Challenges in acid/peptic disorders: a symposium overview

Before 1977, the treatment of peptic ulcer disease consisted primarily of dietary, antacid, and anticholinergic programmes. There were heated controversies regarding rigid vs. liberal ulcer diets, a variety of antacids and dosing patterns to choose from, and conflicting claims over the benefit of various anticholinergic therapies. It was hoped that the dramatic introduction of the H₂-receptor antagonists would simplify our approach to the treatment of peptic ulcer and reflux oesophagitis. Standard doses of H₂-receptor antagonists are effective for acid/peptic disorders, yet it has become clear that some subsets of patients present special management problems, including recurrent ulcers, non-steroidal anti-inflammatory drug (NSAID)-induced disease, stress ulcers, and refractory oesophagitis. New regimens, such as maintenance therapy and once-daily nocturnal dosing, have been indicated for peptic ulcer disease. New drugs have been introduced, such as sucralfate, misoprostol, and omeprazole, each with a different mechanism of action. Therefore, while we have learned considerably more about the pathogenesis of peptic disease, treatment decisions have become more complicated. The Transatlantic Conference on Acid/Peptic Disorders was held on 19 21 January 1990, in Wesley Chapel, Florida. A faculty from the United Kingdom, the United States, and Canada reviewed pathophysiology and the role of pharmacologic agents in the treatment of acid/peptic disorders and outlined clinically useful treatment strategies. The conference was organized into five segments: acid suppression and ulcer healing; acid suppression and control of reflux disease; NSAID-induced ulceration; stress ulceration, rationale for control of rebleeding, and drug interactions; and controversies. The proceedings of the symposium are presented in this supplement.     

Lansoprazole: pharmacokinetics,pharmacodynamics and clinical uses

Lansoprazole (Prevacid?, TAP Pharmaceuticals, Inc.) is a substituted benzimidazole that inhibits gastric acid secretion. This agent is approved for the short-term treatment of erosive reflux oesophagitis, active gastric ulcer, active duodenal ulcer and the treatment of non-steroidal anti-inflammatory drug (NSAID)-induced gastric and duodenal ulcers. It is also approved for the long-term treatment of healed reflux oesophagitis, healed duodenal ulcer, the treatment of hypersecretory conditions such as Zollinger-Ellison syndrome and the eradication of Helicobacter pylori as a component of triple therapy with lansoprazole, clarithromycin and amoxicillin, or dual therapy with lansoprazole and amoxicillin. Its mechanism of action is to selectively inhibit the membrane enzyme H⁺/K⁺ATPase in gastric parietal cells. In clinical trials, lansoprazole is more effective than placebo or histamine (H₂)-receptor antagonists in the treatment of reflux oesophagitis. Lansoprazole administered at a dose of 30 mg daily produced faster relief of symptoms and superior healing rates in patients with gastric or duodenal ulcers or reflux oesophagitis than H₂-receptor antagonists. A daily dose of 30 mg lansoprazole reduced epigastric pain faster than omeprazole 20 mg daily in patients with peptic ulcer disease but healing rates at 4 and 8 weeks were similar with both agents at these dosages. Lansoprazole was more effective than H₂-receptor antagonists in patients with Zollinger-Ellison syndrome and produced similar treatment outcome to omeprazole. Lansoprazole in combination with clarithromycin and amoxicillin produced similar rates of eradication of H. pylori. In clinical trials, lansoprazole is well-tolerated and has a low frequency of side effects similar to that of H₂-receptor antagonists or omeprazole.     

Peptic Ulcer Disease: An Update

Peptic ulcers can develop when there is an imbalance between gastric acid secretion and gastroduodenal mucosal defense. Investigators are looking at the role of Helicobacter pylori in the development of peptic ulcer disease; eradication of the microorganism may reduce recurrence. Approved drug therapy includes H₂-receptor antagonists, omeprazole, sucralfate, and antacids. Recommendations for treating and counseling patients are provided.     

Lansoprazole: A Comprehensive Review

Lansoprazole is the second member of the substituted benzimidazole class of antisecretory agents approved for use in the United States. These drugs decrease parietal cell acid secretion by inhibiting H⁺,K⁺-adenosine triphosphatase, the final step in the secretion of acid. Lansoprazole has been studied extensively for the short-term treatment of duodenal and gastric ulcers, reflux esophagitis, and Helicobacter pylori-positive peptic ulcer disease; long-term treatment of Zollinger-Ellison syndrome; and maintenance treatment of erosive esophagitis. A dosage of 30 mg/day produced higher healing rates and equivalent or faster relief of ulcer symptoms than ranitidine or famotidine in patients with duodenal or gastric ulcers and reflux esophagitis. Compared with omeprazole 20 mg/day, that dosage provided faster epigastric pain relief in these patients after 1 week, although healing rates for the two agents were equivalent at 4 and 8 weeks. In patients with peptic ulcer refractory to 8-week therapy with histamine₂-receptor antagonists, healing rates were not significantly different between lansoprazole and omeprazole. In patients with Zollinger-Ellison syndrome, lansoprazole was superior to histamine₂-receptor antagonists and was similar in efficacy, safety, and duration of action to omeprazole. Combinations of lansoprazole or omeprazole with one or two antibiotics produced equivalent eradication of H. pylori. In clinical trials, lansoprazole was well tolerated, with frequency of adverse effects similar to that reported with ranitidine, famotidine, and omeprazole.     

Omeprazole is superior to ranitidine plus metoclopramide in the short-term treatment of erosive oesophagitis

Histamine H₂-receptor antagonists are moderately effective in symptomatic treatment and healing of erosive oesophagitis, but they are not as effective as the proton pump inhibitor omeprazole. In some studies prokinetic agents seem to increase the effectiveness of H₂-antagonists, but no study comparing the efficacy of omeprazole to H₂-antagonists plus prokinetic agents has been performed. The purpose of this study was to compare the efficacy and tolerability of 20 mg omeprazole daily with 150 mg ranitidine b.d.s. plus the prokinetic agent 10 mg metoclopramide q.d.s. in patients with erosive oesophagitis. After both 4 and 8 weeks of treatment, omeprazole healed the mucosa in significantly more patients than did ranitidine plus metoclopramide. Omeprazole also provided significantly greater relief from daytime heartburn, nighttime heartburn, and acid regurgitation, and was associated with decreased concomitant antacid use. Although the overall incidence of adverse events was similar in the two treatment groups, a significantly higher number of treatment-related adverse events and more treatment-related withdrawals from the study occurred in the ranitidine plus metoclopramide treatment group. Omeprazole is more effective and better tolerated than the combination of standard dose ranitidine plus metoclopramide for patients with erosive oesophagitis.     

Proton pump inhibitors in the treatment of gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GERD) is the most common peptic acid disease in the western world and is the commonest indication for acid suppression therapy. Major advances have been made over the past 30 years in the understanding of lower oesophageal sphincter function and the mechanism of acid secretion. Developments in surgical and pharmacological therapy have paralleled these advances. Pharmacotherapy for GERD has evolved from antacids to H₂-receptor antagonists (H₂RAs) to prokinetics to proton pump inhibitors (PPIs). The H₂RAs, while modestly effective in symptom relief and healing of GERD, are limited by pharmacological tolerance. The prokinetics (metoclopramide and cisapride) are limited by low efficacy, pharmacological tolerance and toxicity. The PPIs have emerged as the most effective therapy for symptom relief, healing and long-term maintenance. They have also proved to be remarkably safe and cost-effective in long-term therapy. This review evaluates the pharmacology, efficacy, tolerability, safety and cost-effectiveness of the four currently available PPIs, lansoprazole, omeprazole, pantoprazole and rabeprazole, in the treatment of GERD.     

Lansoprazole and omeprazole in the prevention of relapse of reflux oesophagitis: a long-term comparative study

Background:

Proton pump inhibitors are superior to H₂-receptor antagonists in the prevention of relapse of oesophagitis, but few data directly compare the relative efficacies of lansoprazole and omeprazole in preventing oesophagitis relapse over a prolonged period.

Methods:

Patients with healed Grade II, III or IV oesophagitis were treated with lansoprazole 30 mg o.d. or omeprazole 20 mg o.d. for 48 weeks. Endoscopy and symptom assessment were performed after 12, 24 and 48 weeks of treatment and an additional symptom assessment 36 weeks after starting treatment.

Results:

Intention-to-treat analysis included 248 patients (lansoprazole n = 126, omeprazole n = 122). Comparison of time to endoscopic and/or symptomatic relapse revealed no difference between the treatments. There was no significant difference between treatments with respect to the proportion of patients in whom endoscopic and/or symptomatic relapse was reported (lansoprazole 12/126 (9.5%), omeprazole 11/122 (9.0%)). No difference between the treatments in either the number or severity of adverse events was reported.

Conclusions:

Continuous treatment with either lansoprazole 30 mg or omeprazole 20 mg is effective in preventing the relapse of oesophagitis over a 48-week period in a majority of patients. Both treatments exhibit a similar side-effect profile.

     

Omeprazole: a pharmacoeconomic evaluation of its use in duodenal ulcer and reflux oesophagitis

Omeprazole regulates gastric acid secretion and is an effective treatment of acute duodenal ulcer and reflux oesophagitis, achieving more rapid healing and symptomatic relief than histamine H 2-receptor antagonists. When administered as maintenance therapy, omeprazole reduces the incidence of relapse. The drug is also highly effective in patients poorly responsive to histamine H 2-receptor antagonists. The daily acquisition cost of omeprazole is higher than that of histamine H 2-receptor antagonists in many countries, and thus it is important to evaluate the pharmacoeconomic impact of omeprazole in the short and long term treatment of duodenal ulcer and reflux oesophagitis. Pharmacoeconomic analyses have been performed in several clinical settings using pooled data from clinical trials or simulated models of clinical practice. In a single analysis using Finnish cost data, omeprazole was more cost effective than ranitidine in the treatment of duodenal ulcer disease over a 6-month period. The cost effectiveness of omeprazole was comparable to that of sucralfate-containing regimens, with patients receiving omeprazole being healed more quickly and experiencing a greater number of healthy days. Using a computer-model simulation and Swedish cost data, omeprazole was more cost effective than ranitidine when administered as intermittent treatment of duodenal ulcer over 5 years. Preliminary reports indicate that regimens which eradicate Helicobacter pylori are more cost effective than those which do not. As short term treatment of reflux oesophagitis, omeprazole 20 to 40 mg/day was the dominating treatment strategy, being less costly and more effective than ranitidine 300 to 1200 mg/day. Omeprazole 20 mg/day produced symptom-free days more cost effectively than either cimetidine 1.6 g/day or ranitidine 300 mg/day. More importantly, as long term (maintenance or intermittent) treatment of reflux oesophagitis, omeprazole 20 mg/day was more cost effective than both ranitidine 150 mg twice daily and 'phase 1' therapy (diet and antacids) over 6 and 12 months. Thus, based on analyses evaluated, omeprazole appears to be more cost effective than ranitidine in the short term treatment of duodenal ulcer. Results for long term treatment are less clear cut, but full details from some studies are not yet available. For the short term treatment of reflux oesophagitis omeprazole is more cost effective than ranitidine or cimetidine and for long term treatment omeprazole is more cost effective than ranitidine. As treatment for reflux oesophagitis, omeprazole is considered to be the dominating treatment strategy.     

Proton Pump Inhibitors and Acid-Related Diseases

Proton pump inhibitors (PPIs) are targeted to the gastric acid pump, H⁺,K⁺-adenosine triphosphatase (ATPase). The drugs accumulate in the acid space of the parietal cell and convert to active sulfenamide by an acid-catalyzed reaction. Consequent covalent inhibition of H⁺,K⁺-ATPase blocks the final step of acid secretion, hence the PPIs omeprazole, lansoprazole, and pantoprazole are more effective than histamine₂-receptor antagonists (H₂RAs) in controlling acid secretion. Preclinical short- and long-term clinical surveillance data show these drugs to be well tolerated and safe. The PPIs heal the lesions of gastroesophageal reflux disease and lessen symptoms more effectively and more quickly than the H₂RAs, and are effective' and faster acting for peptic ulcer disease. Helicobacter pylori is causally implicated in the majority of peptic ulcers and in atrophic gastritis. Since PPIs, but not H₂RAs, are synergistic with antibiotics in eradicating H. pylori, their use is appropriate in all acid-related diseases since all patients who are H. pylori positive require eradication as well as healing.     

Trends in morbidity and mortality from peptic ulcer disease: Tayside versus Scotland

Recent studies have shown that the prophylactic use of H₂-receptor antagonists reduces both ulcer recurrence and the risk of ulcer complications. Despite these results, epidemiological studies have failed to show any evidence of an effect of gastric anti-secretory drugs on complicated ulcer disease in the community. Since 1979, it has been the policy of the gastroenterology department at Ninewells Hospital in Tayside to recommend long-term, continuous therapy with H₂-receptor antagonists for patients with peptic ulcer; in contrast, prophylactic therapy is less commonly used in the rest of Scotland. The difference in the management of peptic ulcer between Tayside and Scotland presented an opportunity to study the population effects of the widespread use of continuous H₂-receptor antagonists on the morbidity and mortality from ulcer disease. This study compared the trends in hospital admissions, gastric surgery, haemorrhage, perforation and mortality from ulcer disease using data supplied by the Information and Statistics Division of the Common Services Agency, Scottish Health Service, Edinburgh. During the 1980s, hospital admissions for peptic ulcer declined significantly in Tayside, whereas in Scotland there was no obvious downward trend. Gastric surgery for ulcer disease declined throughout Scotland although the fall was significantly steeper in Tayside than in the rest of Scotland. For the population in general, the rate of perforation decreased faster in Tayside than in the rest of Scotland, although the difference was not significant. The rate of admissions for ulcer haemorrhage declined substantially in Tayside whereas there was little change in Scotland as a whole. The decrease in mortality from ulcer disease in all groups except younger females was more marked in Tayside than in Scotland, although the differences were not significant. The magnitude of the differences between Tayside and Scotland, and in particular the consistency of these results across a broad range of indicators of ulcer disease, suggests that the policy of prescribing long-term, continuous therapy with H₂- receptor antagonists has reduced both uncomplicated and complicated peptic ulcer in the community in Tayside.     

Intestinal Uptake of Cimetidine and Ranitidine in Rats

The H₂-receptor antagonists exhibit unusual absorption behavior in that double peaks often occur after oral administration. Moreover, administration with some high potency antacids decreases the extent of absorption. To date, no explanation that can completely account for these observations has been advanced. One problem is that there is a lack of consensus as to the mechanism of absorption of the H₂-receptor antagonists from the gastrointestinal tract. In the studies reported here, the mechanism and regional dependence of intestinal uptake of two H₂-receptor antagonists, cimetidine and ranitidine, were investigated in rats using the in vitro everted ring technique. The uptake rate of cimetidine from both jejunum and colon was linear with concentration (in the range of 0.0005-40 mM), and there was no significant competition for uptake in the presence of the structurally similar H₂-receptor antagonists, famotidine and ranitidine. In the case of ranitidine too, the uptake rate from the jejunum and colon was linear with concentration (in the range of 0.0005-5 mM), and there was no competition for uptake by either famotidine or cimetidine. These data indicate that uptake of cimetidine and ranitidine in the rat jejunum and colon occurs by a predominantly passive process. Both cimetidine and ranitidine exhibited regional differences in uptake rate. Uptake tended to be greatest in the ileum, similar in duodenum and jejunum, and lowest in the colon. However, differences in uptake rates between locations in the small intestine appeared to be too modest to account for the double peak behavior of either compound.     

Prognostic factors for relapse and maintenance treatment with cisapride in gastro—oesophageal reflux disease

Aim: To perform a further Cox proportional hazards logistic regression analysis of data from two large-scale placebo-controlled trials with cisapride as maintenance treatment in reflux disease. Results: Analysis of each of the two databases, allowing the model to operate freely, led to the identification of a number of unexpected putative predictors of outcome in the 6 to 12 months following initial healing of oesophagitis with an H₂-receptor antagonist or omeprazole. This allowed us to delineate more accurately the patient population that is likely to respond to long-term continuous treatment with low or standard dose cisapride. The analysis revealed that symptom severity may be more useful than endoscopic severity in predicting relapse or in guiding therapy. Reflux oesophagitis outcome is particularly poor in the presence of treatment-recalcitrant symptoms or severe mucosal damage. Analysis showed cisapride to be effective in the maintenance treatment of patients with non-refractory symptoms, irrespective of the initial severity of oesophagitis, the healing agent used, or a history of previous endoscopic relapses.     

Lansoprazole: pharmacokinetics, pharmacodynamics and clinical uses

Lansoprazole (Prevacid, TAP Pharmaceuticals, Inc.) is a substituted benzimidazole that inhibits gastric acid secretion. This agent is approved for the short-term treatment of erosive reflux oesophagitis, active gastric ulcer, active duodenal ulcer and the treatment of non-steroidal anti-inflammatory drug (NSAID)-induced gastric and duodenal ulcers. It is also approved for the long-term treatment of healed reflux oesophagitis, healed duodenal ulcer, the treatment of hypersecretory conditions such as Zollinger-Ellison syndrome and the eradication of Helicobacter pylori as a component of triple therapy with lansoprazole, clarithromycin and amoxicillin, or dual therapy with lansoprazole and amoxicillin. Its mechanism of action is to selectively inhibit the membrane enzyme H+/K+ ATPase in gastric parietal cells. In clinical trials, lansoprazole is more effective than placebo or histamine (H2)-receptor antagonists in the treatment of reflux oesophagitis. Lansoprazole administered at a dose of 30 mg daily produced faster relief of symptoms and superior healing rates in patients with gastric or duodenal ulcers or reflux oesophagitis than H2-receptor antagonists. A daily dose of 30 mg lansoprazole reduced epigastric pain faster than omeprazole 20 mg daily in patients with peptic ulcer disease but healing rates at 4 and 8 weeks were similar with both agents at these dosages. Lansoprazole was more effective than H2-receptor antagonists in patients with Zollinger-Ellison syndrome and produced similar treatment outcome to omeprazole. Lansoprazole in combination with clarithromycin and amoxicillin produced similar rates of eradication of H. pylori. In clinical trials, lansoprazole is well-tolerated and has a low frequency of side effects similar to that of H2-receptor antagonists or omeprazole.     

Omeprazole. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peptic ulcer disease and Zollinger-Ellison syndrome

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.     

Long term continuous omeprazole treatment of patients with Barrett's oesophagus

Background: The metaplastic columnar epithelium in Barrett's oesophagus has malignant potential. Aim: To determine whether decreasing acid reflux leads to regression of Barrett's epithelium. Method: Twenty-four patients with Barrett's oesophagus were treated with omeprazole 20 mg o.m. in an open, prospective study; 11 were treated for 12 months, and 13 for 24 months. Another group of 17 patients with Barrett's oesophagus was treated with an H2-receptor antagonist in standard dosage for 12-36 (mean 23) months. Patients were assessed endoscopically. Results: No evidence of significant shortening of the length of Barrett's oesophagus was seen in any patient treated for 12 or 24 months with omeprazole. Similarly, no shortening of the length of Barrett's oesophagus was seen in any patient treated with an H₂-receptor antagonist. However, 6 of 11 patients treated with omeprazole for 12 months, and 7 of 13 treated for 24 months, developed macroscopic squamous islands visible below the squamo-columnar junction. This was not seen in any patient treated with an H₂-receptor antagonist. Conclusion: Although there can be reappearance of squamous epithelium in Barrett's oesophagus of some patients during treatment with omeprazole 20 mg o.m. over 12–24 months, a significant shortening of the columnar lined segment is not seen.     

Lansoprazole. A review of its pharmacodynamic and pharmacokinetic properties and its therapeutic efficacy in acid-related disorders.

Lansoprazole is an effective acid pump inhibitor acting at the final enzymatic step of the acid secretory pathway of the parietal cell, decreasing gastric acid secretion regardless of the primary stimulus. Results of short term (less than 8 weeks) clinical trials have shown lansoprazole to be significantly superior to placebo and ranitidine in the treatment of duodenal ulcer, both in the rate of healing and in overall healing at 4 weeks. Lansoprazole appears to heal duodenal ulcer more quickly than famotidine, and demonstrates slightly greater efficacy at 4 weeks, although both drugs appear to have equivalent efficacy overall. Gastric ulcers and reflux oesophagitis are also healed by lansoprazole 30 mg/day for 4 to 8 weeks, with healing rates after 8 weeks of approximately 85 to 95% for both indications. Lansoprazole appears to be superior to ranitidine and comparable to omeprazole in treating reflux oesophagitis. Furthermore, lansoprazole has relieved reflux symptoms more quickly than either ranitidine or omeprazole. Preliminary data also indicate that lansoprazole may be effective in the treatment of peptic ulcer disease and reflux oesophagitis refractory to H2-receptor antagonists, and in patients with Zollinger-Ellison syndrome. While direct comparisons with omeprazole are limited, results suggest that lansoprazole, used for short term treatment, is at least as effective as omeprazole in the treatment of peptic ulcer and reflux oesphagitis. Lansoprazole has been well tolerated in short term clinical trials, with an incidence of adverse effects comparable with that of other agents in its therapeutic class. Trials assessing long term tolerability data are ongoing and will be required as part of the assessment of the safety profile, if lansoprazole is to be used prophylactically to prevent ulcer recurrence. Thus, by virtue of its ability to heal ulcers and rapidly relieve associated symptomatology, lansoprazole represents a useful alternative for the treatment of acid related disorders.