Proton pump inhibitors (PPIs) are drugs which irreversibly inhibit proton pump (H+/K+ ATPase) function and are the most potent gastric acid-suppressing agents in clinical use. There is now a substantial body of evidence showing improved efficacy of PPIs over the histamine H2 receptor antagonists and other drugs in acid-related disorders. Omeprazole 20 mg/day, lansoprazole 30 mg/day, pantoprazole 40 mg/day or rabeprazole 20 mg/day for 2 to 4 weeks are more effective than standard doses of H2-receptor antagonists in healing duodenal and gastric ulcers. Patients with gastric ulcers should receive standard doses of PPIs as for duodenal ulcers but for a longer time period (4 to 8 weeks). There is no conclusive evidence to support the use of a particular PPI over another for either duodenal or gastric ulcer healing. For Helicobacter pylori-positive duodenal ulceration, a combination of a PPI and 2 antibacterials will eradicate H. pylori in over 90% of cases and significantly reduce ulcer recurrence. Patients with H. pylori-positive gastric ulcers should be managed similarly. PPIs also have efficacy advantages over ranitidine and misoprostol and are better tolerated than misoprostol in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In endoscopically proven gastro-oesophageal reflux disease, standard daily doses of the PPIs are more effective than H2-receptor antagonists for healing, and patients should receive a 4 to 8 week course of treatment. For severe reflux, with ulceration and/or stricture formation, a higher dose regimen (omeprazole 40 mg, lansoprazole 60 mg, pantoprazole 80 mg or rabeprazole 40 mg daily) appears to yield better healing rates. There is little evidence that PPIs lead to resolution of Barrett's oesophagus or a reduction of subsequent adenocarcinoma development, but PPIs are indicated in healing of any associated ulceration. In Zollinger-Ellison syndrome, PPIs have become the treatment of choice for the management of gastric acid hypersecretion.

Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders.

This study set out to investigate the effects of omeprazole or ranitidine on the progression of antral gastritis andHelicobacter pylori in patients with active duodenal ulcer. A double-blind, double-dummy trial was performed in 270 patients, 241 of whom were studied histologically for the presence ofH. pylori. Patients were randomized to receive omeprazole, 10 mg every morning, omeprazole, 20 mg every morning, or ranitidine, 150 mg twice a day, for four weeks. Endoscopy was performed on entry and at weekly intervals during the study; at least two antral biopsies were taken on each occasion to assess the activity and degree of chronic inflammation, as reflected by the degree of polymorphonuclear leukocyte infiltration and mononuclear cell infiltration, respectively. Biopsy specimes also were assessed histologically forH. pylori. The sex, age and maximal acid output were comparable in the three treatment groups. The percentages of patients showing an improvement in the activity of gastritis in the four consecutive weeks of treatment were 9%, 40%, 51%, and 53% for omeprazole, 10 mg (N=78); 14%, 42%, 49%, and 53% for omprazole, 20 mg (N=81); and 2%, 23%, 30%, and 33% for ranitidine, 150 mg twice a day (N=82) (life table analysis gaveP<0.01 for both omeprazole regimens compared with ranitidine). The degree of chronic inflammation showed similar changes. The density ofH. pylori decreased significantly after treatment with omeprazole, 10 mg or 20 mg, (both,P<0.00001) but not with ranitidine. The reduction in bacterial density was significantly higher (P<0.003) in those who showed improvement of gastritis than in those who did not. We conclude that effective acid inhibition with omeprazole improves antral gastritis and is accompanied by a reduction in antral bacterial density, suggesting that both acid andH. pylori may be involved in the pathogenesis of antral gastritis.

Effect of omeprazole on duodenal ulcer associated antral gastritis and Helicobacter pylori

Background:

Rabeprazole sodium is the newest member of a class of substituted benzimidazole molecules known as proton pump inhibitors. Other proton pump inhibitors have been shown to be effective in healing active duodenal ulcer.



Method:

This randomized, double-blind, multicentre study, conducted at 25 European sites, compared the efficacy and tolerability of rabeprazole and omeprazole in patients with active duodenal ulcers. One hundred and two patients with active duodenal ulcer received rabeprazole 20 mg and 103 patients omeprazole 20 mg once daily for 2 or 4 weeks, with ulcer healing monitored by endoscopy.



Results:

After 2 weeks, complete ulcer healing was documented in 69% of patients given rabeprazole 20 mg and in 62% of patients given omeprazole 20 mg (N.S.). After 4 weeks, healing rates were 98% in the rabeprazole group and 93% in the omeprazole group (P = 0.083). Rabeprazole-treated patients had significantly greater improvement in daytime pain symptom relief than those treated with omeprazole at the conclusion of the study (P = 0.038). Both drugs were well tolerated over the 4-week treatment period. Mean changes from baseline to end-point in fasting serum gastrin were significantly greater in the rabeprazole group, but at end-point mean values were well within normal limits for both groups. No clinically meaningful changes or other between-group differences were observed in laboratory parameters.



Conclusion:

In this study, rabeprazole produced healing rates equivalent to omeprazole at weeks 2 and 4, and provided significantly greater improvement in daytime pain. Both treatments were well tolerated.

Comparison of rabeprazole 20 mg versus omeprazole 20 mg in the treatment of active duodenal ulcer: a European multicentre study.

In general, peptic ulcer occurs at equal rates in the East and the West but with marked regional differences in both, even within the same country. In the West, the incidence of peptic ulcer, particularly duodenal ulcer, rose sharply at the turn of the century and has shown a rapid decline in the past three decades. In the East, the rise was equally impressive, but the decline appears to have been delayed, only starting in the past decade. Asians present their ulcer symptoms a decade earlier than Caucasians, and it has been suggested that this early presentation may be attributable to Helicobacter pylori (H. pylori) infection at a younger age. Interestingly, the male-to-female ratio is much higher in the East than in the West, and the duodenal-to-gastric ulcer ratio manifests a much wider variation in Asians than in Caucasians. As in Western countries, peptic ulcer occurrence in the East shows a cyclical trend, with a peak frequency in the winter months. In the West, the placebo healing rate varies widely up to 78%, whereas in the East it is rather consistent at around one-third. These variations in geographical distribution, time trends, sex and ulcer ratios, seasonal rates and behavioral response to placebo treatment indicate that while H. pylori is a major cause of peptic ulceration, other environmental and genetic factors contribute to ulcer formation. The parietal cell mass and acid secretory capacity of Asian patients with duodenal ulcer are only slightly more than half of those of Caucasian patients, which may explain why Asian patients respond equally well to half the standard dose of anti-secretory agents used in Caucasians. H. pylori infection is generally more prevalent in the East than in the West and is more resistant to metronidazole. The response to standard triple therapies for eradication, however, appears to be as effective in the East as in the West.

Differences in peptic ulcer between East and West

There is an extensive literature on the adverse effects of drugs that inhibit gastric acid secretion. This study presents a critical examination of interactions between antisecretory drugs and other compounds, the frequency of serious adverse effects relating to various body systems, the safety of antisecretory drugs in pregnancy, and longer-term safety data from postmarketing surveillance studies. While interactions with some other drugs, alcohol, and certain carcinogens are of potential concern, in practice clinically significant reactions appear to be rare if they occur at all. A small number of major side-effects have been documented, but they occur rarely, and postmarketing surveillance has not detected other longer-term sequelae. Safety of these drugs in pregnancy is not established, as data are so few. It is concluded that antisecretory agents, by comparison with most other classes of drugs, are remarkably well tolerated.

Safety of acid-suppressing drugs.

To investigate the efficacy of standard and low dosage of omeprazole in the healing of duodenal ulcer, 270 patients with endoscopically active duodenal ulcer were randomized to receive omeprazole, 10 mg or 20 mg every morning, or ranitidine, 150 mg twice daily, using the double-dummy technique. Forty-six potential prognostic factors for healing including clinical, acid-secretory, and endoscopic characteristics were prospectively obtained and healing was assessed by endoscopy at weekly intervals for up to 4 weeks. The cumulative healing rates in the 4 weeks were 43%, 77%, 94% and 95% for omeprazole, 10 mg (n = 83); 49%, 86%, 93%, and 96% for omeprazole, 20 mg (n = 87); and 29%, 63%, 83% and 93% for ranitidine (n = 84), respectively. Life-table analysis showed P less than 0.03 for omeprazole, 10 mg versus ranitidine and P less than 0.002 for omeprazole, 20 mg versus ranitidine. Life-table analysis also showed that in the omeprazole groups, healing rates were lower in smokers than in non-smokers (P less than 0.001), in late- than in early-onset patients (symptoms starting after or before the age of 30 years, respectively, P less than 0.02), in those with less than 5 months than in those with more than 5 months of remission (P less than 0.05), and in those with increased maximal acid output than in those with normal output (P less than 0.05). Patients with healed ulcer were interviewed at 2-month intervals and endoscoped at 4-month intervals or whenever symptoms recurred. The cumulative ulcer relapse rates in 1 year were not significantly different between omeprazole and ranitidine groups.(ABSTRACT TRUNCATED AT 250 WORDS)

M. M. Taing

Papers

Omeprazole and ranitidine in duodenal ulcer healing and subsequent relapse: a randomized double-blind study with weekly endoscopic assessment.