Subject(s)
Gastric Mucosa/blood supply , Gastrins/blood , Prostaglandins E, Synthetic/pharmacology , Aminopyrine/metabolism , Animals , Dogs , Female , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Histamine/pharmacology , Prostaglandins E/pharmacology , Regional Blood Flow/drug effects , Time FactorsABSTRACT
The gastric antisecretory efficacy of propantheline bromide (PB) as a function of the route of administration was studied in dogs equipped with chronic gastric fistulae. Sectetion was near-maximally stimulated by continuous intravenous (i.v.) infusion of pentagastrin. PB was administered either intragastrically (i.g.) or intravenously as a single bolus dose at the steady-state plateau of gastric secretion. The administration of PB produced a dose-dependent inhibition of gastric secretion (water and acid output). Gastric acid concentration was not appreciably inhibited by PB. The dose-response (inhibition of acid output) curves for i.g. and i.v. administered PB were parallel. The potency (fiducial limits) of i.v. relative to i.g. administration was found to be 0.002 (0,0006--0,0051) when the i.v. value was taken as unity.
Subject(s)
Gastric Juice/metabolism , Pentagastrin/antagonists & inhibitors , Propantheline/pharmacology , Administration, Oral , Animals , Dogs , Female , Injections, Intravenous , Propantheline/administration & dosage , Stimulation, Chemical , Time FactorsABSTRACT
The compound 7-OPyA has been reported to antagonize smooth muscle stimulatory effects of some prostaglandins (PG's) in vitro. The in vivo PG antagonist activity of 7-OPyA has not been adequately diarrhea in mice. We studied the effects of this compound on PGE1. Secretion was stimulated by continuous intravenous infusion of histamine. At the steady-state plateau of gastric secretion, PGE1 methyl ester (PGE1 ME) or PGE1 ME and 7-OPyA were simultaneously infused intravenously. The extent of gastric secretory inhibition afforded by PGE1 ME alone or in the presence of 7-OPyA was assessed. 7-OPyA did not modify PGE1 ME gastric antisecretory actions when administered at doses 20-50 times greater than the dose of PGE1 ME. These results suggest that the prostaglandin antagonist effects of 7-OPyA show organ specificity, which may be of clinical importance.
Subject(s)
Fatty Acids, Unsaturated/pharmacology , Gastric Juice/metabolism , Prostaglandins E/pharmacology , Animals , Chemical Phenomena , Chemistry , Dogs , Fatty Acids, Unsaturated/administration & dosage , Female , Muscle, Smooth/drug effects , Prostaglandin Antagonists/pharmacology , Secretory Rate/drug effects , Time FactorsABSTRACT
The preparation and gastric antisecretory activity of a series of 15-deoxy-16-hydroxyprostaglandin analogues are described. The compounds were tested intravenously in histamine-stimulated Heidenhain pouch dogs in relation to the reference standards PGE1 and PGE1 methyl ester (PGE1ME). The parent compound of this seris, (+/-)-15-deoxy-16alpha,beta-hydroxyprostaglandin E1 methyl ester (3), was found to be equipotent to the reference standard PGE1ME. Methylation at C-16 of 3 produced 8 which was found to be some 40 times more potent than PGE1. In sharp contrast, addition of two methyl groups to 3 at C15 or C17 markedly reduced the antisecretory action. The 16-ethyl analogue of 3 also showed reduced potency. Removal or epimerization of the C-11 hydroxy group of 8 reduced the activity. Likewise, hydrogenation or changing the stereochemistry of the 13,14 double bond from trans to cis decreased the activity. On the other hand, omega-homologation of 8 or the introduction of a cis-5,6 double bond did not affect the potency. From these studies, it appears that 8, 16, and 17 possess optimum gastric antisecretory effects in this series.
Subject(s)
Prostaglandins E, Synthetic/chemical synthesis , Animals , Dogs , Female , Gastric Juice/metabolism , Gastric Mucosa/drug effects , Prostaglandins E, Synthetic/pharmacology , Structure-Activity RelationshipABSTRACT
The gastric antisecretory effects of SC-29333, a novel prostglandin E1 analogs, were compared to the reference standard PGE1 methyl ester (PGE1ME) in gsstric fistula and Heidenhain pouch dogs. Secretion was stimulated submaximally by continuous intravenous infusion of either histamine or pentagastrin. Meal-stimulated gastric secretory studies were also conducted. SC-29333 effectively inhibited volume, acid output, and papsin secretion, in a dose-dependent manner. Intravenously (i.v.), SC-29333 was found to be approximately 30 times more potent than PGE1ME. The ranges of active i.v. bolus doses for SC-29333 and PGE1ME were 0.3-3.0 and 10-30 mug/kg, respectively. Unlike PGE1ME, SC-29333 was orally effective at doses of 10-30 mug/kg and was considerably better tolerated and longer acting than PGE1ME at active antisecretory doses. It is concluded, therefore, that SC-29333 is a potent, long-acting, orally effective inhibitor of gastric secretion in the dog.
Subject(s)
Gastric Juice/drug effects , Animals , Dogs , Female , Gastric Fistula , Gastric Juice/metabolism , Histamine/administration & dosage , Injections, Intravenous , Pentagastrin/administration & dosage , Pepsin A/metabolism , Prostaglandins E/pharmacology , Prostaglandins, Synthetic/metabolism , Prostaglandins, Synthetic/pharmacologyABSTRACT
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.
Subject(s)
Gastric Juice/drug effects , Prostaglandins E/pharmacology , Stomach/drug effects , Animals , Female , Gastric Fistula , Gastric Juice/metabolism , Haplorhini , Histamine/administration & dosage , Histamine/metabolism , Macaca mulatta , Pentagastrin/administration & dosage , Pentagastrin/metabolism , Prostaglandins E/administration & dosage , Prostaglandins E/metabolism , Time FactorsABSTRACT
The influence of transposing the C-15 hydroxy group of prostaglandin E1 methyl ester (PGE2ME) on gastric antisecretory and antiulcer actions was investigated. The compound (+/-)15-deoxy- 16alpha, beta-hydroxy PGE1ME (SC-28904) was equipotent to the reference standard PGE1ME in suppressing histamine-stimulated gastric secretion in the Heidenhain pouch (HP) dog. In contrast to PGE1ME, SC-28904 was longer acting when administered intravenously and also showed significant oral activity in the histamine-stimulated gastric fistula dog. SC-28904 was also equipotent to PGE1ME (range of active doses of 0.5 to 5.0 mg/kg, s.c.) in inhibiting forced-exertion gastric ulceration in rats. The compound (+/-)15-deocy-17alpha, beta-hydroxy PGE1ME (SC-30963) was an inactive antisecretory agent in the dog at the 1.0 mg/kg i.v. bolus dose. This dose was 100 times greater than the active antisecretory dose of PGE1ME. Likewise, SC-30693, when administered subcutaneously at a 5.0 mg/kg dose, was also totally inactive in preventing gastric ulcers induced by forced exertion in rats. The important implications of this work are that some of the receptor sites for the PGE1 molecule could easily accomodate the side chain hydroxy group either in the C-15 or C-16 position. Moreover, the hydroxy group in the latter position significantly improved the biological activity of PGE1ME.
Subject(s)
Gastric Juice/metabolism , Prostaglandins E/pharmacology , Stomach Ulcer/prevention & control , Animals , Depression, Chemical , Dogs , Dose-Response Relationship, Drug , Female , Histamine/pharmacology , Injections, Intravenous , Injections, Subcutaneous , Male , Prostaglandins E/administration & dosage , Rats , Secretory Rate/drug effects , Stomach/physiology , Structure-Activity RelationshipABSTRACT
The influence of methyl esterification of the carboxyl group of PGE1 on the gastric antisecretory and antiulcer activities were studied. The gastric antisecretory effects of PGE1 free acid and PGE1 methyl ester (PGE1ME) were studied in the Heidenhain pouch dog. Secretion was stimulated with constant intravenous infusion of histamine dihydrochloride. When a steady-state plateau of gastric secretion had been reached, the prostaglandins were administered either by a single intravenous bolus (10.0 mug/kg) or by continuous infusion (1.0 mug/kg/min). PGE1ME was found to be slightly more potent and longer-acting than PFE1 when administered by a single i.v. bolus. PGE1ME was also shown to be more potent than PGE1 when infused intravenously for a two-hour period. PGE1ME caused a significant alteration in gastric juice concentration of hydrogen and sodium ions in an inverse relationship. Potassium and chloride concentration were not altered from pre-existing steady-state values following administration of either form of prostaglandin. Similarly, PGE1ME was also found to possess significantly greater antiulcer activity in the rat forced-exertion ulcer test. These findings support the hypothesis that methyl esterification of the prostaglandin molecule will increase some of the biological actions of PGE1 through inhibition of metabolic beta-oxidation of the carboxylic side chain.
