Parenteral control of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

Parenteral control of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome is increasingly required; however, existing methods of determining the required dose are cumbersome and not applicable in all centers. A previous study suggested that the required parenteral dose of histamine H₂-receptor antagonists correlated with the previous oral dose. In the present study, in 31 patients with Zollinger-Ellison syndrome we evaluated the hypothesis that an effective parenteral histamine H₂-receptor antagonist dose could be predicted from the previous oral dose. Twenty-three patients were taking oral ranitidine (mean 1.3 g/day), six patients famotidine (152 mg/day), and two patients cimetidine (1.8 g/day). Each patient was treated with a continuous intravenous infusion of the equivalent dose of ranitidine (mean dose 1 mg/kg/hr with 35% requiring 0.5 mg/kg/hr, 49% 1 mg/kg/hr, 3% 1.5 mg/kg/hr, 10% 2 mg/kg/hr, and 3% 2.5 mg/kg/hr. This dose of ranitidine acutely controlled acid secretion (<10 meq/hr) in all patients. To evaluate long-term efficacy and safety, 20 patients were maintained on this dose through the peri-and postoperative periods. Mean duration was 7.1 days with 25% treated 3–5 days, 40% 6–8 days, 30% 8–10 days, and 5%>10 days. The predicted dose continued to control acid secretion in 95% of patients with one patient requiring one dose adjustment. No biochemical, clinical, or hematological toxicity was seen, although ranitidine was stopped in one patient because of skin rash. These results demonstrate that the parenteral dose of ranitidine required to control acid secretion in patients with Zollinger-Ellison syndrome can be predicted from the oral dose. This predicted dose will be acutely effective in all patients in reducing acid secretion to <10 meq/hr, the established level of control, will remain effective in 95% of patients for up to 11 days, and is safe. By utilizing the oral dose to predict the intravenous dose, repeated dose titrations will be avoided and thus this method should be generally useful in all settings.     

Effect of sham feeding on acid secretion in patients with Zollinger-Ellison syndrome with or without proximal gastric vagotomy

In dogs, vagal stimulation by sham feeding inhibits gastrin-stimulated gastric acid secretion from vagally denervated fundic pouches. To investigate this in humans, we sham fed patients with endogenous hypergastrinemia secondary to the Zollinger-Ellison syndrome. Whether these patients had been treated previously by proximal gastric vagotomy or not, sham feeding did not reduce basal acid secretion. Thus, sham feeding did not inhibit acid secretion in humans with hypergastrinemia, even when the fundus of the stomach had been vagally denervated.     

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.     

Recent advances in the management of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

Several histamine H2 receptor antagonists and the H+,K(+)-ATPase inhibitor, omeprazole, have been shown to be capable of controlling gastric acid secretion safely and effectively in patients with Zollinger-Ellison syndrome. The relative merits of these agents are discussed, and their use in the acute and long-term control of acid hypersecretion and in special circumstances that require particular care are described. The surgical approaches to the control of acid secretion are described, and the current place of surgery in the management of acid hypersecretion is discussed.     

Effects of esomeprazole on acid output in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion

OBJECTIVES: To evaluate the efficacy and safety of oral esomeprazole in the control of gastric acid hypersecretion in patients with hypersecretory states. METHODS: In this 12-month, open-label, multicenter study, acid output (AO) was evaluated at baseline, day 10, and months 3, 6, and 12. The starting dose of esomeprazole was 40 mg or 80 mg twice daily. On day 10, patients with controlled AO were maintained on the same dose, while those with uncontrolled AO had their doses increased (maximum dose 240 mg/day) until control was attained. Esophagogastroduodenoscopy (EGD) was performed at baseline and at 6 and 12 months. Safety and tolerability were assessed throughout the study by EGD, gastric analysis, and adverse events. RESULTS: Twenty-one patients (19 with Zollinger-Ellison syndrome [ZES], 2 with idiopathic gastric acid hypersecretion [IGH]) completed the study. Of the 20 patients with controlled AO at day 10, 18 (90%) had sustained AO control for the rest of the study. At 12 months, AO was controlled in 14 of 16 patients receiving esomeprazole 40 mg twice daily, in all 4 patients receiving esomeprazole 80 mg twice daily, and in the 1 patient receiving esomeprazole 80 mg 3 times daily. At 6 and 12 months, no patient had endoscopic evidence of mucosal disease. Esomeprazole was well tolerated; 1 patient had a serious adverse event (hypomagnesemia) attributed to treatment that resolved with magnesium supplementation during continued treatment. CONCLUSION: Esomeprazole in appropriately titrated doses controls AO over 12 months in patients with hypersecretory states and is well tolerated.     

Thyrotropin-releasing hormone suppressed gastric acid output in patients with Zollinger-Ellison syndrome and systemic mastocytosis

Thyrotropin-releasing hormone administered intravenously was found to be as potent an inhibitor of gastric acid secretion as a conventional dose of oral cimetidine in two patients with Zollinger-Ellison syndrome and one patient with systemic mastocytosis.     

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.     

Physiologic responses to gastric acid hypersecretion in Zollinger-Ellison syndrome

Summary Two patients with gastric acid hypersecretion and intact stomachs had diarrhea with steatorrhea. In 1 patient continuous outpouring of large volumes of alkaline juice into the duodenum, combined with the buffering capacity of food, resulted in normal or near normal pH levels in the upper small intestine for at least 90 min. after a meal. The tryptic activities in intestinal aspirates after the meal were essentially normal. Watery diarrhea was controlled when an anticholinergic drug was given both night and day, but steatorrhea was not reduced. In the other patient the alkaline secretions of the upper intestine were inadequate to neutralize the gastric acid output. The mechanisms by which acid secreted by the stomach is neutralized in the upper small bowel and the mechanisms of diarrhea are discussed.Supported by Grants FR-42 from the Division of Research Facilities and Resources and AM-07120 from the National Institute for Arthritis and Metabolism, U. S. Public Health Service.We wish to thank Dr. F. Avery Jones for allowing us to publish Case 2, and Professor R. A. Gregory for examining the tumors.     

Recklinghausen's disease with digestive localizations associated with gastric acid hypersecretion suggesting Zollinger-Ellison syndrome

We report the case of a 49 year old male patient who had Recklinghausen's disease associated with hyperchlorhydria. The principal features of Recklinghausen's disease were cutaneous localizations and countless digestive tumors, found mainly on the small bowel. The ultrastructural aspect of these tumors was neurinoma or schwannoma. Basal acid gastric hypersecretion and a positive secretin test were highly suggestive of a Zollinger-Ellison syndrome. Gastrinoma was not found at laparotomy even though a gastrin gradient had been demonstrated by pancreatic venous sampling. In a patient with Recklinghausen's disease, neuroendocrine tumors (APUDomas) should be looked for systematically.     

Cimetidine pharmacokinetics in patients with Zollinger-Ellison syndrome

Although most patients with Zollinger-Ellison syndrome can be effectively treated with histamine H2-receptor antagonists, many patients require large doses of drug to inhibit gastric acid secretion adequately. The purpose of the present study was to compare the pharmacokinetics of a 1200-mg oral dose of cimetidine in 9 patients with Zollinger-Ellison syndrome requiring more than 2.4 g/day of cimetidine with 5 age-matched normal volunteers receiving intravenous pentagastrin infusions. Poor responsiveness to cimetidine in patients with Zollinger-Ellison syndrome has several different causes. The concentration of cimetidine in the blood required to inhibit gastric acid secretion by 50% was markedly increased in 3 of the patients with Zollinger-Ellison syndrome, suggesting parietal cell resistance. One patient showed a substantial decrease in cimetidine absorption and 4 patients had delayed cimetidine absorption. Thus 7 of the 9 patients with Zollinger-Ellison syndrome who required more than 2.4 g/day of cimetidine to inhibit gastric acid secretion had abnormal cimetidine pharmacokinetics.     

Reflux esophagitis in patients with Zollinger-Ellison syndrome

The incidence of ulcers of the stomach and duodenum and their response to medical therapy, in patients with Zollinger-Ellison syndrome is well described. However, reflux esophagitis is less well recognized. In this study we determined the frequency of reflux esophagitis in 122 patients with Zollinger-Ellison syndrome and examined their response to medical therapy. Esophageal symptoms, endoscopic abnormalities, or both were present in 61% of patients. Forty-five percent of patients had esophageal symptoms consisting of heartburn, dysphagia, or both. Forty-three percent of patients had endoscopic abnormalities of the esophagus, and 23% demonstrated moderate or severe disease. When sufficient antisecretory medication was administered to lower gastric acid secretion to less than 10 mEq/h in the last hour before the next dose of drug, 67% of the patients with reflux esophagitis responded with complete disappearance of symptoms and normalization of the endoscopic abnormalities. The other 33% of patients required an increase in medication to lower acid output to less than 5 mEq/h in 7% and less than 1 mEq/h in the other 26% to resolve symptoms and signs completely. We conclude that reflux esophagitis occurs in the majority of patients with Zollinger-Ellison syndrome and responds well to medical therapy, although one third of patients require intensive antisecretory medication.     

Use of omeprazole in patients with Zollinger-Ellison syndrome

Omeprazole, a substituted benzimidazole, has been shown to be a potent inhibitor of gastric acid secretion in patients with Zollinger-Ellison syndrome (ZES). We review our experience, as well as the published data on 210 patients with ZES who have required omeprazole for control of gastric acid hypersecretion over the past seven years. The dose of omeprazole required in individual patients ranged from 10 to 180 mg/24 hr with 20-60% requiring a split dosage regimen. Omeprazole was effective in approximately 99% of the patients over a period ranging from 0.5 to 54 months. Twenty-four percent of patients required an increase in omeprazole dose, while 26% required a decrease in dose. Adverse effects attributable to omeprazole were reported in 2% of patients, and in all cases, they were mild (ie, rash, constipation, headache). There was no effect of omeprazole on serum gastrin concentration or on gastric endocrine cells in three studies. Although one patient with multiple endocrine neoplasia, type-I syndrome (MEN-I) in this series developed a gastric carcinoid while taking omeprazole, evidence is presented that suggests the presence of MEN-I per se may be important in determining the development of gastric carcinoid in patients with ZES. It is concluded that omeprazole is safe and effective in patients with ZES, and in these patients, it is the drug of choice for the management of gastric acid hypersecretion. However, yearly assessment is indicated to clearly evaluate the long-term risk of gastric carcinoid as well as therapy directed at the gastrinoma itself.     

Gastric luminal somatostatin secretion of normals and patients with pernicious anemia and with Zollinger-Ellison syndrome

We studied the release of gastric luminal somatostatin-like immunoreactivity (SLI) in response to a pentagastrin infusion (0.9 g/kg/hr, intravenous) in five normal volunteers, five patients with pernicious anemia, and two patients with Zollinger-Ellison syndrome. In addition, we studied the gastric luminal SLI secretion in response to a gastric luminal acid perfusion in two patients with pernicious anemia. Our results have shown that: (1)pentagastrin caused a parallel increase in luminal hydrogen ions and SLI release in normal volunteers; (2) Zollinger-Ellison patients had elevated basal acid and SLI levels that did not increase further with pentagastrin; (3) pentagastrin did not increase gastric acid or luminal SLI secretion in pernicious anemia patients; and (4) in pernicious anemia patients, a gastric luminal acid perfusion caused a significant increase in gastric luminal SLI over baseline values. In conclusion, gastric luminal hydrochloric acid appears to be a factor which stimulates the secretion of luminal SLI in human beings.This study was supported by the Gastroenterology Section Research Fund.This study was presented at the annual meeting of the American Gastroenterological Association in Chicago, Illinois, in May 1987.     

非溃疡性消化不良病人胃粘膜分泌维生素C的研究

目的：研究非溃疡性消化不良病人胃粘膜分泌维生素Ｃ（ＶｉｔＣ）的变化以及与幽门螺杆菌（Ｈｐ）感染、胃酸分泌、年龄和性别的关系。方法：用高铁还原法测定血浆和胃液中ＶｉｔＣ浓度，以１小时内ＶｉｔＣ从血液到胃液中的清除率代表胃粘膜分泌Ｖｉｔｃ的能力。结果：胃粘膜的ＶｉｔＣ分泌与Ｈｐ感染与否无关（Ｐ＞０．０５）：ＶｉｔＣ分泌与胃酸分泌呈明显正相关（ｒ＝０．８４），在给五肽胃泌素后，随着胃酸分泌的增加，ＶｉｔＣ分泌也增加：４０岁以上病人的ＶｉｔＣ分泌明显低于３９岁以下病人（Ｐ＜０．０１）。结论：胃粘膜的ＶｉｔＣ分泌不受Ｈｐ感染的影响：ＶｉｔＣ分泌与胃酸分泌明显相关；另外，ＶｉｔＣ分泌也与年龄有关，４０岁以上病人的Ｖｉｔｃ分泌明显减少，推测其胃癌发生率增高可能与ＶｉｔＣ分泌减少有关。