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

Although in most patients with duodenal ulcer disease the ulcer heals after 8 weeks of treatment with standard doses of H2 blockers or other agents, in about 10% the ulcer does not heal. These patients are considered 'refractory' to treatment. Reasons often cited for non-healing include poor patient compliance, cigarette smoking, and non-steroidal anti-inflammatory drug (NSAID) use. Gastric acid hypersecretion also appears to be an important factor in non-healing with standard doses of antisecretory agents. We have defined idiopathic gastric acid hypersecretion as a basal acid output of greater than 10 mmol/h in the absence of an elevated fasting serum gastrin level (or a negative secretin test if gastrin level greater than 100 pg/ml) to exclude persons with Zollinger-Ellison syndrome. Among the acid/peptic-related disorders in which idiopathic gastric acid hypersecretion should be considered are refractory duodenal ulcer, refractory gastro-oesophageal reflux disease (especially patients with oesophagitis), postbleeding duodenal ulcer, and certain rare disorders such as hereditary angioedema. Some children with atypical abdominal pain may also be hypersecretors of gastric acid. Once identified, patients with refractory duodenal ulcer or gastro-oesophageal reflux disease are treated with incremental doses of ranitidine titrated against the level of gastric acid secretion that remains during therapy. Ranitidine was selected to avoid the dose-related antiandrogenic effects and potential hepatic cytochrome P450 system-related drug interactions that may occur with cimetidine. In most cases of refractory duodenal ulcer, doubling the standard dose of ranitidine (to 300 mg b.d.) is sufficient to achieve symptomatic relief and mucosal healing. Higher doses appear to be necessary for refractory oesophagitis. To date, no side effects have been associated with high doses of ranitidine (up to 1800 mg/day) for periods of longer than 6 months. Idiopathic gastric acid hypersecretion is an important factor in explaining why not all patients respond to a 'standard' ulcer-healing dose of H2 blocker, and it provides a rationale for use of higher-dose therapy as a safe and effective alternative to omeprazole or to combination drug therapy in refractory acid/peptic disease.
 ...
PMID:Idiopathic gastric acid hypersecretion: treatment implications for refractory acid/peptic disorders. 188 34

Omeprazole, a benzimidazole compound which inhibits H+/K+ ATPase in the gut, is used in the treatment of gastroesophageal reflux disease. Clinical and experimental use of omeprazole has been associated with inhibition of the cytochrome P450-dependent metabolism of a few drugs both in vivo in man and in vitro in animals. In these experiments, in vivo administration of omeprazole to rats failed to inhibit the cytochrome P450-dependent metabolism of four prototypic drugs, testosterone or estradiol.
 ...
PMID:Omeprazole and cytochrome P450-dependent hepatic metabolism: a comparison of endogenous and exogenous substrates in male rats. 194 96

Cisapride, a cytochrome P450 3A4 (CYP3A4) substrate, is widely prescribed for the treatment of gastrointestinal motility disorders. Prolongation of QT interval, torsades de pointes, and sudden cardiac death have been reported after concomitant administration with erythromycin or azole antifungal agents, but not with other CYP3A4 inhibitors. A possible drug interaction occurred in a 45-year-old woman who was taking cisapride for gastroesophageal reflux disorder and diltiazem, an agent that has inhibitory effect on CYP3A4, for hypertension. The patient was in near syncope and had QT-interval prolongation. After discontinuing cisapride, the QT interval returned to normal and symptoms did not recur. We suggest that caution be taken when cisapride is prescribed with any potent inhibitor of CYP3A4, including diltiazem.
 ...
PMID:Prolongation of the QT interval related to cisapride-diltiazem interaction. 954 59

Rabeprazole, a newly developed proton pump inhibitor, has been shown to be effective for the treatment of gastric and duodenal ulcers and for gastro-oesophageal reflux disease. It is a rapid and potent inhibitor of gastric H+,K(+)-ATPase, the gastric acid (proton) pump. The maximum plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) are linearly related to dose, while the time to maximum plasma concentration (tmax) and elimination half-life (t1/2) are dose-independent. Rabeprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system, and its metabolites are excreted primarily in the urine. Rabeprazole does not accumulate with repeated dosing. Its bioavailability is not influenced by the coingestion of either food or antacids. The pharmacokinetic profile of rabeprazole is substantially altered in the elderly and patients with stable compensated chronic cirrhosis; however, these alterations are not associated with clinically significant abnormalities in laboratory parameters or serious adverse events. The influence of severe decompensated liver disease on the pharmacokinetics of rabeprazole has not been assessed. The pharmacokinetic profile of rabeprazole is not significantly altered by renal dysfunction requiring maintenance haemodialysis. These findings suggest that dosage adjustment is not required in these special patient populations. Caution should be exercised, however, in patients with severe liver disease.
 ...
PMID:Review article: the pharmacokinetics of rabeprazole in health and disease. 1049 24

The selection of agents to treat patients with acid-related gastrointestinal diseases requires knowledge of their efficacy, tolerability, and ease of dosing among individuals with differing disease severities and other baseline characteristics. The efficacy and favourable benefit-risk profile of rabeprazole, a new proton pump inhibitor, has been demonstrated in controlled clinical trials of patients with gastro-oesophageal reflux disease (GERD), duodenal ulcers, and gastric ulcers. In comparative trials, rabeprazole is at least as effective as omeprazole for the treatment of GERD, duodenal ulcers, and gastric ulcers, and it is superior to histamine2-receptor antagonists for the treatment of GERD and duodenal ulcers. Its once-daily dosing regimen and low potential for interaction with drugs metabolized by the cytochrome P450 system make it a particularly attractive option for the treatment of acid-related diseases among older individuals. Rabeprazole is likely to be a valuable new addition to its class in treating patients with acid-related gastrointestinal diseases given its efficacy in acid suppression, high healing rates, rapid symptom relief, and convenient dosing.
 ...
PMID:Review article: rabeprazole's profile in patients with gastrointestinal diseases. 1055 6

Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend avoiding coadministration of cisapride with amiodarone, cimetidine (alternatives are famotidine, nizatidine, ranitidine or one of the proton pump inhibitors), diltiazem and verapamil (the dihydropyridine calcium antagonists are alternatives), grapefruit juice, isoniazid, metronidazole, quinine, quinupristin/dalfopristin and zileuton (montelukast is an alternative). Pharmacodynamic interactions with cisapride involve drugs that have the potential to have additive effects on the QT interval. We do not recommend use of cisapride with class Ia and III antiarrhythmic drugs or with adenosine, bepridil, cyclobenzaprine, droperidol, haloperidol, nifedipine (immediate release), phenothiazine antipsychotics, tricyclic and tetracyclic antidepressants or vasopressin. Vigilance is advised if anthracyclines, cotrimoxazole (trimethoprim-sulfamethoxazole), enflurane, halothane, isoflurane, pentamidine or probucol are used with cisapride. In addition, uncorrected electrolyte disturbances induced by diuretics may increase the risk of torsade de pointes. Patients receiving cisapride should be promptly treated for electrolyte disturbances.
 ...
PMID:Drug interactions with cisapride: clinical implications. 1092 50

Gastro-oesophageal reflux disease is probably the most common acid-peptic disease in Western countries, and the successful treatment of mild to moderate disease with pharmacotherapy has become commonplace. A large number of effective drugs are now available, and so the decision-making process for physicians increasingly relies on considerations other than pure efficacy. Cost, adverse effects and drug interactions have therefore become important, particularly in the most vulnerable patients - children, the elderly and patients who are ill and are taking medications that may influence the efficacy of antireflux therapy. Important drug interactions with antacids include the prevention of the absorption of antibacterials such as tetracycline, azithromycin and quinolones. H2 antagonists, proton pump inhibitors and prokinetic agents undergo metabolism by the cytochrome P450 (CYP) system present in the liver and gastrointestinal tract. Cimetidine is an inhibitor of CYP3A and it may cause significant interactions with drugs of narrow therapeutic range and low bioavailability that are metabolised by these enzymes. The gastroparietal proton pump inhibitors lansoprazole, omeprazole and pantoprazole are all primarily metabolised by a genetically polymorphic enzyme, CYP2C19, that is absent from approximately 3% of Caucasians and 20% of Asians. These drugs may also interact with CYP3A, but to a lesser extent. Interactions with prokinetic agents carry the greatest potential for harm. Metoclopramide is a dopamine antagonist that may cause extrapyramidal effects when administered alone at high concentrations, or when coadministered with antipsychotic agents such as haloperidol or phenothiazines. Cisapride is clearly able to prolong the electrocardiographic QT interval and cause lethal ventricular arrhythmias when its metabolism is slowed by interaction with inhibitors of CYP3A, such as erythromycin, ketoconazole or itraconazole.
 ...
PMID:Selection of drugs to treat gastro-oesophageal reflux disease: the role of drug interactions. 1106 15

Proton pump inhibitors (PPIs) are now generally considered the drugs of choice for treatment of patients with serious or refractory acid-related diseases. However, despite some popular notions to the contrary, these agents are not equivalent in their pharmacokinetic, pharmacodynamic and efficacy profiles. When the two newest PPIs, rabeprazole and esomeprazole, are compared with the older drugs in this class (omeprazole, lansoprazole and pantoprazole), the newer PPIs offer several key advantages over older agents, particularly in terms of the management of gastro-oesophageal reflux disease. Rabeprazole and esomeprazole achieve more rapid and profound inhibition of acid secretion than do older agents, and they sustain this suppression to provide acid control and symptom relief over 24 h. The balanced hepatic metabolism of rabeprazole, involving both cytochrome P450 (CYP)-mediated reactions in the liver and nonenzymatic reactions, appears to confer an advantage over older PPIs in that genetic polymorphisms for CYP 2C19 do not significantly influence rabeprazole clearance and, potentially, clinical efficacy. The metabolism of esomeprazole also involves CYP 2C19, but the pharmacokinetic effects of genetic differences in the expression of this enzyme are not known. However, esomeprazole is also intended to minimize pharmacological variability. Unlike esomeprazole, the use of rabeprazole is not complicated by clinically significant drug-drug interactions of the type that have been reported for omeprazole and the wide range of medications metabolized by CYP 2C19.
 ...
PMID:New-generation proton pump inhibitors: overcoming the limitations of early-generation agents. 1143 May 8

This article reviews the pharmacokinetics of esomeprazole, the (S)-isomer of the proton pump inhibitor (PPI) omeprazole. Esomeprazole is the first single isomer PPI developed for the treatment of patients with acid-related diseases. In vitro experiments in human liver microsomes demonstrated that the formation of the hydroxy and 5-O-desmethyl metabolites of esomeprazole is via cytochrome P450 (CYP) 2C19, whereas that of the sulphone metabolite is via CYP3A4. The formation rate of the hydroxy metabolite from esomeprazole is lower than for (R)-omeprazole, but that of the 2 other metabolites is higher, demonstrating stereoselective metabolism. The sum of the intrinsic clearances of all 3 metabo- lites for esomeprazole was one-third of that for (R)-omeprazole, suggesting lower clearance of esomeprazole in vivo. In vivo investigations demonstrated that esomeprazole is chirally stable after administration. Esomeprazole is 97% bound to plasma proteins. In normal (extensive) metabolisers with regard to CYP2C19, esomeprazole is metabolised more slowly than omeprazole, resulting in a higher area under the concentration-time curve (AUC) after administration of the same dose. This is more pronounced after repeated administration rather than after a single dose. In poor metabolisers, the AUC is lower for esomeprazole than for omeprazole, contributing to less overall interindividual variability for esomeprazole than for omeprazole. In general, esomeprazole and omeprazole are subject to the same metabolic transformations. Almost complete recoveries were reported and the ratio between urinary and faecal excretion is about 4:1 for both compounds. The dose-dependent increase in AUC of esomeprazole with repeated administration results from a combination of decreased first-pass elimination and decreased systemic clearance. Patients with gastro-oesophageal reflux disease exhibit a pharmacokinetic pattern similar to that in healthy individuals, whereas elderly individuals exhibited a slightly lower metabolism rate. Patients with a severe deficit in their liver function had a lower rate of metabolism, as would be expected, whereas those with mild to moderate liver disease did not exhibit any alteration in the pharmacokinetics. The pharmacokinetics of esomeprazole in individuals with impaired renal function is unlikely to differ from that in healthy individuals. A slight sex difference in the pharmacokinetics of esomeprazole was demonstrated in that the AUC and peak plasma drug concentration were slightly, but not statistically significantly, higher in females than in males.
 ...
PMID:Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole. 1147 67

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).
 ...
PMID:Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. 1466 53


1 2 3 Next >>