On-demand proton pump inhibitor therapy in patients with gastro-oesophageal reflux disease

On-demand therapy is an established modality in long-term therapy with histamine-2-receptor antagonists, in cases of mild non-erosive gastro-oesophageal reflux disease. In the literature, only a few studies have specifically addressed the problem of proton pump inhibitors on-demand treatment. The evidence, so far, available suggests that this might be an effective modality of long-term treatment in the majority of patients with non-erosive gastro-oesophageal reflux disease. This treatment modality appears to be the most cost-effective and the best tolerated medical regimen for gastro-oesophageal reflux disease. It also seems to be able to restore the impairment of health-related quality of life due to gastro-oesophageal reflux disease symptoms. Although the current standard of care for patients with non-erosive gastro-oesophageal reflux disease is maintenance therapy with daily administration of a proton pump inhibitor agent, on-demand therapy, with the same drug, may be a reasonable long-term choice. The ideal proton pump inhibitors for such treatment will be those with a more rapid onset of action, more profound acid inhibition, more predictable therapeutic effect and less drug-drug interactions. Newer proton pump inhibitors, like esomeprazole, the S-chiral isomer of omeprazole, are promising drugs for on-demand treatment of gastro-oesophageal reflux disease.     

Review: Side effects of drug treatments for gastro-oesophageal reflux disease: current controversies

The two main drugs used in the treatment of gastro-oesophageal reflux disease are proton pump inhibitors and histamine-2 receptor antagonists and both these agents have been implicated in a number of adverse effects, leading to considerable controversies related to their long-term use. This paper is aimed at a critical review of the published literature and the clinical significance of these reported side effects, most of which are associations rather than causal.     

Pharmacological and pharmacodynamic essentials of H(2)-receptor antagonists and proton pump inhibitors for the practising physician

The suppression of gastric acid secretion with anti-secretory agents has been the mainstay of medical treatment for patients with acid-related disorders. Although the majority of Helicobacter pylori -related peptic ulcers can be healed with antibiotics, ulcer healing and symptom control can be significantly improved when antibiotics are given with anti-secretory agents, especially with a proton pump inhibitor. There is a dynamic relationship between the suppression of intragastric acidity and the healing of peptic ulcer and erosive oesophagitis and control of acid-related symptoms. The suppression of gastric acid secretion achieved with H(2)-receptor antagonists has, however, proved to be suboptimal for effectively controlling acid-related disorders, especially for healing erosive oesophagitis and for the relief of reflux symptoms. H(2)-receptor antagonists are also not effective in inhibiting meal-stimulated acid secretion, which is required for managing patients with erosive oesophagitis. Furthermore, the rapid development of tolerance to H(2)-receptor antagonists and the rebound acid hypersecretion after the withdrawal of an H(2)-receptor antagonist further limit their clinical use. Although low-dose H(2)-receptor antagonists are currently available as over-the-counter medications for self-controlling acid-related symptoms, their pharmacology and pharmacodynamics have not been well studied, especially in the self-medicating population. Proton pump inhibitors have been proved to be very effective for suppressing intragastric acidity to all known stimuli, although variations exist in the rapidity of onset of action and the potency of acid inhibition after oral administration at the approved therapeutic doses, which may have important clinical implications for the treatment of gastro-oesophageal reflux disease and perhaps for eradicating H. pylori infection when a proton pump inhibitor is given with antibiotics. Once-daily dosing in the morning is more effective than dosing in the evening for all proton pump inhibitors with respect to the suppression of intragastric acidity and daytime gastric acid secretion in particular, which may result from a better bio-availability being achieved with the morning dose. When higher doses are needed, these drugs must be given twice daily to achieve the optimal suppression of 24 hour intragastric acidity. Preliminary results have shown that esomeprazole, the optical isomer of omeprazole, given at 40 mg, is significantly more effective than omeprazole 40 mg, lansoprazole 30 mg or pantoprazole 40 mg for suppressing gastric acid secretion. However, more studies in different patient populations are needed to compare esomeprazole with the existing proton pump inhibitors with regard to their efficacy, cost-effectiveness and long-term safety for the management of acid-related disorders.     

Esophageal pH-impedance monitoring in children: position paper on indications,methodology and interpretation by the SIGENP working group

Multichannel intraluminal impedance pH (MII-pH) monitoring currently represents the gold standard diagnostic technique for the detection of gastro-esophageal reflux (GER), since it allows to quantify and characterize all reflux events and their possible relation with symptoms. Over the last ten years, thanks to its strengths and along with the publication of several clinical studies, its worldwide use has gradually increased, particularly in infants and children. Nevertheless, factors such as the limited pediatric reference values and limited therapeutic options still weaken its current clinical impact. Through an up-to-date review of the available scientific evidence, our aim was to produce a position paper on behalf of the working group on neurogastroenterology and acid-related disorders of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) on MII-pH monitoring technique, indications and interpretation in pediatric age, in order to standardise its use and to help clinicians in the diagnostic approach to children with GER symptoms.     

Widespread use of gastric acid inhibitors in infants:Are they needed? Are they safe?

Gastroesophageal reflux is a common phenomenon in infants,but the differentiation between gastro-esophageal reflux and gastroesophageal reflux disease can be difficult.Symptoms are non-specific and there is increasing evidence that the majority of symptoms may not be acid-related.Despite this,gastric acid inhibitors such as proton pump inhibitors are widely and increasingly used,often without objective evidence or investigations to guide treatment.Several studies have shown that these medications are ineffective at treating symptoms associated with reflux in the absence of endoscopically proven oesophagitis.With a lack of evidence for efficacy,attention is now being turned to the potential risks of gastric acid suppression.Previously assumed safety of these medications is being challenged with evidence of potential side effects including GI and respiratory infections,bacterial overgrowth,adverse bone health,food allergy and drug interactions.     

Potential uses of intravenous proton pump inhibitors to control gastric acid secretion

Proton pump inhibitors are the most effective agents for suppressing gastric acidity and are the preferred therapy for many acid-related conditions. While proton pump inhibitors have been accessible in intravenous formulations in several European countries, they have been available only as oral drugs in the United States. In the near future, the proton pump inhibitor pantoprazole is likely to become available in an intravenous formulation for American patients. Potential uses for intravenous proton pump inhibitors include treatment of Zollinger-Ellison syndrome and peptic ulcers complicated by bleeding or gastric outlet obstruction, as well as prevention of stress ulcers and acid-induced lung injury. These intravenous proton pump inhibitors are also likely to be beneficial to patients undergoing long-term maintenance with oral proton pump inhibitors who cannot take oral therapy for a period of time. Intravenous pantoprazole is especially distinguished in its lack of clinically relevant drug interactions, and it requires no dosage adjustment for patients with renal insufficiency or with mild to moderate hepatic dysfunction. Both omeprazole and pantoprazole are well tolerated in both oral and intravenous forms. Although further studies are needed to define their roles clearly, the availability of intravenous formulations of proton pump inhibitors will certainly assist with the treatment of gastric acid-related disorders.     

Influence of acid suppressants on gastric emptying: cross-over analysis in healthy volunteers

BACKGROUND: Gastric emptying plays an important role in gastroesophageal reflux disease. Acid suppressants such as H2 receptor antagonists and/or proton pump inhibitors are often used in patients with gastroesophageal reflux disease. However, it remains controversial whether H2 receptor antagonists and proton pump inhibitors delay or accelerate gastric emptying. Here, the influence of acid suppressants on gastric emptying was evaluated via a cross-over study using the [13C]-labeled acetate breath test. METHODS: Twenty normal male subjects without gastroesophageal reflux disease symptoms were enrolled. Gastric emptying was investigated five times in every subject by the [13C]-labeled acetate breath test with oral administration of the vehicle, domperidone, and three acid suppressants: ranitidine, famotidine and rabeprazole. Gastric emptying was estimated by the values of T(max-calc), T(1/2) and %dose/2 h calculated from the 13CO2 breath excretion curve. RESULTS: Using the T(max-calc) values, rabeprazole, ranitidine and famotidine did not influence gastric emptying time in comparison with vehicle administration. Using the T(1/2) and %dose/2 h values, rabeprazole tended to delay gastric emptying. Domperidone produced a statistically significant acceleration of gastric emptying for all three variables (P < 0.05). CONCLUSION: Oral dosage of the H2 receptor antagonists, ranitidine and famotidine, has no significant effect on gastric emptying. However, rabeprazole may delay gastric emptying more strongly than H2 receptor antagonists.     

Gastro?sophageale Refluxkrankheit im Kindes- und Jugendalter

The symptomatics, diagnostic and therapeutic procedures as well as the long-term prognosis of gastroesophageal reflux disease show considerable differences in pediatric patients depending on age. For infants in particular the symptoms are completely unspecific and a differentiation of gastroesophageal reflux disease from a residual physiological reflux or cows?? milk allergy is very difficult. Patients with an especially high risk of gastroesophageal reflux disease are children with a central palsy or congenital esophageal malformations, in whom the indications for endoscopy of the upper gastrointestinal tract must be liberally considered. The diagnostic methods for children must be complementary employed according to age, symptoms and the problem in question. For proven gastroesophageal reflux disease, proton pump inhibitors are the first choice medication even for children. However, for infants and young children they should not be used on a trial basis. The indications and type of antireflux surgery should be decided by a pediatric gastroenterologist together with a pediatric surgeon.     

Effect of lansoprazole versus roxatidine on prevention of bleeding and promotion of ulcer healing after endoscopic submucosal dissection for superficial gastric neoplasia

Background  

Proton pump inhibitors have been reported to be more useful than histamine-2 receptor antagonists for the prevention of bleeding after endoscopic submucosal dissection (ESD) for superficial gastric neoplasia. The aim of this study was to assess the effects of the proton pump inhibitor lansoprazole and the histamine-2 receptor antagonist roxatidine for the prevention of bleeding and the promotion of ulcer healing after ESD and to compare the cost-effectiveness of these two drugs.     

Pantoprazole: a proton pump inhibitor with oral and intravenous formulations

Proton pump inhibitors (PPI) are a significant part of therapy for most acid-related diseases including gastroesophageal reflux disease, peptic ulcer disease and acute gastrointestinal bleeding. Pantoprazole is one of several available proton pump inhibitor agents and provides dose-dependent control of gastric acid secretion. Pantoprazole has indications in gastroesophageal reflux disease and peptic ulcer disease, along with indications as co-therapy in the eradication of Helicobacter pylori infection and in the control of the acid secretion associated with the Zollinger–Ellison syndrome, as well as in NSAID ulcer prevention. Pantoprazole is available in both oral and intravenous formulations. It is effective across all age groups, although only indicated in adults (and adolescents in Europe). It has been approved for use in over 100 countries and has been used for over 13 years. Pantoprazole has an excellent safety profile and a low potential for drug–drug interactions. While still widely prescribed, pantoprazole and the other branded proton pump inhibitors are under considerable market pressure from the less expensive but similarly effective generic and over-the-counter formulations of omeprazole.     

Changes in gene expression of gastric mucosa during therapeutic acid inhibition

BACKGROUND: Long-term therapy with potent acid inhibitors is a common treatment for gastro-esophageal reflux disease. Administration of proton pump inhibitors (PPIs) causes profound and continuous hypochlorhydria by inhibition of the proton pump in gastric parietal cells. Long-term hypergastrinaemia increases mucosal thickness and enterochromaffin-like cell density in oxyntic mucosa. OBJECTIVE: The aim of this study was to see whether this very common clinical intervention induces significant changes in the gastric mucosal gene expression pattern. METHODS: Seven patients suffering from gastro-esophageal reflux disease were included in this study. Endoscopic biopsies were taken from the corpus mucosa before and toward the end of a 3-month treatment with the PPI esomeprazole. RESULTS: Microarray analysis identified 186 differentially expressed genes. A high proportion of genes with changed gene expression levels during PPI treatment are involved in proliferation, apoptosis, and stress response. CONCLUSION: This study identified many genes that were not previously known to be affected by inhibition of gastric acid secretion. Further characterization of the functional roles of genes whose expression is modulated by potent acid inhibition may give new insight into the biological responses to potent acid inhibition, including the mucosal response to the moderately increased gastrin levels encountered in clinical practice.     

Gastroesophageal reflux disease in pregnancy

Gastroesophageal reflux disease during pregnancy is common. Altered structure and function of the normal physiological barriers to reflux of gastric contents into the oesophagus explain the high incidence of this problem in pregnant women. For the majority of patients, life-style modifications are helpful, but are not sufficient to control symptoms and medication is required. The optimum management of reflux in pregnant patients requires special attention and expertise, since the safety of the mother, foetus and neonate remain the primary focus. Gastroenterologists and obstetricians should work together to optimise treatment. Typically, one utilises a step-up program that starts with life-style modifications and antacids. If those methods fail, histamine-2 receptor antagonists and proton pump inhibitors are tried. Rarely, promotility agents are used. Initiation of these medications must be undertaken after a careful discussion of risks and benefits with patients. In patients without a prior history of reflux, symptoms usually abate after delivery.     

No significant difference in neutrophil activation found among three H2RAs

BACKGROUND: Even with the most effective treatment, Helicobacter pylori eradication is difficult in some patients. Therefore, patients sometimes require acid-suppressive therapy without H. pylori eradication. It has been reported that ranitidine inhibits neutrophil activation, whereas famotidine does not. However, few studies have been published concerning the activation of neutrophils before and after treatment using clinical doses of histamine-2 receptor antagonists in patients with H. pylori infection. AIM: To examine the effects of neutrophil activation after treatment with three different histamine-2 receptor antagonists. PATIENTS: This prospective, open-label, randomised, parallel-group study was conducted. Thirty patients with H. pylori infection were enrolled. These subjects were randomly assigned to receive one of the following treatments: (a) 150 mg ranitidine, (b) 20mg famotidine, or (c) 10 mg lafutidine b.d., for 4 weeks. Before and after histamine-2 receptor antagonist treatment, histological findings, myeloperoxidase activity, and interleukin-8 in the gastric mucosa were evaluated. RESULTS: On the basis of the histological findings between before and after histamine-2 receptor antagonist treatment, no significant differences were found in any groups. Similarly, there were no significant differences in myeloperoxidase activity or interleukin-8 levels. CONCLUSION: In patients with H. pylori, when used at clinical doses, any histamine-2 receptor antagonists can be used without concerning about inhibition of neutrophil activation.     

Histamine receptor antagonists, proton pump inhibitors and their combination in the treatment of gastro-oesophageal reflux disease

The medical treatment of gastro-oesophageal reflux disease is accomplished with the appropriate use of anti-secretory therapy, principally H(2)-receptor antagonists and proton pump inhibitors. In fact, there is a direct correlation between the length of time, in terms of the number of hours per day that the intragastric pH is above 4, and the healing of the oesophagitis. Nowadays, H(2)-receptor antagonists are of limited use as primary treatment, being inferior to proton pump inhibitors in both healing and symptom relief. Although the majority of patients can be effectively managed with carefully titrated doses of proton pump inhibitors, a small number will continue to show difficulty in the management of their disease, principally because of inadequate nocturnal acid control. These patients may benefit from a combination of proton pump inhibitors twice daily with an H(2)-receptor antagonist at bedtime. This article reviews the use of H(2)-antagonists, proton pump inhibitors and their combination in the management of the patient with gastro-oesophageal reflux disease.     

La deuxième génération des antisécrétoires gastriques: l''oméprazole

Omeprazole is the first representative of a new class of gastric acid secretion inhibitors. It acts by specific and prolonged inhibition of H+K+ ATPase, or proton pump, which is the terminal and compulsory stage of acid secretion by the parietal cells. The drug therefore inhibits both basal and stimulated secretion. It appears from therapeutic trials that omeprazole administered in doses of 20 mg a.m. once a day is superior to the H2-receptor antagonists in the healing of active duodenal ulcers and ulcerated reflux oesophagitis. It is as active or slightly more active than histamine inhibitors in gastric ulcers. Finally, it is the treatment of choice to prevent ulcerations in Zollinger-Ellison syndrome. These are the 4 indications for omeprazole at the moment. The use of that drug for periods of a few weeks has not given rise to any significant side-effect.     

New horizons in the medical treatment of gastro-oesophageal reflux disease

Proton pump inhibitors (PPIs) have revolutionized the treatment of gastro-oesophageal reflux disease (GERD). However, nearly 30% of all GERD patients are still symptomatic despite standard dose PPI treatment. Consequently, better treatment options are needed particularly in nonerosive reflux disease (NERD), which provides the largest number of patients that fail PPI. Transient lower esophageal relaxation (TLESR) is the underlying mechanism for most acid reflux events. Therefore, reducing the rate of TLESRs pharmacologically is an attractive therapeutic approach. Some compounds that were evaluated include: anticholinergics, opioids, cholecystokinin antagonists, nitric oxide antagonists, somatostatin, and GABA-B agonists. Currently, the GABA-B agonist baclofen generated the most promising results. Although data regarding GERD is lacking, visceral pain modulation, either pharmacologically or via mind-body interventions, was found to be efficacious in a variety of functional bowel disorders, including functional chest pain of presumed esophageal origin. Finally, intensive research is currently undergoing to develop newer acid suppressive agents. The acid pump inhibitors are reversible competitive inhibitors of the proton pump. These agents are potent suppressors of gastric acid secretion, and their effect is unrelated to food intake. Moreover, they demonstrate a faster onset of action and a predictable dose response effect as compared to the current PPIs. Although some of the preliminary clinical data is promising, thus far none of these agents is commercially available.     

If no-acid, no-heartburn? New physiopathological mechanisms of the gastroesophageal reflux disease

The role of acid is very well established in the pathogenesis of gastroesophageal reflux disease (GERD). In the current era of frequent use of proton pump inhibitors, we are seeing increasing numbers of patients with symptoms that are refractory to acid suppression. Recent studies suggest that in patients being treated with proton pump inhibitors, non-acid reflux (composed of buffered gastric contents), esophageal hypersensitivity, esophageal motor dysfunction and psychological comorbidity can cause persistent symptoms. Concepts surrounding possible pathogenetic mechanisms leading to heartburn as a result of nonacid reflux and other mechanisms are explored, and potential treatments for this type of reflux are outlined in this review.     

Refractory heartburn to proton pump inhibitors: epidemiology, etiology and management

Patients with refractory heartburn to proton pump inhibitors (PPIs) represent a distinctive group which is difficult to manage. In a systematic review of the relative literature we found that approximately 20% of patients with erosive esophagitis and 15-25% of patients with normal endoscopy and abnormal 24-hour esophageal pH monitoring continue to report heartburn despite treatment with standard dose PPIs. Furthermore, approximately 30-40% of patients with normal endoscopy and 24-hour pH studies and 15-20% of patients with Barrett's esophagus have refractory heartburn to double dose PPIs. In such cases, compliance to therapy, duodeno-gastroesophageal reflux, gastro-esophageal motility disorders and eradication of Helicobacter pylori infection may contribute to symptoms. Based on the available evidence, we suggested an algorithm for the evaluation and management of these patients.     

夜间酸突破研究进展

夜间酸突破现象(NAB)在应用质子泵抑制剂的人群中有很高的发生率,发生机制复杂,其与反流性食管炎、Barrett'食管等酸相关性疾病的关系和治疗原则是近年来研究的热点.已有研究发现NAB的发生和食管酸暴露关系不大;睡前加服H2受体拮抗剂能减少NAB的发生,但疗效短暂;根除幽门螺杆菌会加重NAB的发生;肝药酶CYP2C19基因多态性对NAB发生率产生影响.