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Background and study aims In our endoscopy service, nonanesthetists administered propofol sedation has been used in more than 8000 procedures during the past 3 years. This study prospectively assessed the safety of propofol sedation in outpatient colonoscopy and esophagogastroduodenoscopy (EGD). Patients and methods A total of 300 consecutive outpatients (mean age 53, range 14-94) were enrolled in the study (139 colonoscopies, 161 EGDs). After an initial dose of 0.5 mg/kg (ASA I-II and age III or age >70 years), propofol was titrated in 10 mg boluses to a steady state of sedation by the endoscopy nurse under the endoscopist's supervision. Colonoscopy patients also received 25 mg pethidine (meperidine) and 20 mg butylscopolamine, whereas EGDs were performed with propofol sedation alone, without topical pharyngeal anesthesia. In addition to standard monitoring with pulse oximetry and automated sphygmomanometry, patients were also observed with sidestream capnography or measurement of electrocardiographic impedance changes, providing real-time graphic assessment of respiratory activity. All patients were given oxygen 2 L/min by nasal cannula during the entire procedure. Results Mean dosages of 157 mg (range 70-340) and 180 mg (60-400) propofol were administered for colonoscopy and EGD procedures, respectively. No episodes of apnea occurred. The oxygen saturation fell below 90 % for short periods of time in 11 patients (3.7 %). Three patients required a temporary increase in oxygen delivery. No assisted ventilation was necessary. In 22 patients (7.3 %), the mean blood pressure temporarily decreased below 50 mmHg. Two patients received a 500-ml infusion of normal saline. Conclusions Propofol can be safely administered for sedation during colonoscopy and esophagogastroduodenoscopy by nonanesthetists who are familiar with the pharmacological properties and use of this drug.

Summary Aim : The effect of ABT-229, a new macrolide with no antibacterial activity, on gastro-oesophageal reflux, oesophageal motility and gastric emptying in patients with gastro-oesophageal reflux disease was investigated. Methods : Twenty-one patients were treated with a placebo and ABT-229 (2.5, 5 or 10 mg b.d.) in a randomized, incomplete crossover study design. Ambulatory 24-h pH manometry was performed and gastric emptying was assessed by the 13C-octanoic acid breath test on the seventh day of treatment. Results : A significant decrease was found in the mean (± s.e.) percentage of reflux time (intra-oesophageal pH

Background: Reflux of duodeno-gastric juice into the oesophagus appears to be involved in the pathogenesis of both reflux oesophagitis and oesophageal adenocarcinoma. Although proton pump inhibitors have been shown to decrease acid reflux and heal oesophagitis, their effect on biliary reflux and motility is less clear. Aim: To investigate whether pantoprazole also reduces bile reflux and whether this is paralleled by a change in oesophageal motility. Methods: Combined 24-h measurements of intraoesophageal bilirubin concentration, pH and pressure were performed in 18 symptomatic patients with endoscopically proven reflux oesophagitis before and on day 28 of treatment with pantoprazole, 40 mg/day, under standardized conditions. A reflux symptom score was determined initially and every 2 weeks thereafter. After 56 days on medication, a control endoscopy was performed. Results: The symptom score and the acid and bile reflux improved significantly, whereas the motility parameters did not change during the study period. Helicobacter pylori-positive patients had a significantly higher bile reflux time (32.1 ± 4.3%) than H. pylori-negative patients (16.3 ± 3.1%) (P=0.009). The endoscopic healing rate was 89%. The cough symptoms disappeared in three of four patients. Conclusions: The proton pump inhibitor pantoprazole decreases both acid and bile reflux. The decrease of bile reflux cannot be explained by increased oesophageal clearance as oesophageal motility did not improve with therapy. Interestingly, H. pylori infection of the stomach was associated with higher levels of oesophageal bile reflux.

Background : Over-the-counter status has recently been approved for low-dose H2-antagonists in several countries. Insufficient information is currently available on the effect of food in low-dose H2-antagonist therapy. Aim : Compare the antisecretory efficacy of low-dose ranitidine and famotidine in fasting and non-fasting volunteers. Methods : Twenty volunteers were randomized into a double-blind, placebo-controlled, multiple-step crossover study comparing the antisecretory efficacy of 75 mg ranitidine, 10 mg famotidine and placebo over 12 h using intragastric pH-metry. Two standard meals were given after 4 h and 8 h of medication. Fifteen volunteers also participated in a second study comparing the antisecretory effect of both drugs, both with and without meals. Results : In non-fasting subjects, the percentage of time with pH > 4 was similarly elevated for both drugs compared with placebo over the first 8 h: ranitidine 39.3%, famotidine 29.5%, placebo 9.5% (P 0.05). Comparing the first 4-h period with the second, the percentage of pH > 4 was significantly reduced for both drugs in the second period in the subjects given food at the end of the initial 4-h period (ranitidine 56.9% vs. 26.6%, P = 0.005; famotidine 46.6% vs. 13.3%, P

Esophageal function testing was developed to aid diagnosis in patients with negative endoscopy. Although combined 24-h esophageal pH-manometry is now commercially available, its routine clinical effectiveness has not yet been studied.From 1992 to 1996 we evaluated 303 consecutive patients who were first-time referrals to our unit for 24-h esophageal pH-manometry. The referral indications were gastroesophageal reflux disease, 47.2%; dysphagia, 18.5%; non-cardiac chest pain, 14.9%; connective tissue disease, 13.2%; and symptomatic patients after antireflux surgery, 6.3%.Overall, esophageal function testing altered the diagnosis of 44% of the patients, confirmed it in 38%, and specifically changed the management of 66%. The final clinical 'diagnosis' was reflux disease, 54% (32% with non-specific esophageal motility disorder); connective tissue disease, 9.9%; achalasia, 9.6%; other specific esophageal motility disorders, 3.3%; non-specific esophageal motility disorders, 6.9%; and normal, 16.2%. The cost per testing was estimated to be US$305 and per change in management US$465.Combined 24-h pH-manometry has been shown to be a useful and cost-effective test for the management of selected patients in whom the primary investigation was insufficient.

Die Kombination der beiden typischen Symptome – Sodbrennen und Regurgitation – hat eine hohe Spezifitat fur das Vorliegen einer gastroosophagealen Refluxkrankheit. Die weniger typischen Symptome sind epigastrische Schmerzen, Dysphagie, Odynophagie, Pharyngitis und refluxinduzierte pulmonale Symptome oder intermittierende Thoraxschmerzen. Beim Fehlen von Alarmsymptomen kann die Diagnose indirekt durch Besserung der Symptome unter einer saurehemmenden Therapie bestatigt werden. In alien anderen Fallen ist als erste invasive Maβnahme eine obere Panendoskopie indiziert. Findet man dabei eine Refluxosophagitis, eventuell mit Komplikationen, kann direkt eine spezifische Therapie eingeleitet und, falls notig, der Patient in ein Nachsorgeprogramm aufgenommen werden. Besondere Aufmerksamkeit gilt dabei dem Barrett-Osophagus (Endobrachyosophagus), charakterisiert durch eine Zylinderepithelmetaplasie, als potentiell prakanzerose Veranderung. Beim Fehlen von makroskopischen Schleimhautveranderungen kann dank der ambulanten 24-Stunden-pH-(Mano-)Metrie eine Refluxkrankheit mit hoher Sicherheit erfaβt oder ausgeschlossen werden. Mittels gleichzeitig durchgefuhrter Manometrie konnen relevante Motilitatsstorungen erkannt werden, die teilweise als Begleitphanomen der Refluxkrankheit, teilweise aber auch im Rahmen anderer Grunderkrankungen auftreten. Sie sind als Ursache einer sogenannten sekundaren Refluxosophagitis auszuschlieβen. Weitere diagnostische Maβnahmen wie Rontgenuntersuchungen, Szintigraphie, Provokationsteste und Endosonographie sind nur in speziellen Fallen (vor allem innerhalb klinischer Studien) indiziert.

En tenant compte de plusieurs nouvelles etudes portant sur le developpement et le traitement de la maladie diverticulaire, cet article apporte un eclairage critique sur les traitements standard de reference.

Mit Rucksicht auf mehrere neue Studien zur Entstehung und Behandlung der Divertikelkrankheit werden in diesem Artikel die traditionellen Behandlungsstandards kritisch beleuchtet.

Mit der Einfuhrung neuer antisekretorischer Substanzen hat die medikamentose Therapie der Refluxkrankheit in den letzten zehn Jahren die Antirefluxchirurgie weitgehend verdrangt. Als einzige Indikationen zur Chirurgie blieben therapieresistente Falle oder solche mit Komplikationen wie Strikturen oder Barrett-Osophagus. Dies scheint sich mit dem Aufkommen der laparoskopischen Technik zu andern. Vorgestellt werden die Resultate unserer ersten 7 Falle. Vier der 5 Patienten mit erfolgreicher laparoskopischer Fundoplicatio sind seither beschwerdefrei, bei einem Patienten kam es zum Rezidiv durch Losung der Manschette. Die kurzfristigen Resultate sind bisher mit jenen der konventionellen Technik vergleichbar. Falls sich diese langerfristig bestatigen, wird die laparoskopische Antirefluxtherapie ihren Platz behaupten.

The effect of heparin on thrombogenesis induced by the subendothelium of rabbit aorta was investigated in 24 healthy volunteers after intravenous injection of different doses (0, 1000, 2500, and 5000 IU). By using an ex vivo perfusion chamber system, the interaction between flowing blood and exposed subendothelium was measured at low (50 s-1), intermediate (650 s-1), and high (2600 s-1) wall shear rates. The low shear rate simulated blood flow in venous, the intermediate shear rate in arterial, and the high shear rate in small or stenosed arterial vessels. Deposition of fibrin, platelets, and platelet thrombi on vascular subendothelium (SE) was quantified by morphometrical and immunological techniques. Fibrin deposition prevailed at low shear rates and was only minimal at high shear rates (30 +/- 1% vs. 1 +/- 0.4% coverage of SE with fibrin, means +/- SEM, p less than 0.001). In contrast, the interaction of platelets with SE was more intense at high compared to low shear rates, as indicated by higher platelet adhesion (54 +/- 5% vs. 4 +/- 1% coverage of SE with platelets, p less than 0.001) and platelet thrombus volumes (4.8 +/- 1.3 vs. 0.5 +/- 0.1 microns 3/microns 2, p less than 0.001). Fibrin deposition on SE was inhibited by heparin in a dose-dependent manner and was abolished after high doses. In addition, high doses of heparin reduced the height and volume of platelet thrombi at low and intermediate wall shear rates, but no effect was found at the high shear rate. Our data show that heparin inhibits the formation of both fibrin and platelet thrombi on vascular subendothelium. The lack of effect of heparin on platelet thrombus formation at high shear rates indicates that thrombin modulates the growth rate and/or stability of platelet thrombi at low and intermediate shear rates, whereas additional factors may control platelet thrombus growth and stability at high shear conditions.

Prostaglandins and indomethacin exert trophic effects on the gastric mucosa which could be advantageous to ulcer healing. To examine the possibility of such a role, the effects of high and low doses of prostaglandin, indomethacin and omeprazole were compared in an experimental ulcer model. Gastric ulcers were induced in rats by a crypoprobe. This was followed by 5 to 10 days’ treatment with 16,16-dimethyl dinoprostone (prostaglandin E2) [5 or 100 μg/kg twice daily, intragastrically], omeprazole (40 μmol/kg once daily, subcutaneously), indomethacin (2 mg/kg twice daily, subcutaneously) or placebo. At the end of treatment, plasma gastrin levels, the size and depth of the ulcer and the labelling index in the area neighbouring the ulcer were measured. Omeprazole accelerated ulcer healing, as indicated by a smaller ulcer area and depth after 10 days’ treatment. Prostaglandins did not affect ulcer healing despite an increase in the height of the mucosa adjacent to the ulcer. Indomethacin delayed ulcer healing and reduced the labelling index of ulcer-adjacent mucosa. These observations suggest that the trophic and ‘cytoprotective’ effects of prostaglandins are not relevant for ulcer healing in this model. This is not unexpected, since the trophic effect induced by prostaglandins mainly results from an increase in the life cycle of the superficial mucus-producing cells and not by the enhancement of cell reproduction.

Chronic gastrointestinal bleeding can occur as recurrent overt blood loss (hematochezia, melena or hematemesis) or as occult gastrointestinal bleeding. Occult bleeding from the gastrointestinal tract is typically identified by either a positive stool test for occult blood or by the presence of iron deficiency anemia. The major cause of iron deficiency anemia is blood loss from the gastrointestinal tract. In women, menstrual blood loss must also be considered. Approximately 5% of all patients with gastrointestinal bleeding do not have lesions identified by upper or lower endoscopy. In most of these patients, the bleeding source responsible for the chronic blood loss is located in the small bowel. The most common cause for gastrointestinal bleeding of small bowel origin is angiodysplasia, tumors of the small intestine (primary benign or malignant tumors or metastatic lesions) and various other causes (such as ulcers caused by nonsteroidal antiinflammatory drugs, aortoenteric fistula, diverticula, endometriosis and hemobilia). After negative upper and lower endoscopy, examination of the small bowel is warranted. Methods to evaluate the small bowel include enteroscopy, capsule endoscopy, small bowel radiographic studies and angiography. The role of each examination depends upon the clinical setting and available expertise. Explorative surgery with intraoperative enteroscopy is generally reserved for patients with ongoing transfusion requirement and in those under the age of 5O years (to rule out a small bowel neoplasm). This article reviews the concepts of evaluation and care of patients with chronic gastrointestinal bleeding.

The effect of ABT-229, a new macrolide with no antibacterial activity, on gastro-oesophageal reflux, oesophageal motility and gastric emptying in patients with gastro-oesophageal reflux disease was investigated.Twenty-one patients were treated with a placebo and ABT-229 (2.5, 5 or 10 mg b.d.) in a randomized, incomplete crossover study design. Ambulatory 24-h pH manometry was performed and gastric emptying was assessed by the 13C-octanoic acid breath test on the seventh day of treatment.A significant decrease was found in the mean (+/- s.e.) percentage of reflux time (intra-oesophageal pH4) for ABT-229 5 mg b.d. and 10 mg b.d., but not for 2.5 mg b.d., compared with placebo. For ABT-229 5 mg, it was 8.5 +/- 0.5% vs. 10.7 +/- 0.7% (P0.038) and, for ABT-229 10 mg, it was 6.6 +/- 0.5% vs. 8.4 +/- 0.5% (P0.019). There were no significant differences in any of the analysed manometric parameters. In addition, the gastric half-emptying time for all doses of ABT-229 did not differ significantly from that after placebo.ABT-229 is able to reduce slightly, but significantly, acid reflux in patients with gastro-oesophageal reflux disease. This effect does not appear to be due to a measurable improvement in oesophageal motility or gastric emptying.

Reflux of duodeno-gastric juice into the oesophagus appears to be involved in the pathogenesis of both reflux oesophagitis and oesophageal adenocarcinoma. Although proton pump inhibitors have been shown to decrease acid reflux and heal oesophagitis, their effect on biliary reflux and motility is less clear.To investigate whether pantoprazole also reduces bile reflux and whether this is paralleled by a change in oesophageal motility.Combined 24-h measurements of intraoesophageal bilirubin concentration, pH and pressure were performed in 18 symptomatic patients with endoscopically proven reflux oesophagitis before and on day 28 of treatment with pantoprazole, 40 mg/day, under standardized conditions. A reflux symptom score was determined initially and every 2 weeks thereafter. After 56 days on medication, a control endoscopy was performed.The symptom score and the acid and bile reflux improved significantly, whereas the motility parameters did not change during the study period. Helicobacter pylori-positive patients had a significantly higher bile reflux time (32.1 +/- 4.3%) than H. pylori-negative patients (16.3 +/- 3.1%) (P=0.009). The endoscopic healing rate was 89%. The cough symptoms disappeared in three of four patients.The proton pump inhibitor pantoprazole decreases both acid and bile reflux. The decrease of bile reflux cannot be explained by increased oesophageal clearance as oesophageal motility did not improve with therapy. Interestingly, H. pylori infection of the stomach was associated with higher levels of oesophageal bile reflux.

Over-the-counter status has recently been approved for low-dose H2-antagonists in several countries. Insufficient information is currently available on the effect of food in low-dose H2-antagonist therapy.Compare the antisecretory efficacy of low-dose ranitidine and famotidine in fasting and non-fasting volunteers.Twenty volunteers were randomized into a double-blind, placebo-controlled, multiple-step crossover study comparing the antisecretory efficacy of 75 mg ranitidine, 10 mg famotidine and placebo over 12 h using intragastric pH-metry. Two standard meals were given after 4 h and 8 h of medication. Fifteen volunteers also participated in a second study comparing the antisecretory effect of both drugs, both with and without meals.In non-fasting subjects, the percentage of time with pH4 was similarly elevated for both drugs compared with placebo over the first 8 h: ranitidine 39.3%, famotidine 29.5%, placebo 9.5% (P0. 001); but not for the last 4 h after the second meal (P0.05). Comparing the first 4-h period with the second, the percentage of pH4 was significantly reduced for both drugs in the second period in the subjects given food at the end of the initial 4-h period (ranitidine 56.9% vs. 26.6%, P = 0.005; famotidine 46.6% vs. 13.3%, P0.001). It remained more or less constant, however, for the second 4-h period in fasting subjects (ranitidine 41% vs. 28.1%, P = 0.46; famotidine 52.7% vs. 52.2%, P = 0.12).In non-fasting volunteers both low-dose H2-antagonists had comparable antisecretory effects and were superior to placebo over the first 8 h of therapy. Both drugs achieved a slightly higher antisecretory effect without food intake compared to with food intake.

In healthy subjects and patients with bleeding peptic ulcers, ranitidine and omeprazole, given parenterally, achieve high intragastric pH values on the first day of therapy. However, data on the antisecretory effect beyond the first 24 h is scanty. In addition, the superiority of either infusion or injection of omeprazole remains unproven. Thus, we have compared the antisecretory effect of high dose omeprazole and ranitidine infusion and injection over the critical first 72 h.A total of 34 healthy volunteers were randomized into a double-blind crossover 72 h intragastric pH-metry study (data compared: median pH, percentage of time with pH4 and pH6). Omeprazole-infusion: initial bolus of 80 mg + 8 mg/h; omeprazole-injection: initial bolus of 80 mg + 40 mg/6 h; Ranitidine-infusion: initial bolus of 50 mg + 0.25 mg/kg/h; ranitidine-injection: 100 mg/6 h.Omeprazole-infusion versus ranitidine-infusion: on day 1: median pH 6.1 vs 5.1 (p = 0.01) and 95% vs 70% was pH4 (p0.01); on day 2: median pH 6.2 vs 3.2 (p0.01); and 100% vs 38% was pH4 (p0.01); on day 3: median pH 6.3 vs 2.7 (p0.01); 100% vs 26% was pH4 (p0.01). Injections of both drugs were significantly less effective than the infusions on day 1. Thereafter, omeprazole injection was almost as effective as omeprazole infusion, whereas ranitidine injection and infusion were equally effective.Our study shows, for the first time, that omeprazole infusion was significantly superior to all other regimens by having a high median pH6 on each day. The tolerance effect of ranitidine, however, led to a rapid loss of antisecretory activity on days 2 and 3, rendering it inappropriate for situations in which high intragastric pH-levels appear to be essential.

Continuous Infusion or Repeated Intravenous Bolus Injection of High-Dose Omeprazole in Patients at High Risk of Rebleeding from Peptic Ulcers?

Self-expanding metal stents are a promising alternative in the palliation of malignant esophageal obstruction, but the relative value of different stent types is not well established.During a 3-year enrollment period in four different centers, 82 consecutive patients with malignant dysphagia without tumor recurrence after surgery or esophagorespiratory fistulas received either an uncovered Wallstent (44 patients) or a knitted nitinol stent (38 patients).Age (median: 79 yr), sex (F:M = 33:67), dysphagia score (median: 3), Karnofsky score (median: 53), body mass index (median: 19), type of pretreatment, tumor stage, stricture length (median: 5.4 cm), and stricture location were comparable in both stent groups. After stent placement, median dysphagia score improved markedly in both groups by two points. Procedure-related mortality (16 vs 0%; p0.01), early complication rate (32 vs 8%; p0.01), and severe persistent pain after stent placement (23 vs 0%; p0.002) were higher in the Wallstent compared with the knitted nitinol stent group. In contrast, stent dysfunction (7 vs 32%; p0.005), reintervention rate (9 vs 34%; p0.005), and costs were lower in the Wallstent compared with the nitinol stent group.In malignant esophageal obstruction, both stents markedly improved dysphagia. Uncovered Wallstents seem to cause more early severe complications than knitted nitinol stents. In contrast, stent dysfunction, reintervention rate, and costs appear to be higher in the nitinol stent group.

Despite years of successful use of calcium-containing antacids in acid-related disease, allegations of gastric rebound following their intake has brought these agents into disrepute. By assessing intragastric acidity over the 24-h period, we evaluated whether antacids induce a clinically relevant acid rebound.Twelve healthy volunteers were assigned to a double-blind, placebo-controlled, triple cross-over comparison of placebo, Maalox Liquid, and a calcium-containing antacid, Rennie Liquid. The two antacids had identical neutralizing capacity. Each drug was administered at standard doses q.i.d 1 h after the main meals (at 1000, 1400, and 1900 h) and at bedtime (2300 h). Intragastric acidity was monitored by continuous ambulatory 24-h pH-metry on 3 separate days with a wash-out period of 1 wk. Special attention was given to the acidity of pre-determined postantacid time intervals during the day and night.Both antacids led to a significant increase of the median 24-h pH and the median pH of the first postantacid hour, compared with placebo. Neither Rennie Liquid nor Maalox Liquid led to a drop of intragastric pH during the putative acid rebound time (2nd and 3rd postantacid hr and at night). A marginal increase in serum calcium and gastrin concentration with Rennie Liquid, and magnesium concentration with Maalox Liquid, were observed.No gastric acid rebound was detected with the calcium carbonate-containing antacid, Rennie Liquid, or with Maalox Liquid at standard doses. An identical increase of intragastric pH was achieved with Rennie Liquid and Maalox Liquid during the first postantacid hour and the entire 24-h period.

Conservative treatment of acute pancreatitis is symptomatic and depends on the severity of the disease. For treatment of mild pancreatitis, fasting and intravenous application of fluids and analgetics is usually sufficient. Patients with severe pancreatitis should be monitored in an Intensive Care Unit and may require antibiotics. For treatment of acute pancreatitis, a large number of interventions has been suggested. They include nasogastric tubes, drugs which reduce pancreatic and gastric secretion, and treatments which inhibit activated proteases. Controlled studies have shown that most of these measures are ineffective. The value of early ERCP in acute pancreatitis is still under debate. ERCP appears to be helpful in biliary pancreatitis, especially if choledocholithiasis is present. Surgery should be reserved to those patients who do not respond to conservative treatment.

We describe a 64-year-old woman with a malignant intestinal T-cell lymphoma who presented four years later with disabling osteomalacia and secondary hyperparathyroidism due to malabsorption. Only two years later, when the patient had developed fatty stools, flatulence and weight loss, diagnosis of gluten-sensitive enteropathy (GSE) was confirmed by small-intestine biopsy. This case report illustrates that in adults GSE can be oligosymptomatic for long periods. In cases of osteomalacia or rare intestinal T-cell lymphoma a detailed history of bowel movements, inspection of stools, quantification of fat excretion in stools and laboratory tests for malabsorption are recommended. Positive antibodies against gliadin, endomysium and reticulin may support the diagnosis of GSE. However, intestinal biopsy is necessary to verify the presence of GSE. In view of the unspecific histological changes, a follow-up biopsy is recommended in oligosymptomatic cases. Serial measurements of antibodies allow supervision of compliance for a diet strictly free of gluten. In addition, lactose containing milk products need to be restricted initially because of secondary lactase deficiency.

With the modern antisecretory drugs, healing of gastroduodenal ulcers can be achieved in almost every patient. If helicobacter pylori (H. pylori) infection is treated successfully, relapse rates are reduced by up to 90%. Research on the ideal regimen for H. pylori eradication, i.e. short treatment with only few drugs, is still in progress. The combination of a proton pump inhibitor and a single antibiotic appears most promising. Proton pump inhibitors can successfully heal gastroduodenal ulcers associated with the intake of nonsteroidal anti-inflammatory drugs (NSAIDs), even if drug intake is continued. Ulcer prophylaxis in all patients taking NSAIDs is too expensive and should be restricted to patients with an increased risk for ulcer development.

SUMMARY Background: High-dose once daily oral omeprazole dosing can inhibit acid secretion almost completely but several days elapse before maximum efficacy is established. The acid inhibitory effect obtained with high doses of a histamine H2-receptor antagonist is built up rapidly but has the tendency to fade-the term tolerance’has been applied to characterize this phenomenon. Methods: To obtain more information on the dynamics of acid inhibition during prolonged dosing, we compared the acid suppressory effects of oral high-dose omeprazole with high-dose ranitidine. Twenty-eight healthy volunteers were randomly assigned to a 2-week dosing with omeprazole or ranitidine in a double-blind, double-dummy, parallel-group study design. Omeprazole was given as 1 capsule of 40 mg mane and ranitidine as 2 tabs of 150 mg q.d.s. The median 24-h pH, daytime pH and night-time pH were measured by ambulatory continuous 24-h pH metry on days -8, -6, 1. 2, 7 and 14. Results: High reproducibility was observed for the two baseline acidity measurements. Ranitidine exerted its peak acid suppressant effect on day 1 of dosing; the degree of acid inhibition faded from day 2 to 7, with no significant change thereafter. The decline in antisecretory activity was more pronounced during the day than the night. In contrast, acid inhibition by omeprazole increased throughout the first week, and antisecretory activity was stable thereafter. Despite the considerable differences in median intragastric pH values at the end of the 14-day study, plasma gastrin levels were elevated to a similar degree with both medications. Conclusions: This study confirms the ‘tolerance’phenomenon previously observed with high-dose histamine H2-receptor antagonist dosing. The dynamics with which it occurs exclude a typical exaggerated first-dose response. Prolonged high-dose histamine H2-receptor dosing compromises the feedback mechanism regulating gastrin release, whilst this is maintained during dosing with omeprazole.

At present, an esophageal origin can be identified in as many as 50% of patients with non cardiac chest pain. In about 1/3 of these patients, gastroesophageal reflux can be documented. In the remaining 2/3 of patients, various disorders of esophageal motility have been described. Abnormal esophageal motility may be classified as nutcracker esophagus, diffuse esophageal spasm, achalasia, hypertensive lower esophageal sphincter, and nonspecific esophageal motility disorders. Simultaneous recording of intraesophageal pH, pressure, and symptoms (combined 24-h pH-metry and manometry) makes it possible to test the temporal association between pain, reflux, or abnormal motility. This review describes the diagnostic evaluation and therapeutic options in patients with non cardiac chest pain. Identification of the esophageal origin of chest pain should improve the therapeutic results.

The effect of ranitidine and cisapride on acid reflux and oesophageal motility was investigated in 18 patients with endoscopically verified erosive reflux oesophagitis. Each patient was treated with placebo, ranitidine (150 mg twice daily), and ranitidine (150 mg twice daily) plus cisapride (20 mg twice daily) in a double blind, double dummy, within subject, three way cross over design. Oesophageal acidity and motility were monitored under ambulatory conditions for 24 hours on the fourth day of treatment, after a wash out period of 10 days during which patients received only antacids for relief of symptoms. Acid reflux was monitored by a pH electrode located 5 cm above the lower oesophageal sphincter. Intraoesophageal pressure was simultaneously recorded from four transducers placed 20, 15, 10, and 5 cm above the lower oesophageal sphincter. Upright reflux was three times higher than supine reflux (median (range) 13.3 (3.7-35.0)% v 3.7 (0-37.6)% of the time with pH < 4.0, p < 0.01, n = 18). Compared with placebo, ranitidine decreased total reflux (from 10.0 (3.2-32.6)% to 6.4 (1.2-22.9)%, p < 0.01), upright reflux (p < 0.05), supine reflux (p < 0.001), and postprandial reflux (p < 0.01), but did not affect oesophageal motility. The combination of ranitidine with cisapride further diminished the acid reflux found with ranitidine--that is, cisapride led to an additional reduction of total reflux (from 6.4 (1.2-22.9)% to 3.7 (1.0-12.7)%, p < 0.01), supine reflux (p < 0.05), and postprandial reflux (p < 0.05). Cisapride also reduced both the number (p

Esophageal diseases frequently cause symptoms such as heartburn, epigastric pain and dysphagia. This article discusses the indications, techniques and limitations of currently available diagnostic procedures. Investigation of symptoms should proceed in a logical stepwise manner, beginning with endoscopy to exclude esophagitis or neoplasia. Symptoms due to acid reflux can be identified by 24h esophageal pH-metry to document a temporal association between symptoms and episodes of esophageal acidification. Stationary or ambulatory manometric recording of esophageal pressures can be used to diagnose esophageal motor disorders such as achalasia, nutcracker esophagus, diffuse esophageal spasm, or dysfunction of the upper or lower esophageal sphincter. Combined 24 h pH-manometry should be used to test the temporal association between pain, reflux, or abnormal motility in patients with non-cardiac chest pain. Video-fluoroscopy is the most appropriate technique to diagnose swallowing disorders. Pulmonary aspiration of gastro-esophageal reflux can be documented with scintigraphy.

The diagnosis of gastroesophageal reflux disease (GERD) entails the identification of patients with esophagitis and its complications as well as patients who have symptoms but no mucosal disease. Endoscopy is mandatory to establish a diagnosis of reflux esophagitis, to exclude other esophageal disease and to permit directed biopsy if columnar metaplasia, dysplasia or carcinoma is suspected. The lesions of reflux esophagitis--erosions, ulceration, stricturing and metaplasia--should be identified and graded independently, using a classification system such as the recently described "MUSE" (Metaplasia, Ulcer, Stricture, Erosions) system. Fluoroscopy can identify associated structural changes such as stricturing or esophageal shortening. Measures of esophageal acid exposure time may be used to quantify reflux before and after treatment; however, if the patient has typical symptoms but no esophagitis, a temporal association between symptoms and episodes of esophageal acidification should be sought. Ambulatory 24-hour esophageal pH-monitoring with accurate event-marking provides recordings suitable for an objective statistical analysis, which was evaluated prospectively in 14 patients. Computerized analysis of 24-hour esophageal pH recordings diagnosed 5 patients as having acid-related symptoms although only 3 of 5 patients fulfilling the criteria for pathological reflux had pH-related chest pain. This finding was confirmed by 5 experts who analyzed all recordings visually, unaware of the result of the computer analysis. The Bernstein test should be reserved for patients whose symptoms are too infrequent to permit an objective assessment of symptom occurrence during pH monitoring. In conclusion, i) endoscopy is the test of choice for the diagnosis of esophagitis but it should be supplemented by a standardized and reliable scoring system for disease severity; ii) ambulatory esophageal pH recording with accurate event-marking is the test of choice for the diagnosis of GER-related symptoms, but it should be supplemented by an objective assessment of the temporal relationship between symptoms and esophageal pH; and iii) esophageal manometry is the test of choice for evaluating esophageal peristalsis and LES (lower esophageal sphincter) function but, in the context of GERD, its main indication is the assessment of GERD patients who are being considered for surgery. The widespread use of other tests for clinical purposes must await a better understanding of the pathophysiological mechanisms which can lead to the development of GERD.

We investigated the effect of oral anticoagulation on thrombogenesis induced by the subendothelium of rabbit aorta. Eighteen healthy volunteers underwent a 2-week treatment with the oral coumarin preparation phenprocoumon to a target international normalized ratio (INR) of 5. By using an ex-vivo perfusion chamber system, the interaction between flowing blood and exposed subendothelium was measured at low (50 sec-1) and high (650 sec-1) wall shear rates. The low shear rate simulated blood flow in venous vessels and the high shear rate simulated blood flow in arterial vessels. Deposition of fibrin, platelets, and platelet thrombi on subendothelium was quantified by morphometric and immunologic techniques. Fibrin deposition prevailed at the low shear rate (183 +/- 57 ng/mm2 vs 46 +/- 16 ng/mm2, low vs high shear rate; mean +/- SEM; p less than 0.01). In contrast, the interaction of platelets with subendothelium was more intense at high shear rates when compared with low shear rates, as indicated by higher platelet adhesion (44% +/- 2% vs 9% +/- 1% coverage of subendothelium with platelets, p less than 0.001) and platelet thrombus volumes (3.6 +/- 0.4 microns 3/microns 2 vs 1.3 +/- 0.3 microns 3/microns 2, p less than 0.001). Fibrin deposition on subendothelium was substantially reduced even at a low intensity of anticoagulation (reduction by 60% at INR 2.1 and by 75% at INR 3.7) and was abolished after high coumarin doses (INR 5.2). In contrast, a significant inhibition of platelet thrombus formation could be achieved only by high doses of phenprocoumon (INR 5.2). Our data indicate that relatively low doses of oral anticoagulants (INR between 2 and 3.5) substantially inhibit the fibrin formation on subendothelium prevailing at venous shear conditions, whereas a high intensity of anticoagulation (INR 4 to 5) is necessary to inhibit the formation of platelet-rich thrombi prevailing at arterial shear conditions.

We investigated the effect of oral contraceptives with low and high estrogen concentration on blood coagulation and thrombogenesis, induced by vascular subendothelium of rabbit aorta exposed to flowing human blood. Twenty healthy women intending to take oral contraceptives were studied [1] before drug ingestion (control), and subsequently during the intake of oral contraceptives with [2] low estrogen content (20 micrograms ethinyl estradiol and 150 micrograms desogestrel per day) and [3] high estrogen content (50 micrograms ethinyl estradiol and 125 micrograms desogestrel per day). All experiments were performed between day 17 and 21 of the menstrual cycle and drug effects were studied during the third tablet cycle. Deposition of fibrin, platelets and platelet thrombi on vascular subendothelium was tested at a defined blood flow and wall shear rate (10 ml/min, 650 s-1) and was quantified by morphometrical techniques. Treatment with the low and high dose contraceptive increased the plasma levels of ethinyl estradiol (728 +/- 139 and 1438 +/- 212 vs. 0 fmol/l [low and high dose vs. control], means +/- SEM, P less than 0.001) and fibrinogen (2.3 +/- 0.1 and 2.6 +/- 0.1 vs. 2.0 +/- 0.1 g/l, P less than 0.05); and decreased antithrombin III activity (95 +/- 3 and 92 +/- 3 vs. 101 +/- 3 %, P less than 0.05). Fibrin deposition on vascular subendothelium was enhanced by the high dose contraceptive only (47 +/- 4 vs. 35 +/- 4 % coverage of the subendothelial surface with fibrin, high dose vs. control, P less than 0.05). The subendothelial deposition of platelets and platelet thrombi was not changed by contraceptive treatment. These results indicate that treatment with high dose contraceptives leads to an increase of fibrin-subendothelial interactions, whereas low dose contraceptives do not significantly alter the blood-subendothelium interactions. observed in this ex vivo model of thrombogenesis.

The aim of this study was to assess the role of neutrophilic elastase in anoxia-reoxygenation-induced, neutrophil-mediated injury to microvascular endothelium. Cultured bovine microvascular endothelial cells were grown to confluence and labeled with 51Cr. The endothelial cells were exposed to a 30-min period of anoxia and subsequently reoxygenated. Endothelial cell injury, quantitated as 51Cr release and cell detachment, was determined 8 h after reoxygenation. Addition of neutrophils upon reoxygenation enhanced the anoxia-reoxygenation-induced increase in 51Cr release and cell detachment. The neutrophil-mediated injury was associated with elastase release from the neutrophils. Four agents were used to inhibit neutrophilic elastase activity: Eglin C, methoxysuccunyl-Ala2-Pro-Val-CH2Cl, L658,758, and a monoclonal antibody against neutrophilic elastase. All elastase inhibitors attenuated the neutrophil-mediated endothelial cell detachment but not 51Cr release. Addition of purified human neutrophilic elastase, at a level that mimicked the release from neutrophils, increased cell detachment in endothelial cells exposed to anoxia-reoxygenation but did not affect 51Cr release. Our results indicate that elastase plays an important role in anoxia-reoxygenation-induced, neutrophil-mediated endothelial cell dysfunction.

The major objective of this study was to develop an in vitro model of ischemia/reperfusion (I/R)-induced microvascular injury. Cultured venular endothelial cells were grown to confluency, labeled with 51Cr, and exposed to different durations of anoxia (0.5, 1, 2, 3, and 4 h). 51Cr release and cell detachment (indexes of cell injury) were determined at different times after reoxygenation (1, 2, 4, 6, 8, and 18 h). Because in vivo studies have implicated neutrophils in I/R injury, in some experiments human neutrophils were added to the endothelial cells upon reoxygenation. Periods of anoxia greater than or equal to 2 h resulted in 70-80% 51Cr release and 80-95% cell detachment upon reoxygenation. Under these conditions (near maximal injury), the addition of neutrophils produced negligible effects. Periods of anoxia less than or equal to 1 h resulted in 30-40% 51Cr release and 50-60% cell detachment. Under these conditions (moderate cell injury), addition of neutrophils enhanced endothelial cell injury. Using a 30-min period of anoxia, we also assessed the effects of superoxide dismutase (SOD; 300 U/ml) and allopurinol (20 microM) on anoxia/reoxygenation (A/R)-induced injury in the presence or absence of neutrophils. In the absence of neutrophils, SOD or allopurinol did not protect against A/R-induced injury. However, in the presence of neutrophils, both SOD and allopurinol attenuated the increases in 51Cr release. The results derived using this in vitro model of I/R injury are largely consistent with published in vivo studies. Thus this in vitro model may provide further insights regarding the mechanisms involved in I/R injury.

We assessed the effect of hypoxia/reoxygenation on 14C-albumin flux across endothelial monolayers. Cultured bovine pulmonary artery endothelial cells were grown to confluence on nitrocellulose filters (pore size 12 microns). The endothelialized filters were mounted in Ussing-type chambers which were filled with cell culture medium (M 199). Equimolar amounts (33 nM) of 14C-labeled and unlabeled albumin were added to the hot and cold chambers, respectively. The monolayers were then exposed to successive periods (90 min) of normoxia (pO2 145 mmHg), hypoxia (pO2 20 mmHg), and reoxygenation (pO2 145 mmHg). A gas bubbling system was used to control media pO2 and to ensure adequate mixing. Four aliquots of culture media were taken during each period in order to calculate the 14C-albumin permeability across the endothelialized filter. In some experiments, either the xanthine oxidase inhibitor, oxypurinol (10 microM), or superoxide dismutase (600 U/mL), was added to the media immediately prior to the experiments. As compared to the normoxic control period, albumin permeability was 1.5 times higher during hypoxia (p less than 0.01) and 2.3 times higher during reoxygenation (p less than 0.01). The reoxygenation-induced increase in albumin permeability was prevented by either oxypurinol or superoxide dismutase. These data indicate that xanthine oxidase-derived oxygenmore » radicals contribute to the hypoxia/reoxygenation-induced endothelial cell dysfunction. The altered endothelial barrier function induced by hypoxia/reoxygenation is consistent with the microvascular dysfunction observed following reperfusion of ischemic tissues.« less

Introduction: Preoperative chemoradiotherapy is generally recommended for locally advanced esophageal cancer (clinical stage T3 or T4 or nodal positive disease) but not for early cancer (clinical stage T0 to T2, N0). EUS has been described as the most accurate method to distinguish between early and locally advanced stage in several studies. Recently however, the high accuracy of EUS (90% or higher) was questioned by some investigators. This raises the issue whether the results of studies focused on EUS accuracy may be directly translated into daily clinical practice. Aim & Methods: The aim of this retrospective analysis was to assess the accuracy of preoperative EUS to distinguish between early and locally advanced esophageal cancer in daily clinical practice outside a study setting. EUS was performed by several investigators, including trainees in one university hospital. For this purpose, EUS reports and patient files (medical and surgical) including histological reports of 300 consecutive pts with esophageal tumors were reviewed. In pts with adenocarcinoma or squamous cell cancer and surgical resection without previous radio-/chemotherapy, EUS tumor staging was compared with histological diagnosis. Results: Out of the 300 consecutive pts with esophageal tumor and EUS 102 pts had esophageal surgery after EUS-staging without any radio-/chemotherapy. In 93 pts oesophageal cancer was confirmed, whereas 9 had other tumors. The mean age was 65 years (range 27-89), sex ratio female:male was 1:3.2. To distinguish between early and late tumor stage, the accuracy was 85%. The sensitivity and specificity for early cancer was 59%, and 93%, respectively. The diagnostic accuracy for local tumor spread was 90%, 90%, 68%, 69%, 89% for pT0, pT1, pT2, pT3 and pT4 lesions, respectively. The overall accuracy for T-stage was 74%. For pN-positive staging the accuracy of EUS was 73%. Conclusion: In daily clinical practice, the accuracy of EUS in assessing esophageal tumor staging is lower than in specific studies focusing on EUS accuracy. Mainly early esophageal cancer stages were overstaged. Thus, the implementation of recommendations for diagnostic work-up of esophageal cancer patients resulting from highly specific studies should consider the appropriate clinical setting.