Healing of benign gastric ulcer. A placebo-controlled comparison of two dosage regimens of misoprostol, a synthetic analog of prostaglandin E1.

Misoprostol, a synthetic prostaglandin E1 methyl ester analog with gastric antisecretory and cytoprotective properties, prevents the development of acute experimental gastric and duodenal ulcers in various animal models. This study was designed as a multicenter randomized double-blind parallel-group comparison of the effects of two dosage strengths (25 and 100 micrograms q.i.d.) of orally-administered misoprostol and placebo on the healing of endoscopically-proven benign gastric ulcer in 299 out-patients. Safety was evaluated by comparison of pre- and post-treatment physical examinations, clinical laboratory tests, gastric antral biopsies and monitoring of adverse experiences. A statistically significant difference in gastric ulcer healing rate was seen at eight weeks among the treatment groups in the Intent-to-Treat Cohort: misoprostol 100 micrograms (62.0%), misoprostol 25 micrograms (50.0%), placebo (44.7%). The proportion of subjects healed in up to eight weeks of treatment was greatest in the misoprostol 100 micrograms group in all cohorts. Ulcer pain decreased in all treatment groups in successive weeks and there were no statistical differences among any of the three treatment groups. Diarrhea was the most frequently reported adverse experience: misoprostol 100 micrograms (9.8%), misoprostol 25 micrograms (7.7%), placebo (1.9%). The diarrhea was mild and self-limiting despite continued use of misoprostol. Overall evaluation of gastric antral biopsies showed no adverse changes in the morphology of the antral mucosa. We conclude that misoprostol 100 micrograms q.i.d. for up to eight weeks is safe and effective in the treatment of benign gastric ulcer.

Gastric antisecretory effects of propantheline bromide and metiamide in rhesus monkeys.

The effects of propantheline bromide (PB) and metiamide (M), two dissimilar classes of gastric secretory inhibitors, were studied in chronic gastric fistula rhesus monkeys. Basal and stimulated gastric secretory studies were conducted in conscious monkeys. Multiple s.c. injections of either histamine or pentagastrin were given hourly for four consecutive hours. One hour after the injection of the stimulants a constant plateau of gastric secretion was reached, and the test compounds were then administered as a single i.v. bolus dose. Propantheline bromide at doses of 0.03--0.3 mg/kg inhibited basal and pentagastrin stimulated gastric secretion, but had no effect on histamine stimulation. Total acid output paralleled inhibition of volume of secretion, while there was little or no effect on acid concentration. Metiamide at the doses of 1--10 mg/kg inhibited basal, pentagastrin and histamine stimulated gastric secretion. Metiamide was equally effective in inhibiting the volume of secretion and acid concentration. The scope of the gastric secretory inhibition in the rhesus monkey achieved with these pharmacological agents is very similar to man. These results suggest that the rhesus monkey is an important animal model for predicting clinically useful gastric secretory inhibitors.

Effects of E prostaglandins on canine gastric potential difference.

Measurement of the gastric transmucosal potential difference (PD) was used to study the effect of gastric antisecretory prostaglandins on the integrity of the gastric mucosa of the Heidenhain pouch dog. Intragastric administration of SC-29333 [(+/-)-15-deoxy-16-alpha,beta-hydroxy-16-methyl PGE1 methyl ester] slightly but significantly increased the transmucosal PD when compared to vehicle control. In addition, SC-29333 administered either intravenously or intragastrically, significantly inhibited the PD fall induced by aspirin, a well-established barrier breaker. In contrast, the intragastric administration of 16,16-dimethyl PGE2 methyl ester (Me-PGE2) significantly lowered the transmucosal PD and failed to modify the actions of aspirin on the integrity of the gastric mucosa. However, the intravenous administration of either prostaglandin did not affect the basal transmucosal PD values. These studies suggest that SC-29333 may strengthen the integrity of the gastric mucosal barrier against aspirin, and this could have important therapeutic potential.

Gastric antisecretory effects of E prostaglandins in Rhesus monkeys.

The gastric antisecretory actions of prostaglandin E1 methyl ester (PGE1ME) and prostaglandin E2 (PGE2) were evaluated in unanesthetized gastric fistula rhesus monkeys. Basal and stimulated gastric secretory studies were conducted. Multiple subcutaneous injections of either histamine or pentagastrin were given hourly for four consecutive hours. When a constant plateau of gastric secretion was reached, the PGs were administered as a single intravenous bolus at doses of 10-100 mug/kg. PGE1ME inhibited basal, histamine- and pentagastrin-stimulated gastric secretion. PGE2 was found to inhibit the histamine- stimulated gastric secretion. The PGs showed greater sensitivity to the inhibition of acid concentration rather than the volume of secretion. The PGs signfiicantly altered gastric juice concentration of hydrogen and sodium ion inversely, while potassium and chloride concentration were not altered. These experiments suggest that the rhesus monkey is a useful species for studying the gastric antisecretory effects of E prostaglandins.

Gastric antisecretory actions of (15S)-15-methyl prostaglandin E2 methyl ester and natural prostaglandin E2 in rhesus monkeys.

The gastric antisecretory actions of (15S)-15-methyl prostaglandin E2 methyl ester (Me-PGE2) and Prostaglandin E2 (PGE2) were evaluated in the unanesthetized gastric fistula rhesus monkey. Secretion was submaximally stimulated by multiple subcutaneous injections of histamine acid phosphate given every hour for four consecutive hours. When a steady-state plateau of gastric secretion was reached, the PG's were administered as a single bolus dose either intravenously (i.v.) or intragastrically (i.g.). Both PG's inhibited histamine-stimulated gastric secretion. The PG's showed greater sensitivity in inhibiting acid concentration while not affecting volume output. Active i.v. and i.g. antisecretory doses of ME-PGE2 ranged from 3 to 10 mug/kg, while PGE2 showed significant antisecretory activity at i.v. bolus doses of 30-100 mug/kg and i.g. bolus dose of 1.0 mg/kg. Thus, Me-PGE2 is estimated to be at least 10 and 300 times more potent than PGE2 by the i.v. and i.g. administration routes, respectively. These findings indicate that the rhesus monkey shows some similarities to man in responsiveness to gastric secretory inhibition by E-prostaglandins.