Gastric Proton Pump Inhibitor Research Articles

A comparative study of double track anastomosis and tubular esophagogastric anastomosis in laparoscopic radical proximal gastrectomy for upper gastric carcinoma.

e16117 Background: For the upper gastric cancer, especially adenocarcinoma at the esophagogastric junction, the optimal surgical method is still controversial. The purpose of the study is to evaluate the safety and clinical effect of double track (DT) anastomosis in laparoscopic radical proximal gastrectomy (LRPG). Methods: A retrospective analysis was conducted involving 243 patients who underwent LRPG in the Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University from Jan. 2017 to Dec. 2020. Patients were divided into tubular esophagogastric (TG) anastomosis group and double track (DT) anastomosis group, according to the digestive tract reconstruction. Their intraoperative conditions, perioperative recovery and postoperative follow-up were compared. Patients were divided into ≥60 and < 60 groups according to age, to analysis the pros and cons of the two surgical methods in different age groups. According to whether or not indocyanine green (ICG) tracer technology was used during the operation, DT group was also divided into ICG group and non-ICG group. Results: Compared with the TG group, the DT group had less volume of gastric tube drainage, shorter gastric tube drainage time and proton pump inhibitors application time, and lower reuse rate of proton pump inhibitors. However, the DT group had more total operation time and lymph node dissection time. The median follow-up time of the patients was 36.0 months. At the end of study, the 1-year OS rate and DFS rate were 94.2% and 92.6% in the TG group and 95.8% and 93.7% in the DT group. The 3-year OS rate and DFS rate were 90.2% and 85.2% in the TG group and 91.9% and 87.7% in the DT group. And there was no significant difference in survival outcomes between the two groups. The DT group had a lower anastomotic stenosis at 3rd month after surgery. Moreover, the incidence of reflux esophagitis and Gerd Q score in the DT group were lower compared with the TG group at 3rd month, 1st year and 3rd year after surgery. In addition, elderly patients had a higher incidence of short-term complications in DT group compared with TG group. In the ICG analysis, the ICG DT group had significantly shorter total operation time and lymph node dissection time, less intraoperative blood loss and more lymph nodes obtained compared with the non-ICG DT group. Conclusions: DT anastomosis is a safe and effective way in LRPG for upper gastric carcinoma. Although the operation time of it is longer than that of TG anastomosis, it has a better anti-reflux effect and reduces the incidence of dysphagia and anastomotic stenosis. In elderly patients, it is important to minimize operative time and better to use TG anastomosis. The application of ICG tracer technique in LRPG has positive significance.

A comparative study of double track anastomosis and tubular esophagogastric anastomosis in laparoscopic radical proximal gastrectomy for upper gastric carcinoma.

e16117 Background: For the upper gastric cancer, especially adenocarcinoma at the esophagogastric junction, the optimal surgical method is still controversial. The purpose of the study is to evaluate the safety and clinical effect of double track (DT) anastomosis in laparoscopic radical proximal gastrectomy (LRPG). Methods: A retrospective analysis was conducted involving 243 patients who underwent LRPG in the Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University from Jan. 2017 to Dec. 2020. Patients were divided into tubular esophagogastric (TG) anastomosis group and double track (DT) anastomosis group, according to the digestive tract reconstruction. Their intraoperative conditions, perioperative recovery and postoperative follow-up were compared. Patients were divided into ≥60 and < 60 groups according to age, to analysis the pros and cons of the two surgical methods in different age groups. According to whether or not indocyanine green (ICG) tracer technology was used during the operation, DT group was also divided into ICG group and non-ICG group. Results: Compared with the TG group, the DT group had less volume of gastric tube drainage, shorter gastric tube drainage time and proton pump inhibitors application time, and lower reuse rate of proton pump inhibitors. However, the DT group had more total operation time and lymph node dissection time. The median follow-up time of the patients was 36.0 months. At the end of study, the 1-year OS rate and DFS rate were 94.2% and 92.6% in the TG group and 95.8% and 93.7% in the DT group. The 3-year OS rate and DFS rate were 90.2% and 85.2% in the TG group and 91.9% and 87.7% in the DT group. And there was no significant difference in survival outcomes between the two groups. The DT group had a lower anastomotic stenosis at 3rd month after surgery. Moreover, the incidence of reflux esophagitis and Gerd Q score in the DT group were lower compared with the TG group at 3rd month, 1st year and 3rd year after surgery. In addition, elderly patients had a higher incidence of short-term complications in DT group compared with TG group. In the ICG analysis, the ICG DT group had significantly shorter total operation time and lymph node dissection time, less intraoperative blood loss and more lymph nodes obtained compared with the non-ICG DT group. Conclusions: DT anastomosis is a safe and effective way in LRPG for upper gastric carcinoma. Although the operation time of it is longer than that of TG anastomosis, it has a better anti-reflux effect and reduces the incidence of dysphagia and anastomotic stenosis. In elderly patients, it is important to minimize operative time and better to use TG anastomosis. The application of ICG tracer technique in LRPG has positive significance.

Greenness-sustainability metrics for assessment smart-chemometric spectrophotometric strategy for evaluation of the combination of six gastric proton-pump inhibitors with two selected impurities

Green analytical approaches are employed for the determination of active pharmaceutical ingredients, in conjunction with their impurities. Smart chemometric spectrophotometric techniques, including orthogonal partial least square (OPLS), variable selection such as genetic algorithm (GA-OPLS), and interval selection (i-OPLS), were utilized. These chemometric models were implemented for assessing six proton-pump inhibitors Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, Rabeprazole, and Dexlansoprazole along with two selected official impurities, namely 4-Desmethoxy omeprazole impurity and Rabeprazole-impurity B. Experimental design was implemented to separate impurities, in the process of multivariate calibration, a five-level eight-factor calibration design consisting of 25 samples was selected. This design was deliberately selected to guarantee that the components were mutually orthogonal to assess the model's performance and reliability, a separate validation set of 15 samples was constructed. The best-performing of the proposed techniques were identified by considering the least favorable values of the Correlation Coefficient (R ≥ 0.9995), the Root Mean Square Error of Prediction (RMSEP) values between (0.0102–0.5622), and the Relative Error of Prediction (REP) values between (0.2961–1.1917). The proposed and reported methods' greenness-sustainability was quantitatively evaluated, and a comparative study of the greenness profile was established through a spider chart, the National Environmental Method Index tool, advanced and modified NEMI along with the Hexagon tool, and the whiteness qualities of the presented approaches were assessed by implementing the recently adopted Red-Green-Blue paradigm and White Analytical Chemistry tool. These approaches are well-suited for use in quality control laboratories due to their observed acceptance, long-term sustainability, simplicity, and affordability.

Stereoselective separation of omeprazole and 5-hydroxy-omeprazole using dried plasma spots and a heart-cutting 2D-LC approach for accurate CYP2C19 phenotyping

Omeprazole (OME) is a widely used gastric proton pump inhibitor, marketed as a racemic mixture comprising (S)- and (R)-enantiomers, with distinct pharmacokinetic profiles. OME is primarily metabolized by the cytochrome P450 enzymes 2C19 (CYP2C19) and 3A4 (CYP3A4). OME is a conventional probe for CYP2C19 phenotyping. Accurate measurement of these enantiomers and their metabolites is essential for pharmacokinetic studies. This article presents a sensitive and accurate two-dimensional liquid chromatography-mass spectrometry (LC-MS/MS) method for the simultaneous quantification of OME enantiomers and its hydroxylated metabolite (5-hydroxyomeprazole) in human plasma.The method involves an online extraction using an achiral Discovery HS C18 trapping column for purification (20 × 2.1 mm ID, 5μm particle size, Supelco) and subsequent forward flush elution onto a chlorinated phenylcarbamate cellulose-based chiral column (150x2mm ID, 3 μm particle size, Lux Cellulose-4, Phenomenex). The assay was fully validated and met international validation criteria for accuracy, precision, and stability and ensured high selectivity and sensitivity within a short runtime (<8 min). Application of this method to clinical samples demonstrated its utility in studying OME enantiomer pharmacokinetics, particularly its potential for phenotyping the activity of the CYP2C19 isoenzyme.This robust analytical approach offers a valuable tool for clinicians and researchers studying OME's pharmacokinetics, providing insights into its metabolism and potential implications for personalized medicine.

Clinical effect and follow-up of laparoscopic radical proximal gastrectomy for upper gastric carcinoma.

To evaluate the safety and clinical effect of tubular esophagogastric anastomosis in laparoscopic radical proximal gastrectomy. A retrospective analysis was conducted involving 191 patients who underwent laparoscopic radical proximal gastrectomy in the Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University from January 2017 to October 2020. Patients were divided into tubular esophagogastric anastomosis group (TG group) and traditional esophagogastric anastomosis group (EG group) according to the digestive tract reconstruction. Their intraoperative conditions, perioperative recovery and postoperative follow-up were compared. Patients were also divided into indocyanine green group and non-indocyanine green group according to whether or not indocyanine green tracer technology was used during the operation. Their intraoperative condition and perioperative recovery were compared and analyzed after propensity score matching. The operation was successfully completed in all patients. Compared with the EG group, the TG group had less volume of gastric tube drainage, shorter gastric tube drainage time and proton pump inhibitors application time, and lower reuse rate of proton pump inhibitors. However, the TG group had a higher anastomotic stenosis at three months after surgery, as measured using anastomotic width and dysphagia score. Nevertheless, the incidence of reflux esophagitis and postoperative quality of life score in the TG group were lower compared with the EG group at 1st and 2nd year after surgery. In the indocyanine green analysis, the indocyanine green group had significantly shorter total operation time and lymph node dissection time and less intraoperative blood loss compared with the non-indocyanine green group. However, compared with the non-indocyanine green group, more postoperative lymph nodes were obtained in the indocyanine green group. Laparoscopic radical proximal gastrectomy is safe and effective treatment option for upper gastric cancer. Tubular esophagogastric anastomosis has more advantages in restoring postoperative gastrointestinal function and reducing reflux, but it has a higher incidence of postoperative anastomotic stenosis compared with traditional esophagogastrostomy. The application of indocyanine green tracer technique in laparoscopic radical proximal gastrectomy has positive significance.

Baculovirus-mediated expression of a Helicobacter pylori protein-based multiepitope hybrid gene induces a potent B cell response in mice

Helicobacter pylori is a gram-negative bacterium that is present in over half of the world's population. The colonization of the stomach́s gastric mucosa by H. pylori is related to the onset of chronic gastritis, peptic ulcer, and cancer. The estimated deaths from gastric cancer caused by this bacterial infection are in the 15,000–150,000 range. Current treatment for controlling the colonization of H. pylori includes the administration of two to four antibiotics and a gastric ATPase proton pump inhibitor. Nevertheless, the bacterium has shown increased resistance to antibiotics. Despite an extensive list of attempts to develop a vaccine, no approved vaccine against H. pylori is available. Recombinant viruses are a novel alternative for the control of primary pathogenic agents. In this work, we employed a baculovirus that carries a Thp1 transgene coding for nine H. pylori epitopes, some from the literature, and others were selected in silico from the sequence of H. pylori proteins (carbonic anhydrase, urease B subunit, gamma-glutamyl transpeptidase, Lpp20, Cag7, and CagL). We verified the expression of this hybrid multiepitopic protein in HeLa cells. Mice were inoculated with the recombinant baculovirus Bac-Thp1 using various administration routes: intranasal, intragastric, intramuscular, and a combination of intranasal and intragastric. We identified a strong adjuvant-independent IgG-antibody response in the serum of recombinant baculovirus-Thp1 inoculated mice, which was specific for a strain of H. pylori isolated from a human patient. The bacterium-specific IgG-antibodies were present in sera 125 days after the first vaccine administration. Also, H. pylori-specific IgA-antibodies were found in feces at 82 days after the first inoculation. A baculovirus-based vaccine for H. pylori is promising for controlling this pathogen in humans.

Toxicology of rabeprazole: a literature survey and an in silico study

Rabeprazole (RPZ), a widely used gastric proton pump inhibitor, is evidently toxic to humans. This study aims to sketch a current scenario of its toxicological impacts on humans or other animals on the basis of database reports. Additionally, an in silico study has also been performed to integrate its toxicological prospects as observed in databases. For this, an up-to-date (till March 2023) search was made in a number of databases to obtain the published literature with the specific keywords. Findings suggest that RPZ has many side effects, including nausea, vomiting, diarrhea, headache, rhinitis, myalgia, pharyngitis, abdominal pain, dyspepsia, eye disorders, and so on. Chronic exposure to RPZ causes some important biochemical and hematological alterations and exerts a number of toxicological effects (e.g., hypergastrinaemia, hyperplasia, atrophy of the gastric glands, gastric anti-secretory effect, hypochlorhydria) in humans. The in silico study suggests that RPZ has hepatotoxic and carcinogenic effects. Its AMES toxicity may lead to mutagenicity in humans. In conclusion, RPZ and its formulations have many toxicological impacts on humans and other animals. Adequate precautions should be taken during its long-term use.

Inhibition of gastric acid secretion with omeprazole affects fish specific dynamic action and growth rate: Implications for the development of phenotypic stomach loss.

An acid-secreting stomach provides many selective advantages to fish and other vertebrates; however, phenotypic stomach loss has occurred independently multiple times and is linked to loss of expression of both the gastric proton pump and the protease pepsin. Reasons underpinning stomach loss remain uncertain. Understanding the importance of gastric acid-secretion to the metabolic costs of digestion and growth will provide information about the metabolic expense of acid-production and performance. In this study, omeprazole, a well characterized gastric proton pump inhibitor, was used to simulate the agastric phenotype by significantly inhibiting gastric acidification in Nile tilapia. The effects on post-prandial metabolic rate and growth were assessed using intermittent flow respirometry and growth trials, respectively. Omeprazole reduced the duration (34.4%) and magnitude (34.5%) of the specific dynamic action and specific growth rate (21.3%) suggesting a decrease in digestion and assimilation of the meal. Gastric pH was measured in control and omeprazole treated fish to confirm that gastric acid secretion was inhibited for up to 12 h post-treatment (p < 0.05). Gastric evacuation measurements confirm a more rapid emptying of the stomach in omeprazole treated fish. These findings reinforce the importance of stomach acidification in digestion and growth and present a novel way of determining costs of gastric digestion.

Gastric Volvulus: A Multidisciplinary Approach and Conservative Treatment

Gastric volvulus can be defined as an abnormal rotation of the stomach. It can be both an emergency and a chronic intermittent problem. Being such a rare clinical entity and a difficult condition to diagnose, it is commonly diagnosed at the time of surgery or even at autopsy.We present the case of an 82-year-old independent female with a past medical history of hiatal hernia, who came to the emergency department with hematemesis and severe epigastric pain. An abdominal CT scan revealed an organoaxial stomach volvulus within the intrathoracic cavity.After initial treatment with gastric decompression, IV fluids and proton pump inhibitors, the patient was informed that the surgical intervention would be the only definitive curative treatment for her condition and denied the procedure. She was then discharged after clinical and analytical improvement. She was offered a conservative treatment and follow up by the internal medicine team. After a few months, the patient reported moderate improvement of her symptoms and less episodes of epigastric pain. She was pleased with the conservative management and denied any surgical or invasive procedures. A proximity contact was established with the family doctor, which she maintains.This case report is proof that rare entities can happen to patients presenting common symptoms and better resolutions come from multidisciplinary approaches.

In Vitro Gene Transcription of Listeria monocytogenes After Exposure to Human Gastric and Duodenal Aspirates

The aim of the present study was to assess, for the first time to our knowledge, Listeria monocytogenes CFU changes, as well as to determine the transcription of key virulence genes, namely, sigB, prfA, hly, plcA, plcB, inlA, inlB, inlC, inlJ, inlP, and lmo2672 after in vitro exposure to human gastric and duodenal aspirates. Furthermore, investigations of the potential correlation between CFU changes and gene regulation with factors influencing gastric (proton pump inhibitor intake and presence of gastric atrophy) and duodenal pH were the secondary study aims. Gastric and duodenal fluids that were collected from 25 individuals undergoing upper gastrointestinal endoscopy were inoculated with L. monocytogenes serotype 4b strain LQC 15257 at 9 log CFU·mL-1 and incubated at 37°C for 100 min and 2 h, respectively, with the time corresponding to the actual exposure time to gastric and duodenal fluids in the human gastrointestinal tract. Sampling was performed upon gastric fluid inoculation, after incubation of the inoculated gastric fluids, upon pathogen resuspension in duodenal fluids and after incubation of the inoculated duodenal fluids. L. monocytogenes CFU changes were assessed by colony counting, as well as reverse transcription quantitative PCR by using inlB as a target. Gene transcription was assessed by reverse transcription quantitative PCR. In 56% of the cases, reduction of the pathogen CFU occurred immediately after exposure to gastric aspirate. Upregulation of hly and inlC was observed in 52 and 58% of the cases, respectively. On the contrary, no upregulation or downregulation was noticed regarding sigB, prfA, plcA, plcB, inlA, inlB, inlJ, inlP, and lmo2672. In addition, sigB and plcA transcription was positively and negatively associated, respectively, with an increase of the pH value, and inlA transcription was negatively associated with the presence of gastric atrophy. Finally, a positive correlation between the transcriptomic responses of plcB, inlA, inlB, inlC, inlJ, inlP, and lmo2672 was detected. This study revealed that the CFU of the pathogen was negatively affected after exposure to human gastroduodenal aspirates, as well as significant correlations between the characteristics of the aspirates with the virulence potential of the pathogen.

Facile radiolabeling optimization process via design of experiments and an intelligent optimization algorithm: Application for omeprazole radioiodination.

The major uses of radiopharmaceuticals (RP) in clinical areas are diagnosis and/or therapy. The present study aimed to utilize the application of fractional factorial design analysis (FFDA) coupled with particle swarm optimization algorithm (PSO) to assess the optimization of RP production process. In this regard, omeprazole (OMP), which is gastric parietal cell proton pump inhibitor (PPI), was radiolabeled with iodine-125 (125 I) isotope in order to be used as a radiotracer for stomach imaging. Different factors that affect radiolabeling process were studied. According to the proposed design, just 16 experimental runs of radiolabeling process were performed using the extremes of each factor. In addition, one run was executed at the mean point of each factor. Undesirable maximum radiolabeling yield (RY) of radioiodinated omeprazole (125 I-OMP) was deduced from application of FFDA (88.4%). Furthermore, after applying PSO with changing limits of one factor, the maximum RY of 125 I-OMP was found to be 93.78%. Moreover, the practically verification from optimum conditions, which obtained from PSO, was found to give an RY of 93.99%. Overall, the findings of this study confirmed the potential use of that hybrid design for optimization of radiolabeling processes.

Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation

Giardiasis is a worldwide parasitic disease that affects mainly children and immunosuppressed people. Side effects and the emergence of resistance over current used drugs make imperative looking for new antiparasitics through discovering of new biological targets and designing of novel drugs. Recently, it has determined that gastric proton-pump inhibitors (PPI) have anti-giardiasic activity. The glycolytic enzyme, triosephosphate isomerase (GlTIM), is one of its potential targets. Therefore, we employed the scaffold of PPI to design new compounds aimed to increase their antigiardial capacity by inactivating GlTIM. Here we demonstrated that two novel PPI-derivatives (BHO2 and BHO3), have better anti-giardiasic activity than omeprazole in concentrations around 120–130 µM, without cytotoxic effect on mammal cell cultures. The derivatives inactivated GlTIM through the chemical modification of Cys222 promoting local structural changes in the enzyme. Furthermore, derivatives forms adducts linked to Cys residues through a C-S bond. We demonstrated that PPI can be used as scaffolds to design better antiparasitic molecules; we also are proposing a molecular mechanism of reaction for these novel derivatives.

Novel ciliate lipases for enzyme replacement during exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency caused by inflammation or pancreatic tumors results in nutrient malfunction by a lack of digestive enzymes and neutralization compounds. Despite satisfactory clinical results with current enzyme therapies, a normalization of fat absorption in patients is rare. An individualized therapy is required that includes high dosage of enzymatic units, usage of enteric coating, and addition of gastric proton pump inhibitors. The key goal to improve this therapy is to identify digestive enzymes with high activity and stability in the gastrointestinal tract. We cloned and analyzed three novel ciliate lipases derived from Tetrahymena thermophila. Using highly precise pH-STAT-titration and colorimetric methods, we determined stability and lipolytic activity under physiological conditions in comparison with commercially available porcine and fungal digestive enzyme preparations. We measured from pH 2.0 to 9.0, with different bile salts concentrations, and substrates such as olive oil and fat derived from pig diet. Ciliate lipases CL-120, CL-130, and CL-230 showed activities up to 220-fold higher than Creon, pancreatin standard, and rizolipase Nortase within a pH range from pH 2.0 to 9.0. They are highly active in the presence of bile salts and complex pig diet substrate, and more stable after incubation in human gastric juice compared with porcine pancreatic lipase and rizolipase. The newly cloned and characterized lipases fulfilled all requirements for high activity under physiological conditions. These novel enzymes are therefore promising candidates for an improved enzyme replacement therapy for exocrine pancreatic insufficiency.

The Effect of Helicobacter pylori Infection, Aging, and Consumption of Proton Pump Inhibitor on Fungal Colonization in the Stomach of Dyspeptic Patients.

Background: The importance of coinfection of Helicobacter pylori (H.pylori) and Candida albicans (C. albicans) in the development of gastric diseases is not known. In this study, the frequency of concurrent infection of H. pylori and C. albicans in dyspeptic patients was assessed while considering age, gender, and PPI consumption of patients.Methods: Gastric biopsies were taken from 74 yeast-positive dyspeptic patients and gastric disease, age, gender, and proton pump inhibitor (PPI) consumption of subjects were recorded. One antral biopsy was used for rapid urease test (RUT) and one for H. pylori and yeast cultivation and smear preparation. Bacterial isolates were identified according to spiral morphology and the biochemical characteristics. Yeast isolates were identified on Chromagar and by the Nested-PCR amplification of C. albicans-specific topoisomerase II gene. Twenty-seven biopsy smears were Gram-stained and examined by the light microscope for observing H. pylori and yeast cells.Results: Fifty-four (73%) of patients were >40 year. Of 68 patients with PPI consumption record, 46 (67.6%) consumed PPI (p = 0). Comparison of patients in peptic ulcer group (12, 16.2%) with (6, 8.1%) or without (6, 8.1%) H. pylori or in gastritis group (62, 83.8%) with (25, 33.8%) or without (37, 50%) H. pylori showed no significant difference (p > 0.05). Of the 46 patients who consumed PPI, 13 (17.5%) were H. pylori-positive and 33 (44.6%) H. pylori-negative (p = 0). Ten out of twenty-seven smears showed the occurrence of H. pylori cells, including three with yeast cells. Of the 17 H. pylori-negative smears, three showed the occurrence of yeast cells only. Yeasts stained Gram-positive or Gram-negative and appeared as single or budding cells.Conclusion: The older age and PPI consumption could favor fungal colonization in the human stomach. The occurrence of a considerable number of H. pylori-positive or H. pylori-negative patients with gastritis or peptic ulcer shows that co-infection of Candida and H. pylori or infection of yeast alone could be associated with dyspeptic diseases. The occurrence of yeast cells in gastric biopsies with different Gram's reactions indicates that fungi might change their cell wall components for establishing a persistent colonization in the stomach.

Lansoprazole is an antituberculous prodrug targeting cytochrome bc1.

Better antibiotics capable of killing multi-drug-resistant Mycobacterium tuberculosis are urgently needed. Despite extensive drug discovery efforts, only a few promising candidates are on the horizon and alternative screening protocols are required. Here, by testing a panel of FDA-approved drugs in a host cell-based assay, we show that the blockbuster drug lansoprazole (Prevacid), a gastric proton-pump inhibitor, has intracellular activity against M. tuberculosis. Ex vivo pharmacokinetics and target identification studies reveal that lansoprazole kills M. tuberculosis by targeting its cytochrome bc1 complex through intracellular sulfoxide reduction to lansoprazole sulfide. This novel class of cytochrome bc1 inhibitors is highly active against drug-resistant clinical isolates and spares the human H+K+-ATPase thus providing excellent opportunities for targeting the major pathogen M. tuberculosis. Our finding provides proof of concept for hit expansion by metabolic activation, a powerful tool for antibiotic screens.

Gastric neuroendocrine neoplasms and proton pump inhibitors: fact or coincidence?

Objective. Reporting on three cases of gastric neuroendocrine tumors (g-NETs) in patients taking long-term proton pump inhibitors (PPIs). These tumors are not classifiable considering current criteria. g-NETs are currently grouped as: types 1 and 2, related to hypergastrinemia due to chronic atrophic gastritis and Zollinger-Ellison syndrome respectively, and type 3, normogastrinemic and more aggressive. Although the g-NETs onset in patients taking PPIs is biologically plausible, only a few cases have been reported so far. Materials and methods. From January 2005 to July 2014, 31 g-NETs were referred to our Unit: 24 (77%), one (3%) and three (10%) resulted types 1, 2 and 3, respectively. Three cases (10%) did not meet the current classification criteria. Results. The three patients were administered long-term PPIs for gastro-esophageal reflux disease. Patient 1: a 78-year-old man, with a 4-mm well-differentiated g-NET (Ki-67<1%) and marked hypergastrinemia. Patient 2: a 58-year-old man affected by a 6-mm well-differentiated (Ki-67 = 4%) g-NET, with normal gastrin levels. Patients 3: a 67-year-old woman with an 18-mm well-differentiated g-NET (Ki-67 <2%), with mild hypergastrinemia. In the three patients, histology and pertinent blood tests excluded chronic atrophic gastritis, Helicobacter pylori infection or Zollinger-Ellison syndrome. The first two patients underwent endoscopic polypectomy; in the third case total gastrectomy was performed. Further clinical, endoscopic and imaging follow-up did not show any g-NET recurrence. Conclusions.The present data point to the existence and epidemiological relevance of g-NETs associated with PPIs intake. These neoplasms are not included in the current classification, thus their treatment and follow-up have not been established.

Omeprazole, a Gastric Proton Pump Inhibitor, Inhibits Melanogenesis by Blocking ATP7A Trafficking

Omeprazole is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking ATP4A, a P-type H+/K+ ATPase in gastric parietal cells. We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells, normal human epidermal melanocytes, and in a reconstructed human skin model. Omeprazole topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls. Omeprazole had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase, dopachrome tautomerase, Pmel17, or MITF mRNA levels. Although melanocytes do not express ATP4A, they do express ATP7A, a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase. ATP7A relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole. Omeprazole treatment increased the proportion of EndoH sensitive tyrosinase, indicating that tyrosinase maturation was impaired. In addition, omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide, suggestive of increased degradation. Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting ATP7A and by enhancing degradation of tyrosinase.

S-泮托拉唑的研究进展

泮托拉唑是一种抑制胃酸分泌的质子泵抑制剂。临床研究表明，与消旋体及其对映体相比，S-泮托拉唑抑酸效果好，生物利用度高，毒副作用低。目前报道的制备S-泮托拉唑的方法主要是手性拆分和不对称氧化。本文简要概述了S-泮托拉唑的制备研究状况。 Pantoprazole is one of the blockbuster gastric proton pump inhibitors (PPIs). The clinical study showed that S-pantoprazole provides better acid control, higher bio-availability and lower side effects compared to the racemic pantoprazole and R-panto-prazole. It is reported that the optical pure S-pantoprazole could be prepared by chiral resolution and catalytic asymmetric oxidation. This review briefly described the deve-lopment of the preparation method for the optically pure S- pantoprazole.

A Clinical Study to Examine the Potential Effect of Lansoprazole on the Pharmacokinetics of Bosutinib when Administered Concomitantly to Healthy Subjects

Bosutinib is an orally bioavailable, dual Src and Abl tyrosine kinase inhibitor approved in the USA for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia following development of resistance or intolerance to prior therapy. In vitro studies demonstrated that bosutinib displays pH-dependent aqueous solubility, suggesting that concomitant administration of agents that alter gastric pH could affect bosutinib absorption. The objectives of this study were to evaluate the effect of lansoprazole, a gastric proton pump inhibitor, on the pharmacokinetics and safety of bosutinib. This open-label, non-randomized, phase I study involved inpatients and outpatients at a single site. The study participants were healthy men or women of non-childbearing potential aged 18-50 years. Each subject received bosutinib 400 mg on Day 1, lansoprazole 60 mg on Day 14, and bosutinib 400 mg co-administered with lansoprazole 60 mg on Day 15 under fasting conditions. The main outcome measure was the effect of multiple doses of lansoprazole on the pharmacokinetic profile of a single oral dose of bosutinib. A total of 24 healthy male subjects were enrolled. Co-administration with lansoprazole decreased the mean maximum plasma concentration (C(max)) of bosutinib from 70.2 to 42.9 ng/mL, and the total area under the plasma concentration-time curve (AUC) from 1,940 to 1,470 ng·h/mL. Log-transformed bosutinib pharmacokinetic parameters indicated significant between-treatment differences; the least squares geometric mean ratio for C(max) was 54 % (95 % CI 42-70) and for AUC was 74 % (95 % CI 60-90). Mean apparent total body clearance from plasma after oral administration increased from 237 to 330 L/h, and the median time to reach Cmax increased from 5 to 6 h, although this change may be related to decreased bosutinib absorption when combined with lansoprazole. When co-administered with lansoprazole, bosutinib maintained an acceptable safety profile, which was primarily characterized by diarrhea (33 %), headache (21 %), and nausea (13 %). One subject experienced serious adverse events of diverticulitis, gastritis, and duodenitis after co-administration; however, no participant withdrew because of toxicity. This study demonstrated that bosutinib absorption may be reduced when co-administered with lansoprazole or other proton pump inhibitors. Caution should be used with such drug combinations, as subtherapeutic exposure of bosutinib may limit its clinical antitumor activity; short-acting antacids are recommended instead.

A Review: Development &amp; Validation of HPLC Method for the Determination of Esomeprazole in Pharmaceuticals

Esomeprazole is chemically bis(5methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulfinyl]-1Hbenzimidazole-1-yl). It is a gastric proton-pump inhibitor (PPI) used in treatment of gastric-acid related diseases. Simple, selective and accurate high performance liquid chromatographic (HPLC) methods were developed and validated for the analysis of esomeprazole magnesium. The objective of this review is to describe various analytical methods for estimation of Esomeprazole. All methods are validated as per ICH guidelines. © 2011 IGJPS. All rights reserved.