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PubMed1986

Effects of enprostil on platelets, endothelial cells, and other cell types, and second messenger systems by which these effects are mediated.

In human blood platelets, thromboxane A2, prostaglandin E2, and its analogue enprostil activate protein kinase C and promote the second phase of aggregation, whereas prostacyclin and prostaglandin E1 activate adenylate cyclase and inhibit aggregation. In each case, a characteristic group of proteins is phosphorylated following agonist binding. These observations may be related to the inhibitory effect of enprostil on the activation of adenylate cyclase in gastric parietal cells, which follows binding of histamine to H2 receptors. Another system in which enprostil opposes the effect of histamine is the microvasculature. Histamine binds to H1 sites on endothelial cells and induces changes in their shape that allow macromolecules to pass between them into the extravascular compartment. This effect may be mediated by activation of protein kinase C. Pretreatment with enprostil antagonizes the increase in vascular permeability induced by histamine and presumably other inflammatory mediators. Preservation of the integrity of the microvasculature of the gastric mucosa against the effects of cyclo-oxygenase inhibitors, ethanol, and other damaging agents may contribute to the mucosal protective effects of enprostil and some other prostaglandins.

Adenylyl Cyclases↗
PubMed1996

Prostaglandin E2 derivative, enprostil, reduces hepatic triacylglycerol content in Japanese quail.

This study investigated the effect of prostaglandin E2 derivative, enprostil, on the hepatic lipid metabolism of Japanese quail. In experiment 1, the birds received 0.1, 1, 10 or 100 micrograms enprostil/kg body weight intraperitoneally, and they were killed after 10, 30, 60 and 120 min. After 60 min, hepatic triacylglycerol content was reduced most effectively by 10 micrograms enprostil/kg body weight. In experiment 2, effect of enprostil (10 micrograms/kg body weight) on liver enzyme activities associated with lipid metabolism and plasma lipid concentrations was examined. There were no significant differences in malic enzyme and carnitine palmitoyltransferase activities. Peroxisomal beta-oxidation in birds which received enprostil was significantly lower than that in birds receiving the vehicle. Enprostil caused a significant decrease in plasma triacylglycerol and non-esterified fatty acid concentration. We conclude that the administration of enprostil reduces hepatic triacylglycerol content through the decreased influx of non-esterified fatty acid.

Animals↗
PubMed1987

Twenty-four-hour intragastric acidity and clinical trial of bedtime enprostil 70 micrograms compared with ranitidine 300 mg in duodenal ulcer.

The effects of bedtime 70 micrograms and twice daily 35 micrograms doses of enprostil on 24-hour intragastric acidity were investigated in nine duodenal ulcer patients in remission. Median nocturnal acidity decreased significantly by 30% with 35 micrograms twice daily, and by 48% with 70 micrograms at bedtime. In a clinical trial using bedtime dosing, 102 duodenal ulcer patients randomly received either ranitidine 300 mg or enprostil 70 micrograms. More ulcers healed after 4 and 8 weeks treatment with ranitidine than with enprostil (76% ranitidine vs 52% enprostil, at 4 weeks p = 0.0065 and 94% vs 68%, respectively at 8 weeks, P = 0.0007). However, 6 months after cessation of treatment there was no material difference in overall outcome. Despite combining mucosal protection with acid inhibition enprostil treatment conferred no advantage over simple acid inhibition.

Adult↗
PubMed1990

The effects of enprostil and RS-86505-007 on in-vitro intestinal permeability of rabbit and monkey.

Enprostil is a prostaglandin E2 analogue characterized as a racemic mixture of four stereoisomers. Enprostil and a single isomer, RS-86505-007, were evaluated for their effects on the permeability of actively and passively transported compounds in segments of small intestine from rabbits and monkeys. Consistent with human in-vivo studies, which have demonstrated decreases in absorption of D-xylose, both compounds inhibited D-glucose transport. The passively transported compounds mannitol and progesterone were also less permeable in this model in the presence of enprostil or RS-86505-007. In contrast to the concentration-dependent inhibition displayed by ouabain, RS-86505-007 had no effect on purified Na+K(+)-ATPase. It is suggested that an effect of a general nature, possibly an increase in the barrier properties at the intestinal surface, may explain the transport inhibition. Of two other enprostil isomers, RS-86812-007 inhibited D-glucose transport in rabbit small intestine, while RS-86505-008 had no effect. The prostaglandin E1 analogue misoprostol was ineffective in monkey and poorly effective in rabbit. This suggests that the inhibition of D-glucose transport by enprostil and its active stereoisomers is mediated through some structurally specific receptor interaction.

Animals↗
PubMed1989

Effect of enprostil on gastric emptying, intestinal transit time and post-prandial release of gastro-intestinal peptides.

The effect of an oral dose of 70 micrograms enprostil (a prostaglandin E2 analogue) on the post-prandial hormone response to a test breakfast was examined in a double-blind, placebo-controlled, cross-over study in 10 healthy volunteers. Enprostil markedly reduced the post-prandial rises in insulin and glucose-dependent insulinotropic peptide (GIP) but plasma glucose remained unchanged. To study the effects on gut motility 8 healthy volunteers ingested a liquid meal containing 75 g glucose, 20 g lactulose and 99mTc colloid after taking placebo or 70 micrograms enprostil. Gastric emptying, measured using a gamma camera, was unchanged but mouth-to-caecum transit time was significantly longer on enprostil; time to half maximal breath hydrogen: placebo 119 min, enprostil 200 min (p less than 0.05). This delay was associated with a reduced and delayed post-prandial rise in GIP and insulin and with other changes in the gut hormone profile.

Adult↗
PubMed1989

Protective effect of low dose of enprostil against gastric blood loss induced by aspirin in man.

This study tested the efficacy of enprostil given both at potent antisecretory (35 micrograms twice daily) and weak antisecretory (7 micrograms twice daily) doses in preventing aspirin-induced gastric blood loss measured chemically in gastric washings in 10 volunteers. Aspirin (500 mg four times a day) increased gastric blood loss compared with placebo (p less than 0.001). When enprostil was given in addition to aspirin, gastric blood loss was not significantly different from basal value. The pH of gastric washings was significantly increased by the large but not by the low dose of enprostil compared with placebo. The two doses of enprostil were equally efficacious, suggesting a mucosal protective effect of enprostil independent of acid inhibition.

Adult↗
PubMed1990

Enprostil, a prostaglandin E2 analogue, in the treatment of gastric ulcer--a multicentre comparison with pirenzepine.

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.

Adolescent↗
PubMed1988

Antisecretory effect of a PGE2 derivative, enprostil (TA/RS-84135): inhibitory action of amogastrin-stimulated secretion.

A newly developed prostaglandin E2 derivative, enprostil (TA/RS-84135), was administered to five healthy volunteers in the stomach and duodenum through a teflon tube to examine its effect on amogastrin-stimulated gastric acid secretion. The acid output 1-3 h after administration of enprostil (35 micrograms) decreased remarkably as compared with that in the same period after placebo administration. However, no significant difference in antisecretory effect was observed between the two routes of administration. A decrease in pepsin output occurred in parallel with the decrease in acid output. These results suggest that the antisecretory effect of enprostil is at least partially due to systemic absorption and the predominantly topical action seen in animals does not seem to occur in man. No side-effects attributable to enprostil were observed during the test period. In conclusion, enprostil seems to be clinically useful as an antiulcer agent.

Adult↗
PubMed1994

[Variations of plasma gastrin (basal and postprandial) in ththtreatmentof duodenal ulcer with either enprostil or ranitidine. Correlations with rates of relapse].

Enprostil, a synthetic E2-prostaglandin efficacious for duodenal ulcer healing, presents both antisecretory and antigastrinic effects. This is at variance with the elevation of plasma gastrin observed with ranitidine. OBJECTIVE--This leads us to compare enprostil and ranitidine on the following points: a) variations of plasma gastrin (basal and postprandial) parameters over a 6-week conventional treatment; b) correlation studies between ulcer relapses (frequency and temporal evolution) after treatment discontinuation and various gastrinic criteria. METHODS--Among a group of 642 patients followed for ulcer relapse, 165 were considered for gastrin (78 of the "Enprostil" group and 87 of the "Ranitidine" group). RESULTS--Initially, both populations were comparable for clinical and plasma gastrin parameters. After 6 weeks of treatment, the increases in the various gastrin parameters (basal, postprandial, peak, integraded) were significantly greater and the absolute values higher (Wilcoxon, P < 0.001) with ranitidine than with enprostil. No correlation was found between relapse occurrence after drug discontinuation and these gastrin parameters. CONCLUSIONS--Ranitidine hypergastrinemia seems directly related to gastric hyposecretion whereas its absence with enprostil is likely more dependent upon a specific antigastrinic activity than on a reduced antisecretory activity. Those differences in mechanism of action have no consequence on the stability of ulcer obtained by either drug.

Adolescent↗
PubMed1991

Antroduodenal motility studied by real-time ultrasonography. Effect of enprostil.

Transabdominal real-time ultrasonography was used to investigate antroduodenal motility effects of the prostaglandin E2 analogue enprostil. Ten healthy subjects were studied on two separate days, once after oral administration of one capsule of enprostil 35 micrograms 1 hour before the ingestion of 500 mL of meat soup and once without drug administration before the meal. The ultrasound probe was positioned at the level of the transpyloric plane to visualize the antrum, pylorus, and proximal duodenum simultaneously and thereafter vertically to visualize the antrum, superior mesenteric vein, and aorta simultaneously. The motility was videotaped for 15 minutes. The antroduodenal coordination, frequency and amplitude of antral contractions, and size of antral area were reduced, whereas the time during which the pylorus was wide open (greater than 5 mm) was increased after enprostil. It is concluded that antroduodenal motility can easily be visualized by ultrasonography. Therapeutic doses of enprostil impair antroduodenal peristalsis and coordination and open the pylorus in healthy subjects.

Adult↗
PubMed1993

Antisecretory and cytoprotective doses of enprostil do not alter gastric mucosal blood flow.

Prostaglandins of the E series are antisecretory and cytoprotective. Cytoprotection occurs in the deep but not superficial gastric mucosa. It has been hypothesized that the mechanism of cytoprotection involves increased gastric mucosal blood flow (GMBF). However, basal and stimulated gastric mucosal blood flow is greater in the deep than superficial corpus mucosa. The purpose of this study was to investigate the effect of a prostaglandin E2 analog, enprostil, on GMBF in the deep mucosa, where cytoprotection is observed, in both antisecretory and cytoprotective doses. Gastric mucosal blood flow in the deep half of the mucosa was measured by the hydrogen gas clearance method before, during and after intragastric perfusion of enprostil, 0.1-100 micrograms/kg, in urethane anesthetized rats. Enprostil did not alter GMBF in any of the doses tested. Therefore, the cytoprotective action of enprostil is mediated by factors other than a primary increase in GMBF.

Analysis of Variance↗
PubMed1986

Effect of a single oral dose of enprostil on gastric secretion and gastrin release. Studies in healthy volunteers and patients with pernicious anemia.

In healthy human volunteers, a single oral dose of enprostil (35 micrograms) inhibited basal gastric acid output by a mean of 71 percent, pentagastrin-stimulated output by 46 percent, sham-meal-stimulated output by 48 percent, and histamine-stimulated output by 16 percent. In each case, there was a reduction in both the volume and acidity of the gastric juice. Pepsin output was unchanged. Although enprostil increased the gastric pH, it did not induce basal or post-prandial hypergastrinemia. In patients with hypergastrinemia secondary to achlorhydria, enprostil lowered the basal gastrin level and reduced or abolished the post-prandial gastrin rise in a dose-related fashion. Enprostil reduces basal and stimulated gastric acid secretion and inhibits gastrin release.

Achlorhydria↗
PubMed1985

Protection against aspirin-induced antral and duodenal damage with enprostil. A double-blind endoscopic study.

Prostaglandins protect against aspirin-induced damage to the gastrointestinal tract. This study tested the ability of enprostil, a synthetic analog of prostaglandin E2, given concurrently to prevent gastroduodenal injury. Twenty-four healthy subjects were randomly assigned to one of three groups. All received aspirin 650 mg q.i.d. for 5 days. One group received placebo and the other groups were given either 7 or 70 micrograms of enprostil b.i.d. for 5 days. Upper endoscopy was performed at entry and 2 h after the final dose of aspirin. Enprostil 70 micrograms b.i.d. afforded significant protection of both the antral and duodenal mucosa. The 7-micrograms dose protected only the antral mucosa. Side effects were not observed with the lower dose of enprostil. Serum salicylate levels did not differ significantly between the groups.

Adolescent↗
PubMed1986

Enprostil, in contrast to cimetidine, does not inhibit propranolol metabolism.

Enprostil, an orally active prostaglandin E2 analog, is undergoing clinical trials in the treatment of peptic ulcer disease. Because results of animal studies suggested that prostaglandins might affect both hepatic drug metabolizing ability and hepatic blood flow, the effects of enprostil on drug elimination were studied and compared with those of the standard antiulcer drug cimetidine in a double-blind, randomized, crossover study of nine normal subjects. Cimetidine reduced the oral clearance of propranolol by 50%, consistent with the inhibition of drug metabolism reported in previous studies. On the other hand, enprostil had no effect on propranolol elimination. Neither drug altered liver blood flow as assessed either by the clearance of indocyanine green or by the technique of dual route of administration of propranolol. Thus in contrast to cimetidine, enprostil had no effect on hepatic drug metabolism.

Administration, Oral↗
PubMed1988

Effect of enprostil on plasma glucose, insulin and lipid metabolism in patients with non-insulin-dependent diabetes mellitus.

Measurements of various aspects of glucose, insulin and lipid metabolism were made before and after the administration of enprostil (a synthetic dehydroprostaglandin E2) for one week to ten patients with non-insulin-dependent diabetes mellitus (NIDDM). Both fasting (P less than 0.01) and postprandial (P less than 0.001) plasma glucose concentrations were significantly lower after one week of enprostil, and 24 hour urinary glucose excretion was reduced from (mean +/- SEM) 47 +/- 14 to 25 +/- 9 g/day. There was no change in either fasting or postprandial insulin concentration, but the postprandial GIP response was also significantly reduced (P less than 0.001). In addition, there were significant reductions in postprandial plasma free fatty acid (P less than 0.05) and triglyceride (P less than 0.001) concentrations, associated with a modest fall in fasting plasma triglyceride (P less than 0.05) and cholesterol (P less than 0.07) concentrations when measured after one week of treatment with enprostil. These results raise the possibility that enprostil may be of some benefit in the treatment of patients with non-insulin-dependent diabetes.

Aged↗
PubMed1988

A comparison of enprostil and ranitidine in treatment of duodenal ulcer.

Enprostil is a new synthetic prostaglandin E2 with antisecretory and mucosal-protective effects. We compared it with ranitidine in the healing of duodenal ulcer and also examined the subsequent relapse rate. Three hundred thirteen patients were recruited in 15 centers in Europe, of whom 158 were treated with enprostil (E) 35 micrograms twice daily and 155 with ranitidine (R) 150 mg twice daily for up to 6 weeks, using a double-blind method. Patients in both groups were of comparable demography. Healing was significantly quicker with ranitidine. Of patients randomized to treatment, healing (intention-to-treat analysis) at 4 weeks was E 47% and R 69%, and at 6 weeks it was E 66% and R 88%. In patients who met all protocol criteria and completed treatment, healing at 4 weeks was E 58% and R 80%, and at 6 weeks it was E 81% and R 92%. Early relief of pain, both during the day and at night, was significantly quicker with ranitidine. Nausea, diarrhea, vomiting, and abdominal pain occurred more often with enprostil. There were no clinically important abnormalities in hematology or biochemistry. Relapse rates were similar. In conclusion, enprostil is not as effective as ranitidine in healing duodenal ulcers.

Adolescent↗
PubMed1988

Enprostil, a prostaglandin E2 analogue, in the treatment of duodenal ulcer; a multicentre comparison with cimetidine.

In a multicentre trial, 120 patients with endoscopically diagnosed duodenal ulcer were randomly allocated to treatment with either 35 micrograms enprostil b.d. or 400 mg cimetidine b.d. for up to 6 weeks on a double-blind basis. After 6 weeks, 82% (42/51) of enprostil-treated patients and 92% (44/48) of cimetidine-treated patients were healed. Corresponding healing figures on an intention-to-treat basis were 70% and 76%. No significant differences were detected between treatments with respect to healing rates or symptom control at any time. Side-effects were reported by 14 patients taking enprostil and 17 patients taking cimetidine; none were serious but they resulted in withdrawal of one and two patients respectively. Enprostil was found to be similar in efficacy and tolerance to cimetidine.

Adolescent↗
PubMed1987

Enprostil and ranitidine in prevention of duodenal ulcer relapse: one year double blind comparative trial.

One hundred and forty two patients with duodenal ulcer who after a short term study had relief of pain and healed ulcers proved endoscopically were allocated at random to double blind maintenance treatment with enprostil (a synthetic dehydroprostaglandin E2) 35 micrograms or ranitidine 150 mg at bedtime for up to 12 months. Patients were monitored every third month and examined by endoscopy at three, six, and 12 months, or more often if warranted. The cumulative relapse rates in the enprostil group at three, six, and 12 months were 37% (25/67), 56% (37/66), and 62% (41/66), respectively. The corresponding rates in the ranitidine group were 8% (6/71), 19% (13/69), and 29% (20/69). These differences were highly significant and further enhanced by life table analysis adjusting for withdrawals and by an "intention to treat" analysis in which absence of proof of non-recurrence was counted as failure, more patients in the enprostil group having been withdrawn because of adverse events or recorded as non-compliant with the protocol. Enprostil 35 micrograms at bedtime cannot be recommended for preventing relapse of duodenal ulcer. Furthermore, the results challenge the clinical relevance of using so called "cytoprotection" for preventing recurrence.

Adult↗