16-16-dimethylprostaglandin-e2 and Constipation

M&B 28,767 [(+/-)11-deoxy-16-phenoxy-omega-tetranor PGE1] and 16, 16'-dimethyl PGE2 methylester (DMPG) were compared for their effects on gastric acid secretion (GAS) and gastric ulceration (GU), employing various laboratory models. In anaesthetised rats, GAS was stimulated by a continuous i.v. infusion of pentagastrin (30 micrograms/kg/h), and PG analogues were perfused through the stomach for 1 h. M&B 28,767 (3-15 micrograms/kg/h) and DMPG (3-60 micrograms/kg/h) reduced GAS in a dose-related manner, the ED50 values being 4 and 15 micrograms/kg/h respectively. In conscious rats possessing indwelling gastric cannulae, oral doses of M&B 28,767 (0.025-0.1 microgram/kg) and DMPG (0.50-1.0 microgram/kg) caused a prolonged inhibition of pentagastrin-stimulated GAS. M&B 28,767 was 17 times more potent than DMPG; the respective ED50 values were 0.036 and 0.6 microgram/kg. Indomethacin-induced ulceration in rats, was reduced by both M&B 28,767 and DMPG; the respective ED50 values being 3.0 and 0.8 micrograms/kg. Both compounds given orally increased gastrointestinal motility in mice; M&B 28,767 (1-3 mg/kg) and DMPG (0.1-0.3 mg/kg) caused diarrhoea, the former being about 0.1 times as potent as the latter. In another test, M&B 28,767 (0.5-5.0 mg/kg) and DMPG (10-40 micrograms/kg) overcame morphine-induced constipation in a dose-related manner, the respective ED50s being 0.9-1.4 mg/kg and 20-40 micrograms/kg. Thus, M&B 28,767 had a better profile of activity than DMPG as an antisecretory and antiulcer agent.

Topics: 16,16-Dimethylprostaglandin E2; Alprostadil; Animals; Constipation; Diarrhea; Gastric Acid; Gastrointestinal Motility; Indomethacin; Male; Mice; Morphine; Pentagastrin; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer

The prostaglandins E2 and 16,16-dimethyl-PGE2 methyl ester were compared with the H2-receptor antagonists burimamide and metiamide for their effects on gastric acid secretion (GAS) and gastric mucosal blood flow (MBF) in rats and dogs, and on ulcer formation in rats. Orally, both 16,16-dimethyl-PGE2 methyl ester (20 microgram/kg) and metiamide (6 mg/kg) were markedly effective inhibitors of GAS stimulated by histamine acid phosphate or pentagastrin in Heidenhain pouch dogs, producing a reduction both in volume of gastric juice and in the concentration of titratable acid. In anaesthetised rats, however, the H2-receptor antagonists, when perfused into the gastric lumen, did not consistently inhibit the increased GAS caused by various secretagogues. In contrast, the prostaglandins, under the same conditions, caused marked inhibition of GAS provoked by all secretagogues. Intravenously, both burimamide and metiamide were effective in inhibiting GAS in rats but were less potent than the prostaglandins. The order of potency was: 16,16-dimethyl-PGE2 methyl ester greater than PGE2 greater than metiamide greater than burimamide. By the oral route, the H2-receptor antagonists were found to be very weak inhibitors of indometacin-induced gastric ulcer in rats, as compared to the prostaglandins. MBF studies in rats and in Heidenhain dogs showed that i.v. or p.o. administration inhibited both GAS and MBF in most cases. The ratio r = [MBF (ml/min)/GAS (mumol H+/min)] was generally increased by both types of compounds, suggesting a preferential effect on GAS.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Constipation; Dogs; Female; Gastric Mucosa; Gastrointestinal Motility; Histamine H2 Antagonists; Indomethacin; Male; Mice; Morphine; Prostaglandins E; Prostaglandins E, Synthetic; Rats; Regional Blood Flow; Stomach Ulcer