Potassium-competitive acid blockers: rethinking acid suppression for gastroesophageal reflux disease and Helicobacter pylori.

Gastroesophageal reflux disease (GERD) and Helicobacter pylori (H. pylori) infection are different disease states that are united by the core role of acid suppression in their management. In GERD, proton pump inhibitors (PPIs) have long been standard therapy based on abundant positive clinical trial data supporting their efficacy and safety. In H. pylori, PPIs are also a critical element of therapy in combination with 1 or more antibiotics to achieve and maintain a pH that maximizes the efficacy of therapy. Despite the considerable clinical success and widespread use of PPIs, room remains for agents with differentiated pharmacokinetic and pharmacodynamic profiles. The potassium-competitive acid blockers (PCABs) are mechanistically distinct from PPIs but are acid-stable and do not require activation of the proton pump by coadministration of food. In pharmacodynamic studies, these agents have shown greater durations of acid suppression above the critical threshold of pH 4 (for GERD) and pH 6 (for H. pylori), which have been shown to optimize therapeutic efficacy in these settings. These results have translated in clinical studies to similar and, in some cases, improved outcomes relative to PPIs in these disease states. This review summarizes current knowledge on the physiology of acid secretion, pathophysiology and management of GERD and H. pylori, and key characteristics and clinical trial data for PPIs and PCABs.

[Intracellular Mechanism of Gastric Acid Secretion: What is the True Switch?]

In 1985, I was accepted as postdoc by Professor Forte of UC Berkeley. He discovered H+,K+-ATPase and established the membrane recycling theory as the activation mechanism for acid secretion using whole animals. H+,K+-ATPase is an enzyme that exchanges H+ with K+. In resting state, it locates on the tubulovesicles and the pump does not work because the membrane lacks K+ permeability. Upon stimulation, the tubulovesicles fuse to the apical membrane and acquire K+ permeability, turning the pump on. The main route was known to be protein kinase A (PKA), but its specific targets remained unknown. Right after I joined Forte's lab, I was fortunate enough to reproduce the above mechanism in vitro, and I discovered proteins of molecular weight 120 kDa and 80 kDa that were specifically phosphorylated in stimulated parietal cells. After I returned to Japan, the former was cloned and named as parchorin, which is one of the chloride intracellular channels. Although no progress was made on ezrin, I found out the importance of PIP2 and Arf6 using permeabilized gland models. After I left parietal cell research, the link between ezrin and Arf6 was revealed. PKA phosphorylates S66 of ezrin and also MST4. The former changes the N-terminal structure of ezrin to bind syntaxin3, and the latter phosphorylates ACAP4, an Arf6-GAP, to accelerate binding to ezrin. Subsequently, H+,K+-ATPase, SNAREs, ezrin, and Arf6-GAP are aligned on the apical membrane. However, there are still many unsolved questions and the intracellular mechanism of parietal cells remains an attractive research area.

Gastric Acid-Responsive ROS Nanogenerators for Effective Treatment of Helicobacter pylori Infection without Disrupting Homeostasis of Intestinal Flora.

Helicobacter pylori (H. pylori) has infected more than half of the world's population, and is the major cause of gastric cancer. The efficacy of standard antibiotic-based triple therapy is declining due to drug resistance development. Herein, a pH-responsive reactive oxygen species (ROS) nanogenerator (Fe-HMME@DHA@MPN) composed of acid-responsive metal polyphenol network (MPN) shell and mesoporous metal-organic nanostructure core [Fe-HMME (hematoporphyrin monomethyl ether, sonosensitizer)] loaded with dihydroartemisinin (DHA) is reported. These nanoparticles generate more ROS singlet oxygen than sonosensitizer HMME under ultrasonication, and this sonodynamic process is fueled by oxygen generated through Fenton/Fenton-like reactions of the degraded product in gastric acid Fe (II) and hydrogen peroxide (H2 O2 ) in the infection microenvironment. The encapsulated DHA, as a hydroperoxide source, is found to enhance the peroxidase-like activity of the Fe-HMME@DHA@MPN to generate ROS hydroxyl radical, beneficial for the microenvironment without sufficient H2 O2 . In vitro experiments demonstrate that the ROS nanogenerators are capable of killing multidrug-resistant H. pylori and removing biofilm, and ROS nanogenerators show high therapeutic efficacy in a H. pylori infection mouse model. Unlike the triple therapy, the nanogenerators display negligible side effects toward the normal gut microbiota. Taken together, these self-enhanced ROS nanogenerators have a great potential for treatment of H. pylori infection.

Discovery of novel benzimidazole derivatives as potent potassium-competitive acid blockers for the treatment of acid-related diseases.

H+, K+-ATPase, as the most critical enzyme in gastric acid secretion, has long been an attractive target for the treatment of acid-related diseases. In this study, a series of benzimidazole derivatives were designed and synthesized through conformational restriction and skeleton hopping strategies by using vonoprazan as the lead compound. Among them, compounds A12 (IC50 = 9.32 µM) and A18 (IC50 = 5.83 µM) showed better inhibition at the enzyme level. In addition, gastric acid secretion inhibition was assessed in vivo, and the results showed that A12 and A18 significantly inhibited basal gastric acid secretion, 2-deoxy-d-glucose (2DG) stimulated gastric acid secretion and histamine-stimulated gastric acid secretion. In further in vitro metabolic experiments, A12 and A18 demonstrated excellent stability and low toxicity. Pharmacokinetic studies showed that the p.o. and i.v. half-lives of A18 were 3.21 h and 8.67 ± 1.15 h, respectively. In summary, A18 might be a novel and effective potassium-competitive acid blocker, and this study provides strong support for it use in the treatment of acid-related diseases.

Real-time spatial quantification of gastric acid diffusion in whey protein gels with different NaCl concentrations by wide-field fluorescence microscopy.

Gastric acid diffusion and penetration constitute an essential process in the structural breakdown and enzymatic hydrolysis of solid food during digestion. This study aimed to quantify the real-time diffusion and spatial distribution of gastric acids in whey protein isolate (WPI) gels in the presence of 0-0.05 M NaCl during simulated digestion using a wide-field fluorescence microscope. For all the gels regardless of NaCl concentration, the outer surface rapidly developed a near-saturated layer, resulting in a higher normalized gastric acid concentration in the outer layer than in the inner layer. The pH decrease was more significant for the gels at a higher NaCl concentration (i.e., 0.05 M) due to the formation of a more discontinuous and looser network structure that would facilitate acid diffusion into the gel matrix and decrease the gel buffering capacity. Consistently, the effective diffusion coefficient (DA) estimated via the Fick diffusion model was 6.19 × 10-10 m2/s for 0.05 M WPI-RITC gels, significantly higher than 0.015 M (4.46 × 10-10 m2/s) and 0 M (3.54 × 10-10 m2/s) gels. The present study has provided a quantitative understanding of the diffusion process and spatial distribution of gastric acids within the WPI gel matrix in real-time during in vitro gastric digestion as influenced by NaCl concentration.

Iron absorption and phosphate-lowering effects of ferric citrate hydrate are not influenced by gastric acid secretion inhibitors in patients with chronic kidney disease: a retrospective post hoc analysis.

BACKGROUND: Ferric citrate hydrate (FC), an oral iron product is approved as iron preparation for iron deficiency anemia and phosphate binder for chronic kidney disease (CKD). We investigated whether gastric acid secretion inhibitors (GASI) influenced on iron absorption and phosphate-lowering effects of FC. METHODS: Two phase 3 studies of FC for treatment of hyperphosphatemia in CKD patients (non-dialysis-dependent, 12 weeks, and hemodialysis, 52 weeks), were retrospectively analyzed. Patients were divided into with or without concomitant GASI and levels of iron- and phosphate-related parameters were analyzed. RESULTS: In non-dialysis study (FC, 60 patients; placebo, 30 patients), 14 FC patients and 14 placebo patients used GASI. No significant differences were found between the FC and placebo groups for adjusted mean differences (95% CI) of changes from baseline to end of treatment (EOT) in serum ferritin [104.84 ng/mL (35.97, 173.71) with GASI vs 145.30 ng/mL (96.34, 194.25) without GASI, P = 0.34], and transferrin saturation (TSAT) [12.56% (- 0.83, 25.95) with GASI vs 18.56% (8.15, 28.98) without GASI, P = 0.49]. In hemodialysis study, 95/180 patients used GASI. Mean changes (SD) from baseline to EOT in serum ferritin were 166.32 ng/mL (153.70) with GASI and 155.16 ng/mL (139.47) without GASI, and for TSAT were 16.60% (19.44) with GASI and 16.02% (18.81) without GASI. In both studies, there were no differences in the changes from baseline to EOT in serum phosphate between with and without GASI cohorts. CONCLUSION: GASI did not influence on the changes in serum ferritin, TSAT and serum phosphate by FC administration.

Bitter Peptides YFYPEL, VAPFPEVF, and YQEPVLGPVRGPFPIIV, Released during Gastric Digestion of Casein, Stimulate Mechanisms of Gastric Acid Secretion via Bitter Taste Receptors TAS2R16 and TAS2R38.

Eating satiating, protein-rich foods is one of the key aspects of modern diet, although a bitter off-taste often limits the application of some proteins and protein hydrolysates, especially in processed foods. Previous studies of our group demonstrated that bitter-tasting food constituents, such as caffeine, stimulate mechanisms of gastric acid secretion as a signal of gastric satiation and a key process of gastric protein digestion via activation of bitter taste receptors (TAS2Rs). Here, we tried to elucidate whether dietary non-bitter-tasting casein is intra-gastrically degraded into bitter peptides that stimulate mechanisms of gastric acid secretion in physiologically achievable concentrations. An in vitro model of gastric digestion was verified by casein-fed pigs, and the peptides resulting from gastric digestion were identified by liquid chromatography-time-of-flight-mass spectrometry. The bitterness of five selected casein-derived peptides was validated by sensory analyses and by an in vitro screening approach based on human gastric parietal cells (HGT-1). For three of these peptides (YFYPEL, VAPFPEVF, and YQEPVLGPVRGPFPIIV), an upregulation of gene expression of TAS2R16 and TAS2R38 was observed. The functional involvement of these TAS2Rs was verified by siRNA knock-down (kd) experiments in HGT-1 cells. This resulted in a reduction of the mean proton secretion promoted by the peptides by up to 86.3 ± 9.9% for TAS2R16kd (p < 0.0001) cells and by up to 62.8 ± 7.0% for TAS2R38kd (p < 0.0001) cells compared with mock-transfected cells.

Concomitant Gastric Acid Suppressants on the Survival of Patients with Non-Small-Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Meta-Analysis.

Background: The influence of concomitant use of gastric acid suppressants (AS) on survival of patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inconsistent according to previous studies. We performed a meta-analysis to evaluate the effect of additional AS in patients with NSCLC taking TKIs. Methods: Relevant observational studies were identified by a search of Medline, Embase, and Web of Science databases. Only studies with multivariate analyses were included. A random-effect model was used to combine the results. Results: Thirteen retrospective studies with 12259 patients were included. Pooled results showed that concomitant use of AS was associated with worse progression-free survival (PFS, adjusted hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.31 to 1.89, P < 0.001; I 2 = 65%) and overall survival (OS, adjusted HR: 1.38, 95% CI: 1.19 to 1.61, P < 0.001; I 2 = 70%) in NSCLC patients taking TKIs. Sensitivity analysis limited to studies including NSCLC with EGFR mutation showed consistent results (HR for PFS: 1.53, P=0.003; HR for OS: 1.43, P=0.001). Subgroup analyses indicated that the association between concomitant use of AS and poor survival was not significantly affected by the category of AS used (proton pump inhibitors or histamine type-2 receptor antagonists) or the country of the study (Asian or non-Asian, P for subgroup analysis all >0.05). Conclusions: Concomitant use of AS in patients with NSCLC taking TKIs may be associated with poor survival outcomes.

Effects of CYP3A Inhibition, CYP3A Induction, and Gastric Acid Reduction on the Pharmacokinetics of Ripretinib, a Switch Control KIT Tyrosine Kinase Inhibitor.

Ripretinib is a switch control KIT kinase inhibitor approved for treatment of adults with advanced gastrointestinal stromal tumors who received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are cleared mainly via cytochrome P450 enzyme 3A4/5 (CYP3A4/5), and ripretinib solubility is pH-dependent, thus the drug-drug interaction potentials of ripretinib with itraconazole (strong CYP3A inhibitor), rifampin (strong CYP3A inducer), and pantoprazole (proton pump inhibitor) were each evaluated in open-label, fixed-sequence study designs. Overall, 20 participants received ripretinib 50 mg alone and with itraconazole 200 mg once daily, 24 participants received ripretinib 100 mg alone and with rifampin 600 mg once daily, and 25 participants received ripretinib 50 mg alone and with pantoprazole 40 mg once daily. Ripretinib exposure increased with concomitant itraconazole, with geometric least-squares (LS) mean ratios of ripretinib area under the concentration-time curve from 0 to ∞ (AUC0-∞ ) and maximum observed concentration (Cmax ) of 199% and 136%. Ripretinib exposure decreased with concomitant rifampin: geometric LS mean ratios for ripretinib AUC0-∞ and Cmax were 39% and 82%. Pantoprazole coadministration had no effect on ripretinib pharmacokinetics. No unexpected safety signals occurred. No dose adjustment is required for ripretinib coadministered with gastric acid reducers and strong CYP3A inhibitors; patients also receiving strong CYP3A inhibitors should be monitored more frequently for adverse reactions. Concomitant ripretinib use with strong CYP3A inducers should be avoided. Prescribers should refer to approved labeling for specific dose recommendations with concomitant use of strong and moderate CYP3A inducers.

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump.

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases.

Design, synthesis and biological evaluation of novel 5-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives as potent potassium-competitive acid blockers.

With the aim to discover a novel potent potassium-competitive acid blocker (P-CAB) agent, a series of 5-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives were synthesized, and their H+/K+-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 3'-((3-(2-fluorophenyl)-5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-[1,1'-biphenyl]-3-carboxamide not only exhibited potent H+/K+-ATPase inhibitory activity but olso showed potent inhibitory action in vivo on histamine-stimulated gastric acid secretion. In addition, the lead compound displayed favourable oral pharmacokinetic properties in rats, which was worthy of further study as a novel P-CAB agent.

Expression alteration and dysfunction of ion channels/transporters in the parietal cells induces gastric diffused mucosal injury.

Gastric mucosal injuries include focal and diffused injuries, which do and do not change the cell differentiation pattern. Parietal cells loss is related to the occurrence of gastric mucosal diffused injury, with two phenotypes of spasmolytic polypeptide-expressing metaplasia and neuroendocrine cell hyperplasia, which is the basis of gastric cancer and gastric neuroendocrine tumor respectively. Multiple ion channels and transporters are located and expressed in the parietal cells, which is not only regulate the gastric acid-base homeostasis, but also regulate the growth and development of parietal cells. Therefore, alteration and dysregulation of ion channels and transporters in the parietal cells impairs the morphology and physiological functions of stomach, resulted in gastric diffused mucosal damage. In this review, multiple ion channels and transporters in parietal cells, including K+ channels, aquaporins, Cl- channels, Na+/H+ transporters, and Cl-/HCO3- transporters are described, and their roles in gastric diffused mucosal injury are discussed. We hope to drive researcher's attention to focus on the role of ion channels/transporters loss in the parietal cells induced gastric diffused mucosal injury.

[Different Membrane Environments Generate Multiple Functions of P-type Ion Pumps].

P-type ion pumps (P-type ATPases) are involved in various fundamental biological processes. For example, the gastric proton pump (H+,K+-ATPase) and sodium pump (Na+,K+-ATPase) are responsible for secretion of gastric acid and maintenance of cell membrane potential, respectively. In this review, we summarize three topics of our studies. The first topic is gastric H+,K+-ATPase associated with Cl--transporting proteins (Cl-/H+ exchanger ClC-5 and K+-Cl- cotransporter KCC4). In gastric parietal cells, we found that ClC-5 is predominantly expressed in intracellular tubulovesicles and that KCC4 is predominantly expressed in the apical membrane. Gastric acid (HCl) secretion may be accomplished by the two different complexes of H+,K+-ATPase and Cl--transporting protein. The second topic focuses on the Na+,K+-ATPase α1-isoform (α1NaK) associated with the volume-regulated anion channel (VRAC). In the cholesterol-enriched membrane microdomains of human cancer cells, we found that α1NaK has a receptor-like (non-pumping) function and that binding of low concentrations (nM level) of cardiac glycosides to α1NaK activates VRAC and exerts anti-cancer effects without affecting the pumping function of α1NaK. The third topic is the Na+,K+-ATPase α3-isoform (α3NaK) in human cancer cells. We found that α3NaK is abnormally expressed in the intracellular vesicles of attached cancer cells and that the plasma membrane translocation of α3NaK upon cell detachment contributes to the survival of metastatic cancer cells. Our results indicate that multiple functions of P-type ion pumps are generated by different membrane environments and their associated proteins.

Isolation, identification, and biological characteristics of Clostridium sartagoforme from rabbit.

In order to develop microbial additives for rabbit feed, a spore-forming bacteria was isolated from the feces of Hyla rabbit using reinforced clostridium medium (RCM). The 16S rDNA sequence of the bacterium was subjected to pairwise sequence alignment using BLAST; the colony morphology, and physiological, biochemical, and stress resistance were studied. The results showed that the bacterium was Clostridium sartagoforme, a gram positive anaerobe, which can produce spores. The colony diameter was 0.5 mm-2.5 mm, the diameter of the bacteria was 0.5 µm-1.0 µm × 2.0 µm-6.3 µm, and the spore diameter was 1 µm-1.2 µm × 1 µm-1.2 µm. C. sartagoforme can utilize various sugars and alcohols such as fructose, galactose, sorbitol, and inositol. It secreted cellulase into the extracellular environment to form a transparent hydrolysis circle in Congo red medium, it could not liquify gelatin, and the lysine decarboxylase reaction was positive. In liquid medium it entered the stable growth period after 9 h of inoculation. Additionally, it had good stress resistance with a survival rate that exceeded 53% after gastric juice (pH 2.5) treatment for 3 h, it grew in a medium with a bile salt concentration of 0.3%, and the survival rate exceeded 85% after 10 minutes at 80°C. Moreover, animal testing indicated that this strain has no adverse effects on the morbidity and mortality of rabbits. In summary, C. sartagoforme XN-T4 was isolated from rabbit feces. This bacterium has good resistance to stress, can decompose a variety of monosaccharides and polysaccharides including cellulose, which is relatively harmless for animal health.

A Possible Flow Cytometry-Based Viability and Vitality Assessment Protocol for Pathogenic Vibrio cholerae O1 and O139 Postexposure to Simulated Gastric Fluid.

During the intake of contaminated water, for diarrheal disease to occur, Vibrio cholerae must survive through the bactericidal digestive secretion of gastric fluid during passage through the stomach. Determining the viability of these bacteria is challenging, with the standard cultivation methods for viability being time-consuming and unable to culture cells that may still function accordingly. This study assessed the use of enzyme action and membrane integrity as alternatives for determining vitality and viability, respectively, in gastric acid-stressed pathogenic Vibrio cholerae O1 and O139, using fluorescent probes thiazole orange (TO) for viability based on membrane integrity, carboxyfluorescein diacetate (CFDA) with acetoxymethyl ester (AM) for vitality based on metabolic activity, and propidium iodide (PI) for cell death/damage due to loss of membrane integrity, with flow cytometry. Simulated gastric fluid-treated bacterial cells were labelled with blends of TO+PI and CFDA-AM+PI, and these stained cells were separated into heterologous populations based on their fluorescence signal. The gastric acid exposed cells presented with high green fluorescence signals after staining with the metabolic probe CFDA-AM, which indicated intact (live) cells due to being metabolically active, whereas when the same cells were stained with the DNA probe (TO), these appeared to be in a "stressed state" due to loss of membrane integrity. Damaged cells (dead cells) showed high red fluorescence levels after staining with PI probe. The use of flow cytometry with fluorescent probes is a favorable method for evaluating the vitality and viability of bacteria when cells are labelled with a combination of CFDA-AM+PI.

Gastric Serotonin Biosynthesis and Its Functional Role in L-Arginine-Induced Gastric Proton Secretion.

Among mammals, serotonin is predominantly found in the gastrointestinal tract, where it has been shown to participate in pathway-regulating satiation. For the stomach, vascular serotonin release induced by gastric distension is thought to chiefly contribute to satiation after food intake. However, little information is available on the capability of gastric cells to synthesize, release and respond to serotonin by functional changes of mechanisms regulating gastric acid secretion. We investigated whether human gastric cells are capable of serotonin synthesis and release. First, HGT-1 cells, derived from a human adenocarcinoma of the stomach, and human stomach specimens were immunostained positive for serotonin. In HGT-1 cells, incubation with the tryptophan hydroxylase inhibitor p-chlorophenylalanine reduced the mean serotonin-induced fluorescence signal intensity by 27%. Serotonin release of 147 ± 18%, compared to control HGT-1 cells (set to 100%) was demonstrated after treatment with 30 mM of the satiating amino acid L-Arg. Granisetron, a 5-HT3 receptor antagonist, reduced this L-Arg-induced serotonin release, as well as L-Arg-induced proton secretion. Similarly to the in vitro experiment, human antrum samples released serotonin upon incubation with 10 mM L-Arg. Overall, our data suggest that human parietal cells in culture, as well as from the gastric antrum, synthesize serotonin and release it after treatment with L-Arg via an HTR3-related mechanism. Moreover, we suggest not only gastric distension but also gastric acid secretion to result in peripheral serotonin release.

Effects of pirenzepine on vonoprazan-induced gastric acid inhibition and hypergastrinemia.

BACKGROUND: Compared to proton pump inhibitors, vonoprazan exerts a greater inhibitory effect on gastric acid secretion and is useful for treating acid-related diseases, such as gastro-esophageal reflux disease. However, there is a problem that vonoprazan causes hypergastrinemia, which confers a risk of carcinoid tumor. A previous report demonstrated that pirenzepine, an M1 muscarinic receptor antagonist, enhances the acid inhibitory effects while suppressing hypergastrinemia induced by omeprazole. Here, we examined whether pirenzepine enhances the gastric acid inhibitory effects of vonoprazan without further increasing serum gastrin levels. METHODS: Eleven healthy volunteers were subjected to 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: pirenzepine 75 mg alone, vonoprazan 10 mg alone, and vonoprazan 10 mg plus pirenzepine 75 mg administered in a randomized crossover fashion. RESULTS: Median pH 4 holding time ratios (range) achieved with pirenzepine 75 mg, vonoprazan 10 mg, and vonoprazan 10 mg plus pirenzepine 75 mg were 6.9% (2.4-32.8%), 88.4% (54.6-100%), and 84.2% (40.3-100%), respectively. Respective serum gastrin levels were 79 (75-210) pg/ml, 310 (110-870) pg/ml, and 170 (140-930) pg/ml. In cases with hypergastrinemia (gastrin ≥ 200 pg/ml) induced by vonoprazan 10 mg alone, concomitant treatment with pirenzepine significantly reduced serum gastrin levels from 370 to 180 pg/ml (P = 0.028). CONCLUSION: Although pirenzepine does not enhance acid inhibition, it does improve hypergastrinemia induced by vonoprazan to some extent.

In vivo activation of pH-responsive oxidase-like graphitic nanozymes for selective killing of Helicobacter pylori.

Helicobacter pylori infection is a major etiological factor in gastric diseases. However, clinical antibiotic therapy for H. pylori is limited by continuously decreased therapeutic efficacy and side effects to symbiotic bacteria. Herein, we develop an in vivo activatable pH-responsive graphitic nanozyme, PtCo@Graphene (PtCo@G), for selective treatment of H. pylori. Such nanozymes can resist gastric acid corrosion, exhibit oxidase-like activity to stably generate reactive oxygen species only in acidic gastric milieu and demonstrate superior selective bactericidal property. C18-PEGn-Benzeneboronic acid molecules are modified on PtCo@G, improving its targeting capability. Under acidic gastric pH, graphitic nanozymes show notable bactericidal activity toward H. pylori, while no bacterial killing is observed under intestinal conditions. In mouse model, high antibacterial capability toward H. pylori and negligible side effects toward normal tissues and symbiotic bacteria are achieved. Graphitic nanozyme displays the desired enzyme-like activities at corresponding physiological sites and may address critical issues in clinical treatment of H. pylori infections.

Drug therapies for reducing gastric acidity in people with cystic fibrosis.

BACKGROUND: Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. This is an update of a previously published review. OBJECTIVES: To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic and non-electronic database searches, handsearches of relevant journals,  abstract books and conference proceedings. Both authors double checked the reference lists of the searches Most recent search of the Group's Trials Register: 26 April 2021. On the 26 April 2021 further searches were conducted on the clinicaltrials.gov register to identify any ongoing trials that may be of relevance. The WHO ICTRP database was last searched in 2020 and is not currently available for searching due to the Covid-19 pandemic. SELECTION CRITERIA: All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed trial quality and extracted data. MAIN RESULTS: The searches identified 40 trials; 17 of these, with 273 participants, were suitable for inclusion, but the number of trials assessing each of the different agents was small. Seven trials were limited to children and four trials enrolled only adults. Meta-analysis was not performed, 14 trials were of a cross-over design and we did not have the appropriate information to conduct comprehensive meta-analyses. All the trials were run in single centres and duration ranged from five days to six months. The included trials were generally not reported adequately enough to allow judgements on risk of bias. However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures of respiratory function and one trial reported an adverse effect with prostaglandin E2 analogue misoprostol. No trials have been identified assessing the effectiveness of these agents in improving quality of life, the complications of increased gastric acidity, or survival. AUTHORS' CONCLUSIONS: Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro-intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. Furthermore, due to the unclear risks of bias in the included trials, we are unable to make firm conclusions based on the evidence reported therein. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions.