Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The management of oesophageal reflux disease can and should be highly individualised, depending on the severity of the disease. Mild occasional symptoms of heartburn can often be controlled with conservative measures or changes in diet and antacids. For patients with erosive or ulcerative oesophageal disease, it is becoming clear that acid plays a crucial role in injury and that suppression of acid enhances healing. Antipeptic dosages of histamine receptor antagonists achieve good relief of symptoms but may not always heal erosive oesophagitis. Healing rates are improved with the use of new hydrogen-potassium adenosine triphosphatase (ATPase) pump inhibitors which suppress virtually all acid production. The recurrence of disease is common after acid suppression therapy is discontinued, suggesting the need for some form of long term maintenance therapy. Promotility drugs, which improve oesophageal motility, have inconsistent results in clinical trials and have been associated with a higher rate of adverse drug effects in comparison with acid-suppressive therapies. Surgical treatment should still be considered for patients with chronic recurrent disease who do not respond well to pharmacological therapies.
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PMID:Treatment approaches to reflux oesophagitis. 219 48

Proton pump inhibitors (PPIs) are targeted to the gastric acid pump, H+, K(+)-adenosine triphosphatase (ATPase). The drugs accumulate in the acid space of the parietal cell and convert to active sulfenamide by an acid-catalyzed reaction. Consequent covalent inhibition of H+, K(+)-ATPase blocks the final step of acid secretion, hence the PPIs omeprazole, lansoprazole, and pantoprazole are more effective than histamine2-receptor antagonists (H2RAs) in controlling acid secretion. Preclinical short- and long-term clinical surveillance data show these drugs to be well tolerated and safe. The PPIs heal the lesions of gastroesophageal reflux disease and lessen symptoms more effectively and more quickly than the H2RAs, and are effective and faster acting for peptic ulcer disease. Helicobacter pylori is causally implicated in the majority of peptic ulcers and in atrophic gastritis. Since PPIs, but not H2RAs, are synergistic with antibiotics in eradicating H. pylori, their use is appropriate in all acid-related diseases since all patients who are H. pylori positive require eradication as well as healing.
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PMID:Proton pump inhibitors and acid-related diseases. 901 63

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of pantoprazole are reviewed. Pantoprazole is a gastric hydrogen-potassium adenosine triphosphatase (H+/K(+)-ATPase) inhibitor. It shares the same core structure as other currently available proton-pump inhibitors (PPIs). The FDA-labeled indication is the short-term treatment of erosive esophagitis. PPIs act by selectively inhibiting H+/K(+)-ATPase in the secretory canaliculus of the stimulated parietal cell. Understanding the pharmacodynamics of PPIs is more relevant than knowing their pharmacokinetics, since the duration of action depends on the rate of de novo proton-pump regeneration, not the duration of drug circulation in the body. Pantoprazole is well absorbed, undergoes little first-pass metabolism, and has an absolute bioavailability of approximately 77%. Pantoprazole has been evaluated in more than 100 clinical trials involving more than 11,000 patients. It is effective in treating erosive esophagitis and duodenal and gastric ulcers. It is also effective as adjunctive treatment with antimicrobials in patients infected with Helicobacter pylori. Pantoprazole has been shown to control acid production in Zollinger-Ellison syndrome. Pantoprazole is well tolerated. The most commonly reported adverse effects are headache, diarrhea, and abdominal pain. The recommended oral dosage for erosive esophagitis is 40 mg once a day for up to eight weeks. The recommended i.v. dose is 40 mg given over 15 minutes once a day in patients with gastroesophageal reflux disease who are unable to take oral medication. Pantoprazole appears to be as safe and effective as other PPIs in acid-related disorders.
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PMID:Pantoprazole. 1140 94

Blockade of the gastric acid pump, hydrogen-potassium adenosine triphosphatase (H+,K+-ATPase), by proton pump inhibitors (PPIs) is one of the most effective treatments for gastro-oesophageal reflux disease (GORD). In ideal terms, however, the inhibition of acid secretion should occur rapidly, on the first dose, and remain virtually complete in a dose-dependent manner. Several aspects of PPI biochemistry prevent the achievement of this ideal. PPIs target the final step of acid secretion and, due to the covalent nature of their inhibition of H+,K+-ATPase, cause suppression of acid secretion long after the drug has been eliminated. Their disadvantages stem from their mechanism of action: they require accumulation and activation in active parietal cells and have short plasma half-lives, hence a relatively slow onset of action. An extension of PPI plasma half-lives is an obvious goal, possibly via exploitation of probable differences in the metabolism of the two enantiomers (structural mirror images) present in current PPI formulations: e.g., clinical data on the S-enantiomer of omeprazole (esomeprazole) suggest some improvement in acid control. An alternative is to generate a pro-drug of a PPI; plasma levels of the PPI would thus depend on release of the active metabolite from the pro-drug, again extending drug half-life. Another area of active investigation is the development of acid-pump antagonists to inhibit acid secretion at its final step.
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PMID:Improving on PPI-based therapy of GORD. 1143 May 7

Lansoprazole is a proton pump inhibitor that reduces gastric acid secretion in a dose-dependent manner via inhibition of H+/K+-adenosine triphosphatase in gastric parietal cells. It also exhibits antibacterial activity against Helicobacter pylori in vitro. During almost 10 years of clinical use, lansoprazole has proved effective and well tolerated in a wide range of acid-related disorders, including gastro-oesophageal reflux disease (GORD), duodenal ulcers, gastric ulcers, non-steroidal anti-inflammatory drug-related ulcers, as well as non-ulcer dyspepsia and acid hypersecretion. It is also used, in combination with antibiotics, for H. pylori eradication. In the above indications, lansoprazole has generally proved to be superior to the histamine H2-receptor antagonists, and is at least as effective as the other currently available proton pump inhibitors. This review aims to evaluate the pharmacology, efficacy, safety and cost-effectiveness of lansoprazole in acid-related disorders, with particular emphasis on its use in GORD and H. pylori eradication regimens.
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PMID:An overview of the pharmacology, efficacy, safety and cost-effectiveness of lansoprazole. 1192

The more potent and longer-lasting inhibition of gastric acid secretion provided by proton pump inhibitors (PPIs) as compared with histamine-2-receptor antagonists is caused in large part by differences in their mechanism of action. PPIs block histamine-2-, gastrin-, and cholinergic-mediated sources of acid production and inhibit gastric secretion at the final common pathway of the H+/K+ adenosine triphosphatase proton pump. In contrast, histamine-2-receptor antagonists cannot block receptor sites other than those mediated by histamine. It seems that the rapid loss of acid suppression activity by the histamine-2-receptor antagonists may be attributed to tolerance. Such tolerance has not occurred in patients receiving PPIs because these agents are irreversible inhibitors of the H+/K+ adenosine triphosphatase proton pump. For these reasons, patients who have acid-related disorders that require high levels of acid suppression do not respond well to intravenous histamine-2-receptor antagonists and would be excellent candidates for intravenous PPI therapy. Candidates for intravenous PPIs also include patients who cannot receive oral PPIs and those who may need the higher acid suppression therapy provided by the intravenous rather than the oral route. Clinical studies have demonstrated the efficacy of intravenous pantoprazole in maintaining adequate control of gastric acid output during the switch from oral to intravenous therapy in patients with severe gastroesophageal reflux disease or the Zollinger-Ellison syndrome. Intragastric administration of solutions prepared from oral PPIs has been used as an alternative to the intravenous route in critical care settings. However, decreased bioavailability may limit the value of intragastric delivery of PPIs because of the high frequency of gastric emptying problems in critically ill patients.
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PMID:Pharmacology of acid suppression in the hospital setting: focus on proton pump inhibition. 1207 61

The field of acid suppression has been advanced by therapeutics of increasing specificity for inhibiting gastric acid secretion. Particularly important are proton pump inhibitors (PPIs), which inhibit the activity of the gastric acid pump (H+,K(+)-adenosine triphosphatase), the final common step in gastric acid production. Histamine2-receptor antagonists, which act at an early stage of the acid secretion pathway, are less effective and are subject to intolerance. The PPIs are weak bases that undergo accumulation in the acidic space of the secreting parietal cell and are converted in acid to the active thiophilic form, which then forms disulfide bonds with key cysteines of the gastric acid pump. Pantoprazole differs from other PPIs in terms of its reaction with cysteine 822 in the pump and with cysteine 813, a common binding site for all PPIs. Both cysteines are in the sixth transmembrane segment, which is part of the ion transport pathway. This selective binding may have an impact on the dwell time of pantoprazole versus other PPIs because it is inaccessible to reducing agents, in contrast to cysteine 813. Pantoprazole is also very stable (has a slow rate of activation) at neutral pH values compared with other PPIs and has a relatively robust plasma concentration-time curve. These agents are important in the management of duodenal ulcers, nonsteroidal antiinflammatory drug-induced ulcers, gastroesophageal reflux disease, and dyspepsia, but basic pharmacokinetic and pharmacodynamic differences among them may affect clinical utility.
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PMID:Physiology of the parietal cell and therapeutic implications. 1458 60

Proton pump inhibitors (PPIs) [omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole] are widely utilised for the treatment of gastro-oesophageal reflux disease, as well as other acid-related disorders. All PPIs suppress gastric acid secretion by blocking the gastric acid pump, H(+)/K(+)-adenosine triphosphatase (ATPase), but the physicochemical properties of these drugs result in variations in the degree of acid suppression, as well as the speed of onset of acid inhibition. Such differences may impact on the clinical performance of PPIs, and this manuscript discusses data that may help clinicians choose between the available PPIs for specific clinical situations and indications. The characteristics of PPIs that have been developed subsequent to omeprazole offer several advantages over this prototype PPI, particularly with respect to the onset of acid suppression and reduced potential for inter-individual pharmacokinetic variation and drug interactions. Newer agents inhibit H(+)/K(+)-ATPase more rapidly than omeprazole and emerging clinical data support potential clinical benefits resulting from this pharmacological property. Although key pharmacokinetic parameters (time to maximum plasma concentration and elimination half-life) do not differ significantly among PPIs, differences in the hepatic metabolism of these drugs can produce inter-patient variability in acid suppression, in the potential for pharmacokinetic drug interactions and, quite possibly, in clinical efficacy. All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, there is minimal risk from the administration of any of them - even to patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the cytochrome P450 (CYP) isoenzymes involved in PPI metabolism (CYP2C19), and this polymorphism has been shown to substantially increase plasma levels of omeprazole, lansoprazole and pantoprazole, but not those of rabeprazole. Hepatic metabolism is also a key determinant of the potential for a given drug to be involved in clinically significant pharmacokinetic drug interactions. Omeprazole has the highest risk for such interactions among PPIs, and rabeprazole and pantoprazole appear to have the lowest risk.Thus, whereas all PPIs have been shown to be generally effective and safely used for the treatment of acid-mediated disorders, there are chemical, pharmacodynamic and pharmacokinetic differences among these drugs that may make certain ones more, or less, suitable for treating different patient subgroups. Of course, the absolute magnitude of risk from any PPI in terms of drug-drug interactions is probably low - excepting interactions occurring as class effects related to acid suppression (e.g. increased digoxin absorption or inability to absorb ketoconazole).
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PMID:Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. 1466 53

The development and introduction into clinical practice of proton pump inhibitors (PPIs) have influenced the management of acid-peptic disorders dramatically. PPIs inhibit the gastric hydrogen/potassium adenosine triphosphatase selectively and irreversibly which is the final step in acid secretion. PPIs are currently the most effective form of therapy in acid-peptic diseases. All PPIs are potent, effective and generally safe, but little different in equivalent doses. PPIs undergo hepatic metabolism by cytochrome P450 (CYP) system. Polymorphism of CYP2C19 influences the pharmacokinetics and pharmacodynamics of PPIs. Doses and dosing schemes of PPIs based on CYP2C19 genotype status is expected to increase the efficacy in clinical outcome. The major indication of PPIs are acid-related diseases such as peptic ulcers and their complications, gastroesophageal reflux diseases, Zollinger-Ellison syndrome and eradication of Helicobacter pylori with antibiotics and dyspepsia. The potency and cost-effectiveness of PPIs have extended their clinical uses. However, their widespread and long-term use may limit the therapeutic benefit between efficacy and clinical problems such as acid rebound hypersecretion, enhanced oxyntic gastritis, problems with carcinoids in rodents and long-term concern for gastric cancer development. Further studies are needed to minimize the side effects and to maximize the therapeutic effects of PPIs.
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PMID:[Clinical use of proton pump inhibitors in gastrointestinal diseases]. 1655 71

Proton pump inhibitors (PPIs) are widely used for the treatment of gastroesophageal reflux disease, as well as other acid-related disorders. Omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole effectively suppress gastric acid secretion by blocking the gastric acid pump, H+/K+ -adenosine triphosphatase (ATPase). Understanding the pharmacokinetic properties of PPIs and examining the pharmacogenetic differences may help clinicians to optimize PPI therapy and to perform individual treatment, especially in non-responder patients with GERD or ulcer or after failed eradication therapy.
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PMID:[Clinical pharmacological aspects of the proton pump inhibitor therapy: importance of pharmacogenetic differences in the clinical practice]. 1744 20


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