Meal-stimulated Gastric Acid Secretion Research Articles

Tu1105 Gastric Acid Output Suppression in Response to Proton Pump Inhibitor Therapy in Symptomatic Versus Asymptomatic GERD Patients: Results of a Prospective Study Measuring Control and Meal-Stimulated Gastric Acid Secretion

Background: Gastro-esophageal reflux disease (GERD) is a common acid-related disorder affecting 10-20% of people. GERD is often under-investigated and over-treated, especially in refractory cases. Symptoms are used to guide management despite data showing many acid reflux events are asymptomatic, and many symptomatic events are unrelated to acid reflux. Proton pump inhibitors (PPIs) effectively treat GERD, but are often over-prescribed as non-invasive, accurate methods to measure gastric acid output (GAO) and guide PPI therapy are lacking. Such data might enhance management of patients who remain symptomatic despite appropriate PPI therapy. Recently, a new method for measuring meal-stimulated GAO using a wireless pH-sensing capsule, SmartPill (SP), was validated (Weinstein et al. Aliment Pharmacol Ther 2013). Aim: To evaluate the control and stimulated GAO of GERD patients who are symptomatic (SX) vs. asymptomatic (ASX) on PPI therapy, using traditional aspiration methods and SP, respectively. Methods: A prospective, single center study of symptoms and GAO response to PPI therapy was conducted in non-erosive GERD patients with typical GERD symptoms. GERD symptoms, duration (months) and PPI use were historically recorded. Fasting serum gastrin (pg/mL) was determined. Patients withGI surgery, motility disorders, or H. pylori infection were excluded. Control acid output (CAO; mEq/ hr) was determined by titration of gastric secretions collected by nasogastric tube or EGD just prior to the next PPI dose. Fasting patients ingested a SP, followed by Ensure Plus (240 ml) (EP) diluted to either 1⁄2 or 1⁄4 strength. Meal stimulated acid output, (SP GAO (mEq/ hr)) was calculated from the time to acidify the EP meal from pH 5 to 2. Gastric emptying time (GET; minutes) was measured by SP. Results: Twenty four patients taking PPIs were enrolled; 16 had SX GERD. Mean age was similar for SX vs ASX (44.6 vs 46.1, p=0.75). SX and ASX groups did not differ in mean values for GERD duration (71.4 vs 111.4, p= 0.40), fasting gastrin (149.9 vs 157.8, p=0.90), or GET (135.3 vs 118.8, p=0.63). A nonsignificant trend toward a higher mean PPI dose was seen in SX patients (1.31 vs 1.25 X the standard dose of PPI, p=0.86). Mean CAO (2.31 vs 1.16, p=0.40) and SP GAO (28.2 vs 44.6, p=0.2) were similar in SX and ASX GERD patients. Compared to normal untreated volunteers, SP GAO was significantly lower in both SX (53 vs 28.3, p=0.0004) and ASX (53 vs 30, p=0.0095) groups. Conclusions: SX and ASX GERD patients on PPI therapy have similar CAO and SP GAO, which are significantly lower than untreated volunteers. This suggests less acid suppression is required to relieve symptoms in a subset of GERD patients, who may be less sensitive to acid reflux. Therefore, higher PPI doses may be needed to further suppress acid and relieve symptoms in unresponsive patients.

Chronic Hypergastrinemia: Causes and Consequences

The hormone gastrin plays 2 important roles in gastrointestinal physiology--1 as a major factor in meal-stimulated gastric acid secretion and the other as a trophic hormone for epithelial and enterochromaffin cells. These roles are exaggerated to the point of pathology under conditions of chronic hypergastrinemia as exemplified by the Zollinger-Ellison syndrome and pernicious anemia. More recently, the concern about the potential risk of chronic hypergastrinemia has risen because of the widespread use of proton pump inhibitors for maintenance therapy in reflux esophagitis. For this reason, we present a concise overview of the origin, causes, and potential risks of chronic hypergastrinemia.

Targeted disruption of the murine CCK1 receptor gene reduces intestinal lipid-induced feedback inhibition of gastric function

Cholecystokinin (CCK), acting at CCK1 receptors (CCK1Rs) on intestinal vagal afferent terminals, has been implicated in the control of gastrointestinal function and food intake. Using CCK1R(-/-) mice, we tested the hypothesis that lipid-induced activation of the vagal afferent pathway and intestinal feedback of gastric function is CCK1R dependent. In anesthetized CCK1R(+/+) ("wild type") mice, meal-stimulated gastric acid secretion was inhibited by intestinal lipid infusion; this was abolished in CCK1R(-/-) mice. Gastric emptying of whole egg, measured by nuclear scintigraphy in awake mice, was significantly faster in CCK1R(-/-) than CCK1R(+/+) mice. Gastric emptying of chow was significantly slowed in response to administration of CCK-8 (22 pmol) in CCK1R(+/+) but not CCK1R(-/-) mice. Activation of the vagal afferent pathway was measured by immunohistochemical localization of Fos protein in the nucleus of the solitary tract (NTS; a region where vagal afferents terminate). CCK-8 (22 pmol ip) increased neuronal Fos expression in the NTS of fasted CCK1R(+/+) mice; CCK-induced Fos expression was reduced by 97% in CCK1R(-/-) compared with CCK1R(+/+) mice. Intralipid (0.2 ml of 20% Intralipid and 0.04 g lipid), but not saline, gavage increased Fos expression in the NTS of fasted CCK1R(+/+) mice; lipid-induced Fos expression was decreased by 47% in CCK1R(-/-) compared with CCK1R(+/+)mice. We conclude that intestinal lipid activates the vagal afferent pathway, decreases gastric acid secretion, and delays gastric emptying via a CCK1R-dependent mechanism. Thus, despite a relatively normal phenotype, intestinal feedback in response to lipid is severely impaired in these mice.

Apolipoprotein A‐IV is involved in detection of lipid in the rat intestine

Long chain triglyceride (>C12) in the intestinal lumen potently inhibits gastric emptying and acid secretion via the vagal afferent pathway. While the mechanism of inhibition involves the formation of chylomicrons, the essential role of the apolipoprotein apo A-IV is unclear. Using apo A-IV(-/-) mice, we tested the hypothesis that inhibition of gastric emptying and gastric acid secretion in response to dietary lipid is dependent upon apo A-IV. As measured by nuclear scintigraphy in awake mice, gastric emptying of an ingested whole-egg meal was significantly faster in apo A-IV(-/-) knockout versus A-IV(+/+) controls (34 +/- 1 versus 54 +/- 3 min, P < 0.0001). In anaesthetized A-IV(+/+) mice, meal-stimulated gastric acid secretion was 59% inhibited by intestinal lipid infusion; this was abolished in apo A-IV(-/-) mice. Oral gavage of lipid in awake mice activated neurones throughout the nucleus of the solitary tract (NTS) in A-IV(+/+) mice, measured by immunohistochemical localization of Fos protein expression. However, in the mid region of the NTS (bregma -7.32 to -7.76 mm), Fos expression in response to intestinal lipid was significantly decreased by 50% in apo A-IV(-/-) mice compared to A-IV(+/+) controls. We conclude that activation of the vagal afferent pathway and inhibition of gastric function in response to dietary lipid is partly dependent upon apo A-IV.

Peptone meal-stimulated gastric acid secretion is inhibited more effectively by rabeprazole than omeprazole,

Peptone meal-stimulated gastric acid secretion is inhibited more effectively by rabeprazole than omeprazole,

Rabeprazole is superior to omeprazole for the inhibition of peptone meal‐stimulated gastric acid secretion in Helicobacter pylori‐negative subjects

Peptone meal-stimulated gastric acid output is considered to be a reliable means to evaluate drug-mediated inhibition of stimulated gastric acid output, an important measure of the efficacy of the agents--such as proton pump inhibitors--used to treat acid-related disorders. To compare the initial and overall inhibitory effects on peptone meal-stimulated gastric acid secretion of rabeprazole and omeprazole, 20 mg, in Helicobacter pylori-negative subjects on the first and eighth days of treatment. Healthy volunteers (n = 27) were randomized in a single-centre, double-blind, double-dummy, 2 x 2 cross-over study. Subjects received an oral dose of rabeprazole or omeprazole, 20 mg once daily, for 8 days. After a 2-4-week washout period, subjects were crossed over to receive the other medication for 8 days. Peptone meal-stimulated gastric acid secretion was measured at hours 11 and 23 at baseline and on days 1 and 8 of treatment. On days 1 and 8, rabeprazole demonstrated a significantly greater inhibition of peptone meal-stimulated gastric acid secretion compared with omeprazole at all time points (P < 0.03). Median values of steady-state inhibition on day 1 were statistically significant at hour 23 (rabeprazole 100% vs. omeprazole 74%, P < 0.02). Rabeprazole, 20 mg, demonstrated superior control of peptone meal-stimulated gastric acid secretion compared with omeprazole, 20 mg, after the first dose and after the eighth daily dose. Rabeprazole achieved a more rapid onset of acid inhibition and a greater steady-state reduction in peptone meal-stimulated gastric acid secretion.

Meal-stimulated gastric acid secretion in healthy subjects correlates with postprandial but not fasting gastric acidity

A partially purified pregastric lipase from lambs was used as a catalyst for the hydrolysis of tributyroylglycerol. The reaction was followed by pH-stat autotitration of the released butyric acid. Integral values for pH and temperature were selected for determination of full Michaelis-Menten plots, and a kinetic surface was derived to characterize the activity of the enzyme preparation over a wide combination of these conditions. This surface enclosed a region of maximum activity centered on optimal pH (pH 6.4) and temperature (43°C), although optima were not sharply delineated. The activity in the surrounding region was generally high, and the value of the Michaelis-Menten constant was < 0.2 mM, indicating that tributyroylglycerol was generally a highly favored substrate.

In vivo gastric autotitration: a novel, simple method to measure meal-stimulated gastric acid secretion

In vivo gastric autotitration: a novel, simple method to measure meal-stimulated gastric acid secretion

Rabeprazole is superior to omeprazole for inhibition of meal-stimulated gastric acid secretion in H. pylori-negative subjects

Rabeprazole is superior to omeprazole for inhibition of meal-stimulated gastric acid secretion in H. pylori-negative subjects

Measurement of meal-stimulated gastric acid secretion and exophageal pH in ambulatory subjects who ingest typical meals

Measurement of meal-stimulated gastric acid secretion and exophageal pH in ambulatory subjects who ingest typical meals

Measurement of meal-stimulated gastric acid secretion and exophageal pH in ambulatory subjects who ingest typical meals

Measurement of meal-stimulated gastric acid secretion and exophageal pH in ambulatory subjects who ingest typical meals

Pantoprazole versus omeprazole

To determine the influence of recommended therapeutic doses of pantoprazole and omeprazole on meal-stimulated acid secretion. In this double-blind, placebo-controlled, three-period crossover study, 12 healthy male volunteers received 40 mg pantoprazole od, 20 mg omeprazole od or placebo at 08:00 h for 5 days in a randomized order. Meal-stimulated acid secretion was determined by means of a homogenized test meal, and intragastric titration on day 1, 4-6 h, 8-10 h, 16-18 h, and 24-26 h, and on days 3 and 5, 4-6 h after oral drug administration. On day 1 (4-6 h after oral drug administration), meal-stimulated acid secretion was decreased by 36% and 24% after administration of 40 mg pantoprazole or 20 mg omeprazole, respectively. After 3 and 5 days of dosing, the decreases were 88% and 85% with 40 mg pantoprazole, and 70% and 74% with 20 mg omeprazole. At all measuring points during the 5-day dosing periods, 40 mg pantoprazole proved superior to 20 mg omeprazole in inhibiting meal-stimulated gastric acid secretion. The differences were statistically significant for pantoprazole on day 1, 24-26 h after oral drug administration and on day 3 (P = 0.0425 and P = 0.0244, respectively). On day 1, only pantoprazole was significantly better than placebo (P = 0.0210, 4-6 h after dosing; P = 0.0093, 8-10 h after dosing and P = 0.0068, 16-18 h after dosing). Pantoprazole 40 mg is significantly more effective than omeprazole 20 mg in inhibiting meal-stimulated acid secretion. In addition, pantoprazole exhibits a more rapid onset of action.

Review article: clinical pharmacology of alosetron.

Alosetron, a new 5-HT3 antagonist is in development for the treatment of the irritable bowel syndrome. A series of randomized placebo-controlled double-blind clinical pharmacology studies have been performed in healthy volunteers and irritable bowel syndrome patients to evaluate the pharmacokinetics and some of the pharmacodynamic properties of this drug. Alosetron was shown to dose-dependently inhibit the 5-HT-induced skin flare response, increase colonic transit time and increase basal jejunal water and electrolyte absorption, in healthy volunteers. In irritable bowel syndrome patients, alosetron increased colonic compliance. Alosetron had no effect on the perception of gastric distension or on meal-stimulated gastric acid secretion. Orally alosetron has approximately 60% bioavailability and a half-life of 1.5 h. At doses of 1 mg or more, it has a pharmacodynamic duration of action which justifies twice a day dosing. These data support the potential use of alosetron in the treatment of irritable bowel syndrome.

Effect of gastric feeding on intragastric P co2 tonometry in healthy volunteers

Purpose: The tonometric detection of a high intragastric regional Pco 2 (P rco 2) reflecting an elevated intramucosal Pco 2 can be helpful to diagnose mucosal ischemia, if acid secretion is suppressed to avoid intragastric CO 2 production through buffering of acid by bicarbonate in the stomach. It is recommended to perform tonometry in the fasting state, but this may hamper feeding of the critically ill. On the other hand, postfeeding tonometry could serve as a diagnostic stress test because feeding increases mucosal blood flow demand, provided that the meal itself does not hamper diffusion of CO 2 from mucosa to tonometer balloon and does not generate intragastric CO 2, independently from intramucosal PCO 2. We therefore studied the effect of a standard meal on intragastric P r CO 2 tonometry in healthy volunteers with suppression of meal-stimulated gastric acid secretion and, presumably, with an adequate mucosal blood flow reserve. Material and Methods: The gastric juice pH and tonometric P r co 2 were measured in 14 human volunteers, after gastric acid secretion suppression by either ranitidine (100-mg bolus, followed by 25 mg/h IV, n = 7) or by ranitidine plus pirenzepine (10-mg bolus, followed by 3 mg/h IV, n = 7) to suppress any residual meal-stimulated gastric acid secretion, before and at 30-minute intervals until 120 minutes after oral ingestion of a standard liquid test meal (Pulmocare [Abbott, the Netherlands]; 500 mL, 750 kcal, PCO 2 5 mm Hg, pH 7.50). Results: The gastric juice pH, which was >4.0 in all individuals throughout the study, and the P r co 2 did not depend on the regimen for gastric acid secretion suppression, and therefore the data were pooled. The P rco 2 (median [range]) after feeding was 69% (56% to 170%) of baseline (42 [37–51] mm Hg) from 0 to 30 minutes ( P < .001), 85% (72% to 167%) of baseline from 30 to 60 ( P < .05), 97% (57% to 193%) from 60 to 90 minutes, and 112% (97% to 189%) of baseline from 90 to 120 minutes with a rise above baseline in 10 of 14 patients. In vitro, the liquid test meal generated CO 2 after adding bicarbonate but not after hydrochloric acid. Conclusion: We recommend intragastric tonometry to be performed in the fasting state and discourage tonometry after feeding as a stress test, because a single test meal changes tonometric P r CO 2 in a time-dependent manner until 2 hours after gastric feeding of healthy volunteers. The fall in P r CO 2 directly after feeding can be attributed to dilution, whereas a rise above baseline in some patients may have been caused, as supported by CO 2 production after adding bicarbonate to the test meal in vitro, by CO 2 production through buffering of meal-derived acid by gastric bicarbonate, in the absence of stimulated gastric acid secretion by feeding.

Intestinal fat-induced inhibition of meal-stimulated gastric acid secretion depends on CCK but not peptide YY.

Fat in small intestine decreases meal-stimulated gastric acid secretion and slows gastric emptying. CCK is a mediator of this inhibitory effect (an enterogastrone). Because intravenously administered peptide YY (PYY) inhibits acid secretion, endogenous PYY released by fat may also be an enterogastrone. Four dogs were equipped with gastric, duodenal, and midgut fistulas. PYY antibody (anti-PYY) at a dose of 0.5 mg/kg or CCK-A receptor antagonist (devazepide) at a dose of 0.1 mg/kg was administered alone or in combination 10 min before the proximal half of the gut was perfused with 60 mM oleate or buffer. Acid secretion and gastric emptying were measured. We found that 1) peptone-induced gastric acid secretion was inhibited by intestinal fat (P < 0.0001), 2) inhibition of acid secretion by intestinal fat was reversed by CCK-A receptor antagonist (P < 0.0001) but not by anti-PYY, and 3) slowing of gastric emptying by fat was reversed by CCK-A antagonist (P < 0. 05) but not by anti-PYY. We concluded that inhibition of peptone meal-induced gastric acid secretion and slowing of gastric emptying by intestinal fat depended on CCK but not on circulating PYY.

Influence of pantoprazole 40 MG and omeprazole 20 MG on meal-stimulated gastric acid secretion

Influence of pantoprazole 40 MG and omeprazole 20 MG on meal-stimulated gastric acid secretion

A Double-blind, Placebo-Controlled Study of the Effectiveness and Safety of Nizatidine in the Prevention of Postprandial Heartburn

Heartburn is frequently associated with overindulgence in food and drink, meal-stimulated gastric acid secretion, and a gastroesophageal reflux with a pH of 4 or lower. Nizatidine is a selective histamine2 receptor antagonist that effectively suppresses gastric acid secretion at lower than prescription doses and has been approved for nonprescription use in the prevention of postprandial heartburn. To examine the relative effectiveness of 3 dose levels of nizatidine (225 mg, 75 mg, and 25 mg) in preventing postprandial heartburn. Four hundred thirteen subjects with documented moderate to severe heartburn following a standard meal that provoked heartburn were randomized to receive a single dose of nizatidine at 225 mg (n = 104), 75 mg (n = 101), or 25 mg (n = 105), or placebo (n = 103) 30 minutes before the meal, at 30 minutes (immediately after completing the meal), and at 60, 90, 120, 150, 180, and 210 minutes (from beginning the meal), subjects assessed the presence or absence of heartburn (yes or no) and the severity of heartburn (100-mm visual analog scale). The use of both 225 mg and 75 mg of nizatidine were significantly better than placebo in preventing heartburn in the proportion of subjects with complete prevention of heartburn (15 [14.4%] and 15 [14.9%], respectively, vs 3 [2.9%]; P < .001); the effects of nizatidine, 25 mg, in 7 subjects (7%) were not distinguishable from placebo. Similar results for nizatidine, 225 mg and 75 mg, were seen for longest duration of no heartburn, total duration of no heartburn, the average severity of heartburn, and the peak heartburn severity. All 3 doses of nizatidine were superior to placebo (P < .001) in reducing average and peak heartburn severity and were well tolerated. Single doses of 225 mg and 75 mg of nizatidine administered 30 minutes before a standard meal intended to provoke heartburn are significantly more effective than placebo for the prevention and/or reduction of postprandial heartburn.

Influence of Lansoprazole on Intragastric 24-Hour pH, Meal-Stimulated Gastric Acid Secretion, and Concentrations of Gastrointestinal Hormones and Enzymes in Serum and Gastric Juice in Healthy Volunteers

Twelve healthy volunteers (6 females, 6 males) between 26 and 36 years of age were enroled in this double-blind, randomized, placebo-controlled, three-way cross-over study. The objective was to determine the influence of lansoprazole (Agopton, Takeda Pharma GmbH, Aachen), a novel proton pump inhibitor, in doses of 30 and 60 mg, on the intragastric pH, on meal-stimulated gastric acid secretion and on the concentration of gastrointestinal hormones and enzymes in serum and gastric juice. Active drug or placebo had to be taken as single daily morning doses on an empty stomach for 7 days. Each wash-out period between drug application periods was 2 weeks long. Lansoprazole induced a dose-related increase in intragastric pH as well as a relevant reduction of basal acid output, meal-stimulated acid output and meal-stimulated secretion volume. 60 mg lansoprazole was significantly superior to 30 mg in increasing intragastric pH. The basal secretion volume in volunteers on 30 and 60 mg lansoprazole were lower than in volunteers on placebo. Serum gastrin and serum pepsinogen concentrations increased in a dose-dependent manner. Pepsin output and pepsin activity in gastric juice were slightly decreased in volunteers on 30 mg lansoprazole and markedly suppressed in volunteers on 60 mg lansoprazole 2 h after meal stimulation. Intrinsic factor concentration increased in volunteers on lansoprazole with a clear dose relationship. The evaluation of laboratory data and reported nonserious adverse events proved the relative safety of this new antiulcer agent.

Role of gastrin and cholecystokinin receptors in regulation of peptone-stimulated gastric cid secretion in conscious rats

With the availability of selective gastrin/CCK B (L365,260) and CCK A (L364,718) receptor antagonists the present study was designed to investigate the role of gastrin and cholecystokinin (CCK) receptors in meal-stimulated gastric acid secretion. Gastric acid output was measured by continuous intragastric titration in conscious rats. Vehicle (dimethylsulfoxide/saline, 3:1), L365,260 (3 or 9 mg/kg), or L364,718 (1 mg/kg) was given by i.v. bolus injection. Basal acid output was strongly inhibited by both doses of L365,260 while L364,718 had no effect. Intragastric peptone (4%, w/v) increased acid secretion 40–65% of the response to a maximal dose (2.5 nmol/kg per h) of gastrin-17. L365,260 completely abolished gastrin-17 stimulated acid secretion and partially inhibited peptone-induced acid secretion. Blockade of CCK A receptors by L364,718 did not affect peptone-stimulated acid output. This study demonstrates that gastrin/CCK B receptors are important in regulating basal acid secretion in the conscious rat while CCK A receptors do not appear to influence basal or peptone-stimulated gastric acid secretion. Blockade of gastrin/CCK B receptors partially inhibits intragastric meal-stimulated acid secretion indicating that the gastrin/CCK B receptor has a physiological role as mediator of food-stimulated acid secretory response in conscious rats.

Intestinal fat does not inhibit gastric function through a hormonal somatostatin mechanism in dogs

In awake dogs with chronic gastric, duodenal, and jejunal fistulas, F(ab)1 fragments of somatostatin monoclonal antibody (mAb S607) were administered intravenously (IV) to test the hypothesis that intraintestinal lipid inhibits peptone-stimulated gastric acid secretion and emptying by a hormonal somatostatin mechanism. Plasma somatostatin was increased significantly by duodenal and jejunal perfusion with 20% lipid. Somatostatin administered IV caused dose-dependent inhibition of meal-stimulated gastric acid secretion and gastric emptying similar to that seen after intestinal perfusion with lipid. Administration of mAb S607 F(ab)1 fragments significantly reversed somatostatin (400 pmol · kg−1 · h−1, IV)-induced inhibition of peptonestimulated acid output and gastric emptying. Acid output inhibited by intraduodenal lipid was reversed partially after F(ab)1 administration, but the inhibitory effect of intrajejunal lipid was not altered. Inhibition of acid secretion by IV somatostatin and by intraintestinal fat was not caused by a decrease in circulating gastrin concentrations. Gastric emptying delayed by intraintestinal lipid was unaffected by antibody administration. Somatostatin does not appear to be a major hormonal mediator of intestinal fat-induced inhibition of gastric acid secretion or delayed gastric emptying in dogs.