Gastric Acid-related Disorders Research Articles

Effects of proton pump inhibitor (PPI) use on migraine - a critical review.

Proton pump inhibitor (PPI) drugs are widely used and are among the most significant achievements of modern pharmacology. Their primary purpose is treating and preventing gastric acid-related disorders. Migraine and PPI intake are prevalent, and many people are affected by both. In the last few years, a potential link between PPI intake and the development of headaches-especially migraine-has come to increased attention. In this review, we critically examine the scientific data concerning the co-occurrence of these two entities. There seems to be a possible link between the use of PPIs and the occurrence of headache, especially migraine, suggesting a pathophysiological connection on several levels. Moreover, PPI use is only partially without side effects, even if these may not occur immediately. Whether the relation is causative or merely co-existential is currently not yet clear. The influence of genetics, environment, gut microbiome, medication intake and evolution of headache is multidirectional. A relation between the prevalence of migraine and the use of PPIs on a population and personal level seems likely. Although PPIs have many advantages, they should be prescribed with caution, especially in patients who suffer from headaches and migraine. In this narrative review, we aim to critically evaluate existing data and offer a potential approach to accurately identify any connections and interactions, leading to a better understanding of how these conditions may influence each other.

Proton pump inhibitors and all-cause mortality risk among cancer patients

BACKGROUND Proton pump inhibitors (PPIs) are widely used, including among cancer patients, to manage gastroesophageal reflux and other gastric acid-related disorders. Recent evidence suggests associations between long-term PPI use and higher risks for various adverse health outcomes, including greater mortality. AIM To investigate the association between PPI use and all-cause mortality among cancer patients by a comprehensive analysis after adjustment for various confounders and a robust methodological approach to minimize bias. METHODS This retrospective cohort study used data from the TriNetX research network, with electronic health records from multiple healthcare organizations. The study employed a new-user, active comparator design, which compared newly treated PPI users with non-users and newly treated histamine2 receptor antagonists (H2RA) users among adult cancer patients. Newly prescribed PPIs (esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole) users were compared to non-users or newly prescribed H2RAs (cimetidine, famotidine, nizatidine, or ranitidine) users. The primary outcome was all-cause mortality. Each patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence interval (CI). RESULTS During the follow-up period (median 5.4 ± 1.8 years for PPI users and 6.5 ± 1.0 years for non-users), PPI users demonstrated a higher all-cause mortality rate than non-users after 1 year, 2 years, and at the end of follow up (HRs: 2.34-2.72). Compared with H2RA users, PPI users demonstrated a higher rate of all-cause mortality HR: 1.51 (95%CI: 1.41-1.69). Similar results were observed across sensitivity analyses by excluding deaths from the first 9 months and 1-year post-exposure, confirming the robustness of these findings. In a sensitivity analysis, we analyzed all-cause mortality outcomes between former PPI users and individuals who have never used PPIs, providing insights into the long-term effects of past PPI use. In addition, at 1-year follow-up, the analysis revealed a significant difference in mortality rates between former PPI users and non-users (HR: 1.84; 95%CI: 1.82-1.96). CONCLUSION PPI use among cancer patients was associated with a higher risk of all-cause mortality compared to non-users or H2RA users. These findings emphasize the need for cautious use of PPIs in cancer patients and suggest that alternative treatments should be considered when clinically feasible. However, further studies are needed to corroborate our findings, given the significant adverse outcomes in cancer patients.

DepRescribing inapprOpriate Proton Pump InhibiTors (DROPIT): study protocol of a cluster-randomised controlled trial in Swiss primary care

ObjectivesProton pump inhibitors (PPIs) are widely prescribed medications and commonly used for the treatment of gastric acid-related disorders. Nevertheless, PPIs are often overused leading to potential adverse effects and unnecessary...

Fexuprazan safeguards the esophagus from hydrochloric acid-induced damage by suppressing NLRP1/Caspase-1/GSDMD pyroptotic pathway.

Proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) are widely used to manage gastric acid-related disorders by inhibiting hydrochloric acid (HCl) secretion from parietal cells in the stomach. Although PPIs are known to have anti-inflammatory properties beyond their role in inhibiting gastric acid secretion, research on P-CABs is lacking. In this study, we aimed to investigate whether all available P-CABs exhibit anti-inflammatory effects in gastroesophageal reflux-induced esophagitis and to elucidate the underlying mechanisms. Het-1A cells, normal esophageal epithelial cells, were treated with HCl (pH 4) for 30 min. Esomeprazole, a representative PPI, and three currently marketed P-CABs (vonoprazan, tegoprazan, and fexuprazan) were used for pretreatment. Total RNA sequencing was performed using Het-1A cells pretreated with 1% DMSO or fexuprazan, followed by exposure to HCl. Pyroptosis was measured using lactate dehydrogenase (LDH) release and Annexin V-FITC/PI staining. Western blotting, qRT-PCR, and ELISA were used to determine the expression of the related genes. Pretreatment with esomeprazole, vonoprazan, tegoprazan, and fexuprazan significantly inhibited the HCl-induced pro-inflammatory cytokines, including IL-6, IL-8, IL-1β, and TNF-α. Fexuprazan and vonoprazan significantly attenuated the HCl-induced pyroptosis rate, as assessed by elevated LDH release and Annexin V-FITC/PI staining, whereas esomeprazole and tegoprazan did not. RNA sequencing revealed that NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) was significantly reduced in Het-1A cells pretreated with fexuprazan compared to those treated with DMSO. Fexuprazan and vonoprazan markedly reduced the HCl-induced transcriptional and translational expression of genes involved in the pyroptosis pathway, including NLRP1, Caspase-1, gasdermin D, and IL-1β. Notably, fexuprazan reduced the HCl-induced increase in pyroptosis and IL-1β using siRNA, even in the presence of NLRP1 knockdown. Fexuprazan, tested on inflammatory THP-1 macrophage cells, significantly reduced NLRP1 expression and inhibited lipopolysaccharide-induced pyroptosis. Our findings reveal that all p-CABs exhibit anti-inflammatory properties, while fexuprazan inhibits inflammation and pyroptosis of esophageal cells caused by the gastric acid. Therefore, it is presumed to have additional benefits in gastroesophageal reflux disease in addition to suppressing gastric acid secretion.

Individualized prevention of proton pump inhibitor related adverse events by risk stratification

Proton pump inhibitors (PPIs) are commonly used for gastric acid-related disorders, but their safety profile and risk stratification for high-burden diseases need further investigation. Analyzing over 2 million participants from five prospective cohorts from the US, the UK, and China, we found that PPI use correlated with increased risk of 15 leading global diseases, such as ischemic heart disease, diabetes, respiratory infections, and chronic kidney disease. These associations showed dose-response relationships and consistency across different PPI types. PPI-related absolute risks increased with baseline risks, with approximately 82% of cases occurring in those at the upper 40% of the baseline predicted risk, and only 11.5% of cases occurring in individuals at the lower 50% of the baseline risk. While statistical association does not necessarily imply causation, its potential safety concerns suggest that personalized use of PPIs through risk stratification might guide appropriate decision-making for patients, clinicians, and the public.

Clinical Implications of Proton Pump Inhibitors and Vonoprazan Micro/Nano Drug Delivery Systems for Gastric Acid-Related Disorders and Imaging.

Excessive stomach acid or bacterial infection are the root causes of gastric acid-related disorders, such as peptic ulcer disease and gastroesophageal reflux disease. Proton pump inhibitors including lansoprazole, omeprazole, esomeprazole, rabeprazole, etc. are medications used to treat gastric acid-related diseases. One of the most effective drugs for treating gastroesophageal reflux disease is vonoprazan, owing to its ability to strongly inhibit gastric acid. Proton pump inhibitors and vonoprazan work in distinct ways to prevent the production of stomach acid. Vonoprazan inhibits acid secretion by blocking the potassium-competitive acid blocker receptor, whereas proton pump inhibitors function by irreversibly blocking the proton pump in the parietal cells of the stomach. Delayed release tablets, delayed release capsules, minitablets, pellets, bilayer, floating, mucoadhesive tablets and nanoparticles, are some of the methods used in the development of micro/nano formulations with proton pump inhibitors and vonoprazan. Diagnosis and therapy of gastric acid-related illnesses, particularly those treated with drugs such as vonoprazan and proton pump inhibitors, rely heavily on imaging modalities such as CT scans, X-rays, endoscopy, fluorescence and HRM imaging. This review provides a comprehensive update on various micro/nanoformulations of proton pump inhibitors and vonoprazan. Moreover, we provide an outlook on clinical imaging of proton pump inhibitors and vonoprazan formulation for gastric acid related diseases. We have limited our discussion to case studies and clinical trials on proton pump inhibitors and vonoprazan for gastric acid related disease.

History and Pharmacological Mechanism of Gastric Acid-suppressive Drugs

Gastric acid-related disorders are commonly encountered in clinical practice. Acetylcholine, gastrin, and histamine are physiological agonists that stimulate acid secretion from parietal cells. Histamine plays a decisive role in the transformation of parietal cells into acid-secreting forms. The H<sup>+</sup>, K<sup>+</sup>- ATPase proton pump, which represents the final step of acid secretion, translocates from cytoplasmic tubulovesicles to secretory canaliculi upon parietal cell stimulation and facilitates exchange of intracellular H<sup>+</sup> with extracellular K<sup>+</sup> in a 1:1 ratio. Histamine-2 receptor antagonists and proton pump inhibitors (PPIs) are widely used in clinical practice, and potassium-competitive acid blockers (P-CABs) have gained attention in recent times. P-CABs address the unmet needs of patients who receive conventional PPIs and have broadened the spectrum of drug choices; however, further research is warranted to confirm long-term safety of these drugs. Comprehensive understanding of the mechanisms of actions, characteristics, advantages and disadvantages, and the adverse effect profile is essential for appropriate prescription of gastric acid-suppressive drugs. In this review, we provide a developing history and outline the pharmacological mechanisms underlying various gastric acid-suppressive drugs used in clinical settings.

Role of Potassium-competitive Acid Blockers in the Treatment of Gastric Acid-related Disorders

Owing to their superior pharmacokinetic and pharmacodynamic profiles, potassium-competitive acid blockers (P-CABs) score over proton pump inhibitors (PPIs) in the treatment of gastric acid-related disorders and may provide clinical benefit in the management of these conditions. Previous studies have compared P-CABs with PPIs for treatment of gastric acid-related disorders, and current data show that P-CABs are non-inferior to PPIs in the treatment of erosive esophagitis and as maintenance therapy. P-CABs are useful for effective healing and as maintenance medications in patients with severe esophagitis. These drugs also aid with healing of peptic ulcers and artificial ulcers secondary to gastric endoscopic submucosal dissection (ESD). Few studies have discussed prevention of delayed ulcer bleeding after gastric ESD and ulcers associated with long-term nonsteroidal anti-inflammatory drug administration. Well-controlled, large-scale prospective studies are warranted in future to compare P-CABs with PPIs.

Proton Pump Inhibitor Use and Risk of Serious Infections in Young Children

Proton pump inhibitor (PPI) use may lead to infections through alteration of the microbiota or direct action on the immune system. However, only a few studies were conducted in children, with conflicting results. To assess the associations between PPI use and serious infections in children, overall and by infection site and pathogen. This nationwide cohort study was based on the Mother-Child EPI-MERES Register built from the French Health Data System (SNDS). We included all children born between January 1, 2010, and December 31, 2018, who received a treatment for gastroesophageal reflux disease or other gastric acid-related disorders, namely PPIs, histamine 2 receptor antagonists, or antacids/alginate. The index date was defined as the first date any of these medications was dispensed. Children were followed up until admission to the hospital for serious infection, loss of follow-up, death, or December 31, 2019. PPI exposure over time. Associations between serious infections and PPI use were estimated by adjusted hazard ratios (aHRs) and 95% CIs using Cox models. PPI use was introduced as time-varying. A 30-day lag was applied to minimize reverse causality. Models were adjusted for sociodemographic data, pregnancy characteristics, child comorbidities, and health care utilization. The study population comprised 1 262 424 children (median [IQR] follow-up, 3.8 [1.8-6.2] years), including 606 645 who received PPI (323 852 male [53.4%]; median [IQR] age at index date, 88 [44-282] days) and 655 779 who did not receive PPI (342 454 male [52.2%]; median [IQR] age, 82 [44-172] days). PPI exposure was associated with an increased risk of serious infections overall (aHR, 1.34; 95% CI, 1.32-1.36). Increased risks were also observed for infections in the digestive tract (aHR, 1.52; 95% CI, 1.48-1.55); ear, nose, and throat sphere (aHR, 1.47; 95% CI, 1.41-1.52); lower respiratory tract (aHR, 1.22; 95% CI, 1.19-1.25); kidneys or urinary tract (aHR, 1.20; 95% CI, 1.15-1.25); and nervous system (aHR, 1.31; 95% CI, 1.11-1.54) and for both bacterial (aHR, 1.56; 95% CI, 1.50-1.63) and viral infections (aHR, 1.30; 95% CI, 1.28-1.33). In this study, PPI use was associated with increased risks of serious infections in young children. Proton pump inhibitors should not be used without a clear indication in this population.

Current use of proton pump inhibitors and when to limit, stop or not start treatment

Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion that have changed treatment practice for gastric acid-related disorders. The major adequate indications for their use are treatment of gastro-esophageal reflux disease, peptic ulcers, eradication of Helicobacter pylori infection in combination with antibiotics and prophylaxis for patients on non-steroidal anti-inflammatory or antiplatelet drugs. Since their introduction, clinical success has been accompanied by widespread use of PPIs, which has steadily increased over the last decades without concomitant increase in the incidence of acid-related disorders. PPIs are now among the most widely prescribed class of medications worldwide and around 10% of Icelanders are current PPI users. This increase has been linked to PPI prescription without an indication, or continued use for longer duration than recommended. In recent years, concerns have been raised about PPI overuse and the associated increased risk of harm, not only in terms of increased costs but also the potential risk of physical dependence and long-term side effects of PPIs. The article is based on search in PubMed, the authors' own clinical experience and research, and is intended to provide practice advice on the use of PPIs with focus on appropriate prescription and deprescription of PPIs.

S3707 A Cautionary Side of the Widely Prescribed: A Case of PPI-Induced AIN

Introduction: Proton pump inhibitors (PPIs) are widely prescribed for the treatment of gastric acid-related disorders. While generally well-tolerated, PPIs are not without side effects, including acute kidney injury. Here we highlight a rare case of biopsy proven PPI-induced acute interstitial nephritis (AIN). Case Description/Methods: A 54-year-old male with history of rheumatoid arthritis presented with one week history of fever, fatigue, arthralgias, and weight loss. One month prior he was admitted with upper GI bleeding due to NSAID induced peptic ulcer disease and promptly stopped NSAIDs with strict adherence to PPI therapy. He took no additional medications or supplements. On admission labs were notable for recurrent anemia without melena and new acute kidney injury, creatinine 2.32 mg/dL from baseline of 1. Given recent GI bleed patient underwent repeat EGD which showed a clean based healing antral ulcer. Recurrent anemia was attributed to renal dysfunction, which continued to worsen despite supportive care with peak creatinine 3.8 mg/dL. Urine studies were unrevealing without evidence of obstruction on imaging, but incidentally noted narrowing of the celiac artery was concerning for vasculitis related nephropathy given history of autoimmune disease. Confirmatory contrast enhanced imaging however was negative for evidence of vasculitis with negative serologies. Renal biopsy was performed which showed interstitial inflammation and tubulitis consistent with AIN. Ultimate diagnosis of PPI-induced AIN was made as he took no alternative medications which could be implicated. Patient was started on steroids with notable improvement in renal function. He was switched to an H2 receptor blocker to complete treatment of gastric ulcer and discharged on a steroid taper with complete renal recovery (Figure 1). Discussion: Initially described in 1992, PPI-induced AIN is a well-recognized albeit rare complication. It is thought to arise due to a hypersensitivity reaction, which may explain the classic presenting triad of fever, rash, and eosinophilia. However, studies have shown that this clinical triad is only present in 10% of cases thereby highlighting the difficulties of diagnosing AIN, which may ultimately require renal biopsy for definitive diagnosis. Treatment requires removal of the offending agent as well as initiation of steroids. Even with treatment, 30-70% of patients may develop chronic kidney disease. As such, it is important for clinicians to be cognizant of this potentially life altering complication of PPI.Figure 1.: Kidney biopsy showing inflammatory changes predominantly in the interstitium.

Neuropsychological assessment after long-term omeprazole treatment

Recent studies suggest that Omeprazole, a widely used treatment for gastric acid-related disorders, may have a significant effect on human cognition. However, there is no consensus on the matter. Though some studies suggest the drug is associated with an increased risk of cognitive decline, memory impairment, and dementia, this issue has not been sufficiently studied. Therefore, the goal of this study was to investigate the cognitive impairments associated with long-term Omeprazole treatment, with a focus on memory, attention, and executive functions. Additionally, we sought to verify whether the duration of treatment was associated with the magnitude of the associated cognitive impairments. The sample consisted of 30 participants of both genders treated with Omeprazole (experimental group) and 30 participants who did not use the drug (control group). The cognitive assessment battery: Verbal Fluency, Rey Auditory-Verbal Learning, Attention Assessment Battery, Five Digit Test, Hayling Test, and NEUPSILIN Subtest. The groups were compared using Student’s T-tests, and the association between treatment duration and cognitive performance was examined using Pearson’s coefficients. The results showed significant group differences in verbal fluency, short-term episodic memory, selective attention, and executive functions. The duration of Omeprazole treatment was also positively associated with the magnitude of cognitive impairment.

Biodistribution Study of Pantoprazole Sodium in Rodent Tissues

Background: Pantoprazole sodium is one of the most widely used drugs for treating gastric acid–related disorders as well as is the most popular drug among various cancer therapy protocols for treating gastric disturbances pertained to the chemotherapy. The present study aims to validate high-performance liquid chromatographic (HPLC) method for the quantification of pantoprazole sodium in mice plasma and various tissue homogenates including kidney, heart, prostate, lung, pancreas, liver, and brain. Pantoprazole sodium estimation was done using 100 μL aliquot, which was injected into HPLC system, and the separation was achieved using Shimadzu C18 column at 40°C. Mobile phase composed of acetonitrile/dibasic phosphate buffer (40:60, v/v), pH = 7.4 was isocratically pumped at 1.0 mL min-1, and detection was performed at wavelength of 290 nm. Material and Methods: All the samples including tissues and plasma were collected after 4 h of oral administration of pantoprazole sodium to Swiss albino mice (10 mg/kg, p.o.). Results: Bioanalytical method was further validated according to the standard guidelines and portrays to be selective as well as linear (r2 ≥ 0.999) over the concentration range of 10–50 ng/injection. The intraday (% relative standard deviation [RSD] = 0.29%–1.21%) and inter-day precision (%RSD = 0.52%–2.88%) was found to be within the layout standards by International Council for Harmonization. Pantoprazole sodium extraction recovery was achieved between 64.15% and 78.17% demonstrating the suitability of the method. Conclusion: Bio-distribution study so carried out by bioanalytical technique can be used as an aiding tool for the quantification of pantoprazole sodium in all the studies involving the pharmacokinetic profiling of drug in various tissues of rodents.

Mechanisms of proton pump inhibitor-induced hypomagnesemia.

Proton pump inhibitors (PPIs) reliably suppress gastric acid secretion and are therefore the first‐line treatment for gastric acid‐related disorders. Hypomagnesemia (serum magnesium [Mg2+] <0.7 mmol/L) is a commonly reported side effect of PPIs. Clinical reports demonstrate that urinary Mg2+ excretion is low in PPI users with hypomagnesemia, suggesting a compensatory mechanism by the kidney for malabsorption of Mg2+ in the intestines. However, the exact mechanism by which PPIs cause impaired Mg2+ absorption is still unknown. In this review, we show that current experimental evidence points toward reduced Mg2+ solubility in the intestinal lumen. Moreover, the absorption pathways in both the small intestine and the colon may be reduced by changes in the expression and activity of key transporter proteins. Additionally, the gut microbiome may contribute to the development of PPI‐induced hypomagnesemia, as PPI use affects the composition of the gut microbiome. In this review, we argue that the increase of the luminal pH during PPI treatment may contribute to several of these mechanisms. Considering the fact that bacterial fermentation of dietary fibers results in luminal acidification, we propose that targeting the gut microbiome using dietary intervention might be a promising treatment strategy to restore hypomagnesemia in PPI users.

Analysis of clinical pharmacist interventions in the COVID-19 units of a French university hospital

ObjectivesThe objectives were to compare clinical pharmacist interventions between two care groups: COVID-19-positive and COVID-19-negative patients, and to identify drugs that require particular attention, especially those involved in COVID-19 management.MethodsA...

Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans.

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

Study of effect of Proton Pump Inhibitors on Blood Constituents in Albino Wistar Rats

Proton pump inhibitors (PPIs) are the widely used class of drugs for the treatment of gastric acid-related disorders and also used in almost all types of prescription. PPIs inhibit gastric acid secretion by inhibiting the potassium ATPase, which is responsible for acid production. An investigation was carried out on PPIs inducing an adverse effect cytopenia in wistar albino rats. Two drugs namely omeprazole and rabeprazole had been selected for the investigation. Rats had been divided into two groups as normal group and control group. Control group is further divided into two groups as omeprazole control group and rabiprazole control group. Normal group received saline water and control group received omeprazole (40mg/kg) and rabeprazole (20mg/kg) by PO respectively, for a period of one month. Blood was collected after 30 days of continuously administration of drugs by retro orbital puncture. Blood sample of normal and control groups had been analyzed for complete blood picture (CBP). The data was analyzed by using ANOVA followed by Dennett’s multiple comparison. The results are significant at a level of P&lt;0.05

Utilizing Tiny-TIM to Assess the Effect of Acid-Reducing Agents on the Absorption of Orally Administered Drugs.

Acid-reducing agents (ARAs) are the most commonly used medicines to treat patients with gastric acid-related disorders. ARA administration results in an elevation of intragastric pH and eases symptoms such as acid reflux. However, this effect could also lead to a reduction in the absorption of some co-administered oral medications (i.e. weakly basic drugs) by decreasing their gastric solubility. This in turn can result in a significant reduction of the efficacy of the co-administered oral medications. In order to address this problem, substantial efforts in translational modeling and the development of predictive in-vitro assays to better forecast the effect of ARA on oral absorption are conducted in the pharmaceutical industry. Despite these efforts, it remains challenging to predict the impact of ARAs on co-administered drugs. In this study, we evaluated the utility of Triskelion's Gastro-Intestinal Model (Tiny-TIM) in predicting ARA effect on twelve model drugs whose in-vivo data are available. The Tiny-TIM prediction of the ARA effect matched the observed effect of ARA co-administration in humans for the 12 model compounds. In summary, Tiny-TIM is a very reliable and promising GI model to successfully predict the nature of DDI when ARAs are co-administered with the drug of interest.

Comparison of the pharmacokinetics and pharmacodynamics of YH4808 in healthy subjects for defining an appropriate dosing regimen.

YH4808 is a novel potassium-competitive acid blocker developed for gastric acid-related disorders. Previous studies indicate its potential to improve symptoms of gastric acid-related disorders. The current study was aimed to find the optimal regimen of YH4808 for night time pH control. This study was performed in two parts. Each was a randomized, open-label, active-controlled, multiple-doses, two-treatment, two-period crossover study conducted in 20 healthy Korean volunteers. Subjects were randomly assigned to one of the four groups. The three groups received different dosage regimens of YH4808 (100 mg twice a day, 200 mg once a day, or 200 mg twice a day), and the fourth group received esomeprazole 40 mg twice a day. The pharmacokinetic parameters demonstrated that the systemic exposure of YH4808 increased in a dose-proportional manner. The difference in the proportion of time above pH 4 over 24 h from the baseline was the greatest in the group receiving YH4808 200 mg twice a day. The values of the area under the effect curve at night time (12 A.M.–7 A.M.) were higher in all YH4808 groups than in the esomeprazole group. However, the differences among the YH4808 groups were not statistically significant (p > 0.05). YH4808 exhibited potential for better pH control during the night in comparison to esomeprazole. The optimal regimen for night time pH control among all the YH4808 regimens was 200 mg twice a day.Trial RegistrationClinicalTrials.gov Identifier: NCT01761513

Clinical Significance of Changes in Gut Microbiome Associated with Use of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are commonly used for the treatment of gastric acid-related disorders, and are generally well tolerated. However, by reducing the secretion of gastric acid in the long term, PPI can increase the risk of inducing an imbalance in the gut microbiome composition. Moreover, gastric hypochlorhydria that is caused by PPIs favors the survival and migration of oral bacteria in the lower part of the gastrointestinal tract, with a possible induction of pro-inflammatory microenvironment. Therefore, gut dysbiosis that is associated with the use of PPI has been found to cause adverse infectious and inflammatory diseases. In this regard, adverse effects of the PPI-related gut dysbiosis have been reported in different observational studies, but their clinical relevance remains unclear. Therefore, the aim of this review was to explore the available data on the PPI-related gut dysbiosis in order to better understand its clinical significance.