rp-40749 and Duodenal-Ulcer

Thirteen male patients with a history of duodenal ulcer were given 150 mg RP 40 749 or placebo tablets at bedtime in a double-blind crossover study. The medication was given for two periods of 10 days with an 11-day wash-out period between. pH and pepsin concentrations were determined each hour in aspirates of gastric juice for 24 h on day 1, 10, 22, 31, and a 2-h collection of gastric juice was examined in the middle of the treatment and wash-out periods. At defined hours blood samples were examined for gastrin, somatostatin, and pancreatic polypeptide (PP) by radioimmunological methods, and concentrations of RP 40 749 were determined in blood and gastric juice. Meals were served at fixed hours on days 1, 10, 22, and 31. After treatment with RP 40 749 a highly significant elevation of pH was found after the 1st day compared with placebo, most pronounced during night hours. The pepsin activity was slightly elevated. The serum concentrations of gastrin were increased and those of somatostatin and PP decreased during the first 3-4 h after medication, with a subsequent normalization. No side effects were observed.

Topics: Adult; Anti-Ulcer Agents; Clinical Trials as Topic; Double-Blind Method; Duodenal Ulcer; Gastric Acid; Gastrins; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Pancreatic Polypeptide; Pepsin A; Placebos; Somatostatin; Thiophenes; Time Factors

Topics: Acute Disease; Adult; Aged; Anti-Ulcer Agents; Duodenal Ulcer; Female; Humans; Male; Middle Aged; Thiophenes

The purpose of this work was to compare the effects of a long acting antisecretory drug on 24-h gastric acidity after acute and chronic administration and to correlate the results observed with modifications of pharmacokinetic parameters. 40749 RP is a carbothioamide derivative antisecretory drug with a non anti H2, non anticholinergic mechanism of action. Eleven patients with an endoscopically proven duodenal ulcer received 100 mg of 40749 RP at 8 PM for 3 wk and thereafter a placebo for an additional 3 wk study period. At the end of the active drug treatment period all patients but one had healed. Continuous 24-h gastric pH recordings performed after the first and the last dose of 40749 RP showed a strong and yet still increasing acid inhibition, nine patients being nearly achlorhydric (i. e. pH greater than 3) during night at the end of treatment. Variations of acid inhibition between the start and the end of treatment were significantly correlated with modifications of pharmacokinetic parameters. Eight days after discontinuation of 40749 RP, basal acid secretion remained strongly inhibited. However at the end of the placebo period, endoscopy showed ulcer relapse in 4 patients (previously resistant to H2-blockers). These results confirmed that 40749 RP is a powerful and very long-acting antisecretory drug. They showed that the antisecretory effects of a long-acting drug should be assessed in conditions of chronic administration when therapeutic dose and regimen are to be determined.

Topics: Adult; Aged; Anti-Ulcer Agents; Drug Evaluation; Duodenal Ulcer; Female; Gastric Acid; Gastrins; Humans; Kinetics; Male; Middle Aged; Thiophenes; Time Factors

40749 RP is a pyridil-2-tetrahydrothiophene derivative, belonging to a new class of gastric antisecretory drugs. We compared its effects on gastric secretion with cimetidine. Intragastric acidity, nocturnal acid output, gastrin and pepsinogen-I profiles were measured in patients with duodenal ulcer in clinical remission. A single dose of 100 mg 40749 RP reduced median 24 h gastric acidity as effectively as cimetidine 1000 mg given as four divided doses, 0.63 vs 1.6 mmol/l. Continued treatment with 40749 RP for 10 days reduced the median 24 h gastric acidity even further, to 0.006 mmol/l (p less than 0.001) and significantly increased fasting concentrations of gastrin and pepsinogen-I (p = 0.02). The incremental gastrin secretion to a standard meal was significantly increased after 10 days treatment with 40749 RP when compared with the first day of 40749 RP, or with cimetidine. These results show that 40749 RP exerts a powerful inhibitory effect on gastric acid secretion after a single 100 mg dose, and that this inhibitory effect increases with continued administration.

Topics: Adult; Anti-Ulcer Agents; Cimetidine; Depression, Chemical; Drug Evaluation; Duodenal Ulcer; Gastric Acid; Gastric Juice; Gastrins; Humans; Hydrogen-Ion Concentration; Male; Pepsinogens; Thiophenes; Time Factors

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 micrograms/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 increase 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.

Topics: Adult; Aged; Anti-Ulcer Agents; Creatinine; Dose-Response Relationship, Drug; Duodenal Ulcer; Duodenoscopy; Female; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Pepsinogens; Pyloric Antrum; Thiophenes

The aim of this study was to investigate the effects of a new antisecretory compound (40749 RP) on the pentagastrin stimulated gastric secretion (6 micrograms.kg-1 b. w. h-1) in 30 patients with duodenal ulcer. The drug was administered directly into the gastric lumen. Four different doses were tested: 50 mg (7 patients), 100 mg (6 patients), 150 mg (8 patients), and 200 mg (9 patients). 40749 RP produced a dose-dependent inhibition of maximal acid secretion (p less than 0.001). Fifty per cent inhibition was obtained with a dose of 0.916 mg.kg-1 b. w. corresponding to a dose of 60 mg per day for a patient weighting 65 kg. The inhibitory effect resulted from a decrease in both volumes and H+ concentrations, the influence of the later being prevalent at high dosages. Peptic concentrations were not significantly decreased and inhibition of peptic secretion correlated only with the reduction of volumes. These results showed that 40749 RP is a potent antisecretory drug which could be of benefit in the treatment of peptic ulcer disease. With regard to the duration of action of 40749 RP, a 60 to 100 mg dose administered once a day at bedtime appeared to be optimal regimen for future therapeutic trials.

Topics: Adult; Anti-Ulcer Agents; Dose-Response Relationship, Drug; Duodenal Ulcer; Female; Gastric Juice; Humans; Male; Pentagastrin; Thiophenes