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)

Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprazole, are mainly metabolized by CYP2C19 in the liver. There are genetically determined differences in the activity of this enzyme. The genotypes of CYP2C19 are classified into the three groups, rapid extensive metabolizer (RM), intermediate metabolizer (IM), and poor metabolizer (PM). The pharmacokinetics and pharmacodynamics of PPIs depend on CYP2C19 genotype status. Plasma PPI levels and intragastric pHs during PPI treatment in the RM group are lowest, those in the IM group come next, and those in the PM group are highest of the three groups. These CYP2C19 genotype-dependent differences in pharmacokinetics and pharmacodynamics of PPIs influence the cure rates for the gastro-esophageal reflux disease and H. pylori infection by PPI-based therapies. For the better PPI-based treatment, doses and dosing schemes of PPIs should be optimized based on CYP2C19 genotype status.
 ...
PMID:Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies. 1598 17

The article covers the modem concept of gastroesophageal reflux disease (GERD) pharmacogenomics. Special attention is payed to polymorphism of CYP2C19 gene and its influence on the metabolism of modern antisecretory agents, such as proton pump inhibitors (PPI). The authors summarize data which demonstrate that the differences in the pharmacodynamics and clinical effects of PPI are caused by CYP2C19 gene polymorphism. The paper shows that this factor should be considered when planning GERD therapy with PPI in order to achieve a complete remission and make the therapy economically rational.
 ...
PMID:[Pharmacogenomical aspects of gastroesophageal reflux disease]. 1602 10

Proton pump inhibitors (PPIs) have been used recently for gastrointestinal esophageal reflux disease (GERD) in children older than one year with good results. However, the pharmacokinetics of PPIs have not been studied in children less than two years old. The aim of our study was to evaluate the frequency of the main phenotypes of the metabolizing enzymes CYP2C19 and CYP3A4 in Mexican infants. Our results indicate no significant difference between the 0.5 and the 1.5 mg/kg doses. The percentage of CYP2C19-poor metabolizers was 17% in babies below 4 months and was not detected in children above 3 months. When a combined CYP2C19- and CYP3A4- phenotype was estimated, omeprazole levels were significantly higher in poor metabolizers than in extended metabolizers. The percentage of ultra-extensive metabolizers in children older than 3 months were 20% and 33% for CYP2C19 and CYP3A4 respectively, compared to only 6% and 9% respectively, in babies between 1 and 3 months old. In general children, under 4 months had higher omeprazole levels and an immature metabolism. Studies in children older than 2 years old have showed similar pharmacokinetics to adults. For children between 1 month old and up to 9 months, we suggest the use of the 0.5 mg/kg dose, since it prevents accumulation in poor metabolizers, caution is recommended to identify ultra-fast metabolizers, but this would require new studies.
 ...
PMID:Metabolism of omeprazole after two oral doses in children 1 to 9 months old. 1641 73

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.
 ...
PMID:[Clinical use of proton pump inhibitors in gastrointestinal diseases]. 1655 71

Proton pump inhibitors (e.g. omeprazole/esomeprazole, lansoprazole, pantoprazole, rabeprazole) have a prominent role in the short- and long-term management of acid-related intestinal disease. They are eliminated by the hepatic route and the polymorphic CYP2C19 is involved in their metabolism. Three phenotypes have been identified in various populations: extensive metabolizers (homEM), poor metabolizers (PM) and individuals carrying one wild type and one mutant allele (hetEM). Therefore, systemic drug exposure (AUC) varies widely between these three populations and the AUC for omeprazole, lansoprazole and rabeprazole are approximately 7.5-, 4.5- and 4-fold higher in PM than in homEM. Since the pharmacodynamic response to proton pump inhibitors (PPIs) is related to their AUC, intragastric pH is much more elevated in PM (median around 6) and hetEM (4 - 5) than in homEM (3 - 4). This genotype-dependent increase in AUC and intragastric pH has clinical consequences because the healing rate in peptic ulcer (PU, target pH > or = 3) and gastroesophageal reflux disease (GERD, target pH > or = 4) and the eradication of Helicobacter pylori (Hp) depend on a long-lasting (> or = 16 hours) and effective inhibition of acid secretion. Several clinical studies have shown that PM and hetEM benefit from an approximately 18% higher Hp eradication rate compared to homEM when standard dosages of PPIs are administered orally. In our own study with lansoprazole (+ amoxicillin, clarithromycin, metronidazole) the eradication rates were 100, 98 and 80% in PM, hetEM and homEM, respectively, and in patients with GERD treated with lansoprazole (30 mg/day) the healing rates after 8 weeks were much higher in PM (85 - 100%) and hetEM (68 - 95%) than in homEM (46 - 77%). In a further study with esomeprazole (40 mg/day) in 205 patients with GERD we were surprised to observe that the healing rate after 4 weeks was not dependent on the CYP2C19 genotype. In an accompanying pharmacokinetic trial in 10 patients with GERD, both esomeprazole and 5-OH-esomeprazole (formed by CYP2C19) plasma levels and those of omeprazole-sulfone (formed by CYP3A4) were determined. Based on the calculated metabolic ratios it could be shown that CYP3A4 plays a major role in kinetics of esomeprozale, particularly after multiple dosing when there is a metabolic shift in favor of the formation of the sulfone. In conclusion, for most PPIs the activity of CYP2C 19 determines the level of drug exposure (AUC), pharmacodynamic response (elevation of intragastric pH and serum levels of gastrin) and clinical outcome (Hp eradication, healing rates of PU and GERD). Thus, a genotype-adjusted dosage regimen will improve therapeutic efficacy of PPIs.
 ...
PMID:Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. 1741 15

Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole and rabeprazole, are metabolized by CYP2C19 in the liver. There are genetic differences in the activity of this enzyme. Genotypes of CYP2C19 are classified into three groups, rapid metabolizer (RM: *1/*1), intermediate metabolizer (IM: *1/*X) and poor metabolizer (PM: *X/*X) (*1 and 'X' represent the wild-type and mutant allele, respectively). The pharmacokinetics and pharmacodynamics of PPIs differ among three different CYP2C19 genotype groups. Plasma PPI levels and intragastric pHs during PPI treatment in the RM group are lowest, those in the IM group come next, and those in the PM group are highest of the three groups. These CYP2C19 genotypic differences in pharmacokinetics and pharmacodynamics of PPIs influence the healing and eradication rates for the gastro-esophageal reflux disease and Helicobacter pylori infection by PPI-based regimens. Recently, the CYP2C19 genotype-based tailored therapy for H. pylori infection has been found to be effective. CYP2C19 pharmacogenetics should be taken into consideration for the personalization of a PPI-based therapy.
 ...
PMID:CYP2C19 pharmacogenomics associated with therapy of Helicobacter pylori infection and gastro-esophageal reflux diseases with a proton pump inhibitor. 1792 35

Rabeprazole is a proton pump inhibitor. Pharmacodynamic data show rabeprazole can achieve optimal acid suppression since the first administration and can maintain this advantage in the following days of therapy. Moreover, rabeprazole has the highest pKa (~ 5.0, the pH at which a drug becomes 50% protonated), and hence the molecule can be activated at higher pH levels much faster than other PPIs. Due to its peculiar catabolic pathway, ie, a prevalent metabolism through a non-enzymatic pathway, rabeprazole is less susceptible to the influence of genetic polymorphisms for CYP2C19, resulting in minor influences on its pharmacokinetics and pharmacodynamics. In terms of clinical efficacy, rabeprazole 20 mg uid or 10 mg bid produced healing rates at 8 weeks similar to those obtained with omeprazole 20 mg uid in erosive esophagitis patients, and in NERD patients doses of 10 or 20 mg are equivalent and both are better than placebo at 2 and 4 weeks. To prevent symptomatic relapse, on-demand strategy with rabeprazole 10 mg daily appears to be ideal, due to its rapidity of onset; results on NERD patients have documented its superiority over placebo. Continuous treatment, however, up to 5 years, seems to achieve better results than on-demand therapy, particularly in patients with esophagitis. It is debated whether in the latter halved doses (10 mg) are really equivalent to full dose (20 mg). Rabeprazole has been used with success in the treatment of some atypical GERD manifestations, such as dysphagia associated with GERD, GERD-related asthma and chest-pain, and in the therapy of Barrett's esophagus. Finally, rabeprazole achieves similar Helicobacter pylori eradication rates compared with omeprazole and lansoprazole when co-administrated with low or high doses of antibiotics (amoxicillin and clarithromycin). In addition, low doses of rabeprazole (10 mg/bid) may be effective in eradicating the pathogen.
 ...
PMID:A review of rabeprazole in the treatment of acid-related diseases. 1848 81

Proton pump inhibitors (PPIs) are extensively metabolized in the liver by CYP2C19, that demonstrates genetic polymorphism with 21 mutant alleles. The subjects can be divided into 2 groups with respect to CYP2C19 phenotypes viz., extensive metabolizers (EMs) and poor metabolizers (PMs) of PPIs. This division results in marked interindividual variations in the pharmacokinetics and pharmacodynamics of PPIs in the population. Intragastric pH values and the plasma concentration of PPIs after oral ingestion were significantly lower in EMs namely normal homozygotes (CYP2C19*1/*1) and heterozygotes (CYP2C19*1/*X) compared to PMs namely mutant homozygotes (CYP2C19*X/*X) where 'X' represents the mutant allele. Hence, association has been found between the genetic polymorphism of CYP2C19 and therapeutic response to PPIs. CYP2C19 polymorphism affected eradication of Helicobacter pylori using diferent PPI based eradication therapies as PM patients demonstrated significantly higher eradication rates compared to EMs. CYP2C19 genetic polymorphism also affects the therapeutic outcome of gastroesophageal reflux disease (GERD), reflux oesophagitis and duodenal ulcers. For optimal therapeutic response with PPIs, CYP2C19 pharmacogenetics should be taken into consideration. This shall help in the prescription of optimal doses of PPIs, thus paving the way for personalized medication.
 ...
PMID:Genetic polymorphism of CYP2C19 & therapeutic response to proton pump inhibitors. 1876 69

Rabeprazole is a proton pump inhibitor that can be used in the treatment of acid-peptic-related disorders (gastroesophageal reflux disease [GERD], duodenal ulcer, gastric ulcer, gastric acid hypersecretory syndromes) and Helicobacter pylori. Pharmacodynamic data has demonstrated that rabeprazole, with a high pKa of approximately 5.0, can be activated at a higher pH than other proton pump inhibitors. This possibly results in faster onset of action. Owing to its non-enzymatic pathway of metabolism, rabeprazole is also less influenced by genetic polymorphisms of the CYP2C19, which others proton pump inhibitors are dependent on. In a 2-week, placebo-controlled trial, rabeprazole was both rapid and effective in relieving heartburn on day 1 of therapy and improved other GERD-related symptoms including regurgitation, belching, bloating, early satiety and nausea. For oesophageal reflux disease without erosions both 10 and 20 mg of rabeprazole are equivalent and better than placebo at 2 and 4 weeks. An on-demand approach to non-erosive reflux disease with 10 mg of rabeprazole has also been documented as superior to placebo. Some success in the treatment of extra-oesophageal manifestations of GERD, such as asthma and chronic laryngitis, has also been achieved with rabeprazole. Overall, rabeprazole with very few side effects is a safe and efficacious medication for acid suppression therapy.
 ...
PMID:Rabeprazole: a pharmacologic and clinical review for acid-related disorders. 1923 23

The Asia-Pacific Consensus Conference was convened to review and synthesize the most current information on Helicobacter pylori management so as to update the previously published regional guidelines. The group recognized that in addition to long-established indications, such as peptic ulcer disease, early mucosa-associated lymphoid tissue (MALT) type lymphoma and family history of gastric cancer, H. pylori eradication was also indicated for H. pylori infected patients with functional dyspepsia, in those receiving long-term maintenance proton pump inhibitor (PPI) for gastroesophageal reflux disease, and in cases of unexplained iron deficiency anemia or idiopathic thrombocytopenic purpura. In addition, a population 'test and treat' strategy for H. pylori infection in communities with high incidence of gastric cancer was considered to be an effective strategy for gastric cancer prevention. It was recommended that H. pylori infection should be tested for and eradicated prior to long-term aspirin or non-steroidal anti-inflammatory drug therapy in patients at high risk for ulcers and ulcer-related complications. In Asia, the currently recommended first-line therapy for H. pylori infection is PPI-based triple therapy with amoxicillin/metronidazole and clarithromycin for 7 days, while bismuth-based quadruple therapy is an effective alternative. There appears to be an increasing rate of resistance to clarithromycin and metronidazole in parts of Asia, leading to reduced efficacy of PPI-based triple therapy. There are insufficient data to recommend sequential therapy as an alternative first-line therapy in Asia. Salvage therapies that can be used include: (i) standard triple therapy that has not been previously used; (ii) bismuth-based quadruple therapy; (iii) levofloxacin-based triple therapy; and (iv) rifabutin-based triple therapy. Both CYP2C19 genetic polymorphisms and cigarette smoking can influence future H. pylori eradication rates.
 ...
PMID:Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection. 2218 25


<< Previous 1 2 3 4 Next >>