Gastric Acid Hypersecretion In Patients Research Articles

Effects of Esomeprazole on Acid Output in Patients With Zollinger-Ellison Syndrome or Idiopathic Gastric Acid Hypersecretion

To evaluate the efficacy and safety of oral esomeprazole in the control of gastric acid hypersecretion in patients with hypersecretory states. 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. 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. Esomeprazole in appropriately titrated doses controls AO over 12 months in patients with hypersecretory states and is well tolerated.

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

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. 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). 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. 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.

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.

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

Mechanism of gastric acid hypersecretion in patients with islet cell tumor without hypergastrinemia: Studies in rats

BACKGROUND & AIMS: A nongastrin acid-stimulating peptide (NGASP) has been found in ulcerogenic pancreatic tumor syndrome without hypergastrinemia. The mechanism of gastric acid hypersecretion by NGASP was investigated in rats.METHODS: In vivo, gastric acid secretion and in vitro histamine release from enterochromaffin-like (ECL) cells in responses to tumor extract (TE) and synthetic human gastrin-17 I or pentagastrin (PG) were studied. Whether the 2 secretagogues potentiate each other was determined.RESULTS: TE dose-dependently stimulated histamine release, which was not blocked by a cholecystokinin (CCK)-B receptor antagonist. When TE was incubated with trypsin, the activity was abolished but was not affected by antibody. However, when rats were pretreated with antigastrin serum or CCK-B receptor antagonist, the acid secretion by TE was virtually abolished. The dose response of acid secretion to TE in the rats receiving PG in a threshold dose was significantly greater than that achieved by TE alone. Similarly, the dose response to PG combined with a threshold dose of TE was significantly greater than that produced by PG alone.CONCLUSIONS: NGASP stimulates histamine release from ECL cells, but the release is not mediated via CCK-B/gastrin receptor. NGASP and gastrin may potentiate each other to produce acid hypersecretion in ulcerogenic pancreatic tumor syndrome.(Gastroenterology 1997 Oct;113(4):1129-35)

Gastrointestinal endocrine tumours: Medical management

With the introduction of longer-acting somatostatin analogues symptomatic relief is easy to achieve in patients with functionally active endocrine tumours and will be further facilitated by still longer-acting formulations. The consequences of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome can be prevented by all proton-pump inhibitors currently on the market. Despite the various antiproliferative strategies that have been offered to patients with metastatic disease, available data are controversial and, more importantly, are supported by few prospective and controlled studies. Most experts agree that surgery with curative extirpation of the primary in the absence of metastases and tumour debulking in metastatic disease should be intended wherever possible. Controversy concerns residual disease. According to our view, any further antiproliferative strategy should consider the growth characteristics and biology of a given tumour (Figure 4). In the case of rapid progression, chemotherapy should be offered if tumours originate from the pancreas or reveal an undifferentiated histology. In contrast, chemotherapy should not be offered to patients with well-differentiated non-functional or functional tumours (carcinoid syndrome) arising from the intestine. The same applies for patients with tumours with no or only slow growth within an given observation period of 3–12 months. These patients should be treated only symptomatically. ▪ Patients with tumours of slow progression might favourably respond to long-acting somatostatin analogues. We start with octreotide and offer patients not responding to octreotide monotherapy additional IFNα. If further tumour progression takes place, hepatic artery embolization is the next step (Figure 5) followed by chemotherapy, the latter in patients with tumours of pancreatic origin only. This strategy recognizes the severity of side-effects of the different therapeutic modalities and starts with octreotide because of its very few side-effects. Other groups start with chemoembolization followed by octreotide, α-interferon or its combinations (Ahlman et al, 1996). Ongoing studies will, it is hoped, answer the question of the ideal sequence of therapeutic strategies. Every available patient with metastasised gastrointestinal endocrine tumours should be included in one of the ongoing European multicentre trials. ▪

Eradication of Helicobacter pylori in patients with duodenal ulcer lowers basal and peak acid outputs to gastrin releasing peptide and pentagastrin.

Patients with duodenal ulcer (DU) have high basal (BAO) and peak (PAO) acid outputs. The effect of Helicobacter pylori eradication on these variables is unclear. To discover if gastric acid hypersecretion in patients with DU is caused by H pylori. BAO, gastrin releasing peptide (GRP), and pentagastrin stimulated PAO in 10 H pylori negative controls, and in 10 H pylori positive patients with DU was measured before and six months after H pylori eradication. H pylori status was determined by histology, culture, and by the 13C-urea breath test. After collecting a 30 minute basal aspirate, GRP 40 pmol/kg/h was infused for 45 minutes, and after a 30 minute washout, pentagastrin 6 micrograms/kg was injected intramuscularly. Basal and stimulated acid output (PAOGRP and PAOPg) were significantly higher in H pylori positive DU than in H pylori negative controls. Six months after H pylori eradication, basal and stimulated acid outputs were all significantly lower than before H pylori eradication. This study has shown that BAO, PAOGRP, and PAOPg are higher in H pylori positive DU than in H pylori negative controls. All decreased significantly six months after H pylori eradication, to fall within the range of controls. These results are compatible with a hypothesis that acid hypersecretion in duodenal ulcer disease is caused by H pylori infection.

Medical treatment of metastasizing carcinoid tumors.

Long-acting somatostatin analogs, such as octreotide, comprise the therapeutic modality of choice for the symptomatic relief of flush and diarrhea in patients with carcinoid syndrome. The sequelae of gastric acid hypersecretion in patients with gastrin-producing duodenal carcinoids (gastrinoma) are perfectly controlled by proton pump inhibitors. Antiproliferative medical strategies to control the growth of metastatic carcinoid tumors include long-acting somatostatin analogs, interferon alpha, and the combination of the two. However, the success rate is less than 50%, and it is questionable whether true tumor regression can be expected. Controlled prospective studies are mandatory to address the question whether interferon or somatostatin analogs or the combination of the two should be used as first-line medical strategies and if hepatic artery embolization in patients with liver metastases should be performed before beginning medical therapy. Chemotherapy, including etoposide and cisplatin, has been shown to be effective only for purely differentiated neuroendocrine carcinomas and not for slowly growing carcinoids.

Mechanism of gastric acid hypersecretion in patients with islet cell tumors involves potentiation between gastrin and a non-gastrin acid stimulating peptide: [formula omitted], T-M Chang, H-O Jin, KY Lee and WY Chey. University of Rochester Medical Center, Rochester, NY

Mechanism of gastric acid hypersecretion in patients with islet cell tumors involves potentiation between gastrin and a non-gastrin acid stimulating peptide: [formula omitted], T-M Chang, H-O Jin, KY Lee and WY Chey. University of Rochester Medical Center, Rochester, NY

Inhibitory Effects of Intravenous Lansoprazole on Gastric Acid Hypersecretion in Patients with Postoperative Stress

The inhibitory effects of intravenous lansoprazole on gastric acid hypersecretion caused by stress after surgical invasion were studied in patients who underwent surgery under general anesthesia for gastrointestinal diseases. Patients in this study received either 15 mg or 30 mg of lansoprazole by slow intravenous injection twice daily for 3 days (six injections). The total number of patients studied was 82, with 41 patients in each group. Intragastric pH was measured every 8 h after the start of administration, and the inhibitory effects of intravenous lansoprazole on postoperative gastric acid secretion were evaluated using four grades: excellent, good, fair, and poor. In the 15-mg group, 65.8% (25 of 38 patients) were classified as good or excellent, and in the 30-mg group, 75.7% (28 of 37 patients) were good or excellent. No adverse effects directly attributable to the administration of lansoprazole were observed.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Parenteral antisecretory drug therapy in patients with Zollinger-Ellison syndrome

Forty-six patients with Zollinger-Ellison syndrome were studied prospectively to determine a safe and effective method and criterion for controlling gastric acid hypersecretion during periods when oral antisecretory agents could not be used. In each patient it was possible to reduce acid secretion to ≤ 10 mEq/h after an i.v. bolus of 150 or 300 mg of cimetidine and a stepwise titration of cimetidine given by continuous infusion. The mean dose given by i.v. infusion was 2.9 mg/kg body wt · h but there was a wide range (0.5–7.0 mg/kg body wt · h) and the minimal dose had to be determined individually for each patient. The minimal i.v. cimetidine dose did not correlate with basal or maximal acid output or fasting gastrin concentration, but correlated closely with either the previous oral dose of cimetidine (r = 0.96, p < 0.001) or the previous oral dose of ranitidine or famotidine (r = 0.95, p < 0.001). To study the efficacy and safety of an i.v. infusion of cimetidine, 34 patients undergoing surgery were maintained on i.v. cimetidine for a mean of 12 days (range 1–83 days). One-half of the patients did not require dose adjustment, whereas the remainder required an average of 2 adjustments, usually in the first 3 postoperative days. No patient developed complications attributable to gastric acid hypersecretion in the postoperative period, and there was no detectable neurologic, hematologic, or hepatic toxicity. This study demonstrates that a continuous i.v. infusion of cimetidine adequately inhibits gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. However, high doses were frequently required, the dose had to be determined in a stepwise fashion individually for each patient, and the i.v. dose correlated with the previous oral dose. Reducing acid secretion to ≤ 10 mEq/h was a safe criterion during surgery and continuous i.v. cimetidine was safe and effective in achieving this degree of control for up to 83 days.

Omeprazole. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peptic ulcer disease and Zollinger-Ellison syndrome.

Omeprazole is a substituted benzimidazole derivative which markedly inhibits basal and stimulated gastric acid secretion. It has a unique mode of action, irreversibly blocking the so-called proton pump of the parietal cell which is supposedly the terminal step in the acid secretory pathway. In animals, on a weight basis, omeprazole is 2 to 10 times more potent than cimetidine in inhibiting gastric acid secretion. Toxicological studies in rats have shown that very high doses of omeprazole administered for 2 years produce hyperplasia of gastric enterochromaffin-like cells and carcinoids, a few with proliferations into the submucosa. The significance of such findings to the clinical situation is wholly speculative and requires further research. Preliminary studies in patients with duodenal ulcers or Zollinger-Ellison syndrome have found no mucosal changes which would suggest that the drug represents a risk for development of carcinoid tumours at therapeutic dosages. In patients with duodenal ulcers omeprazole, at dosages of at least 20mg once daily, produced ulcer healing rates of between 60 and 100% after 2 weeks and between 90 and 100% after 4 weeks, even in patients resistant to treatment with H2-receptor antagonists. Comparative trials clearly demonstrated that omeprazole 20 to 40 mg administered once daily was significantly more effective than usual dosage regimens of cimetidine and ranitidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present no data are available evaluating omeprazole as maintenance therapy once ulcers have healed. Other clinical trials have also shown that omeprazole is effective for treating gastric ulcers, ulcerative peptic oesophagitis, and Zollinger-Ellison syndrome. In patients with Zollinger-Ellison syndrome the profound and long lasting antisecretory activity of omeprazole may make it the drug of choice for treating the massive acid hypersecretion associated with the disease, especially when H2-receptor antagonists are ineffective. During clinical trials reported to date omeprazole has been very well tolerated but further clinical experience is essential to fully evaluate its safety profile. Thus, omeprazole represents a pharmacologically unique antisecretory drug which is very effective for rapidly healing peptic ulcers and peptic oesophagitis, and for reducing gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. If the apparent absence of undesirable mucosal morphological changes during treatment with usual doses in patients with peptic ulcer disease is confirmed, it may be a major advance in the treatment of these diseases.

Basal hyposecretion of gastric inhibitory polypeptide after Roux-Y hepaticojejunostomy in man

We previously showed that basal and pentagastrin-stimulated gastric acid secretion, gastrin in serum and gastrin in antral mucosa were significantly greater in patients with Roux-Y hepaticojejunostomy than in those with choledochoduodenostomy. These findings prompted investigation of basal secretion of gastric inhibitory polypeptide (a peptide with an enterogastrone as well as an insulinogenic effect), insulin and glucose in the same patients. Basal gastric inhibitory polypeptide was significantly lower in patients with Roux-Y hepaticojejunostomy than in those with choledochoduodenostomy, whereas glucose and insulin did not differ in the two groups. No correlation could be demonstrated between gastric inhibitory polypeptide, gastric acid secretion and gastrin, suggesting that hyposecretion of gastric inhibitory polypeptide is not a pathogenetic factor for the hypersecretion of gastric acid secretion in patients with Roux-Y hepaticojejunostomy. Hyposecretion of gastric inhibitory polypeptide and gastric acid hypersecretion in patients with bile diversion seem to be two independent phenomena.