CYP2C19 polymorphism affects personality traits of Japanese females

It has been suggested that personality traits are heritable. The polymorphic cytochrome P450 (CYP) 2C19 metabolizes sex hormones and 5-hydroxytryptamine, which are involved in multiple brain functions. In the present study, the relationship between the CYP2C19 polymorphism and personality traits was examined in 487 Japanese healthy volunteers. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the two mutated alleles causing absent CYP2C19 activity were identified by a PCR-RFLP method. In females, the scores of reward dependence (p=0.026), cooperativeness (p=0.001), and self-transcendence (ST) (p=0.049) were significantly lower in poor metabolizers (PMs) than in extensive metabolizers (EMs). In males, none of the seven TCI dimensions was significantly different between EMs and PMs. The present study thus suggests that the CYP2C19 polymorphism affects personality traits of Japanese females.     

Disposition and mass balance of [14C]vernakalant after single intravenous and oral doses in healthy volunteers

Vernakalant hydrochloride is a novel antiarrhythmic drug for the rapid conversion of atrial fibrillation to sinus rhythm and prevention of relapse. In this open-label, parallel design study, 8 healthy men received single 240-mg doses of [(14)C]vernakalant hydrochloride, given as a 10-minute intravenous (IV) infusion on day 1, and as an oral gel capsule on day 22. Plasma, urine, and fecal samples were collected for 7 days after dosing to measure vernakalant and its metabolites and to estimate mass balance of total [(14)C] recovery. The disposition and metabolic profile of vernakalant after both IV and oral administration, depended on cytochrome P450 (CYP)2D6 genotype. Vernakalant underwent rapid and extensive distribution during infusion, which resulted in similar maximum plasma concentrations in extensive metabolizers (EMs) and poor metabolizers (PMs) for IV but not oral administration. Vernakalant was metabolized rapidly and extensively to a 4-O-demethylated metabolite with glucuronidation in EMs; direct glucuronidation predominated in PMs. Slower clearance in PMs contributed to 3- and 6-fold higher drug exposure (AUC(0-∞); IV and oral dosing, respectively). Urinary recovery of unchanged vernakalant was higher in PMs as well. Total [(14)C] was recovered predominantly in urine, while lower levels were recovered in feces. Mass balance was achieved, with a mean recovery of 99.7% of the IV dose and 98.7% of the oral dose, in EMs, and 89.2% and 88.2% of the IV and oral doses, respectively, in PMs. Vernakalant was well tolerated. The pharmacokinetics and metabolism of vernakalant depend on CYP2D6 genotype with more pronounced effects on exposure following oral administration; however, the differences between EMs and PMs are unlikely to be clinically significant following short-term IV infusion.     

Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19

Pharmacogenetics has arrived in clinical psychiatric practice with the FDA approval of the AmpliChip CYP450 Test that genotypes for two cytochrome P450 2D6 (CYP2D6) and 2C19 (CYP2C19) genes. Other pharmacogenetic tests, including those focused on pharmacodynamic genes, are far from ready for clinical application. CYP2D6 is important for the metabolism of many antidepressants and antipsychotics, and CY2C19 is important for some antidepressant metabolism. Poor metabolizers (PMs), lacking the enzyme, account for up to 7% of Caucasians for CYP2D6 and up to 25% of East Asians for CYP2C19. Patients having three or more active CYP2D6 alleles (up to 29% in North Africa and the Middle East), are called CYP2D6 ultra-rapid metabolizers (UMs). CYP2D6 phenotypes (particularly PMs) are probably important in patients taking tricyclic antidepressants (TCAs), venlafaxine, typical antipsychotics, and risperidone. The CYP2C19 PM phenotype is probably important in patients taking TCAs and perhaps citalopram, escitalopram, and sertraline. On the basis of the literature and the authors' clinical experience, the authors provide provisional recommendations for identifying and treating CYP2D6 PMs, CYP2C19 PMs, and CYP2D6 UMs. The next few years will determine whether CYP2D6 genotyping is beneficial for patients taking the new drugs aripiprazole, duloxetine, and atomoxetine. Practical recommendations for dealing with laboratories offering CYP2D6 and CYP2C29 genotyping are provided.     

Development and clinical application of invader assay--detection of resistant mutation to clarithromycin in Helicobacter pylori

Invader Assay is a novel technology used for the direct analysis of genomic DNA without PCR amplification, including the detection of single nucleotide polymorphisms (SNPs) in human genome. It has high accuracy and reproducibility. We have previously developed SNPs assays of cytochrome P450 (CYP) 2C19 and many other drug metabolized enzymes by Invader technology to realize personalized medicine. Here, we developed Invader assays to detect mutations with resistance to clarithromycin (CAM) in H. pylori which achieves resistance by A2143G or A2142G mutation of 23S rRNA. The sensitivity of this assay is 10(3) copies/ gastric tissue sample, and it can detect 5% existence of mutant bacteria in wild type-bacteria. We examined the A2143G genotypes of 6 colonies picked up from each culture dish of gastric tissue samples. These samples were categorized three groups; all colonies are wild-type (genotype A) or mutant-type (genotype G), and intermingled-type, including genotype A, genotype B and genotype A/G. The genotypes of each colony from the group of intermingled samples were compared with MIC values of the CAM susceptibility test. All colonies of genotype A and genotype B were consistent with the MIC value. Inconsistencies were observed for some colonies of genotype A/G. Proton pump inhibitor (PPI), CAM and amoxicillin were given to eradicate H. pylori. PPI is influenced by SNPs of CYP2C19, and mutations become resistant to CAM. It was shown that the determination of these two genotypes before setting doses was very important for to obtain a high cure rate.     

Cytochrome P450 2C19 polymorphism is associated with reduced clopidogrel response in cerebrovascular disease

Purpose

Clopidogrel is a prodrug that requires transformation into an active metabolite by cytochrome P450 (CYP) in the liver in order to irreversibly inhibit the P2Y12 adenosine diphosphate platelet receptor. CYP2C19 polymorphism has been reported to correlate with reduced antiplatelet activity of clopidogrel in coronary artery disease. We assessed the association between CYP2C19 polymorphism and clopidogrel resistance in patients with cerebrovascular disease.

Materials and Methods

We retrospectively gathered data from patients who experienced cerebrovascular disease, received clopidogrel, and were tested for clopidogrel resistance and CYP2C19 polymorphism. Clopidogrel resistance was tested by the VerifyNow P2Y12 system, and the CYP2C19 polymorphism was tested by the Seeplex CYP2C19 ACE Genotyping system. Clopidogrel resistance was expressed in P2Y12 reaction units (PRU) and percent inhibition. High PRU and low percent inhibition suggests clopidogrel resistance. CYP2C19 polymorphisms were expressed as extensive, intermediate, and poor metabolizers. Clopidogrel resistance was assessed according to the subgroup of CYP2C19 polymorphism.

Results

A total of 166 patients were evaluated. The PRU values of extensive CYP2C19 metabolizers (195.0±84.9) were significantly lower than those of intermediate and poor metabolizers (237.9±88.0, 302.2±58.9). The percent inhibition of extensive metabolizers (44.6±21.8) was significantly higher than that of intermediate and poor metabolizers (30.5±21.5, 14.0±13.4).

Conclusion

Intermediate and poor metabolizing CYP2C19 polymorphism is associated with reduced clopidogrel antiplatelet activity in patients with cerebrovascular disease. The clinical implications of this finding require further investigation.     

Genotype-Phenotype Analysis of CYP2C19 in Healthy Saudi Individuals and its Potential Clinical Implication in Drug Therapy

CYP2C19 is a cytochrome P450 enzyme, which is involved in the metabolism of some clinically important medications and is encoded by a highly polymorphic gene. There is no available data on the distribution of the CYP2C19 *4 and *17 mutant alleles in the Saudi Arabian population. The aim of the study was to determine different CYP2C19 mutant allele (*2, *4 and *17) frequencies in healthy Saudi subjects and to determine genotype frequencies for these mutations. The CYP2C19 genotypes were then classified into phenotypes. Result: In 201 adults of Saudi ethnicity, the allele frequencies were CYP2C19*1 (62.9%), *17 (25.7%), *2 (11.2%) and *4 (0.2%). The most prevalent genotype combinations were CYP2C19 *1/*1 (40.3%) and *1/*17 (30.4%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM) 77.6%, intermediate metabolizers (IM) 14.9%, ultra-rapid metabolizers (UM) 7% and poor metabolizers (PM) 0.4%. This finding has important clinical implications for the use of CYP2C19 metabolized medications in the Saudi population and further studies are needed.     

CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial

PurposeCYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of CYP2D6-guided opioid prescribing on pain control.MethodsParticipants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (n = 235) or usual care (n = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS® measures.ResultsOn stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (n = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P = 0.540).ConclusionThese data support the potential benefits of CYP2D6-guided pain management.     

Mutant genes of cytochrome P-450IID6, glutathione S-transferase class Mu,and arylamine N-acetyltransferase in lung cancer patients

Summary Epidemiological studies suggested a protective effect of certain phenotypes of polymorphic foreign-compound-metabolizing enzymes in some types of cancer. Poor metabolizers (PM) of debrisoquine 4-hydroxylase (cytochrome P-450IID6, CYP2D6) were found to be underrepresented among patients with lung cancer. Recent advances in molecular genetic characterization of CYP2D6, glutathione S-transferase (GST) class Mu, and arylamine N-acetyltransferase enabled genotypical determination of mutant alleles in lung cancer patients. Restriction fragment length polymorphism (RFLP) with a cDNA gene probe of CYP2D6 was analyzed in 79 lung cancer patients who were phenotyped with debrisoquine. Mutant alleles were detected by allele-specific polymerase chain reaction (PCR). In the same individuals, genotype of GST class Mu was analyzed by PCR and correlated with ex vivo activity of glutathione conjugation towards trans-stilbene oxide. RFLP patterns allowed discrimination between the slow and fast genotype of N-acetyltransferase as well as the heterozygotes. Three phenotypical PMs of debrisoquine (3.8%) were confirmed by PCR and RFLP. No PM could be unambiguously recognized only by RFLP patterns. The PMs were characterized by PCR and RFLP as carriers of the 29B/29B (n=1), 29A/29B (n=1), and 29A/44 (n = 1) mutant alleles. Higher debrisoquine hydroxylase activities were found in the homozygous EMs, who possess two active genes, as compared to heterozygous EMs, who have only one active gene. The patients with phenotypically impaired GST Mu activity were confirmed as such by PCR. A complete correspondence between phenotyping of N-acetyltransferase (with caffeine) and genotyping was found. The new genetic techniques proved to be powerful tools for molecular-epidemiological studies aimed at establishing host factors of cancer susceptibility.Abbreviations AFMU 5-acetylamino-6-formylamino-3methyluracil - by base pair - cDNA complementary DNA - CYP2D6a cytochrome P-450IID6 (debrisoquine hydroxylase) - CYP2D6a gene locus coding for CYP2D6 - EM extensive metabolizer - GST glutathione S-transferase - MR metabolic ratio - NAT arylamine N-acetyltransferase - NATa gene locus coding for NAT - PCR polymerase chain reaction - PM poor metabolizer - RFLP restriction fragment length polymorphism - wt wild type - 1X 1-methylxanthine     

Novel mutations in the cytochrome P450 2C19 gene: a pitfall of the PCR-RFLP method for identifying a common mutation

CYP2C19 is a clinically important enzyme involved in the metabolism of therapeutic drugs such as (S)-mephenytoin, omeprazole, proguanil, and diazepam. Individuals can be characterized as either extensive metabolizers (EM) or poor metabolizers (PM) on the basis of CYP2C19 enzyme activity. The PM phenotype occurs in 2–5% of Caucasian populations, but at higher frequencies (18–23%) in Asians. CYP2C19*2 and CYP2C19*3, which are single-nucleotide polymorphisms of CYP2C19, are the main cause of PM phenotyping in homozygotes or compound heterozygotes. We report two novel mutations in the CYP2C19 gene identified by direct sequencing and subcloning procedures. One of these mutations was considered to be CYP2C19*3 by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). This result suggests that mutations classed as CYP2C19*3 might include other mutations. Further studies are needed to clarify the relationship between these novel mutations and enzyme activity.The DDBJ accession number of the novel mutation is AB113829     

Enantioselectivity of debrisoquine 4-hydroxylation in Brazilian Caucasian hypertensive patients phenotyped as extensive metabolizers

Debrisoquine (D), an antihypertensive drug metabolized to 4-hydroxydebrisoquine (4-OHD) by CYP2D6, is commonly used as an in vivo probe of CYP2D6 activity and can be used to phenotype individuals as either extensive (EMs) or poor metabolizers (PMs) of such drugs as beta-adrenergic blockers, tricyclic antidepressants, and class 1C antiarrhythmics. This report describes reversed-phase HPLC systems by which D and 4-OHD or S-(+) and R-(-)-4-OHD in urine are more selectively quantified without the need for derivatization techniques. We also studied the urinary excretion of R-(-)- and S-(+)-4-hydroxydebrisoquine in EM hypertensive patients in order to determine weather 4-OHD formation exhibits enantioselectivity. Twelve patients with mild to severe essential hypertension were admitted to the study. They received a single tablet of Declinax containing 10 mg debrisoquine sulfate. All the urine excreted during the following 8 h was collected. The debrisoquine metabolic ratio (DMR) was calculated as % of dose excreted as D/% of dose excreted as 4-OHD and the debrisoquine recovery ratio (DRR) was calculated as % of dose excreted as 4-OHD/% of dose excreted as D+4-OHD. Debrisoquine and its metabolite were determined in urine by HPLC using a reversed-phase Select B LiChrospher column, a mobile phase of 0.25 N acetate buffer, pH 5-acetonitrile (9:1, v/v) and a fluorescence detector. The limit of quantitation was determined to be 25.0 ng/ml for D and 18.75 ng/ml for 4-OHD. Intra- and inter-day relative standard deviations (RSDs) were less than 10%. All hypertensive patients studied showed a DMR of less than 12.6 or a DRR higher than 0.12 and were classified as EMs. Direct enantioselective separation on chiral stationary phase involved resolution of S-(+)-4-OHD and R-(-)-4-OHD on a Chiralcel OD-R column with a mobile phase of 0.125 N sodium perchlorate, pH 5-acetonitrile-methanol (85:12:3, v/v/v). The quantitation limit of each enantiomer was 3.75 ng/ml of urine. Intra- and inter-day RSDs were less than 10% for each enantiomer. A high degree of enantioselectivity in the 4-hydroxylation of D favouring the S-(+) enantiomer was observed, resulting in R-(-)-4-OHD not detected in the urine of the EM hypertensive patients studied.     

Drug-drug interaction in pharmacogenetics and pharmacogenomics

Drug metabolism and excretion is composed of four steps: Absorption, distribution, metabolism and excretion. The four steps are often abbreviated as ADME. Drug-drug interaction may occur at each step of ADME. Reported examples of drug-drug interaction occur mainly at the level of "drug metabolizing enzymes(DME)". The mechanisms of drug-drug interaction are: 1) Competitive inhibition of DME, 2) Destruction or irreversible inhibition of DME, 3) Induction of DME. Co-administration of 5-fluorouracil and sorivudine resulted in severe gastrointestinal and bone marrow toxicities. The toxicity is due to irreversible inhibition of dihydropyrimidine dehydrogenase by a sorivudine metabolite, which plays a role in detoxification of 5-fluorouracil. However, there is an example of beneficial drug-drug interaction, where proton pump inhibitor, omeprazole, antibiotics, amoxicillin and clarithromycin, are co-administered for eradication of Helicobacter pylori. Omeprazole is metabolized by CYP2C19 and CYP3A4. In poor metabolizers of omeprazole, a higher area under the drug concentration curve(AUC) and higher efficacy are achieved as compared to extensive metabolizers of omeprazole. In this regimen, co-administration of clarithromycin which is metabolized by CYP3A4 effectively raises the AUC of omeprazole. Thus, this drug combination results in a beneficial drug-drug interaction.     

Adverse drug reaction monitoring in Jena: Relevance of polymorphic drug metabolizing enzymes for inducing adverse drug reactions

Inter-subject variability in therapeutic drug response and drug toxicity is a major problem in clinical practice. In this field genetic polymorphisms of drug metabolizing enzymes play an important role. In a multicenter study supported by the German Federal Institute for Drugs and Medical Devices (BfArM, Z 12.01-68502-201) adverse drug reactions (ADRs) leading to hospital admission to departments of internal medicine have been registered and evaluated. The aim of the presented part of the study was to look for evident differences in genotypes for polymorphic drug metabolizing enzymes between adverse drug reaction cases and controls. All cases found in the local area – Jena and Weimar – were genotyped for N-acetyl-transferase 2 (NAT2), cytochrom P450 (CYP) 2D6 and 2C19 in comparison to a control population of the same region. The investigation on genotype was carried out for about 2 years (2000–2002). 254 blood samples from patients of the ADR study were analyzed. The genotype of drug metabolizing enzymes was determined by means of polymerase chain reaction using allel specific primers or restriction enzyme analysis. Within all ADRs cases genotyped, no exceptional frequencies for slow acetylators or poor metabolizers (PM) of CYP2D6 or CYP2C19 were found. About 65% of the individuals with ADR genotypically displayed a slow acetylator state. 6.3% PM for CYP2D6, including CYP2D6*3, *4 and *6 alleles, and 2.0% PM frequency for CYP2C19 (*2) have been found in ADR cases. A direct connection between PM genotype and the ADR observed may be assumed only in few of them. Further investigations on genotype and ADR-associated drugs require a much larger sample of patients to obtain more data allowing to focus an association on specific drugs, ADR and polymorphisms genotype of drug metabolizing enzymes might be useful.     

Reduced CYP2D6 activity is a negative risk factor for methamphetamine dependence

Because methamphetamine (METH) is metabolized by CYP2D6 at the first step of hydroxylation and demethylation, it is possible that functional variants of CYP2D6 alter susceptibility to methamphetamine-induced dependence. We genotyped CYP2D6*1, *4, *5, *10, and *14 for 202 patients with METH dependence and 337 controls in a Japanese population and found a significant association of the CYP2D6 gene with METH dependence (p=0.0299). The patients had fewer *10 and *14 alleles, which are hypofunction alleles, than the controls. CYP2D6 genotypes were divided into three phenotypes: extensive metabolizers, intermediate metabolizers, and poor metabolizers. There was no poor metabolizer among our Japanese subjects, and intermediate metabolizers of CYP2D6 were significantly fewer in methamphetamine-dependent subjects than in controls (p=0.0212), with an odds ratio of 0.62 (95% confidence interval: 0.51-0.76). The present study demonstrated that reduced CYP2D6 activity was a negative risk factor for methamphetamine dependence.     

Pharmacogenomical aspects of gastroesophageal reflux disease

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.     

Treatment of Helicobacter pylori infections

The treatment of Helicobacter pylori (H.p.) infection is based on the recommendations of the Maastricht consensus conference 1996. The main indications for eradication of H.p. are peptic ulcer disease, gastritis with severe histological abnormalities, low grade gastric MALT lymphoma and a history of resection for gastric cancer. The results of recent studies demonstrate that the symptoms of non-ulcer dyspepsia are not improved by H.p. eradication. A family history of gastric cancer and an earlier operation for peptic ulcer are considered advisable indications for the treatment of H.p. infection. Triple therapies consisting of a proton pump inhibitor (PPI) or ranitidine bismuth citrate plus 2 antibiotics are established as effective and well-tolerated first line regimens. The most important antibiotics are clarithromycin and amoxicillin. The efficacy of metronidazole is impaired by an increasing rate of resistant strains. Only few new antibiotics are currently tested in clinical trials. After the failure of a first anti-H.p. treatment it is advisable to change antibiotics according to the probability of resistance, to increase dosage and duration of treatment and to include bismuth compounds in the second line regimen. An alternative option after failed triple therapies may be a high dosage and prolonged dual regimen with a PPI and amoxicillin or quadruple therapy consisting of a PPI, bismuth subcitrate, tetracycline and metronidazole.     

Low clarithromycin resistance in virulent Helicobacter pylori from dyspeptic patients at a tertiary care centre in Odisha

PurposeUniversal eradication or use of failing antibiotic can add fuel to the antimicrobial resistance pandemic. Outcome of Helicobacter pylori (HP) infection depends at least partly virulence factors and its eradication as preventive measure against gastric cancer is advocated by some guidelines. There is need to identify candidates at risk for gastric cancer and antimicrobial resistance in HP for rational management. Such candidates could be identified by studying the association of virulence factors with clinical outcome. As this data is lacking from Odisha this study was undertaken.Methods113 consecutive dyspeptic patients who underwent endoscopy at our hospital were recruited to obtain gastric biopsies for culture and antibiotic susceptibility, histological examination, molecular detection of HP, virulence typing (cagA, EPIYA typing, vacA, vacA s1/s2, vacA m1/m2 and babA2) by conventional PCR and identification of clarithromycin resistance by real-time PCR. Cultured isolates were subjected to antibiotic sensitivity using e strips as per EUCAST guidelines.Results93 (82.3%) dyspeptic patients were infected by HP by histology & PCR, while 90 (79.6%) were rapid urea test positive, and HP was cultured from 32 (28.3%) of these patients. Eleven (11.8%) of the 93 samples with HP were resistant to clarithromycin by real-time PCR. Of the 93 patients with HP infection by histopathology and PCR, 62 (66.7%), 87(93.5%) and 43 (46.2%) harboured cagA, vacA and babA2 genes. The western cagA found in 33 (35.5%) samples and vacA s1m1 in 50 (53.8%) samples were the commonest virulence subtypes. No association was found between virulence factors and outcome except vacA s2m2 and vac s1/m1m2, which were significantly associated with peptic ulcers. Phenotypically 11(34.4%), 1(3.1%), 21(65.6%) and 26 (81.2%) isolates were resistant to clarithromycin, amoxicillin, levofloxacin, and metronidazole.ConclusionsThis is the first study that explored the antibiotic resistance of HP, and its virulence factors in dyspeptic patients from this region of India.     

幽门螺旋杆菌感染对反流性食管炎发病和治疗的影响

目的探讨幽门螺旋杆菌（HP）感染对反流性食管炎（RE）发病和治疗的影响。方法收集西安市中心医院2011年6月至2013年6月的门诊病人642例，记录其性别、年龄、体重、反流性食管炎分级及HP感染严重程度。结果RE组HP（＋）感染率明显高于HP（-），差异有统计学意义（P〈0．05），而非RE组HP（＋）感染率与HP（-）间无明显差异（P〉0．05）。b组（C—D级）患者HP感染（＋＋／＋＋＋）明显高于a组（A—B级），差异有统计学意义（P〈0．05）。A组（HP根除＋PPI）与B组（PPI）GERD—Q评分、心理SF-36评分和生理SF-36评分相比无明显差异（P〉0．05）。结论HP感染与反流性食管炎的发病可能存在一定的关联，根除HP未能明显改善反流性食管炎的预后。     

Establishment of a pharmacogenomic testing system for the realization of individual pharmacotherapy

The metabolism of and sensitivity to drugs differ from individual to individual, and one base polymorphism of drug-metabolizing enzymes is known to play an important role in this difference between individuals. The genotyping of drug-metabolizing enzymes prior to drug administration would help to predict individual reactivity to drugs and possible adverse reactions that may occur, which is essential to realize tailor-made therapy for individual patients. In July 2005, the Pharmacogenomics Working Group, composed of members of the Clinical Genomic Medicine Unit, Pharmaceutical Department, Medical Informatics Department, Clinical Laboratory, Gastroenterology, Cardiovascular Medicine, and Department of Neurology, was established in our university hospital in an attempt to introduce such pharmacogenomic testing. The project was approved by the Institutional Research Ethics Committee of the Faculty of Medicine, the University of Tokyo, and, in August 2006, testing for CYP2C19*2 and CYP2C19*3, enzymes involved in the metabolism of proton pump inhibitors, was started. Furthermore, in August 2007, testing for CYP2C9*3, the enzyme involved in the metabolism of Warfarin, and vitamin K epoxidereductase1 (VKORC1) 6484 C>T was started. In the CYP2C19 genotyping, the high incidence of poor metabolizers has been demonstrated; it was speculated that the test could confirm the adverse effects of the drug, i.e., after administration of the drug to patients. Moreover, testing for CYP2C9*3 and VKORC1 6484 C>T was shown to be useful for the safe administration of warfarin. The pharmacogenomic testing system was successfully established in our university hospital, and the Pharmacogenomics Working Group is still active, playing an important role in this project.     

Eradication therapy of Helicobacter pylori infection

Helicobacter pylori(H. pylori) infection is recognized to be a pathogen of various gastro-duodenal diseases. Eradication therapy of H. pylori reduces the recurrence of gastro-duodenal ulcer, and improves gastritis histologically. Recently, proton pump inhibitor(PPI) based triple therapy, that combining PPI, clarithromycin, amoxicillin is widely accepted throughout the world, and shows high eradication rate which ranged about 80-90%. In Japan, one week triple therapy is recommended for the treatment of gastro-duodenal ulcer, though it is expected the improvement of recurrent peptic ulcer. In the present studies, the rate of clarithromycin resistant strains has been increased gradually, and this fact may lead to the development of failure of PPI based triple therapy. Another problem is suggested by several studies that gastro-esophageal reflux disease(GERD) may increase after successful eradication of H. pylori. Reflux esophagitis and Barrett's esophagus are recognized as precancerous lesion of esophageal adenocarcinoma, but the association of newly occurrence of GERD after H. pylori eradication and increase of esophageal adenocarcinoma is not clear. Merits and demerits of H. pylori eradication need to be observed carefully over a long term.