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Enprostil is a synthetic prostaglandin E2 analogue with gastric antisecretory and mucosal protective properties. We compared the effects of enprostil and ranitidine on the healing of gastric ulcers and the subsequent relapse rates over 6 months. Patients (N = 156) were recruited for a double-blind study from 12 centers in Europe; 71 were randomly assigned to oral treatment with 35 micrograms enprostil twice daily and 85 to 150 mg ranitidine twice daily for up to 8 weeks. Both groups were of similar demography; their healing rates were also similar. Cumulative intent-to-treat healing rates were at 4 weeks enprostil 48%, ranitidine 41%: at 6 weeks enprostil 65%, ranitidine 68%; and at 8 weeks enprostil 72%, ranitidine 80%. Of those patients who met all protocol criteria and completed treatment, and were endoscoped at the prescribed times, healing rates were at 4 weeks enprostil 55%, ranitidine 54%, at 6 weeks enprostil 75%, ranitidine 84%; and at 8 weeks enprostil 80%, ranitidine 90%. Relief of pain was rapid and similar in both groups. The incidence of adverse events was low and similar in the two groups. The treatment-free relapse rate at 6 months was enprostil 64%, ranitidine 49%; the median times to relapse were 169 and 203 days, respectively. Enprostil and ranitidine appear to be equally effective in healing gastric ulcers.

Gastric ulcers in children are often seen as a result of an imbalance between nocive factors and the resistance of the mucosa. Glanzmann's thromboastenia is a defect in platelet aggregation and its nature may be associated to local factors which precipitate or perpetuate bleeding. Prostaglandins are hormones of local action which inhibit the secretion of acid and therefore protect the mucosa. We report a case of an 18 year old male youngster with Glanzmann's thromboastenia and a gastric ulcer previously unsuccessfully treated with cimetidine, aluminum hydroxide solution, ranitidine, sucralfate and later controlled with PGE2. In sum, the usefulness of the cytoprotecting effects of the prostaglandins are successfully evaluated in a young man with platelet aggregation abnormalities.

In a double-blind, multicentre study 77 patients with benign gastric ulcer were randomly allocated to treatment with either enprostil 35 micrograms bd or pirenzepine 50 mg bd. After four weeks of treatment 13/26 (50 per cent) of evaluable enprostil-treated patients and 9/30 (30 per cent) of evaluable pirenzepine-treated patients were healed. Corresponding healing figures after eight weeks were 20/25 (80 per cent) and 25/31 (81 per cent). Both drugs rapidly reduced the severity of ulcer pain and the need for antacid use. No statistically significant differences were detected between the treatments with respect to healing rate or symptom control. Adverse events were reported by eight patients taking enprostil and by 17 patients taking pirenzepine. Two patients withdrew from each treatment group because of adverse events. None of these was serious. In conclusion, enprostil and pirenzepine were equally effective in healing gastric ulcers and no statistically significant differences in safety and efficacy were detected. There was a tendency for earlier healing and fewer side effects in the enprostil-treated patients.

The effect of 15(R)-15 methyl PGE2 on the evolution of gastric ulcers induced by endoscopic Nd:YAG laser photocoagulation was studied. By continuous application of 50 to 70 watt power for 4 sec at a distance of 15 mm from the gastric mucosa, reproducible ulcers can be induced. The effect of the drug in nonantisecretory doses (10 micrograms/kg) on the acute ulcer formation and on the healing rate was evaluated in mongrel dogs by light microscopy. Local administration or oral pretreatment did not influence the size or depth of acute ulcers (7.4 mm in diameter) as compared to a control series (7.2 mm). Pretreatment for several days, however, had a marked beneficial effect on the healing rate of the ulcers (1.71 mm after 7 days compared to 2.76 mm for the control series). From these data it may be concluded that 15(R)-15 methyl PGE2 has a beneficial effect on ulcer healing, even in nonantisecretory doses.

Prostanoids decrease gastric acid secretion and exert cytoprotective properties. The effect of several synthetic prostanoids on gastric ulcer healing was evaluated. The first trials were performed on a small number of patients with PGE2 analogs and their results were inconclusive. Two huge multicenter trials tested the efficacy of misoprostol, a synthetic PGE1 analog, in comparison to placebo and cimetidine. In the placebo-controlled trial, following 8 weeks of therapy, misoprostol 100 micrograms q.i.d was significantly better than placebo. In the cimetidine controlled trial, 2 doses of misoprostol were tested, 50 micrograms and 200 micrograms q.i.d. Ulcer healing rates following 4 weeks were 39%, 51%, and 58% in the misoprostol 50 micrograms, 200 micrograms, and cimetidine treatment groups, respectively. There was no statistically significant difference in the healing rates at 4 weeks between the misoprostol 200 micrograms and cimetidine 300 mg q.i.d groups (P = 0.16). The healing rate with the misoprostol 200 micrograms dose was significantly better than with the 50 micrograms dose (P = 0.008). Cimetidine 300 mg relieved global pain significantly better than misoprostol 200 micrograms at 2 weeks (P = 0.047) but not at 4 weeks. The 200 micrograms dose of misoprostol relieved pain significantly better than the 50 micrograms dose at 4 weeks (P = 0.019), but not at 2 weeks. All 3 treatments were well tolerated. Severe adverse events were rare. The efficacy of enprostil, another PGE2 analog, on gastric ulcer healing was also found to be better than placebo and not significantly different from ranitidine. The synthetic prostanoids, misoprostol and enprostil, appear to be safe and effective in the treatment of gastric ulcer.

Unlabelled: Focal ischemia is postulated to contribute to gastric mucosal stress ulceration. This study evaluated directly whether or not mucosal ulceration during hemorrhagic shock is preceded by focal gastric mucosal blood flow changes, and whether or not topical Dm-PGE2 (16,16-dimethyl prostaglandin E2) affects focal gastric mucosal blood flow during hemorrhagic shock. Twelve anesthetized miniature swine had pyloric ligation and intragastric infusion of 5 ml/kg autogenous bile in 140 mM HCl. Gastric mucosal blood flow was documented by radiolabeled microspheres during normotension, initial hemorrhagic shock (50 mm Hg), and hemorrhagic shock + 50 micrograms topical Dm-PGE2. Stable shock was then maintained for 3 hr. During this time ulceration developed, shedding radiolabeled microsphere-bearing mucosa into the lumen. Intact gastric mucosa and luminal contents were collected, weighed, and gamma counted. Blood flow to intact mucosa was calculated by standard techniques. The weight of shed tissue, as well as the blood flow to shed tissue, was calculated from luminal microspheres., Results: gastric mucosal blood flow was decreased 35% with hemorrhagic shock (28.8 +/- 4.0 vs 18.7 +/- 2.7 ml/100 g/min, P less than 0.05). Blood flow to tissue which was subsequently shed averaged 6.4 +/- 3.1 ml/100 g/min at the same time period (P less than 0.05 vs surrounding tissue). Addition of Dm-PGE2 increased blood flow to shed tissue from 29 +/- 8% to 48 +/- 10% of blood flow to intact tissue (P less than 0.05)., Conclusions: (1) gastric mucosal ulceration is preceded by focal decreases in gastric mucosal blood flow, and (2) topical Dm-PGE2 reverses focal mucosal ischemia during hemorrhagic shock. Dm-PGE2's ability to reverse focal ischemia suggests a mechanism for prostaglandin-mediated cytoprotection.

In a randomized, double-bind, parallel, multi-clinic study, the safety and efficacy of enprostil (35 micrograms twice daily) and ranitidine (150 mg twice daily) were compared in the treatment of active gastric ulcer in 93 outpatients (47 enprostil-treated patients and 46 ranitidine). The two treatment groups were well matched for demographic characteristics. The healing rates in the enprostil group were 22, 58, 80, and 86 percent at two, four, six, and eight weeks, respectively. The corresponding rates in the ranitidine group were 22, 66, 84, and 89 percent. None of these differences was statistically significant. The area of the ulcer at baseline and smoking status did not appear to influence healing rates. There were no significant differences between treatment groups in time to relief of ulcer symptoms, frequency of daytime or nighttime ulcer pain, or antacid use. Side effects attributable to enprostil treatment were diarrhea (10 percent versus 6 percent with ranitidine), gastrointestinal pain, and vomiting. These side effects, however, did not influence the patients' assessments of their overall response to enprostil and ranitidine therapy. Six enprostil-treated patients and one ranitidine-treated patient withdrew from the trial prematurely because of adverse experiences. Monitoring of clinical laboratory test results showed no significant changes in the two treatment groups. This study demonstrates that a prostaglandin E2 analogue, enprostil, in a dose of 35 micrograms twice daily, is similarly safe and effective as ranitidine in the treatment of active gastric ulcer.

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.

This study was undertaken to determine if the cytoprotective effect of prostaglandin and the H2 histamine receptor antagonist cimetidine involves protection against disruption of the gastric mucosal barrier. Groups of anesthetized, vagotomized rats received one of the following parenterally: saline (control), mepyramine--an H1 histamine receptor antagonist, cimetidine, cimetidine and mepyramine, or 16,16 dimethyl prostaglandin E2. Parameters of barrier disruption were then determined before and after exposure of the gastric mucosa to 40mM acetylsalicylic acid. At the end of the study, gastric lesions were scored according to size and number. Lesion score and fall in potential difference were significantly lower in rats receiving cimetidine, cimetidine and mepyramine, and prostaglandin. Other parameters of barrier disruption--H+ back diffusion, Na+ and K+ influx, and protein outpouring--exhibited the same pattern and correlated with change in potential difference. We conclude that both prostaglandin and cimetidine, but not mepyramine, protect against barrier disruption by topical aspirin, and this may be a factor in the mechanism of their cytoprotective action.

In a randomized, endoscopically controlled double-blind trial the effectiveness of a twice daily dose of the prostaglandin E2-analogue enprostil was compared with ranitidine given to 93 ambulatory patients with benign gastric ulcers. Under 35 micrograms b.i.d. enprostil the ulcer healing rates after 2, 4, 6 and 8 weeks averaged 22% (10/46), 58% (26/45), 80% (35/44) and 86% (37/43). The corresponding values for ranitidine 150 mg b.i.d. were 22% (10/46), 66% (29/44), 84% (38/45) and 89% (41/46). The differences were not statistically significant. Both drugs had a similar influence on the ulcer symptoms and were well tolerated. The findings suggest that enprostil can be given in a twice daily dosage in the treatment of benign gastric ulcers.

The present study investigates whether prostaglandins "cytoprotect" the gastric mucosa against hemorrhage-induced stress ulceration by assessing the influence of 16,16-dimethyl prostaglandin E2 (16,16-dm PGE2) on gross and microscopic lesion formation, intramucosal tissue pH, H+ back-diffusion, and mucosal blood flow in rat gastric mucosa exposed to luminal acid (100 mM HCl) during hemorrhagic shock (13 ml/kg for 20 min). Intramucosal tissue pH was measured using pH-sensitive antimony microelectrodes, and mucosal blood flow was measured by the radiolabeled microsphere technique. 16,16-dm PGE2 (5 micrograms/ml topically) significantly protected the gastric mucosa against gross (lesion index 2.25 +/- 0.34 vs 0.87 +/- 0.21) and microscopic (lesion index 2.12 +/- 0.20 vs 0.87 +/- 0.09) damage during the shock. This protection was associated with a significantly lesser acidification of the mucosa during the shock (intramural tissue pH 6.67 +/- 0.08 vs 6.03 +/- 0.17). In order to elucidate whether the lesser intramucosal acidification was due to diminished entry of H+ (H+ back diffusion) into or better disposal of H+ from the mucosa, the influences of 16,16-dm PGE2 on transmucosal H+ fluxes and mucosal blood flow were determined. It appeared that 16,16-dm PGE2 had no influence on the rate of H+ back-diffusion, but it significantly enhanced mucosal blood flow both in the corpus (0.23 +/- 0.04 vs 0.14 +/- 0.03 ml/min/g) and in the antrum (0.24 +/- 0.03 vs. 0.14 +/- 0.03 ml/min/g) during the shock.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized, double-blind, placebo-controlled, multiclinic trial evaluated arbaprostil [15(R)-15 methyl prostaglandin E2] for the treatment of acute gastric ulcer, achieving an overall enrollment of 124 patients (of which 113 were considered evaluable). This 6-wk trial used an arbaprostil dose of 10 micrograms q.i.d., which has little gastric acid antisecretory activity. Endoscopies were performed after 21 and 42 days of treatment, at which times the arbaprostil and placebo healing rates, respectively, were 6/59 (10.2%) and 4/53 (7.6%) on day 21 and 25/59 (42.4%) and 16/50 (32.0%) on day 42. No significant differences between the treatment groups were found for pain relief, antacid consumption, and mucosal healing. This trial documents that a 10-micrograms dose of arbaprostil (which may be considered cytoprotective because of its small effect on gastric acid secretion), although safe and associated with no side effects, is not efficacious in healing acute gastric ulcers.

An experimental model was used which includes intragastric instillation of 80 mM HCl and 0.6 ml bile/kg followed by intravenous infusion of live E coli in cats for up to three hours. This procedure regularly induces gastric mucosal ulcerations. Mucosal blood flow was measured by microspheres before, early, and late in sepsis. Total gastric blood flow was recorded electromagnetically. Mucosal regeneration capacity as reflected by the RNA/DNA ratio was measured. Misoprostol (a PGE1 analogue) was infused iv (5 micrograms/kg X h) or given locally in the stomach (10 micrograms/kg) before bacteriemia. Misoprostol did not influence the haemodynamic response to bacteria. The gastric mucosal damage was assessed either as an index representative for the entire corpus-fundus region or as the number of areas with intact surface epithelium within the series. Misoprostol iv protected the mucosa from ulceration compared with untreated septic controls while misoprostol intragastrically significantly reduced the number of damaged areas only. Topical misoprostol increased total gastric and mucosal blood flows early in sepsis compared to iv or no pretreatment while no difference was seen during late sepsis. The protective effect of misoprostol was thus not dependent on increased gastric mucosal blood flow. Nor was it mediated through effects on mucosal nucleic acid concentrations or ratio.

In order to investigate the cytoprotective action of 16-16-dimethyl-prostaglandin E2 (16-16D), we studied its effect on sacs of isolated amphibian gastric mucosa known to ulcerate with high frequency in the absence of nutrient HCO3-. The actions of 16-16D, 2.85 X 10(-6) M, were also studied in an in vitro chamber. The incidence of ulceration in HCO3- -free nutrient media containing 10(-4) M histamine was significantly reduced by 16-16D. When artificial gastric juice (AGJ) was instilled into the lumen of the sac, protection occurred only after a pretreatment period of 60 min. Cytoprotection was not observed when active secretion of H+ was inhibited with 10(-3) M metiamide, and AGJ was placed in the lumen of the sac. In open sheets of fundus stimulated with 10(-4) M histamine, 16-16D did not influence H+ secretion. Isc was significantly higher than in control tissues. We conclude that 16-16D is cytoprotective in amphibian gastric mucosa by an action independent of changes in acid secretion or in blood flow. In addition, our studies suggest that 16-16D may increase the availability to the surface cells of nutrient HCO3- produced by actively secreting oxyntic cells.

This study evaluated the efficacy of two dosage levels of enprostil in 129 patients with gastric ulcer disease. Patients with endoscopically diagnosed gastric ulcer were randomly assigned to receive enprostil 70 micrograms, enprostil 35 micrograms, or a matching placebo capsule twice daily for six weeks. Ulcer healing rates were similar in all treatment groups after two weeks of therapy, but began to show some differences in favor of the enprostil treatment groups after four weeks. Greater differences were noted after six weeks of therapy, with healing rates of 70 percent in the 70-micrograms enprostil group, 82 percent in the 35-micrograms enprostil group, and 50 percent in the placebo group. The six-week healing rate in the 35-micrograms enprostil group was significantly greater than the placebo rate (p = 0.005). Comparison of healing rates in the active treatment groups and the placebo group after six weeks of therapy showed a correlation between therapeutic effect and ulcer size at baseline. This trend is illustrated by a 24 percent difference between the 35-micrograms enprostil group and the placebo group among patients with small (3 to 9 mm) ulcers, compared with a 46 percent difference between these two groups among patients with large (20 to 30 mm) ulcers. Thus, the effectiveness of enprostil is more readily demonstrable in patients with larger ulcers.

This study compares the gastroprotective effects of colloidal bismuth subcitrate (De-Nol) with those of sucralfate and a methylated analogue of prostaglandin E2 (PGE2) against acute gastric lesions induced by acidified aspirin and absolute ethanol in rats. Both De-Nol and sucralfate given orally prevented dose dependently the formation of gastric lesions by these ulcerogens, De-Nol being, respectively, twice and seven times more potent, on a weight basis, than sucralfate. As the gastroprotective activities of both De-Nol and sucralfate on ethanol lesions can be reversed by pretreatment with indomethacin and as De-Nol and sucralfate increase the mucosal generation and luminal release of PGE2, we postulate that mucosal prostaglandins may be involved in the mechanism of action of these drugs on the gastric mucosa.

Most research on the beneficial effects of pharmacologic agents on stress-induced acute gastric erosions in animals is directed at prevention. It is only the rare study that has been concerned with treatment of established erosions. A treatment model has been created using cervical cord-injured male Sprague-Dawley rats which consistently developed extensive linear erosions of the glandular portions of the stomach within 12 hr. A group of spinal rats was sacrificed after 12 hr to serve as a base of pretreatment ulcer severity. Treatment of established erosions with cimetidine 25 mg/kg every 2 hr in one group and 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) 5 micrograms/kg every 2 hr in a second group was compared to saline-treated controls. All drugs were administered by intraperitoneal route. Treatment began 12 hr after the cord transection and continued for another 12 hr at which time the rats were sacrificed. Both cimetidine and 16,16-dmPGE2 significantly inhibited the degree of erosion progression after 12 hr compared to saline controls (P less than 0.05). Acid output studies were carried out on a second set of rats subjected to the same experimental conditions with the addition of pyloric ligation 6 hr prior to sacrifice. A significant decrease in acid output (P less than 0.05) occurred only in the cimetidine group compared to control. It is concluded that both cimetidine and 16,16-dmPGE2 can arrest the progression of erosive changes in the stomach after cervical cord injury in rats. This is likely related to acid reduction by cimetidine and cytoprotection by prostaglandin.

117 patients were submitted to the randomized double-blind clinical trial. Methylated analogues of prostaglandin E2 administered orally markedly suppressed gastric acid secretion and--in comparison to placebo--accelerated cicatrization of duodenal ulcers, but not of gastric ulcers. The resistance of some ulcers to healing was not dependent on gastric acid secretion.

Gastric mucosal damage produced by topical application of necrotizing agents is diminished by topical or systemic pretreatment with a variety of E and F prostaglandins. The rat restraint model of gastric mucosal injury is more analogous to clinical stress ulceration than are models using intragastric application of toxic solutions; however, previous use of prostaglandin E1 in the restraint model resulted in a prohibitive incidence of GI morbidity. The current study used the restraint model of stress ulceration to compare the effects of a more potent prostaglandin analogue, 16,16-dimethyl prostaglandin E2, with hyperosmolar glucose and antacids. All three agents afforded significant protection from grossly apparent mucosal lesions, alone and in combination. Although other physiologic effects of each agent differed, the only effect which correlated with prevention of mucosal lesions was suppression of gastric acidity. Since effective doses of cytoprotective prostaglandins did not produce notable morbidity in comparison with other agents, they may prove to be a useful adjunct to stress ulcer prophylaxis in clinical settings.

Acute erosions of the stomach may occur in association with human spinal cord injuries. Erosion of the glandular portion of the stomach also occurs after cervical cord transection in the rat. Reports on the effects of antacids and cimetidine in the prevention of acute "stress" erosions in animals and humans have shown conflicting results. A prostaglandin analog, 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) has been shown to prevent gastric erosions in rats produced by nonsteroid antiinflammatory compounds. Cimetidine 50 mg/kg (intraperitoneal), 16,16-dmPGE2 10 micrograms/kg (intraperitoneal), and antacid 2 ml (intragastric) were individually given to groups of spinal rats at 0 and 4 hr. 16,16-dmPGE2 and antacid both resulted in significant reduction in mean ulcer length compared to controls after 8 hr (P less than 0.05) whereas cimetidine showed no significant effect, even though cimetidine caused a significant decrease in gastric acid output compared to both 16,16-dmPGE2 and controls (P less than 0.01). It is concluded that cimetidine on this dosage schedule is not effective in the prevention of gastric erosions in a cervical cord section rat model, whereas the ulceroprotective effects of 16,16-dmPGE2 and antacids are significant. It is suggested that the gastric mucosal cells remain vulnerable to injury in the cimetidine-treated spinal rat due to secretory inhibition, but are protected by buffering action of antacids or by "cytoprotective" effects of prostaglandin.

The present study investigated the preventive and curative effects of prostaglandins (PGs) on gastric ulcer in rats induced by physical or psychological stresses; some rats were electrically shocked, while others were exposed to affective stimuli arising from the shocked animals. The synthetic PGs dimethyl-PGE2 and rioprostil were administered orally, and their preventive effect on gastric ulceration was evaluated by determining the incidence and the ulcer index of lesions. The curative effect of drugs on ulcer healing was evaluated by determining a time-dependent change in the mucosal surface of the stomach with an endoscopic technique. Oral administration of dimethyl-PGE2 or rioprostil (25 and 50 micrograms/kg) prevented gastric ulceration significantly. Oral administration of these drugs (50 micrograms/kg, twice per day) significantly promoted the healing process of lesions 24 and 36 hr after termination of stress loading. The present results give direct evidence of the curative effect of PGs on stress ulcers and suggest that application of the endoscopic technique to the pathology of the rat's stomach may be a substantial aid in the preclinical evaluation of antiulcer drugs.

This study was designed to determine the gastroprotective actions of an antacid (Maalox 70) and its components, Al(OH)3 and Mg(OH)2, against acute gastric lesions induced by absolute ethanol, acidified aspirin (ASA), and water immersion and restraint stress in rats. Given orally, the antacid prevented dose-dependently the formation of gastric lesions by all three ulcerogens, and these effects were similar to those obtained with a methylated prostaglandin E2 (PGE2) analog. Active Al(OH)3 gel was equipotent with Maalox, whereas Mg(OH)2 was significantly less effective in gastroprotection than Maalox 70. Chemically inactive Al(OH)3 wet gel showed only small and insignificant protective properties. Since the gastroprotective activities of Maalox 70 against ethanol lesions cannot be reversed by pretreatment with indomethacin, and since neither Maalox 70 nor its active components affected the mucosal generation of PGE2 and leukotriene C4, we postulate that mucosal prostanoids are not the primary mediators in the mechanism of their protective action on the gastric mucosa.

Chronic gastric ulcers were produced by injection of 20% acetic acid (0.05 ml) into the submucosal layer of the rat stomach in order to determine the effects of the prostanoid trimoprostil on the healing and recurrence of ulcers. Local injection of acetic acid solution produced large demarcated ulcers in all animals on day 5, which rapidly decreased to reach low levels on days 40-80 and then became exacerbated on day 100. The exacerbation of the ulcer is probably recurrence. Trimoprostil was administered ad libitum in drinking water containing 0.1, 0.3 and 1.0 microgram/ml (average dose 12.4, 37 and 124 micrograms/kg/day) for a period of 14 days (day 1-15) to assess its effect on healing and for a period of 40 days (day 60-100) to assess its ability to prevent recurrence. The higher two doses of trimoprostil accelerated the spontaneous healing of the ulcers. Furthermore, trimoprostil, at both doses, prevented the observed recurrence of this type of ulcer. Trimoprostil dose-dependently (30-300 micrograms/kg, p.o.) inhibited gastric secretion in pylorus-ligated rats. Cimetidine at the antisecretory dose (1 mg/ml, 132 mg/kg/day) failed to affect the healing process of gastric ulcers, but tended to prevent the recurrence of gastric ulcers. Our present study suggests that trimoprostil is a promising antiulcer drug for the treatment of chronic gastric ulcer.

Twenty outpatients with an endoscopic diagnosis of gastric ulcer were evaluated for 6 wk in a randomized, double-blind trial comparing 15(R)-15-methyl prostaglandin E2 (Arbacet) (10 micrograms, 0.5 h before each meal and at bedtime) with placebo. Endoscopy was performed at 3 wk and 6 wk during the study period. Five of nine patients (56%) taking Arbacet and seven of 11 patients (64%) in the placebo group had complete healing of their gastric ulcer. Healing occurred in four patients from the Arbacet group and three patients in the placebo group at 3 wk. A cytoprotective dose of Arbacet (40 micrograms daily) is not significantly better than placebo in healing gastric ulcers.

We investigated whether the trophic actions of prostaglandins, omeprazole, and indomethacin on gastric mucosa lead to accelerated healing of gastric ulcers in the rat. Cryoulcers were produced in the corpus area and treated with 16,16-dimethyl prostaglandin E2 (5 or 100 micrograms/kg b.i.d., intragastrically), omeprazole (40 mumol/kg once daily, subcutaneously), indomethacin (2 mg/kg b.i.d., subcutaneously), or placebo. At the end of the treatment, plasma gastrin, cell labeling index (autoradiography with [3H]thymidine), and the size and depth of mucosal defects were measured. Compared with placebo, omeprazole accelerated ulcer healing as indicated by a smaller ulcer area [1.1 +/- 0.2 vs. 4.8 +/- 1.2 mm2 (mean +/- SEM)] and smaller ulcer depth (383 +/- 31 vs. 488 +/- 41 microns) after 10 days of treatment. Prostaglandins did not affect ulcer healing despite thickening of gastric corpus mucosa. Indomethacin delayed ulcer healing and reduced the labeling index. Omeprazole induced a marked hypergastrinemia (208 +/- 12 vs. 66 +/- 12 pmol/L on day 5, and 469 +/- 23 vs. 58 +/- 16 pmol/L on day 10). The results indicate that abolishment of acid secretion by omeprazole accelerates healing. Trophic actions and "cytoprotective" effects by prostaglandins are not relevant for ulcer healing in this model.

Anti-ulcerogenic effects of trimoprostil, a prostaglandin E2 (PGE2) derivative, were studied in comparison with those of PGE2, cimetidine and sulpiride. Trimoprostil and PGE2 given p.o. prevented the formation of gastric lesions produced by absolute ethanol, 0.2N NaOH, 0.6N HCI and hypertonic NaCl solutions in rats and aspirin-induced fecal occult bleeding in dogs. Although both prostaglandins did not alter the gastric mucus content, they equivalently prevented the stress-induced decrease in the mucus content in rats. The duration of these effects of trimoprostil was longer than those of PGE2. Cimetidine and sulpiride did not exert such cytoprotective effects. Trimoprostil inhibited stress-induced gastric ulcer formation in rats more markedly than PGE2, cimetidine and sulpiride. Trimoprostil and PGE2 at the cytoprotective dose (30 micrograms/kg, p.o.) did not change the gastric blood flow in conscious rats. In Shay rats, trimoprostil at doses larger than the cytoprotective doses inhibited the gastric acid secretion when given p.o., but was not effective when given i.d. PGE2 exerted the similar action, but the potency was clearly weaker than that of trimoprostil. In Heidenhain-pouch dogs, trimoprostil also inhibited the gastric acid secretion stimulated by pentagastrin more markedly than did cimetidine. In conclusion, trimoprostil at doses smaller than the antisecretory doses exerted gastric cytoprotective action with a longer duration than that of PGE2, probably through the preservation of the mucus barrier. Such cytoprotection was not found with cimetidine and sulpiride.

The role of gastric mucus in the pathogenesis of septic erosions and as an explanation for prostaglandin cytoprotection is unclear. In a reproducible canine septic model bacterial peritonitis was induced in three groups of dogs. One group served as a control and each of the remaining groups received 16,16 dimethyl PGE2 either 0.2 microgram/kg. or 0.4 microgram/kg. I.M. q6h beginning 24 hours prior to peritonitis and continued during the septic period. Gastroscopy was performed and basal gastric juice collected prior to peritonitis and during the septic period. All animals in the control group developed acute gastric erosions and gastric juice protein significantly decreased while sialic acid and fucose significantly increased during the septic period. In the animals receiving 16,16 dimethyl PGE2 acute gastric erosions did not develop; sialic acid and fucose were significantly elevated compared to control dogs during sepsis. We conclude that prostaglandin cytoprotection may be related to increases in gastric glycoprotein secretion.

Stress ulcer is a common phenomenon after hepatectomy for cirrhotic liver. We examined experimentally the influence of cimetidine and 16,16-dm PGE2 dosaged as counter-measures against stress ulcer on liver regeneration after partial hepatectomy for cirrhotic liver. Using cimetidine and 16,16-dm PGE2, there was a noticeable suppression of the onset of water immersion stress ulcer, and both a decline in the blood flow in the wall of the stomach and a drop in PH in the stomach were inhibited after partial hepatectomy for cirrhotic liver. The group given 16,16-dm PGE2 after partial hepatectomy had a higher rate of DNA synthesis as compared with the group which had only partial hepatectomy. No difference was seen between the group given cimetidine and the only partial hepatectomy groups. The group given indomethacin before partial hepatectomy for cirrhotic liver had a noticeable decrease in mitotic index 30 hours after partial hepatectomy. However, the group given both indomethacin and 16,16-dm pGE2, showed some recovery of the mitotic index.