Influence of RP 40749 on basal and meal-stimulated serum-gastrin,serum-pepsinogen I,and gastrin-content of the antral mucosa in duodenal ulcer patients

Eighteen patients with active duodenal ulcer were treated with a novel antisecretory drug, RP 40749, either 100 mg or 150 mg as a daily nocturnal dose for 28 days. In these patients we evaluated the clinical course, endoscopic healing rates after 28 days, routine laboratory parameters, basal serum gastrin and pepsinogen I levels, meal-stimulated serum gastrin concentration, and the gastrin content of the antral mucosa. All nine patients receiving 150 mg RP 40749 and eight of nine patients receiving 100 mg RP 40749 healed their ulcers completely within 28 days, becoming rapidly symptom-free after an average of three days. The basal (53.8±5.2 vs 99.8±11.4 pg/ml) and meal-stimulated serum gastrin levels (109.2±12.1 vs 189.2±16.7 pg/ml) rose significantly after treatment with RP 40749, as did the gastrin content of the antral mucosa (11.3±2.1 vs 26.0±5.1 g/g), suggesting increased synthesis and secretion of gastrin. Between the 100 mg and 150 mg groups, no significant differences in response were observed. Serum pepsinogen I levels (64.9±7.3 vs 147.9±17.9 ng/ml) increased after treatment; the increase after 150 mg RP 40749 was significantly greater than that after 100 mg RP 40749. The increased of serum pepsinogen levels are probably due to a spillover effect resulting from a blockade in exocrine secretion into the lumen. There were no relevant changes in routine laboratory parameters.     

Helicobacter pylori eradication improves gastric histology and decreases serum gastrin, pepsinogen I and pepsinogen II levels in patients with duodenal ulcer

Background and Aim: The aim of this study was to assess the gastric histopathology and serum gastrin‐17 and pepsinogens profiles in patients with duodenal ulcer before and after Helicobacter pylori eradication in a population with a very high prevalence of H. pylori. At the same time we assessed the role of H. pylori density on these variables. Methods: Eighty Caucasian patients with H. pylori–associated duodenal ulcer before treatment and 1 year after randomized eradication were studied. Among patients with unsuccessful eradication two groups were distinguished according to the data obtained after treatment: the group with negative rapid urease test and decreased bacterial density according to morphological score (partial elimination group); the group with positive rapid urease test and high bacterial density (failed eradication group). Results: One year after successful eradication, serum levels of gastrin‐17, pepsinogen I and pepsinogen II decreased. Similar changes of serum pepsinogen I and pepsinogen II levels were observed in patients with partial elimination of H. pylori infection. In the group with successful eradication, inflammation, activity, atrophy and number of lymphoid follicles in the antral mucosa fell. In the group with partial elimination, antral mucosa activity and H. pylori score reduced. Other morphological changes were statistically non‐significant. Conclusion: Patients with duodenal ulcer after successful eradication have improvement of morphological and functional characteristics of gastric mucosa.     

Cigarette smoking, gastric acid secretion, and serum pepsinogen I concentrations in duodenal ulcer patients.

Cigarette smoking has been linked with duodenal ulcer disease although the mechanism of this association is unclear. This study assessed basal gastric secretory response to acute smoking of smokers with an active duodenal ulcer; in addition the possible effects of chronic smoking on gastric secretory capacity, as expressed by pentagastrin stimulated gastric acid secretion and fasting serum pepsinogen I (PG I) concentrations, were investigated in patients with active duodenal ulcer, or non-ulcer dyspepsia. In 10 smokers with duodenal ulcer smoking four cigarettes during 40 minutes did not influence basal gastric secretion of acid and pepsin, or serum PG I and gastrin concentrations. In 136 patients with duodenal ulcer and 90 controls with non-ulcer dyspepsia, pentagastrin stimulated acid secretion and fasting serum PG I concentrations were significantly higher among habitual heavy smokers than among non-smokers. These findings suggest that in heavy smokers with duodenal ulcer acid- and pepsin-secreting cell function is not affected by acute cigarette smoking. By contrast, chronic cigarette smoking seems to be associated either with an increase of parietal- and chief-cell mass, or with an enhancement of their secretory capacity.     

The effect of 20 Mg omeprazole daily on serum gastrin, 24-h intragastric acidity, and bile acid concentration in duodenal ulcer patients

Serum gastrin, 24-h intragastric acidity, and bile acid concentrations were measured during physiologic conditions in 10 patients with duodenal ulcer disease. Omeprazole, 20 mg daily, for 8 days reduced acidity by greater than or equal to 99% in six patients and by 47-54% in four patients. The degree of acid reduction was related to the area under the plasma omeprazole concentration time curve (AUC). Serum gastrin levels were not significantly increased by omeprazole. Intragastric bile acid concentrations were increased by omeprazole, but this seems to be of little importance for the healing of duodenal ulcers.     

Comparison of the effects of ranitidine, cimetidine and placebo on the 24 hour intragastric acidity and nocturnal acid secretion in patients with duodenal ulcer.

Twenty-four hour intragastric acidity and nocturnal acid secretion were measured in 10 males with duodenal ulcer in four separate 24 hour studies, during which the subjects ate normal meals, had unrestricted physical activity, and consumed their customary quantities of tobacco. The medication consisted of either placebo, cimetidine 200 mg tds and 400 mg at night, or ranitidine 150 mg bd, or 200 mg bd. Ranitidine 150 mg bd decreased mean 24 hour hydrogen ion activity from 41.8 mmol/l to 13.1 mmol/l (-69%, P less than 0.001) and nocturnal acid output from 6.1 mmol/h to 0.6 mmol/h (-90%, P less than 0.01). This degree of inhibition was significantly greater than that due to cimetidine (P less than 0.001 for 24 hours acidity, less than 0.05 for night time acid output). Plasma concentrations of ranitidine were greater than the IC50 for more than eight hours after the 150 mg dose. Ranitidine 200 mg conferred no additional advantage. Ranitidine 150 mg bd should be tested in therapeutic trials.     

Tiotidine,a new H2-receptor antagonist,is a potent inhibitor of nocturnal acid secretion in duodenal ulcer patients

The efficacy of tiotidine, a new H₂-receptor antagonist, in reducing nocturnal acid secretion of duodenal ulcer patients (N=12, ages 21–60 years) was investigated. Different doses of tiotidine, 25, 50, 100, and 150 mg or placebo, were given as a single oral dose and acid secretion collected overnight. Tiotidine produced a significant, prolonged, and dose-related reduction of the nocturnal acid secretion without important side effects. The inhibition of cumulative H⁺ secretion after 25, 50, 100, and 150 mg tiotidine was 80, 89, 96, and 98% of that observed after placebo, while 300 mg of cimetidine caused an 87% inhibition. Compared to cimetidine, tiotidine appears to be approximately eight times more potent on a molar basis than cimetidine as an inhibitor of acid secretion, and the tiotidine effect is more prolonged. This strong and safe H₂-receptor antagonist may be an important addition to the treatment of acid hypersecretory states.     

Effects of transdermal scopolamine, alone or in combination with cimetidine, on total 24 hour gastric acid secretion in patients with duodenal ulcer.

Transdermal scopolamine is an antimuscarinic preparation approved for use in the United States for prevention of motion sickness. A recent study using this drug (0.5 mg/patch) suggested that enough scopolamine was absorbed through the skin to reduce basal gastric acid secretion in patients with duodenal ulcer. We have compared the effect of transdermal scopolamine and oral cimetidine (400 mg twice daily) in seven men with chronic duodenal ulcer, both alone and in combination, on acid secretion throughout an entire 24 hour period in a placebo-controlled, randomised, double blinded cross over study. The effect of these drugs on basal, interprandial, and nocturnal gastric juice volume and hydrogen ion concentration also was measured. Transdermal scopolamine had no significant effect on mean 24 hour acid secretion (placebo, 409.4 mmol/day; scopolamine, 364.0 mmol/day) nor did it have a significant effect on gastric juice volume or hydrogen ion concentration. The combination of transdermal scopolamine plus cimetidine was not more effective than cimetidine alone in reducing total 24 hour acid secretion (mean, 231.8 versus 235.3 mmol/day) nor in reducing gastric juice volume or hydrogen ion concentration.     

Plasma gastrin, daytime intragastric pH, and nocturnal acid output before and at 1 and 7 months after eradication of Helicobacter pylori in duodenal ulcer subjects.

Nine patients with Helicobacter pylori-related antral gastritis and history of duodenal ulceration were studied before and at 1 and 7 months after eradication of the infection by a 4-week course of tripotassium dicitrato bismuthate, metronidazole, and amoxycillin. The median basal gastrin concentration before eradication was 30 ng/l (range, 20-60) and fell to 20 ng/l (5-20) at 1 month (p less than 0.02) and 15 ng/l (5-20) at 7 months (p less than 0.01) after eradication. The integrated gastrin response to a peptide meal was 3650 ng/l.min (range, 1875-6025) before treatment compared with 1800 ng/l.min (range, 1200-3075) at 1 month (p less than 0.01) and 1312 ng/l.min (875-2625) at 7 months (p less than 0.03). Daytime intragastric pH (0900-2100 h) was similar before treatment (median, 1.4; range, 1.1-2.1) and at 1 month (1.4; 1.1-2.3) and 7 months (1.4; 1-2.2) after eradication. In five of the patients nighttime acid output (2300-0900 h) was also studied and was similar before (median, 86 mmol/10 h; range, 52-114) and at 1 month (76 mmol/10 h; 50-143) and 7 months (94 mmol/10 h; 63-106) after eradication. In conclusion, eradication of H. pylori is accompanied by a sustained fall in serum gastrin concentrations but is not accompanied by an early or late reduction of daytime intragastric acidity or nighttime acid output.     

Effect of a new potent H2-receptor antagonist on meal-stimulated gastric acid secretion and serum gastrin concentration in duodenal ulcer patients

We evaluated the effect of 20-, 40-, 60-, and 80-mg doses of SKF 93479, a new H2-receptor antagonist, on food-stimulated gastric acid secretion in duodenal ulcer patients. Medications were given as a single oral dose in the morning with a breakfast meal, and acid secretion was measured by in vivo intragastric titration in response to four blended steak meals infused into the stomach at intervals over a 24-hr period. A breakfast meal was infused immediately after medication; a luncheon meal was given 5 hr after drug, and a dinner meal was instilled 10 hr later. A second breakfast meal was infused 24 hr after medication. For comparison, the effect of 300 mg cimetidine, given as normally prescribed (with meals and at bedtime), on acid secretion was also studied. Food-stimulated acid secretion was inhibited in a dose-related manner by each of the four doses of SKF 93479. The antisecretory effect was most dramatic following the luncheon meal, and there was still significant (P less than 0.05) inhibition of acid secretion at the dinner meal with all doses of SKF 93479. With the second breakfast meal 24 hr after medication, the 80-mg dose alone achieved significant (P less than 0.05) inhibition of acid secretion. Inhibition of acid secretion was correlated positively with blood SKF 93479 levels. When compared with placebo results, serum gastrin concentration, measured 5 and 10 hr after medication, was significantly higher (P less than 0.05) with SKF 93479.     

Behaviour of acid secretion, gastrin release, serum pepsinogen I, and gastric emptying of liquids over six months from eradication of helicobacter pylori in duodenal ulcer patients. A controlled study.

The behaviour of basal and stimulated acid secretion, gastrin release, serum pepsinogen I, and gastric emptying of liquids was studied in 19 consecutive patients with Helicobacter pylori positive duodenal ulcer, over a follow up period of six months. Eleven patients were studied before and at three and six months after eradication with lansoprazole plus amoxicillin and tinidazole (case group), whereas the remainder, with persistent H pylori infection, were studied before and after three and six months from ulcer healing, thus constituting the control group. In the case group, three months after eradication, fasting serum pepsinogen I fell from (mean (SEM)) 91.9 (6.9) (pretreatment) to 72.2 (5.1) ng/l and the integrated gastrin response to a meal reduced from 11,470 (1174) (pretreatment) to 8130 (608) pg/ml/h (p < 0.05). Fasting serum gastrin concentrations and maximal acid output reduced significantly only six months after eradication. In contrast, no significant change of any of these measurements was seen in the control group either at three or six months from healing compared with the pretreatment values. Gastric emptying of liquids did not change over the entire period of follow up in both study groups. In conclusion, eradication of H pylori in duodenal ulcer patients is accompanied by a rapid fall in serum pepsinogen I and plasma gastrin concentrations, whereas a slight but significant reduction of maximal acid secretion takes place later on. In contrast, gastric emptying of liquids does not seem to be influenced by H pylori status.     

Gastric and extragastric gastrin release in normal subjects in duodenal ulcer patients, and in patients with partial gastrectomy (Billroth I).

In 10 normal subjects, in 32 patients with duodenal ulcer (DU), and in 11 patients with partial gastrectomy (Billroth I), serum gastrin rose significantly after an oral and intraduodenal test meal. The highest increases were observed in DU patients after the oral as well as after the intraduodenal test meal. After the intraduodenal test meal in 4 normal subjects and in 17 DU patients an increase of gastric acid secretion and serum gastrin was measured. In basal state, after an intraduodenal or an oral test meal, DU patients with normal gastric acid secretory capacity had higher serum gastrin concentrations than DU patients with gastric hypersecretion. There was a good correlation between peak serum gastrin levels after the oral and after the intraduodenal test meal. From these data it is concluded: (1) Intraduodenal application of a test meal results in release of gastrin from extragastric sites. (2) Extragastric gastrin is biologically active. (3) DU patients are able to release more antral and more extragastric gastrin in response to a test meal. Further studies, however, are necessary to show the significance of these findings in the pathogenesis of peptic ulcer disease.     

The effect of 15(R)-15-methyl prostaglandin E2 on meal-stimulated gastric acid secretion,serum gastrin,and pancreatic polypeptide in duodenal ulcer patients

The effects of 100-g doses of 15(R)-15-methyl prostaglandin E₂ on meal-stimulated acid secretion, serum gastrin, and pancreatic polypeptide concentrations were measured in patients with duodenal ulcer. The drug given in encapsulated or unencapsulated form significantly reduced gastric acid secretion by 59% or 70%, respectively. Rises in serum gastrin and pancreatic polypeptide concentrations after the meal were significantly blunted by 15(R)-15-methyl prostaglandin E₂. This dose of prostaglandin led to no side effects and merits clinical evaluation in the treatment of peptic ulcer disease.Supported in part by grant AM17328 from the National Institutes of Arthritis, Metabolism, and Digestive Diseases and by the Veterans Administration.     

The effect of cimetidine, a new histamine H2-receptor antagonist, on meal-stimulated acid secretion, serum gastrin, and gastric emptying in patients with duodenal ulcer.

Meal-stimulated acid secretion, measured by in vivo intragastric titration, was progressively inhibited by increasing oral doses of cimetidine (25 to 400 mg). Four hundred milligrams suppressed acid secretion by 73% for the first 3 hr after the meal, whereas it inhibited acid secretion by 94% during the 30-min period of maximal inhibition. The dose of cimetidine required to suppress acid secretion by 50% during the 30-min period of maximal inhibition was 25 mg. The duration of action of a 300-mg dose was at least 7 hr. Cimetidine was equally effective in inhibiting meal-stimulated acid secretion at two physiological intragastric pH levels (5.0 and 2.5). Cimetidine had no effect on serum gastrin concentration when intragastric pH was maintained at 5.0, but when pH was allowed to seek its own level, serum gastrin concentration was higher after cimetidine than after placebo. Cimetidine had no effect on gastric emptying. No side effects were noted in any patients.     

Action of omeprazole (a benzimidazole derivative) on secretory responses to sham feeding and pentagastrin and upon serum gastrin and pancreatic polypeptide in duodenal ulcer patients.

The effects of omeprazole, a benzimidazole derivative, have been determined on the secretory responses to modified sham feeding and pentagastrin, and upon serum gastrin and pancreatic polypeptide concentrations in duodenal ulcer patients. Intragastric administration of omeprazole in doses of 2 and 6 mumol/kg produced, respectively, about 50% and 90% reduction in acid outputs in responses to modified sham feeding and pentagastrin without affecting serum gastrin and pancreatic polypeptide response to modified sham feeding.     

Temporary cessation of long-term maintenance treatment with omeprazole in patients with H2-receptor-antagonist-resistant reflux oesophagitis. Effects on symptoms, endoscopy, serum gastrin, and gastric acid output

To study the effects of sudden withdrawal of long-term maintenance therapy with omeprazole for up to 4 years, 14 patients with resistant reflux oesophagitis were asked to stop their treatment temporarily. Ten days after withdrawal median basal acid output had increased significantly (p = 0.01) from 0 (range, 0-1.18) on day 1 to 1.95 (range, 0-8.45) mmol/h on day 10. Median serum gastrin levels were raised during treatment with omeprazole but decreased significantly from 166 to 42 ng/l within the 10 days of the study (p = 0.01). The median integrated gastrin response after meal stimulation decreased significantly (p less than 0.001) from 758.6 ng/l on day 1 to 267.9 ng/l on day 10. On day 10 after withdrawal of omeprazole all patients had endoscopic and symptomatic evidence of recurrent oesophagitis. Reflux patients receiving maintenance treatment with omeprazole for up to 4 years showed prompt normalization of serum gastrin levels and return of gastric acid production within 10 days after stopping the treatment. Consequently, there was a fast recurrence of aggravation of reflux symptoms and oesophagitis.     

Effect of synthetic 15-methyl analog of PGE2 on gastric acid and serum gastrin response to peptone meal,pentagastrin, and histamine in duodenal ulcer patients

The effect of 15(S)-15-methyl PGE₂, methyl ester (15-ME-PGE₂), used intravenously in a standard dose of 0.5 μg/kg-hr on gastric secretion and serum gastrin level was studied in 6 duodenal ulcer patients. 15-Me-PGE₂ caused an immediate and almost complete inhibition of basal gastric acid and pepsin secretion. Acid secretion induced by a peptone meal and determined by intragastric titration technique was almost as high as the maximal response to histamine and accompanied by a significant rise in serum concentration of immunoassayable gastrin. 15-Me-PGE₂ caused a sudden and complete inhibition of gastric acid response to a peptone meal. 15-Me-PGE₂ did not significantly affect serum gastrin levels both under basal conditions and in response to a peptone meal. Gastric acid and pepsin outputs induced by maximal stimulation with pentagastrin (4 μg/kg-hr) was inhibited by 15-Me-PGE₂ by about 70% and that induced by histamine by about 45%. After the with-drawal of 15-Me-PGE₂ infusion, gastric secretion remained reduced for the remainder of the test. We concluded that 15-Me-PGE₂ is a very strong inhibitor of gastric acid and pepsin secretion induced by various secretory stimuli, particularly under basal conditions and in response to a meal. In view of prolonged inhibitory activity, 15-Me-PGE₂ may have clinical potential in the treatment of peptic ulcer disease.     

Inhibition of basal and stimulated gastric H+ and pepsin secretion in duodenal ulcer patients by metiamide,an H-2 histamine antagonist

Metiamide was given orally in one dose of 200 mg in 23 studies in patients with duodenal ulcer, 4 in the basal state, 11 during histamine infusion, and 8 before insulin hypoglycemia stimulation. In the latter 8 patients insulin was given at another time without metiamide. In 17 studies acid secretion was suppressed by metiamide—up to 75% in the basal state, 53% after histamine, and 80% after insulin. Pepsin secretion was reduced to the same extent as H⁺ in the histamine studies but not in the basal (57%) or insulin (44%) studies, so that in the latter pepsin/acid ratios were 3-fold greater than in controls. Blood levels of metiamide were measured in 17 studies. In 10 out of 11 who showed inhibition of 40% or more, peak blood levels of metiamide were 0.45 g/ml to 1.25 g/ml. In 5 of 6 who did not show inhibition, blood levels were 0.05–0.4 g/ml; in the sixth it was 0.8 g/ml. Therefore a critical blood level for suppression of basal or stimulated secretion appears to be 0.45 g/ml.Supported by Public Health Service Grants AM09260 and AM05286; and by a Grant-in-Aid from Smith Kline & French Laboratories; Veterans Administration Hospital, Birmingham, Alabama, Research Project 3649-01.     

Gastric acid secretion stimulated by modified sham-feeding,and the effects of histamine H2-antagonist and anti-muscarinic agent in patients with duodenal ulcer

Patients with duodenal ulcer (DU) were classified into responders to H₂-antagonist and non-responders in whom DU did not heal within 3 months with the antagonist. In these patients and healthy controls, a modified sham-feeding (MSF) test was performed to elucidate the pathogenesis of resistance to H₂-antagonist. By MSF stimulation, gastric acid secretion significantly increased in all subjects. The mean acid output by MSF amounted to about 52 of the tetra-gastrin maximum in controls (12 cases), 46% in responders (12 cases) and 72% in non-responders (14 cases). The mean acid output in non-responders was significantly higher than in controls under baseline conditions, MSF and gastrin stimulations, but was higher than in responders during MSF stimulation. The effects of H₂-antagonist (cimetidine lmg/kg/h), anti-muscarinic agent (pirenzepine 0.3mg/kg/h), or both on the acid secretion were examined on non-responders (6 cases), responders (6 cases) and healthy controls (6 cases). The acid secretion stimulated by MSF was significantly inhibited by pirenzepine in responders and controls, but not in non-responders. With cimetidine, the acid output was significantly inhibited in all groups, but was still higher in non-responders than in controls and responders, indicating that the reduction of acid output by a H₂-antagonist is significantly less in non-responders than in other groups. The combined use of pirenzepine and cimetidine almost completely inhibited the acid output in all groups. These data suggest that the vagal activity in non-responders to H₂-antagonist is higher than in responders and healthy subjects, and H₂-antagonist combined with anti-muscarinic agent is more effective in reducing the gastric acid secretion in non-responders.