[New epidemiology of acute gastrointestinal hemorrhage]. / Neue Epidemiologie der akuten gastrointestinalen Blutung.

Due to progress in general medicine and especially in gastroenterology, the incidence of acute gastrointestinal hemorrhage could be expected to have decreased during the last 25 years. However, published epidemiological data cannot, in general, fulfill this hope. The interpretation of potential trends is, however, often limited by low study quality. For example, questionable bleeding sources such as erosions in the upper gastrointestinal tract or colon diverticula are often rather uncritically named the definitive causes of bleeding. However, there is clear evidence of changes in grouping of patients. After the almost complete disappearance of Helicobacter pylori in younger indigenous populations of most industrialized countries, it is mostly elderly comorbid people with additional risk factors (NSAID use, low-dose aspirin, anticoagulation) who are affected. Not unexpectedly, this group has generally experienced no change in incidence and in fact shows a deterioration of prognosis in case of acute bleeding.

Sucralfate and ranitidine in the treatment of acute duodenal ulcer. Healing and relapse. Ulcer Study Group.

Healing and relapse of acute duodenal ulcer were investigated in an endoscopically controlled multicenter study using a double-blind design. Patients with acute uncomplicated duodenal ulcer were randomly assigned to treatment with sucralfate (1 g four times per day) or ranitidine (150 mg twice per day) for four to eight weeks. After healing, all anti-ulcer treatment was discontinued except for low-dose antacids needed for occasional upper abdominal pain, and the patients were observed for up to one year. Endoscopy was repeated after one year or at any time earlier if symptoms suggested ulcer relapse. Of the 83 patients who entered the study, 75 (sucralfate 40, ranitidine 35) underwent endoscopy after four weeks and could be fully evaluated. Healing rates after four and eight weeks were similar in the two groups (four- and eight-week healing rates after sucralfate and ranitidine: 78 and 74 percent, and 95 and 94 percent, respectively). Fifty-three patients with healed ulcers (sucralfate 29, ranitidine 24) were observed for up to one year. Duodenal ulcers occurred somewhat later after sucralfate than after ranitidine treatment, but life table analysis showed no significant difference. Thus, this study confirms a similar efficacy of sucralfate and ranitidine in healing of duodenal ulcer. A tendency to delayed relapse early after discontinuation of sucralfate failed to reach statistical significance.

Comparison of pantoprazole and ranitidine in the treatment of acute duodenal ulcer. Pantoprazole-Duodenal Ulcer-Study Group.

BACKGROUND: Pantoprazole is a new substituted benzimidazole that blocks the H+/K(+)-ATPase in the gastric mucosa and thus inhibits acid secretion. METHODS: Efficacy and tolerability of pantoprazole (40 mg at breakfast) and ranitidine (300 mg at bedtime) in the treatment of uncomplicated acute duodenal ulcer were compared in a double-blind randomized multicentre trial. RESULTS: Of 202 outpatients who entered the study, 185 terminated the treatment without violation of the protocol. After 2 weeks of treatment, healing rates (protocol correct) with pantoprazole and ranitidine were 81 and 53%, respectively (P < 0.001), the corresponding results after 4 weeks were 97 and 83% (P < 0.01). Pantoprazole was more effective with respect to symptom relief. Both treatments were well tolerated. CONCLUSION: Pantoprazole 40 mg at breakfast is superior to ranitidine 300 mg at bedtime in the short-term treatment of acute, uncomplicated duodenal ulcer.

A summary of Food and Drug Administration-reported adverse events and drug interactions occurring during therapy with omeprazole, lansoprazole and pantoprazole.

BACKGROUND: Pantoprazole is claimed to have a lower potential for drug interaction than other proton pump inhibitors. AIM: To estimate the frequency of adverse events and drug interactions reported to the Food and Drug Administration in patients receiving omeprazole, lansoprazole or pantoprazole. METHODS: The study involved a search of the Food and Drug Administration's database for adverse events and drug interactions with omeprazole, lansoprazole or pantoprazole as primary or secondary suspect drug. An estimate of the amount of drug dispensed during the adverse event collection period (from US drug launch) was obtained from the International Medical Statistics health database. RESULTS: Of the suspected drug interactions recorded, vitamin K antagonist interactions, although rare, were the most common. The frequency of vitamin K antagonist interactions was 0.09 per million packages for omeprazole and 0.11 per million packages for lansoprazole and pantoprazole. Interactions with benzodiazepines or phenytoin were even rarer, being reported in less than 10 patients on each proton pump inhibitor. CONCLUSION: The frequency of reported drug interactions was low for omeprazole, lansoprazole and pantoprazole and vitamin K antagonist interactions were by far the most common. These potentially important drug interactions, although rare, were no less frequent on pantoprazole than on omeprazole or lansoprazole, suggesting a class effect.

Limited usefulness of the breath test in evaluation of drug metabolism: a study in human oral contraceptive users treated with dimethylaminoantipyrine and diazepam.

Demethylation of 14C-dimethyl-N-aminoantipyrine (aminopyrine) and 14C-diazepam was measured by means of a breath test in women taking oral contraceptive steroids (OCS) and in controls not receiving OCS. Short-term half-life of 14CO2 in the breath after intake of 2 muCi of aminopyrine was significantly prolonged in women taking OCS when compared with controls. After intake of 2 muCi diazepam there were no statistically significant differences between the two groups. With 2 muCi diazepam or 10 muCi aminopyrine a biexponential decline of 14CO2 content in the breath was superimposed on a circadian, rhythm. 14CO2 in the aminopyrine breath test in the morning increased after the patients had risen from bed, whereas in the diazepam breath test the 14CO2 content decreased. It is concluded that the effect of OCS on drug metabolism is very specific. Furthermore, the appearance of 14CO2 in the breath does not depend only on hepatic microsomal demethylation.

PIP: 30 healthy female volunteers were tested in 5 groups of 6 persons each to evaluate whether oral contraceptives (OCs) had inhibiting effects on the disposal, via the hepatic microsomal enzyme system, of radiolabeled diazepam. Therefore, demethylation of radiolabeled aminopyrine and diazepam was measured by a breath test in women using OCs and in controls. Short-term half-life of radiolabeled carbon dioxide in the breath after ingestion of 2 mcCi of aminopyrine was significantly prolonged in women using OCs compared with controls. After ingestion of 2 mcCi of diazepan there was no statistically significant difference between the 2 groups. With 2 mcC; of diazepam or 10 mcCi of aminopyrine, a biexponential decline of radiolabeled carbon dioxide content in the breath was superimposed on a circadian rhythm, and the carbon dioxide in the aminopyrine breath test increased after patients had risen from bed whereas it decreased in the diazepam test. It is concluded that the effect of OCs on drug metabolism is very specific, and that furthermore, the appearance of radiolabeled carbon dioxide in the breath does not depend only on hepatic microsomal demethylation.

How often does peptic ulcer produce "typical" ulcer symptoms?

Subjective symptoms of 876 hospitalized patients who underwent upper fiber-panendoscopy were evaluated in a prospective study. Ulcer-like symptoms were defined as pain-like discomfort with a regular food-related rhythm. These symptoms indicate ulcer disease with high specificity (96%) but low sensitivity (28%). In particular old patients with second disease rarely have ulcer-like symptoms. In spite of their high specificity, however, ulcer-like symptoms are not proof of active ulceration. Patients with scars but no ulcers may also have ulcer-like symptoms.

[Recurrence of reflux esophagitis can be prevented with maintenance therapy with sucralfate]. / Recidief van reflux-oesofagitis te voorkomen met onderhoudstherapie van sucralfaat.

OBJECTIVE: To determine whether the recurrence of reflux oesophagitis can be prevented with sucralfate suspension 2 g daily. DESIGN: Double-blind, placebo-controlled, multinational drug study. SETTING: Sixteen research centres in Switzerland, Germany and the Netherlands. METHOD: 184 Patients whose earlier reflux oesophagitis Savary-Miller grades I and II were cured by an antisecretory therapy before being included in the study. For 6 months, they were given 2 g of a sucralfate suspension or a placebo twice daily, with random division. The symptoms were checked monthly. Endoscopy was performed at the end of the study or when there was a clinical suspicion of recurrence. RESULTS: Eighty-eight patients of the sucralfate group and 93 of the placebo group could be evaluated. The proportion of endoscopical recurrence was significantly reduced (31 in the sucralfate group as against 55 in the placebo group; p < 0.001). This decrease was particularly clear where symptomatic recurrences were concerned (10 and 34%, respectively; p < 0.001). CONCLUSION: This is the first trial that demonstrates that sucralfate suspension can prevent recurrences of reflux oesophagitis in patients with solitary or confluent erosions previously cured with an antisecretory therapy.

[Therapy of the acute ulcer attack]. / Therapie des akuten Ulkusschubes.

Medical treatment of acute ulcers can be optimized by paying attention to risk factors for slow healing and for rapid recurrence. Therapy-resistant ulcers have become virtually unknown with modern drugs, so elective ulcer surgery is nowadays rarely needed for this reason. While drug therapy of acute ulcer hemorrhage is probably of little, if any, benefit for stopping bleeding, endoscopic treatment reduces the risk of continuous or recurrent bleeding, the need for emergency surgery, and mortality of this most common complication.

[Prevention of recurrence of ulcer disease: indications and choice of procedure]. / Rezidivprophylaxe der Ulkuskrankheit: Indikation und Verfahrenswahl.

In this contribution we discuss the relapse prophylaxis of ulcers by nonmedicamentous measures, by long-term drug therapy and, in particular, with inhibitors of secretion, by eradication therapy of Helicobacter pylori and by surgical therapy. Besides secondary prophylaxis (prevention of ulcer relapses), primary prophylaxis (prevention of the first episode) is also briefly treated.

Protective drugs in the treatment of gastroduodenal ulcer disease.

Reduction of gastric acidity by the inhibition of secretion or neutralization is the therapeutic principle most widely used in peptic ulcer disease. From a pathophysiological standpoint, this does not appear logical, because in a majority of patients gastric acid secretion is not increased. In addition, there is some concern about the consequences of a reduction in gastric acidity, especially in the long term. And finally, all available inhibitors of gastric acid secretion have a systemic action and may thus cause systemic side effects. Carbenoxolone, sucralfate, and tri-potassium dicitrato bismuthate have been shown to accelerate healing of ulcers without appreciable acid inhibition. Despite an apparently different mode of action, the healing rates are similar to those of commonly used acid inhibitors. Several possible mechanisms of action have been claimed for each of these agents, but none has been convincingly demonstrated to be essential in ulcer healing. This may reflect ignorance of the relevant events rather than an action by a combined principle.

Treatment of reflux esophagitis with H2-blockers, antacids and prokinetic drugs. An analysis of randomized clinical trials.

Randomized clinical trials comparing H2-receptor antagonists, antacids, antacid/alginate and prokinetic drugs with placebo and other substances were analyzed. Symptomatic improvement has been shown for H2-receptor antagonists, antacids in very high doses and prokinetic drugs. H2-receptor antagonists, the present mainstay of reflux therapy, improve esophagitis, but they are insufficient in the treatment of severe esophagitis where omeprazole may become the therapy of choice. The evidence is weak that antacids, antacid/alginate, metoclopramide and domperidone heal esophagitis.

Gastric acid in vertebrates.

Gastric secretion of hydrochloric acid appears to be unique to vertebrates and is almost ubiquitous in all fishes, amphibians, reptiles, birds and mammals. Comparative anatomy and physiology suggest that gastric acid has evolved approximately 350 million years ago. The similarity of the acid-secreting mechanism across all classes of vertebrates implies a major advantage for selection, but the evidence regarding its precise purpose remains inconclusive.

Clinical relevance of mucosal protection.

An inquiry was made among 70 of the 76 participants of an international symposium entitled 'Future Directions in Peptic Ulcer Research', held in Bellagio, Italy, in April 1986. There was almost unanimous agreement that research in the development of protective drugs should be intensified. The participants felt that in future studies the prevention of ulcer relapse, concomitant administration with potentially ulcerogenic drugs, prevention of stress ulceration, and treatment of ulcer hemorrhage should be emphasized rather than the healing of uncomplicated ulcers. They were not generally satisfied with the performance of available prostaglandin analogues in ulcer treatment. The moderate commercial success of sucralfate was attributed mainly to the complicated mode of intake, but also to the unknown mechanism of action of this substance. It was felt likely that antacids have a clinically relevant protective effect on gastroduodenal mucosa.

Effect of acid inhibition on the growth of parietal cells.

Studies in the rat have shown that prolonged inhibition of acid secretion by high doses of a histamine H2 antagonist is followed by a 20-30% increase in the number of parietal cells, and that this is paralleled by an augmentation of the maximum acid output. A similar effect has been shown after prolonged acid neutralization with high doses of an antacid. These trophic effects are not unexpected. An increase in gastric pH is followed by gastrin release, and the parietal cell mass may be augmented by repeated exogenous administration of gastrin or by endogenous hypergastrinaemia following surgery. To further evaluate whether a direct correlation exists between the magnitude of drug-induced hypergastrinaemia and parietal cell hyperplasia, rats were treated for 24 days with two acid inhibitors which differ markedly in the degree of acid inhibition and acute or chronic gastrin release. Six animals each were treated with either omeprazole (40 mumol/kg once daily), or atropine (3 mg/kg twice daily), or omeprazole combined with atropine or with placebo. On day 24, plasma gastrin was elevated more than 10-fold in both groups of rats treated with omeprazole but not in animals given atropine alone. As compared to placebo treatment, total parietal cell volume was significantly higher in animals treated with atropine (102 +/- 9 mm3 versus 140 +/- 18 mm3), but was unchanged in the other two groups. These studies demonstrate that marked prolonged drug-induced hypergastrinaemia does not necessarily exert trophic effects on parietal cells. Furthermore, the finding that omeprazole abolishes the effect of atropine suggests that omeprazole interferes with trophic actions on parietal cells.

Influence of 16,16-dimethyl prostaglandin E2 on morphology and brush border enzymes of small-bowel mucosa. Differences in reactivity between adult and suckling rats.

High doses of 16,16-dimethyl prostaglandin E2 (dmPGE) are trophic to the small bowel of adult and suckling rats. In suckling rats this effect is paralleled by an increase in brush border enzyme activities, possibly indicating accelerated mucosal maturation. To investigate the possible physiological significance of this phenomenon, we examined whether this induction of intestinal enzyme activities can be reproduced in adult rats and whether cell growth and enzyme activity might be suppressed by indomethacin. Treatment twice daily for 2 weeks with 100 micrograms/kg dmPGE by intragastric instillation increased villus length in the proximal and distal small bowel by 36% and 40%, respectively, while 2 mg/kg indomethacin by subcutaneous injection had no effect. Maltase, trehalase, lactase, and sucrase activities were unchanged after dmPGE or indomethacin. [3H]-thymidine incorporation into DNA was not significantly influenced for up to 24 h after a single dose of both 100 micrograms/kg PGE intragastrically or 10 mg/kg indomethacin subcutaneously. These studies confirm that in adult rats large doses of 16,16-dm PGE2 increase the volume of the small-bowel mucosa. In contrast to the situation in suckling rats, the activity of hydrolytic brush border enzymes is not increased. There is thus no evidence that endogenous prostaglandins are trophic or influence brush border enzymes in the adult rat.

16,16-Dimethyl prostaglandin E2 stimulates growth and maturation of rat gastric and small-intestinal mucosa.

In adult rats topical application of 16,16-dm PGE2 (PGE) every 8 h for three weeks led to a dose-dependent increase of the height of the gastric and duodenal mucosa, especially pronounced in the antrum (+115% with the high dose). In the gastric corpus this resulted from an enlargement of the lamina propria and the epithelial cell mass, the latter mainly from a hyperplasia of the surface and foveolar mucous cells. In contrast, the number of parietal cells was not affected. These findings were corroborated by the observation that an increase of antral mucosal height was also induced by a similar parenteral PGE treatment regimen (dosage 25 micrograms/kg). Both longterm intragastric and intraperitoneal PGE treatment led to an increase in DNA synthesis within the mucosa of the gastric antrum and corpus by 19 to 74%. In a third study 25 or 100 micrograms/kg of PGE applied every 8 h intragastrically to 10 suckling rats from the 7th to 11th postnatal day resulted in a dose-dependent increase in the length of the villi and the disaccharidase activities (30-630%). These studies suggest that 16,16-dm PGE2 exhibits a trophic effect on both the stomach and the small bowel.

Both topical and systemic treatments with 16,16-dimethyl prostaglandin E2 are trophic to rat gastric mucosa.

As shown in a previous study, intragastric administration of 16,16-dimethyl prostaglandin E2 (PGE, 100 micrograms/kg t.i.d.) for three weeks induces growth of the gastric mucosa. The present experiments were designed to study the time course of histological changes after intragastric PGE and to test whether a similar effect could be observed after parenteral administration. Significant thickening of the corpus, but not the antral mucosa was observed after 3 days of intragastric treatment with PGE (100 micrograms/kg t.i.d.), whereas after three weeks the effect was more marked in the antrum than in the corpus. At a dose of 25 micrograms/kg t.i.d., intraperitoneal PGE increased the height of antral mucosa to a similar degree as seen after intragastric treatment. DNA synthesis as assessed by autoradiography after administration of 3H-thymidine at the end of the three week PGE treatment was increased both in the gastric corpus and antrum. Preliminary studies in suckling rats provide evidence that intragastric administration of PGE (100 micrograms/kg t.i.d.) from day 7 to 11 accelerates maturation of the gastric mucosa. It is concluded that thickening of gastric mucosa can be induced by both local and systemic administration of PGE and is due, at least in part, to increased proliferation of gastric mucosal cells.

[Ulcer prevention during anti-rheumatism therapy and in intensive medicine]. / Ulkusprophylaxe unter Antirheumatikatherapie und in der Intensivmedizin.

Gastrointestinal side effects are common to all nonsteroidal anti-inflammatory drugs (NSAID). Relevant to the patient are NSAID-induced dyspepsia and ulcer complications such as hemorrhage and perforation. The most important prophylactic means is repeated verification that the NSAID cannot be replaced by other measures, e.g. physical therapy or simple analgesics. If a NSAID is needed, it should be administered at the lowest effective dose. The present drugs used in preventing NSAID-induced ulcers and their complications are far from perfect. Major problems are adverse effects, high costs and insufficient efficacy in the prevention of ulcer complications. Thus, prophylactic antiulcer treatment is recommended in high-risk patients (as a primary prophylaxis) and in patients with previous ulcers (as a secondary prophylaxis). Similar arguments apply for prevention of ulcers in intensive-care patients. Patients at risk are critically ill, those with previous ulcers and in particular those with clotting disorders. Acid-reducing drugs are recommended for nonintubated patients, whereas sucralfate is preferred in patients on artificial ventilation because it is associated with a lower risk for nosocomial pneumonias.

Evolution of gastro-oesophageal reflux disease over 5 years under routine medical care--the ProGERD study.

BACKGROUND: The evolution of gastro-oesophageal reflux disease (GERD) under current management options remains uncertain. AIM: To examine whether, depending on the initial presentation, non-erosive (NERD) and erosive reflux disease (ERD) without Barrett's oesophagus will progress to more severe disease under current routine care following the resolution of the initial condition. METHODS: Patients with the primary symptom of heartburn were included at baseline, and stratified into non-erosive (NERD) and erosive reflux disease (ERD), LA grades A-D (Los Angeles classification). After a 2- to 8-week course with esomeprazole therapy to achieve endoscopic healing in ERD and symptom relief in NERD, patients were treated routinely at the discretion of their physician. We report oesophagitis status and the presence of endoscopic and confirmed Barrett's oesophagus after 5 years. RESULTS: A total of 6215 patients were enrolled in the study of whom 2721 patients completed the 5-year follow-up. Progression, regression and stability of GERD severity were followed from baseline to 5 years. Only a few patients with NERD and mild/moderate ERD progressed to severe forms of ERD and even Barrett's oesophagus. Most patients remained stable or showed improvement in their oesophagitis; 5.9% of the NERD patients, 12.1% of LA grade A/B patients and 19.7% of LA grade C/D patients in whom no Barrett's oesophagus was recorded at baseline progressed to endoscopic or confirmed Barrett's oesophagus at 5 years. CONCLUSION: Most GERD patients remain stable or improve over a 5-year observation period under current routine clinical care.