The effects of Histamine-2 receptor antagonists and proton pump inhibitors on the gastrointestinal motility have not yet been sufficiently investigated. The aim of this study was to determine the effects of intravenous bolus administration of famotidine and omeprazole on the rate of gastric emptying using the continuous (13)C breath test (BreathID system, Exalenz Bioscience Ltd, Israel).

Twelve healthy male volunteers participated in this randomized, 3-way crossover study. After fasting overnight, the subjects were randomly assigned to receive 20 mg of famotidine, 20 mg of omeprazole or 20 mL of saline alone by intravenous bolus injection before a test meal (200 kcal per 200 mL, containing 100 mg of (13)C-acetate). Gastric emptying was monitored for 4 hours after the ingestion of test meal by the (13)C-acetic acid breath test performed using the BreathID system.

No significant differences in the calculated parameters, namely, the T(1/2), T(lag), GEC, β and κ, were observed among the 3 test conditions.

The study revealed that intravenous administration of gastric acid suppressant drugs had no significant influence on the rate of gastric emptying in comparison with that of saline alone as a placebo. Our results indicating the absence of any effect of either famotidine or omeprazole on accelerating the rate of gastric emptying suggest that both medications can be administered safely to patients suffering from hemorrhagic peptic ulcers who need to be kept nil by mouth from the viewpoint of possible acceleration of gastrointestinal motility in the clinical setting.

The proton pump inhibitor (PPI) is widely used for the treatment of gastroesophageal reflux disease, peptic ulcer diseases, and functional dyspepsia. The pathogenesis of these acid-related and/or functional upper gastrointestinal disorders is potentially associated with abnormal gastric emptying. To date, variable effects of PPIs on gastric emptying have been reported. Therefore, it is relevant to gather and analyze published information on this topic. A systematic literature search has been performed, showing that the delaying effect of PPIs on gastric emptying of solid meals is consistent, whereas the effect of PPIs on the emptying of liquids is inconsistent. The underlying mechanisms whereby PPIs may affect gastric emptying have been discussed, most of which still remain hypothetic. Gastric emptying of solids involves a process of peptic hydrolysis. PPIs impair the hydrolytic digestion by inhibiting acid-dependent peptic activity, thereby delaying the solid emptying. Gastric emptying of liquids largely depends on volume and energy density of intragastric contents. PPIs variably modify the volume and the energy density by reducing gastric fluid secretion, thereby modifying the liquid emptying in an unpredictable manner. Hypergastrinemia has been considered to delay gastric emptying, but it seems of minor importance in the regulation of gastric emptying during PPI use. The delayed emptying of solids due to PPI therapy may have clinical implications in the management of gastroesophageal reflux disease, functional dyspepsia, as well as diabetes.

Gastric emptying plays an important role in gastroesophageal reflux disease. Acid suppressants such as H2 receptor antagonists and/or proton pump inhibitors are often used in patients with gastroesophageal reflux disease. However, it remains controversial whether H2 receptor antagonists and proton pump inhibitors delay or accelerate gastric emptying. Here, the influence of acid suppressants on gastric emptying was evaluated via a cross-over study using the [13C]-labeled acetate breath test.

Twenty normal male subjects without gastroesophageal reflux disease symptoms were enrolled. Gastric emptying was investigated five times in every subject by the [13C]-labeled acetate breath test with oral administration of the vehicle, domperidone, and three acid suppressants: ranitidine, famotidine and rabeprazole. Gastric emptying was estimated by the values of T(max-calc), T(1/2) and %dose/2 h calculated from the 13CO2 breath excretion curve.

Using the T(max-calc) values, rabeprazole, ranitidine and famotidine did not influence gastric emptying time in comparison with vehicle administration. Using the T(1/2) and %dose/2 h values, rabeprazole tended to delay gastric emptying. Domperidone produced a statistically significant acceleration of gastric emptying for all three variables (P < 0.05).

Oral dosage of the H2 receptor antagonists, ranitidine and famotidine, has no significant effect on gastric emptying. However, rabeprazole may delay gastric emptying more strongly than H2 receptor antagonists.

To evaluate the gastric emptying inhibitory effects of sugar and levodopa on H pylori eradication period.

A total of 139 consecutive patients were randomized into 6 groups. The participants with peptic ulcer disease or non-ulcer dyspepsia non-responding to other medications who were also H pylori-positive patients either with positive rapid urease test (RUT) or positive histology were included. All groups were pretreated with omeprazole for 2 d and then treated with quadruple therapy regimen (omeprazole, bismuth, tetracycline and metronidazole); all drugs were given twice daily. Groups 1 and 2 were treated for 3 d, groups 3, 4 and 5 for 7 d, and group 6 for 14 d. Groups 1 to 4 received sugar in the form of 10% sucrose syrup. Levodopa was prescribed for groups 1 and 3. Patients in groups 2 and 4 were given placebo for levodopa and groups 5 and 6 received placebos for both sugar and levodopa. Upper endoscopy and biopsies were carried out before treatment and two months after treatment. Eradication of H pylori was assessed by RUT and histology 8 wk later.

Thirty patients were excluded. Per-protocol analysis showed successful eradication in 53% in group 1, 56% in group 2, 58% in group 3, 33.3% in group 4, 28% in group 5, and 53% in group 6. Eradication rate, patient compliance and satisfaction were not significantly different between the groups.

It seems that adding sugar or levodopa or both to anti H pylori eradication regimens may lead to shorter duration of treatment.

The classification of functional dyspepsia into meaningful subgroups remains an important goal. The aim of this investigation was to determine correlations between dyspeptic symptoms with gastric physiology and psychologic distress.

Consecutive patients with functional dyspepsia were evaluated with electrogastrography (EGG), drink test, and solid phase gastric emptying. Subjects also completed the Nepean Dyspepsia Index, Psychologic General Well-Being Index, SCL-90R, and SF-36.

Eighty-one patients were evaluated. Gastric emptying was performed in 29 of 81 patients and was abnormal in 21%, but no correlation existed between symptoms and T1/2 or TLAG. EGG was abnormal in 42% and drink test was abnormal in 40% of patients. Both were significantly associated with nausea but not with other symptoms. Significant correlations existed with 10 of 15 assessed symptoms and various subscales of the SCL-90R. Somatization was associated with abdominal burning, chest pain, abdominal pressure, abdominal discomfort, bad breath, chest burning, excessive fullness, bloating, abdominal pain, and regurgitation. Anxiety was associated with abdominal burning, chest pain, abdominal pressure, and abdominal discomfort. Anger-hostility was associated with abdominal burning and abdominal pressure. Increased interpersonal sensitivity was associated with abdominal burning and chest burning. SCL-90R Global Symptom Score was associated with abdominal burning, chest pain, abdominal discomfort, and bad breath.

Abnormal gastric physiology as measured in this study was not associated with symptoms other than nausea. Significant associations existed between measures of psychiatric distress and digestive symptoms. Symptoms in functional dyspepsia had greater associations with psychologic distress than with commonly employed tests of gastric physiology.

We previously showed that oral administration of a liquid soup preload was associated with a slower rate of gastric emptying and suppressed appetite more compared with intragastric administration of the same soup [Appetite 31(1998)377]. The present study was designed to investigate whether these results could be explained by the cephalic stimulation of acid secretion induced by oral administration. Eight healthy male subjects took part in a double-blind placebo controlled study comparing the effects of omeprazole and placebo on gastric emptying, appetite ratings and subsequent food intake following the ingestion of a liquid soup. Subjects were administered with a single oral dose of 80 mg omeprazole or placebo 3 h prior to ingesting the radiolabelled soup preload (400 kcal; 425 ml) over 15 min. Ratings of hunger, desire to eat and fullness were recorded over 135 min and gastric emptying was measured by scintigraphy. Food intake was evaluated from a test meal (yoghurt drink) given 120 min after the end of the soup ingestion. Analysis of data showed that there was no significant difference between omeprazole and placebo in gastric emptying, appetite or subsequent energy intake from the test meal. The results suggest that gastric acid secretion is not responsible for the differences in gastric emptying and appetite observed between intragastrically infused and orally administered soup preloads.

Proton pump inhibitors have been reported to delay gastric emptying, but this effect is controversial. Our aim was to determine the effect of rabeprazole sodium on several parameters of gastric function including gastric emptying, myoelectrical activity and ingested water volume required to produce fullness. Fifteen healthy males underwent assessment of solid-phase gastric emptying with the [13C] Spirulina platensis breath test as well as electrogastrography and satiety testing using a 5-min water load. Subjects were evaluated at baseline, after administration of placebo, and after rabeprazole sodium 20 mg daily for one week. No significant differences were seen between groups with respect to solid-phase gastric emptying as measured by T1/2 or T(lag). No differences were seen between baseline, placebo, and rabeprazole with respect to the number of normal electrogastrograms and the volume of water required to produce fullness. In conclusion, one week of therapy with rabeprazole sodium does not significantly alter gastric emptying, myoelectrical activity or threshold to fullness.

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.

Gastric acid suppression therapy has for many years been the cornerstone of the treatment of peptic disease. The availability of more potent inhibitors of gastric acid secretion and the increasing demand for maintenance therapy has renewed interest in the potential side-effects of profound and/or long-lasting therapy. This chapter focuses on the potential interference of gastric acid suppression therapy with the process of the digestion and absorption of nutrients. The theoretical mechanisms by which hypochlorhydria resulting from gastric acid suppression therapy may hamper digestion and absorption are multiple and well documented. Clinical studies evaluating the effect of gastric acid suppression therapy on the assimilation of nutrients are, on the other hand, scarce and have, moreover, yielded conflicting results. The reason for the latter may be related, at least in part, to elements of study design. Data indicating overt malabsorption or clear deficiencies in patients on long-term gastric acid suppression therapy are currently lacking. Nevertheless, it seems prudent, while awaiting the results of additional long-term studies, regularly to monitor these patients, especially those with increased nutrient demand, poor intake or suboptimal stores.

Barrett's metaplasia is an acquired condition resulting from longstanding gastroesophageal reflux disease. Approximately 10% of esophagitis patients develop Barrett's esophagus. There is increasing evidence that duodenogastroesophageal reflux plays a role in the progression of disease. We further analyzed the correlation of acid and biliary reflux with reflux esophagitis and Barrett's esophagus and tested the effects of proton pump inhibitor therapy.

Patients with either reflux esophagitis (group 1) or Barrett's esophagus (group 2) prospectively underwent simultaneous 24-h esophageal pH and bile reflux testing without any therapy affecting acid secretion or GI motility. A total of 16 patients in group 1 and 18 patients in group 2 were tested again under proton pump inhibitor therapy.

Acid and bile exposure were significantly increased in Barrett's patients (n = 23) compared to 20 esophagitis patients (median percentage of time that pH was <4 was 24.6% vs 12.4%, p = 0.01, median percentage of time that bilirubin absorbance was >0.2 was 34.7% vs 12.8%, p < 0.05). During therapy, both acid and bile reflux decreased significantly in both groups. Median percentage of time that pH was <4 and bilirubin absorbance was >0.2 before and during therapy was 18.2%/2.3% and 29.8%/0.7% (p = 0.001 and p = 0.001) in Barrett's esophagus patients versus 14.5%/3.6% and 21.5%/0.9% (p = 0.002 and p = 0.011) in esophagitis patients. There was no significant difference between the groups. In two esophagitis patients, bile reflux increased during therapy.

There is a good correlation of the duration of esophageal exposure to acid and bile with the severity of pathological change in the esophagus. Both acid and bile reflux is significantly suppressed by proton pump inhibitor therapy with exceptions among individual esophagitis patients. The prolonged simultaneous attack of bile and acid may play a key role in the development of Barrett's metaplasia.

Because of its minimal gastric toxicity, acetaminophen is the analgesic of choice for patients with gastric acid-related disorders. Because proton pump inhibitors are widely used, concomitant prescription of acetaminophen and lansoprazole would be prevalent. This crossover study was conducted to investigate an acetaminophen-lansoprazole interaction. On one occasion, each of six healthy, fasted, male volunteers ingested 1.0 g acetaminophen dissolved in 200 mL water. On another occasion, at least 1 week apart, 30 mg lansoprazole was administered orally, simultaneously with acetaminophen, after pretreatment with the same dose of lansoprazole once daily for 2 days. Plasma acetaminophen concentrations were measured at 0, 0.25, 0.5, 0.75, 1, 2, 3, 5, and 8 hours after dosing. The peak plasma concentration of acetaminophen and the time to its occurrence were significantly higher and shorter, respectively, during the lansoprazole session than during the control session. Neither the elimination half-life nor the area under the curve was significantly different between the two sessions. Lansoprazole hastens the absorption of acetaminophen solution, but little modifies its elimination rate and bioavailability.

Both acid and duodenal contents are thought to be responsible for the mucosal damage in Barrett's oesophagus, a condition often treated medically. However, little is known about the effect of omeprazole on duodenogastric reflux (DGR) and duodenogastro-oesophageal reflux (DGOR).

To study the effect of omeprazole 20 mg twice daily on DGR and DGOR, using the technique of ambulatory bilirubin monitoring.

Twenty three patients with Barrett's oesophagus underwent manometry followed by 24 hour oesophageal and gastric pH monitoring. In conjunction with pH monitoring, 11 patients (group 1) underwent oesophageal bilirubin monitoring and 12 patients (group 2) underwent gastric bilirubin monitoring, both before and during treatment with omeprazole 20 mg twice daily.

In both groups there was a significant reduction in oesophageal acid (pH<4) reflux (p<0.005) and a significant increase in the time gastric pH was above 4 (p<0.005). In group 1, median total oesophageal bilirubin exposure was significantly reduced from 28.9% to 2.4% (p<0.005). In group 2, median total gastric bilirubin exposure was significantly reduced from 24.9% to 7.2% (p<0.005).

Treatment of Barrett's oesophagus with omeprazole 20 mg twice daily results in a notable reduction in the exposure of the oesophagus to both acid and duodenal contents. In addition, delivery of duodenal contents to the upper gastric body is reduced.

Although the role of gastric digestion (by acid-dependent pepsins) in overall protein assimilation has never thoroughly been studied, it is generally considered to be limited. Protein that escapes assimilation in the small intestine is intensely fermented by the colonic flora. Phenol and p-cresol are specific bacterial metabolites of tyrosine.

To elucidate the role of gastric digestion of protein by evaluating the influence of acid suppression therapy on overall protein assimilation and fermentation.

Protein assimilation was studied in 16 healthy subjects under basal conditions and after omeprazole treatment using the combined 14C-octanoic acid/13C-egg white breath test. The degree of protein fermentation was estimated by measuring the urinary output of phenol and p-cresol in 41 healthy volunteers and in 17 patients treated for more than 1 month with omeprazole because of peptic disease.

Protein assimilation was significantly impaired after omeprazole treatment. Gastric emptying, conversely, was not affected. The urinary output of phenol and p-cresol was increased in patients treated with omeprazole as compared to untreated controls.

Gastric acid suppression therapy hampers protein assimilation and may promote protein malabsorption. Gastric digestion is likely to play a substantial role in overall protein assimilation.

The present study was designed to investigate whether an effect of omeprazole on gastric emptying is related to changes in the secretion of selected gut hormones.

The studies were performed in healthy men after 10 days' treatment with 40 mg omeprazole daily/placebo. Food ingestion took place in a duodenal phase, I and the meal consisted of an omelette labelled with technetium Tc 99m, followed by 150 ml water labelled with indium In 111. Plasma concentrations of gastrin, cholecystokinin (CCK), and motilin were measured.

Pretreatment with omeprazole reduced gastric emptying rates. This applied to all variables and was most pronounced with regard to amounts of solid (median (95% confidence interval)) emptied at 180 min (71% (48 - 86) for omeprazole versus 96% (87 - 100) for placebo; P < 0.01). All median values of plasma gastrin concentrations from the omeprazole series were higher than the corresponding values from the placebo series, and omeprazole induced a tenfold increase in incremental integrated area (IIA, pmol/l x 180 min) of the gastrin concentration curve (5250 (2570 - 9680) versus 575 (240 - 1485); P < 0.01). New findings include a lower postprandial secretion of CCK in the omeprazole series, and consequently, a difference in total integrated area (TIA, pmol/l x 180 min) (88 (21 - 147) versus 217 (104 - 267); P < 0.05) and IIA (pmol/l x 180 min) (52 (2 - 142) versus 165 (104 - 195); P < 0.05), respectively; a difference in IIA-30 (pmol/l x 30 min) of plasma motilin concentrations (270 (140 - 595) (omeprazole) versus 460 (285 - 655); P < 0.05); and a direct relationship between the amounts of liquid emptied at 30 min and the corresponding TIA-30 of plasma motilin in the omeprazole (Rs = 0.677; P < 0.05) and the placebo series (Rs = 0.767; P < 0.05).

Pretreatment with 40 mg omeprazole daily decreases the gastric emptying rates and has a substantial influence on the secretion of gastrin, motilin, and CCK. The finding of an omeprazole-induced decrease in CCK release may have clinical implications. Further investigation into the possible effect of proton-pump inhibitors on biliary tract motility and cholesterol solubilization in gallbladder bile is warranted.

Omeprazole is inactivated by exposure to gastric acid and is formulated as a gelatin capsule containing enteric-coated granules that release the drug in alkaline medium. In clinical situations where patients are unable to take the capsule orally, the optimum means of administration is uncertain. Eleven normal volunteers were given omeprazole 20 mg every day for one week before breakfast in random order as either a 20-mg capsule with water or free enteric-coated granules with either 8 oz of orange juice, 8 oz of water with 2 Alka-Seltzer antacid tablets (aspirin free), or 1 teaspoon of apple sauce. On day 7 of each regimen, an 8-hr intragastric pH study was performed following omeprazole 20 mg and standard breakfast. The median percentage of time of gastric acid pH > 4 after an omeprazole capsule was 68.5 (25-100); after granules with orange juice 59 (43-100); after granules in Alka-Seltzer solution 63 (31-100), and after granules in apple sauce 65 (30-99), with no significant differences (ANOVA). The time for the gastric pH to reach <4' after having been above was also similar for all four regimens (ANOVA). Omeprazole granules administered orally in a variety of ways achieve gastric acid suppression as effectively as the intact capsule.

Drugs are absorbed after oral administration as a consequence of a complex array of interactions between the drug, its formulation, and the gastrointestinal (GI) tract. The presence of food within the GI tract impacts significantly on transit profiles, pH, and its solubilization capacity. Consequently, food would be expected to affect the absorption of co-administered drugs when their physicochemical properties are sensitive to these changes. The physicochemical basis by which ingested food/lipids induce changes in the GI tract and influence drug absorption are reviewed. The process of lipid digestion is briefly reviewed and considered in the context of the absorption of poorly water-soluble drugs. The effect of food on GI pH is reviewed in terms of location (stomach, upper and lower small intestine) and the temporal relationship between pH and drug absorption. Case studies are presented in which postprandial changes in bioavailability are rationalized in terms of the sensitivity of the physicochemical properties of the administered drug to the altered GI environment.

We have studied gastric emptying of a solid, realistic meal (800 cal, 15% protein, 45% fat, 40% carbohydrate) in 21 healthy subjects twice, with and without a four-day pretreatment with 40 mg omeprazole. The last dose of the drug was taken 24 hr before the test, to avoid hypothetical nonsecretory side effects of the drug . Gastric emptying was measured by ultrasound of antral diameters. The results show that basal and maximal postprandial antral cross-sectional areas were the same during the two tests. A greater residual distention of the antrum was present throughout the study after the omeprazole treatment, the difference being significant at time 120 and 240. Omeprazole induced a highly significant delay in gastric emptying [control 199.6 (12.6) vs omeprazole 230.9 (12.7) min, mean (1 SEM); P<0.003]. The delay was not due to a prolonged lag phase, but rather to an effect on the slope of the emptying curve. This study shows that in normal subjects omeprazole delays gastric emptying of a digestible solid meal.

The effects of a potent proton pump inhibitor on postprandial digestive functions were compared with those of a placebo in a double-blind randomized crossover study. Six healthy male volunteers received 30 mg/day of lansoprazole or placebo for 7 days, with a wash-out period of 14 days. As compared to placebo, lansoprazole induced a marked decrease of mean +/- S.E.M. 3-h gastric acid secretion from 46.8 +/- 10.8 mmol to 10.9 +/- 2.5 mmol (P < 0.05), and a decrease of the volume of gastric contents emptying into the duodenum from 1043 +/- 139 ml to 660 +/- 87 ml (P < 0.05). However, gastric emptying remained unchanged with meal gastric emptying half times of 66 +/- 5 min and 67 +/- 13 min, respectively. During the 3-h postprandial period, duodenal lipase and chymotrypsin outputs were 366 +/- 123 KIU and 56 +/- 11 KIU with lansoprazole and 436 +/- 119 KIU and 49 +/- 8 KIU with placebo (N.S.). Bile acid outputs were 5.3 +/- 0.7 mmol and 6.0 +/- 1.0 mmol, respectively (N.S.) There was no change in kinetic profiles of biliary-pancreatic secretion. We conclude that potent inhibition of gastric secretion by chronic administration of a proton pump inhibitor at usual therapeutic dose alters neither meal gastric emptying nor postprandial biliary-pancreatic secretion.

Some commonly used H2-receptor antagonists affect gastric first-pass metabolism of ethanol and lead to unexpectedly high blood alcohol concentrations after consumption of alcohol. To investigate whether omeprazole--a substituted benzimidazole recently approved for clinical use--has a similar harmful effect, we administered a moderate dose of ethanol (0.3 g/kg body wt) orally to seven normal volunteers before and after one week of omeprazole administration (20 mg daily). No significant effect of the drug was found on either mean peak blood alcohol concentrations or on areas under the blood alcohol curve; neither did these parameters differ significantly before or after an acute dose of omeprazole (13.2 mg/kg body wt) in rats, whether ethanol (0.25 g/kg body wt) was administered intragastrically or intravenously. In vitro, omeprazole in concentrations likely to occur in the gastric lumen (0.01-1.0 mM), did not affect gastric alcohol dehydrogenase activity of humans or rats. Thus omeprazole does not affect gastric first-pass metabolism of ethanol and can be considered as a safe choice for the treatment of patients who do not refrain from alcohol consumption during therapy.

Altogether, 138 patients were included in a study aimed at evaluating the effect of cisapride on healing and relapse of oesophagitis shown endoscopically. In the first phase of the study cisapride was given in an open fashion at 10 mg four times a day for 8 to 16 weeks, and healing was obtained in 69% of patients. Healing occurred later in patients with grades II to IV oesophagitis. The total score for reflux symptoms decreased by 67%. Eighty of the healed patients were included in the second phase. They were randomly assigned to double blind treatment with either cisapride 10 mg (n = 37) or placebo (n = 43) twice a day. Control endoscopy was performed when symptoms recurred or at the end of the six month trial. The cumulative percentage of patients in remission was higher (p = 0.06, survival analysis) in the cisapride group than in the placebo group, the relapse rates being 20% and 39%. The duration of remission tended to be longer in patients with a lower initial degree of oesophagitis. Adverse effects were no more frequent with cisapride than with placebo. In conclusion, cisapride is efficacious in healing oesophagitis, and, unlike other gastrointestinal prokinetic drugs or low dose cimetidine (400-800 mg daily) or ranitidine (150 mg daily), it may prevent relapse of oesophagitis.

Omeprazole, a substituted benzimidazole, is a specific inhibitor of the enzyme H+/K(+)-ATPase, which is found on the secretory surface of the parietal cell. This enzyme, the "proton pump," catalyzes the final step in acid secretion. Omeprazole is a powerful inhibitor of gastric acid secretion. At the time of writing, omeprazole has been licensed in the United States for the treatment of severe grades of gastroesophageal reflux disease (GERD) as well as GERD unresponsive to treatment with currently available agents, and for the treatment of Zollinger-Ellison syndrome and other gastric hypersecretory states. Most recently, it has been recommended by the FDA advisory committee for approval as first-line therapy in duodenal ulcer disease.

The aim of the study was to investigate a possible effect of omeprazole on the characteristics of the gastric emptying of liquid and solid in healthy subjects. The study was performed as a double-blind crossover study and the gastric emptying studies were performed after 10 days of treatment with placebo or omeprazole 40 mg o.m. Omeprazole was without effect on the characteristics of liquid emptying or the lag phase of solid. It does, however, decrease the emptying rate of solid as the omeprazole group had a median half-time duration of the linear emptying period which had twice the duration of the corresponding figure in the placebo group.

Omeprazole represents the first agent of a unique class of acid inhibitory drugs, the proton pump inhibitors. Omeprazole inhibits basal gastric acid secretion, as well as gastrin-, histamine-, or pentagastrin-stimulated secretion, which results in decreased gastric acidity, decreased gastric acid output, and decreased gastric volume. Omeprazole is acid labile, necessitating its oral administration in an enteric-coated formulation. Bioavailability appears to be dose-dependent, with more drug being absorbed with increasing dosage as well as after repeated dosing. This is probably secondary to decreased gastric acidity and, therefore, less degradation of the administered drug. Despite its relatively short half-life (1-2 h), omeprazole's pharmacologic action is prolonged. Clinical trials have shown omeprazole to be at least as effective as histamine2-receptor antagonists in the treatment of gastric ulcers, duodenal ulcers, gastroesophageal reflux, and Zollinger-Ellison syndrome. Adverse reactions have been minimal. Omeprazole has been approved by the Food and Drug Administration for short-term therapy of severe erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, and long-term management of Zollinger-Ellison syndrome.

We have studied the response of erosive or ulcerative esophagitis to treatment with omeprazole and its subsequent relapse on cessation of therapy in 196 patients. In the first phase of the study omeprazole (20 or 40 mg daily) was compared with placebo in 64 patients. After 4 wk there was endoscopic healing in 81% (25 of 31) of omeprazole-treated patients and in only 6% (2 of 32) of placebo-treated patients. Endoscopic healing of esophagitis was accompanied by symptom relief and histologic healing of ulceration. In the second (dose finding) phase a further 132 patients were randomized to omeprazole (20 or 40 mg daily) and endoscopic healing was assessed. In patients with the mildest grade of ulcerative esophagitis (grade 2), healing occurred at 4 wk in 87% receiving 20 mg and in 97% receiving 40 mg. In patients with grade 3 esophagitis, 67% (20 mg) and 88% (40 mg) were healed. Less than half the patients with grade 4 esophagitis (Barrett's ulcers or confluent ulceration) healed with either 20 mg (48%) or 40 mg (44%). Regression analysis in the 164 omeprazole-treated patients showed no evidence that healing was influenced by factors other than severity of esophagitis at entry and omeprazole dose. In phase 3 of the study the rate of endoscopic relapse was determined in 107 endoscopically healed patients after stopping omeprazole. Erosive or ulcerative esophagitis recurred in 88 of 107 (82%) by 6 mo. Neither initial dose, grade of esophagitis, nor smoking was shown to influence relapse rate. Omeprazole is a highly effective treatment for peptic esophagitis. The 40-mg/day dosage produces endoscopic healing slightly more quickly than the 20-mg/day dosage, and the initial endoscopic gradings are of prognostic value. Relapse occurs rapidly when treatment is stopped.

Omeprazole is a substituted benzimidazole derivative which markedly inhibits basal and stimulated gastric acid secretion. It has a unique mode of action, irreversibly blocking the so-called proton pump of the parietal cell which is supposedly the terminal step in the acid secretory pathway. In animals, on a weight basis, omeprazole is 2 to 10 times more potent than cimetidine in inhibiting gastric acid secretion. Toxicological studies in rats have shown that very high doses of omeprazole administered for 2 years produce hyperplasia of gastric enterochromaffin-like cells and carcinoids, a few with proliferations into the submucosa. The significance of such findings to the clinical situation is wholly speculative and requires further research. Preliminary studies in patients with duodenal ulcers or Zollinger-Ellison syndrome have found no mucosal changes which would suggest that the drug represents a risk for development of carcinoid tumours at therapeutic dosages. In patients with duodenal ulcers omeprazole, at dosages of at least 20mg once daily, produced ulcer healing rates of between 60 and 100% after 2 weeks and between 90 and 100% after 4 weeks, even in patients resistant to treatment with H2-receptor antagonists. Comparative trials clearly demonstrated that omeprazole 20 to 40 mg administered once daily was significantly more effective than usual dosage regimens of cimetidine and ranitidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present no data are available evaluating omeprazole as maintenance therapy once ulcers have healed. Other clinical trials have also shown that omeprazole is effective for treating gastric ulcers, ulcerative peptic oesophagitis, and Zollinger-Ellison syndrome. In patients with Zollinger-Ellison syndrome the profound and long lasting antisecretory activity of omeprazole may make it the drug of choice for treating the massive acid hypersecretion associated with the disease, especially when H2-receptor antagonists are ineffective. During clinical trials reported to date omeprazole has been very well tolerated but further clinical experience is essential to fully evaluate its safety profile. Thus, omeprazole represents a pharmacologically unique antisecretory drug which is very effective for rapidly healing peptic ulcers and peptic oesophagitis, and for reducing gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. If the apparent absence of undesirable mucosal morphological changes during treatment with usual doses in patients with peptic ulcer disease is confirmed, it may be a major advance in the treatment of these diseases.

We report a patient whose severe recurrent anemia was due to overt and occult hemorrhage from peptic esophagitis. Cimetidine treatment was successful for seven years but dose reduction was followed by intractable hemorrhage which did not respond to H2-receptor antagonists. Omeprazole therapy produced dramatic remission of symptoms and anemia.