Yu X.,University of Arkansas for Medical Sciences |
Kubota T.,Chiba Institute of Science |
Dhakal I.,University of Arkansas for Medical Sciences |
Hasegawa S.,Sekino Clinical Pharmacology Clinic |
And 3 more authors.
Pharmacogenomics and Personalized Medicine | Year: 2013
Sulfotransferase isoform 1A1 (SULT1A1) plays a key role in the metabolism of a variety of endo-and xenobiotics and it's activity could influence response to drugs. Our previous studies have focused on the impact of genetic variants of SULT1A1 on enzymatic activity in Caucasians and African-Americans. However, the contribution of genetic variants to SULT1A1 activity in Asians has not been explored. In this study, we investigated the collective effects of both SULTl A1 copy number variants (CNVs) and single nucleotide polymorphisms (SNPs) in the promoter region, coding region, and 3′ untranslated region on SULT1A1 activity in Japanese subjects. SNPs in the SULT1A1 promoter and 3′ untranslated region were not associated with SULT1A1 activity (P > 0.05). SULT1A1 *l/2 (Arg213His) was marginally associated with SULT1A1 activity (P = 0.037). However, SULT1A1 CNVs were strongly associated with SULT1A1 activity (trend test P = 0.008) and accounted for 10% of the observed variability in activity for Japanese subjects. In conclusion, SULT1A1 CNVs play a pivotal role in determination of SULT1A1 activity in Japanese subjects, highlighting the influence of ethnic differences in SULT1A1 genetic variants on drug metabolism and therapeutic efficacy. © 20l3 Yu et al, publisher and licensee Dove Medical Press Ltd.
Tovar V.,Hitachi Chemical Research Center Inc |
Ogura M.,Hitachi Chemical Research Center Inc |
Kobayashi A.,Sekino Clinical Pharmacology Clinic |
Kimura S.,Sekino Clinical Pharmacology Clinic |
And 5 more authors.
Journal of Nutritional Science and Vitaminology | Year: 2010
In order to develop a new model of diet research, blood was drawn from 12 adult volunteers for 3 wk on regular diets as controls, and for a subsequent 3 wk supplemented with 18.5 g of freeze-dried tofu (Koya tofu) every day. Triplicate aliquots of 0.06 mL each of whole blood were stimulated ex vivo with phytohemagglutinin (PHA)-P, heat aggregated human IgG (HAG), lipopolysaccharide (LPS), zymosan A, and anti-T cell receptor (TCR) monoclonal antibody to activate specific subsets of leukocytes, then the levels of various inflammatory cytokine mRNA were quantified by real time PCR. Koya tofu significantly (p <0.05) augmented the fold increase of PHA-induced tumor necrosis factor superfamily (TNFSF) 15, IL6, and IL8, HAG-induced TNFSF15 and IL8, LPS-induced IL6 and IL8, zymosan- induced TNFSF15, IL6 and IL8, and TCR-induced TNFSF2 in comparison to the regular diet. Such increase was due to the reduction of baseline mRNA expression, not the enhancement of mRNA induction after specific stimulations. Six (TNFSF15), 4 (IL6), and 3 (IL10) subjects showed significant reduction of baseline mRNA during the Koya tofu diet compared to that of the control diet. Despite large individual-to-individual and day-to-day variation of mRNA, the method employed in this study was sensitive enough to identify statistically significant results as a group as well as on an individual basis, which will be a foundation for tailored diet in the future. The results also indicated that Koya tofu had a power to alter mRNA expression in leukocytes, and TNFSF15, IL6, and IL10 would be biomarkers for soy.
Kobayashi M.,Sanofi S.A. |
Kajiwara M.,Sanofi S.A. |
Hasegawa S.,Sekino Clinical Pharmacology Clinic |
Hasegawa S.,Pharmaspur Inc
Journal of Atherosclerosis and Thrombosis | Year: 2015
Aim: We investigated the safety of 600/150 mg regimen of clopidogrel and the pharmacodynamics and pharmacokinetics of both 300/75 mg regimen and 600/150 mg regimen of clopidogrel in 72 Japanese subjects. Methods: A randomized study was conducted in healthy Japanese male subjects. Eligible subjects were stratified by dose regimen (300 mg loading dose of clopidogrel on day 1 followed by a 75 mg maintenance dose from days 2 to 7 or a 600 mg loading dose of clopidogrel on day 1 followed by a 150 mg maintenance dose from days 2 to 7) and CYP2C19 metabolizer group [extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs)]. Platelet aggregation and platelet reactivity were evaluated by measuring the maximum platelet aggregation intensity (MAI) induced by 5 and 20 μM ADP, phosphorylation of vasodilator-stimulated phosphoprotein (VASP), and P2Y12 reaction units (PRU) using the VerifyNow system, respectively. We also measured the plasma concentrations of clopidogrel and its active metabolite H4. Results: No treatment emergent adverse events in the 300/75 mg and 600/150 mg regimen were observed in EMs, IMs, and PMs. All CYP metabolizer groups exhibited a lower MAI (%) induced by ADP in the 300/75 mg and 600/150 mg clopidogrel regimens, and MAI (%) in IM group was equipotent to EM irrespective of the clopidogrel dosage. The double dose regimen decreased MAI in the PM group as equipotent to the IM group receiving the standard dose regimen without the extension of bleeding time. No clear relationship of exposure to clopidogrel and CYP2C19 function was observed, whereas active metabolite H4 exposure was likely to be related to CYP2C19 function. Conclusion: Clopidogrel in the 600/150 mg regimen was well tolerated. All CYP metabolizer groups exhibited a lower MAI (%) induced by ADP and anti-platelet activities analyzed by VASP and VerifyNow test in the 300/75 mg and 600/150 mg regimens in healthy Japanese subjects. © 2015, Japan Atherosclerosis Society. All rights reserved.
Hayato S.,Eisai Co. |
Hasegawa S.,Sekino Clinical Pharmacology Clinic |
Hojo S.,Eisai Co. |
Okawa H.,Eisai Co. |
And 7 more authors.
European Journal of Clinical Pharmacology | Year: 2012
Purpose: This study was designed to investigate the anti-secretory activity of rabeprazole administered once daily in doses of 5, 10, 20, and 40 mg and different cytochrome P450 2C19 (CYP2C19) genotypes on gastric pH in healthy individuals. Additional objectives were delineating the nighttime from the daytime effect and determining the relationships between the pharmacokinetics and pharmaco-dynamics of rabeprazole. Methods: Eight individuals of each of the three genotypes of CYP2C19 - homozygous extensive metabolizers (homo-EMs), heterozygous EMs (hetero-EMs), and poor metabolizers (PMs) - were recruited. Twenty-four individuals received a once-daily dose, with dosing interval 24 h of 5, 10, 20, or 40 mg rabeprazole for 5 days in a 4-period crossover fashion. Twenty-four-hour intragastric pH and plasma rabeprazole concentrations were determined on day 5. Results: A dose-dependent increase in median pH and in pH 4 holding time was observed across all CYP2C19 genotypes. When rabeprazole was increased from 20 mg to 40 mg, the differences and 95% confidence intervals (CIs) of nighttime pH 4 holding time between 40 mg and 20 mg in homo-EMs, hetero-EMs, and PMs were 8.0% (-5.0%-21.0%), 28.7% (15.7%-41.6%), and 16.9% (3.9%-29.9%), respectively. The relationship between the area under the plasma concentration-time curve up to the last time point at which rabeprazole was quantifiable (AUC 0-t) and the pH 4 holding time could be described using a sigmoid maximum effect (E max) model. Conclusions: Our data demonstrate that increasing rabeprazole dose up to 40 mg once daily results in an increasing pharmacodynamic effect, which is most apparent for the control of nocturnal gastric acid secretion. © Springer-Verlag 2011.
Kaito C.,University of Tokyo |
Saito Y.,University of Tokyo |
Ikuo M.,University of Tokyo |
Omae Y.,University of Tokyo |
And 12 more authors.
PLoS Pathogens | Year: 2013
Community acquired-methicillin resistant Staphylococcus aureus (CA-MRSA) is a socially problematic pathogen that infects healthy individuals, causing severe disease. CA-MRSA is more virulent than hospital associated-MRSA (HA-MRSA). The underlying mechanism for the high virulence of CA-MRSA is not known. The transcription product of the psm-mec gene, located in the mobile genetic element SCCmec of HA-MRSA, but not CA-MRSA, suppresses the expression of phenol-soluble modulin α (PSMα), a cytolytic toxin of S. aureus. Here we report that psm-mec RNA inhibits translation of the agrA gene encoding a positive transcription factor for the PSMα gene via specific binding to agrA mRNA. Furthermore, 25% of 325 clinical MRSA isolates had a mutation in the psm-mec promoter that attenuated transcription, and 9% of the strains had no psm-mec. In most of these psm-mec-mutated or psm-mec-deleted HA-MRSAs, PSMα expression was increased compared with strains carrying intact psm-mec, and some mutated strains produced high amounts of PSMα comparable with that of CA-MRSA. Deletion of psm-mec from HA-MRSA strains carrying intact psm-mec increased the expression of AgrA protein and PSMα, and virulence in mice. Thus, psm-mec RNA suppresses MRSA virulence via inhibition of agrA translation and the absence of psm-mec function in CA-MRSA causes its high virulence property. © 2013 Kaito et al.
PubMed | Sekino Clinical Pharmacology Clinic
Type: Journal Article | Journal: Investigational new drugs | Year: 2012
Heparinized human whole blood from 16 adult volunteers was stimulated with achievable blood concentrations of trastuzumab and rituximab at 37 degrees C for 4 h, then CCL20, IL8, and beta-actin mRNA were quantified. The fold increase of beta-actin was all less than 1.5, and heat aggregated IgG induced both IL8 and CCL20 mRNA in all cases, suggesting that the assay was performed appropriately. Rituximab reduced the levels of CCL20 mRNA in approximately 1/3 of subjects, whereas 50 g/ml trastuzumab induced IL8 and CCL20 mRNA in more than half of subjects. Although the results do not directly indicate the toxicity of antibody medicines, the individual variation found under physiological ex vivo condition will be an interesting clinical research model for drug safety analysis.