Omeprazole: Effective, Convenient Therapy for Zollinger-Ellison Syndrome

Transcription

1 GASTROENTEROLOGY 1985;88: Omeprazole: Effective, Convenient Therapy for Zollinger-Ellison Syndrome KATHERINE E. carthur, ARTIN J. COLLEN, PAUL N. ATON, JAY A. CHERNER, JOHN. HOWARD, CECELIA A. CIARLEGLIO, ARY JO CORNELIUS, ROBERT T. JENSEN, and JERRY D. GARDNER Digestive Diseases Branch, National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, aryland The acute and long-term effects of omeprazole on gastric acid secretion were examined in 11 patients with Zollinger-Ellison syndrome. Basal gastric acid secretion was inhibited by 50% 3 h after a single 60- mg dose of omeprazole and 78% 4 h after administration of omeprazole. Patients were treated with a single daily dose of omeprazole, and the dose requirement was defined as the lowest dose of omeprazole that would reduce gastric acid secretion to < 10 meq/h during the last hour before the next dose. The mean daily dose requirement was 70 mg (range mg). Ten of the 11 patients were given omeprazole once a day and 1 patient required omeprazole every 12 h. When omeprazole was discontinued after several months of therapy, mean basal gastric acid secretion was inhibited by >50% 48 h after administration of omeprazole. Omeprazole continued to inhibit gastric acid secretion during 1-9 mo of therapy and patients remained free of toxicity or side effects related to omeprazole. Omeprazole is a highly effective inhibitor of gastric acid secretion in patients with Zollinger-Ellison syndrome. Because of its potency and long duration of action, omeprazole offers an advance in convenient medical therapy for Zollinger-Ellison syndrome compared with the histamine Hrreceptor antagonists. Patients with Zollinger-Ellison syndrome, once routinely managed with total gastrectomy, can usually be treated medically with the histamine Hz-receptor antagonists cimetidine or ranitidine (1-3). The hista- Received July 12, Accepted October 15, Address requests for reprints to: Dr. Jerry D. Gardner, Building 10, Room 9C-l03, National Institutes of Health, Bethesda, aryland by the American Gastroenterological Association /85/$3.30 mine Hz-receptor antagonists effectively inhibit gastric acid secretion with few serious side effects, but these drugs have several disadvantages in many patients with Zollinger-Ellison syndrome. Large doses of cimetidine or ranitidine must be taken at frequent intervals to adequately inhibit gastric acid secretion (4). Patients who require large doses of one drug will require large doses of the other for satisfactory inhibition of gastric acid secretion (4). The requirement for either drug tends to increase over time (5), and some patients may also require an anticholinergic drug for adequate inhibition of gastric acid secretion (4). In addition, up to 50% of men with gastric hypersecretory states treated with high doses of cimetidine develop impotence, gynecomastia, or breast tenderness (6). Omeprazole, a substituted benzimidazole, is a potent, long-acting inhibitor of gastric acid secretion in animals and humans (7,8). Unlike cimetidine or ranitidine, which inhibit gastric acid secretion by antagonizing the action of histamine on the gastric parietal cell, 'omeprazole acts by inhibiting H,Kadenosinetriphosphatase, which is responsible for hydrogen ion secretion by the gastric parietal cell (9,10). Omeprazole inhibits gastric acid secretion stimulated by meals, pentagastrin, cholinergic agents, or histamine (11-13), and the effects of the drug on gastric acid secretion last up to 3 days. Lamers et al. (14) recently reported that symptoms resolved and peptic lesions healed in 7 patients with Zollinger-Ellison syndrome treated with omeprazole for an average of 14 mo. In the present study we have examined the acute and long-term effects of omeprazole on gastric acid secretion in 11 patients with Zollinger-Ellison syndrome. In addition, we assessed the toxicity and side effects of omeprazole therapy lasting up to 9 mo.

2 940 carthur ET AL. GASTROENTEROLOGY Vol. 88,. 4 ethods Patients Eleven patients with Zollinger-Ellison syndrome were studied after giving written informed consent to a protocol approved by the Institutional Human Research Review Committee on December 27, The clinical and laboratory characteristics of the patients used for the present study are given in Table 1. All patients had been treated with histamine Hz-receptor antagonists alone or in combination with an anticholinergic agent for 3 mo to 8 yr before starting the study. The dose and frequency of administration of histamine Hzreceptor antagonist were adjusted so that gastric acid secretion was <10 meq/h for the last hour before the next scheduled dose of medication. Previous studies have shown that this degree of inhibition of gastric acid secretion allows healing of peptic ulcers and prevents further acid-peptic complications (1,15). Drugs used before the study were cimetidine (Tagamet; Smith Kline and Beckman Laboratories, Philadelphia, Pa.), ranitidine (Zantac; Glaxo, Inc., Research Triangle Park, N.C.), propantheline bromide (Pro-Banthine; Searle Laboratories, Chicago, Ill.), isopropamide iodine (Darbid; Smith Kline and Beckman Laboratories), and pirenzepine (Boehringer-Ingelheim, Richfield, Conn.). All patients were treated with omeprazole (AB Hassle, olndal, Sweden) after giving informed consent. Omeprazole was prepared as enteric-coated granules contained in hard gelatin capsules. Each capsule contained 20 mg of omeprazole. Investigations Eleven patients with Zollinger-Ellison syndrome were studied from July 1983 to arch Serum gastrin concentrations were determined by Bioscience Laboratories (New York, N.Y.). As described previously (1), gastric acid secretion was determined by positioning a nasogastric tube in the gastric antrum and continuously aspirating the gastric contents. Each sample was collected for 15 min and was titrated to ph 7.0 with 0.01 N sodium hydroxide. Basal acid output and maximal acid output were measured as described previously (1). Tumor status was evaluated in each patient by liver-spleen scan, computed tomography, ultrasound, and selective pancreatic and hepatic angiography. Within 1 wk before the start of the study, each patient had a history taken and underwent physical examination, which was repeated at 2, 4, 6, and 9 mo. Electrocardiogram, chest radiograph, ophthalmologic examination, and upper gastrointestinal endoscopy were performed before the study and 6 mo later. Urinalysis, complete blood count and differential, creatinine clearance and fasting serum chemistry concentrations, thyroid function, and serum gastrin concentration were measured before the study and then at intervals of 1 wk, 3 wk, 2,4,6, and 9 mo. The experimental design included four types of gastric secretory studies to determine (a) the acute effect of omeprazole on basal acid secretion, (b) the maintenance dose requirement of omeprazole, (c) the duration of action of omeprazole, and (d) the long-term effectiveness and stability of dose requirements of omeprazole. The acute effect of omeprazole was examined in 9 patients. Each patient discontinued all antisecretory medications. Intravenous infusion of cimetidine was discontinued at least 12 h before testing and oral administration of cimetidine or ranitidine was discontinued at least 24 h before testing, because plasma concentrations of drug and inhibition of gastric acid secretion are not detectable after these intervals (unpublished data). Anticholinergic medication was discontinued at least 72 h before measuring basal acid output. After an overnight fast, a nasogastric tube was placed in the stomach. An intravenous infusion of 5% (wt/vol) dextrose, 0.9% (wt/vol) saline, and 20 meqll of potassium chloride was begun at 125 ml/h plus the volume of gastric output for the previous hour. Gastric contents were aspirated continuously and divided into 15-min collections. After six collections, omeprazole (60 mg) was administered orally with 120 ml of water. After clamping the nasogastric tube for 2 h, gastric contents were aspirated and discarded. The gastric contents were collected contin- Table 1. Characteristics of Patients With Zollinger-Ellison Syndrome Treated With Omeprazole Patient number 5 6 Age (yr) Sex ultiple endocrine neoplasia, type I Tumor status Q etastases b Basal acid output (meq/h). aximal acid output : (meq/h) Fasting serum gastrin (pg/ml) F , F F, female;, male. Q Gastrinoma either biopsy-proven or suspected on basis of ultrasound, computed tomography, or angiography (). tumor found at surgery or suspected on basis of ultrasound, computed tomography, or angiography (-). b etastatic gastrinoma by angiography (). tumor metastases found at surgery or suspected on basis of ultrasound, computed tomography, or angiography.

3 April 1985 OEPRAZOLE IN ZOLLINGER-ELLISON SYNDROE 941 uously and pooled in 15-min collections for an additional 6 h. For patient safety, if gastric acid secretion was >20 meq/h after 8.h an additional dose of omeprazole was administered. Otherwise, gastric acid secretion was measured 24 h after the initial dose. To establish the maintenance dose of omeprazole all patients were given the drug once in the morning every 24 h, starting with 60 mg of omeprazole as the first dose. Gastric acid secretion was measured during the last 2 h before the next dose of medication. The dose requirement was the smallest dose of omeprazole necessary to reduce gastric acid secretion to <10 meq/h for the last hour before the next dose. The smallest possible dose was 20 mg/day. If the patient required >200 mg of omeprazole per day, the dose was divided and given every 12 h. After the dose requirement of omeprazole was determined for an individual patient, gastric acid secretion was again measured the subsequent day to ensure that secretory control was adequate. The dose requirement was then called the maintenance dose. In 5 patients maintained on omeprazole for 2-6 mo, the duration of action of the maintenance dose was examined by discontinuing omeprazole therapy and measuring gastric acid secretion for 1 h at 8-h intervals for 48 h, or until the patient secreted >30 meq/h of gastric acid. In all patients the long-term effectiveness and stability of the maintenance dose were determined by measuring gastric acid secretion for the last hour before the next dose at 1 wk, 3 wk, 2, 4, 6, and 9 mo and adjusting the dose of omeprazole as necessary to reduce gastric acid secretion to <10 meq/h. Results The characteristics of the 11 patients with Zollinger-Ellison syndrome studied are shown in Table 1. The median age was 55 yr (range yr). The patients in the present study closely resemble the entire group of patients with Zollinger-Ellison syndrome followed by the National Institutes of Health in terms of age, sex, tumor status, serum gastrin concentration, and basal and maximal gastric acid output. In 9 patients a single dose of omeprazole (60 mg) inhibited basal gastric acid secretion by 50% 3 h after omeprazole administration and by 78% 4 h after omeprazole administration (Figure 1). Eight hours after taking omeprazole, gastric acid secretion was still inhibited by 86%. In 7 patients examined 24 h after administration of omeprazole, gastric acid secretion was still inhibited by 80% (data not shown). In 2 patients, gastric acid secretion was >20 meq/h at the end of the eighth hour after the initial dose of orneprazole, and a second dose of omeprazole was given. The patients achieved the greatest reduction in gastric acid secretion an average of 4.7 h after omeprazole was given (range 4-7 h, data not shown). The dose and frequency of antisecretory medication necessary to reduce gastric acid secretion to <10 60 Omeprazole E w 50 z 0 40 a: u w Vl 30 0 U 20 u a: I- Vl ; TIE (hi Figure 1. The effect of a single dose of omeprazole (60 mg) on gastric acid secretion in 9 patients with Zollinger Ellison syndrome (patients 1-9, Table 1). Results given are means from 9 subjects. Vertical bars represent 1 SE. meq/h before ana auring omeprazole therapy for each of the 11 patients is shown in Table 2. For the 5 patients who were given cimetidine, the mean dose was 1650 mg every 6 h (mean total daily requirement 6.6 g). For the 6 patients who were given ranitidine, the mean dose was 1100 mg taken at 4- to 8-h intervals (mean total daily requirement 5.2 g). Three patients also required an anticholinergic drug in addition to a histamine H 2 -receptor antagonist to control gastric acid secretion. The average total daily dose requirement for omeprazole was 70 mg (range mg). Ten of the 11 patients were given omeprazole once daily and 1 patient required orneprazole every 12 h. patient who was treated with omeprazole needed an anticholinergic drug to adequately inhibit gastric acid secretion. When the maintenance dose of omeprazole was plotted as a function of the maintenance dose of cimetidine there was a significant positive correlation (r = 0.936, P < 0.05). Similarly, when the maintenance dose of omeprazole was plotted as a function of the maintenance dose of ranitidine, there was a significant positive correlation (r = 0.913, P < 0.05). The maintenance dose of omeprazole (Table 2) correlated positively with basal add output (r = 0.713, P < 0.05) and with maximal acid output (r = 0.611, P < 0.05) (Table 1). When omeprazole therapy was discontinued in 5 patients on maintenance therapy, inhibition of gastric acid secretion persisted for up to 48 h (Figure 2). The average omeprazole dose for these patients was 56 mg (range mg). Basal gastric acid secretion in the 5 patients was inhibited by >80% during the first 24 h after omeprazole therapy and by >50% during the 24th-48th hour after omeprazole therapy. Only 1 patient had reached his pretreatment level of basal acid secretion by the end of 48 h. When patients were treated with omeprazole and reevaluated, omeprazole continued to control gastric acid secretion in all cases. One patient has taken omeprazole for 9 rna, 3 patients for 7 rna, 3 patients

4 942 carthur ET AL. GASTROENTEROLOGY Vol. 88,.4 Table 2. Dose and Type of Antisecretory edication Required to Control Gastric Acid Secretion in 11 Patients With Zollinger-Ellison Syndrome Patient Histamine Hz-receptor antagonist number ± anticholinergic drug Omeprazole 1 Ranitidine 1550 mg/4 h 100 mg/day 2 Cimetidine 3000 mg/6 h 100 mg/day 3 Cimetidine 300 mg/6 h 20 mg/day 4 Ranitidine 900 mg/6 h 60 mg/day 5 Cimetidine 450 mg/6 h 20 mg/day 6 Ranitidine 900 mg/4 h 100 mg/day Pirenzipine 25 mg/4 h 7 Cimetidine 1500 mg/6 h 20 mg/day 8 Ranitidine 600 mg/6 h 40 mg/day 9 Cimetidine 3000 mg/6 h 100 mg/day Isopropamide 5 mg/6 h 10 Ranitidine 2400 mg/6 h 80 mg b.i.d Propantheline bromide 7.5 mg/6 h 11 Ranitidine 300 mg/8 h 40 mg/day The dose, type, and frequency of histamine H 2-receptor antagonist ± anticholinergic drug was that required to reduce gastric acid secretion to < 10 meq/h for the last hour before the next dose of medication for each patient prior to the present study. The dose and frequency of omeprazole were determined as described in ethods. for 6 rna, 1 patient for 4 rna, 1 patient for 2 mo, and 2 patients for 1 mo. One patient (patient 2) was removed from the protocol after 4 mo because of unreliability due to heavy alcohol use. During treatment with omeprazole, patients have been free of heartburn, epigastric pain, and diarrhea. patient has had esophageal disease or gastroduodenal ulceration on upper gastrointestinal endoscopy. For patients observed for more than 6 mo, ophthalmologic examinations, electrocardiograms, and chest radiographs have not changed. Fasting serum gastrin concentration did not change significantly in any patient who was treated with omeprazole. ean concentrations of serum glutamic oxaloacetic transaminase activity and serum glutamic pyruvic transaminase activity did not change significantly for the group. Creatine clearance, urinalysis, complete blood count, and other serum chemistry measurements were unchanged throughout the period of treatment with omeprazole. The dose requirement of omeprazole did not change in 9 of the patients during the study. The dose requirement of omeprazole increased in 1 patient (patient 1, Table 1) and decreased in 1 patient (patient 4). Discussion The present study shows that omeprazole inhibits gastric acid secretion in patients with Zollinger-Ellison syndrome both acutely and for periods of up to 9 mo. Patients treated with omeprazole are free of acid-related symptoms. Dose require- ments are usually stable and patients taking omeprazole do not develop tachyphylaxis. Patients have no side effects or toxicity related to omeprazole throughout the duration of the study. In all patients, omeprazole treatment results in a decrease in dose and frequency of medication when compared with treatment with histamine H 2 -receptor antagonists. A single dose of omeprazole (60 mg) produces maximal inhibition of gastric acid secretion about 4 h after administration. Similarly, maximal inhibition of gastric acid secretion occurs about 3 h after administration of cimetidine or ranitidine to patients with Zollinger-Ellison syndrome (4). Lamers et al. (14) found that maximal inhibition of gastric acid secretion occurred 6 h after a single dose of omeprazole (80 mg) in 5 patients with Zollinger-Ellison syndrome, but these investigators did not measure acid secretion at earlier times. Lind et al. (12) found that in normal subjects maximal inhibition of pentagastrin-stimulated gastric acid secretion occurred 1 h after administration of omeprazole. Because omeprazole is chemically altered by gastric acid (data on file; AB Hassle; Sweden), Lind et al. used a bicarbonate-buffered suspension of omeprazole from which the drug is absorbed rapidly (data on file; AB Hassle, Sweden). Patients in the present study took omeprazole in enteric-coated granules, which are absorbed more slowly because the protective coating of the granules does not dissolve until the granules have reached an area of alkaline ph in the intestine (data on file; AB Hassle, Sweden). The enteric-coated granules of omeprazole were effective in the patients in the present study despite the large amounts of gastric acid secreted at the time of omeprazole administration, indicating that no special precautions are necessary in beginning omeprazole therapy in patients with Zollinger-Ellison syndrome. :2 :ff 50 E w Vl o Ba Ou _ 20 La" Do", of U Omeprazole 10 I t;; «(!l TIE (hi Figure 2. Inhibition of gastric acid secretion after discontinuing omeprazole (mean dose, 56 mg) in 5 patients (patients 1, 4, 5, 7, and 8, Table 1). Basal acid output is the gastric acid secretion in milliequivalents per hour (meq/h) measured after discontinuing all antisecretory medications as determined at the beginning of the study. Results given are the means from the 5 subjects. Vertical bars represent 1 SE.

5 April 1985 OEPRAZOLE IN ZOLLINGER-ELLISON SYNDROE 943 In patients with Zollinger-Ellison syndrome, omeprazole is a much more potent inhibitor of gastric acid secretion than either cimetidine or ranitidine as shown by comparing the drug requirement for histamine H 2 -receptor antagonist with that for omeprazole (Table 2). As expected, omeprazole has a much longer duration of action in patients with Zollinger Ellison syndrome than the histamine H 2 -receptor antagonists. Ten of 11 patients in the present study required omeprazole once a day to adequately inhibit gastric acid secretion. These patients had required cimetidine or ranitidine every 4-8 h to inhibit gastric acid secretion to the same extent. patient required an anticholinergic drug in addition to omeprazole to control gastric acid secretion, although anticholinergic drugs were necessary in 3 patients treated with histamine H 2 -receptor antagpnists. There was a close correlation between the maintenance dose of omeprazole and the maintenance dose of cimetidine or ranitidine used before the study. Because omeprazole and the histamine H 2 -receptor antagonists have different mechanisms of action, the reasons for the correlation between maintenance doses for the two classes of drugs are not clear. Although the maintenance dose of omeprazole correlates positively with basal acid output and with maximal acid output, the maintenance dose of cimetidine and ranitidine did not correlate with either basal or maximal acid output, probably because of small numbers of patients in each group treated with cimetidine or ranitidine. Drug absorption ma,y markedly alter drug requirements for the histamine H 2 - receptor antagonists (16,17) and probably influences omeprazole requirements as well; this factor was not examined in the present study. The average maintenance dose requirement for omeprazole in the present study is similar to the dose requirement in the 7 patients with Zollinger-Ellison syndrome studied by Lamers et a1. (14). The present study, however, included a wider range of single doses of omeprazole ( mg) than the range used by Lamers et a1. (40-80 mg). If gastric acid secretion was >10 meq/h 24 h after administration of 80 mg of omeprazole, Lamers et a1. divided the dose and administered omeprazole twice a day. Lamers et a1. treated 2 patients with omeprazole every 12 h; however, our results suggest that it may have been possible to control gastric acid secretion in these 2 patients with one larger daily dose, because in the present study, 4 patients were controlled by 100 mg of omeprazole daily who were not controlled by 80 mg of omeprazole daily. One patient in the present study (patient 10, Table 1) required omeprazole every 12 h. Although in this patient an initial single dose of omeprazole (60 mg) inhibited the basal acid secretion of 118 meq/h by >85% 24 h later, gastric acid secretion was still >10 meq/h. Increasing single daily doses of up to 200 mg of omeprazole produced no further reduction in gastric acid secretion. However, gastric acid secretion was 1 meq/h 12 h after administration of 80 mg of omeprazole. Basal acid output in this patient was much higher than in any other patient in the study; however, he was similar to the other patients in other characteristics. Patients treated with omeprazole developed no significant evidence of toxicity throughout the duration of the study. Lamers et a1. (14) found no evidence of hepatic toxicity in 7 patients treated for from 8 to 14 mo with doses of omeprazole similar to those used in the present study. In contrast, Gustavsson et a1. (18) noted slight increases in the concentrations of serum glutamic pyruvic transaminase in patients with duodenal ulcers after 2 wk of therapy with 20 mg or 60 mg of omeprazole. These alterations occurred primarily in the group of patients treated with 20 mg of omeprazole daily (data on file; AB Hassle, Sweden). ore patients need to be treated with Qmeprazole to evaluate toxicity, but hepatotoxicity does not appear to be a common problem in patients with Zollinger-Ellison syndroml'l. Serum gastrin concentrations were unchanged throughout the study, which was expected, because patients with Zollinger-Ellison syndrome have autonomous gastrin-producing tumors. In contrast, normal subjects develop a small reversible elevation in serum gastrin after 1 wk of treatment with 30 mg of omeprazole daily, probably in response to increased intragastric ph (19). Recently, the manufacturers of omeprazole released preliminary results of toxicity testing in animals. These results showed that some rats but no mice treated with large doses of omeprazole for 1.5 yr developed histologically benign gastric carcinoid. The smallest dose of omeprazole used was -10 times the largest dose of omeprazole currently used in humans. It is not known if the development of gastric carcinoid in these animals is a direct effect of omeprazole or is mediated through another mechanism, such as elevated serum gastrin concentration or achlorhydria, or both, resulting from treatment with omeprazole. Rats made hypergastrinemic by antral exclusion develop hypertrophy and hyperplasia of the endocrine cells in the gastric mucosa (20). The reason for the contrasting findings in rats and mice is not clear. Gastric carcinoid is rare in humans (21), and its etiology is not known. In a series of 30 patients with gastric carcinoid reported by Carney et a1. (22), 12 patients had normal gastric mucosa, 16 patients had atrophic gastritis, and 2 patients had hyperplastic mucosa secondary to Zollinger-Ellison syndrome. Of the group with atrophic gastritis, 12 patients had pernicious anemia. In the group with

6 944 carthur ET AL. GASTROENTEROLOGY Vol. 88,.4 atrophic gastritis serum gastrin concentrations were markedly elevated in 8 patients, normal in 4 patients who had undergone antrectomies, and not measured in 4 patients. Although these results suggest that hypergastrinemia may predispose one to the development of gastric carcinoid, this neoplasm is uncommon in patients with Zollinger-Ellison syndrome. At the present time it is not known if omeprazole increases the risk of gastric carcinoid in humans. Until more information is available, we are restricting the use of omeprazole in Zollinger-Ellison syndrome to patients who have metastatic tumor or who cannot be treated easily with histamine H 2 -receptor antagonists. Omeprazole offers patients with Zollinger-Ellison syndrome a great improvement in effective convenient therapy compared with the histamine H 2 - receptor antagonists. Our results indicate that patients with Zollinger-Ellison syndrome who presently require large doses of histamine H 2 -receptor antagonist can be effectively treated with omeprazole. If omeprazole proves safe for long-term use in humans, its use will be a major advance in the medical therapy of patients with Zollinger-Ellison syndrome. References 1. ccarthy O, Olinger EJ, ay RJ, Long BW, Gardner JD. H z- histamine receptor blocking agents in the Zollinger-Ellison syndrome. Ann Intern ed 1977;87: Stage JF, Stadil F, Fischerman K. New aspects in the treatment of Zollinger-Ellison syndrome. In: Creutzfeld W, ed. Cimetidine. Amsterdam: Excerpta edica, 1978: ccrthy O. The place of surgery in the Zollinger-Ellison syndrome. N Engl J ed 1980;302: Collen J, Howard J, carthur KE, et al. Comparison of ranitidine and cimetidine in the treatment of gastric hypersecretion. Ann Intern ed 1984;100: Allende HD, Bissonnette B, Raufman J-p, et al. Progressive increase in drug requirement in the long-term medical management of patients with Zollinger-Ellison syndrome (abstr). Gastroenterology 1982;82: Jensen RT, Collen J, Pandol SJ, et al. Cimetidine-induced impotence and breast changes in patients with gastric hypersecretory states. N Engl J ed 1983;308: Larsson H, Carlsson E, Junggren U, et al. Inhibition of gastric acid secretion by omeprazole in the dog and rat. Gastroenterology 1983;85: Olbe L, Haglund U, Leth R, et al. Effects of substituted benzimidazole (H 149/94) on gastric acid secretion in humans. Gastroenterology 1982;83: Fellenius E, Berglindh'T, Briindstrom A, et al. The inhibitory action of substituted benzimidazoles on isolated oxyntic glands and H IK -ATPase. In: Schulz I, Sachs G, Forte J, Ullrich KJ, eds. Hydrogen ion transport in epithelia. Amsterdam: Elsevier, 1980: Fellenius E, Berglindh T, Sachs G, et al. Substituted benzimadazoles inhibit gastric acid secretion by blocking (H K) ATPase. Nature 1981;290: Londong W, Londong V, Cederberg C, Steffen H. Dose-response study of omeprazole on meal-stimulated gastric acid secretion and gastrin release. Gastroenterology 1983;85: Lind T, Cederberg C, Ekenved G, Haglund U, Olbe L. Effect of omeprazole-a gastric proton pump inhibitor-on pentagastrin stimulated acid secretion in man. Gut 1983;24: Konturek SJ, Cieszkowski, Kwiecien N, Koriturek J, Tasler J, Bilski J. Effects of omeprazole, a substituteld b\'lnzimidazole, on gastrointestinal secretions, serum gastrin, and gastric mucosal blood flow in dogs. Gastroenterology 1984;86: Lamers BHW, Lind T, oberg S, Jansen J, Olbe L. Omeprazole in Zollinger-Ellison syndrome. Effects of a single dose and of long-term treatment in patients resistant to histamine H z - receptor antagonists. N Engl J ed 1984;310: Raufman J-p, Collins S, Pando 1 SJ, et al. Reliability of symptoms in assessing control of gastric acid secretion in patients with Zollinger-Ellison syndrome. Gastroenterology 1983;84: Ziemniak JA, adura, Adamonis AJ, Olinger EJ, Dreyer, Schentag JJ. Failure of cimetidine in Zollinger-Ellison syndrome. Dig Dis Sci 1983;28: Vallot T, ignon, azure R, Bonfils S. Evaluation of antisecretory drug therapy of Zollinger-Ellison syndrome (ZES) using 24-hour ph monitoring. Dig Dis Sci 1983;28: Gustavsson S, Adami H-O, Loof L, Nyberg A, Nyren O. Rapid healing of duodenal ulcers with omeprazole: double-blind dose-comparative trial. Lancet 1983;ii: Festen H, Thus J, Lamers C, et al. Effect of oral omeprazole on fasting and meal stimulated serum gastrin and serum pepsinogen levels in healthy volunteers. Gut 1983;24: Alumets J, EI unshid HA, Hakanson R, et al. Effect of antrum exclusion on endocrine cells of rat stomach. J Physiol 1979;286: Godwin JD II. Carcinoid tumors: an analysis of 2,837 cases. Cancer 1975;36: Carney JA, Go V, Fairbanks VF, oore SB, Alport EC, ra FE. The syndrome of gastric argyrophil carcinoid tumors and nonantral gastric atrophy. Ann Intern ed 1983;99:761-6.