Acid Breakthrough Research Articles

Tegoprazan to treat gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is the most common upper gastrointestinal disorder in the United States. Although proton pump inhibitors (PPIs) are the mainstay of therapy for GERD and its complications, they have several limitations, including incomplete symptom resolution. Potassium-competitive acid blockers (P-CABs) were developed to address the limitations of PPIs as well as the need for improved antisecretory effects. Tegoprazan, the newest P-CAB, was approved in 2018 in South Korea for the treatment of erosive esophagitis (EE) and nonerosive reflux disease (NERD). A highly selective inhibitor of the H+/K+-ATPase, tegoprazan is also safe and effective for nocturnal acid breakthrough (NAB) and motility. Further studies of tegoprazan are warranted to define its potential role in the treatment of acid-related disorders.

Diffusion cell investigations into the acidic degradation of organic coatings

Protective organic coatings work by preventing contact between an aggressive environment and a vulnerable substrate. However, the long required lifetime of a barrier coating provides a challenge when attempting to evaluate coating performance. Diffusion cells can be used as a tool to estimate coating barrier properties and lifetime. In this work, a diffusion cell array was designed, constructed, and compared to previous designs, with simplicity being the most important design parameter. Sulfuric acid diffusion through five different coatings was monitored using a battery of cells, and a mathematical model was developed to simulate the experimental data and to study diffusion mechanisms. The diffusion cells allowed an objective and fast analysis of coating barrier properties. It was found that sulfuric acid deteriorated these properties as it diffused through the films. This was also expressed in the modeling results, where a three-step time dependency of the diffusion coefficient was required to simulate both acid breakthrough time and the subsequent steady-state flux. A vinyl ester-based coating proved to be the most effective barrier to sulfuric acid diffusion, followed by a polyurethane coating. Amine-cured novolac epoxies provided the least effective protection.

A Novel Model for Carbonate Formation Acidizing Based on Equivalent Permeability

Based on the equivalent permeability tensor theory, a novel carbonate acidizing mathematical model is developed, which can be adopted to simulate the simulation process for carbonate matrix-acidizing and vuggy carbonate acidizing. Wormhole-channel in the core BC21 and BC10 was simulated based on the Omer Izgec experimental data. The comparative result between the experiment and the simulation shows that the two dominating wormhole-channels, the variation of pressure-drop curve and the pressure values at the inlet of the core are almost the same. The acid-flowing channel is significantly influenced by mineral distribution heterogeneity and macropore distribution pattern in the core. The acid breakthrough volume is defined as 1.5 PV divided by pore volume of core (PV is the acid volume consumed to form the dominating wormhole channel.). If the acid is injected continuously while the wormhole has completely broken through the core, the wormhole shape only changes a little, but the end-face dissolution will be formed at the end of the core. And the conclusion could be used to optimize the acid consumption volume.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Modeling and Analysis on the Effect of Two-Phase Flow on Wormhole Propagation in Carbonate Acidizing

Summary Matrix acidizing is a stimulation technique aiming at improving formation permeability or bypassing damaged zones. In this process, acid is injected through the well into the wellbore vicinity to dissolve the rock. For either production or injection wells, the formation may contain multiple phases (oil and water) near the wellbore region when acid treatment begins. In this paper, a two-phase two-scale continuum model is developed to simulate wormhole propagation under radial coordinates. The model describes the mechanisms of convection, dispersion, and reaction in two-phase flow during matrix acidizing. We have validated the simulation model with two methods: one is to compare with the previous simulation results; the other is to compare with the analytical solution. We have investigated conditions that will affect the wormhole-propagation process, including rock wettability, oil viscosity, and initial oil saturation. It is found that the water/oil mobility ratio is a key factor that affects acidizing efficiency. In addition, we have proposed a new criterion for acid breakthrough because the pressure response is affected not only by reaction, but also by overall mobility change in the formation. The traditional criterion for the single-phase model is no longer applicable to the current two-phase model. The results show that adverse water/oil mobility ratio leads to a higher efficiency for wormhole breakthrough. In carbonate reservoirs with heterogeneity, water/oil displacement and wormhole propagation contribute to narrower, less-branched channels. For the first time, it is possible to simulate formations with multiple phases during carbonate acidizing. The presented model improves our understanding in the optimization of carbonate acidizing.

Augmentation of Permeability of Drugs having P-Glycoprotein Inhibition for Efficiency in Nocturnal Acid Breakthrough

Purpose : Ranitidine is a BCS class III drug having low oral, lipophilicity and is susceptible to the Pglycoprotein (P-gp) efflux mechanism. Permeation enhancers enhance the bioavailability of ranitidine by increasing the partition coefficient (K oct/buffer there by increasing the lipophilicity and permeability. The main) aim of the present work is to overcome the problems of ranitidine bioavailability by expending permeation enhancers and P-gp inhibitors. Methodology : The existence of synergistic activity in permeation enhancement effect was studied using EDTA, citric acid, oleic acid, caprylic acid, sodium glycocholate and sodium deoxycholate. The P-gp inhibitor used here was felodipine, a first generation inhibitor showed P-gp inhibition activity at a concentration where it shows it pharmacological action. Three formulations were formulated and subjected to various physiochemical evaluations like weight variation, friability, hardness, drug content, in vitro drug release and kinetic studies.A continuous dissolution-absorption system was designed using everted intestine segment. Results : Synergistic effect in enhancing the permeability of ranitidine was found to exist between chelating agents in combination with fatty acids and its derivatives. From the precompression parameters data of the lubricated blend, it was found that the flow ability was good and can be compressed into tablets by direct compression method. The formulated ranitidine immediate release tablets exhibited first order release kinetics, resulting in rapid and complete release for two h. Conclusion : The effective drug permeability (P eff ) after three h or formulations TAB, TAB37, TAB37-PGP and TAB-MARK is 2.60, 3.17, 3.66 and 2.68, respectively. This shows that the permeability through chick intestine is more from TAB37-PGP by increased P-gp inhibition.

Possibilities of pH impedance and high-resolution manometry in managing patients with refractory gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is a common condition that has a substantial impact on quality of life in patients and is a leading risk factor for esophageal adenocarcinoma. Now therapy with proton pump inhibitors (PPIs) is a basic method in the treatment of patients with GERD; however, one third of the patients do not respond to the therapy used. The causes of refractory GERD are a fairly large group of heterogeneous factors contributing to the inefficacy of PPIs in adequate dosage. Among these factors, there is low compliance by patients to the prescribed treatment regimen; nocturnal acid breakthrough; СУР2С19 gene polymorphism; chiasm syndrome with functional diseases of the gastrointestinal tract; non-acidic refluxes in a patient; thoracic esophageal motility disorders; the increased number and duration of transient lower esophageal sphincter relaxation periods; hiatus hernia; and misdiagnosis. 24-hour pH impedance and high-resolution esophageal manometry are now the most informative diagnostic techniques in patients who fail to respond to PPI therapy. These techniques allow one to timely recognize the causes of refractory GERD, to make a differential diagnosis with other nosological entities, and to timely correct therapy for each individual patient.

The Effect of H2 Receptor Antagonist in Acid Inhibition and Its Clinical Efficacy.

The first histamine H2 receptor antagonists (H2RAs) were developed in the early 1970s. They played a dominant role in treating peptic ulcer disease and gastroesophageal reflux disease (GERD). H2RAs block the production of acid by H+, K+-ATPase at the parietal cells and produce gastric luminal anacidity for varying periods. H2RAs are highly selective, and they do not affect H1 receptors. Moreover, they are not anticholinergic agents. Sequential development of H2RAs, proton pump inhibitors (PPIs), and discovery of Helicobacter pylori infection changed the paradigm of peptic ulcer disease with marked decrease of morbidity and mortality. PPIs are known to be the most effective drugs that are currently available for suppressing gastric acid secretion. Many studies have shown its superiority over H2RAs as a treatment for acid-related disorders, such as peptic ulcer disease, GERD, and Zollinger-Ellison syndrome. However, other studies have reported that PPIs may not be able to render stomach achlorhydric and have identified a phenomenon of increasing gastric acidity at night in individuals receiving a PPI twice daily. These nocturnal acid breakthrough episodes can be eliminated with an addition of H2RAs at night. The effectiveness of nighttime dose of H2RA suggests a major role of histamine in nocturnal acid secretion. H2RAs reduce secretion of gastric acid, and each H2RA also has specific effects. For instance, nizitidine alleviates not only symptoms of GERD, but also provokes gastric emptying, resulting in clinical symptom improvement of functional dyspepsia. The aim of this paper was to review the characteristics and role of H2RAs and assess the future strategy and treatment of upper gastrointestinal disease, including acid related disorders.

Laryngopharyngeal reflux disease (LPRD) –Review article-

Laryngopharyngeal reflux disease (LPRD) is caused by the back-flow of stomach contents and/or gastric acid into the laryngopharynx. Symptoms of laryngopharyngeal reflux (LPR) include hoarseness, sore throat, throat-clearing, chronic cough, globus sensation, dysphagia, and postnasal drip. LPRD is diagnosed in approximately 10% of patients presenting to outpatient otolaryngology clinics and in more than 50% of patients presenting with voice complaints. Gastroesophageal reflux disease (GERD) and LPRD may be associated with periodontitis, sleep disorders, and otolaryngology disease.Gastric acid reflux with LPRD is thought to cause laryngeal granulomas.The most useful endolaryngeal signs for diagnosing LPRD are erythema, edema, and interarytenoid hypertrophy. Ambulatory 24-h dual-probe pH monitoring can be misleading; false-positive outcomes may occur due to artifacts in the upper probe, and false-negative outcomes can occur as a result of the intermittent character of reflux episodes. In patients with LPRD, proton pump inhibitors (PPIs) have been shown to significantly improve reflux laryngitis. However, some patients are resistant to antacid therapy. Nocturnal acid breakthrough (NAB) on PPI has been suggested as one reason for resistance to PPI therapy. Administration of a PPI with the additional bedtime administration of a histamine-2 receptor antagonist has been shown to be an effective treatment of LPRD with NAB. Recently, potassium-competitive acid blockers have been proposed as an effective treatment of antacid-resistant disease.

NMR as a Characterization Tool for Wormholes

Summary Acidizing is a common practice that aims to recover the initial skin factor or even decrease it further. Acids tend to create conductive channels (wormholes) through carbonate formations that connect the reservoir to the wellbore and bypass the damaged zones. Optimum wormholes are formed when certain conditions are met, such as optimum acid concentration and optimum injection rate. To thoroughly grasp wormhole creation, several characterization techniques should be performed. Computed-tomography (CT) scan and differential-pressure data are two practices commonly used for characterization of wormholing in laboratories by use of core-plug samples. Differential-pressure data and CT scan can verify the occurrence of acid breakthrough and qualitatively suggest the size and path of a wormhole. Nuclear magnetic resonance (NMR) was introduced in earlier studies as a new characterization tool for wormholes. NMR can detect the changes in micro- and macropores that are caused by acid injection, and it can indicate changes in interconnectivity between different pore systems and detect the materialization of formation damage induced by injected acids. However, the NMR technique cannot detect the new porosity corresponding to the generated wormhole because of an inability to sustain saturation fluids inside the core-plug samples. In this study, the NMR measuring method is further improved by use of a customized polytetrafluoroethylene (PTFE) tube as a container for core-plug samples. Because PTFE material does not interfere with NMR readings, this improvement allows the core-plug samples to maintain full saturation, which enables the detection of the new wormhole porosity. As a result, NMR can indicate different characteristics of the generated porosity, including the size of the wormhole and the changes in diffusion coupling and the distribution of each pore size. This technique can elaborate new aspects of wormhole generation and characteristics in carbonate reservoirs, in addition to assessing the damage caused by the stimulation fluid.

Controlling on-demand gastric acidity in obese subjects: a randomized, controlled trial comparing a single dose of 20 mg rabeprazole and 20 mg omeprazole.

BackgroundObesity is associated with a risk of gastroesophageal reflux disease. The pharmacodynamic efficacy of proton pump inhibitors has not been specifically evaluated in obese subjects. The aim of this study was to compare the antisecretory response to a single oral dose of 20 mg rabeprazole, 20 mg omeprazole and placebo in obese subjects.MethodsGastric pH was monitored for 24 hours on three separate occasions in eighteen H. pylori-negative, asymptomatic obese subjects. Subjects were given omeprazole, rabeprazole or placebo in a randomized order and in a double-blind fashion. The main analysis criterion was 24-h percent of time post dose with intragastric pH above 3; secondary criteria were percentage of time above pH 4, median pH, [H+] concentrations and nocturnal acid breakthrough (NAB). Results were analyzed using linear mixed models and Wilks test comparing variances.Results24-h median [IQ] percentages of time with gastric pH above 3 and 4 were higher with rabeprazole than omeprazole (46 [37–55] vs. 30 [15–55] %, 9 [5-11] % for placebo) but the differences did not reach statistical significance (p = 0.11 and 0.24, respectively). Median acid concentrations were significantly lower with rabeprazole than with omeprazole and placebo (22 [14–53] vs. 54 [19–130] and 95 [73–170] mmoles/l, p < 0.01) for all periods. The number of NAB was significantly lower with rabeprazole than with omeprazole (median 1 [1,2] vs. 2 [1-3], p = 0.04). Variances of 24-h data (pH above 3 and 4, median pH, [H+] concentrations) were significantly lower with rabeprazole than with omeprazole (p < 0.0001).ConclusionsIn asymptomatic obese subjects the gastric antisecretory response to a single dose of rabeprazole and omeprazole was strong and not significantly different between drugs despite a significantly more homogeneous response with rabeprazole.Trial registrationClinicalTrial.gov: NCT01136317

Most Infants with Dilating Vesicoureteral Reflux can be Treated Nonoperatively

Dilating vesicoureteral reflux provokes concern for physicians and parents that often leads to corrective surgery in young children. Since there are limited data describing the natural history of dilating vesicoureteral reflux in infants, we identified factors predictive of resolution/improvement in infants initially treated nonoperatively. We reviewed the medical records of 90 infants 6 months old or younger from 2004 to 2010 who were referred for prenatal hydronephrosis or initial febrile urinary tract infection and found to have dilating vesicoureteral reflux (grade 3 or greater). Variables of interest included presentation, dimercapto-succinic acid results, sex, breakthrough febrile urinary tract infections, reflux grade and bilateral reflux. Cox regression analysis was performed to determine predictors of spontaneous resolution and/or improvement to reflux grade less than 3 as well as predictors of surgical intervention. Included in final analysis were 80 infants (113 renal units). Of the patients 51 (64%) experienced spontaneous resolution/improvement with a mean followup of 29 months before resolution, discharge home and/or end of followup. Only 20 patients (25%) underwent surgery. Cox regression analysis revealed that a normal initial dimercapto-succinic acid scan, initial reflux grade less than 5 and absent breakthrough febrile urinary tract infections were predictive of reflux resolution/improvement (p <0.05). Dimercapto-succinic acid scan abnormalities, prenatal hydronephrosis and breakthrough febrile urinary tract infections were significant predictors of surgery (p <0.05). Dilating vesicoureteral reflux in infancy often resolves/improves spontaneously. Therefore, surgery should be directed toward patients unlikely to experience resolution, ie those with an abnormal initial dimercapto-succinic acid scan, grade 5 vesicoureteral reflux and breakthrough febrile urinary tract infections.

Primary Care Practitioners’ Views on the Use of Proton Pump Inhibitors Associated with Alginate-Antacids for Better Gastroesophageal Reflux Disease Symptom Control: Results of a National Survey in Spain

Background: Gastroesophageal reflux disease (GERD) is a prevalent disease in Western countries. Despite effective treatment modalities, in some patients total symptom control is not achieved in clinical practice. A cross-sectional study was designed to assess primary care practitioners’ views on the effectiveness of proton pump inhibitors (PPI) as monotherapy in the control of the most common symptoms of GERD (heartburn and regurgitation), as well as to determine the level of implementation of the “combined therapy” (PPI + alginate-antacids). Methods: A questionnaire on different aspects of the management of GERD was completed by 1491 primary care physicians. The questionnaire was composed of 11 close-ended questions with one-choice answer, with a total of 52 items, covering the main data from patients presenting with GERD. Results: Treatment with PPI alone was mostly considered insufficient for the control of GERD symptoms. The combined treatment of PPI + alginate-antacids was used for 37% and 21% of physicians for treating heart-burn and regurgitation, respectively. A better control of symptoms, an increase in the onset of action and to reduce nocturnal acid breakthrough were the most frequently argued reasons for the use of PPI + alginate-antacids. A high percentage of participants believed that treatment with PPI alone was insufficient for the control of symptoms and 39.8% of physicians reported the persistence of heartburn, 38.6% the persistence of regurgitation and 43.2% the persistence of epigastric discomfort in more than 25% of their patients treated with PPI as monotherapy. The most common schedule for the use of the antacid medication was on demand. Conclusions: Spanish primary care physicians consider that a high proportion of GERD patients continue to suffer from symptoms during PPI treatment alone. Ondemand “combined therapy” (PPI + antacid) is considered an efficient option to control reflux symptoms still troublesome in patients with PPI treatment alone.

Experimental Study of a Viscoelastic Surfactant-Based in Situ Self-Diverting Acid System: Results and Interpretation

Recently, self-diverting acid systems based on viscoelastic surfactants (SDVAs) have been successfully used for carbonate reservoir treatment. Changes in the SDVA viscosity during the interaction with carbonate reservoirs are associated with the transformation of spherical surfactant micelles into worm-shaped micelles as the acid concentration decreases and the fluid salinity increases. The highly viscous fluid acts as a temporary barrier and diverts the acid fluid into the untreated lower permeability zones. After treatment, the SDVA barrier breaks down when it makes contact with newly formed hydrocarbons. The objectives of this study were to examine in detail the viscoelastic surfactant effect on the HCl and calcite reaction and to examine the effects of the surfactant and acid concentrations on the SDVA apparent viscosity. Rheological measurements were conducted using rotational viscometers at 25 °C. A proposed semi-empirical rheological model describes the relationships between the apparent viscosity, rate, and HCl concentration. The core flooding tests were conducted in a specialized laboratory unit to simulate the downhole conditions. The testing unit allows for control of the pressure, temperature, and injected volume of acid flowing across the core sample. The results showed that the pressure drop varies as a function of the pumped fluid pore volume. The steady increase in the pressure as the fluid entered the core was a good indication of the actual viscosity increase in the porous rock during acid spending. The experiments were conducted using various flow rates. The core flow tests indicated that the SDVA surfactant delayed the acid breakthrough in carbonate cores. The mathematical model describing the results, obtained from the acidification experiments, is presented.

New Insights Into the Propagation of Emulsified Acids in Vuggy Dolomitic Rocks

Summary Carbonate formations are very complex in their pore structure and exhibit a wide variety of pore classes, such as interparticle porosity, moldic porosity, vuggy porosity, intercrystalline porosity, and microporosity. Understanding the role of pore class in the performance of emulsified-acid treatments and characterizing the physics of the flow in the acid propagation are the objectives of our study. The study was performed by use of vuggy-dolomite cores that represent mainly the vuggy-porosity-dominated structure, whereas the homogeneous cores used represent the intercrystalline pore structure. Coreflood experiments were conducted on 6 × 1.5-in. cores by use of emulsified acid formulated at 1 vol% emulsifier and 0.7 acid volume fraction. The objective of this set of experiments is to determine the acid pore volume (PV) to breakthrough for each carbonate pore class at different injection flow rates. In this paper, we examine whether the heterogeneities observable at the thin-section scale have a significant influence on the results of the emulsified-acid coreflood experiments. The heterogeneities were characterized by use of thin-section observations, tracer experiments, scanning electron microscopy (SEM), and resistivity measurements. Thin-section observations provide means to study the size of vugs and their distribution and connectivity, and to explain the contribution of the pore class in the acid propagation. Also, the rotating-disk experiments of emulsified acid with dolomite were related to our coreflood experimental results. The acid PV to breakthrough for vuggy-porosity-dominated rocks, ranging from 0.1 to 0.3, was observed to be low when compared with homogeneous carbonates (intercrystalline pore structure) with PVbt ranging from 2.5 to 3.5. Also, the wormhole dissolution pattern was found to be significantly different in vuggy rocks than that in homogeneous ones. Thin-section observations, tracer results, and the coreflood experiments indicate that the vugs are distributed in a manner that creates a preferential flow path, which can cause a rapid acid breakthrough and effective wormholing rather than those with a uniform pore structure. The rotating-disk results also showed that the reaction kinetics played a role in determining the wormhole pattern.

Statistical Optimization and Fabrication of a Press Coated Pulsatile Dosage Form to Treat Nocturnal Acid Breakthrough

Present work focuses on the use of mimosa seed gum to develop a drug delivery system making combined use of floating and pulsatile principles, for the chrono-prevention of nocturnal acid breakthrough. The desired aim was achieved by fabricating a floating delivery system bearing time - lagged coating of Mimosa pudica seed polymer for the programmed release of Famotidine. Response Surface Methodology was the statistical tool that was employed for experiment designing, mathematical model generation and optimization study. A 3(2) full factorial design was used in designing the experiment.% weight ratio of mimosa gum to hydroxy propyl methyl cellulose in the coating combination and the coating weight were the independent variables, whereas the lag time and the cumulative % drug release in 360 minutes were the observed responses. Results revealed that both the coating composition and the coating weight significantly affected the release of drug from the dosage form. The optimized formulation prepared according to the computer generated software, Design-Expert(®) deciphered response which were in close proximity with the experimental responses, thus confirming the robustness as well as accuracy of the predicted model for the utilization of natural polymer like mimosa seed gum for the chronotherapeutic treatment of nocturnal acid breakthrough.

Tu1830 Predictors of Slow Healing of Reflux Esophagitis With Potent Acid Suppression

Introduction: Proton pump inhibitors (PPIs) are now widely used for the treatment of acidrelated diseases, such as peptic ulcer and gastroesophageal reflux disease (GERD). PPIs which are weak-base prodrugs are activated in an acidic condition and only inhibit H+/K+ATPase that has already been activated. Therefore, the effect of PPIs on acid-related diseases is slow onset and their maximum efficacy can be achieved after several days of dosing, leading to unmet medical needs such as nocturnal acid breakthrough and unsatisfied symptom relief. Methods: We investigated the pharmacological profiles of YH4808, a novel potent, highly selective K+-competitive acid blocker (P-CAB), in terms of hog gastric H+/K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in animal models, in comparison with esomeprazole. In addition, a quantitative whole body autoradiography (QWBA) study was performed with [14C]YH4808 (10 mg/kg) in rats to characterize tissue distribution. Results: YH4808 inhibited H+/K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 3.4 nM which is more potent than that of esomeprazole. The inhibitory mechanism of YH4808 on H+/K+-ATPase was a competitive antagonism to the K+-binding site of H+/K+-ATPase, and it was also a reversible inhibition. In a selectivity assay, YH4808 showed 3,000-fold greater selectivity against Na+/K+-ATPase. In pylorus-ligated rats, oral administration of YH4808 inhibited basal acid secretion in a dose-dependent manner with the ID50 value of 1.1 mg/kg. Anti-secretory activity of YH4808 against histamine-stimulated acid secretion in rats after IV injection (ID50=0.1 mg/kg) was stronger than that of esomeprazole (ID50=0.9 mg/kg). In Heidenhain pouch dogs, IV administration of YH4808 inhibited histamine-stimulated acid secretion in a dose-dependent manner with almost complete inhibition at the dose of 0.6 mg/kg. In a reflux esophagitis model, intraduodenal administration of YH4808 prevented esophageal lesions by 30, 82 and 91% at a dose of 1, 3, and 10 mg/kg, respectively while esomeprazole reduced the lesion by 47% at 10 mg/kg. A QWBA study in rats showed YH4808 accumulated and was retained in the gastric tissue for more than 24h after oral administration. Conclusion: YH4808, a novel selective P-CAB exerted a potent, longer-lasting anti-secretory efficacy through high accumulation in the gastric tissue, which translated into the more effective inhibition of reflux esophagitis than esomeprazole. These findings indicate that YH4808 can provide significant clinical benefits to patients with acid-related diseases.

Tu1827 Yh4808, a Potent, Highly Selective K+-Competitive Acid Blocker, Suppressed Rat Acute Reflux Esophagitis More Effectively Than Esomeprazole

Introduction: Proton pump inhibitors (PPIs) are now widely used for the treatment of acidrelated diseases, such as peptic ulcer and gastroesophageal reflux disease (GERD). PPIs which are weak-base prodrugs are activated in an acidic condition and only inhibit H+/K+ATPase that has already been activated. Therefore, the effect of PPIs on acid-related diseases is slow onset and their maximum efficacy can be achieved after several days of dosing, leading to unmet medical needs such as nocturnal acid breakthrough and unsatisfied symptom relief. Methods: We investigated the pharmacological profiles of YH4808, a novel potent, highly selective K+-competitive acid blocker (P-CAB), in terms of hog gastric H+/K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in animal models, in comparison with esomeprazole. In addition, a quantitative whole body autoradiography (QWBA) study was performed with [14C]YH4808 (10 mg/kg) in rats to characterize tissue distribution. Results: YH4808 inhibited H+/K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 3.4 nM which is more potent than that of esomeprazole. The inhibitory mechanism of YH4808 on H+/K+-ATPase was a competitive antagonism to the K+-binding site of H+/K+-ATPase, and it was also a reversible inhibition. In a selectivity assay, YH4808 showed 3,000-fold greater selectivity against Na+/K+-ATPase. In pylorus-ligated rats, oral administration of YH4808 inhibited basal acid secretion in a dose-dependent manner with the ID50 value of 1.1 mg/kg. Anti-secretory activity of YH4808 against histamine-stimulated acid secretion in rats after IV injection (ID50=0.1 mg/kg) was stronger than that of esomeprazole (ID50=0.9 mg/kg). In Heidenhain pouch dogs, IV administration of YH4808 inhibited histamine-stimulated acid secretion in a dose-dependent manner with almost complete inhibition at the dose of 0.6 mg/kg. In a reflux esophagitis model, intraduodenal administration of YH4808 prevented esophageal lesions by 30, 82 and 91% at a dose of 1, 3, and 10 mg/kg, respectively while esomeprazole reduced the lesion by 47% at 10 mg/kg. A QWBA study in rats showed YH4808 accumulated and was retained in the gastric tissue for more than 24h after oral administration. Conclusion: YH4808, a novel selective P-CAB exerted a potent, longer-lasting anti-secretory efficacy through high accumulation in the gastric tissue, which translated into the more effective inhibition of reflux esophagitis than esomeprazole. These findings indicate that YH4808 can provide significant clinical benefits to patients with acid-related diseases.

Tu1828 Impact of Regurgitation on Health-Related Quality of Life (HRQoL) in Gastroesophageal Reflux Disease (GERD)

Introduction: Proton pump inhibitors (PPIs) are now widely used for the treatment of acidrelated diseases, such as peptic ulcer and gastroesophageal reflux disease (GERD). PPIs which are weak-base prodrugs are activated in an acidic condition and only inhibit H+/K+ATPase that has already been activated. Therefore, the effect of PPIs on acid-related diseases is slow onset and their maximum efficacy can be achieved after several days of dosing, leading to unmet medical needs such as nocturnal acid breakthrough and unsatisfied symptom relief. Methods: We investigated the pharmacological profiles of YH4808, a novel potent, highly selective K+-competitive acid blocker (P-CAB), in terms of hog gastric H+/K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in animal models, in comparison with esomeprazole. In addition, a quantitative whole body autoradiography (QWBA) study was performed with [14C]YH4808 (10 mg/kg) in rats to characterize tissue distribution. Results: YH4808 inhibited H+/K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 3.4 nM which is more potent than that of esomeprazole. The inhibitory mechanism of YH4808 on H+/K+-ATPase was a competitive antagonism to the K+-binding site of H+/K+-ATPase, and it was also a reversible inhibition. In a selectivity assay, YH4808 showed 3,000-fold greater selectivity against Na+/K+-ATPase. In pylorus-ligated rats, oral administration of YH4808 inhibited basal acid secretion in a dose-dependent manner with the ID50 value of 1.1 mg/kg. Anti-secretory activity of YH4808 against histamine-stimulated acid secretion in rats after IV injection (ID50=0.1 mg/kg) was stronger than that of esomeprazole (ID50=0.9 mg/kg). In Heidenhain pouch dogs, IV administration of YH4808 inhibited histamine-stimulated acid secretion in a dose-dependent manner with almost complete inhibition at the dose of 0.6 mg/kg. In a reflux esophagitis model, intraduodenal administration of YH4808 prevented esophageal lesions by 30, 82 and 91% at a dose of 1, 3, and 10 mg/kg, respectively while esomeprazole reduced the lesion by 47% at 10 mg/kg. A QWBA study in rats showed YH4808 accumulated and was retained in the gastric tissue for more than 24h after oral administration. Conclusion: YH4808, a novel selective P-CAB exerted a potent, longer-lasting anti-secretory efficacy through high accumulation in the gastric tissue, which translated into the more effective inhibition of reflux esophagitis than esomeprazole. These findings indicate that YH4808 can provide significant clinical benefits to patients with acid-related diseases.

A novel once daily microparticulate dosage form comprising lansoprazole to prevent nocturnal acid breakthrough in the case of gastro-esophageal reflux disease: preparation, pharmacokinetic and pharmacodynamic evaluation

The objective of this study was to formulate and evaluate the lansoprazole (LPZ)-loaded microparticles to prevent nocturnal acid breakthrough in the case of gastro-esophageal reflux disease (GERD). The microparticulate delivery system was prepared by solvent evaporation method using Eudragit RS100 as a matrix polymer followed by enteric coated with Eudragit S100 and hydroxypropyl methylcellulose phthalate HP55 using spray drying method. The enteric coated microparticles were stable in gastric pH condition. In vivo pharmacokinetic and pharmacodynamic studies in male Wistar rats demonstrated that enteric coated microparticles sustained release of LPZ and promoted ulcer healing activity. In other words, the microparticulate dosage form provided effective drug concentration for a longer period as compared to conventional extended release dosage form, and showed sufficient anti-acid secretion activity to treat acid related disorders including the enrichment of nocturnal acid breakthrough event based on a once daily administration.