A significant percentage of patients with gastroesophageal reflux disease (GERD) will not respond to proton pump inhibitor (PPI) therapy. The causes of PPI-refractory GERD are numerous and diverse, and include adherence, persistent acid, functional disorders, nonacid reflux, and PPI bioavailability. The evaluation should start with a symptom assessment and may progress to imaging, endoscopy, and monitoring of esophageal pH, impedance, and bilirubin. There are a variety of pharmacologic and procedural interventions that should be selected based on the underlying mechanism of PPI failure. Pharmacologic treatments can include antacids, prokinetics, alginates, bile acid binders, reflux inhibitors, and antidepressants. Procedural options include laparoscopic fundoplication and LINX as well as endoscopic procedures, such as transoral incisionless fundoplication and Stretta. Several alternative and complementary treatments of possible benefit also exist.

The prokinetic agent cisapride is effective for the treatment of gastroesophageal reflux disease (GERD) in infants and children, but is no longer used for this purpose because of safety concerns. Therefore, other pharmacological agents need to be investigated for efficacy in GERD treatment. In this study, we examined the effectiveness and safety of mosapride for the treatment of neurologically impaired children and adolescents with GERD.

Mosapride (0.3 mg/kg/day) was administered to 11 neurologically impaired patients with GERD (five male; median age, 12.3 years). Esophageal acid exposure was measured using esophageal pH monitoring before and at >5 days after the start of mosapride treatment. The pressure and length of the lower esophageal sphincter were compared before and after mosapride treatment.

In the 11 patients, median reflux index (percentage of the total monitoring period during which recorded pH was <4.0) was 17.5% (range, 4.4-59%) before and 8.2% (range, 2.8-20.7%) after mosapride treatment (P = 0.02). Median esophageal clearance was 1.0 min/reflux (range, 0.5-2.1 min/reflux) before and 0.7 min/reflux (range, 0.4-1.2 min/reflux) after treatment with mosapride (P = 0.02). The median number of reflux episodes before (219) and after (122) drug treatment did not differ significantly.

The decreased reflux index in neurologically impaired patients with GERD is due to mosapride, therefore mosapride may be a candidate for GERD treatment.

The management of patients with refractory GERD (rGERD) is a major clinical challenge for gastroenterologists. In up to 30% of patients with typical GERD symptoms (heartburn and/or regurgitation), acid-suppressive therapy does not provide clinical benefit. In this Review, we discuss the current management algorithm for GERD and the features and management of patients who do not respond to treatment (such as those individuals with an incorrect diagnosis of GERD, inadequate PPI intake, persisting acid reflux and persisting weakly acidic reflux). Symptom response to existing surgical techniques, novel antireflux procedures, and the value of add-on medical therapies (including prokinetics and reflux inhibitors) for rGERD symptoms are discussed. Pharmaceutical agents targeting oesophageal sensitivity, a condition that can contribute to symptom generation in rGERD, are also discussed. Finally, on the basis of available published data and our expert opinion, we present an outline of a current, usable algorithm for management of patients with rGERD that considers the timing and diagnostic use of pH-impedance monitoring on or off PPI, additional diagnostic tests, the clinical use of baclofen and the use of add-on neuromodulators (tricyclic agents and selective serotonin reuptake inhibitors).

Oesophagitis arises when reflux of acid from the stomach into the oesophagus causes mucosal inflammation. It is a common problem and a systematic review on the optimum treatment would be useful.

To assess the effectiveness of proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), prokinetic therapy, sucralfate and placebo in healing oesophagitis or curing reflux symptoms or both. To compare adverse effects with the different treatments.

We searched MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and the National Research Register until December 2004 and reference lists of articles. We also contacted manufacturers and researchers in the field.

Randomised controlled trials assessing the healing of oesophagitis or reflux symptoms or both. Treatment involving PPIs, H2RAs, prokinetics, sucralfate and combinations either in comparison to another treatment regimen or to placebo for 2 and 12 weeks.

Two reviews independently assessed trial quality and extracted data.

We included 134 trials involving 35,978 oesophagitis participants. Five RCTs evaluated standard dose of PPI versus placebo in 965 participants. There was a statistically significant benefit of taking standard dose PPI therapy compared to placebo in healing of oesophagitis (RR = 0.22; 95% CI 0.15 to 0.31). Ten RCTs reported on the outcome for H2RA versus placebo evaluating 1241 participants. There was statistically significant benefit of taking H2RA compared to placebo in healing of oesophagitis (RR 0.74,95% CI = 0.66 to 0.84). Three RCTs evaluated prokinetic therapy versus placebo in 198 participants. There was no statistically significant benefit of taking prokinetic therapy compared to placebo in healing of oesophagitis (RR 0.71, 95% CI 0.46 to 1.10). Twenty six RCTs reported the outcome for PPI versus H2RA or H2RA plus prokinetics, evaluating 4032 participants. There was statistically significant benefit of taking PPI therapy compared to H2RA or H2RA plus prokinetics in healing of oesophagitis (RR 0.51, 95% CI 0.44 to 0.59).

PPI therapy is the most effective therapy in oesophagitis but H2RA therapy is also superior to placebo. There is a paucity of evidence on prokinetic therapy but no evidence that it is superior to placebo.

Esophagitis caused by gastroesophageal reflux disease (GERD) results in appreciable morbidity and economic burden. No systematic review has addressed the effectiveness of prokinetic drugs in the treatment of GERD esophagitis in adults.

To determine the utility of prokinetic drugs in improving symptoms and endoscopic lesions in patients with GERD esophagitis.

We included randomized controlled trials that compared prokinetic drugs with placebo. A systematic search included the Cochrane Controlled Trial Register, MEDLINE, CINAHL, LILACS, EMBASE, a manual search of books and article references, and contact with pharmaceutical companies. Reviewers assessed methodological quality and extracted data that were combined using a random effects model.

Eighteen articles met the eligibility criteria; of these, 13 used prokinetic drugs alone, 4 tested prokinetic drugs as additional therapy in patients receiving histamine-2 receptor blockers, and 1 tested them in patients receiving proton pump inhibitors. Seven studies evaluated clinical improvement only, 5 addressed endoscopic improvement only, and 6 reported both outcomes. Four studies failed to provide adequate data for pooling; 3 of the 4 reported results that suggested symptomatic benefit with prokinetic agents. Nine studies (379 patients) that provided the required data suggested a higher incidence of clinical improvement with prokinetic drugs versus placebo (relative risk [RR] 1.70, 95% confidence interval [CI] 1.37-2.12, heterogeneity p = 0.47, I(2) = 0%). Clinical improvement occurred in 53 out of 175 patients (30%) of the control group; applying the relative risk of 1.70 and associated confidence interval suggests that absolute increases in patients improved might vary from 18% to 41% (number needed to treat approximately 3 to 6). Improvement was similar in 4 studies in which the prokinetic agent was added to an antisecretory drug. The funnel plot, however, suggests the possibility of publication bias. Eleven studies (887 patients) suggested a higher likelihood of endoscopic improvement or healing esophagitis with prokinetic drugs (RR 1.26, 95% CI 1.03-1.53) but with significant heterogeneity (heterogeneity p = .05, I(2) = 46.2%) that we couldn't explain with an a priori hypothesis. When we evaluated endoscopic healing as the main outcome we observed a trend toward better results in the treatment group, also with inexplicable heterogeneity (RR 1.36, CI 95% 0.97-1.89, I(2) = 61%).

Randomized controlled trials provide moderate-quality evidence that prokinetic drugs improve symptoms in patients with reflux esophagitis and low-quality evidence that they have an impact on endoscopic healing.

Oesophagitis arises when reflux of acid from the stomach into the oesophagus causes mucosal inflammation. It is a common problem and a systematic review on the optimum treatment would be useful.

To assess the effectiveness of proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), prokinetic therapy, sucralfate and placebo in healing oesophagitis or curing reflux symptoms or both. To compare adverse effects with the different treatments.

We searched MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and the National Research Register until December 2004 and reference lists of articles. We also contacted manufacturers and researchers in the field.

Randomised controlled trials assessing the healing of oesophagitis or reflux symptoms or both. Treatment involving PPIs, H2RAs, prokinetics, sucralfate and combinations either in comparison to another treatment regimen or to placebo for 2 and 12 weeks.

Two reviews independently assessed trial quality and extracted data.

We included 134 trials involving 35,978 oesophagitis participants. Five RCTs evaluated standard dose of PPI versus placebo in 965 participants. There was a statistically significant benefit of taking standard dose PPI therapy compared to placebo in healing of oesophagitis (RR = 0.22; 95% CI 0.15 to 0.31). Ten RCTs reported on the outcome for H2RA versus placebo evaluating 1241 participants. There was statistically significant benefit of taking H2RA compared to placebo in healing of oesophagitis (RR 0.74,95% CI = 0.66 to 0.84). Three RCTs evaluated prokinetic therapy versus placebo in 198 participants. There was no statistically significant benefit of taking prokinetic therapy compared to placebo in healing of oesophagitis (RR 0.71, 95% CI 0.46 to 1.10). Twenty six RCTs reported the outcome for PPI versus H2RA or H2RA plus prokinetics, evaluating 4032 participants. There was statistically significant benefit of taking PPI therapy compared to H2RA or H2RA plus prokinetics in healing of oesophagitis (RR 0.51, 95% CI 0.44 to 0.59).

PPI therapy is the most effective therapy in oesophagitis but H2RA therapy is also superior to placebo. There is a paucity of evidence on prokinetic therapy but no evidence that it is superior to placebo.

Gastroesophageal reflux disease (GERD) is the most common disease of the gastrointestinal system. Heartburn, regurgitation, and dysphagia are the most common symptoms of GERD. However, chest pain, chronic cough, laryngitis, hoarseness, and other otolaryngologic manifestation can be the primary manifestations of the disease. Endoscopy, barium studies, and especially pH monitoring and therapeutic trials may help in establishing the diagnosis of GERD. The introduction of H2 antagonists and especially of proton pump inhibitors (PPI) has brought symptomatic relief in most patients. However, surgical procedures, especially laparoscopic fundoplication, are still required in some patients. Barrett's esophagitis is the most common complication of GERD and is associated with a high prevalence of esophageal adenocarcinoma. Whether or not treatment with either PPIs or H2 antagonists can prevent this complication is still under investigation.

Difficult asthma is defined as asthma that is not controlled despite treatment with> 800 micro g budesonide or equivalent per day. Poor control is defined as the need for bronchodilators more than three times a week, school absence of more than five days a term, or one episode or more of wheezing each month. Common causes of poor response to treatment include; wrong diagnosis, inappropriate medications or improper inhalation technique, poor adherence to medications and co-morbidity. Steroid resistant asthma is uncommon and estimated to be 1 in 1000-10000 asthmatic patients. If there is no functional improvement to prednisolone 2 mg/kg/day for 2 weeks with adherence checked by measuring serum prednisolone and cortisol levels, a fibreoptic bronchoscopic examination with bronchoalveolar lavage and large airway biopsy should be considered. Eosinophilic inflammation identified on the biopsy in a child who is unresponsive to prednisolone may benefit from alternative anti-inflammatory treatments such as cyclosporin. Neutrophilic infiltration in biopsy may benefit with macrolide antibiotics, 5-lipogenase inhibitors or theophyllines.

Symptoms are an important outcome for measurement in clinical trials into gastro-oesophageal reflux disease, but the optimal approach to symptom assessment has not been formally evaluated. The authors conducted a systematic review to assess how reflux symptoms have been evaluated and how well these correlate with oesophagitis healing and relapse.

Elderly patients with nocturnal symptoms of gastro-oesophageal reflux disease (GORD) usually experience a more aggressive and complicated disease course compared with younger patients, resulting in impaired quality of life. The severity of disease and possible complications should be evaluated with upper endoscopy once the diagnosis is suspected. Elderly patients with nocturnal symptoms of GORD and evidence of endoscopic complications (oesophagitis, Barrett's oesophagus, etc.) and those with severe endoscopically negative reflux disease (ENRD) should be treated with proton pump inhibitors. Histamine H(2) receptor antagonists are suitable for mild-to-moderate ENRD. Antacids and lifestyle modifications may be incorporated into the management as adjuncts to more potent and durable therapeutic agents. Effective treatment of nocturnal GORD symptoms in the elderly will result in relief of symptoms, healing of oesophagitis and improved quality of life, and should be maintained indefinitely to prevent relapses of the disease.

To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine(2) receptor antagonists in gastroesophageal reflux disease (GERD).

Clinical literature identified through MEDLINE (January 1966-August 2001). Key search terms included gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine(2); therapy, combination drug; therapy, combined modality; and combinations, drug.

Approximately 80-90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy. Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for > or =60 min during the night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1-time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid breakthrough. However, the clinical significance of this finding is not clear.

No studies in patients with GERD demonstrate that the addition of histamine(2) receptor antagonists to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far--nocturnal acid breakthrough--has not been proven to correlate with improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs.

Gastro-oesophageal reflux disease (GORD) has been described as a motility disorder of the upper gastrointestinal tract. Disturbances of lower oesophageal sphincter function, lower oesophageal body motility, oesophageal clearance and gastric emptying are well accepted. Cisapride improves most of these but its clinical benefits have been relatively modest. Some recent studies have indicated that the improvements achieved with cisapride may be less marked than originally thought. Furthermore, the agent has no effect on transient lower oesophageal sphincter relaxations, nor on other important factors influencing gastro-oesophageal junction competence, such as the external sphincter function of the diaphragmatic crus and mechanical influences such as lower oesophageal sphincter length exposed to intra-abdominal pressure changes. More potent, specific and predictable prokinetic agents would be welcome, but are unlikely to be effective as single agents across the range of GORD. There is certainly a need for such agents, including cisapride, as adjuncts to acid suppression in patients who fail to respond to the latter.

Although a proton pump inhibitor (PPI) and a prokinetic drug are often combined for the medical treatment of gastro-oesophageal reflux disease (GORD), there are few well-conducted clinical studies on the efficacy and tolerability of this therapy. This study investigates whether pantoprazole plus cisapride leads to an additional benefit in comparison to pantoprazole alone.

Randomized double-blind prospective multicentre study conducted in patients of 33 hospitals in Ireland, South Africa and the UK.

A total of 350 intention-to-treat (ITT) patients aged 18 years or older with GORD of grade II and III were included in the study. The per-protocol (PP) population comprised 152 patients in the pantoprazole group and 136 in the pantoprazole plus cisapride group.

Patients received either pantoprazole 40 mg once daily or pantoprazole 40 mg once daily plus cisapride 20 mg twice daily. Treatment outcome was assessed after 4 and 8 weeks. The primary criterion was endoscopically confirmed healing after 4 weeks. Additionally, relief of leading symptoms was studied.

The prior null hypothesis was no difference in healing rates between both treatment groups.

After 4 weeks of treatment 81% and 82%, and after 8 weeks 89% and 90%, of PP patients treated with pantoprazole or pantoprazole plus cisapride were healed, respectively. Thus, equivalence of the two treatment strategies could be proven. Additionally, improvement of symptom relief showed no significant difference between the two regimens. In contrast to disease grade at baseline, Helicobacter pylori status did not influence the healing rates in our study. Both study medications were tolerated well.

Addition of cisapride to pantoprazole provides no further benefit in the treatment of GORD.

Gastroesophageal reflux has been implicated in the pathogenesis of a wide variety of otolaryngologic disorders. Patients with otolaryngologic disorders associated with gastroesophageal reflux infrequently have the classic symptoms of gastroesophageal reflux, such as heartburn. Clinical presentation of laryngopharyngeal reflux is commonly characterized by chronic intermittent symptoms. A meticulous synthesis of the information obtained from a complete otolaryngologic examination, diagnostic tests, and response to treatment is essential for the efficient management of patients with otolaryngologic disorders associated with laryngopharyngeal reflux.

To provide Canadian primary care physicians with an evidence-based clinical management tool, including diagnostic and treatment recommendations, for patients who present with uninvestigated dyspepsia.

The management tool has 5 key decision steps addressing the following: (1) evidence that symptoms originate in the upper gastrointestinal tract, (2) presence of alarm features, (3) use of nonsteroidal anti-inflammatory drugs (NSAIDs), (4) dominant reflux symptoms and (5) evidence of Helicobacter pylori infection. All patients over 50 years of age who present with new-onset dyspepsia and patients who present with alarm features should receive prompt investigation, preferably by endoscopy. The management options for patients with uninvestigated dyspepsia who use NSAIDs regularly are: (1) to stop NSAID therapy and assess symptomatic response, (2) to treat with NSAID prophylaxis if NSAID therapy cannot be stopped or (3) to refer for investigation. Gastroesophageal reflux disease can be diagnosed clinically if the patient's dominant symptoms are heartburn or acid regurgitation, or both; these patients should be treated with acid suppressive therapy. The remaining patients should be tested for H. pylori infection, and those with a positive result should be treated with H. pylori-eradication therapy. Those with a negative result should have their symptoms treated with optimal antisecretory therapy or a prokinetic agent. VALIDATION AND EVIDENCE: Evidence for resolution of the dyspepsia symptoms was the main outcome measure. Supporting evidence for the 5 steps in the management tool and the recommendations for treatment were graded according to the strength of the evidence and were endorsed by consensus of committee members. If no randomized controlled clinical trials were available, the recommendations were based on the best available evidence.

Evidence was obtained from MEDLINE searches for pertinent articles published from 1966 to October 1999. The searches focused on dyspepsia, diagnosis and treatment. Additional articles were retrieved through a manual search of bibliographies and abstracts from international gastroenterology conferences.

This paper presents a synopsis of the pathophysiology of gastroesophageal reflux disease (GERD) and the efficacy, safety, and cost of the agents commonly used in its treatment.

Symptomatic relief of GERD can be obtained with lifestyle changes (avoidance of factors that may exacerbate symptoms, such as overeating and use of alcohol and tobacco) and use of over-the-counter medications such as antacids or histamine-2 (H2)-receptor antagonists. When these measures are unsuccessful, treatment with prescription-strength medications is required to prevent complications, such as Barrett's esophagus or esophageal adenocarcinoma.

Current guidelines for the management of GERD were identified through a MEDLINE search of the English-language literature from January 1995 through December 1999 and a search of the bibliographies of identified articles.

Patients who do not respond to initial therapy should be managed with prescription-strength H2-receptor antagonists. Endoscopy should be considered for patients with atypical or refractory symptoms. Patients with a confirmed diagnosis of refractory GERD, severe esophagitis, Barrett's esophagus, or peptic stricture should be treated with and maintained on a proton-pump inhibitor.

To compare the expected costs and outcomes of alternative strategies for the management of patients with erosive oesophagitis.

There were 3 components to the overall analytic approach. First, a decision model was constructed to compare expected costs and outcomes of 6 management strategies. Second, principles of quantitative literature review and meta-analysis were used to determine probabilities of clinical events (i.e. oesophagitis healing and recurrence). Finally, principles of cost-effectiveness analysis were used to compare treatment alternatives in terms of dominance and incremental cost effectiveness. The viewpoint for the study was that of a provincial government payer for healthcare over a 1-year period.

Healing rates were significantly higher for proton pump inhibitors (PPI) [p < 0.001]. Recurrence rates were significantly higher for intermittent therapy (placebo) and lower for regular dose PPI (p < 0.001). Maintenance prokinetic agent (PA) is dominated (i.e. more costly and less effective) and step-down maintenance PPI is dominated through principles of extended dominance. The 'efficient frontier' is represented by: maintenance H2-receptor antagonist (H2RA), intermittent PPI, step-down maintenance H2RA and maintenance PPI.

The price of H2RA is a key factor influencing whether step-down maintenance PPI forms part of, or is contained within, the 'efficient frontier' of long term management for erosive oesophagitis.

Gastroesophageal reflux disease (GERD) is an extremely common disorder. Many patients require lifelong medical therapy for symptom control. In patients being considered for antireflux surgery, thorough evaluation is required. Laparoscopic antireflux surgery is a safe and effective method of treating patients who have severe, refractory, or complicated GERD. Excellent long-term results are obtained with minimal morbidity, freeing the patient from the burden of chronic medical therapy.

There appears to be a hierarchy in the efficacy of therapies that are directed against GERD. A summary of this hierarchy, including therapies [table: see text] not approved by the U.S. Food and Drug Administration, is presented in Table 4. The individual practitioner must evaluate the appropriate point at which to place each patient on this hierarchy. Whether it is best to begin with the drug with the highest efficacy and step-down as possible for maintenance, never to step down, or to start with a less efficacious therapy and step up must also be individualized because there are no clear data to support a universal approach to all or even most GERD patients.

Cardiac and musculoskeletal disease should be excluded before considering an esophageal etiology for chest pain. Acid reflux is a common cause of chest pain and should be identified and treated. A therapeutic trial should consist of a proton pump inhibitor (omeprazole 20 mg or lanzoprazole 30 mg) given one or two times per day for at least 6 to 8 weeks. An alternative is to use an ambulatory pH study to confirm reflux. Also, if the patient fails the initial treatment, reflux should be confirmed with pH testing before increasing the dose of proton pump inhibitor or considering combination or surgical therapy. Esophageal manometry should be considered in patients with chest pain and dysphagia. It is also reasonable to perform manometry before a pH study since manometric localization of the lower esophageal sphincter (LES) is needed to ensure accurate pH probe placement. Only after manometric confirmation of a spastic esophageal motility disorder should patients be treated for esophageal spasm. In these patients, it is reasonable to try a long-acting formulation of a calcium-channel blocker or nitrate. Patients with chest pain who have a negative cardiac evaluation and who do not have reflux may have an abnormality in esophageal or cardiac sensation. These patients should be treated with a trial of an antidepressant and considered for referral to a mental health practitioner. All medication trials should continue at least 6 to 8 weeks to avoid a placebo effect and to allow adequate time for a therapeutic response.

Gastroesophageal reflux is a common pediatric complaint and a frequent reason for pediatric patients to be referred to a gastroenterologist. The pathophysiology and clinical manifestations of this disorder differ according to patient age. The diagnosis is suggested by the history and can be confirmed by a pH probe. In the appropriate clinical setting, anatomic obstruction may need to be ruled out by contrast study. Endoscopy is used to assess associated complications, including esophagitis, esophageal strictures, Barrett's transformation, and failure to thrive. Other complications are controversial, including pulmonary disease, apnea, and sudden infant death syndrome. Treatment depends on the severity of disease. Conservative therapy includes behavorial modifications, prokinetic agents, and H2 antagonists. Proton pump inhibitors are generally reserved for refractory esophagitis. Surgical treatment may be necessary for gastroesophageal reflux resistant to medical management or for severe complications. Gastroesophageal reflux beyond infancy tends to be chronic; therefore, lifelong behavioral modifications or repeated courses of medical therapy may be necessary. An algorithm for the suggested diagnostic approach to gastroesophageal reflux is presented herein.

The goals of modern medical therapy for gastroesophageal reflux disease are threefold: first, eliminate symptoms; second, heal injured esophageal mucosa; third, manage and/or prevent complications. Selection of a particular medical regimen depends on the severity of the disease, effectiveness of the therapy, cost, and convenience of the medical regimen. An accurate diagnosis needs to be made in patients suspected with esophageal strictures. If there is a treatable underlying disease, specific therapy is essential. The goal of dilation therapy should be established and set about to accomplish in a timely, but unhurried fashion. Fluoroscopy and wire-guided dilators should be used liberally, especially for difficult strictures.

Gastro-oesophageal reflux disease (GERD) is primarily due to incompetence of the lower oesophageal sphincter (LOS) and crural diaphragm, with transient LOS relaxation frequently accounting for daytime reflux. In the absence of drugs that adequately correct the motility defects of GERD, treatment is directed towards decreasing gastric acidity. Oesophageal healing is related to control of 24-h intragastric acidity, the degree of acid suppression and duration of treatment. H2-receptor antagonists are generally less effective in GERD than in peptic ulcer disease. While providing symptomatic relief in non-erosive GERD, they are often ineffective in healing erosive oesophagitis. Proton pump inhibitors provide more rapid and complete healing and symptom resolution. They are superior to H2-receptor antagonists in the long-term management of erosive oesophagitis and in reducing recurrence of oesophageal stricture following mechanical dilatation. In Barrett's oesophagus, high-dose proton pump inhibitors in combination with laser/photodynamic ablation therapy can produce metaplastic regression, although this does not preclude future emergence of adenocarcinoma. Surgical morbidity and mortality rates in GERD generally remain higher than those associated with long-term pharmacotherapy. However, direct comparisons between laparascopic anti-reflux surgery and proton pump inhibitor maintenance therapy remain to be performed. Although there is no evidence that H. pylori infection worsens the severity of oesophagitis or that H. pylori is carcinogenic in the metaplastic oesophageal mucosa. It has been suggested that H. pylori-positive patients requiring long-term proton pump inhibitor therapy receive bacterial eradication therapy to reduce the risk of developing atrophic gastritis.

Cisapride is a prokinetic agent which restores motility of the gastrointestinal tract in conditions of decreased bowel transit. It may also alter the absorption of coadministered drugs. The absorption of morphine, diazepam, cyclosporin, alcohol (ethanol) and levodopa are increased. Initial absorption of cimetidine and raniditine is also increased, but overall absorption is lower due to increased bowel transit. The absorption of digoxin, propranolol and the anticoagulants warfarin and phenprocoumon appears unaffected by cisapride, although increase thrombotest values were seen with acenocoumarol (nicoumalone). Drug interactions leading to increased plasma concentrations of cisapride may produce an increase in adverse effects. The most important of these is QT interval prolongation and ventricular arrhythmias. Phenytoin does not appear to affect protein binding of cisapride. Cisapride metabolism is inhibited by the antifungals ketoconazole, fluconazole, itraconazole and miconazole, and by the antibacterials erythromycin, troleandomycin and clarithromycin. Cisapride should not be coadministered with these drugs. Cimetidine produces a small increase in cisapride plasma concentrations, which may be due to inhibition of metabolism. Cisapride absorption is unaffected by other antacids. Atropine may reverse the cisapride-induced increase in peristalsis. Prescribers should remain vigilant to the presence of these and other, as yet unreported, reactions.

Dyspepsia and heartburn are common symptoms in primary care practice. This article outlines the diagnosis and management of these problems with an emphasis on cost-effectiveness as well as the prevention of complications. It reviews what evaluations and treatments have been shown in the literature to be helpful and which have been found to be ineffective or much more expensive without clear benefit. It also clarifies the various diseases that can present as dyspepsia and refers readers to the appropriate articles included in this book.

Gastroesophageal reflux (GER) is one of the most frequent symptomatic clinical disorders affecting the gastrointestinal tract of infants and children. During the past 2 decades, GER has been recognized more frequently because of an increased awareness of the condition and also because of the more sophisticated diagnostic techniques that have been developed for both identifying and quantifying the disorder. Gastroesophageal fundoplication is currently one of the three most common major operations performed on infants and children by pediatric surgeons in the United States. Normal gastroesophageal function is a complex mechanism that depends on effective esophageal motility, timely relaxation and contractility of the lower esophageal sphincter, the mean intraluminal pressure in the stomach, the effectiveness of contractility in emptying of the stomach, and the ease of gastric outflow. More than one of these factors are often abnormal in the same child with symptomatic GER. In addition, in patients with GER disease, and particularly in those patients with neurologic disorders, there appears to be a high prevalence of autonomic neuropathy in which esophagogastric transit and gastric emptying are frequently delayed, producing a somewhat complex foregut motility disorder. GER has a different course and prognosis depending on the age of onset. The incompetent lower esophageal sphincter mechanism present in most newborn infants combined with the increased intraabdominal pressure from crying or straining commonly becomes much less frequent as a cause of vomiting after the age of 4 months. Chalasia and rumination of infancy are self-limited and should be carefully separated from symptomatic GER, which requires treatment. The most frequent complications of recurrent GER in childhood are failure to thrive as a result of caloric deprivation and recurrent bronchitis or pneumonia caused by repeated pulmonary aspiration of gastric fluid. Children with GER disease commonly have more refluxing episodes when in the supine position, particularly during sleep. The reflux of acid into the mid or upper esophagus may stimulate vagal reflexes and produce reflex laryngospasm, bronchospasm, or both, which may accentuate the symptoms of asthma. Reflux may also be a cause of obstructive apnea in infants and possibly a cause of recurrent stridor, acute hypoxia, and even the sudden infant death syndrome. Premature infants with respiratory distress syndrome have a high incidence of GER. Esophagitis and severe dental carries are common manifestations of GER in childhood. Barrett's columnar mucosal changes in the lower esophagus are not infrequent in adolescent children with chronic GER, particularly when Heliobacter pylori is present in the gastric mucosa. Associated disorders include esophageal dysmotility, which has been recognized in approximately one third of children with severe GER. Symptomatic GER is estimated to occur in 30% to 80% of infants who have undergone repair of esophageal atresia malformations. Neurologically impaired children are at high risk for having symptomatic GER, particularly if nasogastric or gastrostomy feedings are necessary. Delayed gastric emptying (DGE) has been documented with increasing frequency in infants and children who have symptoms of GER, particularly those with neurologic disorders. DGE may also be a cause of gas bloat, gagging, and breakdown or slippage of a well-constructed gastroesophageal fundoplication. The most helpful test for diagnosing and quantifying GER in childhood is the 24-hour esophageal pH monitoring study. Miniaturized probes that are small enough to use easily in the newborn infant are available. This study is 100% accurate in diagnosing reflux when the esophageal pH is less than 4.0 for more than 5% of the total monitored time.

Gastroesophageal reflux is a common disease. Its chronic course, even if mild, is sometimes complicated by erosive oesophagitis. Drug therapy acts against gastric acidity and motility disorders. Treatment of gastroesophageal reflux disease has three aims: improvement of symptoms and quality of life, healing erosive lesions and prevention of symptomatic and endoscopic relapses. Non-drug measures are always useful, even if their efficacy is not well established. Initial therapy of a symptomatic reflux or mild oesophagitis is most of the time effective (antacids, prokinetics, H2 receptor antagonists). Proton-pump inhibitors are also effective in healing and preventing severe oesophagitis. Questions about long-term treatment adverse events with powerful acid inhibitors, such as hypergastrinemia and the risk of gastric carcinoid tumours seem to be resolved. Studies are requested to define the optimal long-term maintenance treatment with cisapride, H2 receptor antagonists or proton-pump inhibitors at low doses in prevention of symptomatic and mild oesophagitis relapses.

Gastro-oesophageal reflux disease (GORD) ranges from episodic symptomatic reflux without oesophagitis to severe oesophageal mucosal damage, such as Barrett's metaplasia or peptic stricture. The multifactorial pathogenesis of GORD prevents medical cure of the disease. GORD is a chronic disease with a high tendency to relapse, requiring a long term treatment strategy in practically all patients. Complete healing of all mucosal lesions is not necessarily the aim of treatment in all patients. In milder forms of reflux disease, symptom relief is the most important goal. Many patients with mild GORD do well on symptomatic self-care with antacids and/or alginate. In addition, lifestyle changes should be advised to all patients: these improve symptoms and enhance the efficacy of therapy. In the acute treatment of GORD the prokinetic drug cisapride has been shown to be effective in relieving symptoms and healing grade I to II oesophagitis. Cisapride decreases symptomatic and endoscopic relapse in patients with mild GORD. Histamine H2-receptor antagonists are effective in relieving reflux symptoms in about 50% of patients, but with regard to healing, H2-antagonists appear to be mainly effective in grades I and II and not in higher grades of oesophagitis. Maintenance treatment with H2-antagonists is mainly symptomatically effective in patients with mild GORD. Proton pump inhibitors (PPIs) provide significantly higher healing rates of reflux oesophagitis than H2-antagonists, even in the more severe cases of oesophagitis and Barrett's ulcers. PPIs are also effective in patients with oesophagitis refractory to treatment with H2-antagonists. PPIs have become the drugs of first choice in healing of all patients with more severe forms of reflux oesophagitis, and increasingly also for patients with milder forms of oesophagitis, certainly those who fail to respond to other drugs. In maintenance treatment of GORD, PPIs are the most effective drugs, offering the possibility of keeping nearly all patients in remission with adjusted doses. Current patient data of up to 5 years indicate the safety of this strategy for this period, but the exact consequences of strong acid inhibition over a longer period still have to be clarified. At present, all but a few patients with GORD can be managed adequately by medical therapy.

The healing of oesophagitis, both symptomatic and endoscopic, can be obtained with cisapride, the results being equivalent to what has been achieved with H2RAs. For many patients, however, GORD is a chronic relapsing disease.

At least 40-50% of patients relapse within a year of initial healing. Important predictors for relapse are the severity of symptoms, the degree of mucosal damage, and the time it takes for the initial lesions to heal. Another important predictor of relapse, as shown in the cisapride maintenance studies, is the need for PPIs, probably because the most recalcitrant patients were selected for this therapy.

Patients with mild or moderate disease should be treated with intermittent or prolonged therapy with cisapride or H2RAs. Patients with severe disease should be given prolonged or permanent therapy with a PPI or with cisapride in combination with either an H2RA or a PPI. For the latter group, antireflux surgery should also be considered, especially in younger patients who have a completely incompetent closing mechanism of the lower oesophageal sphincter.

To review recent advances in the diagnosis and treatment of gastroesophageal reflux disease (GERD).

Original English language reports were obtained through a Medline search of the National Library of Medicine up to and including 1993. The reference lists of all original reports and review articles were searched to locate any further material. In the evaluation of therapeutic efficacy, randomized studies were preferentially considered; greatest priority was given to double-blind, placebo-controlled trials. Abstracts, nonrandomized trials, and non-English language publications were considered only when other data were unavailable.

Information obtained from histories and physical examinations suggests that GERD occurs in many patients. Evaluation of mucosal injury with use of either endoscopy or air contrast barium radiography is an important early step in the diagnosis of GERD. Endoscopy obtains tissue for histologic study, especially in Barrett's esophagus. Prolonged esophageal pH monitoring is the most useful determinant of the presence and amount of reflux of acid. Patients with GERD should be counseled on lifestyle modification and the use of antacids and antirefluxants. Histamine type 2 receptor antagonists provide symptomatic relief in 32 to 82% of patients with GERD and resolution of verified esophagitis in 0 to 82%. Responses with omeprazole therapy are higher; symptomatic responses were noted in 62 to 94% of patients, and healing of esophagitis occurred in 71 to 96%. Promotility agents and surgical therapy have a role in selected patients.

GERD is a chronic disorder that often necessitates individualized lifelong therapy. Many questions remain to be answered about the cost-effectiveness of both diagnostic tests and therapy for GERD.

Gastro-oesophageal reflux disease is a common disorder and symptoms can be mild to severe. Management of the disease should be individualized. Life-style changes are important for all patients. Drug therapy is often necessary but only very few patients with severe disease need surgical treatment. The purpose of this article is to focus on drug therapy and to review the clinical trials of all the drugs used for gastro-oesophageal reflux disease. Thereafter, judged solely on the data derived from these trials, a practical approach to the management of gastro-oesophageal reflux disease is suggested.

To summarize the pharmacology, pharmacokinetics, efficacy, and safety of cisapride, and to evaluate its potential therapeutic role.

A computerized search of the MEDLINE database was used to identify English-language publications of cisapride data in humans. The MEDLINE search was supplemented by review article bibliographies. There was no attempt to limit the search to a specific gastrointestinal motility disorder.

The MEDLINE search alone identified 165 citations. Because of the volume of available human cisapride data, the focus of the efficacy section is on complete published reports of controlled clinical studies. Abstracts and uncontrolled data are discussed only when other information is unavailable to address important aspects.

Information regarding study design, study population, results, and safety was recorded from each publication. The placebo response to gastrointestinal complaints in patients with motility disorders is high. Therefore, objective evidence of improvement was emphasized when documentation was available.

Cisapride stimulates the motility of smooth muscle lining the esophagus, stomach, small intestine, and colon, and increases the tone of gut sphincters in vitro and in vivo. In controlled investigations, cisapride was superior to placebo in relieving symptoms associated with reflux esophagitis, nonulcer dyspepsia, and gastroparesis. Similar symptom and healing effects were observed with cisapride and histamine (H)2-antagonists in reflux esophagitis. Cisapride was either equal to or superior to metoclopramide in relieving reflux symptoms. However, metoclopramide was associated with significantly more central nervous system adverse effects. Cisapride was well tolerated, with adverse effects limited primarily to the gastrointestinal tract.

Cisapride represents an attractive alternative to metoclopramide for the treatment of a variety of motility disorders. Because it addresses a primary underlying cause of reflux esophagitis, cisapride may also prove to be an effective alternative to acid suppressants in the management of this disorder.

Cisapride is an orally administered prokinetic agent which facilitates or restores motility throughout the length of the gastrointestinal tract. It is a substituted piperidinyl benzamide, chemically related to metoclopramide, but unlike metoclopramide, cisapride is largely devoid of central depressant or antidopaminergic effects. In placebo-controlled trials, cisapride improved healing rates and symptoms in both adults and children with reflux oesophagitis. Maintenance therapy with cisapride at half the healing dose is effective in reducing the incidence of relapse. Symptoms are also alleviated in patients with functional dyspepsia, and gastric emptying and symptoms are improved in most patients with gastroparesis, an effect which is sustained during long term administration. However, the efficacy of cisapride in end-stage gastroparesis remains less clear. Cisapride increases stool frequency in patients with chronic constipation, and limited data suggest that the drug may also be beneficial in treating chronic intestinal pseudo-obstruction and irritable bowel syndrome. Cisapride demonstrated efficacy comparable with or superior to that of metoclopramide, and was at least as effective as cimetidine and ranitidine in patients with reflux disease. In patients with functional dyspepsia, cisapride has shown at least equal efficacy to domperidone, metoclopramide and ranitidine, and superior efficacy to cimetidine in the small comparative trials conducted to date. Adverse effects in patients receiving cisapride are generally transient and mild, with abdominal cramping, borborygmi, diarrhoea or loose stools most frequently reported. Central nervous system adverse effects are rare. Thus, with its favourable tolerability profile and demonstrated efficacy in a variety of gastrointestinal motility disorders, the position of cisapride as a valuable agent in the management of patients with gastrointestinal motility disorders is strengthening. However, larger well-controlled comparative trials of the drug with other agents are necessary before the relative position of cisapride in therapy can be categorically defined.

We conducted a double-blind study comparing two dosage regimens of a prokinetic drug, cisapride (10 mg q.d.s. and 20 mg b.d.), with a low dose of a H2-receptor antagonist (150 mg ranitidine b.d.) in the treatment of 155 patients with reflux oesophagitis as determined by endoscopy. The active treatment took 8 to 12 weeks depending on whether complete healing was found at endoscopy. Improvement in oesophagitis grades from baseline to endpoint was observed in 68% of patients in the 10 mg cisapride q.d.s. group, 83% in the cisapride 20 mg b.d. group and 81% in the ranitidine group (N.S.). At endpoint, the percentages of endoscopically cured patients with initial grades I or II were 52% for 10 mg cisapride q.d.s., 71% for 20 mg cisapride b.d. and 80% for ranitidine (N.S.). The proportional improvement of the overall reflux symptom score (60%) also showed no significant difference between the three groups. In the treatment of mild reflux oesophagitis (grades I and II) similar results can be expected from 20 mg cisapride b.d. and 150 mg ranitidine b.d. As the results of the two dosage regimens of cisapride were not different, the 20 mg twice daily regimen is preferred because it will improve patient compliance. It is concluded that in reflux oesophagitis grades I and II, the efficacy of 20 mg cisapride b.d. and 150 mg ranitidine b.d. are broadly similar.

Prokinetic agents are being used increasingly in medical therapy for gastro-oesophageal reflux disease (GERD). This study examined the effect of 10 mg q.d.s., oral cisapride, or placebo, taken for 12 weeks, on 48 patients with symptoms and endoscopic evidence of GERD. Objective evaluation of benefit was obtained by endoscopy and biopsy, oesophageal manometry, acid reflux provocation test and 24-h oesophageal pH monitoring. Cisapride significantly increased lower oesophageal sphincter pressure (P = 0.003) against baseline and also against placebo, in patients (n = 9) with an hypotensive lower oesophageal sphincter pressure (P < 0.01). The frequency of dyspeptic symptoms was significantly improved in the cisapride group (P = 0.03). Antacid intake, global evaluation of symptoms and a VAS score for symptoms were all better than placebo but failed to reach significance (global evaluation by patients, P = 0.07). Overall, there was no significant improvement in oesophagitis at either 6 weeks (P < 0.05 > 0.3) or 12 weeks (P = 0.07). However, if patients with grades I and II oesophagitis at entry were excluded, cisapride had a significantly greater effect than placebo, 6 weeks (P = 0.05), 12 weeks (P = 0.04). In those with oesophageal ulceration, cisapride was significantly more effective than placebo in inducing healing. Gastro-oesophageal reflux was very variable on both 24-h pH monitoring and acid reflux provocation test. In spite of a 50% decrease in acid exposure on 24-h pH monitoring (cisapride group, mean % pH < 4 day: entry 18.9%, 12 weeks 9.6%), there were no significant intra- or intergroup differences for percentage of time < pH 4, or frequency and duration of episodes, neither pre- or post-prandially, day or night, except for the number of post-prandial episodes during acid reflux provocation tests, which decreased significantly more with cisapride than with placebo (P < 0.05). Thus, oral cisapride when taken for 12 weeks promoted healing of oesophagitis and improved symptoms in patients with GERD; although an increase in lower oesophageal sphincter pressure was observed and a reduction in acid reflux was measured, no significant decrease of acid exposure was seen.

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.

Prokinetic agents are drugs that increase contractile force and accelerate intraluminal transit. They are often used in treating disorders of gastrointestinal motility including gastro-oesophageal reflux disease (GERD). The most widely studied agents include bethanechol, metoclopramide, domperidone and cisapride. These drugs act either by enhancing the effect of acetylcholine or by blocking the effect of an inhibitory neurotransmitter such as dopamine. With the exception of cisapride, the clinical efficacy of the various prokinetic agents in treating GERD has not been confirmed consistently. These agents have variable effects on oesophageal and gastric motor function and are fraught with side-effects. They are effective in relieving mild reflux symptoms but do not predictably heal oesophagitis. On the other hand, cisapride is thus far the most effective prokinetic agent studied for the treatment of GERD. It relieves reflux symptoms and promotes healing of grade I-II oesophagitis, with few side-effects or tachyphylaxis. Its most important role may be in the maintenance treatment of GERD either as a single agent or in combination therapy with an H2-antagonist after oesophagitis healing.

Effective and safe maintenance medical therapy for uncomplicated reflux esophagitis is now feasible with omeprazole and it is likely that other H+K+ATPase blockers, and possibly very high dose H2 receptor antagonist regimens, will also be acceptable. In addition, many patients with ulceration, strictures, and Barrett's esophagus will respond to conservative medical therapy and a proportion of patients with erosive esophagitis may remain in remission with cisapride or with low dose H2 receptor antagonists, if disease is less severe. Thus, there is now a medical "gold standard" against which surgical therapy for uncomplicated esophagitis must be judged and it is essential that all future studies be conducted with clearly defined criteria for the assessment of the symptoms and endoscopic signs of esophagitis and its complications. As ever, the patient's wishes are paramount, but he or she must be allowed to select his or her therapy on the basis of a balanced and fully informed assessment of the long-term and short-term risks of all therapeutic modalities. The burdensome prospect of lifelong tablet ingestion and its potential dangers must be weighed against the alternative, in up to 30% of cases, that surgery may produce dysphagia, gas bloat, or dumping with no guarantee of a long-term cure.

Gastro-oesophageal reflux disease is a common condition with a complex pathophysiology. Despite the spectrum of abnormalities, gastric acid has a central role in mucosal damage, and the mainstay of medical treatment is suppression of gastric acid secretion. The results of antisecretory treatment as assessed by endoscopic healing are reviewed. H2 receptor antagonists give more rapid symptom relief than placebo and can produce endoscopic improvement in 31-88% of cases depending on the severity of oesophagitis. Complete healing, however, is seen only in 27-45% of patients and these have mainly grades I-II disease. Improved healing rates can be obtained by increasing the degree of acid suppression or the length of treatment. The addition of a prokinetic agent may be beneficial. Omeprazole heals 67-92% of patients overall and although most successful in the lower grades of oesophagitis, can also heal 48-62% of patients with grade IV disease. The degree and rate of healing seem to be related to the reduction in oesophageal acid exposure and thus may correlate with the degree and duration of acid suppression over 24 hours obtained by the various treatments. The underlying pathophysiology is unchanged, however, and long term treatment may be needed to maintain remission.

Sixty patients entered a double-blind clinical trial comparing the effect of 1 g of sucralfate granulate given four times daily and cimetidine, 400 mg twice daily. Twenty-six patients treated with sucralfate and 26 treated with cimetidine were examined with short-term pH monitoring before and after 12 weeks of treatment. Thirty patients, 19 treated with cimetidine and 11 treated with sucralfate, had esophageal motility studied by a radionuclide test before and after 12 weeks of treatment. The efficacy of the treatments was judged by symptoms and endoscopic response after 4, 8, and 12 weeks of treatment. The endpoint healing rate was approximately 60% in both groups and symptoms were relieved in half of the patients in both groups (difference not significant). The effect of the treatments on pH and number of spikes reflected the different pharmacodynamic profiles of the drugs, whereas the mean transit time (MTT) was not changed by the treatments. The residual activity after radionuclide transit in the sitting position was significantly increased after treatment with cimetidine. The data support the hypothesis that primary dysmotility might be involved in the pathogenesis of reflux esophagitis in about 33% of the patients. Possibilities for a combination therapy with sucralfate and cimetidine are stressed.

1. Cisapride is a novel prokinetic drug which facilitates or restores motility throughout the gastrointestinal tract. Its mechanism of action is thought to involve enhancement of acetylcholine release in the myenteric plexus of the gut. 2. The effect of intravenous cisapride 10 mg on gastro-oesophageal dysfunction was investigated in 20 patients with systemic sclerosis, using a double-blind, randomised, cross-over, placebo-controlled manometric study design. 3. The increase in lower oesophageal sphincter pressure was significantly higher after cisapride (mean +/- s.e. mean, 8.3 +/- 2.1 cm H2O) than after placebo (mean +/- s.e. mean. 0.1 +/- 0.3 cm H2O) (P less than 0.001). The increase in the number of fundic gastric contractions during the 30 min study period was significantly higher after cisapride (mean +/- s.e. mean, 7.7 +/- 2.3) than after placebo (mean +/- s.e. mean, 0.9 +/- 0.6) (P less than 0.01). 4. No serious clinical adverse effects were observed. 5. The study demonstrates that intravenous cisapride induces a significant increase in lower oesophageal sphincter pressure and in the number of fundic gastric contractions, which may be beneficial in the treatment of scleroderma gastro-oesophageal dysfunction. Further long-term studies of the effect of oral cisapride in patients with systemic sclerosis are warranted.

The advent of histamine H2 receptor antagonists (H2-RA) has allowed the treatment of reflux esophagitis (RE) to be controlled over a relatively long term. The authors have experienced some cases resistant to H2-RA, but it was revealed that these cases can be successfully treated with proton pump inhibitors. It has been suggested that esophagogastric dysmotility can lead to RE. RE has been treated for many years by using GI-prokinetic agents, which theoretically inhibit acid reflux and improve esophageal acid clearance. In order to compare the effects on acid reflux of an H2-RA (famotidine), a proton pump inhibitor (omeprazole) and a GI-prokinetic agent (cisapride), we measured the 24-hour pH in the esophagus and stomach simultaneously, before and after treatment in 17 patients with RE. It was found that the proton pump inhibitor was the most effective drug for inhibiting esophageal acidification, followed by famotidine and then cisapride. Furthermore, we found that cisapride often actually exacerbated acid reflux. The differences in inhibitory effects on acidification allowed us to draw conclusions regarding the treatment of RE. It was concluded that the stronger the inhibitory effect of a drug on acid secretion, the more useful it was in the treatment of RE. The GI-prokinetic drug did not inhibit acid reflux as much as we had expected.