Search

Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger-Ellison syndrome (ZES), etc.] can result in vitamin B 12 (VB 12 ) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB 12 deficiency, determined by assessing serum VB 12 levels, measurements of VB 12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB 12 deficiency with significantly lower serum and body VB 12 levels ( p < 0.0001). The presence of VB 12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB 12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB 12 levels and decreased VB 12 -body stores, which can result in VB 12 deficiency.

Purpose: Gastrinoma with Zollinger-Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features., Methods: Consecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort., Results: Of 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger (p = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES (p = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p = 0.034). At univariate-logistic regression, age at diagnosis (p = 0.01, OR = 1.1), G3 grading (p = 0.003, OR = 21.3), Sp-ZES (p = 0.02, OR = 0.3) and presence of extrahepatic metastases (p = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age (p = 0.04, OR = 1.0), size (p = 0.039, OR = 1.0), G3 grade (p = 0.008, OR = 14.6) and extrahepatic metastases (p = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases (p = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS (p = 0.0227). After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively., Conclusion: MEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response., (© 2022. The Author(s).)

Purpose: Zollinger Ellison syndrome (ZES) is a rare syndrome caused by gastrin hypersecretion from a gastrinoma. Gastrinoma treatment has two goals: the control of acid hypersecretion and the control of tumor growth. While therapy for the syndrome is univocally based on proton pump inhibitors, the one for disease control is still debated. We here aimed at evaluating the role of somatostatin analogs (SSAs) in the control of tumor progression in a series of ZES patients., Methods: A retrospective analysis of a prospectively collected database of ZES patients, followed and managed from 1990 to 2019, was performed. The patients' clinical, pathological, treatment, and follow-up data were analyzed. Data regarding SSAs therapy start, dosage, duration, and side effects were collected., Results: 33 patients with ZES were diagnosed. Fourteen patients (42%) had a grade 1 (G1) neuroendocrine neoplasm (NEN), five had G2 (15%), none had G3. Fifteen patients (45%) had metastatic disease. Overall, 12 (36%) underwent SSAs therapy. The median treatment duration was 36 months. Eight patients (67%) had a sustained response to SSAs, four (33%) showed an early progression, with a significant difference in terms of PFS between the patients with early and late progression (84 vs 2 months, p = 0.004). No differences in terms of OS and PFS were observed between the treated and non-treated patients, despite the proportion of metastatic patients was greater in the SSAs-treated group (75% vs 29% in the non-treated group, p = 0.01)., Conclusion: Present data support the use of SSAs in ZES, considering that gastrinoma is mainly a well-differentiated low-grade tumor (G1 or G2), with a high expression of somatostatin receptors., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin's effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.

This article reviews the role of surgical and medical management in patients with Zollinger-Ellison syndrome (ZES) due to a gastrin-secreting neuroendocrine tumor (gastrinoma). It concentrates on the status at present but also briefly reviews the changes over time in treatment approaches. Generally, surgical and medical therapy are complementary today; however, in some cases, such as patients with ZES and multiple endocrine neoplasia type 1, the treatment approach remains controversial., (Published by Elsevier Inc.)

Gastrinoma, an infrequent diagnosis in middle-aged dogs, occurs with nonspecific gastrointestinal morbidity. Laboratory tests can yield a presumptive diagnosis, but definitive diagnosis depends on histopathology and immunohistochemistry. We describe a malignant pancreatic gastrinoma with lymph node metastases and corresponding Zollinger-Ellison syndrome in a Mexican gray wolf ( Canis lupus baileyi) and review this endocrine neoplasm in domestic dogs. A 12-y-old, captive, male Mexican gray wolf developed inappetence and weight loss. Abdominal ultrasonography revealed a thickened duodenum and peritoneal effusion. Two duodenal perforations were noted on exploratory celiotomy and were repaired. Persisting clinical signs led to a second celiotomy that revealed a mesenteric mass, which was diagnosed histologically as a neuroendocrine carcinoma. During the following 16 mo, the wolf received a combination of H 2 -receptor antagonists, proton-pump inhibitors, gastroprotectants, and anti-emetics, but had recurrent episodes of anorexia, nausea, acid reflux, and remained underweight. Worsening clinical signs and weakness prompted euthanasia. The antemortem serum gastrin concentration of 414 ng/L (reference interval: 10-40 ng/L) corroborated hypergastrinemia. Autopsy revealed a mass expanding the right pancreatic limb; 3 parapancreatic mesenteric masses; duodenal ulcers; focal duodenal perforation with septic fibrinosuppurative peritonitis; chronic-active ulcerative esophagitis; and poor body condition. The pancreatic mass was diagnosed histologically as a neuroendocrine carcinoma and the parapancreatic masses as lymph node metastases. Immunohistochemistry of the pancreatic mass was positive for gastrin and negative for glucagon, insulin, pancreatic polypeptide, serotonin, somatostatin, and vasoactive intestinal peptide.

Zollinger-Ellison syndrome (ZES) is a clinical syndrome characterized by gastric acid hypersecretion due to the ectopic secretion of gastrin by a gastrinoma, a neuroendocrine tumor (NET) which mostly develops in the duodenum and in the pancreas. This syndrome was first described by Zollinger and Ellison in 1964; if left untreated, ZES can lead to multiple complications mainly due to gastric hypersecretion and some patients can suffer from the complications of an advanced metastatic disease. Although its clinical features are considered typical, the diagnosis of ZES is often challenging for the clinician. A previous review was published in 2005 by our group, but in 12 years many things have changed: the diagnostic tools have been improved and many different therapeutical options are now available.

Purpose: Analyze the role of somatostatin analogues (SSAs) in the treatment of sporadic and MEN1-related gastrinomas, trying to define whether recent trials have changed the landscape of gastrinoma therapy., Methods: We evaluate the rationale of SSA use in the treatment of gastrinomas, summarize the current literature concerning the effect of SSAs on the control of Zollinger-Ellison syndrome (ZES) and gastrinomas tumor progression and discuss their role in the most recent guidelines., Results: The medical treatment of gastrinoma and related ZES is aimed at controlling acid hypersecretion and tumor progression, in inoperable patients. The use of proton pump inhibitors (PPIs) to control the syndrome is a cornerstone in the ZES therapy. SSAs are not usually indicated for antisecretory purpose, because PPIs are considered the treatment of choice, due to their long lasting high efficacy and oral availability. The antiproliferative effect of SSAs has been established by two placebo-controlled trials that have clearly demonstrated a significant increase in progression free survival in patients affected by non-functioning well-differentiated advanced neuroendocrine tumors (NETs). The recent ENETS guidelines recommend the use of SSAs in advanced well differentiated NETs as antiproliferative agents., Conclusions: The high sstr-expression in gastrinomas make them highly responsive to SSAs and support the use of such drugs to counteract the tumour growth in patients not amenable to surgical cure. Unfortunately, limited data, mainly case reports or small series, support the use of SSAs in advanced gastrinomas, therefore, it is difficult to quantify their ability to control tumour growth and disease progression.

The advent of powerful acid-suppressive drugs, such as proton pump inhibitors (PPIs), has revolutionized the management of acid-related diseases and has minimized the role of surgery. The major and universally recognized indications for their use are represented by treatment of gastro-esophageal reflux disease, eradication of Helicobacter pylori infection in combination with antibiotics, therapy of H. pylori-negative peptic ulcers, healing and prophylaxis of non-steroidal anti-inflammatory drug-associated gastric ulcers and control of several acid hypersecretory conditions. However, in the last decade, we have witnessed an almost continuous growth of their use and this phenomenon cannot be only explained by the simple substitution of the previous H2-receptor antagonists, but also by an inappropriate prescription of these drugs. This endless increase of PPI utilization has created an important problem for many regulatory authorities in terms of increased costs and greater potential risk of adverse events. The main reasons for this overuse of PPIs are the prevention of gastro-duodenal ulcers in low-risk patients or the stress ulcer prophylaxis in non-intensive care units, steroid therapy alone, anticoagulant treatment without risk factors for gastro-duodenal injury, the overtreatment of functional dyspepsia and a wrong diagnosis of acid-related disorder. The cost for this inappropriate use of PPIs has become alarming and requires to be controlled. We believe that gastroenterologists together with the scientific societies and the regulatory authorities should plan educational initiatives to guide both primary care physicians and specialists to the correct use of PPIs in their daily clinical practice, according to the worldwide published guidelines., (Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Objectives: Zollinger-Ellison syndrome (ZES) is characterized by hypergastrinemia and gastric acid hypersecretion resulting in peptic ulcer disease, diarrhea, and weight loss. Acid secretion can be controlled with medication, and biochemical cure is possible with surgery. Data on how these interventions affect patients' weight are lacking. We aimed to determine how medical and surgical acid control affects weight over time., Methods: We performed a retrospective cohort study on 60 ZES patients. Acid control was achieved with appropriate-dose proton pump inhibitor (PPI) therapy. Surgery was performed for curative intent when appropriate. Weight change was assessed versus pre-acid control or immediate preoperative weights and expressed as absolute and percent change from baseline at 6, 12, 18, and 24 months., Results: A total of 30 PPI-controlled patients and 20 surgery-controlled patients were analyzed. Weight gain was noted at all time points while on appropriate-dose PPI therapy (P < 0.005). Of patients who had surgery with curative intent, weight gain was noted at 12 months (7.9%, P = 0.013) and 18 months (7.1%, P = 0.007). There was a trend toward weight gain seen at all time points in the patients who were surgically cured., Conclusions: These data represent a novel description of weight gain after acid suppression in ZES.

A patient suffering from Zollinger-Ellison was treated with Nexium, but after patent expiry only the costs of generic omeprazol were reimbursed. Generic tablets and capsules, pantoprazol and rabeprazol, were tried without success and finally the pharmacist dispensed Nexium at his own expense. Registered generic drugs have been shown to be bioequivalent with the originator drug within narrow margins. When two batches of the originator are compared, the same requirements are valid. Although the subject has received a lot of negative publicity, meta-analyses on outcome comparison support generic substitution; problems associated with switching can be partially explained by the loss of trust in the treatment, and differences in appearance also cause confusion. Generic prescribing should be encouraged to keep medical treatment affordable; however, in order to prevent the problems described it is desirable to keep to the same product as far as possible. Effective education and patient information are essential if switching is to be successful.

The association between proton pump inhibitor (PPI) therapy and hypomagnesaemia has been recognized since 2006. We report the case of a 51-year-old woman who developed severe symptomatic hypomagnesaemia after a long-term PPI therapy given for recurrent peptic ulcer disease. Hypomagnesaemia could only partially be resolved during substitution therapy, but was corrected after withdrawal of the PPI. Recurrence of hypomagnesaemia occurred after retreatment with PPIs, supporting the causal relationship. An underlying gastric acid hypersecretion (Zollinger-Ellison syndrome) was highly suspected and eventually controlled by a combination of a histamine 2-receptor antagonist and octreotide, without the need for further PPI therapy after 2 years of follow-up.

Introduction: The role of pharmacotherapy in the management of patients with Zollinger-Ellison syndrome (ZES) is often equated with the medical management of acid hypersecretion. However, pharmacotherapy is also increasingly involved in the other management areas of these patients., Areas Covered: This paper reviews the role of pharmacotherapy in all aspects of the management of patients with ZES. Newer aspects are emphasized. This includes the difficulty of diagnosing ZES in patients taking proton pump inhibitors. Also covered is the role of pharmacotherapy in controlling acid hypersecretion and other hormonal hypersecretory states these patients may develop, including hyperparathyroidism in patients with multiple endocrine neoplasia type 1 and ZES; tumor localization; and the treatment of advanced metastatic disease. The last includes chemotherapy, liver-directed therapies, biotherapy (somatostatin/interferon), peptide radio-receptor therapy and molecular-targeted therapies including the use of mTor inhibitors (everolimus) and tyrosine kinase inhibitors (sunitinib)., Expert Opinion: Pharmacotherapy is now involved in all aspects of the management of patients with ZES, with the result that ZES has progressed from being considered an entirely surgical disease initially to the present where medical treatment plays a major role in almost all aspects of the management of these patients.

History and Clinical Findings: A 14-year-old boy was admitted to hospital because of chronic episodic diarrhea lasting for 4 years. Previous investigations in the past had not revealed the cause of the symptoms., Investigations: The 13C-triglyceride breathing test showed a diminished intestinal lipolysis. Endoscopic examination demonstrated small gastroduodenic ulcers. During therapy with proton-pump inhibitors the diarrhea stopped., Diagnosis, Treatment and Course: The combination of gastroduodenic ulcers and improvement of diarrhea with PPI-therapy were suggestive of Zollinger-Ellison syndrome. Endosonography and MR-scan showed an extrapancreatic mass with marked activity during somatostatin receptor scintigraphy. The primary tumor was excised, a liver metastasis was treated with radiofrequency ablation. The histological examination confirmed the diagnosis of a gastrinoma., Conclusion: In patients with chronic diarrhea, especially if the symptoms are PPI-sensitive, a gastrinoma should be considered., (© Georg Thieme Verlag KG Stuttgart · New York.)

Proton pump inhibitors are widely used for the treatment of acid-related disorders. Rabeprazole is a potent and irreversible inhibitor of H(+)/K(+)-ATPase gastric pump, and it is indicated for the treatment of gastroesophageal reflux disease, Zollinger Ellison syndrome, duodenal and gastric ulcers and for the eradication of Helicobacter pylori in combination with antibiotics. Pharmacokinetic and pharmacodynamic data show that rabeprazole achieves a pronounced acid suppression from the first administration that is maintained with repeated use; this may translate into faster onset of symptom relief for patients, particularly suitable when the indication is for the on-demand long-term maintenance of gastroesophageal reflux disease. Due to its predominantly nonenzymatic metabolism, rabeprazole has a lower potential for drug-drug interactions. The objective of this article is to update efficacy and safety data of rabeprazole in the treatment of acid-related disorders, following a previous review dated 2008.

Background & Aims: Patients with Zollinger-Ellison syndrome (ZES) are treated by proton pump inhibitors (PPIs) to protect them from severe and potentially lethal peptic complications related to massive gastric acid hypersecretion. We report here on the dangerous consequences of interrupting PPI therapy., Methods: We describe 2 ZES patients in whom interruption of PPI treatment for diagnostic evaluation generated severe health complications., Results: Less than 48 hours after stopping PPIs, patient 1 developed multiple strictures of the esophagus caused by massive vomiting of gastric acid, and patient 2 presented with severe abdominal pain with intestinal microperforation from duodenal ulcers. Because of persistent gastrin stimulatory drive and because of the abolition of reflex protective defense mechanisms against gastric acid hypersecretion during PPI treatment, patients with ZES under PPI therapy are exposed to severe peptic complications when facing rebound acid secretion at the interruption of their antisecretory treatment., Conclusions: PPI treatment interruption has dangerous consequences, and PPI therapy always should be maintained in patients known or suspected of ZES. Diagnostic evaluations should be performed under PPI protection., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Recent series describing the clinical presentation, response to therapy, and long-term outcome of Zollinger-Ellison syndrome are limited., Aims: To assess the clinical characteristics and long-term outcome of patients with Zollinger-Ellison syndrome., Methods: Over a 20-year period, patients with Zollinger-Ellison syndrome were enrolled in a prospective trial evaluating the efficacy of lansoprazole. Following dose stabilization, patients were followed on a 6-monthly basis with interval history, physical examination, endoscopy with gastric biopsies, gastric acid analysis and laboratory studies., Results: 72 patients (mean age 54±12 years, % male 58%, % Caucasian 69%) were prospectively enrolled. The clinical presentation was stereotypical for Zollinger-Ellison syndrome. Symptoms had been reported for a median of 9 years prior to diagnosis. Cross-sectional abdominal imaging was often negative for demonstrable tumour. All patients had gastric acid hypersecretion controlled with variable doses of lansoprazole (median dose 60 mg/day, range 15-480 mg/day). The median survival from the time of diagnosis was 6.6 years; only two of 19 deaths were due to metastatic gastrinoma., Conclusions: The clinical presentation of Zollinger-Ellison syndrome was similar to prior reports. Acid hypersecretion was controlled in all patients with variable doses of lansoprazole. Long-term survival was principally related to underlying co-morbidity., (Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: It has been demonstrated that genetic variation in CYP2C19 has a significant influence upon H. pylori eradication rates. We have determined a dosage regimen of lansoprazole that will provide EMs with exposure approximately equivalent to that obtained by PMs treated with standard doses and determined the exposure that a PM would experience if they were to be treated with this 'EM optimised' lansoprazole dose., Methods: Non-compartmental pharmacokinetic parameters (AUC, C(max), t(max)) for CYP2C19 genotypes were obtained from the literature. Primary pharmacokinetic parameters (CL, Vd, ka) for 200 virtual patients were calculated from the weighted non-compartmental variables and used to simulate a 7 day treatment course of twice daily lansoprazole, at standard and optimised doses for 1,000 patients., Results: The administration of 180 mg twice daily to CYP2C19 EMs results in approximately equivalent exposure to lansoprazole as the administration of standard 30 mg twice daily doses to PMs. Administration of this six-fold dose increase to EMs is predicted to result in only a 2.5-fold increase in C(max) when compared with PMs receiving the standard 30 mg dose., Conclusion: We present a potential lansoprazole dosing regimen that should result in improved H. pylori eradication within CYP2C19 EMs and may not require individualization. Whilst the optimised dose represents a significant increase, it is below that reported in the chronic management of Zollinger-Ellison syndrome. On the basis that treatment is of limited duration and lansoprazole is generally well tolerated, such an approach warrants further in vivo evaluation to confirm drug exposure, efficacy and tolerability.

Proton pump inhibitors (PPI) are one of the most widely used classes of drugs. PPIs have a very favorable safety profile, and it is unusual for a patient to stop them because of side effects. However, with increasing numbers of patients chronically taking PPIs for gastroesophageal reflux disease and other common, persistent conditions, the long-term potential adverse effects are receiving increasing attention. An insufficiently studied area receiving much attention is the long-term effect of chronic acid suppression on the absorption of vitamins and nutrients. This increased attention results from the reported potential adverse effect of chronic PPI treatment leading to an increased occurrence of bone fractures. Interest in this area has led to examination of the effects of PPIs on calcium absorption/metabolism and numerous cohort, case-control, and prospective studies of their ability to affect bone density and cause bone fractures. In this article, these studies are systematically examined, as are studies of the effects of chronic PPI use on absorption of VB(12), iron, and magnesium. Studies in each area have led to differing conclusions, but when examined systematically, consistent results of several studies support the conclusion that long-term adverse effects on these processes can have important clinical implications.

Background: Zollinger-Ellison syndrome (ZES) is associated with complicated ulcer disease of the upper gastrointestinal tract. While management of ZES has dramatically improved with proton pump inhibitor therapy, quality of life in medically treated patients has not been evaluated., Methods: Over a 3-year period, 52 patients with ZES were prospectively evaluated at 6-month intervals with upper endoscopy and gastric acid analysis to evaluate the efficacy of current drug therapy and completion of SF36v2 forms. At each 6-month visit, patients' medication and problem lists were reviewed, comorbidities assessed, and any gastrointestinal symptoms recorded. Co-morbidity was represented as a simple illness count for the main analysis. The chronic disease score and the Charlson index were used for sensitivity analyses., Results: The unadjusted norm-based estimate of mental component score (MCS) for 52 patients with ZES (mean age 58, 65% male) was 49.8 (95% CI 46.4, 53.1). The unadjusted estimate of the physical component score (PCS) was 42.3 (95% CI 38.9, 45.7). As the number of illnesses or number of medications increased, there was a monotonic decrease in PCS scores. With multivariable adjustment, the coefficient for number of medications became non-significant. An increase in each of the co-morbidity indexes was associated with a decrease in PCS. Results did not vary by representation of co-morbidity. MCS was not significantly different from the general population., Conclusions: Patients with medically managed ZES have norm-based estimates of the mental component scores as measured by the SF-36v2 that approximate normal values, while the physical component scores were decreased with this reduction largely explained by co-morbid illness.

Background: Zollinger-Ellison syndrome (ZES) is a rare disorder caused by tumor secretion of the hormone gastrin, which results in gastric acid hypersecretion and secondarily complicated peptic ulcer and diarrhea. Until the development of H(2)-receptor antagonists and later proton pump inhibitors (PPIs), the disease was virulent, often associated with ulcer-related mortality, and the mainstay of treatment was total gastrectomy., Objective: To evaluate current approaches to diagnosis and therapy, focusing on the role of PPIs., Methods: An extensive literature search through PubMed using the search term 'Zollinger-Ellison syndrome' from 1964 to the present was performed. Primary articles were identified, and pertinent articles obtained from the reference lists were also examined., Results/conclusions: The clinical manifestations of ZES are well described, but overlaps with other more common disorders delay diagnosis. The use of abdominal imaging with somatostatin receptor scintigraphy and endoscopic ultrasound has improved tumor staging. PPI therapy is remarkably effective in controlling gastric acid hypersecretion, thereby reducing morbidity and potential mortality of this syndrome. The dose of drug necessary to control symptoms is highly variable but, even when used in high doses for prolonged periods of time, the disease remained controlled with very few drug-related side effects.

A case of carcinoid syndrome in a patient receiving treatment for a malignant non-B-cell tumor of the pancreas is presented, and a survival of >14 years is noted. The probable cause is discussed. The literature is reviewed. It was found that such a presentation is rare, and long-term survival in these cases exceedingly rare.

Rabeprazole is a proton pump inhibitor (PPI) presenting a very advantageous pharmacodynamic and pharmacokinetic profile over older PPIs. In particular, this drug has a very fast onset of action, due to a short activation time and a very high pKa, and may therefore be defined as a 'second generation' PPI. The aim of this article is to provide an update on the pharmacology and clinical profile of rabeprazole and its use in acid-related disorders, with a particular focus on its role in gastroesophageal reflux disease; in the treatment and prevention of duodenal and gastric ulcers and Zollinger-Ellison syndrome; in the therapy of the extraesophageal manifestations of gastroesophageal reflux disease (in particular the respiratory and ear, nose and throat ones); and in the eradication of Helicobacter pylori.

Background: Proton pump inhibitors (PPIs) may cause cyanocobalamin (vitamin B12) malabsorption, but measuring serum B12 alone may underestimate the prevalence. However, B12 deficiency elevates methylmalonic acid and homocysteine, both additional markers of B12 deficiency., Aim: To determine the true prevalence of B12 deficiency and whether acid suppression by PPI caused it., Methods: Sixty-one acid hypersecretors (basal acid output >15 mmol/h), 46 with gastrinoma [Zollinger-Ellison (ZE) syndrome] and 15 without [acid hypersecretor without gastrinoma (pseudo-ZE)], were treated with lansoprazole to determine its long-term (up to 18 years) pharmacological and clinical efficacy and safety, particularly as regards malabsorption of B12., Results: Of 61 patients, six (10%) had low serum B12. Additional tests uncovered B12 deficiency in 13 (31%) of 41 still-available patients, despite normal serum B12. B12 replacement reduced elevated homocysteine and methylmalonic acid, supporting the diagnosis. Also, measuring both basal and stimulated gastric secretion, we found that acid suppression was neither prolonged nor profound enough to explain the B12 deficiency., Conclusions: In long-term recipients of PPIs, B12 deficiency was more frequent (29%) than detected by measuring only serum B12, and there was not enough acid suppression to explain this deficiency.

Background: The relationship between proton pump inhibitor therapy and other acid suppressing medications and the risk of gastrointestinal infections remains controversial., Methods: Patients enrolled in a long-term trial of lansoprazole for Zollinger-Ellison syndrome and other acid hypersecretory states had interval histories taken every six months regarding hospitalizations or other intercurrent medical conditions. All medications taken were also reviewed at each visit. In addition, available patients were specifically queried during the study period 2006-2007 regarding the development of any gastrointestinal infections, hospitalizations, and prescriptions for antibiotics., Results: Ninety patients were enrolled in our long-term study and 81 were available for review. The median basal gastric pH for the cohort after stabilization on therapy was 2.9 and ranged from 1.1 - 8.4 with a median pentagastrin stimulated gastric pH of 1.60 (range 1.0 - 8.2). No patient developed a clinically significant gastrointestinal infection during the study. The median patient years of follow-up were 6.25 years., Conclusion: In a cohort of patients with gastric acid hypersecretion in whom acid secretion status was monitored on lansoprazole, all were free of significant gastrointestinal infections on long-term follow-up., Trial Registration: NCT00204373.

Esomeprazole (Nexium); S-omeprazole) is a single optical isomer proton-pump inhibitor (PPI) approved for the management of reflux oesophagitis, the symptomatic treatment of gastro-oesophageal reflux disease (GORD), the prevention and healing of NSAID-associated gastric ulcer disease (and the prevention of NSAID-associated duodenal ulcers in the UK), the treatment of Helicobacter pylori infection and associated duodenal ulcer disease (and prevention of relapse of H. pylori-associated peptic ulcers in the UK), and the treatment of Zollinger-Ellison syndrome (and other hypersecretory syndromes in the US).Once-daily oral esomeprazole 40 mg demonstrates greater antisecretory activity than other PPIs. Overall, in well designed clinical studies of 4 weeks' to 6 months' duration in patients with GORD, esomeprazole had similar or better efficacy than other agents. In patients requiring ongoing treatment with NSAIDs, co-therapy with once-daily esomeprazole 20 or 40 mg achieved relief of gastrointestinal symptoms or prevented ulcer occurrence, more effectively than placebo. Esomeprazole was also better than ranitidine 150 mg twice daily in healing NSAID-associated gastric ulcers. In addition, the drug has demonstrated efficacy as part of a triple-therapy regimen for the eradication of H. pylori infection, the healing of H. pylori associated duodenal ulcers and the prevention of relapse of gastric ulcers. Esomeprazole also effectively treated patients with Zollinger-Ellison syndrome. Esomeprazole is generally well tolerated with an adverse-event profile similar to that of other PPIs. Thus, the efficacy and tolerability of esomeprazole for the management of GORD and H. pylori eradication remains undisputed, and the data support its use for the first-line treatment of NSAID-associated gastric ulcer disease and Zollinger-Ellison syndrome.

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.

Background: Chromogranin has been proposed as a marker for gastrin-dependent enterochromaffin-like cell proliferation., Aim: To examine this question in three populations: acid hypersecretors with gastrinoma (Zollinger-Ellison), or without gastrinoma (non-Zollinger-Ellison), and also in pernicious anaemia with achlorhydria-caused hypergastrinaemia., Methods: We measured serum chromogranin, gastrin, gastric secretion and counted and quantified hyperplasia of enterochromaffin-like cells in gastric biopsies from 38 Zollinger-Ellison and 13 non-Zollinger-Ellison patients being treated with lansoprazole, for 5 years (median) and again 2.5 years later. We also studied 12 patients with pernicious anaemia, half with gastric enterochromaffin-like cell carcinoids., Results: Serum chromogranin was elevated in patients with gastrinoma, even without any enterochromaffin-like cell proliferation, but not in non-Zollinger-Ellison acid hypersecretors with normal gastrin (P < 0.001). In the hypersecretors chromogranin correlated well with serum gastrin (r = 0.82), but not with enterochromaffin-like cell proliferation. Moreover, chromogranin was normal or near normal (<75 ng/mL) despite very high serum gastrin in five of six patients with pernicious anaemia and enterochromaffin-like cell carcinoids., Conclusions: Chromogranin is not a reliable marker for enterochromaffin-like cell activity or proliferation up to and including carcinoid; chromogranin originates in the gastrinoma and, like gastrin, is a marker for gastrinoma in acid hypersecretors.

Background: Zollinger Ellison syndrome (ZES), an ulcerative disease of the upper gastrointestinal tract that involves the production of high levels of gastrin and gastric acid, is a rare, symptomatic, endocrine neoplastic disease., Case: We report a rare case of gastrinoma that was first diagnosed during pregnancy in which the primary tumor was located in the liver. The ZES was well controlled with Zoton (Lansoprazole) following surgery. The patient had an uneventful pregnancy and delivery without significant complications., Conclusions: The present case suggests that treatment with Zoton for ZES during pregnancy is safe and effective.

The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH > 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day.

Gastrinomas are functional neuroendocrine tumors of the gastroenteropancreatic system. Surgery is first line treatment in gastrinomas, however often fails to be curative. This manuscript reviews current strategies of medical treatment of surgically non-curable gastrinoma. Symptomatic treatment with H(+)-K(+)-ATPase proton-pump inhibitors suppresses hypersecretion of gastric acid and substantially improves quality of life in patients with Zollinger-Ellison syndrome. Further medical therapy is only recommended in cases of progressive metastatic gastrinoma. In well differentiated neuroendocrine carcinoma (G1 and G2) a so-called biotherapy with somatostatin analogues exists as first-line and chemotherapy with streptocotozin plus doxorubicine/5-FU as second-line medical treatment option. In poorly differentiated neuroendocrine carcinoma (G3) chemotherapy with etoposide plus cisplatin is possible. Prospective future therapeutic strategies may include treatment with novel somatostatin analogues as well as angiogenesis inhibitors and kinase inhibitors targeting tumor-specific signaling cascades.

Background: Omeprazole and lansoprazole are both of proven efficacy in the treatment of Zollinger-Ellison syndrome and idiopathic gastric acid hypersecretion. Rabeprazole, which has a similar mechanism of action, has not previously been studied in these diseases., Aim: To determine the dose of rabeprazole that decreased basal acid output to safe levels in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion., Methods: Patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion were given rabeprazole 60 mg once daily for uncomplicated disease or 40 mg twice daily for complicated disease. Doses were titrated according to response and continued for 2 years. Efficacy was assessed primarily by measuring basal acid output., Results: All patients had basal acid output before the next dose controlled to <10 mmol/h either at the starting dose or after minor dose titration. Control of acid output was maintained for 2 years. Consistent with this, most patients reported few gastrointestinal symptoms. Gastric biopsy showed no enterochromaffin-like cell dysplasia or neoplasia., Conclusions: Rabeprazole was an effective and well-tolerated treatment for Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion, which reliably reduced gastric acid output to safe levels. Although a dose of 60 mg once daily was appropriate for most patients in this study, doses may need adjustment according to individual response.

Zollinger-Ellison syndrome is characterised by refractory peptic ulcer disease, diarrhoea and gastric acid hypersecretion associated with a gastrin-secreting tumour. The incidence is unknown, but, in the US, the frequency is 0.1-3.0 million people. Zollinger-Ellison syndrome is associated with multiple endocrine neoplasia type 1 in 25-35% of the cases. The diagnosis of Zollinger-Ellison syndrome is suggested when plasma gastrin is > 1000 pg/ml and the basal acid output is > 15 mEq/h or when associated with a pH < 2. The treatment is focused on controlling gastric acid hypersecretion and localisation of the tumour and its metastases. Proton pump inhibitors are the most effective antisecretory drugs and can be administered at high dosages. This review focuses on the role of the proton pump inhibitors in the management of gastric acid hypersecretion in Zollinger-Ellison syndrome.

Background: Zollinger-Ellison syndrome and idiopathic hypersecretion are gastrointestinal hypersecretory conditions requiring long-term maintenance., Aims: The safety and efficacy data for short-term (6-month) treatment of Zollinger-Ellison syndrome and idiopathic hypersecretion with oral pantoprazole were previously published. This study extends the initial observations to 3 years., Methods: The primary efficacy end point for this report was the control of gastric acid secretion in the last hour before the next dose of oral pantoprazole (acid output of <10 mmol/h; <5 mmol/h in subjects with prior acid-reducing surgery). Dose titration was permitted to a maximum of 240 mg per 24 h., Results: Twenty-four subjects completed the study. The acid output of 28 of 34 subjects was controlled at initial enrolment. The mean acid output rates were <10 mmol/h throughout the 36 months of treatment for 90-100% of the patients. The majority of the patients were controlled with b.d. doses of 40 or 80 mg pantoprazole at 36 months (acid output was controlled in 24 of 24 subjects). Pantoprazole was generally well tolerated with minimal adverse events reported., Conclusions: Maintenance oral pantoprazole therapy up to 3 years at dosages of 40-120 mg b.d. was effective and well tolerated in patients with Zollinger-Ellison syndrome and other hypersecretory conditions.

Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo-/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.

Endocrine pancreatic tumours (EPTs) are uncommon tumours occurring in approximately 1 in 100,000 of the population, representing 1-2% of all pancreatic neoplasms. Some of the tumours may be part of multiple endocrine neoplasia type one (MEN-1) syndrome or von Hippel-Lindau (vHL) disease. EPTs are classified as functioning or non-functioning tumours on the basis of their clinical manifestation. The biochemical diagnosis of EPT is based on hormones and amines released. Besides specific markers such as insulin, there are also general tumour markers such as chromogranin A, which is the most valuable marker and has been reported to be increased in plasma in 50-80% of patients with EPTs and correlates with tumour burden. The location of endocrine tumours of the pancreas includes different techniques, from endoscopic investigations to scintigraphy (e.g. somatostatin receptor scintigraphy) and positron emission tomography. The medical treatment of endocrine pancreatic tumours consists of chemotherapy, somatostatin analogues and alpha-interferon. None of these can cure a patient with malignant disease. In future, therapy will be custom-made and based on current knowledge of tumour biology and molecular genetics.

Many gastric acid hypersecretory states (basal acid output of greater than 15.0 mEq/h) exist for which the etiology is known, such as Zollinger-Ellison syndrome, systemic mastocytosis, antral exclusion, antral predominant Helicobacter pylori gastritis (antral G cell hyperplasia), chronic gastric outlet obstruction, short gut syndrome and basophilic leukemias. However, many hypersecretory patients have no identified etiology for their acid hypersecretion and are designated as idiopathic gastric acid hypersecretors with a basal acid output of greater than 10 mEq/h and a normal serum gastrin level. Because of the gastric acid hypersecretion these patients also commonly have an increased frequency of stools. Idiopathic gastric acid hypersecretion represents a known cause of gastric acid hypersecretion that is far more common than Zollinger-Ellison syndrome and it has a markedly different treatment regimen and natural history. We report a case of a patient with idiopathic gastric acid hypersecretion previously misdiagnosed as having Crohn's disease because of a presenting complaint of diarrhea and mimicking Zollinger-Ellison syndrome because her fasting serum gastrin level was elevated when incorrectly measured in the presence of antisecretory treatment.

Background & Aims: Unremitting gastric acid and pepsin hypersecretion causes serious persistent and relapsing lesions, but the natural history with medical treatment alone has not been well-defined. The aims of this study were to heal and prevent relapse of acid/peptic lesions during acid suppression and to analyze benefits and risks during long-term lansoprazole treatment., Methods: Sixty-seven patients (49 with Zollinger-Ellison syndrome [ZES], 18 without), with basal acid output (BAO) >15 mmol/h or >5 mmol/h if post-antrectomy (n = 9, all ZES), were treated with individually optimized doses of lansoprazole (7.5-450 mg/day; median, 75 mg/day) to reduce BAO to <5 mmol/h or <1 mmol/h post-antrectomy and underwent endoscopy every 3-6 months for up to 13 years (median, 6.25 years)., Results: Before treatment, 94% had duodenal ulcer, 64% had esophagitis, 60% had 1 or more bleeding episodes, 13% had perforated ulcers, 90% had pain, 60% had heartburn, and 40%-48% had diarrhea, vomiting, and/or weight loss. Forty-seven patients (70%) remained symptom- and lesion-free, whereas 13 (20%) had mild, transient relapses, and 7 (10%) had more complicated relapses. Overall, symptoms were reduced 90+%; ulcer or esophagitis relapsed in 4.8% of patients/year, unrelated to Helicobacter pylori , whereas complications declined to <2%/y. Post-antrectomy ZES patients had 3.6-fold higher relapse rates than unoperated ZES patients (67% vs 18%, respectively). With BAO >5 mmol/h in intact patients, relative risk of relapse was 4.1, confidence interval 2.1-8.1, P < .001. Twenty patients died, 3 as a result of ZES (2 metastatic gastrinomas)., Conclusions: With individually optimized medical suppression of acid secretion, 90% of patients had good to excellent long-term outcomes without surgery, with an annualized total relapse rate of <5%.

Despite advances in medical management, gastrointestinal bleeding remains a substantial cause of morbidity and mortality. At risk are patients with history of the event, those taking nonsteroidal antiinflammatory agents, and those with active peptic ulcer disease. Endoscopy may be performed for diagnosis and treatment. Antisecretory therapy may be employed to control gastric acid secretion, treat active peptic ulcer disease, and control symptoms such as diarrhea and abdominal pain. Options for antisecretory therapy include histamine2-receptor antagonists (H2RAs) that target the histamine pathway, and proton pump inhibitors (PPIs) that target the final step in acid secretion. The H2RAs generally are ineffective at reaching a target pH of 6 in patients with gastrointestinal bleeding because of tachyphylaxis. The PPIs are more effective and do not lead to tachyphylaxis. With the availability of an intravenous PPI, pantoprazole, options for managing hospitalized patients with gastrointestinal bleeding are expanding.

Objectives: Hypochlorhydria, hypergastrinaemia, inflammation and Helicobacter pylori infection, dose and duration of omeprazole treatment may separately, or in combination, influence the proliferation of enterochromaffin-like (ECL) cells and parietal cell changes in gastric mucosa. To assess the effects of these variables comparisons were carried out in patients with the acid related Zollinger-Ellison syndrome (ZES) versus patients with progressive systemic sclerosis (PSS) and gastro-oesophageal reflux disease., Methods: Twenty-five patients with PSS and 16 patients with ZES were included and received continuous omeprazole treatment for a mean of 7.5 and 9 years. The patients were investigated every 6-12 months with endoscopy, biopsies and histology, and plasma gastrin measurements. PSS patients were titrated by 24 h pH-metry to oesophageal pH>4, and all ZES patients were titrated to a basal acid output of zero H+., Results: Changes towards diffuse and linear ECL cell hyperplasia were observed in 41% of the PSS patients. Micronodular hyperplasia and neoplasia were not seen. In the ZES patients changes towards linear and micronodular hyperplasia were observed in all patients. Two patients developed ECL cell carcinoids; one of these had MEN-1 syndrome. Also parietal cell changes were more pronounced in the ZES group than in the PSS group., Conclusions: In patients without intrinsic acid hypersecretion and hypergastrinaemia significant proliferation of ECL cells is not an issue irrespective of gastric mucosal inflammation, omeprazole dose, duration of treatment and acid inhibition. The level of gastrin secretion and high plasma gastrin appear to accelerate ECL cell proliferation and parietal cell changes possibly influenced by chronic gastritis and H. pylori infection.

Objective: Maintenance proton pump inhibitor (PPI) therapy is effective for gastric acid hypersecretory states, although data with pantoprazole are limited. The aim of this study was to evaluate the safety and efficacy of long term p.o. pantoprazole in individuals with hypersecretion., Methods: All subjects had Zollinger-Ellison syndrome or idiopathic hypersecretion. Baseline acid output was measured in the presence of prior maintenance antisecretory therapy before pantoprazole exposure. The starting dose was 40 mg b.i.d. in most cases, and the dose was adjusted to document control within the first 2 wk of therapy. The maximal allowable dose was 240 mg daily. Acid output was measured on day 28 and then quarterly from month 3. The primary efficacy endpoint was documented control of acid secretion at 6 months, i.e., acid output in the last 1 h before the next dose of therapy of <10 mEq/h (<5 mEq/h in subjects with prior acid-reducing surgery)., Results: A total of 26 subjects had Zollinger-Ellison syndrome (six with multiple endocrine neoplasia syndrome type 1) and nine had idiopathic hypersecretion. Pre-enrollment therapy included omeprazole in 27 subjects and lansoprazole in eight, and 82.4% of subjects were controlled on their prior regimens. With upward dose titration, acid output was controlled in all subjects by day 10 and in all but two (6%) at the 6-month time point. Median acid secretion on therapy at 6 months was <2 mEq/h (mean 2.2 mEq/h; range 0-10.5 mEq/h) at a dose of 40 mg b.i.d. for 24 subjects, 80 mg b.i.d. for seven subjects, and 120 mg b.i.d. for two subjects. During the course of the study, five subjects required doses of 240 mg daily. Pantoprazole was generally well tolerated. No cases of anterior optic ischemic neuropathy occurred. Five subjects died during follow-up, all because of events unrelated to the study drug., Conclusions: Maintenance p.o. pantoprazole therapy at a dose of 80-240 mg/day in divided doses was both effective and generally well tolerated for patients with Zollinger-Ellison syndrome and idiopathic hypersecretion.

Zollinger-Ellison syndrome is characterised by refractory peptic ulcer disease, severe diarrhoea and gastric acid hypersecretion associated with an islet-cell tumour of the pancreas (gastrinoma). The true incidence and prevalence of this rare disease is unknown; in the US, the frequency is one per one million people and the age at presentation varies from 7 to 90 years. Zollinger-Ellison syndrome is sporadic in 62-80% of cases and in 20-38% of cases is associated with multiple endocrine neoplasia type 1 (MEN 1). The diagnosis of Zollinger-Ellison syndrome is certain when the plasma gastrin is >1000 pg/mL and the basal acid output is >15 mEq/h in patients with an intact stomach, >5 mEq/h in gastrectomised patients, or when this hypergastrinemia is associated with a pH <2. The treatment is based on control of gastric acid hypersecretion and of the malignant tumour and its possible metastases. Proton pump inhibitors are the most effective antisecretory drugs and can be administered in the elderly at high dosages without drug-related adverse effects. As an initial therapy, daily dosages of omeprazole 80-100 mg or pantoprazole 40-160 mg are employed. In long-term treatment the doses can be greatly reduced once effective control of the gastric output has been established. Intravenous proton pump inhibitors may be administered when patients cannot take oral therapy, particularly in acute conditions. All sporadic localised gastrinomas should be excised if possible. When liver metastases are also present, their debulking may improve symptoms and survival, and facilitate medical treatment. There is some controversy as to the surgical approach for gastrinomas associated with MEN 1. Somatostatin analogues can be useful in reducing gastric acid hypersecretion, serum gastrin and gastric enterochromaffin-like (ECL) cells and can thus contribute to treating the disease more effectively. Their antiproliferative effect can be used in treating liver metastases. Chemotherapy is not the therapy of choice in patients with gastrinomas and is indicated only in those with malignant progressive disease; interferon alpha, embolisation and chemoembolisation are not advisable for the elderly. The treatment of elderly Zollinger-Ellison syndrome patients, similarly to all elderly oncological patients, should be based on the use of comprehensive geriatric assessment. This will enable the clinician to define the functional status of the elderly person, to decide whether the patient can tolerate surgery and/or the stress of antineoplastic therapy, and finally, to determine whether this patient can tolerate an aggressive treatment for Zollinger-Ellison syndrome or whether the only possible choice is palliative relief of symptoms.

Pantoprazole (Protonix) is an irreversible proton pump inhibitor (PPI) that reduces gastric acid secretion. In combination with two antimicrobial agents (most commonly metronidazole, clarithromycin or amoxicillin) for 6-14 days, pantoprazole 40 mg twice daily produced Helicobacter pylori eradication rates of 71-93.8% (intent-to-treat [ITT] or modified ITT analysis) in patients without known antibacterial resistance. Pantoprazole-containing triple therapy was at least as effective as omeprazole- and similar in efficacy to lansoprazole-containing triple therapy in large trials. In the treatment of moderate to severe gastro-oesophageal reflux disease (GORD), oral pantoprazole 40 mg/day was as effective as other PPIs (omeprazole, omeprazole multiple unit pellet system, lansoprazole and esomeprazole) and significantly more effective than histamine H(2)-antagonists. Pantoprazole 20 mg/day provided effective mucosal healing in patients with GORD and mild oesophagitis. Intravenous pantoprazole 40 mg/day can be used in patients who are unable to take oral medication. Oral pantoprazole 20-40 mg/day for up to 24 months prevented relapse in most patients with healed GORD. According to preliminary data, oral pantoprazole 20 or 40 mg/day was effective at healing and preventing non-steroidal anti-inflammatory drug (NSAID)-related ulcers, and intravenous pantoprazole was at least as effective as intravenous ranitidine in preventing ulcer rebleeding after endoscopic haemostasis. Oral or intravenous pantoprazole up to 240 mg/day maintained target acid output levels in most patients with hypersecretory conditions, including Zollinger-Ellison syndrome. Oral and intravenous pantoprazole appear to be well tolerated in patients with acid-related disorders in short- and long-term trials. Tolerability with oral pantoprazole was similar to that with other PPIs or histamine H(2)-antagonists in short-term trials. Formal drug interaction studies have not revealed any clinically significant interactions between pantoprazole and other agents. In conclusion, pantoprazole is an effective agent in the management of acid-related disorders. As a component of triple therapy for H. pylori eradication and as monotherapy for the healing of oesophagitis and maintenance of GORD, pantoprazole has shown similar efficacy to other PPIs and greater efficacy than histamine H(2)-antagonists. Limited data suggest that it is also effective in Zollinger-Ellison syndrome and in preventing ulcer rebleeding. Pantoprazole is well tolerated with minimal potential for drug interactions. The availability of pantoprazole as both oral and intravenous formulations provides flexibility when the oral route of administration is not appropriate. Thus, pantoprazole is a valuable alternative to other PPIs in the treatment of acid-related disorders.