Inhibition Of Acid Secretion Research Articles

Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Antisecretory drugs such as histamine H2-receptor antagonists (H2-RAs) and proton pump inhibitors (PPIs) are commonly used for the treatment of gastric and duodenal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, the effects of these drugs on NSAID-induced small intestinal ulcers are not fully understood. The effects of H2-RAs and PPIs on NSAID-induced gastrointestinal lesions and small intestinal motility were examined in rats. Male Wistar rats (180-220 g) were used. Indomethacin (10 mg/kg) was administered orally in fasted or fed rats, and gastrointestinal lesions were examined 24 h after indomethacin administration. Intestinal motility was measured by using a balloon method under urethane anesthesia. Indomethacin produced multiple lesions in the gastric corpus in fasted rats and in the small intestine in fed rats: 1) H2-RAs (cimetidine, ranitidine, and famotidine) and PPIs (omeprazole, lansoprazole, and rabeprazole) markedly inhibited the formation of gastric lesions. 2) The drugs, except for lansoprazole, increased intestinal lesions. 3) H2-RAs augmented the increase in intestinal motility caused by indomethacin, and the effects of H2-RAs on motility and intestinal lesions were markedly inhibited by atropine. 4) Lansoprazole inhibited the formation of intestinal lesions, and the effect was prevented by both pharmacological ablation of capsaicin-sensitive sensory neurons and pretreatment with N-nitro-l-arginine methyl ester, a selective inhibitor of nitric-oxide synthesis. The results suggest that: 1) inhibition of acid secretion by antisecretory drugs may exacerbate NSAID-induced intestinal lesions, 2) H2-RAs further aggravate lesions by increasing intestinal motility via the activation of cholinergic pathways, and 3) lansoprazole protects the intestinal mucosa against NSAID-related ulcerative stimuli.

Al-induced secretion of organic acid, gene expression and root elongation in soybean roots

Al-activated organic acid transporter genes (ALMT and MATE) and plasma membrane H+-ATPase gene (PHA) are known to contribute to the regulation of organic acid secretion in several crops. However, it remains unclear how these genes interact to modulate organic acid exudation in the same plant species. In this study, Al-induced expression of genes (GmALMT1, GmMATE1 and GmPHA1), secretion of organic acid and root elongation were characterized in soybean roots. Results indicated that treatment with 50 μM Al activated the expression of GmALMT1, GmMATE1 and GmPHA1, and the exudation of citrate and malate significantly in apical 5 mm region of soybean seedlings, but inhibited root elongation by 57.8 %. The highest malate exudation rate and the maximal expression of GmALMT1 and GmPHA1 were observed after 2 h of 50 μM Al treatment, while the corresponding values for citrate exudation rate and GmMATE1 expression occurred at 8 h. The exudation of malate and citrate contributed to but could not recover Al-triggered root elongation. A root-split experiment indicated that Al-activated gene expression, organic acid secretion and root growth inhibition required the direct contact of Al3+. The removal of shoots in soybean seedlings decreased Al-activated gene expression by 26.1–40.5 %, and secretion of organic acid by 14.7–40.2 %. Furthermore, shoot excision aggravated Al-inhibited root elongation, indicating the existence of other Al tolerance mechanism except the exudation of organic acid. These results suggested that Al-activated expression of GmPHA1-, GmMATE1- and GmALMT1-mediated exudation of malate and citrate, and shoots played an important role in Al toxicity resistance in soybean roots.

Proton Pump Inhibitor Therapy before and after Endoscopic Submucosal Dissection: A Review

Endoscopic submucosal dissection (ESD) is a novel endoscopic procedure first developed in the 1990s which enables en bloc resection of gastric neoplastic lesions that are difficult to resect via conventional endoscopic mucosal resection. However, given that ESD increases the risk of intra- and post-ESD delayed bleeding and that platelet aggregation and coagulation in artificial ulcers after ESD strongly depend on intragastric pH, faster and stronger acid inhibition via proton pump inhibitors (PPIs) and histamine 2-receptor antagonists (H2RAs) as well as endoscopic hemostasis by thermocoagulation during ESD have been used to prevent ESD-related bleeding. Because PPIs more potently inhibit acid secretion than H2RAs, they are often the first-line drugs employed in ESD treatment. However, acid inhibition after the initial infusion of a PPI is weaker in the early phase than that achievable with H2RAs; further, PPI effectiveness can vary depending on genetic differences in CYP2C19. Therefore, optimal acid inhibition may require tailored treatment based on CYP2C19 genotype when ESD is performed, with a concomitant infusion of PPI and H2RA possibly most effective for patients with the rapid metabolizer CYP2C19 genotype, while PPI alone may be sufficient for those with the intermediate or poor metabolizer genotypes.

Why dyspepsia can occur without organic disease: pathogenesis and management of functional dyspepsia

Functional dyspepsia (FD), one of the most common conditions in medicine, is a gastrointestinal disorder in which the patient suffers from chronic dyspeptic symptoms such as epigastralgia and a heavy feeling in the stomach despite the absence of organic disease. Elucidating the pathogenesis of FD means answering the question, "Why do symptoms occur?" The factors contributing to symptom manifestation in FD probably should be divided into 3 categories: (1) physiological abnormalities that directly induce symptoms, (2) factors that modify those physiological abnormalities, and (3) factors that govern abnormal responses to stress. The symptoms of FD are directly caused by two major physiological abnormalities-abnormal gastric motility and visceral hypersensitivity-occurring in patients who have acquired excessive responsiveness to stress as a result of the environment during early life, genetic abnormalities, residual inflammation after gastrointestinal infections, or other causes, with the process modified by factors including psychophysiological abnormalities, abnormal secretion of gastric acid, Helicobacter pylori infection, diet, and lifestyle. If the basis of this model of FD pathogenesis is excessive responsiveness of gastrointestinal function to stress and external stimuli, psychosomatic approaches to alter stress perception could be important treatment options. However, in the primary care setting, the treatment of FD has focused on local gastric factors, including abnormal gastric acid secretion, abnormal gastric motility, and H. pylori infection. Acid secretion inhibitors and prokinetics have been commonly used, and H. pylori eradication therapy has been carried out, but the effectiveness of drug therapy has been limited.

Commentary: netazepide for gastric acid suppression – another kid on the block?

Just when it seemed all over, the manuscript by Boyce et al.1 examining the pharmacokinetics and pharmacodynamics of single dose administration of netazepide, a peripheral CCK-B (gastrin) receptor antagonist, in normal volunteers will most certainly reinvigorate interest in gastric acid secretion and its pharmacological inhibition. Netazepide appears to be a potent inhibitor of gastric acid secretion with rapid onset and a prolonged duration of action.1 If it can be shown to be both safe and effective as maintenance therapy, it may well give proton pump inhibitors (PPIs) a real run for their money. The PPIs, which irreversibly block the final common path of gastric acid production,2 have been the dominant class of antisecretory drugs for over two decades and their continuing supremacy was all but assured with the demise of the potassium competitive acid blockers (PCABs) (although there may be a comeback for this class of agents too3). In addition, concerns have surfaced recently about potential adverse effects from prolonged PPI use4 which has opened the door to other novel compounds such as netazepide. Of course, much work remains to be done with this agent and there are, as yet, many unanswered questions (some of which the authors may well address in two upcoming manuscripts concerning repetitive dosing of netazepide). For example, will tachyphylaxis develop after repeated administration of this competitive receptor antagonist, a phenomenon that has been well described with histamine H2 receptor antagonists, which act one step further along the gastric acid secretory pathway?5 In addition, the endocrine, neurocrine and paracrine networks that control gastric acid secretion and its feedback are redundant.6 It remains to be seen whether upregulation of other pathways could occur leading to additional loss of efficacy (tolerance) with time. Alternatively, will the drug, which appears to have a long secondary half-life, accumulate after repeated dosing leading to unexpected side effects? Moreover, little is known about the metabolism of this agent which has only been administered to a small cadre of normal volunteers. Will the effect of this agent be predictable in patients or will alterations in metabolism lead to ‘slow’ and ‘fast’ metabolisers and unpredictable antisecretory effects? Finally, will potent ECL-cell inhibition by netazepide lead to G-cell hyperplasia and hypergastrinaemia, with the potential for rebound ECL-cell histamine release and excessive gastric acid production4 on withdrawal of the drug? This possibility is of some interest given current concerns regarding rebound gastric acid hypersecretion in double-blind randomised trials of PPI use vs. placebo in normal volunteers.7, 8 On the other hand, judicious use of netazepide in concert with PPIs may lead to more precise titration of individual antisecretory effects, thereby mitigating ECL-cell hyperplasia and parietal cell hypertrophy. This is an exciting and provocative first-in-human study of a novel compound with significant potential. I fully agree with the authors' conclusions that ‘studies of repeated doses of netazepide are justified’.1 Declaration of personal interests: David Metz has served as a consultant and advisory board member for Novartis, as a consultant for AstraZeneca and Takeda, and has received research funding from Fercica. Declaration of funding interests: None

Is routine stress ulcer prophylaxis of benefit for patients undergoing cardiac surgery?

A best evidence topic in cardiac surgery was written according to a structured protocol. We address whether routine pharmacological stress ulcer prophylaxis is of benefit for patients undergoing cardiac surgery. One hundred and fifty-six papers were found using the reported search, of which 10 represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group, study type, relevant outcomes and results of these papers were tabulated. The results show that the incidence of stress ulcers following cardiac surgery is low (0.45%), but remains associated with significant morbidity and mortality. Five of the 7 studies demonstrated suppression of acid secretion or decreased incidence of gastric complications in patients given pharmacological stress ulcer prophylaxis, with the remaining two suggesting no clinical benefit. One prospective study of 210 patients, randomized equally between a proton pump inhibitor (PPI), histamine antagonist and teprenone, found that PPIs were the most effective at reducing gastric complications after cardiac surgery, including ulcer formation and upper gastrointestinal bleeding (UGIB). However, a separate retrospective study suggested no difference in the outcomes between the use of a PPI and a histamine antagonist. Of the studies focused on histamine antagonists, one randomized control trial (RCT) showed that cimetidine can reduce surgical stress, augment the immune system and reduce the intubation time after cardiac surgery, although no direct association with UGIB was made. A second prospectively randomized study of histamine antagonists demonstrated superior pH control with famotidine and ranitidine, when compared with cimetidine. Furthermore, haematological and neurological side-effects were noted only with the use of cimetidine. A recent meta-analysis and systematic review of the literature associated gastric acid suppression with an increased risk of pneumonia. Two prospective cohort studies that examined the use of PPI in conjunction with clopidogrel in patients with coronary artery disease concluded that there was no association with an increase in major adverse cardiovascular events with the use of PPIs. We conclude that the current evidence is marginally in favour of the use of prophylactic PPIs. However, this is associated with an increased risk of hospital-acquired pneumonia.

Clinical study on the effects of nizatidine on gastric motility and cardiac autonomic function. Investigations using electrogastrography and spectral analysis of heart rate variability.

Nizatidine (CAS 76963-41-2, Acinon), an H2 receptor antagonist, not only inhibits acid secretion but also improves gastrointestinal motility. However, autonomic nervous function has not been studied in detail using electrogastrography (EGG). In the present study, two protocols were adopted to study nizatidine's effects on cardiac autonomic function and gastric motility. Protocol I--Acute: "Group C-I": 10 healthy volunteers received a single oral dose of nizatidine 150 mg. Protocol II--Chronic: "Group DM without N": 15 patients with diabetes mellitus (DM) were observed prior to administration of nizatidine. "Group DM with N": The same 15 patients with DM received nizatidine 300 mg/day for more than 30 days. "Group C-II": This control group was composed of 15 healthy volunteers not receiving nizatidine. In all groups, EGGs were recorded before and after a meal, and autonomic nervous function and QT interval of ECG dispersions were simultaneously evaluated. In Group C-I, nizatidine significantly increased the peak power amplitude of 3 cycles/min (cpm) frequency, but did not significantly change the dominant frequency of the 3-cpm waves. In Group DM with N, nizatidine administration significantly increased the peak power amplitude from 2.4 cpm or a lower frequency (bradygastria) to 3 cpm. Prior to nizatidine administration but after eating a meal, the peak power amplitude on EGG was not increased in Group DM without N. In Group DM with N, however, the EGG peak power amplitude increased to levels similar to those of the healthy subjects (Group C-II). Neither the single nor the chronic administration of nizatidine significantly prolonged the QT interval or increased the QT dispersion. A spectral analysis of heart rate variability showed that nizatidine administration, whether acute or chronic, did not significantly change the indices of autonomic nervous activity. Nizatidine may promote gastric emptying by inhibiting acetylcholine esterase, thus increasing cholinergic activity, and by acting directly on gastric smooth muscle. The results indicate that because nizatidine increases gastric motility without exerting a negative influence on the autonomic nerves, it may be a useful drug in patients with diabetic neuropathy.

Over-Prescription of Acid-Suppressing Medications in Infants: How It Came About, Why It’s Wrong, and What to Do About It

It has been almost 20 years since proton pump inhibitors (PPIs) were initially shown to be effective, safe, and well-tolerated for the short-term treatment of gastroesophageal reflux disease (GERD) in children over 1 year of age 1 ; GERD diagnosed on the basis of symptoms and hard diagnostic evidence of erosive esophagitis seen at endoscopy. 2 In these studies, mostly performed in children 2 to 17 years of age, 1-3 PPIs were shown to effectively treat symptoms and erosive esophagitis that were refractory to histamine-2receptor antagonists (H2RA), buffering agents, prokinetics, and in some subjects, antireflux surgery. Subsequent to those studies with omeprazole, other PPIs were found to be similarly effective. 4-8 Efficacy and safety were also shown for maintenance of remission of chronic, relapsing erosive esophagitis in prospective studies as long as 2 years, 9 and retrospective studies as long as 11 years of use. 10 Approximately 80% 10 of children who require long-term treatment for GERD have underlying disorders that predispose them to GERD, such as neurologic impairment, repaired congenital esophageal anomalies (eg, esophageal atresia), chronic lung disease, hiatal hernia, a strong family history of GERD, Barrett’s esophagus, or esophageal adenocarcinoma, or obesity. 11 In children without these underlying disorders, GERDisusuallynotchronicorsevere, 12 andmostcommonly follows a presumed upper gastrointestinal infection with post-infectious dysmotility and delayed gastric emptying, which resolves with time. In other words, in most otherwise healthy children, GERD is not chronic. In children in whom it is, the use of PPIs has revolutionized the long-term treatment of GERD, much for the better, including allowing for significantly decreased rates of antireflux surgery in some centers. 13 In this overall context, the topic of reflux in infants (ie, 7-fold increase in PPI prescription. One of the PPIs, available in a child-friendly liquid formulation, saw a 16-fold increase in use during that 6-year period. 14 Overall, approximately 0.5% of the approximately one million infants in the study database received a PPI during their first year of life. Approximately 50% of the infants started taking a PPI before 4 months of age. 15 These data would imply that somehow the diagnosis of GERD has been missed over the past several decades or has recently become a major scourge of infants in the developed world, with acid suppressing drugs becoming a new essential food group in their own right. This change in practice has come about for several reasons, none based in medical science. There is, however, data to show that this practice does not serve our patients. Two phenomena have long been observed in otherwise healthy, thriving infants. First, many of them spit up on a daily basis—some 40% to 70%. 16,17 The developing, rapidly-growing infant takes in feeding volumes that on a per-kg basis are huge compared with older children or adults. Infants have relatively poor gastric compliance and a short esophagus; therefore, some of the large volume intake simply overflows upward, or sometimes ‘‘spills’’ (lingua Australiana) out through the mouth. This has long been recognized as physiologic reflux not reflux disease [ie, not GERD]), and it is self-resolving in approximately 95% of

Tamoxifen Induces Rapid, Reversible Atrophy, and Metaplasia in Mouse Stomach

Tamoxifen, a selective estrogen receptor modulator, is widely used in research and clinically in patients. We find that treatment of normal mice with a single ≥3 mg/20 g body weight dose of tamoxifen leads to apoptosis of >90% of all gastric parietal cells (PCs) and metaplasia of zymogenic chief cells within 3 days. Remarkably, gastric histology returns to nearly normal by 3 weeks. Tamoxifen toxicity occurs by oral and intraperitoneal administration, in both sexes, in multiple strains, and does not depend on estrogen, though acid secretion inhibition is partially protective. Thus, substantial gastric toxicity is a heretofore unappreciated tamoxifen side effect.

Inhibitors of acid secretion can benefit gastric wound repair independent of luminal pH effects on the site of damage

Background and aimsThe authors' goal was to measure pH at the gastric surface (pHo) to understand how acid secretion affects the repair of microscopic injury to the gastric epithelium.MethodsMicroscopic gastric...

Famotidine and Omeprazole Both Induce Gastric Transmucosal Leak

Background: Our group has recently published that proton pump inhibitors (PPIs) induce transmucosal, paracellular, bidirectional leakage in the gastric corpus epithelium to a wide range of molecules. Aim: This study was undertaken to determine if H-2 blocker medications also induce such leakage, or whether it is a result of specific inhibition of H + ,K + -ATPase. Methods: At the beginning and end of a dosage regimen of omeprazole or famotidine, healthy volunteers with no history of gastrointestinal disease consumed a (probe) solution of 100 gms of sucrose in 200 cc of water. Subsequently an 8 hr urine specimen was collected. The sucrose concentration in the urine specimen (mg/ml) multiplied by the total urine vol- ume equaled the amount of sucrose (mg) which leaked from the gastric lumen into the bloodstream. Results: Like omeprazole, famotidine was also able to induce significant transmucosal leakage across the mucosal barrier of the upper gastrointestinal tract. Famotidine-induced leakage exhibited a narrower time course than was observed with omeprazole. Conclusions: The fact that both classes of acid suppressive medications induce leak implies that leak results not from di- rect inhibition of the H + ,K + -ATPase, or from a side effect of omeprazole-like molecules, but is more generally related to the overall inhibition of acid secretion. The medical significance of such gastric leak is discussed.

Inhibitors of gastric acid secretion increase the risk of prion infection in mice

Gastric juice is a unique combination of hydrochloric acid and the proteolytic enzyme pepsin. Its main function is to inactivate ingested microorganisms. Prions cause fatal transmissible degenerative encephalopathies in animals and man. These diseases have attracted attention due to the proposed link between bovine spongiform encephalopathy in cattle and the occurrence of a new variant Creutzfeldt-Jakob disease in humans where the most probable route of transmission is via contaminated food. The role of gastric juice in the protection against these agents is not settled. Objective. The aim of this study was to examine if drug-induced gastric hypoacidity increases the susceptibility of prion infection transmitted by the oral route. Material and methods. Forty-six mice (tg338) were given brain homogenates contaminated with scrapie by gastric intubation. Twenty-two of these animals were concomitantly dosed with omeprazole increasing the median gastric pH from 1.2 to 5.3. After 381 days, the animals were sacrificed and all the brains were examined for detection of pathogenic prion proteins by enzyme-linked immunosorbent assay and western blot. Results. Drug-induced decrease in gastric acidity more than doubled the rate (59% vs. 25%, p < 0.035) of brain infection compared to controls with normal gastric acidity at the time of inoculation. Conclusions. Our results demonstrate that the normal gastric juice constitutes a significant defense against prion disease in mice. Thus, gastric hypochlorhydria would be expected to enhance the susceptibility to prion infection by the oral route. This finding may have relevance to the pathogenesis of the new variant Creutzfeldt-Jakob disease and prion diseases in general.

Antisecretory actions of Baccharis trimera (Less.) DC aqueous extract and isolated compounds: Analysis of underlying mechanisms

Baccharis trimera (Less.) DC. (Asteraceae) is a species native to South America used in Brazilian folk medicine to treat gastrointestinal and liver diseases, kidney disorders and diabetes. Previous studies from this laboratory confirmed the antacid and antiulcer activities of the plant aqueous extract (AE) in rat and mouse models. To investigate the mechanisms involved in the antacid action of AE and isolated compounds from Baccharis trimera. AE was assayed in vivo in cold-restraint stress gastric ulcers and in pylorus-ligated mice. Nine fractions (F2-F10) previously isolated from AE were assayed in vitro on acid secretion measured as [(14)C]-aminopyrine ([(14)C]-AP) accumulation in rabbit gastric glands, and on gastric microsomal H(+), K(+)-ATPase preparations. Chlorogenic acids (F2, F3, F6, F7), flavonoids (F9), an ent-clerodane diterpene (F8) and a dilactonic neo-clerodane diterpene (F10) have been identified in these fractions. Intraduodenal injection of AE (1.0 and 2.0 g/kg) in 4h pylorus-ligated mice decreased the volume (20 and 50%) and total acidity (34 and 50%) of acid secretion compared to control values. Administered orally at the same doses AE protected against gastric mucosal lesions induced in mice by restraint at 4°C. Exposure of isolated rabbit gastric glands to fractions F8 (10-100 μM) and F9 (10-300 μg/ml) decreased the basal [(14)C]-AP uptake by 50 and 60% of control (Ratio=6.2±1.1), whereas the remaining fractions were inactive. In the presence of the secretagogues F2 and F4 (30-300 μg/ml) decreased the [(14)C]-AP uptake induced by histamine (His) with a 100-fold lower potency than that of ranitidine. F5 and F6 reduced the [(14)C]-AP uptake stimulated by carbachol (CCh), but they were 10 to 20-fold less potent than atropine. F8 (diterpene 2) and F9 (flavonoids) decreased both the His- and CCh-induced [(14)C]-AP uptake, whereas F10 (diterpene 1) was inactive against the [(14)C]-AP uptake stimulated by secretagogues. Diterpene 2 was the most active of all tested compounds being 7-fold less potent than ranitidine and equipotent to atropine in reducing acid secretion in vitro. This compound also reduced the gastric H(+), K(+)-ATPase activity by 20% of control, while the remaining fractions were inactive on the proton pump in vitro. The results indicate that Baccharis trimera presents constituents that inhibit gastric acid secretion by acting mainly on the cholinergic regulatory pathway. The plant extract also contains compounds that exert moderate inhibition of the histaminergic regulatory pathway of acid secretion and the gastric proton pump. Altogether these active constituents appear to provide effective inhibition of acid secretion in vivo, which may explain the reputed antiulcer activity of the plant extract.

Bacterial Factors Other Than Injected CagA and Those Mediating IL-8 Induction Participate in H. pylori-Mediated Gastric H,K-ATPase Repression

We previously reported that acute H. pylori infection of gastric epithelial (AGS) cells and human gastric biopsies causes H,K-ATPase α subunit (HKα) gene repression and inhibits acid secretion, events that may facilitate gastric H. pylori colonization and underlie transient clinical hypochlorhydria (Gastroenterology, 139:239, 2010; Gut, 59:874, 2010). In those studies, HKα repression was abrogated by infection with H. pylori isogenic mutant strains deficient in the cag pathogenicity island genes cagL, cagE or cagM, each of which fails to inject CagA into host cells or to induce interleukin-8 (IL-8) expression; HKα repression was partially abrogated by a cagA-deficient strain that induces IL-8. To test the hypothesis that bacterial factors other than those mediating CagA injection or IL-8 induction participate in HKα repression, AGS cells transfected with HKα promoter-Luc reporter constructs were infected (8 h, multiplicity of infection=50) with wild-type (WT) H. pylori strain 7.13 or isogenic mutants previously reported to be competent for CagA injection and IL-8 induction (cagζ, cage, cagN, cagZ or cagD), or competent only for IL-8 induction (cagβ [virD4]). AGS cell fractions were immunoblotted with anti-CagA antibodies, and IL-8 in cell-conditioned media was measured by ELISA. CagA was detected in cytoplasmic fractions of cells infected with WT H. pylori or cagζ, cage, cagN, cagZ or cagD mutants, but not with the virD4 mutant. AGS cell IL-8 secretion induced by the cagζ and cage mutants was comparable to WT; the virD4 mutant induced 22% less IL-8 than WT (P<0.01); and the cagN, cagZ and cagD mutants induced 32%, 68%, and 81% less IL-8 respectively than WT (all P<0.01). AGS cell infection by WT H. pylori inhibited HKα promoter activity (measured by luminometry) by 63% (P<0.01); the cagA-deficient mutant had minor effects on activity. The virD4 mutant inhibited HKα promoter activity by 23% (P<0.002), cagζ, cagN, cagZ and cagD mutants inhibited HKα by 40-50% (all P<0.01), and the cage mutant inhibited HKα by 87% (P<0.001). These data indicate that (i) CagA injection is associated with varying degrees of HKα repression, which is not abrogated by complete absence of CagA; (ii) HKα repression is poorly correlated with H. pylori-mediated induction of IL-8 gene expression; (iii) virD4, which encodes a cytoplasmic type IV secretion system nucleoside triphosphatase coupling protein, is necessary for bacterial signals culminating in HKα repression and consequent acid secretory inhibition; and (iv) neither CagA nor perturbation of signaling pathways leading to IL-8 induction are solely responsible for HKα repression. These findings are significant because hypochlorhydria is a predisposing factor for gastric epithelial progression to neoplasia, andH. pylori factors other than CagA and/or signaling to IL-8 are thus implicated in gastric carcinogenesis.

The effect of ciprofibrate on gastric secretion in the rat.

The potential of ciprofibrate to inhibit gastric secretion has been investigated in the rat. A significant gastric antisecretory effect was observed following a single oral administration of 300 and 500 mg kg-1 and following a single intraduodenal dose of 100, 300 and 500 mg kg-1. The toxicological significance of this finding is discussed in the light of a spate of recent publications linking changes in gastric morphology with hypergastrinaemia produced as a secondary effect of inhibition of acid secretion.

Kir4.1 Channel Expression Is Essential for Parietal Cell Control of Acid Secretion

Kir4.1 channels were found to colocalize with the H(+)/K(+)-ATPase throughout the parietal cell (PC) acid secretory cycle. This study was undertaken to explore their functional role. Acid secretory rates, electrophysiological parameters, PC ultrastructure, and gene and protein expression were determined in gastric mucosae of 7-8-day-old Kir4.1-deficient mice and WT littermates. Kir4.1(-/-) mucosa secreted significantly more acid and initiated secretion significantly faster than WT mucosa. No change in PC number but a relative up-regulation of H(+)/K(+)-ATPase gene and protein expression (but not of other PC ion transporters) was observed. Electron microscopy revealed fully fused canalicular membranes and a lack of tubulovesicles in resting state Kir4.1(-/-) PCs, suggesting that Kir4.1 ablation may also interfere with tubulovesicle endocytosis. The role of this inward rectifier in the PC apical membrane may therefore be to balance between K(+) loss via KCNQ1/KCNE2 and K(+) reabsorption by the slow turnover of the H(+)/K(+)-ATPase, with consequences for K(+) reabsorption, inhibition of acid secretion, and membrane recycling. Our results demonstrate that Kir4.1 channels are involved in the control of acid secretion and suggest that they may also affect secretory membrane recycling.

A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands

TAK-438 is a novel potassium-competitive acid blocker (P-CAB) type antisecretory agent that reversibly inhibits gastric H +, K +-ATPase. Previously, we showed that TAK-438 has superior efficacy compared to lansoprazole, a proton pump inhibitor, in the inhibition of acid secretion in vivo. In this study, we investigated the differences in the mode of actions of the two drugs using primary cultured rabbit gastric glands. TAK-438 and lansoprazole inhibited gastric acid formation in acutely isolated gastric glands (IC 50 values, 0.30 and 0.76 μM, respectively). In cultured gastric glands that were preincubated with TAK-438, the inhibitory effect on forskolin-stimulated acid formation was augmented over the incubation period, whereas the inhibitory effect of lansoprazole was not affected by time of incubation. Next, we evaluated the durations of the actions of TAK-438 and lansoprazole after gastric glands were incubated with either drug for 2 h followed by washout. Even 8 h after the drug washout, TAK-438 at higher concentrations inhibited acid formation, but the inhibitory effect of lansoprazole disappeared immediately after washout. Additionally, only a small amount of [ 14C] lansoprazole accumulated in resting glands, and this accumulation was enhanced by treatment with 1 μM of forskolin. In contrast, high levels of [ 14C] TAK-438 accumulated in both resting and forskolin-treated glands. Furthermore, a 2-h preincubation followed by washout demonstrated a slow clearance of [ 14C] TAK-438 from the glands. These findings suggest that TAK-438 exerts a longer and more potent antisecretory effect than lansoprazole as a result of its high accumulation and slow clearance from the gastric glands.

Safety profile of six months lansoprozole treatment in children

Proton pump inhibitors (PPIs) block acid production through H/K ATPase inhibition which is the final pump in the acid secretion pathway. They are generally well tolerated in the short term both in adults and children. However, prolonged suppression of acid secretion may interfere with absorption of various minerals, vitamins, and hematinic factors [1]. Although parietal cells are the major site for PPI activation, H/K ATPase pumps which are found in leukocytes and osteoclasts may also be a target for PPIs, which may therefore have some other deleterious effects beside gastric acid inhibition. We evaluated the impact of six months’ lansoprazole treatment on hemoglobin (Hb), serum iron (Fe), ferritin, total iron binding capacity (TIBC), vitamin B12, calcium (Ca), phosphate (P), alkaline phosphatase (ALP) level, urine Ca/Cr, bone turnover, bone mineralization, community acquired pneumonia, and acute gastroenteritis in children. Forty-five children (22 female), aged between 4–17 years (mean 12), who were diagnosed as GERD and had received lansoprozole (1–1.4 mg/kg/day, max 60 mg), and sodium alginate (0.25 mg/kg/dose three times a day) for six months during November 2007 to May 2009, were eligible for the study. None of these children had any systemic illness. GERD was diagnosed by 24 hours esophageal pH monitoring. Patients with symptoms suggestive of gastritis or peptic ulcer underwent gastroduodenoscopy. In each visit (2 months interval), parents were asked for signs of acute gastroenteritis and pneumonia in the preceding 2 months and encouraged to get in touch with the clinic in any kind of infectious or adverse event. Endoscopy was performed in 27 patients, and revealed antral gastritis in 19 and mild duodenitis in 14. Among them, 8 patients had also corpus gastritis and 16 had H. pylori infection. H. pylori-infected children were included in the study 8 weeks after H. pylori eradication was achieved. The mean levels of hemoglobin, serum iron, ferritin, total iron binding capacity, Ca, P, alkaline phosphatase, vitamin B12, urine calcium/creatinine ratio, mean L1-4 bone mineral density, and Z score at baseline were similar to those at six months of lansoprazole treatment (Table 1). L1–L4 total bone mineral content increased significantly (55.9%, p=0.021). One patient developed two episodes of pneumonia. None of the patient developed acute gastroenteritis. Gastric acidity reduces ferric iron to the more soluble ferrous form and facilitates iron absorption [2]. Studies indicating the potential of iron deficiency anemia development, with long term PPI treatment in the clinical practice are restricted with only few case reports in adults [3]. We did not detect an association between iron deficiency anemia and lansoprozole treatment in children. Vitamin B12 requires gastric acidity in order to be released from foods [2]. It has been proposed that reduction of M. Eren (*) Department of Pediatrics, Section of Gastroenterology and Hepatology, Eskisehir Osmangazi University, Faculty of Medicine, Eskisehir, Turkey e-mail: makbule99@yahoo.com

Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption

BackgroundBone resorption is initiated by osteoclastic acidification of the resorption lacunae. This process is mediated by secretion of protons through the V-ATPase and chloride through the chloride antiporter ClC-7. To shed light on the intracellular signalling controlling extracellular acidification, we screened a protein kinase inhibitor library in human osteoclasts.MethodsHuman osteoclasts were generated from CD14+ monocytes. The effect of different kinase inhibitors on lysosomal acidification in human osteoclasts was investigated using acridine orange for different incubation times (45 minutes, 4 and 24 hours). The inhibitors were tested in an acid influx assay using microsomes isolated from human osteoclasts. Bone resorption by human osteoclasts on bone slices was measured by calcium release. Cell viability was measured using AlamarBlue.ResultsOf the 51 compounds investigated only few inhibitors were positive in both acidification and resorption assays. Rottlerin, GF109203X, Hypericin and Ro31-8220 inhibited acid influx in microsomes and bone resorption, while Sphingosine and Palmitoyl-DL-carnitine-Cl showed low levels of inhibition. Rottlerin inhibited lysosomal acidification in human osteoclasts potently.ConclusionsIn conclusion, a group of inhibitors all indicated to inhibit PKC reduced acidification in human osteoclasts, and thereby bone resorption, indicating that acid secretion by osteoclasts may be specifically regulated by PKC in osteoclasts.

Epigenetic Silencing of Somatostatin in Gastric Cancer

Somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, has potent antitumor and anti-secretory activity in several human cancers. This study was performed to investigate the SST gene expression levels and possible epigenetic mechanisms that regulate expression of SST in gastric adenocarcinomas. Quantitative real-time (RT)-PCR and quantitative bisulfite pyrosequencing were used to study primary gastric cancer tissue samples and cell lines. Quantitative RT-PCR analysis revealed down-regulation of the SST transcript in 93% of gastric carcinoma samples (30/32), compared with 21 normal samples (P<0.001). Because of the presence of a large CpG island in the SST promoter, we next examined its promoter DNA methylation levels by use of quantitative bisulfite pyrosequencing. The results revealed a significant increase in SST promoter DNA methylation in tumor samples compared with normal samples (P<0.05). Promoter DNA hypermethylation and silencing of SST was also detected in seven gastric cancer cell lines that we tested. To confirm the role of promoter DNA methylation as an epigenetic mechanism regulating SST expression, AGS gastric cancer cells were treated with 5-Aza-dc. This treatment led to reduction of promoter DNA methylation levels of SST accompanied by restoration of its mRNA expression. Our results indicate that promoter DNA methylation levels play a critical role in regulating SST expression in gastric cancer. This finding provides a foundation for further studies on the role of SST in gastric carcinogenesis and its potential as a biomarker for gastric cancers.