Uncommon Endoscopic Findings in a Tylosis Patient: A Case Report.

Palmoplantar tylosis is a focal non epidermolytic palmoplantar hyperkeratosis and is associated with a very high lifetime risk of developing squamous cell carcinoma of the esophagus (OSCC). It is generally inherited as an autosomal dominant trait with complete penetrance involving the RHBDF2 gene located on 17q25.1. The data regarding endoscopic appearance of the mucosa in patients with tylosis before development of cancer is limited. Surveillance endoscopy is recommended in family members which include annual esophagogastroscopy with biopsy of suspicious lesion with quadratic biopsies from upper, middle and lower esophagus. We describe characteristic endoscopy findings in a tylosis with no evidence of cancer. Prospective documentation of endoscopic findings of similar mucosal changes and disease process to establish a better screening protocol and supplemental intervention with agents like carotenoids (beta-carotene, alpha-carotene, lycopene, beta-cryptoxanthin, lutein, and zeaxanthin) may delay the progression and possibly revert to normal.

Characterization of insulin-like growth factor I receptors in human esophageal epithelial cells.

In the present study we used 125I-labeled insulin-like growth factor I (125I-IGF-I) to identify and characterize IGF-I receptors in the well-characterized and propagable human esophageal epithelial (HEE) cell line and to characterize their role in cell growth. Binding of 125I-IGF-I was saturable, time and temperature dependent, reversible, and specific for IGF-I and related peptides. Scatchard analysis of binding data demonstrated that HEE cells possess two classes of IGF-I receptors: high affinity [dissociation constant (Kd) = 0.058 nM] and low capacity (13,870 receptors/cell), and low affinity (Kd = 2.2 nM) and high capacity (39,000 receptors/cell). Binding of 125I-IGF-I was inhibited with the following relative potencies (half-maximal inhibition): IGF-I (3.0 pM) > IGF-II (1.2 mM) >> insulin (1.0 microM). Affinity cross-linking of cell membranes using disuccinimidyl suberate as a cross-linking agent under reducing conditions revealed a single polypeptide band (relative mol wt 133,000) representing the alpha-subunit of the IGF-I receptor. IGF-I stimulated [3H]thymidine incorporation and cell proliferation in a dose-dependent manner with detectable effect observed with 0.5 nM IGF-I and maximal effect at 50 nM IGF-I. IGF-I occupation of low-affinity IGF-I receptors appears to mediate cell growth. The present results demonstrate that HEE cells possess two classes of IGF-I receptors: one class has a high affinity and low capacity and the other has a low affinity and high capacity for IGF-I. Occupation of low-affinity IGF-I receptors by IGF-I appears to mediate cell growth.

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)

A newly recognized action of cholecystokinin on pancreatic acini-release of lactate dehydrogenase.

In the course of examining the actions of the cholecystokinin octapeptide (CCK-8) on pancreatic acini we found that CCK-8 can stimulate release of the large-molecular-weight cytoplasmic protein, lactate dehydrogenase (LDH) by as much as 6-fold. CCK-8-stimulated LDH release is mediated by a CCK-preferring receptor, detectable at 100 pM CCK-8, maximal at 100 nM CCK-8, constant for up to 30 min, reversible, not desensitized, and dependent on oxidative metabolism and incubation temperature but not on calcium in the extracellular medium. This action of CCK-8 is blocked by inhibitors of protein kinases, staurosporine, H-7, H-8 and H-9, but not by calmodulin antagonists, chlorpromazine, trifluoperazine or W-7. This action of CCK-8 on LDH release is not reproduced by TPA, 8Br-cAMP or A23187. Thus, it appears to be mediated by a previously uncharacterized protein kinase or an isoform of protein kinase C that is not maximally stimulated by TPA.

Occupation of low-affinity cholecystokinin (CCK) receptors by CCK activates signal transduction and stimulates amylase secretion in pancreatic acinar cells.

Based on the effects of monensin on binding of 125I-CCK-8 and its lack of effect on CCK-8-stimulated amylase secretion we previously proposed that pancreatic acinar cells possess three classes of CCK receptors: high-affinity receptors, low-affinity receptors and very low-affinity receptors [1]. In the present study we treated pancreatic acini with carbachol to induce a complete loss of high-affinity CCK receptors and then examined the action of CCK-8 on inositol trisphosphate IP3(1,4,5), cytosolic calcium and amylase secretion in an effort to confirm and extend our previous hypothesis. We found that first incubating pancreatic acini with 10 mM carbachol decreased binding of 125I-CCK-8 measured during a second incubation by causing a complete loss of high-affinity CCK receptors with no change in the low-affinity CCK receptors. Carbachol treatment of acini, however, did not alter the action of CCK-8 on IP3(1,4,5), cytosolic calcium or amylase secretion or the action of CCK-JMV-180 on amylase secretion or on the supramaximal inhibition of amylase secretion caused by CCK-8. The present findings support our previous hypothesis that pancreatic acinar cells possess three classes of CCK receptors and suggest that high-affinity CCK receptors do not mediate the action of CCK-8 on enzyme secretion, that low-affinity CCK receptors may mediate the action of CCK on cytosolic calcium that does not involve IP3(1,4,5) and produce the upstroke of the dose-response curve for CCK-8-stimulated amylase secretion and that very low-affinity CCK receptors mediate the actions of CCK on IP3(1,4,5) and cytosolic calcium and produce the downstroke of the dose-response curve for CCK-8-stimulated amylase secretion. Moreover, CCK-JMV-180 is a full agonist for stimulating amylase secretion by acting at low-affinity CCK receptors and is an antagonist at very low-affinity CCK receptors.

Carbachol does not down-regulate substance P receptors in pancreatic acini.

In a previous study, we found that first incubating guinea pig pancreatic acini with carbachol caused desensitization of the enzyme secretory response to cholecystokinin-octapeptide (CCK-8), bombesin, and carbachol but not that to substance P. This carbachol-induced desensitization could be accounted for by carbachol-induced down-regulation of receptors for CCK-8, bombesin, and carbachol. Although carbachol did not desensitize the enzyme secretory response to substance P, an effect of carbachol on substance P receptors was not examined. In the present study, in dispersed acini from guinea pig pancreas, substance P caused a twofold increase in amylase secretion. Stimulation was half-maximal at 0.7 nM and was maximal at 10 nM. Analysis of the ability of substance P to inhibit binding of 125I-substance P to substance P receptors indicated that acini possess a single class of receptors for substance P (Kd = 0.8 +/- 0.1 nM; Bmax = 1,037 +/- 145 fmol/mg of DNA). There was a close correlation between the relative potency with which substance P stimulated amylase secretion (0.7 nM) and the potency for inhibiting binding of 125I-substance P (Kd = 0.8 nM). First incubating pancreatic acini with carbachol did not alter either substance P-stimulated enzyme secretion or binding of 125I-substance P to substance P receptors, whereas in the same experiments, carbachol reduced binding of 125I-CCK-8 to cholecystokinin receptors by 50% and decreased in CCK-8-stimulated enzyme secretion by 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of oral and intravenous omeprazole in patients with the Zollinger-Ellison syndrome.

The pharmacokinetics and pharmacodynamics of oral and IV omeprazole after a single dose were studied in 9 patients with the Zollinger-Ellison syndrome to determine whether the increased dose required to control gastric acid hypersecretion could be explained on the basis of altered pharmacokinetics. Each patient was studied both after receiving a single IV bolus of omeprazole (40 mg) and after receiving a single oral dose of omeprazole (80 mg). Intravenous and oral omeprazole doses were administered 1 week apart. Gastric acid secretion and plasma concentrations of omeprazole after drug administration were determined in each patient. The area under the plasma concentration curve, clearance, and volume of distribution after IV omeprazole administration and the area under the plasma concentration curve, peak plasma concentration, and time required to reach the peak after oral omeprazole administration were not different from those reported previously for normal subjects and patients with peptic ulcer disease. Mean (+/- SEM) bioavailability of oral omeprazole for all patients was 68% +/- 16%, which was similar to the bioavailability reported previously for normal subjects. Three patients had a significantly lower bioavailability reported previously for normal subjects. Three patients had a significantly lower bioavailability (20% +/- 8%) than the others, and their basal acid outputs were significantly higher than those of the other 7 patients. For all patients there was an inverse correlation between bioavailability and basal acid output (r = 0.76; P less than 0.02). The mean (+/- SEM) elimination half-lives of IV and oral omeprazole were not different (2.3 +/- 0.4 vs. 2.4 +/- 0.5 hours) but were significantly longer than those reported previously for normal subjects (P less than 0.02). The duration of action correlated with the elimination half-life of the drug (r = 0.87; P less than 0.003) and area under the plasma concentration curve (r = 0.72; P less than 0.03). The mean durations of action of IV and oral omeprazole were not significantly different (34 +/- 7.2 vs. 35 +/- 6.2 hours). It was concluded that altered pharmacokinetics do not account for the increased drug requirement of omeprazole in patients with the Zollinger-Ellison syndrome. In contrast to a previous study, the oral and IV omeprazole had the same duration of action, suggesting that intermittent bolus administration of parenteral omeprazole will obviate the need for continuous infusion of histamine H2-receptor antagonists in patients requiring parenteral antisecretory drugs. Furthermore, an IV dose every 12 hours controlled acid secretion in all patients, suggesting this as the recommended dose interval in patients requiring parenteral drug therapy.

Bombesin receptor antagonists. 2. Analogues based on substance P antagonists.

Although bombesin (BN) and substance P share only the C-terminal dipeptide amide, some substance P receptor antagonists are also weak bombesin receptor antagonists. In order to increase the selectivity of the antagonism for the BN receptor, a series of hybrid peptides were synthesized by the solid-phase methodology, and screened on 3T3 fibroblasts for binding and mitogenic activity. The analogues inhibiting BN-induced thymidine incorporation were further tested for peripheral (amylase release and urinary bladder contraction) and central activity (grooming behaviour).

Down-regulation and recycling of high affinity cholecystokinin receptors on pancreatic acinar cells.

First incubating dispersed acini from rat pancreas with monensin, a cation ionophore that can inhibit recycling of receptors, inhibited binding of 125I-cholecystokinin 8 (125I-CCK-8) measured during a second incubation by as much as 50%. A maximal effect of monensin required 90 min of first incubation. Detectable inhibition of binding of 125I-CCK-8 occurred with 300 nM monensin, and inhibition increased progressively with concentrations of monensin up to 25 microM. Pancreatic acini possess two classes of receptors that bind 125I-CCK-8. One class has a high affinity (Kd = 461 pM) and a low capacity for CCK (512 fmol/mg DNA); the other class has a low affinity (Kd = 47 nM) and a high capacity for CCK (18 pmol/mg DNA). First incubating acini with monensin caused an 84% decrease in the number of high affinity CCK receptors with no change in the number of low affinity CCK receptors or the values of Kd for either class of receptors indicating that there is recycling of high affinity CCK receptors but not low affinity CCK receptors. First incubating acini with monensin did not alter CCK-stimulated amylase secretion indicating that in contrast to previous conclusions, occupation of low affinity CCK receptors mediates CCK-stimulated enzyme secretion. Moreover, the biphasic dose-response curve for CCK-stimulated enzyme secretion from monensin-treated acini suggests that pancreatic acini also possess a third, previously unrecognized class of very low affinity CCK receptors.

Zollinger-Ellison syndrome: prospective assessment of abdominal US in the localization of gastrinomas.

The ability of abdominal ultrasound (US) to help localize gastrinomas was prospectively studied in 79 patients with Zollinger-Ellison syndrome. The results were assessed by means of laparotomy, autopsy, or percutaneous liver biopsy. For hepatic gastrinoma, US had a sensitivity of 63% and a specificity of 100%, with a positive predictive value of 100% and a negative predictive value of 89%. US was slightly less sensitive for detecting gastrinoma in the liver than were computed tomography (CT) (66%) and selective angiography (78%). For detection of extrahepatic gastrinoma, US had a sensitivity of 30%, a specificity of 94%, a positive predictive value of 100%, and a negative predictive value of 25%. US enabled detection of tumor in eight cases not detected with CT and in four not detected with angiography. Specificity for extrahepatic gastrinoma was similar for all three modalities (89%-95%). CT and US were equally effective for the detection of extrahepatic gastrinoma, and angiography was significantly more effective than both US and CT (P less than .01). The authors conclude that US, although of low sensitivity, remains useful as the initial imaging modality in patients with Zollinger-Ellison syndrome.

Detection of duodenal gastrinomas by operative endoscopic transillumination. A prospective study.

The ability of operative endoscopic transillumination of the bowel wall to detect duodenal gastrinoma was evaluated prospectively in 26 patients with the Zollinger-Ellison syndrome. The results were assessed by exploratory laparotomy and compared with the results of other localization techniques. Twelve duodenal gastrinomas were resected from 10 patients. Operative endoscopic transillumination detected 10 of the 12 gastrinomas, a sensitivity of 83%, which was significantly greater (P less than 0.05) than that for either preoperative imaging (25%) or intraoperative ultrasonography and palpation (42%). The sensitivity of operative endoscopic transillumination was a result of the ability to detect focal areas that did not transilluminate on the serosal side of the duodenum, and not the mucosal appearances seen through the endoscope, which were not helpful. Operative endoscopic transillumination detected gastrinomas less than 1 cm in diameter throughout the duodenum. Of the patients in this study, 39% had duodenal gastrinomas, a greater frequency than previously reported. These results indicate that operative endoscopic transillumination is the most sensitive technique yet described for detecting duodenal gastrinomas and should be performed routinely in all patients with the Zollinger-Ellison syndrome who undergo exploratory laparotomy for cure.

Intravenous omeprazole in patients with Zollinger-Ellison syndrome undergoing surgery.

Twenty patients with Zollinger-Ellison syndrome who were undergoing surgery were studied prospectively to assess the efficacy and safety of IV omeprazole. During the preoperative period, in 19 of 20 patients, omeprazole 60 mg administered as an IV bolus every 12 hours inhibited acid output to less than 5 mEq/h measured in the last hour before the next dose of drug. In one patient, acid output was 25 mEq/h 12 hours after omeprazole, 60 mg, and increasing the dose to 100 mg every 12 hours reduced acid output to less than 5 mEq/h. During the operative and postoperative periods, IV omeprazole controlled gastric acid hypersecretion in all patients for up to 15 days. During this time, all patients received the dose determined preoperatively. No patient developed any clinical, hematological, or biochemical toxicity that could be attributed to omeprazole therapy during the preoperative or postoperative period. The present study demonstrates that omeprazole administered by IV bolus is safe and effective for controlling gastric acid hypersecretion. In contrast to IV histamine H2-receptor antagonists, IV omeprazole has the advantages of not requiring continuous infusion or postoperative dose adjustments. Intravenous omeprazole will become the drug of choice in patients with Zollinger-Ellison syndrome undergoing surgery.

Zollinger-Ellison syndrome. Recent advances in the management of the gastrinoma.

Because of increasingly effective oral antisecretory agents, gastric acid hypersecretion is now able to be controlled in all patients with Zollinger-Ellison syndrome with the result that the natural history of the gastrinoma is becoming the major determinant of long-term survival. In this article recent advances in the management of the gastrinoma itself are reviewed, including results with new modalities such as intraoperative ultrasound, MRI, and selective gastrin sampling to localize gastrinoma in patients with Zollinger-Ellison syndrome, as well as recent results of the treatment of metastatic and localized gastrinomas.

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.

Carbachol desensitizes pancreatic enzyme secretion by downregulation of receptors.

First incubating guinea pig pancreatic acini with carbachol reduced the subsequent stimulation of amylase release caused by carbachol, cholecystokinin octapeptide (CCK-8), and bombesin but not that caused by vasoactive intestinal peptide, substance P, 8-bromoadenosine 3',5'-cyclic monophosphate, A23187, or 12-O-tetradecanoylphorbol-13-acetate. Carbachol also reduced the subsequent binding of N-[3H]methylscopolamine, 125I-CCK-8, and 125I-[Tyr4]bombesin. Pancreatic acini possess a high-affinity class of cholinergic receptors and a low-affinity cholinergic receptors appears to produce the reduction in carbachol-stimulated amylase release and binding of N-[3H]methylscopolamine. First incubating acini with carbachol caused a complete loss of high-affinity cholinergic receptors with no change in the number or affinity of low-affinity cholinergic receptors. Carbachol occupation of low-affinity cholinergic receptors appears to produce the reduction in CCK-8- and bombesin-stimulated amylase release and in binding of 125I-CCK-8 and 125I-[Tyr4]bombesin. Acini possess two classes of CCK receptors. One class has a high affinity for CCK-8; the other class has a low affinity for CCK-8. First incubating acini with carbachol caused a 60% decrease in the number of high-affinity CCK receptors with no change in the number of low-affinity receptors or the affinities of either class of receptors for CCK-8. Acini possess a single class of bombesin receptors, and first incubating acini with carbachol caused a 40% decrease in the number of bombesin receptors with no change in their affinity for bombesin. 12-O-tetradecanoyl phorbol-13-acetate reproduced the action of carbachol on binding of N-[3H]methylscopolamine and 125I-CCK-8 but not on binding of 125I-[Tyr4]bombesin, suggesting that carbachol activation of protein kinase C may in some way mediate the effect of carbachol on receptors for carbachol and those for CCK but not that on receptors for bombesin.

Carbachol-induced down-regulation of receptors for pancreatic secretagogues.

Pancreatic acini possess a high affinity class of cholinergic receptors and a low affinity class of cholinergic receptors. Carbachol occupation of high affinity cholinergic receptors produces a reduction in binding of [3H]N-methylscopolamine. First incubating acini with carbachol caused a complete loss of high affinity cholinergic receptors with no change in the number or affinity of low affinity cholinergic receptors. Carbachol occupation of low affinity cholinergic receptors appears to produce a reduction in binding of 125I-CCK-8 and 125I-[Tyr4]bombesin. Acini possess two classes of CCK receptors. One class has a high affinity for CCK-8; the other class has a low affinity for CCK-8. First incubating acini with carbachol caused a 60% decrease in the number of high affinity CCK receptors with no change in the number of low affinity receptors or the affinities of either class of receptors for CCK-8. Acini possess a single class of bombesin receptors and first incubating acini with carbachol caused a 40% decrease in the number of bombesin receptors with no change in their affinity for bombesin.

Secretin and calcium provocative tests in the Zollinger-Ellison syndrome. A prospective study.

STUDY OBJECTIVE: To evaluate criteria of positivity for and usefulness of both the secretin and calcium gastrin-provocative tests in patients with the Zollinger-Ellison syndrome. DESIGN: Prospective trial in consecutive patients. SETTING: Referrals to a clinical research center. PATIENTS: Consecutive sample of 80 patients with the Zollinger-Ellison syndrome. INTERVENTION: Kabi-secretin (2 U/kg body weight) given by intravenous bolus and calcium gluconate (10%) (54 mg/kg.h [5 mg/kg.h of calcium]) given by continuous intravenous infusion for 3 hours. Serum gastrin measured at -15, and -1 minutes before, and 2, 5, 10, 15, 20, and 30 minutes after secretin, or every 30 minutes for 3 hours during the calcium infusion. Serum calcium and serum gastrin were measured simultaneously during the calcium infusion. MEASUREMENTS AND MAIN RESULTS: There was no significant difference in the responses of patients with different extents or locations of the tumor, presence or absence of multiple endocrine neoplasia, type-I, or with fasting gastrin less than or greater than 1000 pg/mL. In patients with fasting gastrin of less than 1000 pg/mL, the sensitivity of the secretin test using the criterion of an increase in gastrin of at least 110 pg/mL was 93% (CI, 76% to 99%) and for an increase of 200 pg/mL it was 85% (CI, 66% to 96%), (P greater than 0.05). With the calcium infusion test, the sensitivity using the criterion of an increase of 395 pg/mL was 43%, (CI, 23% to 66%) and for an increase of 50% was 74% (CI, 52% to 90%), (P less than 0.01). The calcium infusion test was positive in 33% of patients with a negative secretin test. With the secretin test, 75% of patients had a positive response by 5 minutes, 95% by 10 minutes, 100% by 15 minutes, and 6% only at 2 minutes. With calcium infusion, patients had positive responses at 120 to 180 minutes. CONCLUSIONS: The secretin test is preferred over the calcium test because of its greater sensitivity and simplicity. The recommended criteria are a 200 pg/mL increase for the secretin test and a 395 pg/mL increase for the calcium test. The calcium test should be reserved for patients having a negative secretin test, gastric acid hypersecretion, and a strong clinical suspicion of the Zollinger-Ellison syndrome.

Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study.

To determine the long-term efficacy, safety, and toxicity of omeprazole, we studied 40 patients with Zollinger-Ellison syndrome given omeprazole for 6-51 mo (median 29). The mean daily dose of omeprazole required to control gastric acid secretion was 82 +/- 31 mg. Thirty-one patients required omeprazole once per day. In 9 patients acid output was not controlled by 120 mg once per day, but was controlled by 60 mg every 12 h. The daily dose of omeprazole correlated with the previous dose of histamine H2-receptor antagonist (r = 0.89, p less than 0.001), basal acid output (r = 0.43, p less than 0.01), and maximal acid output (r = 0.39, p less than 0.02) but not with serum concentration of gastrin (r = -0.32). Increases in the dose of omeprazole were required in 9 patients. Twenty-nine patients had mild peptic symptoms with acid outputs less than 10 mEq/h while taking histamine H2-receptor antagonists. Symptoms resolved completely in 23 patients and partially in 3 when taking omeprazole. Omeprazole prevented mucosal disease in all patients including 17 in whom histamine H2-receptor antagonists had produced only partial resolution despite acid output being less than 10 mEq/h and in those with symptoms during omeprazole therapy. Omeprazole therapy was not associated with any significant side effects, nor with any evidence of hematologic or biochemical toxicity. Serum concentrations of gastrin did not change significantly during therapy. In 6 patients treated with omeprazole for 1 yr there was no change in basal or maximal acid output. In all patients, gastric morphology and histopathology demonstrated no evidence of gastric carcinoid formation. These results demonstrate that with long-term treatment of up to 4 yr, omeprazole is safe, with no evidence of hematologic, biochemical, or gastric toxicity. Furthermore, omeprazole remained effective, with only 23% of patients requiring an increase in dose, and continued to control symptoms in patients who had not been entirely symptom-free despite high doses of histamine H2-receptor antagonists. Omeprazole is now the drug of choice in patients with Zollinger-Ellison syndrome.