Gastric Acid Hypersecretion Research Articles

Replacement of oral proton pump inhibitors with intravenous pantoprazole to effectively control gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

OBJECTIVES: In patients with Zollinger-Ellison syndrome (ZES) or other conditions requiring oral doses of proton pump inhibitors, it frequently becomes necessary to use parenterally administered gastric acid inhibitors. However, i.v. histamine-2 receptor antagonists are not effective at usual doses and lose their effectiveness because of tachyphlaxis. With the approval in the United States of i.v. pantoprazole, a substituted benzimidazole available in i.v. formulation, it will become possible to acutely manage gastric acid secretion in the acute care setting of a hospital. This study was developed to monitor the safety and establish the efficacy of i.v. pantoprazole as an alternative to oral proton pump inhibitors for the control of gastric acid hypersecretion in patients with ZES. METHODS: The efficacy of replacing oral PPI therapy with i.v. pantoprazole was evaluated in 14 ZES patients. After study enrollment, patients taking their current doses of oral PPI (omeprazole or lansoprazole) were switched to pantoprazole i.v. for 6 days during an 8-day inpatient period in the clinical research center. Effective control was defined as an acid output (AO) of <10 mEq/h (<5 mEq/h in patients with prior gastric acid-reducing surgery). RESULTS: The mean age of the 14 patients enrolled in the study was 52.4 yr (range = 38–67). Mean basal AO was 0.55 ± 0.32 mEq/h and mean fasting gastrin was 1089 pg/ml (range = 36–3720). Four patients were also diagnosed with the multiple endocrine neoplasia type I syndrome, nine were male, and two had previously undergone acid-reducing surgery. Before study enrollment, gastric acid hypersecretion was controlled in nine of 14 patients with omeprazole (20–200 mg daily) and five of 14 with lansoprazole (30–210 mg daily). In the oral phase of the study all patients had adequate control of gastric acid secretion, with a mean AO of 0.55 ± 0.32 mEq/h (mean ± SEM). Thereafter, 80 mg of i.v. pantoprazole was administered b.i.d. for 7 days by a brief (15 min) infusion and the dose was titrated upward to a predetermined maximum of 240 mg/24 h to control AO. A dose of 80 mg b.i.d. of i.v. pantoprazole controlled AO in 13 of 14 of the patients (93%) for the duration of the study ( p > 0.05 compared to baseline values for all timepoints). One sporadic ZES patient (oral control value = 0.65 mEq/h on 100 mg of omeprazole b.i.d. p.o.) was not controlled with 80 mg of i.v. pantoprazole b.i.d. and dosage was titrated upward to 120 mg b.i.d. after day 2. CONCLUSIONS: There were no serious adverse events observed. Intravenous pantoprazole provides gastric acid secretory control that is equivalent to the acid suppression observed with oral proton pump inhibitors. Most ZES patients (93%) maintained effective control of AO previously established with oral PPIs when switched to 80 mg of i.v. pantoprazole b.i.d.; however, for difficult-to-control patients, doses >80 mg b.i.d. may be required.

Occurrence and relapse of bleeding from duodenal ulcer: respective roles of acid secretion and Helicobacter pylori infection.

Helicobacter pylori infection, gastric acid hypersecretion and NSAID consumption may cause peptic ulcer. To investigate the respective roles of H. pylori and acid secretion in bleeding duodenal ulcer. A total of 99 duodenal ulcer patients were referred for evaluation of acid secretion: seven with Zollinger-Ellison Syndrome; 14 with hypersecretory duodenal ulcer, defined by the coexistence of elevated basal acid output and pentagastrin acid output; and 78 duodenal ulcer patients with normal acid output. All non-Zollinger-Ellison Syndrome patients were H. pylori-positive and cured of infection. All patients were followed-up for a 36-month period, to assess the occurrence of bleeding episodes. Twenty-nine patients had at least one bleeding episode in the 4 years before the study. Bleeding was more frequent in males and in patients on NSAIDs. The mean basal acid output was not higher among bleeders. In the 21 patients (14 hypersecretory duodenal ulcer, seven Zollinger-Ellison Syndrome) with basal acid output > 10 meg/h and pentagastrin acid output > 44.5 meg/h, the risk of bleeding was higher (OR 6.5; 95% CI: 2-21). In the follow-up period, three out of 83 (3.3%) non-Zollinger-Ellison Syndrome patients had a H. pylori-negative duodenal ulcer with bleeding. The risk of bleeding after H. pylori cure was not higher in hypersecretory duodenal ulcer patients (P > 0.3), nor among patients with previous bleeding episodes (P > 0.2). In H. pylori-positive duodenal ulcer patients, the coexistence of elevated basal acid output and pentagastrin acid output leads to a sixfold increase in the risk of bleeding. After H. pylori cure, gastric acid hypersecretion is not a risk factor for bleeding. However, duodenal ulcer recurrence with bleeding may occasionally occur in patients cured of H. pylori, even if acid output is normal.

Gastric secretion in Zollinger-Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis--a prospective NIH study of 235 patients and a review of 984 cases in the literature.

We prospectively studied 235 patients with Zollinger-Ellison syndrome (ZES) (205 without and 30 with prior acid-reducing surgery) and compared the results with 984 patients from 182 reports in the literature. The aims of the study were to evaluate the sensitivity of proposed acid secretory criteria for the diagnosis of ZES, propose new criteria, evaluate the variability and methodology of gastric secretory testing, and correlate the symptoms and signs of ZES, tumor extent, and primary tumor size and location with the degree of gastric acid hypersecretion. Multiple endocrine neoplasia-type 1 (MEN1) occurred in 22% of patients. The mean basal acid output (BAO) in patients without and with prior acid-reducing surgery was 41.2 +/- 1.7 mEq/hr (range, 1.6-118.3 mEq/hr) and 27.6 +/- 3.5 mEq/hr (range 5.9-102.9 mEq/hr), respectively. In patients with MEN1, those with female gender, Hispanic, or Asian race had lower BAOs. Diarrhea, esophageal stricture, and pyloric scarring were associated with a higher BAO. Neither other symptoms nor the tumor extent, primary tumor location, or size correlated with the magnitude of acid hypersecretion. ZES diagnosis was delayed a mean of 5.5 +/- 0.4 yr. Patients who were misdiagnosed as having either Crohn or celiac disease had higher BAOs. The sensitivities from our study and the literature review of the proposed BAO criteria for the diagnosis of ZES in patients without previous gastric acid-reducing surgery were 91% and 90% for BAO > or = 15 mEq/hr, 86% and 82% for BAO > or = 18 mEq/hr, 69% and 67% for BAO > 25 mEq/hr, and 31 mEq/hr, respectively. The specificities of all the proposed BAO criteria were high. Both the criterion of BAO > or = 15 mEq/hr and BAO > or = 18 mEq/hr had good specificities and equal sensitivity. With prior acid-reducing surgery, the sensitivities in our study and from the literature review were 100% and 81% for BAO > or = 5 mEq/hr, 73% and 45% for BAO > 14.4 mEq/hr, and 37% and 31% for BAO > 19.2 mEq/hr, respectively. The reported mean specificity for the criterion of BAO > or = 5 mEq/hr was 85%, while it was 100% for the other 2 criteria. The maximal acid output (MAO) criterion of > 70 mEq/hr had sensitivities in the present National Institutes of Health (NIH) study and the literature review of 39% and 31%, respectively, and the criterion of MAO > 100 mEq/hr had a sensitivity of 0.6 had a low sensitivity. The proposed criterion of the ratio of basal and maximal acid H+ concentration (BAC/MAC ratio) > or = 0.6 had an excellent sensitivity-- > or = 89% in patients with or without previous acid-reducing surgery. The reported specificity for both the BAO/MAO criterion and the BAC/MAC criterion were similar, but BAC/MAC had a better sensitivity. Combination criteria of BAO generally did not improve sensitivity. The criterion of pH 160 mL/hr in patients without prior acid-reducing surgery occurred in > 86% of patients, and > 140 mL/hr in 87% of patients with prior acid-reducing surgery; these, thus, are neglected findings that have good sensitivities. Our analysis shows criteria based on MAO, pH, and BAO/MAO ratio do not have high sensitivities and thus are not useful. In patients without prior acid-reducing surgery, the criteria of BAO > or = 15 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 160 mL/hr are useful for the diagnosis of ZES and have good specificities. In patients with prior acid-reducing surgery, the criteria of BAO > or = 5 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 140 mL/hr have high sensitivities. In patients with sporadic ZES without acid-reducing surgery, the criterion of BAO > or = 18 mEq/hr is recommended as it has a similar sensitivity but higher specificity than the criterion of BAO > or = 15 mEq/hr. Only 1 patient in either data set (NIH or the literature) with or without previous acid-reducing surgery had a basal gastric pH > 2, therefore this finding essentially excludes the diagnosis of ZES. Gastric secretory measurements for 30 minutes, but not 15 minutes, give results comparable to those for a full hour. On the basis of these results, a number of gastric secretory criteria are proposed, including some for the first time, and alterations in methodology are proposed that should prove useful in the diagnosis of ZES.

Surgery of reflux esophagitis--a renaissance

Gastroesophageal reflux disease (GERD) has a high prevalence of 40% in Western countries. A dysfunction of the lower esophageal sphincter of unknown origin is the main etiology. Less common pathophysiological reasons are disorders of esophageal motility, delayed gastric emptying, gastric acid hypersecretion and bile reflux. As causal surgical therapy for these disorders fundoplication has been developed 50 years ago. This technique uses a wrap of gastric fundus around the distal esophagus as reflux barrier. Because of severe postoperative complications (dysphagia, gas bloat syndrome, gastric ulcer) and recurrence after fundoplication, medical therapy became the treatment of choice with the development of H2-receptor antagonists and proton pump inhibitors in the 1970s. However, after improvement of surgical technique and introduction of laparoscopic fundoplication in 1991 surgery offers a secure and effective causal therapy. Randomized controlled trials proof the superiority of fundoplication versus medical therapy in regard of long term results, recurrence and cost effectiveness as well as the superiority of laparoscopic versus conventional open fundoplication in regard of recovery and cost effectiveness with equal long term results. Therefore, laparoscopic fundoplication by an experienced laparoscopic surgeon is the surgical therapy of choice. However the high prevalence of GERD requires careful selection of patients for surgery. A thorough preoperative evaluation including upper gastrointestinal endoscopy with biopsy, esophageal manometry and 24 h-pH monitoring as well as upper gastrointestinal contrast study is essential. Today the indication for fundoplication is seen in young symptomatic patients, requiring a long-term medical therapy, in hiatal hernia with threatening complications as well as in complications of severe GERD, especially Barrett-esophagus. At present the advantages of total (Nissen) or partial (Toupet) wrap as well as the benefit of dissection of the short gastric vessels for total fundoplication are still unclear, especially concerning long-term results. To answer these technical questions further randomized controlled trials with long-term follow-up have to be performed.

Oral pantoprazole for acid suppression in the treatment of patients with Zollinger-Ellison syndrome.

The management of patients with gastric acid hypersecretion due to gastrinoma, usually recognized as Zollinger-Ellison syndrome (ZES), was radically changed 10 years ago by the use of proton pump inhibitors. Surgical treatment now concentrates on tumour excision, and in the majority of patients, gastrectomy is no longer required to prevent complications of acid hypersecretion that can be managed pharmacologically. To verify the ability of pantoprazole to control gastric acid hypersecretion and the clinical effects of acid hypersecretion in seven patients with documented ZES. Pantoprazole was administered at an initial dose of 80 mg daily for seven days before basal acid output (BAO) was measured at 08:00, ie, 1 h before the next dose of pantoprazole was normally ingested. A lower (40 mg) or higher (120 mg or more) dose of pantoprazole was then used to keep the BAO in the therapeutic range (between 0.1 and 10 mmol/h) and to control clinical symptoms such as acid-related pain or diarrhea. BAO and clinical symptoms were controlled with pantoprazole 40 mg daily in one patient, 80 mg daily in two patients, 120 mg daily in three patients and 160 mg daily in one patient. Pantoprazole was able to control acid hypersecretion in ZES patients when administered in doses between 40 and 160 mg daily. An initial dose of 120 mg given before further titration of the drug regimen appears to be a reasonable therapeutic strategy.

Gastric antral juxtamucosal pH in helicobacter pylori positive and negative dyspeptic patients

Maintenance of gastric juxtamucosal pH at a stable near neutral value may be the cumulative effect of the various components of the mucosal defense system. In order to assess the effect of helicobacter pylori (HP) infection on mucosal defense, we measured the gastric antral juxtamucosal pH in 40 dyspeptic patients by using a flexible glass pH microelectrode which can be passed down the instrument channel of standard gastroscopes. HP status was determined using serology, culture, histology and urease test. We also investigated the relationship between juxtamucosal pH and the severity of antral HP infection. The mean antral juxtamucosal pH in 26 (65%) HP positive patients was 6.49 +/- 0.20 compared to 6.19 +/- 0.21 in 14 (35%) HP negative patients (p < 0.00001). Other factors like age, sex, duodenogastric reflux or presence of chronic duodenal ulcer did not significantly affect juxtamucosal pH (p > 0.05). Subset analysis of data on HP positive patients (n = 26) revealed no significant correlations between antral chronic gastritis anti-HP IgG titre and antral juxtamucosal pH (p > 0.05). This study shows that HP increases gastric antral juxtamucosal pH. This finding supports the suggested role of HP in producing hypergastrinaemia and gastric acid hypersecretion.

Management of the patient with short bowel syndrome.

Extensive resection of the small bowel results in impaired digestion of macronutrients and malabsorption of nutrients, fluid, electrolytes, and minerals. Gastric acid hypersecretion and alterations in gut hormonal response further contribute to the problem. Diarrhea, dehydration, electrolyte and acid/base abnormalities, and macronutrient and micronutrient deficiencies ensue, and is termed the short bowel syndrome (SBS). Rare disorders, such as essential fatty acid deficiency and D-lactic acidosis, are a greater concern for the SBS patient. These patients' lives are significantly impacted, and they require close monitoring by a medical team knowledgeable about the disease and its nutritional, metabolic, and psychosocial consequences. Immediate therapies are directed toward fluid resuscitation, wound healing, and initiation of early nutrition support. After medical stabilization, multiple nutritional and medicinal therapies are used to aid bowel adaptation and prevent medical crisis. Advanced practice nurses should be knowledgeable about SBS to educate patients and families about this disease, associated therapies and changes in lifestyle, and how to detect and manage acute changes in medical condition.

Practical use of iv pantoprazole in the intensive care unit: four case presentations

Purpose: PPIs are effective agents to control gastric acid output (AO), however, none are approved in the US for parenteral administration in patients. Our aim was to determine the efficacy of IV-Panto in 4 patients with gastric acid hypersecretion in ICU settings under compassionate use (treatment) INDs approved by the FDA.

GASTROINTESTINAL ABNORMALITIES AND INVOLVEMENT IN SYSTEMIC MASTOCYTOSIS

Recent studies have shown that involvement of the gastrointestinal tract is much more frequent than originally reported in patients with systemic mastocytosis. Seventy percent to 80% of patients with systemic mastocytosis are found to have gastrointestinal symptoms when a careful history is taken, and abnormalities in the gastrointestinal tract are frequently detected by endoscopic studies, functional studies of absorption, and barium studies. Because of the rarity of the disease, there are few prospective studies of gastrointestinal involvement, so the actual frequency of upper and lower gastrointestinal lesions is unknown. Furthermore, there have been no studies correlating endoscopic abnormalities of the lower gastrointestinal tract with the presence or absence of diarrhea, which is a frequent symptom (mean, 43% [range 14%-100%]). A review of gastric acid studies reveals that a proportion of patients develop gastric acid hypersecretion because of the hyperhistaminemia, which can result in ulcer disease that in turn can cause dyspeptic pain, small intestinal mucosal damage, and malabsorption. In some patients gastric acid hypersecretion in the range seen in Zollinger-Ellison syndrome can develop. A number of studies suggest that the prevalence of peptic ulcer disease has been underestimated in these patients and is certainly higher than the general population. The exact physiologic basis for the diarrhea or nondyspeptic abdominal pain remains largely unknown in these patients. Whereas some studies suggest small intestinal mucosal abnormalities are responsible for most cases of malabsorption not associated with gastric acid hypersecretion, this supposition also remains unproven. Hepatomegaly, portal hypertension, splenomegaly, and ascites occur frequently in patients with systemic mastocytosis, especially those with category II through IV disease. Whereas the histology of the liver and spleen and alterations in hepatic function studies have been well studied, the pathogenesis of each of these abnormalities has not been well studied, and almost all the information comes from a few well-studied case reports.

Salivary and gastric epidermal growth factor in patients with Zollinger-Ellison syndrome: its protective potential.

Evidence is accumulating that epidermal growth factor (EGF) is a major molecule contributing to the maintenance of the integrity of the upper alimentary tract mucosa before and after injury by acid and pepsin. Patients with Zollinger-Ellison Syndrome (ZES) typically have hypersecretion of acid and pepsin; however, the concentration and rate of secretion of salivary and gastric EGF that could counteract these potentially aggressive factors are unknown. Accordingly, this study was conducted to determine whether EGF affords mucosal protection in ZES patients. The concentration and output of salivary (sEGF) and gastric epidermal growth factor (gEGF) were measured in eight patients with ZES and the results compared to those in 17 patients with nonulcer dyspepsia (NUD), serving as a control group. All patients had normal esophageal and gastric mucosa as determined by endoscopy. Total saliva was collected during 1-h parafilm- and 1-h pentagastrin/parafilm-stimulated conditions, as well as basal and pentagastrin-stimulated gastric juice. The concentration and output of EGF were determined by radioimmunoassay. The concentration of EGF in saliva collected from ZES patients after parafilm chewing was significantly higher compared to that in NUD patients (4.61 +/- 0.59 vs 2.75 +/- 0.50 ng/ml, p < 0.05). The concentration of EGF in saliva collected after pentagastrin stimulation in ZES patients was also significantly higher than in NUD patients (4.37 +/- 0.73 vs 2.22 +/- 0.37 ng/ml, p < 0.05). Salivary EGF output during parafilm chewing in ZES and NUD were similar (68 +/- 6.4 vs 109 +/- 25.2 ng/h). Salivary EGF output after administration of pentagastrin in ZES and NUD was also similar (66 +/- 6.1 vs 132 +/- 45.4 ng/h). Basal EGF output in the gastric juice of patients with ZES was 3-fold higher than in patients with NUD (801 +/- 73 vs 271 +/- 32 ng/h, p < 0.01). Pentagastrin-stimulated EGF output was similar in both groups (705 +/- 92 vs 675 +/- 168 ng/h). Patients with ZES have a significantly higher EGF concentration in saliva and EGF output in basal gastric juice. This elevated content of salivary and gastric EGF in ZES patients may play a protective role in preventing the development of reflux esophagitis and gastric ulcer under the impact of gastric acid and pepsin hypersecretion.

Salivary and gastric epidermal growth factor in patients with Zollinger-Ellison syndrome: its protective potential

OBJECTIVE: Evidence is accumulating that epidermal growth factor (EGF) is a major molecule contributing to the maintenance of the integrity of the upper alimentary tract mucosa before and after injury by acid and pepsin. Patients with Zollinger-Ellison Syndrome (ZES) typically have hypersecretion of acid and pepsin; however, the concentration and rate of secretion of salivary and gastric EGF that could counteract these potentially aggressive factors are unknown. Accordingly, this study was conducted to determine whether EGF affords mucosal protection in ZES patients. METHODS: The concentration and output of salivary (sEGF) and gastric epidermal growth factor (gEGF) were measured in eight patients with ZES and the results compared to those in 17 patients with nonulcer dyspepsia (NUD), serving as a control group. All patients had normal esophageal and gastric mucosa as determined by endoscopy. Total saliva was collected during 1-h parafilm- and 1-h pentagastrin/parafilm-stimulated conditions, as well as basal and pentagastrin-stimulated gastric juice. The concentration and output of EGF were determined by radioimmunoassay. RESULTS: The concentration of EGF in saliva collected from ZES patients after parafilm chewing was significantly higher compared to that in NUD patients (4.61 ± 0.59 vs 2.75 ± 0.50 ng/ml, p < 0.05). The concentration of EGF in saliva collected after pentagastrin stimulation in ZES patients was also significantly higher than in NUD patients (4.37 ± 0.73 vs 2.22 ± 0.37 ng/ml, p < 0.05). Salivary EGF output during parafilm chewing in ZES and NUD were similar (68 ± 6.4 vs 109 ± 25.2 ng/h). Salivary EGF output after administration of pentagastrin in ZES and NUD was also similar (66 ± 6.1 vs 132 ± 45.4 ng/h). Basal EGF output in the gastric juice of patients with ZES was 3-fold higher than in patients with NUD (801 ± 73 vs 271 ± 32 ng/h, p < 0.01). Pentagastrin-stimulated EGF output was similar in both groups (705 ± 92 vs 675 ± 168 ng/h). CONCLUSIONS: Patients with ZES have a significantly higher EGF concentration in saliva and EGF output in basal gastric juice. This elevated content of salivary and gastric EGF in ZES patients may play a protective role in preventing the development of reflux esophagitis and gastric ulcer under the impact of gastric acid and pepsin hypersecretion.

Intravenous pantoprazole rapidly controls gastric acid hypersecretion in patients with Zollinger–Ellison syndrome

Background & Aims: Parenteral control of gastric acid hypersecretion in conditions such as Zollinger–Ellison syndrome (ZES) or idiopathic gastric acid hypersecretion is necessary perioperatively or when oral medications cannot be taken for other reasons (e.g., during chemotherapy, acute upper gastrointestinal bleeding, or in intensive care unit settings). Methods: We evaluated the efficacy and safety of 15-minute infusions of the proton pump inhibitor pantoprazole (80–120 mg every 8–12 hours) in controlling acid output for up to 7 days. Effective control was defined as acid output >10 milliequivalents per hour (mEq/h) (<5 mEq/h in patients with prior acid-reducing surgery) for 24 hours. Results: The 21 patients enrolled had a mean age of 51.9 years (range, 29–75) and a mean disease duration of 8.1 years (range, <0.5–21); 13 were male, 7 had multiple endocrine neoplasia syndrome type I, 4 had undergone acid-reducing surgery, 2 had received chemotherapy, and 13 had undergone gastrinoma resections without cure. Basal acid output (mean ± SD) was 40.2 ± 27.9 mEq/h (range, 11.2–117.9). In all patients, acid output was controlled within the first hour (mean onset of effective control, 41 minutes) after an initial 80-mg intravenous pantoprazole dose. Pantoprazole, 80 mg every 12 hours, was effective in 17 of 21 patients (81%) for up to 7 days. Four patients required upward dose titration, 2 required 120 mg pantoprazole every 12 hours, and 2 required 80 mg every 8 hours. At study end, acid output remained controlled for 6 hours beyond the next expected dose in 71% of patients (n = 15); mean acid output increased to 4.0 mEq/h (range, 0–9.7). No serious or unexpected adverse events were observed. Conclusions: Intravenous pantoprazole, 160–240 mg/day administered in divided doses by 15-minute infusion, rapidly and effectively controlled acid output within 1 hour and maintained control for up to 7 days in all ZES patients. GASTROENTEROLOGY 2000;118:696-704

Hypersecretory duodenal ulcer and Helicobacter pylori infection: for-year follow-up study

Background. About 10% of duodenal ulcer patients are characterized by gastric acid hypersecretion with normal gastrin values. Relapsing duodenal ulcer after Helicobacter pylori cure has been related to high acid output and maintenance antisecretory therapy has been suggested in hypersecretory duodenal ulcer patients. The role of Helicobacter pylori infection and the effects of Helicobacter pylori cure in hypersecretory duodenal ulcer patients still remain to be fully studied. Aim. To study: a) whether gastric acid hypersecretion “per se” is a risk factor for duodenal ulcer recurrence; b) whether maintenance antisecretory therapy is necessary after eradication in hypersecretory duodenal ulcer patients. Patients. The study population comprised 8 hypersecretory duodenal ulcer patients, selected from a population of 79 Helicobacter pylori-positive duodenal ulcer patients. Methods. Hypersecretory duodenal ulcer patients were followed-up for at least 4 years after eradication. Gastric acid secretion was measured again 12 months after Helicobacter pylori eradication. Gastroscopy with histology was performed 3, 6, 12 and 36 months after treatment, 13C-urea breath test after 42 months; clinical questionnaires were completed every 6 months. Results. After eradication, despite a not significantly reduced high acid output (median value of basal acid output and pentagastrin-stimulated acid output, respectively, 23.1 mEg/h and 64. 1 mEg/h before treatment vs 16 mEg/h and 49.7 mEq/h 12 months after treatment), all patients were free from symptoms, none of them had duodenal ulcer relapse or complications ( 7 8 before treatment), or needed antisecretory maintenance therapy, except for one patient taking non-steroidal anti-inflammatory drugs. Conclusions. These findings, obtained in a selected population of hypersecretory duodenal ulcer patients with long-term follow-up, suggest that after successful Helicobacter pylori eradication gastric acid hypersecretion “per se” is not able to determine the recurrence of duodenal ulcer.

Changes in gastric acid secretion assayed by endoscopic gastrin test before and after Helicobacter pylorieradication

BACKGROUNDIt remains controversial whether or not Helicobacter pyloriinfection causes altered gastric acid secretion. A novel test for evaluating gastric acid secretion (endoscopic gastrin test; EGT) has recently been developed.AIMTo investigate...

Review article: pharmacokinetic concerns in the selection of anti-ulcer therapy.

Rabeprazole is a new, highly potent proton pump inhibitor (PPI) being introduced for the treatment of disorders of gastric acid hypersecretion. Rabeprazole joins other drugs in this class, such as omeprazole, pantoprazole, and lansoprazole, which share a common mechanism of action. Each of these drugs is a substituted benzimidazole, which inhibits activity of the H+, K+ -ATPase located on the apical surface of parietal cells, thereby preventing the secretion of gastric acid. As a result of structural and functional similarities, the PPIs share many pharmacokinetic features. They have comparable rates of absorption, maximum plasma concentrations, and total drug absorptions resulting in similar bioavailability after single-dose administration. With multiple dosing, rabeprazole differs from omeprazole in that its pharmacokinetic profile does not change significantly over the course of therapy. All the PPIs are metabolized rapidly, resulting in short half-lives. However, their duration of activity is much longer, due to the way in which they bind to H+, K+ -ATPase. All are metabolized by hepatic cytochrome P450 enzymes, although only omeprazole has demonstrated significant interactions with other drugs metabolized by this pathway. Rabeprazole, which has a low potential for interacting with drugs metabolized by cytochrome P450, does interfere with the absorption of digoxin and ketoconazole because of its antisecretory effects. The pharmacokinetics of rabeprazole are altered slightly in elderly subjects and in patients with renal and moderate hepatic disease. However, the pharmacokinetic findings suggest that no dosage adjustment is required in these special populations.

Lessons from genetically engineered animal models. III. Lessons learned from gastrin gene deletion in mice.

Gastrin is the principal hormonal inducer of gastric acid secretion. Chronic hypergastrinemia, leading to hypersecretion of gastric acid and increased proliferation of parietal and enterochromaffin-like (ECL) cells, has been well described. In contrast, the physiological consequences of chronic gastrin deficiency had been poorly understood until the recent genetic engineering of mouse mutants containing a gastrin gene deletion by homologous recombination in embryonic stem cells. This themes article describes the consequences of constitutive gastrin deficiency on the development and physiology of the stomach. A lack of gastrin disrupts basal gastric acid secretion and renders the acid secretory system unresponsive to acute histaminergic, cholinergic, and gastrinergic stimulation. The defect in acid secretion is greater than would have been predicted from previous studies in which gastrin action was acutely blocked. Cellular changes include thinning of the gastric mucosa in the gastrin-deficient mice, with a reduction in parietal cells and reduced expression of markers of parietal and ECL cell-differentiated functions. The results suggest that gastrin is required for the functional maturation of the acid-secretory system.

CCK 1 and CCK 2 receptors regulate gastric pepsinogen secretion

The present study investigated (1) the pharmacological profile of cholecystokinin (CCK) receptor subtypes involved in the regulation of gastric pepsinogen secretion, (2) the influence of gastric acidity on peptic responses induced by CCK-8-sulfate (CCK-8S) or gastrin-I; and (3) the mechanisms accounting for the effects of CCK-like peptides on pepsinogen secretion. In anaesthetized rats, i.v. injection of CCK-8S or gastrin-I increased both pepsinogen and acid secretion. The pepsigogue effect of CCK-8S was higher than that of gastrin-I, whereas acid hypersecretion after CCK-8S was lower than that induced by gastrin-I. Peptic output following CCK-8S was partly blocked by i.v. injection of the CCK 1 receptor antagonist, devazepide (−75.3%), or the CCK 2 receptor antagonist, l-365,260 [3 R(+)- N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1 H-1,4-benzodiazepine-3yl)- N′-(3-methyl-phenyl)urea; −27.9%], but was fully prevented by combined administration of devazepide and l-365,260. The gastric acid hypersecretory effect of CCK-8S was enhanced by devazepide (+84.5%) and blocked by l-365,260. In contrast, the gastric secretory actions of gastrin-I were insensitive to devazepide, but abolished by l-365,260. Excitatory effects of CCK-8S and gastrin-I were not modified by vagotomy or atropine, whereas cimetidine or α-fluoromethylhistidine (irreversible blocker of histidine decarboxylase) partly prevented acid hypersecretion induced by both peptides without affecting their pepsigogue effects. After pretreatment with omeprazole, both CCK-8S and gastrin-I failed to stimulate acid secretion, while they increased pepsinogen output. In rats with gastric perfusion of acid solutions, CCK-8S or gastrin-I increased peptic output in a pH-independent manner either with or without pretreatment with omeprazole. Ablation of capsaicin-sensitive sensory nerves as well as application of lidocaine to the gastric mucosa failed to modify the excitatory effects of CCK-8S or gastrin-I on pepsinogen and acid secretion. Blockade of the nitric oxide (NO) synthase pathway by N G-nitro- l-arginine-methyl ester prevented the pepsigogue actions of both CCK-8S and gastrin-I (−61.8% and −71.7%, respectively), without affecting the concomitant increase in acid output. In addition, both these peptides significantly increased the release of NO breakdown products into the gastric lumen. The present results suggest that: (1) both CCK 1 and CCK 2 receptors mediate the peptic secretory responses induced by CCK-like peptides; (2) the excitatory inputs of CCK-8S and gastrin-I to chief cells are not driven through acid-dependent mechanisms or capsaicin-sensitive afferent sensory nerves; and (3) under in vivo conditions, the stimulant actions of CCK-like peptides on pepsinogen secretion are mediated, at least in part, by an increase in NO generation.

Zollinger-Ellison Syndrome.

The first goal of therapy is the control of gastric acid hypersecretion using PPIs or high-dose H2R antagonists. The diagnosis of Multiple Endocrine Neoplasia (MEN I) should be established early in the disease. Localization of gastrinoma tumor should be performed using a combination of endoscopic ultrasonography (EUS), somatostatin receptor scintigraphy (SRS), and computerized tomography (CT), or Magnetic Resonance Imaging (MRI). Surgical resection in sporadic ZES should be performed to attempt cure of tumor. Surgery, hormonal, chemotherapy, embolization therapy or therapeutic OctreoScan should be considered in patients with metastatic tumor.

An Explanation of Gastric Hypersecretion in the Pylorus-ligated Rat

The hypersecretion of gastric acid in the pylorus-ligated rat has been shown to be of vagal origin. The present series of experiments were performed to identify the stimulus. The pyloric sphincter was ligated in a series of Sprague Dawley rats. Along with pylorus ligation, various other surgical manipulations were performed. Intestinal obstruction by ligation approximately 20 cm aboral to the cecum reduced unstimulated gastric secretion in the pylorus-ligated rat. However, perfusion of the lower small intestine with bicarbonate (143 mEq/L) stimulated secretion. Perfusion with either saline or deoxycholic acid (20 mEq/L) did not alter secretion. This supports a role for bicarbonate in the hypersecretion of gastric acid in the pylorus-ligated rat. The reflex appears to involve the myenteric plexus, since section of the pylorus seemed to attenuate gastric secretion. Plasma from animals with pylorus ligation, either alone or with intesti nal ligation, equally inhibited gastric secretion. This suggests that while some factor inhibiting gastric secretion may be present, it appears to be unrelated to pylorus ligation.

Functional dyspepsia: New insights into the pathophysiology

The pathogenesis of functional dyspepsia remains poorly understood. There is increasing evidence pointing to a predominant role of gastroduodenal visceral hypersensitivity in the pathogenesis, where patients have abnormally reduced gastric and small intestinal sensory thresholds. Motor abnormalities observed in subgroups of patients include delayed gastric emptying, antral hypomotility, gastric dysrhythmias, abnormal gastrointestinal reflexes and small intestinal dysmotility, but these may be secondary pheno nena. The central nervous system modifies peripheral visceral afferent pathways and, hente, psychological factors may possibly alter symptom status. Other putative mechanisms include Helicobacter pylori gastritis and gastric acid hypersecretion or sensitivity, but the role of these remain controversial.