Potent Antisecretory Drugs Research Articles

A combination of naproxen and esomeprazole: Analgesic therapy on balancing cardiovascular and gastrointestinal risks

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most important tool to control pain in rheumatic diseases; however, their application is limited by the risk of serious complications in the cardiovascular system and gastrointestinal tract (GIT). The advent of a Russian new drug that is a naproxen and esomeprazole combination (Vimovo™) extends the possibilities of NSAIDS use. This review considers the benefits of both NEC components. The former is naproxen, a traditional NSAIDS that is in common use as an effective analgesic worldwide. Its chief merit is the least cardiovascular risk among all NSAIDs (aside from aspirin). Esomeprazole is a representative of the group of proton pump inhibitors, a potent antisecretory drug that has passed major tests as an agent for the prevention of NSAID-related GIT complications. This drug combination allows patient incompliance to gastroprotective therapy to be eliminated. Large-scale clinical trials have confirmed a considerable reduction in the frequency of GIT complications with NSAIDS use as compared to the standard enteric-coated naproxen, including in patients receiving low-dose aspirin. Comparison of NEC with celecoxib has indicated that the new medication is as effective as a selective COX-2 inhibitor in both efficacy and GIT safety.

Endoscopic therapies of gastroesophageal reflux disease.

The high prevalence of gastroesophageal reflux disease (GERD) in Western societies has accelerated the need for new modalities of treatment. Currently, medical and surgical therapies are widely accepted among patients and physicians. New potent antisecretory drugs and the development of minimally invasive surgery for the management of GERD are at present the pivotal and largely accepted approaches to treatment. The minimally invasive treatment revolution, however, has stimulated several new endoscopic techniques for GERD. Up to now, the data is limited and further studies are necessary to compare the advantages and disadvantages of the various endoscopic techniques to medical and laparoscopic management of GERD. New journal articles and abstracts are continuously being published. The Food and Drug Administration has approved 3 modalities, thus gastroenterologists and surgeons are beginning to apply these techniques. Further trials and device refinements will assist clinicians. This article will present an overview of the various techniques that are currently on study. This review will report the efficacy and durability of various endoscopic therapies for gastroesophageal reflux disease (GERD). The potential for widespread use of these techniques will also be discussed. Articles and abstracts published in English on this topic were retrieved from Pubmed. Due to limited number of studies and remarkable differences between various trials, strict criteria were not used for the pooled data presented, however, an effort was made to avoid bias by including only studies that used off-PPI scoring as baseline and intent to treat.

Somatostatin and its analogues in peptic ulcer bleeding: Facts and pathophysiological aspects

Peptic ulcer bleeding remains a common medical emergency and despite recent advances in management is still associated with high mortality. Endoscopic treatment remains the cornerstone for the effective management of high-risk patients. Recent evidence suggests that potent antisecretory drugs that inhibit gastric acid secretion, such as proton pump inhibitors, may be of help alone or in combination with endotherapy in the management of peptic ulcer bleeding. Somatostatin appears to offer a distinct advantage over antisecretory drugs, as it inhibits both acid and pepsin secretion and combines these effects with a reduction in gastroduodenal mucosal blood flow which seems to be important in the pathophysiology of peptic ulcer bleeding. Additionally, the inhibition of pepsin secretion might induce a decreased proteolytic activity preventing the dissolution of freshly formed clots at the site of bleeding. Despite its theoretical advantages, there has been very little evidence in the recent past in setting of randomised, controlled, clinical trials. In reviewing the available data, we found that the efficacy of somatostatin and its analogue octreotide are different in the control of peptic ulcer bleeding and this might be due to the different distribution of its receptors through the GI tract. Further studies are needed to define the exact role, if any, of somatostatin and its analogues, in high-risk patients with peptic ulcer bleeding and this might be a rather interesting area for future research.

Endoscopic antireflux therapy.

The management of gastroesophageal reflux disease has gained increasing attention during the past two decades due to a high prevalence in Western societies, new insights in pathophysiology, new potent antisecretory drug therapy, and the advent of minimal invasive surgery. There has always been some discussion between gastroenterologists and surgeons about conservative or surgical treatment options. Others view these different therapies as complementary concepts and both options are needed. There is evidence that the majority of patients with gastroesophageal reflux disease are best treated by proton pump inhibitors (PPIs). There is also evidence that the principle of mechanical augmentation of the gastroesophageal junction by a fundoplication is a good treatment option in patients with severe progressive reflux disease. Recently, several consensus projects developed evidence-based criteria for the indication for conservative and surgical therapy [9, 18, 21]. More than 10 years ago, the British gastroenterologist Paul Swain developed a sewing machine handled by flexible endoscopy to perform limited surgical maneuvers in the gastrointestinal lumen [30, 44, 45]. The idea of minimizing surgical trauma even more by performing operative procedures inside the gastrointestinal (GI) tract opens a new perspective in minimal invasive treatment. As a consequence, in the past few years a whole spectrum of new endoscopic techniques have been developed to treat gastroesophageal reflux disease by intraluminal therapeutic action. This article provides an overview of the available techniques.

PGI12: ESTIMATING POTENTIAL UTILIZATION OF ESOMEPRAZOLE BY ASSESSING GERD SYMPTOM CONTROL ON TRADITIONAL PPI'S

OBJECTIVES: Approximately one-half of the American population experiences weekly symptoms of gastroesophageal reflux disease (GERD). With the hypothesis that not all patients are completely symptom free on proton pump inhibitor's (PPI's), the pharmaceutical industry is formulating more potent anti-secretory drug therapies. In November of 2000 the FDA approved esomeprazole for the treatment of Erosive Esophagitis (EE). Esomeprazole is a more potent inhibitor of gastrin and gastric acid, with clinical studies demonstrating quicker symptom relief with more complete 24-hour acid control. If complete acid control translates into better long-term symptom relief for chronic symptomatic GERD it may play a vital role in refractory GERD patients. The purpose of this cross-sectional survey study is to estimate the percentage of patients actively treated with PPI's (omeprazole and lansoprazole), who perceive control of their symptoms. The Gastrointestinal Symptom Rating Scale (GSRS), a validated rating scale to assess GERD patients' quality of life, was utilized. The study hypothesis is that 80% of the patients will perceive their symptom control is very good or excellent. METHODS: An unblinded self-administered questionnaire, including the GSRS, was mailed to 300 patients who were currently receiving GERD maintenance therapy with a PPI. Patients were asked questions regarding the duration and severity of symptoms, dosing of medication, contributing lifestyle factors and debilitation of disease. RESULTS: 153 questionnaires were returned fully completed, a 51% response rate. The surveyed patients were 60 ± 14 years with 89% of respondents being male. Of the PPI's prescribed 86% and 14% were lansoprazole and omeprazole respectively. The median total score of the GSRS was 19, representing mild to moderate patient symptomatology. CONCLUSIONS: 66% of respondents treated with currently prescribed PPI's had very good or excellent symptom control, however the need exists for a more effective PPI for adequate symptom control in 34% of patients.

Gastric antisecretory drug-induced achlorhydria causes decreases in serum vitamin B12 levels in patients with zollinger-ellison syndrome (ZES): A prospective study

Markedly decreased acid secretion is known to decrease vitamin B~2 absorption. However, it is controversial whether prolonged treatment with potent gastric antisecretory drugs will caused decreased serum vitamin Btz levels (Bt2 levels). This could be a potentially important problem in conditions such as GERD or ZES, requiring continuous long-term treatment. In a previous study we reported that B~z levels, but not serum folate levels, determined at one time correlated inversely with the length of omeprazole treatment in patients with ZES. In the present study to provide insights into the possible effects of long-term acid suppression on B~2 levels in a given patient, we have analyzed sequential results from 68 patients with ZES who were followed for at least 5 years. Patients had yearly B~ levels and determinations of acid secretory control taken one hour before the next dose of antisecretory drug. The mean age of the patients was 55 ± 1 yrs, there were 22 females and 46 males, and the total duration of gastric antisecretory treatment was 14 _+0.5 yrs. Fifty-two patients were being treated with omeprazole (mean time ± 1SEM=5 ± 1 yrs) and 17 patients with histamine Hz inhibitors. The mean initial B~2 level was 439 ± 21 pg/ml (normal=165-1000 pg/ml) and the last Ba2 level, a mean of 6.3 ± 1.2 yrs later, was 427 ± 21 pg/ml, was not significantly different. The patients had a mean basal acid output of 25 ± 2 mEq/h and M An of 54-+ 4 mEq/h. The patients' acid secretory rate on antisecretory drug for each of the last 5 years was reviewed and 21/68 (30%) had complete achlorhydria defined as no basal acid secretion during each of the last 3 years. The B~ levels over the 6.3 ± 1.1 yrs from the first to the last Bl~ level in the achlorhydric patients showed a highly significant (p=0.001) decrease from 419 _+ 38 to 305 ± 24 pg/ml. In contrast, for the 47 patients without complete achlorhydria over a 6.3 ± 1.2 year period of antisecretory drug treatment, the B~2 levels did not change significantly (447 ± 26 vs 480 ± 35 pg/ml). A significantly higher proportion (p=0.002) [18/21 (86%)] of patients with complete achlorhydria had a decrease in their B~2 levels over this time period compared to the patients without achlorhydria [22/47 (47%)]. These results demonstrate that profound acid inhibition, which occurs in 32% of patients with ZES, lead to a highly significant decrease in serum vitamin levels over a 6-year period. In other studies > 80% of patients with GERD treated long-term with potent antisecretory drugs also have such acid hyposecretion that hypergastrinemia develops. These results suggest that in patients with such conditions as ZES or GERD undergoing prolonged daily treatment with potent gastric acid suppressants such as omeprazole or lansoprazole, routine monitoring of B~2 levels should be considered.

H. Pylori, NSAID and peptic ulcers—finally a link!: Chan FKL, Sung JJY, Chung SCS, et al. Randomised trial of eradicaton of Helicobacter pylori before non-steroidal drug therapy to prevent peptic ulcers. Lancet 1997:350:975–9

The rapidly declining prevalence of Helicobacter pylori infection and widespread use of potent anti-secretory drugs means peptic ulcer disease has become substantially less prevalent than it was two decades ago. Management has, however, become more challenging than ever because of the threat of increasing antimicrobial resistance worldwide and widespread use of complex anti-thrombotic therapy in the ageing population. Peptic ulcers not associated with H pylori infection or the use of non-steroidal anti-inflammatory drugs are now also imposing substantial diagnostic and therapeutic challenges. This Seminar aims to provide a balanced overview of the latest advances in the pathogenetic mechanisms of peptic ulcers, guidelines on therapies targeting H pylori infection, approaches to treatment of peptic ulcer complications associated with anti-inflammatory analgesics and anti-thrombotic agents, and the unmet needs in terms of our knowledge and management of this increasingly challenging condition.

Omeprazole administration does not impair gastrointestinal mucosal perfusion, oxygenation, and hexosamine generation

Omeprazole is a potent antisecretory drug that acts by inhibiting the gastric proton pump. In the present study, we have observed the effects of this drug on gastrointestinal mucosal perfusion, oxygenation, and hexosamine generation in humans. Sixteen healthy volunteers were included. Gastrointestinal mucosal perfusion and oxygenation (duodenum, antrum, and corpus) were assessed by laser-Doppler flowmetry and reflectance spectrophotometry. Biopsy specimens were also taken from each location to determine hexosamine content as a quantitative indicator of mucus generation. In addition, serum gastrin level was measured. After baseline data were obtained, subjects were randomly assigned to receive 20 mg of oral omeprazole once daily for 7 days (n = 8) or placebo (n = 8). All measurements were performed again after double-blinded drug administration. No effect was found after placebo administration. In contrast, omeprazole administration significantly increased serum gastrin level (p < .05), suggesting an inhibition of acid secretion. However, this drug did not alter either laser-Doppler signal or oxygen saturation at each location. In addition, no change in mucosal hexosamine content was observed at each location. We conclude that oral omeprazole, despite its well-established antisecretory effect, has no adverse effect on the mucosal defense in humans.

Mean acidity or percentage reflux time in oesophageal pH-monitoring

Objectives: The reflux parameter mean acidity, which is independent of any pH threshold, was compared with the established parameter percentage of time when the pH is less than 4 with respect to the discriminatory diagnostic accuracy in gastro-oesophageal reflux disease and the evaluation of drug effects. Methods: Normal values, sensitivity and specificity of pH-monitoring were calculated using receiver operating characteristic (ROC) analysis in 35 reflux patients and 19 healthy controls. In addition, 32 patients were studied twice, without medication (baseline) and with either antacids (five patients), ranitidine (13 patients) or omeprazole (14 patients). Results: The percentage reflux time was superior to the mean acidity in the diagnosis of gastro-oesophageal reflux disease (maximal sensitivity/specificity was 91/95% compared with 83, 84%). Antacids did not reduce the percentage reflux time or the mean acidity. Ranitidine only reduced the percentage reflux time for the supine body position from 7.7 (0.2–46.4) to 0.72% (0.0–14.9, P < 0.05). Omeprazole reduced all reflux parameters; the percentage reflux time for the upright body position from 9.6 (5.0–52.3) to 1.6% (0.0–22.5, P < 0.01) and for the supine position from 4.9 (0.0–23.7) to 0.0% (0.0–48.5, P < 0.050, and the mean acidity from 0.84 (0.02–76.0) to 0.01 mmol/l (0.0–0.71, P < 0.001). Mean acidity described the effect of omeprazole significantly better than percentage reflux time. Conclusions: In the diagnosis of gastro-oesophageal reflux disease, percentage reflux time is superior to mean acidity. Mean acidity, however, seems to be the better parameter to describe the reduction in acid gastro-oesophageal reflux afforded by potent antisecretory drugs.

DNA fingerprints of Helicobacter pylori before and after treatment with omeprazole.

To test whether a hypoacidic environment may potentially "stress" Helicobacter pylori DNA, encouraging the emergence of strain variation. This hypothesis was tested by inducing prolonged hypoacidity with omeprazole, a potent antisecretory drug. The genomic DNA of H pylori was studied by electrophoretic separation of restriction endonuclease fragments followed by rRNA gene hybridisation in seven patients infected with H pylori before and after treatment with omeprazole 20-40 mg daily for six to eight weeks. DNA was isolated and purified using the guanidium thiocyanate reagent method. DNA samples were digested with Hae III, electrophoresed, vacublotted, and hybridised using a biotinylated cDNA probe prepared from 16S and 23S rRNA from H pylori NCTC 11638. Isolates were compared using their ribopatterns (DNA fingerprints). A total of 26 isolates were obtained; all DNA isolates were cut by Hae III, which was the enzyme that gave the best resolved hybridisation patterns for analysis. No two patients harboured the same strain. The isolates from two patients showed evidence of subtypic variation; one patient had two distinct strains and four patients had their own indistinguishable strains before and after treatment with omeprazole. For each patient, the paired ribopatterns of H pylori DNA were not affected by treatment with omeprazole for six to eight weeks. The H pylori genome is relatively stable when exposed to the conditions of prolonged hypoacidity that result from treatment with omeprazole.

Medical treatment of peptic ulcer disease

The past decade has seen considerable advances in our treatment of peptic ulcer disease, with more potent antisecretory drugs, and a new armamentarium of prostaglandins, surface-active agents, and, perhaps most importantly, treatment against Helicobacter pylori. This past year we have seen publications that suggest better rationales for treatment by acid suppression (both dose and duration), and we have evidence that Helicobacter treatment may favorably alter the gastrin-acid physiologic mechanism. Finally, we are seeing some long-term results of treatment, with reports of 5-year periods with H2 blockers. The publications of the past year, however, have been more incremental than landmark.

The Medical Management of Zollinger-Ellison Syndrome

Diagnosis is always difficult when a rare condition gives rise to a common symptom. The Zollinger-Ellison syndrome causes symptoms which are often indistinguishable from those of peptic ulceration, yet it affects only about one in 1000 ulcer patients. The first major advance in the management of this condition was the demonstration by Gregory et al. that the syndrome was due to hypersecretion of gastrin [1], and the subsequent development of a radioimmunoassay for gastrin. Fasting serum gastrin assay (performed after anti-secretory drugs have been stopped for at least 48 hours) has since been used as the mainstay of diagnosis, but although serum concentrations in excess of 1000 pg/ml are diagnostic, concentrations are usually lower and in about 30 per cent of cases they overlap the range of gastrin concentrations found in uncomplicated duodenal ulceration [2]. The excessive production of gastrin results in a 4-6-fold increase in parietal cell mass [3] and there is typically a high basal acid secretion (> 15 mmol HCl/hour) which is greater than 60 per cent of the maximal acid output after administration of exogenous pentagastrin. In some cases, however, there may be a misleading response to pentagastrin, as reported by Collins et al. who describe their experience of 16 patients with Zollinger-Ellison syndrome [4]. In such cases the secretin provocation test may be very helpful: intravenous administration of exogenous secretin usually results in a marked increase in serum gastrin and gastric acidity in patients with Zollinger-Ellison syndrome while having little if any effect on duodenal ulcer patients. The effect of intravenous secretin on serum gastrin on its own may be unreliable, as shown by Collins et al., but an acid output of > 18 mmol/hour after intravenous secretin is highly suggestive of the diagnosis [5]. The diagnosis should be considered in any patient with peptic ulceration who has persistent diarrhoea: this was a major feature in 38 per cent of patients in the series reported here. It should also be excluded in patients with multiple or unusually distal ulcers, ulcers that are resistant to conventional medical therapy and in patients with recurrent ulcers after surgery. The median duration of symptoms of 5.5 years before diagnosis reported by Collins et al. typifies the difficulties in diagnosis and, in view of this delay and the fact that about 60 per cent of gastrinomas are malignant, it is not surprising that surgery has rarely proved curative. As a result the standard policy for many years has been to recommend total gastrectomy, paying little attention to finding and removing the primary tumour. This has changed radically since the introduction of potent antisecretory drugs.

The significance of gastrin in the pathogenesis and therapy of peptic ulcer disease.

Gastrin, a polypeptide hormone secreted by G (gastrin)-cells in the antroduodenal mucosa, is not only a potent stimulant of gastric acid secretion but also exerts trophic actions on the parietal, chief and enterochromaffin-like cells in the oxyntic mucosa. Gastrin plays a crucial role in the pathogenesis of hypergastrinaemic peptic ulcer disease, i.e. in the Zollinger-Ellison syndrome, antral G-cell hyperfunction and retained excluded antrum after subtotal gastrectomy. In patients with normogastrinaemic duodenal ulcer disease the feedback mechanism between gastric acid and gastrin secretion is impaired, while in gastric ulcer patients gastrin secretion is appropriately regulated by gastric acid. Antisecretory drugs may exert varying effects on gastrin secretion. Potent antisecretory drugs, such as omeprazole, increase serum and antral gastrin concentrations, whereas histamine H2-receptor antagonists, such as cimetidine, ranitidine, famotidine and roxatidine, have little influence on gastrin. Interestingly, antisecretory doses of prostaglandin E2-analogues, such as enprostil and arbaprostil [15(R)-15-methylprostaglandin E2], inhibit gastrin secretion, while gastrin is not influenced by prostaglandin E1-analogues, e.g. misoprostol. Somatostatin and the somatostatin-analogue SMS 201-995 reduce serum gastrin levels and gastric acid secretion.

Hormonal regulation of gastric acid in peptic ulcer disease.

Although the pathogenetic role of gastrin in gastric acid hypersecretion and peptic ulcer is well established in a number of uncommon disorders, such as Zollinger-Ellison syndrome, antral G-cell hyperfunction, and retained, excluded antrum after subtotal gastrectomy, the significance of hormonal abnormalities in normogastrinaemic peptic ulcer is less obvious. Most studies have pointed to an impaired feedback mechanism between gastric acid and antral gastrin secretion in duodenal ulcer disease, possibly due to antral somatostatin deficiency. Furthermore, antisecretory drugs may induce abnormalities of gastrointestinal hormones. Potent antisecretory drugs, such as omeprazole, increase serum and antral gastrin and reduce antral somatostatin, whereas certain prostaglandin E2 analogues inhibit serum gastrin secretion after feeding.

Current management of Zollinger-Ellison syndrome.

Patients with Zollinger-Ellison syndrome require that management decisions be made to control the gastric acid hypersecretion and treatment directed at the gastrinoma itself. The advent of newer antisecretory drugs and increased knowledge of the natural history of this disease have led to major changes in the management of each of these two areas. Recent studies have demonstrated that treatment with the currently available histamine H2-receptor antagonists (cimetidine, ranitidine) with or without an anticholinergic agent will control gastric acid secretion in almost all patients. These studies have also shown that most patients require higher doses than those used routinely to treat peptic ulcer, treatment is only successful if an adequate dose of antisecretory drug is used and must be monitored by measuring gastric acid hypersecretion, and established criteria to regulate the dose must be used. Newer more potent antisecretory drugs such as famotidine or omeprazole will facilitate management of gastric hypersecretion but are not yet currently available. Highly selective vagotomy should be considered in those patients who require high doses of cimetidine or ranitidine. Total gastrectomy should be reserved for those patients unwilling or unable to take oral medication. Although aggressive surgery is not warranted in most patients because overall prognosis is excellent, tumour status should be assessed in all patients by imaging studies (CT scan, ultrasound, selective angiogram). Patients without metastatic disease and without the MEN-1 syndrome (multiple-endocrine-neoplasia type 1) should undergo exploratory laparotomy by a surgeon experienced in treating this disease, with studies suggesting a cure rate of approximately 20%.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric Endocrine Cells in Omeprazole-Treated and Untreated Patients with the Zollinger-Ellison Syndrome

We have investigated the gastric endocrine cells in 19 patients with the Zollinger-Ellison syndrome. Six received a long-term treatment with omeprazole, 5 one with H2 receptor antagonists and 8 had no medical treatment. Fifteen patients (79%) had hyperplasia of the endocrine cells in the oxyntic mucosa independent of treatment. The hyperplasia involved both enterochromaffin-like (ECL) and D1 cells and was positively related to the duration of disease (p less than 0.05). The duration of hypergastrinaemia was longer in the omeprazole-treated patients, but the hyperplasia was not significantly more pronounced in these patients. Gastric carcinoid tumours consisting mainly of ECL cells are rare in man and are most often seen in states of hypergastrinaemia such as chronic atrophic gastritis. It has seldomly been reported in Zollinger-Ellison patients; but now, when potent antisecretory drugs make it possible to avoid total gastrectomy, a raised incidence might result, and an increased attention to this aspect seems appropriate.

On the long acting gastric antisecretory activity of LM 24056 A non H 2 antagonist

LM 24056, a phenothiazine derivative with no central effects, can be classified as a non anti H 2 antisecretory agent with a long duration of action. Its activity was demonstrated orally at low dose in pentagastrin stimulated Shay rat and in Heidenhain pouch in dog against gastrin, pentagastrin, carbachol and test meal. LM 24056 was inactive in histamine induced secretion. LM 24056 possesses very weak affinity to muscarinic receptors in vitro and in vivo. It has negligible anticholinergic properties in rats and mice at the peripheral level but no effect at the central level. The long lasting antisecretory action of LM 24056 may be supported by the persistent presence in plasma of a desmethyl metabolite at higher concentrations tham that of LM 24056 at any time. Contrary to LM 24056 sulfoxide and LM 24056 sulfone, desmethyl LM 24056 is a more potent antisecretory drug than LM 24056. Desmethyl LM 24056 possesses more marked affinity to peripheral muscarinic receptor than LM 24056. As the administration of therapeutic doses of LM 24056 was not followed by anticholinergic side-effects, it may be suggested that LM 24056 activity is related to a “prodrug like effect”. Finally the activity of LM 24056 may be related to LM 24056 itself and/or a desmethyl metabolite.

24-hour intragastric acidity and nocturnal acid secretion in patients with duodenal ulcer during oral administration of cimetidine and atropine.

Cimetidine markedly inhibits gastric acid secretion, but from the therapeutic point of view it is important to know whether concurrent treatment with an anticholinergic increases its effect. This possibility has been investigated by measuring the 24 h intragastric acidity and nocturnal output of acid in four duodenal ulcer patients, each receiving on separate occasions cimetidine 1 g/day and placebo, atropine 2-4 mg/day and placebo, cimetidine and atropine, or two placebos. Cimetidine alone decreased mean hourly hydrogen ion activity by 63% of control values, decreased mean hourly hydrogen ion concentration (total acid) by 41%, inhibited nocturnal acid secretion by 83% and resulted in half the nocturnal samples being anacidic. Atropine alone had no effect when compared with control and combined treatment with both drugs was not superior to cimetidine alone. Atropine did not affect the absorption or urinary excretion of cimetidine. Fasting serum gastrin concentrations were not changed by any of the treatments. At the doses studied, the combination of cimetidine with an anticholinergic appears to offer no advantages over treatment with the H2-antagonist alone. Cimetidine is the only potent anti-secretory drug that does not cause acute side-effects and this important advantage would be lost if it were given with a maximal dose of an anticholinergic.