Control Of Gastric Acid Secretion Research Articles

Vzácná příčina mnohočetných vředů tenkého střeva

Zollinger-Ellison syndrome is a very rare disease characterized by increased production of gastric acid that leads to peptic ulcer disease and diarrhea. It is caused by disproportionate ectopic secretion of gastrin from the cells of the endocrine tumor of digestive system – gastrinoma. It occurs sporadically or as a part of multiple endocrine neoplasia type 1. The tumor is localized mostly in duodenum and pancreas. The treatment combines control of gastric acid secretion, nowadays mainly by proton pump inhibitors and the treatment of gastrinoma itself – surgical or oncological (chemotherapy, biological treatment). In our paper, we present a case of a middle-aged woman examined for abdominal pain and diarrhea. Her initial gastroscopy showed erosive duodenitis; we excluded the infectious etiology of the diarrhea. During the examination process, there were severe complications of peptic ulcer disease for which several surgeries were done. From all the laboratory results and imaging methods, the final diagnosis was made – Zollinger-Ellison syndrome due to gastrinoma of the tail of pancreas and the patient underwent surgery. Unfortunately, there was a progression of the disease in a short time that requested another oncological and surgical treatment.

Prescribing pattern of proton pump inhibitors in the management of acid peptic disorders, focus on ilaprazole

Background: Acid peptic disorders (APDs) result from characteristic but overlapping pathogenic mechanisms that involve acid effects on diminished mucosal defense. Proton pump inhibitors (PPIs) have become a mainstay in the APDs. This survey was aimed to determine the usage profile of different proton pump inhibitors and overall physicians’ opinion about the clinical experience with newer PPI, ilaprazole.Methods: This survey was based on the clinical experience of 107 randomly selected physicians on an aggregate patient basis in the management of acid-peptic disorders from different parts of India. A data report form (DRF) comprising of various questions was answered by these physicians. The responding physicians answered the DRF of patients who suffered from acid-peptic disorders and were eligible for PPI therapy. A minimum of 50 patients per physician were evaluated in this survey.Results: The commonly encountered APD in physicians’ clinical practice were gastroesophageal reflux disorder (GERD) followed by non-ulcer disease. 58.88% physicians highlighted the prevalence of night time symptoms of APD reported by the patients. About 1/4th physicians were of the opinion that long-acting PPIs would be the preferred to offer 24 hour control of gastric acid secretion thereby controlling the nocturnal symptoms. 63.73% of physicians reported significantly better symptomatic relief with once daily dose of ilaprazole than existing PPIs.Conclusions: This survey highlights the lack of 24 hour acid control in APDs with use of conventional PPIs leading to variety of symptoms, especially at night, seriously hampering the sleep quality. Ilaprazole displays important advantages in the clinical settings, with regard to better probability of extending the inhibition of acid secretion over 24 hours as compared to conventional PPIs.

Histamine receptors and antihistamines: from discovery to clinical applications.

The synthesis and the identification of histamine marked a milestone in both pharmacological and immunological research. Since Sir Henry Dale and Patrick Laidlaw described some of its physiological effects in vivo in 1910, histamine has been shown to play a key role in the control of gastric acid secretion and in allergic disorders. Using selective agonists and antagonists, as well as molecular biology tools, four histamine receptors (H1R, H2R, H3R and H4R) have been identified. The Nobel Prize in Physiology and Medicine was awarded to Daniel Bovet in 1957 for the discovery of antihistamines (anti-H1R) and to Sir James Black in 1988 for the identification of anti-H2R antagonists. Anti-H1R and anti-H2R histamine receptor antagonists have revolutionized the treatment of certain allergic disorders and gastric acid-related conditions, respectively. More recently, anti-H3R antagonists have entered early-phase clinical trials for possible application in obesity and a variety of neurologic disorders. The preferential expression of H4R by several immune cells and its involvement in the development of allergic inflammation provide the rationale for the use of anti-H4R antagonists in allergic and in other immune-related disorders.

Zollinger-Ellison syndrome: recent advances and controversies.

To review the recent advances and current controversies in patients with Zollinger-Ellison syndrome (ZES). Recent advances in the management of ZES include: improved understanding of the pathogenesis of gastrinoma and pancreatic neuroendocrine tumors, new prognostic classification systems, new diagnostic algorithms, more sensitive localization studies, new treatment strategies including improved control of gastric acid secretion and role for surgery, and new approaches to patients with advanced disease. Controversies include: the best approach to a patient with hypergastrinemia suspected of possibly having ZES, the appropriate gastrin assay to use, the role of surgery in patients with ZES, especially those with multiple endocrine neoplasia type 1, and the precise order of therapeutic modalities in the treatment of patients with advanced disease. This review updates clinicians regarding important advances and controversies required to optimally diagnose and manage patients with ZES.

Signaling pathways in control of gastric acid secretion and food‐stomach‐bone axis revealed by gene expression profiling in the stomach of genetically targeted mice deficient in CCK1 receptor and gastrin/CCK2 receptor

Stomach plays important roles in the regulations of digestion, food intake, and mineral homeostasis, which involve CCK1 and gastrin/CCK2 receptors. The aim of this study was to reveal signaling pathways for drug development. Genome‐wide gene expression profiling was performed in the stomachs of wild‐type (WT) and CCK1 and/or CCK2 receptor knockout (KO) mice in response to food intake. The results showed that the KEGG “gastric acid secretion pathway” was neither altered in CCK1 receptor KO, CCK2 receptor KO nor in CCK1+2 receptor double KO mice, which was in line with normal ultrastructural appearance of the parietal cells in all the three mutant strains. A novel “ECL cell pathway” was found and it was inhibited in CCK2 receptor KO mice, but not in CCK1 receptor KO nor CCK1+2 receptor double KO mice. The typical WT ECL cells remained in CCK1 receptor KO mice, disappeared in CCK2 receptor KO mice, and re‐appeared in CCK1+2 receptor KO mice. The ECL cells contain pthlh gene‐related peptide gastrocalcin, a PTH‐like hormone, which was up‐regulated by food intake in WT mice but downregulated in both CCK2 receptor KO and CCK1+2 receptor double KO mice compared with WT mice. In addition, immune signaling pathways, TFF2, BMP, vitamin D synthesis and A‐like cell ghrelin were found to be altered. Perturbation of these signaling pathways might lead to the development of osteoporosis, which is a phenotype of CCK2 receptor KO mice. In conclusion, the revealed signaling pathways represent new targets for the control of acid secretion and for the bone metabolism and mineral homeostasis.

Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease

Gastro-esophageal reflux disease (GERD) is one of the most prevalent chronic diseases. Although proton pump inhibitors (PPIs) represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief, several studies have shown that up to 40% of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily. Several mechanisms have been proposed as involved in PPIs resistance, including ineffective control of gastric acid secretion, esophageal hypersensitivity, ultrastructural and functional changes in the esophageal epithelium. The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation, upper endoscopy, esophageal manometry and ambulatory pH-impedance monitoring, which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn. Treatment has been primarily based on doubling the PPI dose or switching to another PPI. Patients with proven disease, not responding to PPI twice daily, are eligible for anti-reflux surgery.

Expression of Toll-Like Receptors in Enterocromaffin-Like Cells and Their Function in Histamine Release

Enterocromaffin-like cells (ECL) are specialized endocrine gastric cells able to release histamine, which in turn controls gastric acid production by parietal cells. Helicobacter pylori infection and other conditions signal in the gastrointestinal tract via Toll-like receptors (TLRs) and modify gastric acid production, but there is no evidence of expression and function of TLRs in ECL cells. In this work, we analyzed gene and protein expression of TLR-2, 4, 5, and 9, and other molecules involved in TLR signaling in ECL cells. ECL cells were isolated from Sprague-Dawley rats. The histamine-releasing ability of TLR ligands was also evaluated after culture of the ECL cells for a short time. With ECL cells that expressed the TLR-2, TLR-4, TLR-5, and TLR-9 genes we were able to confirm protein expression for TLR-2, TLR-5, and TLR-9. Functionally, ECL cells were able to release histamine in response to TLR-2 stimulation by peptidoglycan (PGN), a TLR-2 ligand. After PGN stimulus, IRAK and p38 phosphorylation could be observed. SB 203580, a p38 inhibitor, reversed PGN-induced histamine release. Lipopolysaccharide (LPS), a TLR-4 ligand, was also able to induce histamine release in ECL cells, but by a mechanism independent of TLRs. We have demonstrated for the first time that ECL cells express TLRs and respond to TLR-2 ligand by increasing histamine release. This response could be involved in host defense against gastrointestinal bacterial pathogens but could also contribute to control of gastric acid secretion in the absence of pathogens.

Investigation of the role of histamine H1-receptors in the control of gastric acid secretion in the rat.

Investigation of the role of histamine H1-receptors in the control of gastric acid secretion in the rat.

Comparative Evaluation of the Anti-ulcer Activity of Curcumin and Omeprazole during the Acute Phase of Gastric Ulcer—Efficacy of Curcumin in Gastric Ulcer Prevention against Omeprazole

We have confirmed in our laboratory the antiulcer activity of curcumin during the acute chronic phase of gastric ulcer disease at doses of 20, 40 and 80 mg/kg (dissolved in saline solution). In the previous study, the potent effective dose of curcumin was 80 mg/kg that appears a propitious protective effect against gastric ulcer development. Therefore, the comparison between such recommended dose of curcumin and one of the proton pump inhibitors (PPIs) staff is worth-while. Since, the pharmacological control of gastric acid secretion is the main desired goal for gastro-cytoprotection, particularly, the H+/K+-ATPase (acid proton pump) inhibitors. Nevertheless, several studies have indicated that long-term inhibition of gastric acid secretion results in mucosal hyperplasia and carcinoid tumor development, due to increase circulating gastrin levels. Ulcer and the preventive indexes were scored, mucin, juice volume, total acidity, luminal haemoglobin, total antioxidant and total peroxide were evaluated. The pro-inflammatory cytokine IL-6 and the major angiogenic growth factor VEGF levels were measured. Conclusion, curcumin and omeprazole are potentially preventing gastric lesions development in the gastric wall during the acute phase of gastric ulcer diseases, but curcumin was more potent in its effect. Curcumin promotes gastric ulcer prevention/healing by induction of angiogenesis in the granular tissue of ulcers. That may be via upregulation of VEGF expression as reflected from VEGF level in serum and gastric juice, however, omeprazole might be has no role in this story.

Trends in peptic ulcer disease and the identification of Helicobacter Pylori as a causative organism: Population-based estimates from the US nationwide inpatient sample

Background:Peptic ulcer disease can lead to serious complications including massive hemorrhage or bowel perforation. The modern treatment of peptic ulcer disease has transitioned from the control of gastric acid secretion to include antibiotic therapy in light of the identification of Helicobacter pylori as a causative infectious organism. We sought to determine trends related to this discovery by using a national database.Materials and Methods:Patient discharges with peptic ulcer disease and associated sequelae were queried from the Nationwide Inpatient Sample, 1993 to 2007, under the auspices of a data user agreement. To account for the Nationwide Inpatient Sample weighting schema, design-adjusted analyses were used. Standard error was calculated using SUDAAN software (Research Triangle International, NC, USA).Results:Decreases in the incidences of gastrointestinal perforation, gastrointestinal hemorrhage, and surgical procedures most specific to peptic ulcer disease were statistically significant over the study period [range of P value (two tailed) = 0.000 – 0.00353; significant at P < 0.001 to < 0.01]. The incidence of H. pylori rose dramatically, peaking at an estimated 97,823 cases in 1998 [SE = 3155; 95% CI = 6,184]. Since that time it has decreased and then stabilized.Conclusions:The identification of H. pylori as the causative agent in the majority of peptic ulcer disease has revolutionized the understanding and management of the disease. Medical conditions and surgical procedures associated with end-stage peptic ulcer disease have significantly decreased according to analysis of selected index categories. Resident physician education objectives may need to be modified in light of these trends.Review Criteria:We reviewed patients with peptic ulcer disease. The database used was the Nationwide Inpatient Sample, 1993 to 2007.Message for the Clinic:Medical therapy has resulted in decreased morbidity from H. pylori infection as it is the causative agent in the majority of peptic ulcer disease. Aggressive screening and treatment of this infection will lead to further reduction in morbidity.

Endogenous Gastric Mediators: Patho‐Physiological Role and Measurements

The protocols described in this unit are designed to present the major endogenous gastric mediators involved in the control of gastric acid secretion, namely gastrin and histamine, and in the regulation of gastric motility, which include motilin and ghrelin, under physiological and pathological conditions. The measurement of these mediators in plasma or serum of humans and animals by radioimmunoassay are described and their pathophysiological role is discussed.

Evidencias e incertidumbres del uso clínico de los inhibidores de la bomba de protones

Proton pump inhibitors (PPI) are the most potent and effective drugs for the control of gastric acid secretion and constitute one of the most widely prescribed pharmacological groups worldwide. The safety and efficacy of PPI have been demonstrated in clinical practice and these drugs are currently the treatment of choice in peptic ulcer diseases, Helicobacter pylori infection, gastroesophageal reflux disease, nonsteroidal antiinflammatory drug gastropathy and functional dyspepsia. However, despite the excellent pharmacological profile of current PPI, their rapidity of action may be insufficient in some diseases, 24-hour acid inhibition is not always achieved and - to a greater or lesser extent depending on the distinct molecules of the PPI - there is interindividual variability in gastric antisecretory efficacy, depending on genetic polymorphism of CYP2C19, which could affect individual metabolism of the distinct PPI. New generations of these drugs will probably eliminate these deficiencies.

Effects of omeprazole treatment on nucleoside transporter expression and adenosine uptake in rat gastric mucosa

Increased adenosine concentration inhibits gastric acid secretion in rat via adenosine A1 and A2A receptors, whereas achlorhydria suppresses A1 and A2A receptor gene expression. This study aimed to examine the effects of omeprazole-induced achlorhydria on the expression and functional activity of nucleoside transporters in rat gastric mucosa. Wistar rats were treated for either 1 or 3 days with 0.4 mmol/kg omeprazole via gavage; controls were treated with vehicle. The expression of nucleoside transporters at the transcript level was explored by quantitative real-time polymerase chain reaction assays; the functional activity of nucleoside transporters in gastric mucosa was explored by observing [3H]adenosine uptake in vitro. Gastric mucosa expressed rat equilibrative nucleoside transporter (rENT) 1 and 2, and rat concentrative nucleoside transporter (rCNT) 1, 2, and 3 at the transcript level, and the estimated values for the threshold cycles for target amplification (Ct) were 31.5 +/- 2, 28.5 +/- 2.1, 32.9 +/- 2.2, 29.1 +/- 2, and 28.9 +/- 2.5, respectively (n = 3 or 4). The Ct value for rat beta-actin was 21.9 +/- 1.8 (n = 4). In vitro uptake of [3H]adenosine by gastric mucosa samples consisted of Na+-dependent and Na+-independent components. One-day omeprazole treatment caused no change in nucleoside transporter mRNA levels or in [3H]adenosine uptake. Three-day omeprazole treatments, however, led to a 12-fold and 17-fold increase in rENT2 and rCNT1 mRNA levels, respectively. Samples taken after 3 days of treatment also took up significantly more [3H]adenosine than did samples from the corresponding control. In conclusion, the possible modification of nucleoside transport activities by changes in intraluminal acidity may have significance as part of a purinergic regulatory feedback mechanism in the control of gastric acid secretion.

W2001 Colonic Microflora Are Under the Control of Gastric Acid Secretion

W2001 Colonic Microflora Are Under the Control of Gastric Acid Secretion

Role of the Ventromedial Hypothalamic Orexin‐1 Receptors in Regulation of Gastric Acid Secretion in Conscious Rats

Orexins play an important role on the central nervous system to modulate gastric acid secretion. The orexin receptors are distributed within the hypothalamus, and expression of orexin-1 receptors (OX1R) is greatest in the anterior hypothalamus and ventromedial nucleus. Therefore, we hypothesised that ventromedial hypothalamic OX1R may be involved in the control of gastric acid secretion. To address this question, we examined the effects of orexin-A and a selective OX1R antagonist, SB-3345867, on gastric acid secretion in pyloric-ligated conscious rats. Intraventromedial injection of orexin-A (0.5-2 microg/microl) stimulated gastric acid secretion in a dose-dependent manner. This stimulatory effect of orexin-A persisted over 3 h. In some experiments, SB-3345867 (10 mg/kg i.p.) was administered 30 min before orexin-A or saline injections. We found that i.p. injection of SB-334867 suppressed stimulated gastric acid secretion induced by orexin-A (2 microg/microl). Atropine (5 mg/kg) also inhibited the stimulatory effect of central injection of orexin-A on acid secretion. In conclusion, the present study suggests that endogenous orexin-A acts on the ventromedial hypothalamus to stimulates acid secretion. This stimulatory effect is probably mediated through OX1R.

Pantoprazole: a proton pump inhibitor with oral and intravenous formulations

Proton pump inhibitors (PPI) are a significant part of therapy for most acid-related diseases including gastroesophageal reflux disease, peptic ulcer disease and acute gastrointestinal bleeding. Pantoprazole is one of several available proton pump inhibitor agents and provides dose-dependent control of gastric acid secretion. Pantoprazole has indications in gastroesophageal reflux disease and peptic ulcer disease, along with indications as co-therapy in the eradication of Helicobacter pylori infection and in the control of the acid secretion associated with the Zollinger–Ellison syndrome, as well as in NSAID ulcer prevention. Pantoprazole is available in both oral and intravenous formulations. It is effective across all age groups, although only indicated in adults (and adolescents in Europe). It has been approved for use in over 100 countries and has been used for over 13 years. Pantoprazole has an excellent safety profile and a low potential for drug–drug interactions. While still widely prescribed, pantoprazole and the other branded proton pump inhibitors are under considerable market pressure from the less expensive but similarly effective generic and over-the-counter formulations of omeprazole.

Control of Gastric Acid Secretion in Somatostatin Receptor 2 Deficient Mice: Shift from Endocrine/Paracrine to Neurocrine Pathways

The gastrin-enterochromaffin-like (ECL) cell-parietal cell axis is known to play an important role in the regulation of gastric acid secretion. Somatostatin, acting on somatostatin receptor type 2 (SSTR(2)), interferes with this axis by suppressing the activity of the gastrin cells, ECL cells, and parietal cells. Surprisingly, however, freely fed SSTR(2) knockout mice seem to display normal circulating gastrin concentration and unchanged acid output. In the present study, we compared the control of acid secretion in these mutant mice with that in wild-type mice. In SSTR(2) knockout mice, the number of gastrin cells was unchanged; whereas the numbers of somatostatin cells were reduced in the antrum (-55%) and increased in the oxyntic mucosa (35%). The ECL cells displayed a reduced expression of histidine decarboxylase and vesicle monoamine transport type 2 (determined by immunohistochemistry), and an impaired transformation of the granules to secretory vesicles (determined by electron microscopic analysis), suggesting low activity of the ECL cells. These changes were accompanied by an increased expression of galanin receptor type 1 in the oxyntic mucosa. The parietal cells were found to respond to pentagastrin or to vagal stimulation (evoked by pylorus ligation) with increased acid production. In conclusion, the inhibitory galanin-galanin receptor type 1 pathway is up-regulated in the ECL cells, and the direct stimulatory action of gastrin and vagal excitation is enhanced on the parietal cells in SSTR(2) knockout mice. We suggest that there is a remodeling of the neuroendocrine mechanisms that regulate acid secretion in these mutant mice.

Protective Roles of α-Calcitonin and β-Calcitonin Gene-Related Peptide in Spontaneous and Experimentally Induced Colitis

Calcitonin gene-related peptide (CGRP) is thought to be involved in the regulation of gastric and mesenteric blood flow, in the control of gastric acid secretion and in the modulation of intestinal motility, yet the precise physiological roles of CGRP remain to be elucidated. To further examine the role(s) of CGRP in gastrointestinal function, we examined mutant mice lacking alphaCGRP or betaCGRP expression. Mutant mice did not demonstrate any overt phenotypic changes, yet exhibited a spontaneous, adult-onset colitis and increased colonic damage using a dextran sulfate sodium model of experimental colitis. Surprisingly, mice lacking betaCGRP show no obvious alterations in CGRP immunoreactivity in the gut, accompanied by an increase in alphaCGRP messenger RNA expression, suggesting an adaptive mechanism to compensate for the lack of betaCGRP. These data demonstrate that both alphaCGRP and betaCGRP play a protective role in the generation of spontaneous colitis, supporting a role for both extrinsic and intrinsic CGRP-containing neurons.

Gastric Inflammation, Metaplasia, and Tumor Development in Gastrin–Deficient Mice

Gastrin deficiency and proton pump inhibitor treatment cause achlorhydria, which predisposes to disease. To elucidate the underlying molecular biology, we examined the changes in gastric gene expression in both types of achlorhydria. We also explored the associated changes in the gastric microflora and the long-term consequences of gastrin-deficient achlorhydria. Expression profiles were generated from gastric RNA from wild-type mice, gastrin knockout (KO) mice, gastrin KO mice after 1 week of gastrin infusion, and wild-type mice treated for 1 month with a proton pump inhibitor. The results were confirmed using real-time polymerase chain reaction and immunohistochemistry. Selective media were used to characterize the gastric microflora. The number of gastric bacteria was increased in both gastrin KO and PPI-treated mice. The expression profiles revealed activation of immune defense genes, interferon-regulated response genes, and intestinal metaplasia of the gastric mucosa. In young gastrin-deficient mice, gastrin infusions reversed the changes. Over time, the changes accumulated, became irreversible, and progressed into metaplasia and polyp development. Finally, the study showed that gastrin regulated the expression of genes encoding extracellular matrix proteins. Independently of gastrin, achlorhydria is associated with gastric bacterial overgrowth and intestinal gene expression patterns and is associated with predisposition to disease. Gastrin is therefore essential for prevention of gastric disease, mainly through control of acid secretion but to a lesser extent also through control of gastric gene expression. The gastrin-deficient mouse serves as a useful new model for gastric metaplasia and neoplasia.

Three‐year oral pantoprazole administration is effective for patients with Zollinger–Ellison syndrome and other hypersecretory conditions

Zollinger-Ellison syndrome and idiopathic hypersecretion are gastrointestinal hypersecretory conditions requiring long-term maintenance. The safety and efficacy data for short-term (6-month) treatment of Zollinger-Ellison syndrome and idiopathic hypersecretion with oral pantoprazole were previously published. This study extends the initial observations to 3 years. The primary efficacy end point for this report was the control of gastric acid secretion in the last hour before the next dose of oral pantoprazole (acid output of <10 mmol/h; <5 mmol/h in subjects with prior acid-reducing surgery). Dose titration was permitted to a maximum of 240 mg per 24 h. Twenty-four subjects completed the study. The acid output of 28 of 34 subjects was controlled at initial enrolment. The mean acid output rates were <10 mmol/h throughout the 36 months of treatment for 90-100% of the patients. The majority of the patients were controlled with b.d. doses of 40 or 80 mg pantoprazole at 36 months (acid output was controlled in 24 of 24 subjects). Pantoprazole was generally well tolerated with minimal adverse events reported. Maintenance oral pantoprazole therapy up to 3 years at dosages of 40-120 mg b.d. was effective and well tolerated in patients with Zollinger-Ellison syndrome and other hypersecretory conditions.