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N Shirai

Publications and source records attributed to N Shirai.

At least 19 recordsLinked to original sources

Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori.

Helicobacter pylori eradication rates by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin at standard doses depend on bacterial susceptibility to clarithromycin and patient CYP2C19 genotypes. We examined the usefulness of a personalized therapy for H. pylori infection based on these factors as determined by genetic testing. First, optimal lansoprazole dosing schedules that would achieve sufficient acid inhibition to allow H. pylori eradication therapy in each of different CYP2C19 genotype groups were determined by a 24-h intragastric pH monitoring. Next, 300 H. pylori-positive patients were randomly assigned to the standard regimen group (lansoprazole 30 mg twice daily (b.i.d.)), clarithromycin 400 mg b.i.d., and amoxicillin 750 mg b.i.d. for 1 week) or the tailored regimen group based on CYP2C19 status and bacterial susceptibility to clarithromycin assessed by genetic testing. Patients with failure of eradication underwent the second-line regimen. The per-patient cost required for successful eradication was calculated for each of the groups. In the first-line therapy, the intention-to-treat eradication rate in the tailored regimen group was 96.0% (95% CI=91.5-98.2%, 144/150), significantly higher than that in the standard regimen group (70.0%: 95% CI=62.2-77.2%, 105/150) (P<0.001). Final costs per successful eradication in the tailored and standard regimen groups were $669 and $657, respectively. In conclusion, the pharmacogenomics-based tailored treatment for H. pylori infection allowed a higher eradication rate by the initial treatment without an increase of the final per-patient cost for successful eradication. However, the precise cost-effectiveness of this strategy remains to be determined.

2-Pyridinylmethylsulfinylbenzimidazoles↗

Poor metabolizer genotype status of CYP2C19 is a risk factor for developing gastric cancer in Japanese patients with Helicobacter pylori infection.

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) polymorphism has been associated with the development of lung, liver or oesophageal cancer by detoxification of carcinogen(s) or activation of procarcinogen(s). AIM: To clarify the association between CYP2C19 polymorphisms and gastric cancer development in Japanese. Methods : We determined CYP2C19 genotypes (CYP2C19*1, *2 and *3) in 111 Helicobacter pylori-positive patients with gastric cancer and 315 H. pylori-positive controls without gastric cancer consisting of patients with gastritis only or peptic ulcer. Frequencies of CYP2C19 genotypes and serum pepsinogen I and II levels, a biomarker of gastric atrophy, in the gastric cancers and controls were compared. RESULTS: Frequencies of homozygous extensive metabolizers, heterozygous extensive metabolizers and poor metabolizers were 31.5%, 42.3% and 26.2% in the gastric cancers and 38.1%, 47.0% and 14.9% in the controls, respectively (P = 0.046). Poor metabolizers were associated with an increased risk for developing gastric cancer with the age- and sex-adjusted odds ratio (OR) of 1.975 [95% confidence interval (CI): 1.068-3.649], especially for diffuse type (OR: 3.385, CI: 1.187-9.648). There is no significant association between CYP2C19 genotypes and serum pepsinogen I level or pepsinogen I/II ratios, although serum pepsinogen I level in gastric cancers were significantly decreased. CONCLUSIONS: In H. pylori-positive Japanese, poor metabolizers of CYP2C19 appear to be at an increased risk for developing gastric cancer, especially diffuse type, and may require an intensive follow-up for scrutinizing possible gastric cancer development.

Aged↗

Effect of concomitant dosing of famotidine with lansoprazole on gastric acid secretion in relation to CYP2C19 genotype status.

BACKGROUND: Famotidine increases Helicobacter pylori-eradication rates by a triple lansoprazole/amoxicillin/clarithromycin therapy in patients with the rapid extensive metabolizer genotype of CYP2C19. AIM: To determine the effect of famotidine on the gastric acid inhibition by lansoprazole in relation to CYP2C19 genotypes. METHODS: Twenty healthy volunteers with different CYP2C19 genotypes--consisting of six rapid extensive metabolizers, nine intermediate metabolizers and five poor metabolizers--underwent three 7-day courses with placebo, lansoprazole 30 mg twice daily, and lansoprazole 30 mg twice plus famotidine 20 mg twice daily. Lansoprazole was dosed after breakfast and dinner. Famotidine was dosed after lunch and at bedtime. Intragastric pH monitoring was performed for 24 h on day 7 of each course. RESULTS: With placebo, no difference was observed in intragastric pH profiles among the three CYP2C19 genotype groups. With lansoprazole 30 mg twice daily, the median of 24-h intragastric pH in poor metabolizers (6.1) was significantly higher than those of rapid extensive metabolizers (4.5) and intermediate metabolizers (5.0), respectively (P = 0.0176 and 0.0388), whereas with lansoprazole 30 mg twice and famotidine 20 mg twice daily, the medians were 5.4, 5.7, and 6.1, respectively (not significant). CONCLUSION: Acid inhibition by lansoprazole was influenced by CYP2C19 genotype status. This influence was offset by the concomitant use of famotidine.

2-Pyridinylmethylsulfinylbenzimidazoles↗

Concomitant dosing of famotidine with a triple therapy increases the cure rates of Helicobacter pylori infections in patients with the homozygous extensive metabolizer genotype of CYP2C19.

BACKGROUND: Proton-pump inhibitors, such as lansoprazole, are metabolized in the liver by CYP2C19 and cannot inhibit acid sufficiently in homozygous extensive metabolizers of CYP2C19. AIM: To examine whether famotidine would increase the cure rates of Helicobacter pylori infection by a standard triple therapy. METHODS: A total of 177 H. pylori-positive patients were randomly assigned to either lansoprazole 30 mg b.d., clarithromycin 200 mg b.d. and amoxicillin 750 mg b.d. for 1 week (LCA group; n = 89) or famotidine 20 mg b.d., lansoprazole 30 mg b.d., clarithromycin 200 mg b.d. and amoxicillin 750 mg b.d. for 1 week (FLCA group; n = 88). Famotidine was administered after lunch and before sleep, and the others were after breakfast and dinner. CYP2C19 genotypes were determined by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: In the LCA group, the eradication rates for homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 63%, 87%, and 100%, respectively (P = 0.014). Those in the FLCA group were 85%, 85%, and 100%, respectively (N.S.). The cure rate for homozygous extensive metabolizers in the FLCA group was significantly higher than that in the LCA group (P = 0.035). CONCLUSION: Famotidine improves the cure rate of H. pylori infection by a triple therapy in CYP2C19 homozygous extensive metabolizers patients.

Adult↗

Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells.

Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is a target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). In this study, we examined whether GO was effective on all-trans retinoic acid (ATRA)- or arsenic trioxide (ATO)-resistant APL cells. Cells used were an APL cell line in which P-gp was undetectable (NB4), ATRA-resistant NB4 (NB4/RA), NB4 and NB4/RA that had been transfected with MDR-1 cDNA (NB4/MDR and NB4/RA/MDR, respectively), ATO-resistant NB4 (NB4/As) and blast cells from eight patients with clinically ATRA-resistant APL including two patients with ATRA- and ATO-resistant APL. The efficacy of GO was analyzed by (3)H-thymidine incorporation, the dye exclusion test and cell cycle distribution. GO suppressed the growth of NB4, NB4/RA and NB4/As cells in a dose-dependent manner. GO increased the percentage of hypodiploid cells significantly in NB4, NB4/RA and NB4/As cells, and by a limited degree in NB4/MDR and NB4/RA/MDR cells. Similar results were obtained using blast cells from the patients with APL. GO is effective against ATRA- or ATO-resistant APL cells that do not express P-gp, and the mechanism of resistance to GO is not related to the mechanism of resistance to ATRA or ATO in APL cells. Leukemia (2005) 19, 1306-1311. doi:10.1038/sj.leu.2403807; published online 26 May 2005.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Acute improvement of atrial mechanical stunning after electrical cardioversion of persistent atrial fibrillation: comparison between biatrial and single atrial pacing.

OBJECTIVE: To evaluate the acute effects of atrial pacing at different pacing sites on mechanical stunning after cardioversion of atrial fibrillation (AF). SETTING: Tertiary referral centre. PATIENTS: 20 patients with persistent AF were studied. INTERVENTIONS: Spontaneous echo contrast (SEC), left atrial appendage emptying velocity (LAAEV), and left atrial appendage emptying fraction (LAAEF) were assessed by transoesophageal echocardiography (TOE) during AF, after conversion to sinus rhythm, and during atrial pacing from the right atrial appendage, left lateral atrium, and both atria simultaneously. Transmitral inflow velocity of the atrial wave (TMIF-A) by TOE and the maximum P wave duration in 12 lead ECG were also measured during sinus rhythm and atrial pacing. MAIN OUTCOME MEASURES: Comparison of atrial mechanical function and P wave duration in 12 lead ECG during atrial pacing from different sites after cardioversion of AF. RESULTS: Compared with sinus rhythm, atrial pacing at 80 beats/min increased LAAEV from mean (SD) 14.6 (10.1) to 33.4 (19.8) cm/s (p = 0.001), LAAEF from 13.8 (8.5) to 32.1 (11.2)% (p < 0.001), and TMIF-A from 24.6 (11.9) to 45.6 (21.0) cm/s (p < 0.001) and reduced SEC grade from 2.6 (1.0) to 1.6 (0.9) (p < 0.001). These effects had a positive force-frequency relation. Biatrial pacing produced the shortest P wave duration and resulted in the most significant improvement in atrial function (LAAEV, 33.2 (19.3) v 53.7 (23.9) cm/s, p = 0.0001; LAAEF, 31.9 (11.1) v 46.2 (12.6)%, p < 0.0001; TMIF-A, 37.7 (18.3) v 54.1 (21.2) cm/s, p < 0.001; SEC grade, 1.4 (1.1) v 0.8 (0.9), p = 0.001, right atrial appendage versus biatrial pacing). CONCLUSIONS: Atrial pacing at increased rates can improve atrial mechanical function after cardioversion of persistent AF. Biatrial pacing may be the most effective technique to reverse atrial mechanical stunning.

Adolescent↗

Differential expression of cornified cell envelope precursors in normal skin, intraorally transplanted skin and normal oral mucosa.

BACKGROUND: Skin flaps have routinely been used as substitutes for oral mucosa after extensive resection of oral tissues. However, it remains unknown how the transplanted skin flaps perform as a host defence in the new environment of the oral cavity. OBJECTIVES: To evaluate the expression of cornified cell envelope (CCE) precursors in pretransplanted (normal) skin, intraorally transplanted skin and normal oral mucosa, because CCEs are highly responsible for a protective barrier in each type of epithelium. METHODS: We used immunohistochemistry and immunoelectron microscopy to examine the expression of CCE precursors, small proline-rich protein (SPR) 2 and 3 and loricrin, in biopsy specimens of normal skin, transplanted skin and normal oral mucosa, including buccal and lingual (non-keratinized) mucosae, and palatal (keratinized) mucosa. RESULTS: Transplanted skin flaps were classified into two groups. About two-thirds of the transplanted skin flaps displayed a reddish appearance and were devoid of the stratum corneum (SC) together with a psoriasiform inflammatory tissue reaction. Others showed a native appearance, retaining the SC. While SPR2 expression was limited to the stratum granulosum (SG) in both normal and transplanted skin retaining the SC, it extended to the stratum spinosum (SS) of the transplanted skin lacking the SC and that of the normal oral mucosa. Although SPR3 expression was not found in normal skin or in the transplanted skin retaining the SC, it was strongly expressed in the SS of the transplanted skin lacking the SC and the non-keratinized oral mucosa, and in the SS and SG of the keratinized oral mucosa. Loricrin, which was expressed in the SG of normal skin, the transplanted skin retaining the SC and the keratinized oral mucosa, was not detected in the transplanted skin lacking the SC or in the non-keratinized oral mucosa. Immunoelectron microscopy confirmed the ultrastructural localization of SPR3 directly under the cytoplasmic membrane of keratinocytes of the transplanted skin lacking the SC and that of the oral mucosa. CONCLUSIONS: The altered expression of SPR2, SPR3 and loricrin reflects the possible adaptation of epidermal keratinocytes in the new environment of the oral cavity.

Cheek↗

Therapeutic impact of CYP2C19 pharmacogenetics on proton pump inhibitor-based eradication therapy for Helicobacter pylori.

Current regimens for the eradication of Helicobacter pylori consist of a proton pump inhibitor (PPI) plus one or two antibacterial agents, such as amoxicillin (AMPC), clarithromycin (CAM) or metronidazole (MNZ). PPIs are mainly metabolized by S-mephenytoin 4'-hydroxylase (CYP2C19) in the liver. The polymorphism of CYP2C19 is associated with the pharmacokinetics and pharmacodynamics of PPIs. Eradication rates by PPI-based therapies are also affected by this genotype, as well as bacterial resistance to antibiotics. An individualized treatment strategy based on CYP2C19-related pharmacogenetics or pharmacogenomics and bacterial resistance is expected to increase the cure rate of the initial treatment. It is also necessary to recognize that there is a possible drug-drug interaction between some of the drugs used in this treatment regimen.

Anti-Bacterial Agents↗

Effect of Helicobacter pylori infection and its eradication on nutrition.

AIMS: To investigate the effects of Helicobacter pylori infection and eradication on nutrition. METHODS: The body weight, height, blood pressure, gastric juice pH and fasting serum levels of glucose, total protein, albumin, total cholesterol and triglyceride were measured in H. pylori-positive and H. pylori-negative subjects, and the effect of eradication of H. pylori on these parameters was determined. The development of gastro-oesophageal reflux disease after treatment was also examined. Eight patients underwent a pancreatic function test before and after H. pylori eradication therapy. RESULTS: The incidence of hypoproteinaemia in H. pylori-positive subjects was significantly higher than that in H. pylori-negative subjects. After eradication of H. pylori, the gastric juice pH values were significantly decreased, and the body weight and serum levels of total cholesterol, total protein and albumin were significantly increased. The incidence of hyperlipidaemia significantly increased and that of hypoproteinaemia significantly decreased in the group with eradication. Pancreatic function improved significantly after eradication of H. pylori. No significant changes in these parameters were observed in the group without eradication. Obese patients had a higher risk of the development of gastro-oesophageal reflux disease after eradication of H. pylori infection. CONCLUSIONS: The eradication of H. pylori appears to improve some nutritional parameters.

Blood Pressure↗

Comparison of lansoprazole and famotidine for gastric acid inhibition during the daytime and night-time in different CYP2C19 genotype groups.

BACKGROUND: The acid inhibitory effect of lansoprazole depends on the S-mephenytoin 4'-hydroxylase (CYP2C19) genotype status. The effect of famotidine is independent of this genotype. AIM: To investigate the acid inhibitory effects of lansoprazole vs. famotidine during the daytime and night-time with reference to different CYP2C19 genotypes. METHODS: Fifteen healthy volunteers were given 20 mg famotidine twice a day or 30 mg lansoprazole once a day for 8 days. On post-dose day 8, 24-h intragastric pH monitoring was performed. RESULTS: During the daytime, the intragastric pH with lansoprazole was significantly higher than that with famotidine in the heterozygous extensive metabolizer group, whereas no significant difference was observed in the homozygous extensive metabolizer group. During the night-time, the intragastric pH with famotidine was quite similar to that with lansoprazole in the heterozygous extensive metabolizer and poor metabolizer groups. However, during the night-time, the intragastric pH with famotidine was significantly higher than that with lansoprazole in the homozygous extensive metabolizer group. CONCLUSIONS: An insufficient acid inhibition by lansoprazole during the night-time in the homozygous extensive metabolizer group could be compensated for by famotidine. CYP2C19 genotype testing appears to be useful for predicting the optimal acid inhibitory drug treatment collated with circadian intragastric pH change.

2-Pyridinylmethylsulfinylbenzimidazoles↗

Proliferative activity of canine mast cell tumours evaluated by bromodeoxyuridine incorporation and Ki-67 expression.

The proliferative activity of 91 canine mast cell tumours was assessed on the basis of the Ki-67 positive index (Ki-67 PI) and mitotic index (MI) and, in 15 cases, also by the labelling index of bromodeoxyuridine (BrdU; an analogue of tritiated thymidine) incorporated in vivo into S-phase cells. BrdU and Ki-67 were detected immunohistochemically. The tumours were graded histologically (I, II or III). The BrdU labelling index (BrdU LI) tended to increase as the grade became higher. In terms of the mean values of Ki-67 PI, significant differences were found between histological tumour grades I and II (P < 0.01) and between grades II and III (P < 0.01). In terms of mean MI, grades I and II were found to differ significantly (P < 0.05). With Spearman rank correlation coefficient and linear regression analysis, the BrdU LI and Ki-67 PI showed a highly significant correlation. This strong correlation indicated that Ki-67 was, like BrdU, a useful marker for proliferative potential in canine mast cell tumours; moreover, its use did not require the prior administration of any reagent to the live animal.

Animals↗

Spawning and season affect lipid content and fatty acid composition of ovary and liver in Japanese catfish (Silurus asotus).

The influences of spawning and season on lipid content, lipid classes, and fatty acid composition were assessed in ovary and liver of wild and cultured Japanese catfish (Silurus asotus). The lipid content (7.3+/-1.6 g/100 g wet wt.) of ovary from wild catfish at spawning was higher than that at post-spawn. However, no influence of spawning on the lipid content of liver was observed. Docosahexaenoic acid [DHA, C22:6(n-3)] in ovary lipids was 12.3+/-0.5% of total fatty acids. The percentage of n-7 monounsaturated fatty acids in triacylglycerol from the ovary and liver in the spawning season was high. Percentages of C22:6(n-3) in phosphatidylcholine and phosphatidylethanolamine from ovary were higher during spawning than after spawning. No significant differences were observed in the lipid content of ovary and liver from cultured catfish between seasons (summer vs. winter). Content of arachidonic acid (C20:4n-6) in ovary and liver from cultured catfish was higher in summer than in winter. There were differences in lipid classes of ovary and liver by spawning and season. These results suggest that the lipid metabolism in Japanese catfish is greatly influenced by spawning and season.

Animals↗

Production and chemiluminescent free radical reactions of glyoxal in lipid peroxidation of linoleic acid by the ligninolytic enzyme, manganese peroxidase.

Glyoxal is a key compound involved in glyoxal oxidase (GLOX)-dependent production of glyoxylate, oxalate and H2O2 by lignin-degrading basidiomycetes. In this paper, we report that glyoxal was produced from a metabolite of ligninolytic fungi, linoleic acid, by manganese peroxidase (MnP)-dependent lipid peroxidation. In the absence of the parent substrate of linoleic acid, the dialdehyde was oxidized by MnP and Mn(III) chelate to start free radical reactions with emission of chemiluminescence at 700-710 nm. The spectroscopic profile of the light emission is distinguishable from (a) singlet oxygen, (b) triplet carbonyls from dioxetane and alpha-hydroxyperoxyl radicals, and (c) biacyl triplet formed by the coupling of two acyl radicals. The photon emission of glyoxal by MnP was activated by co-oxidation of tartrate. The MnP-dependent oxidation of glyoxal in tartrate buffers continued for 10 days without addition of exogenous H2O2. The importance of these results is discussed in relation to the free radical chemistry of lignin biodegradation by wood rot fungi.

Biodegradation, Environmental↗

Involvement of cyclooxygenase-2 in hyperplastic gastritis induced by Helicobacter pylori infection in C57BL/6 mice.

BACKGROUND AND AIMS: The hyperplastic changes observed in Helicobacter pylori-associated gastritis have been considered to increase the risk of gastric cancer. The aim of this study was to determine whether cyclooxygenase-2 is involved in the hyperplastic changes in mice infected with H. pylori. METHODS: Seven-week-old, male C57BL/6 mice (n=40) were inoculated with the Sydney strain of H. pylori. Control mice (n=40) were treated with vehicle only. Half of the infected and control mice were fed an experimental diet containing etodolac (10 mg/kg/day) from 1 week after inoculation until the end of the experiment. The thickness of gastric pits, COX-2 mRNA and protein levels, and prostaglandin E2 (PGE2) levels in the gastric mucosa were determined before and 12, and 24 weeks after inoculation. RESULTS: The thickness of gastric pits, COX-2 mRNA and protein levels, and PGE2 levels were significantly increased at 24 weeks after inoculation of H. pylori compared with the control groups. Treatment with etodolac resulted in significant decreases in PGE2 production and in the thickness of gastric pits in the infected groups at 24 weeks after inoculation. CONCLUSIONS: Our findings suggest that COX-2 is involved in the development of hyperplastic gastritis caused by H. pylori infection via the production of PGE2.

Animals↗

Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH.

BACKGROUND: Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non-enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual's CYP2C19 status. AIM: To investigate the acid inhibitory effects and plasma levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes. METHODS: Fifteen healthy volunteers took a daily dose of 20 mg of omeprazole or rabeprazole for 8 days. On post-dose days 1 and 8, 24-h profiles of intragastric pH were recorded and plasma concentrations of omeprazole, rabeprazole and their metabolites were determined. RESULTS: After single and repeated doses of omeprazole, the intragastric pH values and plasma concentrations of omeprazole and its metabolites were significantly dependent on the CYP2C19 genotype. Significant differences in the same kinetic and dynamic parameters were also observed after single doses of rabeprazole. Although the plasma levels of rabeprazole differed among the different CYP2C19 genotype groups after repeated doses, no significant differences in intragastric pH values were observed. CONCLUSIONS: The acid inhibitory effects of omeprazole and rabeprazole are significantly dependent on the CYP2C19 genotype status, as well as on their intrinsic pharmacokinetic and pharmacodynamic characteristics and dosing schemes.

2-Pyridinylmethylsulfinylbenzimidazoles↗

Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin.

BACKGROUND: Proton pump inhibitors such as omeprazole and lansoprazole are mainly metabolized by CYP2C19 in the liver. The therapeutic effects of proton pump inhibitors are assumed to depend on CYP2C19 genotype status. OBJECTIVE: We investigated whether CYP2C19 genotype status was related to eradication rates of H pylori by triple proton pump inhibitor-clarithromycin-amoxicillin (INN, amoxicilline) therapy and attempted to establish a strategy for treatment after failure to eradicate H pylori. METHODS: A total of 261 patients infected with H pylori completed initial treatment with 20 mg of omeprazole or 30 mg of lansoprazole twice a day, 200 mg of clarithromycin three times a day, and 500 mg of amoxicillin three times a day for 1 week. CYP2C19 genotypes of patients were determined with polymerase chain reaction-restriction fragment length polymorphism analysis. Patients without eradication after initial treatment were retreated with 30 mg of lansoprazole four times daily and 500 mg of amoxicillin four times daily for 2 weeks. RESULTS: Eradication rates for H pylori were 72.7% (95% confidence interval, 64.4%-81.8%), 92.1% (confidence interval, 86.4%-97.3%), and 97.8% (confidence interval, 88.5%-99.9%) in the homozygous extensive, heterozygous extensive, and poor metabolizer groups, respectively. Thirty-four of 35 patients without eradication had an extensive metabolizer genotype of CYP2C19. Nineteen of those patients were infected with clarithromycin-resistant strains of H pylori. However, there were no amoxicillin-resistant strains of H pylori. Re-treatment of H pylori infection with dual high-dose lansoprazole-amoxicillin therapy succeeded in 30 of 31 patients with extensive metabolizer genotype of CYP2C19. CONCLUSION: The majority of patients without initial eradication of H pylori had an extensive metabolizer CYP2C19 genotype but were successfully re-treated with high doses of lansoprazole and an antibiotic to which H pylori was sensitive, such as amoxicillin, even when the patients were infected with clarithromycin-resistant strains of H pylori.

2-Pyridinylmethylsulfinylbenzimidazoles↗

Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19.

BACKGROUNDS AND AIM: Lansoprazole is mainly metabolized by cytochrome P4502C19 (CYP2C19) in the liver. The effect of lansoprazole is assumed to be insufficient in subjects who are homozygous extensive metabolizers of CYP2C19. This study aimed to examine whether the CYP2C19 genotype status affected the acid-inhibitory effects of lansoprazole and to develop a strategy to overcome this pharmacogenetic problem. METHODS: Eighteen Helicobacter pylori-negative healthy volunteers, whose CYP2C19 genotypic status had been assessed, participated in the study. They consisted of 7 subjects who were homozygous extensive metabolizers, 7 subjects who were heterozygous extensive metabolizers, and 4 subjects who were poor metabolizers of CYP2C19, who took a placebo or lansoprazole 30 mg once daily in the morning for 8 days. On day 8 of dosing, 24-hour intragastric pH values were recorded. Five of the homozygous extensive metabolizer subjects underwent the 24-hour intragastric pH monitoring on day 8 of dosing of lansoprazole 30 mg 4 times daily. RESULTS: When lansoprazole 30 mg was given once daily, the mean 24-hour intragastric pH values in the subjects who were homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 4.5, 4.9, and 5.5, respectively (P <.005). On day 8 of dosing of lansoprazole 30 mg 4 times daily in subjects who were homozygous extensive metabolizers, the mean 24-hour intragastric pH value was 7.4. CONCLUSION: The effect of lansoprazole on intragastric pH depended significantly on CYP2C19 genotype status. Complete acid inhibition could be achieved by the frequent administration of lansoprazole (eg, 30 mg 4 times daily) in subjects who were homozygous extensive metabolizers. A genotyping test of CYP2C19 status appears useful for prescribing an optimal dosing scheme of lansoprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗