16-16-dimethylprostaglandin-e2 and Duodenal-Ulcer

Oral 16,16-dimethyl prostaglandin E2 is a potent inhibitor of meal-stimulated gastric acid secretion and gastrin release in humans. Experiments were performed in 5 patients with inactive duodenal ulcer to determine the effect of graded doses of intravenous 16,16-dimethyl PGE2 on meal-stimulated gastric acid secretion and gastrin release to demonstrate whether it is necessary for 16-16-dimethyl PGE2 to come into direct luminal contact with the oxyntic and antral gland portions of the stomach to produce its inhibitory effects. All doses of 16,16-dimethyl PGE2, between 0.01 and 0.1 microgram/kg i.v. and between 0.01 and 1.0 microgram/kg orally produced significant postprandial inhibitory effects on both gastric acid secretion and gastrin release as compared with saline control. 0.1 microgram/kg of intravenous of 1 microgram/kg of oral 16,16-dimethyl PGE2 inhibited meal-stimulated acid secretion and gastrin by 80-90%. In 6 unoperated Zollinger-Ellison syndrome patients, 1 microgram/kg of oral 16,16-dimethyl PGE2 significantly inhibited fasting gastric acid hypersecretion by approximately 85% without significantly altering serum gastrin. Each of the oral doses of 16,16-dimethyl PGE2 (0.01-1 microgram/kg) were without untoward effect, as were intravenous doses of 0.01-01 microgram/kg. Maximal inhibition of acid secretion was found with 0.1 microgram/kg 16,16-dimethyl PGE2 i.v. as compared with 1.0 microgram/kg orally. Since 16,16-dimethyl PGE2, whether given orally or intravenously, is a potent inhibitor of both gastric acid secretion and meal-stimulated gastrin release, without apparent untoward side effects, clinical trials with 16,16-dimethyl PGE2 are indicated in patients with acid peptic disease.

Topics: 16,16-Dimethylprostaglandin E2; Administration, Oral; Adult; Aged; Duodenal Ulcer; Food; Gastric Juice; Gastrins; Humans; Injections, Intravenous; Male; Middle Aged; Prostaglandins E, Synthetic; Zollinger-Ellison Syndrome

Enteroscopic observation has clearly demonstrated that non-steroidal anti-inflammatory drugs/low-dose aspirin (usually enteric-coated) induces hemorrhagic lesions, including ulcers and bleeding, in the small intestine of patients at a high incidence. Such intestinal lesions induced by NSAIDs have been confirmed in animal experiments. With aspirin, however, it has long been believed that it is difficult to induce any damage in the intestinal mucosa of laboratory animals. Therefore, we established a new method of inducing intestinal hemorrhagic lesions in rats by injecting aspirin into the proximal duodenum.. Under ether anesthesia, aspirin (50-200 mg/body), suspended in 2% methylcellulose (with or without 0.1 N HCl), was injected into the proximal duodenum of normally fed or 20-h non-fed rats (male Sprague-Dawley, 9 weeks old). At 1 h after treatment, the animals were killed with ether and the entire small intestine was removed for histological examination. In some experiments, 1% Evans blue was injected (i.v.) into the rats 1 h after aspirin treatment to visualize the lesions. An image analyzer determined the total area of the intestinal lesions. Oral proton pump inhibitors and histamine H(2)-receptor blockers were given 1 h before aspirin injection. 16,16-dimethyl prostaglandin E(2) (dmPGE(2)) was given s.c. 30 min before aspirin injection.. Aspirin alone clearly induced severe lesions (including bleeding and ulcers) mainly in the jejunum at 100% incidence. Total score of lesions per rat obtained by histological examination was similar to the damaged area quantified with the dye method. Dose-related induction of lesions by aspirin was confirmed both by the histological and dye methods. The irritable effect of aspirin suspended in 0.1 N HCl solution was the same as that of aspirin alone; 0.1 N HCl alone induced only minor lesions in the intestine. Both proton pump inhibitors and histamine H(2)-receptor blockers, at doses that inhibit gastric acid secretion, had no or little effect on aspirin-induced intestinal lesions. Pretreatment with dmPGE(2) (3, 10, 30 microg/kg) showed significant prevention of both aspirin- and HCl/aspirin-induced intestinal lesions.. This new aspirin lesion model will be useful for screening defensive drugs against aspirin-induced intestinal lesions and to elucidate the underlying mechanism.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Aspirin; Disease Models, Animal; Dose-Response Relationship, Drug; Duodenal Ulcer; Duodenum; Histamine H2 Antagonists; Injections; Intestinal Mucosa; Jejunum; Male; Microscopy, Electron, Scanning; Peptic Ulcer Hemorrhage; Proton Pump Inhibitors; Rats; Rats, Sprague-Dawley

We examined the prophylactic effect of lafutidine, a novel histamine H(2)-receptor antagonist [(+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyr idyl]oxy- (Z)-2 butenyl]acetamide], on indomethacin-induced small intestinal ulcers in rats and investigated the relation of this action to capsaicin-sensitive sensory neurons.. Subcutaneously administered indomethacin (10 mg/kg) provoked ulceration in the small intestine, mainly the jejunum and ileum, accompanied by increases in myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities as well as the enterobacterial numbers invading the mucosa. Intestinal ulcerogenic response to indomethacin was prevented by 16,16-dimethyl prostaglandin E(2) (10 microg/kg, p.o.) and capsaicin (10 mg/kg, p.o. ) as well as ampicillin (800 mg/kg, p.o.), but not omeprazole (100 mg/kg, p.o.). Likewise, lafutidine (1-10 mg/kg, p.o.), but not cimetidine (100 mg/kg, p.o.), reduced the occurrence of intestinal ulcers in response to indomethacin in a dose-dependent manner, and a significant effect was observed at 3 mg/kg or greater. The protective action of lafutidine as well as capsaicin was almost totally abolished by chemical ablation of capsaicin-sensitive sensory neurons. Both lafutidine and capsaicin significantly suppressed the increases in MPO and iNOS activities as well as enterobacterial numbers in the mucosa. These agents also significantly enhanced mucus secretion in the small intestine.. These results suggest that lafutidine protects the small intestine against ulceration via stimulation of capsaicin-sensitive sensory neurons. This action may be attributable to inhibition of enterobacterial invasion in the intestinal mucosa, probably by increasing the mucus secretion.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ampicillin; Animals; Capsaicin; Dose-Response Relationship, Drug; Duodenal Ulcer; Histamine H2 Antagonists; Indomethacin; Intestinal Mucosa; Male; Neurons, Afferent; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley

Repeated administration of diethyldithiocarbamate (DDC: 750 mg/kg, s.c.), a superoxide dismutase (SOD) inhibitor, to fed rats induced ulcers in the duodenum with less lesion in the stomach. DDC not only reduced basal acid output but also impaired duodenal alkaline secretion under both basal and acid-stimulated conditions. The duodenal ulcers induced by DDC were significantly prevented by either allopurinol, SOD or dmPGE2 at the doses which significantly reversed the inhibited alkaline responses caused by DDC. The pathogenesis of DDC-induced duodenal ulcers may involve impairment of duodenal alkaline secretion, probably caused by insufficiency of antioxidant machinery in the mucosa.

Topics: 16,16-Dimethylprostaglandin E2; Alkalies; Allopurinol; Animals; Ditiocarb; Dose-Response Relationship, Drug; Duodenal Ulcer; Duodenum; Male; Rats; Rats, Inbred Strains; Superoxide Dismutase

Topics: 16,16-Dimethylprostaglandin E2; Animals; Carbachol; Dinoprostone; Duodenal Ulcer; Female; Gastric Juice; Indomethacin; Pentagastrin; Prostaglandins; Prostaglandins E; Rats

A method for measurement of human basal and stimulated gastric bicarbonate secretion was developed in the present investigation. The mechanisms involved in the regulation of basal, vagus nerve stimulated as well as fundic distension induced bicarbonate secretion were studied. The investigations were performed in healthy subjects and duodenal ulcer patients, the latter group before and/or after a proximal gastric vagotomy operation. Healthy subjects as well as ulcer patients were premedicated with a histamine H2-receptor antagonist and gastric bicarbonate secretion was determined by use of a gastric perfusion system in combination with computerized continuous recordings of pH and PCO2. The contribution of alkaline saliva to the measured gastric bicarbonate secretion was minimized by continuous salivary suction and correction was made for swallowed saliva by measurement of amylase in the gastric aspirate. A high rate of gastric perfusion facilitated the identification of alkaline duodenogastric reflux and also eliminated its influence on the measurement of gastric bicarbonate secretion. Validation of the measuring system by instillation of small amounts of bicarbonate showed a satisfactory correlation between added and recovered bicarbonate in the range of bicarbonate determinations usually recorded. Decreasing intragastric pH to between 3 and 4 converted all secreted bicarbonate into CO2, but did not affect the measured value of bicarbonate secretion. Vagal stimulation accomplished by sham feeding increased gastric bicarbonate secretion in sixteen healthy subjects from 410 +/- 39 mumol/h to 692 +/- 67 mumol/h (mean +/- SEM, p less than 0.001). This response was independent of intragastric pH in the range of 2 to 7. The muscarinic receptor antagonist, benzilonium bromide, almost abolished the sham feeding response while indomethacin left it nearly unchanged. Nine duodenal ulcer patients had identical basal and vagally stimulated bicarbonate output as healthy subjects. Two months after proximal gastric vagotomy, the basal bicarbonate secretion was significantly increased, whereas the output in response to sham feeding was unaltered. In the early postoperative period, anticholinergics reduced the enhanced basal bicarbonate secretion to a preoperative level. In six healthy subjects, graded fundic distension with a balloon to volumes of 150 ml, 300 ml and 600 ml, each distension period lasting 60 minutes, increased the bicarbonate secretion by 46% (p less than

Topics: 16,16-Dimethylprostaglandin E2; Adult; Bicarbonates; Carbachol; Duodenal Ulcer; Female; Gastric Juice; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Partial Pressure; Vagus Nerve

The purpose of these studies was to determine the role played by endogenous prostaglandins in the development of gastric ulcers produced by indomethacin, and of duodenal ulcers produced by mepirizole in rats. Indomethacin (10 mg/kg subcutaneously) produced gastric ulcers, whereas mepirizole (100 mg/kg subcutaneously) produced exclusively duodenal ulcers. Both drugs, given at ulcerogenic doses, reduced the gastric and duodenal generation of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2. In this regard, the extent of reduction was more pronounced after indomethacin than after mepirizole. Despite this greater inhibition of prostaglandin synthesis by indomethacin, this drug did not produce duodenal ulcers, whereas mepirizole was duodenoulcerogenic. In addition, mepirizole increased gastric acid secretion by 74%, whereas indomethacin had no effect on acid secretion. Oral administration of 16,16-dimethyl PGE2, given at nonantisecretory doses (0.5-5 micrograms/kg), prevented formation of indomethacin-induced gastric ulcers, whereas antisecretory doses were required to prevent formation of mepirizole-induced duodenal ulcers. We conclude that a reduction of prostaglandin formation in the duodenal mucosa is not by itself sufficient to induce duodenal ulcers. We hypothesize that three changes, produced by mepirizole, must be present for duodenal ulcers to develop: increased gastric acid secretion, decreased duodenal bicarbonate secretion (as demonstrated earlier), and decreased duodenal content of prostaglandins. The decreased prostaglandin formation, although not causing duodenal ulcers, may lower the resistance of duodenal mucosa to the hyperacidity induced by mepirizole. On the other hand, in the case of gastric ulcers following administration of indomethacin, a decrease in gastric mucosal levels of prostaglandins may play a more important role than changes in gastric acidity.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Dose-Response Relationship, Drug; Drug Interactions; Duodenal Ulcer; Duodenum; Epirizole; Female; Gastric Mucosa; Indomethacin; Intestinal Mucosa; Prostaglandins; Pyrazoles; Rats; Rats, Inbred Strains; Stomach Ulcer; Time Factors

The possible role of local motility in the pathogenesis of duodenal ulcers was investigated in rats using cysteamine. Duodenal motor activity was measured as intraluminal pressure recordings by means of a balloon positioned in the proximal duodenum. Subcutaneous administration of cysteamine (100 mg/kg) produced two linear bandlike lesions in the proximal duodenum within 6 hr. This dose of cysteamine significantly increased gastric acid secretion in acute fistula rats, and decreased duodenal HCO3- secretion caused by acid. During this period, this agent inhibited gastric motility but did produce markedly enhanced contractions in the duodenum. The changes in duodenal motility appeared within 5-10 min and were dose-dependent for cysteamine (10-100 mg/kg). Pretreatment with subcutaneously administered atropine (10 mg/kg), 16,16-dmPGE2 (30 micrograms/kg) or dopamine (10 or 30 mg/kg) significantly reduced the development of duodenal lesions caused by cysteamine, the inhibition being 86.8%, 49.7%, 54.5% or 67.8%, respectively. In the presence of cysteamine, dopamine had minimal effect on both acid and HCO3- secretion, while atropine or 16,16-dmPGE2 markedly inhibited acid secretion or increased HCO3- secretion, respectively. The enhanced duodenal motility induced by cysteamine was blocked partially by atropine and only slightly by 16,16-dmPGE2. Dopamine showed a dose-dependent inhibition on the duodenal hypermotility following cysteamine, and at 30 mg/kg almost completely abolished the development of contractions. These results suggest that abnormal hypermotility in the duodenum may be partly involved in the pathogenesis of cysteamine-induced duodenal ulcers.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Atropine; Cysteamine; Dopamine; Dose-Response Relationship, Drug; Duodenal Ulcer; Duodenum; Gastric Acidity Determination; Gastrointestinal Motility; Intestinal Secretions; Male; Rats; Rats, Inbred Strains; Time Factors

We studied the effects of elcatonin (eel calcitonin), on various gastric and duodenal lesions, gastric acid and duodenal alkaline secretion, and gastric motility in rats. Elcatonin at 1-30 unit/kg, given subcutaneously, dose-dependently inhibited the development of HCl-aspirin-, HCl-ethanol-, water-immersion stress- and indomethacin-induced gastric lesions. This agent also significantly prevented the formation of duodenal lesions induced by indomethacin plus histamine at 30 unit/kg, although it showed only a tendency of inhibition against mepirizole-induced duodenal lesions. 16, 16-Dimethyl prostaglandin E2 (3-30 micrograms/kg), given orally as a reference drug, showed a potent inhibition against all types of lesions tested herein at the dose of 3 micrograms/kg or greater. Elcatonin dose-dependently inhibited gastric secretion (volume, acid and pepsin output) in pylorus-ligated rats and gastric motility in conscious rats, but had no effect on duodenal alkaline secretion in anesthetized rats. On the other hand, 16, 16-dimethyl prostaglandin E2 at 10 micrograms/kg, given intraduodenally, significantly inhibited gastric secretion and motility, but stimulated duodenal alkaline secretion. We conclude that elcatonin markedly protects the gastrointestinal mucosa from injury induced by stress or various irritants. These effects might be in part accounted for by the antisecretory and antimotility activities of this peptide, although some other unknown mechanisms may be involved in the mucosal protection afforded by elcatonin.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Calcitonin; Duodenal Ulcer; Gastric Mucosa; Gastrointestinal Motility; Intestinal Mucosa; Male; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological

Mefenamic acid, given orally to rats at a single dose of 1200 mg/kg, produced renal papillary necrosis (RPN) in 63% of animals. The incidence was reduced to 27% by 16,16-dimethyl PGE2 (dmPGE2), given at an oral dose of 0.75 mg/kg t.i.d. RPN is likely to be caused by the renal prostaglandin depletion elicited by mefenamic acid, an inhibitor of prostaglandin cyclooxygenase. Substitution with dmPGE2 reduces RPN presumably by preventing the prostaglandin depletion. We conclude that the prostaglandin used is cytoprotective for the kidney. Mefenamic acid, like most nonsteroidal anti-inflammatory compounds (NOSAC), produced ulcerations of the small intestine (jejunum and ileum). These were prevented by dmPGE2 (intestinal cytoprotection). Unlike most other NOSAC, however, mefenamic acid produced duodenal ulcers in nearly all animals (80%). Of these ulcers, 88% were perforated. Twenty-five of the twenty-six animals that died had a perforated ulcer. These duodenal ulcers were also prevented by dmPGE2. Mefenamic acid-induced ulcers could be used as an experimental model for testing agents with a potential for preventing or healing duodenal ulcers.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Duodenal Ulcer; Female; Intestinal Diseases; Kidney Papillary Necrosis; Mefenamic Acid; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer

Mepirizole (60 and 200 mg/kg) administered s.c. induced damage in the surface epithelial cells of the rat proximal duodenum as early as 2 hr after the treatment. 16,16-Dimethyl prostaglandin E2 (dmPGE2, 30 micrograms/kg) administered s.c. significantly protected the duodenal mucosa against mepirizole-induced damage for up to 6 hr. Gastric acid secretion in acute fistula preparations was significantly reduced 1 hr after administration of mepirizole (60 and 200 mg/kg). The secretion reverted to the control level 2 hr later. In the 60 mg/kg-treated group, however, there was a significant increase in the acid output for up to 6 hr. Duodenal HCO3- secretion, stimulated with 10 mM HCl was significantly inhibited with mepirizole (60 and 200 mg/kg). Mepirizole (60 and 200 mg/kg) significantly increased the amount of acid in the duodenum for 2 to 6 hr after the treatment. dmPGE2 (30 micrograms/kg) significantly inhibited gastric acid secretion, stimulated duodenal HCO3- secretion, and reduced the increased amount of acid in the duodenum in response to mepirizole. Endogenous prostaglandin E2 and 6-keto prostaglandin F1 alpha in the duodenal mucosa were significantly reduced by mepirizole (200 mg/kg) 1 to 2 hr later. Mepirizole-induced duodenal damage appears to be caused by the increased amount of acid in the duodenum.

Topics: 16,16-Dimethylprostaglandin E2; 6-Ketoprostaglandin F1 alpha; Animals; Bicarbonates; Duodenal Ulcer; Epirizole; Gastric Juice; Intestinal Mucosa; Male; Prostaglandins; Pyrazoles; Rats; Rats, Inbred Strains

We standardized a new method for producing duodenal ulcers in rats by administering indomethacin plus histamine, and investigated the pathogenesis. Indomethacin (5 mg/kg) was first given subcutaneously to rats fasted for 24 h, and subsequently histamine dihydrochloride (40 mg/kg) was given subcutaneously three times, at 2.5-h intervals, beginning 30 min after injection of indomethacin. This combined treatment induced one or two round lesions (9.8 +/- 1.4 mm2) in the proximal duodenum at an incidence of 100%, and a few lesions in the corpus and antrum of the stomach as well. Indomethacin or histamine alone had no effect on either the duodenum or the stomach. The lesions in the duodenum and antrum were inhibited by oral cimetidine (3-100 mg/kg) and 16,16-dimethyl prostaglandin E2 (dmPGE2) (3-30 micrograms/kg) in a dose-related manner, whereas those in the corpus were inhibited only by cimetidine. Indomethacin alone had no effect on gastric acid secretion, but did potentiate the increase of acid secretion caused by histamine. Histamine did not affect duodenal HCO3-secretion, whereas indomethacin slightly inhibited the basal HCO3-secretion and completely blocked the acid-stimulated HCO3-secretion. Intraduodenally administered cimetidine (30 mg/kg) or dmPGE2 (30 micrograms/kg) significantly inhibited acid secretion or increased HCO3-secretion, respectively, and both reduced the amount of acid emptied into the duodenum after treatment with indomethacin plus histamine. These results indicate that the development of duodenal lesions induced by indomethacin plus histamine in rats is due to both an increase in gastric acid secretion and an impairment of acid-induced duodenal HCO3-secretion. This newly established model will be useful for studying the pathogenesis of duodenal ulcers and for screening antiulcer agents.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Bicarbonates; Cimetidine; Dose-Response Relationship, Drug; Duodenal Ulcer; Duodenum; Gastric Acid; Histamine; Indomethacin; Male; Rats; Time Factors

The mechanisms by which the potent antiinflammatory agent, mepirizole, causes duodenal ulceration were investigated in the rat. After subcutaneous administration of 200 mg/kg of mepirizole, basal gastric acid secretion remained unchanged for 5 h but duodenal alkaline output, reliably measured, decreased significantly (p less than 0.05) within 2 h. The decrease was maximal (-45%) at 3 h and persisted for a total of 6 h. The duodenal alkaline secretion returned to near normal by 24 h. A dose-response study showed that the threshold ulcerogenic dose of mepirizole (30 mg/kg) did not significantly reduce alkaline secretion, whereas higher doses did. Plasma levels of immunoreactivity of gastrin, pancreatic polypeptide, vasoactive intestinal polypeptide, and secretin were not changed at either 6 or 24 h after oral mepirizole. Vasoactive intestinal peptide levels in the duodenal mucosa were increased by 158% at 24 h after administration. Secretin levels in the duodenal mucosa were decreased by greater than 60% at both 6 and 24 h after drug treatment. Intravenous secretin (1 CU/kg X h) had no effect on duodenal alkaline secretion in either saline- (154 mM NaCl) or mepirizole-treated animals. Exogenous 16,16-dimethyl prostaglandin E2 (10 micrograms/kg X h, i.v.) reversed the action of mepirizole on duodenal alkaline secretion. These findings suggest that mepirizole causes a reduction in duodenal alkaline secretion that can be reversed by administration of an exogenous prostaglandin.

Topics: 16,16-Dimethylprostaglandin E2; Alkalies; Animals; Dose-Response Relationship, Drug; Duodenal Ulcer; Duodenum; Epirizole; Gastric Acid; Gastrins; Injections, Subcutaneous; Male; Pyrazoles; Radioimmunoassay; Rats; Rats, Inbred Strains; Secretin; Time Factors; Vasoactive Intestinal Peptide