogenesis of GERD involves an interplay of chemical, mechanical, psychologic, and neurologic mechanisms, which contribute to symptom presentation, diagnosis, and treatment. As such, GERD should be approached as a disorder beyond acid. This review will investigate the major factors that contribute to the development of GERD, including factors related to the refluxate, esophageal defenses, and factors that promote pathologic reflux into the esophagus. In reviewing GERD pathogenesis, this paper will highlight therapeutic advances, with mention of future opportunities of study when approaching GERD.

S2933 Vanishing Polyps: Can Switching From a PPI to an H2 Blocker Cause Regression of Fundic Gland Polyps?

INTRODUCTION: Fundic gland polyps (FGPs) are identified as a sequalae of prolonged acid suppression. Though some studies show that acid suppression with a proton pump inhibitor (PPI) or Histamine 2 receptor blockers (H2RB) may cause FGPs, stronger evidence supports PPIs as a culprit. Studies have shown improvement of FGPs with cessation of acid suppression, but few studies investigated the effect of changing therapy to an H2RB. This case demonstrates a reduction of polyp size and number upon transition to an H2RB in a patient who developed FGPs as a result of long-term PPI use. CASE DESCRIPTION/METHODS: An 85-year-old female with rheumatoid arthritis on methotrexate and prednisone and on chronic PPI for 15 years for acid reflux presented to the gastroenterology clinic for possible gastritis. Upper endoscopy was performed and showed multiple 5–50 mm pedunculated and sessile polyps throughout the entire stomach. A majority of the polyps were about 3–5 cm. A hot snare and a Roth net were used to remove polyps to confirm histopathology (Figure 1). Gastric biopsies revealed FGPs without evidence of H. pylori, intestinal metaplasia, dysplasia or malignancy. Despite concern for FAP, malignancy, or high-grade dysplasia, the patient elected for continued endoscopic surveillance. She transitioned from a PPI to an H2RB. Serial endoscopies showed marked improvement in the size and number of gastric polyps at 6-months (Figure 2) and at 1-year (Figure 3). DISCUSSION: Some studies have shown a 4 fold increased risk of FGP formation in patients on chronic PPI. These polyps likely form as a response to low acid production causing increased parietal cell growth due to increased gastrin and chromogranin-A circulation causing gland proliferation. Few case reports demonstrate improvement of polyp size and number with transitioning therapy from PPI to H2RB and no large trials support changing therapy to H2RB. Still, H2RBs may be an ideal alternative since studies have shown an improvement in polyp size with cessation of PPI. Though FGPs are benign, PPI may increase the risk of adenomatous polyps and biopsy is necessary to differentiate these, particularly in patients with FAP. Our case demonstrates that discontinuing PPI for H2RB may lead to a sheer reduction in both number of polyps and polyp size, making lesions more amenable to continued resection and sampling and, therefore decreasing and minimizing risk of malignancy.Figure 1.: Initial endoscopy showing multiple large Fundic Gland Polyps in patient on chronic PPI for 15 years.Figure 2.: Repeat Endoscopy 6 months after transitioning from PPI to H2RB and showing smaller and fewer number of Fundic Gland Polyps.Figure 3.: Repeat Endoscopy 1 year after transitioning to H2RB and demonstrating continued, marked improvement in the size and number of Fundic Gland Polyps.

Pharmacologic treatment of GERD: Where we are now, and where are we going?

The introduction of acid inhibition in clinical practice has revolutionized the management of acid-related diseases, leading to the virtual abolition of elective surgery for ulcer disease and relegating antireflux surgery to patients with gastroesophageal reflux disease (GERD) not adequately managed by medical therapy. Proton pump inhibitors (PPIs) are the antisecretory drugs of choice for the treatment of reflux disease. However, these drugs still leave some unmet clinical needs in GERD. PPI-refractoriness is common, and persistent symptoms are observed in up to 40-55% of daily PPI users. Potassium-competitive acid blockers (P-CABs) clearly overcome many of the drawbacks and limitations of PPIs, achieving rapid, potent, and prolonged acid suppression, offering the opportunity to address many of the unmet needs. In recent years, it has been increasingly recognized that impaired mucosal integrity is involved in the pathogenesis of GERD. As a consequence, esophageal mucosal protection has emerged as a new, promising therapeutic avenue. When P-CABS are used as add-on medications to standard treatment, a growing body of evidence suggests a significant additional benefit, especially in the relief of symptoms not responding to PPI therapy. On the contrary, reflux inhibitors are considered a promise unfulfilled, and prokinetic agents should only be used on a case-by-case basis.

Novel Therapies for Gastroesophageal Reflux Disease: Beyond Proton Pump Inhibitors.

Despite the many areas of unmet needs in gastroesophageal reflux disease (GERD), proton pump inhibitors (PPIs) remain the cornerstone of medical therapy. However, since their introduction, the therapeutic limitations of PPIs in GERD management have been increasingly recognized. In this review we discuss the new medical, endoscopic, and surgical therapeutic modalities that have been developed over the last decade. They include the potassium-competitive acid blockers (P-CABs) which provide a rapid onset, prolonged, and profound acid suppression, mucosal protectants which promote the physiological protective barrier of the esophageal mucosa, new prokinetics and neuromodulators. There are growing numbers of novel therapeutic endoscopic techniques that are under investigation or were recently introduced into the market, further expanding our therapeutic armamentarium for GERD. The development of diverse therapeutic modalities for GERD, despite the availability of PPIs, suggests that there are many areas of unmet need in GERD that will continue and drive future exploration for novel therapies.

Does Gastric Acid Suppression Encourage Antibiotic Resistance

The safety of prolonged gastric acid suppression remains unclear. A recent large randomized trial supported the overall safety of proton-pump

THE PHYSIOLOGICAL ASPECTS OF EFFECTIVE AND SAFE PROTON PUMP INHIBITOR THERAPY FOR ACID SUPPRESSION IN QUETTA

ABSTRACT
 
 The prescribing proton pump inhibitors for longtime is a rational practice now adays. In some cases patiants with peptic ulcers have to take them for whole life. The patient should have to use PPIs and there is evolved distress for the strong antagonistic effects as a result of its continuous therapy. The first discovered proton pump inhibitor is omeprazole and after some time of discovery of omeprazole , the French gastroenterologist Jean Paul Galmiche has anticipating that the unprecedented clinical effectiveness of this medicine would have lead (patients and physicians alike) to dependence, and indeed, this is the case. Once proton pump inhibitor PPI, used by large number of patients for long-term, the proton pump inhibitors, often , may result in bone weakness and sometimes cardiac distress. especially the mature women Even though PPIs being the ideal anti-secretory drugs and that innovative longer-acting compounds that developed prolonged acid suppression and they stay, no doubt, the PPIs are prescribing in all age group and give very effective result in all available medications

The Reduction in Gastric Atrophy after Helicobacter pylori Eradication Is Reduced by Treatment with Inhibitors of Gastric Acid Secretion.

Background: Helicobacter pylori (H. pylori) eradication therapy may improve gastric atrophy and intestinal metaplasia, but the results of previous studies have not always been consistent. The aim of this study was to compare the histological changes of intestinal metaplasia and gastric atrophy among the use of acid-suppressing drugs after H. pylori eradication. Methods: A cohort of 242 patients who underwent successful eradication therapy for H. pylori gastritis and surveillance endoscopy examination from 1996 to 2015 was analyzed. Changes in the histological scores of intestinal metaplasia and atrophy according to drug use (proton-pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and non-acid suppressant use) were evaluated in biopsies of the antrum and corpus using a generalized linear mixed model in all patients. Results: The mean follow-up period and number of biopsies were 5.48 ± 4.69 years and 2.62 ± 1.67 times, respectively. Improvement in the atrophy scores of both the antrum (p = 0.042) and corpus (p = 0.020) were significantly superior in patients with non-acid suppressant drug use compared with those of PPI and H2RA use. Metaplasia scores in both the antrum and corpus did not improve in all groups, and no significant differences were observed among groups in the antrum (p = 0.271) and corpus (p = 0.077). Conclusions: Prolonged acid suppression by PPIs or H2RAs may limit the recovery of gastric atrophy following H. pylori eradication.

Probing the Role of Imidazopyridine and Imidazophosphorine Scaffolds To Design Novel Proton Pump Inhibitor for H+,K+-ATPase: A DFT Study

Clinically used proton pump inhibitors (PPIs) are not perfectly suitable for prolonged acid suppression because of the short plasma half-lives of 1–1.5 h. However, tenatoprazole, an imidazopyridine...

GASTRIC FUNDIC GLAND POLYPS: CAN HISTOLOGY BE USEFUL TO PREDICT PROTON PUMP INHIBITORS USE?

Fundic gland polyps allegedly increased in frequency in recent decades, and had attracted great attention due to possible association with prolonged proton pump inhibitor therapy. Prolonged use of this drug could cause parietal cell hyperplasia, obstruction of glandular lumen and cystic dilation of the gland. This study aims to analyze clinical and pathological features of fundic gland polyps in patients with and without proton pump inhibitor therapy in a selected population from Brazil. It was selected a sample of 101 Brazilian patients (78 females and 23 males), from a five years retrospective search of the files from a private pathology laboratory. The patients had an average age of 57 years and we included patients with a histological diagnosis of fundic gland polyp. The clinical data were obtained from their files and all histological slides were reviewed and examined with hematoxylin and eosin (HE) and Giemsa. Information about the use or non-use of proton pump inhibitors (PPI) was obtained in 84 patient files. In 17 cases we could not determine if PPI were used or not. Among those in which the information was available, a positive history of anti-acid therapy was observed in 63 (75.0%) patients. Parietal cell hypertrophy/hyperplasia and parietal cell protrusions were detected in most slides. Histological findings were identical in PPI users and PPI negative patients. Helicobacter pylori infection was detected in just two samples. Epithelial dysplasia or adenocarcinoma were not observed in our cases. Histopathological analysis of fundic gland polyps could not distinguish between PPI and non-PPI related cases. Parietal cell cytoplasmic protrusions, an alleged marker of prolonged acid suppression therapy, was detected in both groups. Histological features could not discriminate anti-acid therapy related fundic glands polyps in our patients.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

The newer therapeutic alternatives to the acid‐oriented approach via targeting endothelial metabolism in esophagoprotection by 5‐hydroxytryptamine (5‐HP) and melatonin (MT)

Existing treatment of erosive and nonerosive esophagitis (NEE) which incidence has risen dramatically in recent years are mostly based on potent acid suppression. Modern data revealed that the prolonged acid suppression is associated with dismotility in foregut, extraesophageal disorders, abnormal microbiota, and induction selective apoptosis for cancer. We hypothesized that endothelial metabolism is key in multifactorial esophageal mucosa (EM) defense and studied 5‐HT/MT specific effects on EM endothelial metabolism during NEE associated to stress model (WRS) and 28 days of postprandial hyperglycemia (PPH) in rats was studied without/with 5‐HT (100 mg/kg) and MT (20 mg/kg) via VEGF, EGF, IL‐1β, TNFα synthesis by ELISA; EM injury via histological score index (HSI); functional reorganization of microangioarchitecture by mannose specific labeling.ResultsNNE constantly increased HSI in 150% in binary PPH and WRS; 5‐HT/MT decreased HIS 38% & 57%, respectively; potent MT and 5‐HT modulation vascular tone were through VEGF, TNFα synthesis better then 5‐HT. Changes in alfa‐DMan>;D‐Gal EM expression confirmed key role of endothelial metabolism in NEE and MT decreased expression of endothelial dysfunction. We concluded that MT has potent esophagoprotective effect then 5‐HT via decreasing endothelial permeability, thus may be alternative to the acid‐orientated approach.

Rabeprazole extended-release 50 mg compared with esomeprazole 40 mg and rabeprazole delayed release 20 mg

Rabeprazole extended-release 50 mg compared with esomeprazole 40 mg and rabeprazole delayed release 20 mg

A rare association of inlet patch with laryngospasm:

The inlet patch (IP) is an area of heterotopic gastric mucosa in the cervical esophagus commonly seen during upper endoscopy. Although generally asymptomatic IP has been associated with esophageal and supraesophageal symptoms and, though rare, in adult with malignant transformation. We describe two cases of recurrent episodes of laryngospasm associated with IP. In both cases there was a good response to prolonged acid suppression therapy.

An open-label, parallel, multiple-dose study comparing the pharmacokinetics and gastric acid suppression of rabeprazole extended-release with esomeprazole 40 mg and rabeprazole delayed-release 20 mg in healthy volunteers

Novel rabeprazole extended-release (ER) formulations were developed to provide prolonged gastric acid suppression and potentially improved clinical outcomes in GERD patients. To evaluate the pharmacodynamics and pharmacokinetics of six rabeprazole-ER formulations vs. esomeprazole 40 mg and rabeprazole delayed-release (DR) 20 mg. Helicobacter pylori-negative healthy subjects were randomised to receive one of eight treatments once daily for 5 days. Twenty-four-hour intragastric pH was monitored on days -1, 1 and 5. Rabeprazole plasma concentrations were measured on day 5. A total of 248 subjects (N=31/group) were enrolled in the study. On day 5, rabeprazole-ER groups provided mean durations of 18.5-20.2 h (77.0-84.1% of 24-h) with intragastric pH >4.0 vs. esomeprazole 40 mg (15.9 h/66.1% of 24-h) and rabeprazole-DR 20 mg (15.2 h/63.2% of 24-h). A similar increase was observed on day 1. While percentage of daytime (8 am-10 pm) with intragastric pH >4.0 on day 5 was overall similar across the groups, percentage of night-time (10 pm-8 am) with intragastric pH >4.0 was higher with the rabeprazole-ER groups (57.0-72.4%) vs. esomeprazole 40 mg (32.8%) and rabeprazole-DR 20 mg (34.0%). Rabeprazole-ER once daily for 5 days demonstrated a significantly longer duration of gastric acid suppression in 24 h vs. esomeprazole 40 mg and rabeprazole-DR 20 mg. The increase in acid suppression was predominantly due to prolonged acid suppression during the night-time; this was supported by the extended-release pharmacokinetic characteristics.

The pharmacodynamics and pharmacokinetics of S‐tenatoprazole‐Na 30 mg, 60 mg and 90 mg vs. esomeprazole 40 mg in healthy male subjects

Racemic tenatoprazole 40 mg/day provides more prolonged acid suppression than esomeprazole 40 mg/day. To compare pharmacodynamic and pharmacokinetic profiles of tenatoprazole and esomeprazole. A single-centre, double-blind, double-dummy, randomized, 4-way, cross-over study was conducted in 32 healthy male subjects. S-tenatoprazole-Na 30, 60 or 90 mg, or esomeprazole 40 mg was administered once daily for 5 days with 10-day washout intervals. The 24-h intragastric pH was recorded at baseline and on day 5 of each period. On day 5, median pH (5.34 +/- 0.45 and 5.19 +/- 0.52 vs. 4.76 +/- 0.82, respectively, P < 0.002) and percentage time with pH > 4 (80 +/- 11 and 77 +/- 12, vs. 63 +/- 11 respectively, P < 0.0001) for 24-h were higher with S-tenatoprazole-Na 90 mg and 60 mg than esomeprazole. In nocturnal periods, S-tenatoprazole-Na 90 mg, 60 mg and 30 mg were superior to esomeprazole with regard to median pH (5.14 +/- 0.64, 4.94 +/- 0.65, 4.65 +/- 0.86 and 3.69 +/- 1.18 respectively, P < 0.0001) and percentage time with pH > 4 (77 +/- 12, 73 +/- 17, 64 +/- 17 and 46 +/- 17 respectively, P < 0.0001). Proportion of subjects with nocturnal acid breakthrough with S-tenatoprazole-Na 90 mg, 60 mg and 30 mg was significantly less than with esomeprazole (54.8, 43.3, 56.7 and 90.3 respectively, P < 0.04). The proportion of subjects with >16 hrs with pH >4 was significantly higher with S-tenatoprazole-Na 90 mg and 60 mg than with esomeprazole (87.1%, 83.3% and 41.9% respectively, P < 0.02). S-tenatoprazole-Na produced significantly greater and more prolonged dose-dependent 24-h and nocturnal acid suppression than esomeprazole. S-tenatoprazole-Na may provide greater clinical efficacy compared with current PPIs for patients with ineffective once-daily therapy.

AGN 201904Z provides a greater and more prolonged acid suppression than esomeprazole.

AGN 201904Z provides a greater and more prolonged acid suppression than esomeprazole.

Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904‐Z

AGN 201904-Z is a new, slowly absorbed, acid-stable pro-proton pump inhibitor (pro-PPI) rapidly converted to omeprazole in the systemic circulation giving a prolonged residence time. To investigate pharmacodynamics and pharmacokinetics of AGN 201904-Z compared to esomeprazole. A randomized, open-label, parallel group, investigator-blinded intragastric pH study was conducted in 24 healthy Helicobacter pylori negative male volunteers. AGN 201904-Z enteric-coated capsules (600 mg/day) or esomeprazole delayed-release tablets (40 mg/day) were administered for 5 days. Twenty-four-hour intragastric pH recordings were acquired at baseline, days 1, 3 and 5 with blood levels of omeprazole, AGN 201904-Z and gastrin. On day 1, median nocturnal pH and proportion of nocturnal time with pH >or=4 and 24-h and nocturnal time pH >or=5 were significantly higher with AGN 201904-Z than esomeprazole. At day 5, 24-h and median nocturnal pH were significantly higher for AGN 201904-Z than esomeprazole (P < 0.0001). There was also a marked reduction in periods of nocturnal pH <4.0. Area under curve of the AGN 201904-Z active metabolite (omeprazole) in the blood was twice that of esomeprazole at day 5. AGN 201904-Z produced a significantly greater and more prolonged acid suppression than esomeprazole, and nocturnal acid suppression was more prolonged over all 5 days. AGN 201904-Z should provide true once-a-day treatment and better clinical efficacy than current PPIs.

GERD

Gastroesophageal reflux disease (GERD) is a common acid-related disorder presenting with a broad spectrum of symptoms with or without esophageal mucosal damage and/or complications. In general, the frequency and severity of symptoms and esophagitis correlate with the severity and duration of acid exposure, particularly during the nighttime. Acid suppression, with proton pump inhibitors (PPIs), is the mainstay of acute and maintenance treatment of GERD. Optimizing the choice of PPI and dose is essential for controlling GERD symptoms, accelerating healing of esophagitis, and preventing the long-term complications. Postprandial acid control is needed during the day particularly to control the symptoms. Additionally, acid control especially in those with nighttime symptoms or severe mucosal injury is important for preventing complicated GERD. However, there is a substantial proportion of patients who do not respond to routine PPI therapy probably because of inadequate acid suppression or nonacid-related problems. Failure to respond to twice daily PPIs can be partly explained by the short half-lives of currently available PPIs that may fail to adequately control acid secretion after midnight, even if given before the evening meal. There has been considerable discussion in recent years over nocturnal acid breakthrough, which is really a misnomer, as this represents the pattern of acid secretion when there is no drug available to inhibit secretion. Several approaches to properly controlling acid secretion have included b.i.d. dosing of PPIs, adding an H2-receptor antagonist at night and the development of an instant release PPI. The former approaches have not been universally effective and clinical studies not yet performed with the latter. There are several new acid suppressing drugs in development and these include PPIs with longer half-lives, which give more prolonged acid suppression. In addition, there are drugs which block the potassium channel (potassium competitive acid blockers) of the proton pump and which have a rapid onset of action. These drugs are under investigation and some may require more than 1 dose daily to adequately control acid secretion. In this review, we further explore different aspects of the need for new PPIs for the optimal management of GERD.