Updated on 2021/12/16

写真a

 
ARIYOSHI Noritaka
 
Organization
Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
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Degree

  • (BLANK)

Research Interests

  • Clinical Pharmacology

  • Pharmacogenetics

  • 薬物代謝学

  • 薬理遺伝学

  • personalized preventive healthcare

  • personalized medicine

  • Personalized preventive healthcare

  • Personalized medicine

Research Areas

  • Life Science / Clinical pharmacy

  • Life Science / Nutrition science and health science

  • Life Science / Pharmacology

  • Life Science / Pharmaceutical hygiene and biochemistry

Education

  • Kyushu University   薬学研究科   博士(薬学)

    - 1995

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  • Kyushu University   薬学研究科   薬学修士

    - 1990

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    Country: Japan

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  • Nagasaki University   薬学部   薬学

    - 1988

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    Country: Japan

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Research History

  • Professor

    2016.8

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  • 岡山大学大学院医歯薬学総合研究科   教授

    2016.8

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  • 千葉大学医学部 助教授

    2001 - 2016.7

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  • Associate Professor

    2001 - 2016.7

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  • Associate Professor

    1997 - 2001

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  • 北海道大学大学院薬学研究科 助教授

    1997 - 2001

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  • Research Associate

    1995 - 1996

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  • 米国ウィスコンシン大学マディソン校

    1995 - 1996

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  • Assistant Professor

    1992 - 1997

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  • Kyushu University   School of Pharmaceutical Sciences

    1992 - 1997

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Professional Memberships

Committee Memberships

  • 日本薬学会   代議員  

    2021.4   

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  • Journal of Xenobiotics   editorial board member  

    2021.1   

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    Committee type:Academic society

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  • 国際個別化医療学会   理事  

    2017.1   

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    Committee type:Academic society

    日本医療薬学会

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  • 日本薬物動態学会   代議員  

    2004.11   

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    Committee type:Academic society

    日本薬物動態学会

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Papers

  • Blood concentrations of tacrolimus upon conversion from rabeprazole to vonoprazan in renal transplant recipients: Correlation with cytochrome P450 gene polymorphisms. Reviewed International journal

    Shogo Watari, Motoo Araki, Jun Matsumoto, Kasumi Yoshinaga, Takanori Sekito, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Koichiro Wada, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Shinji Kitamura, Hitoshi Sugiyama, Noritaka Ariyoshi, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Drug metabolism and pharmacokinetics   40   100407 - 100407   2021.10

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    We evaluated the impact of vonoprazan on blood concentrations of tacrolimus via a retrospective analysis of 52 renal transplant recipients who took tacrolimus and converted from rabeprazole to vonoprazan between August 2018 and September 2019. We compared tacrolimus trough levels upon conversion among groups that were classified based on cytochrome P450 (CYP) gene polymorphisms. CYP3A5 groups were heterozygous or homozygous for CYP3A5∗1 and CYP3A5∗3 alleles. CYP2C19 genotypes were classified as extensive (∗1/∗1), intermediate (∗1/∗2 and ∗1/∗3) or poor metabolizers (∗2/∗2, ∗2/∗3 and ∗3/∗3). Tacrolimus trough levels increased only 0.3 ng/mL upon conversion in the CYP3A5∗3/∗3 group: 5.8 [3.4-7.2] vs 6.1 [3.8-7.9]; p = 0.06. No statistically significance changes in tacrolimus levels also occurred in the CYP3A5∗1/∗1 or CYP3A5∗1/∗3 groups. Subgroup analyses of CYP3A5∗3/∗3 demonstrated low changes for all three CYP2C19 subgroups: 5.2 [4.3-6.5] vs 6.2 [4.3-7.9]; p = 0.07, 6.1 [3.4-7.2] vs 6.7 [4.6-7.9]; p = 0.12 and 5.4 [3.6-6.5] vs 4.7 [3.8-6.3]; p = 1.00, respectively. Conversion to vonoprazan thus resulted in little increase of tacrolimus trough levels, even in the group predicted to be most susceptible (CYP3A5∗3/∗3 and 2C19∗1/∗1), thus supporting the safety of concomitant use of vonoprazan with tacrolimus.

    DOI: 10.1016/j.dmpk.2021.100407

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  • Differential Impact of Clinical and Genetic Factors on High Platelet Reactivity in Patients with Coronary Artery Disease Treated with Clopidogrel and Prasugrel. Reviewed

    Yuichi Saito, Takeshi Nishi, Shinichi Wakabayashi, Yuji Ohno, Hideki Kitahara, Noritaka Ariyoshi, Yoshio Kobayashi

    Journal of atherosclerosis and thrombosis   2021.7

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    AIM: High platelet reactivity (HPR) is associated with increased risks of thrombotic events in patients with coronary artery disease. The recently developed ABCD-GENE score identified five clinical and genetic factors (age, body mass index, chronic kidney disease, diabetes, and the CYP2C19 loss-of-function allele) for HPR, although the significance of various stages of each factor is unclear. METHODS: Four prospective studies were pooled, in which platelet reactivity was measured using the VerifyNow assay with clopidogrel and prasugrel; genotyping of CYP2C19 was also performed. Each component of the ABCD-GENE score was divided into three subcategories. VerifyNow P2Y12 reactivity units >208 were defined as HPR. RESULTS: A total of 184 patients were included, of which 111 (60%) and 51 (28%) had HPR with clopidogrel and prasugrel. Chronic kidney disease had an impact on HPR on both clopidogrel and prasugrel, whereas the impact of diabetes was more evident in patients treated with prasugrel. Although the number of CYP2C19 loss-of-function alleles was clearly associated with a likelihood of HPR with clopidogrel, P2Y12 reactivity units with prasugrel treatment were also significantly and progressively higher in patients with more CYP2C19 loss-of-function alleles. CONCLUSIONS: Clinical and genetic factors had a differential effect on a P2Y12 inhibitor reactivity with clopidogrel and prasugrel in patients with coronary artery disease. The severity of the factors also had a different impact on HPR.

    DOI: 10.5551/jat.63035

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  • Relevance of CYP3A5 Expression on the Clinical Outcome of Patients With Renal Cell Carcinoma. Reviewed International journal

    Jun Matsumoto, Yumi Kotera, Shogo Watari, Koichi Takeuchi, Hideo Ueki, Toshihiro Koyama, Koichiro Wada, Masachika Fujiyoshi, Yasutomo Nasu, Noritaka Ariyoshi

    Anticancer research   41 ( 5 )   2511 - 2521   2021.5

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    BACKGROUND/AIM: This study aimed to elucidate the detailed characteristics of CYP3A5 expression and the association between CYP3A5 expression and clinical outcomes in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: This study retrospectively enrolled 124 Japanese patients with RCC treated at the Okayama University Hospital. The commonest CYP3A5 gene polymorphism, CYP3A5*3, and expression levels of CYP3A5 mRNA and protein in each tissue were examined. RESULTS: Expression of CYP3A5 mRNA and protein in RCC tissues was significantly down-regulated compared to that in adjacent normal tissues. High level of CYP3A5 mRNA expression significantly extended cancer-specific survival (p=0.004) and overall survival (p=0.002). The CYP3A5 mRNA expression level was identified as a significant independent prognostic factor for both cancer-specific survival and overall survival. CONCLUSION: CYP3A5 could serve as a potential marker for prognostication and treatment planning for patients with RCC.

    DOI: 10.21873/anticanres.15029

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  • Validation of the ABCD-GENE score to identify high platelet reactivity in east Asian patients undergoing percutaneous coronary intervention. Reviewed International journal

    Yuichi Saito, Takeshi Nishi, Shinichi Wakabayashi, Yuji Ohno, Hideki Kitahara, Noritaka Ariyoshi, Yoshio Kobayashi

    International journal of cardiology   327   15 - 18   2021.3

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    BACKGROUND: High platelet reactivity (HPR) is associated with subsequent thrombotic events in patients undergoing percutaneous coronary intervention (PCI). Recently, the ABCD-GENE score was developed to identify patients at risk for HPR, incorporating both clinical and genetic factors. However, this score was derived and validated in mostly Caucasian subjects and it has not been validated in an East Asian population. METHOD: Individual patient data from 4 prospective studies were pooled, in which platelet reactivity was measured using the VerifyNow assay on clopidogrel and genotyping of CYP2C19 was performed after PCI. Study populations included patients with general stable coronary artery disease, hemodialysis, age ≥75 and/or body weight <50 kg, and acute coronary syndrome. VerifyNow P2Y12 reactivity units >208 was defined as HPR. RESULTS: Of 184 patients, 111 (60%) had HPR on clopidogrel. In the receiver operating characteristics curve analyses, the ABCD-GENE score significantly predicted HPR on clopidogrel (AUC 0.78, best cut-off value 9, p < 0.001). Across the 4 studies and their combinations, the diagnostic ability and cut-off values of ABCD-GENE score for HPR on clopidogrel were consistent. CONCLUSIONS: The ABCD-GENE score had significant and moderate diagnostic ability for HPR on clopidogrel in Japanese patients undergoing PCI. The predictivity was consistent across a broad spectrum of patient populations, suggesting the applicability of this novel scoring system in clinical practice worldwide.

    DOI: 10.1016/j.ijcard.2020.11.022

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  • 【コロナ禍における医療人育成】薬学領域 コロナ禍における薬学実務実習での工夫

    猪田 宏美, 藤吉 正哉, 西原 茂樹, 松本 准, 有吉 範高, 千堂 年昭

    医学教育   51 ( 5 )   541 - 543   2020.10

  • Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro: a different effect on asunaprevir versus daclatasvir and beclabuvir. Reviewed International journal

    Jun Matsumoto, Su Nwe San, Masachika Fujiyoshi, Ayano Kawauchi, Natsumi Chiba, Ran Tagai, Ryoko Sanbe, Shiho Yanaka, Hiroaki Sakaue, Yoshinori Kato, Hiroyoshi Nakamura, Harumi Yamada, Noritaka Ariyoshi

    Journal of human genetics   65 ( 2 )   143 - 153   2020.1

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    Direct-acting antivirals, asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are known to be mainly metabolized by CYP3A enzymes; however, the differences in the detailed metabolic activities of CYP3A4 and CYP3A5 on these drugs are not well clarified. The aim of the present study was to elucidate the relative contributions of CYP3A4 and CYP3A5 to the metabolism of ASV, DCV, and BCV, as well as the effect of CYP3A5*3 genetic variant in vitro. The amount of each drug and their major metabolites were determined using LC-MS/MS. Recombinant CYP3As and CYP3A5*3-genotyped human liver microsomes (CYP3A5 expressers or non-expressers) were used for the determination of their metabolic activities. The contribution of CYP3A5 to ASV metabolism was considerable compared to that of CYP3A4. Consistently, ASV metabolic activity in CYP3A5 expressers was higher than those in CYP3A5 non-expresser. Moreover, CYP3A5 expression level was significantly correlated with ASV metabolism. In contrast, these observations were not found in DCV and BCV metabolism. To our knowledge, this is the first study to directly demonstrate the effect of CYP3A5*3 genetic variants on the metabolism of ASV. The findings of the present study may provide basic information on ASV, DCV, and BCV metabolisms.

    DOI: 10.1038/s10038-019-0685-2

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  • A randomized controlled, open-label early phase II trial comparing incidence of FOLFIRI.3-induced diarrhoea between Hangeshashinto and oral alkalization in Japanese patients with colorectal cancer. Reviewed International journal

    Kaori Yamazaki, Noritaka Ariyoshi, Hideaki Miyauchi, Gaku Ohira, Noriko Kaneya, Kohei Yamamoto, Kenichi Arai, Shingo Yamazaki, Hisahiro Matsubara, Takaaki Suzuki, Itsuko Ishii

    Journal of clinical pharmacy and therapeutics   44 ( 6 )   946 - 951   2019.12

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    WHAT IS KNOWN AND OBJECTIVE: We conducted a pilot clinical trial to investigate whether Hangeshashinto (TJ-14) could be substituted for oral alkalization in patients scheduled to undergo chemotherapy by FOLFIRI.3 regimen for colorectal cancer (CRC). METHODS: Patients with CRC were randomized 1:1 to a TJ-14 (7.5 g/day) group or an oral alkalization (sodium bicarbonate, 1.8 g/day; ursodeoxycholic acid, 300 mg/day) group. The primary endpoint was incident of late-onset diarrhoea. A total of 30 patients were randomized to either the TJ-14 group or the alkalization group. RESULTS AND DISCUSSION: There was no statistical difference in age, concomitantly used drugs or UGT1A1 genotypes between the groups. In the alkalization group (n = 15), the frequency of grade 0/1/2 and grade 3 diarrhoea was 73% and 27%, respectively. In the TJ-14 group (n = 14), the frequency of grade 0/1/2 and grade 3 diarrhoea was 79% and 21%, respectively. Grade 4 diarrhoea was not observed in either group. There was no statistically significant difference in other adverse events or in response to FOLFIRI.3 between the groups. WHAT IS NEW AND CONCLUSION: This pilot trial suggests that TJ-14 is a promising alternative treatment option to reduce FOLFIRI.3-induced late-onset diarrhoea, although additional clinical study with a larger number of patients is necessary to confirm these results.

    DOI: 10.1111/jcpt.13020

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  • Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro. Reviewed International journal

    Su Nwe San, Jun Matsumoto, Yumi Saito, Masako Koike, Hiroaki Sakaue, Yoshinori Kato, Masachika Fujiyoshi, Noritaka Ariyoshi, Harumi Yamada

    Xenobiotica; the fate of foreign compounds in biological systems   49 ( 8 )   935 - 944   2019.8

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    Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir. The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on in vitro PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5) and human liver microsomes (HLMs) genotyped as either CYP3A5*1/*1, CYP3A5*1/*3 or CYP3A5*3/*3. The intrinsic clearance (CLint, Vmax/Km) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in CYP3A5*1/*1 and CYP3A5*1/*3 HLMs expressing CYP3A5 was comparable to that in CYP3A5*3/*3 HLMs, which lack CYP3A5. CYP3A4 expression level was significantly correlated with PTV disappearance rate and metabolite formation. In contrast, there was no such correlation found for CYP3A5 expression level. This study represents that the major CYP isoform involved in PTV metabolism is CYP3A4, with CYP3A5 having a minor role in PTV metabolism. The findings of the present study may provide foundational information on PTV metabolism, and may further support dosing practices in HCV-infected patients prescribed PTV-based therapy.

    DOI: 10.1080/00498254.2018.1524947

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  • A proposed simple screening method to determine relative contributions of CYP3A4 and CYP3A5 to drug metabolism in vitro. Reviewed

    Matsumoto J, Nakamura H, San NS, Sato H, Takezawa M, Kishi R, Kito Y, Sugano J, Izuki M, Yanagisawa N, Ikeda N, Saito Y, Kato Y, Yamada H, Fujiyoshi M, Ariyoshi N

    Pers Med Univers.   8   41 - 44   2019.7

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  • High residual platelet reactivity after switching from clopidogrel to low-dose prasugrel in Japanese patients with end-stage renal disease on hemodialysis. Reviewed International journal

    Yuji Ohno, Hideki Kitahara, Kenichi Fujii, Yukinori Kohno, Noritaka Ariyoshi, Takeshi Nishi, Yoshihide Fujimoto, Yoshio Kobayashi

    Journal of cardiology   73 ( 1 )   51 - 57   2019.1

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    BACKGROUND: High on-treatment platelet reactivity (HPR) under clopidogrel treatment is frequently observed in hemodialysis (HD) patients. In such patients, 10mg of prasugrel has reportedly inhibited platelet reactivity more adequately compared with 75mg of clopidogrel. However, the efficacy of 3.75mg prasugrel in Japanese HD patients is largely unknown. METHODS: A total of 41 Japanese coronary artery disease patients under HD who received aspirin and clopidogrel were enrolled. Clopidogrel was switched to 3.75mg prasugrel. At day 14, prasugrel was switched to clopidogrel. Platelet reactivity was measured using VerifyNow assay (Accumetrics, San Diego, CA, USA) at baseline, day 14, and day 28. VerifyNow P2Y12 reaction units (PRU) >208 was defined as HPR. RESULTS: The PRU level on prasugrel therapy was significantly lower than that on clopidogrel therapy before switching (219.1±62.3 PRU vs. 238.2±68.0 PRU, p=0.02). Although the prevalence of HPR was numerically lower on prasugrel therapy compared with clopidogrel therapy before and after switching, the differences did not reach a statistical significance (57.6% vs. 75.7% vs. 74.2%, p=0.13). Even under prasugrel treatment, more than half of patients showed HPR. CONCLUSIONS: Although low-dose prasugrel had somewhat better antiplatelet effect than clopidogrel, it could not significantly improve the prevalence of HPR in Japanese HD patients. Higher doses of prasugrel might be needed to achieve adequate platelet inhibition in this high thrombotic risk population.

    DOI: 10.1016/j.jjcc.2018.07.001

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  • Efficacy of 2.5-mg Prasugrel in Elderly or Low-Body-Weight Patients. Reviewed

    Shinichi Wakabayashi, Noritaka Ariyoshi, Hideki Kitahara, Kenichi Fujii, Yoshihide Fujimoto, Yoshio Kobayashi

    Circulation journal : official journal of the Japanese Circulation Society   82 ( 9 )   2326 - 2331   2018.8

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    BACKGROUND: Due to concern about bleeding complications, a maintenance dose of prasugrel 2.5 mg may be used in elderly or low-body-weight patients in Japan. There is little information, however, on the efficacy and safety of a 2.5-mg maintenance dose of prasugrel. Methods and Results: In this single-center, prospective, open-label, cross-over study, a total of 44 elderly (≥75 years old) or low body-weight (<50 kg) Japanese patients >1 month after percutaneous coronary intervention who were treated with aspirin 81-100 mg and clopidogrel 75 mg were randomized to either prasugrel 2.5 mg or 3.75 mg instead of clopidogrel for 14 days, with a cross-over directly to the alternate treatment for another 14 days. Platelet inhibition was assessed with the VerifyNow assay (Accumetrics, San Diego, CA, USA) at 3 time points: baseline; day 14; and day 28. P2Y12 reaction units (PRU) ≤95 was defined as low on-treatment platelet reactivity (LPR), and PRU ≥262 as high on-treatment platelet reactivity (HPR). The prevalence of LPR was 2.2% in patients treated with clopidogrel, 2.2% in those with prasugrel 2.5 mg, and 22.7% in those with prasugrel 3.75 mg (P<0.001). Clopidogrel resulted in the higher prevalence of HPR compared with 2.5-mg and 3.75-mg prasugrel (40.9% vs. 18.2% vs. 6.8%, P<0.001). CONCLUSIONS: Prasugrel 2.5 mg may be more appropriate in elderly or lower-body-weight Japanese patients.

    DOI: 10.1253/circj.CJ-18-0337

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  • Platelet inhibition after loading dose of prasugrel in patients with ST-elevation and non-ST-elevation acute coronary syndrome. Reviewed

    Shinichi Wakabayashi, Hideki Kitahara, Takeshi Nishi, Kazumasa Sugimoto, Takashi Nakayama, Yoshihide Fujimoto, Noritaka Ariyoshi, Yoshio Kobayashi

    Cardiovascular intervention and therapeutics   33 ( 3 )   239 - 246   2018.7

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    The PRASFIT-ACS study showed the antiplatelet effect 2-4 h after prasugrel loading. However, there is little information about the antiplatelet effect <2 h after prasugrel loading dose, especially in patients with acute coronary syndrome (ACS). There had not been any comparison between ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation ACS (NSTE-ACS). Fifty patients with ACS (15 with STEMI and 35 with NSTE-ACS) were enrolled. They received a 20-mg prasugrel loading dose followed by a maintenance dose of 3.75 mg. Platelet reactivity [P2Y12 reaction units (PRU)] was evaluated by the VerifyNow assay at baseline, 30 min, 1, 2, 4, and 6 h, 1 week under prasugrel, and at 1 month after switching to clopidogrel. The primary end point was the change of PRU compared to the baseline. Furthermore, PRU after prasugrel loading between STEMI and NSTE-ACS was compared. A significant reduction in PRU from baseline was observed at ≥2 h after administration of prasugrel. In STEMI patients, a significant reduction in PRU was observed at 4 h after prasugrel loading. STEMI patients had higher PRU compared to NSTE-ACS patients at 2, 4, and 6 h after prasugrel loading. Utilizing >208 PRU as a cutoff value, STEMI patients had a higher prevalence of high on-treatment platelet reactivity at 2-6 h and 1 week after loading. Rapid antiplatelet effect is not achieved by low-dose prasugrel loading in STEMI patients. Platelet inhibition occurs earlier in NSTE-ACS patients, although it takes ≥2 h after loading in the majority of patients.

    DOI: 10.1007/s12928-017-0475-8

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  • HPLC-UVを用いたソホスブビルの定量法の確立(Determination of sofosbuvir via a high-performance liquid chromatography method using ultraviolet detection)

    Su Nwe San, 松本 准, 小池 雅子, 斎藤 祐実, 坂上 弘明, 加藤 芳徳, 有吉 範高, 山田 治美

    国際医療福祉大学学会誌   23 ( 1 )   130 - 136   2018.3

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    Sofosbuvir(SOF)は、C型肝炎ウイルスの増殖を阻害するヌクレオチドアナログ薬である。本研究において、我々は、水溶液およびヒト血漿中SOF濃度の簡便、特異的、高感度および精密なUV検出を用いた高速クロマトグラフィー法による測定方法の確立を試みた。0.25mLの水溶液またはヒト血漿からアセトニトリルを含む抽出液で抽出し、C18逆相カラムを用いて分析した。ソラフェニブを内標準物質(IS)とし、移動相は酢酸アンモニウム緩衝液、メタノールおよびアセトニトリルを用いた。流速は1.0mL/min、UV検出波長は265nmとした。SOFとISの検出時間はそれぞれ7.8minおよび9.1min、1検体の測定時間は15.0minであった。検量線は、0.1-10.0μg/mLの範囲で直線性を得た。それぞれの検出限界は0.1μg/mL、ヒト血漿試料からの回収率は99%以上であった。水溶液およびヒト血漿中の日内、日間変動係数はそれぞれ1.41-10.06%および0.21-6.53%であった。日内、日間精度はそれぞれ92.71-98.41%および89.31-101.21%であった。本方法は、非常に簡便でかつ試料から良好な回収が可能でありSOFの薬物動態研究を行うために用いることができる。(著者抄録)

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J05958&link_issn=&doc_id=20180426420014&doc_link_id=http%3A%2F%2Fid.nii.ac.jp%2F1065%2F00000857%2F&url=http%3A%2F%2Fid.nii.ac.jp%2F1065%2F00000857%2F&type=%8D%91%8D%DB%88%E3%97%C3%95%9F%8E%83%91%E5%8Aw%81F%8D%91%8D%DB%88%E3%97%C3%95%9F%8E%83%91%E5%8Aw%83%8A%83%7C%83W%83g%83%8A&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80077_3.gif

  • An extremely high bioavailability of orally administered vancomycin in a patient with severe colitis and renal insufficiency Reviewed

    Shingo Yamazaki, Takaaki Suzuki, Tatsuya Suzuki, Hirokazu Takatsuka, Masayuki Ishikawa, Noriyuki Hattori, Takeshi Fujishiro, Hideaki Miyauchi, Takehiko Oami, Noritaka Ariyoshi, Shigeto Oda, Hisahiro Matsubara, Itsuko Ishii

    JOURNAL OF INFECTION AND CHEMOTHERAPY   23 ( 12 )   848 - 851   2017.12

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    Because there is little absorption of orally administered vancomycin hydrochloride (VCM) through the normal intestinal microvillus membrane, the pharmacokinetics of VCM absorbed from the digestive tract are mostly unknown. Here we report a case of severe colitis and renal insufficiency in which the serum concentration of VCM reached the supratherapeutic range after oral administration. A 54-year-old man receiving outpatient chemotherapy for rectal cancer was admitted to our hospital for severe sepsis and acute renal failure. Multimodal therapy including continuous renal replacement therapy (CRRT) and mechanical ventilation was initiated, and oral VCM administration (0.5 g every 6 h) was begun for suspected severe pseudomembranous colitis with large amounts of watery stool. Despite continued CRRT, the serum VCM concentration increased to 30.6 mg/mL after 4 days. Based on pharmacokinetic analysis, the bioavailability of VCM was estimated to be over 54.5%. Colonoscopy showed that the mucosa was severely damaged throughout the large intestine, resulting in considerable exudation of plasma and blood. This case indicates the need for careful and early monitoring during high-dose oral VCM administration to patients with severe mucosal injury and renal insufficiency. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jiac.2017.08.004

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  • Impact of chronic kidney disease on platelet inhibition of clopidogrel and prasugrel in Japanese patients. Reviewed International journal

    Takeshi Nishi, Noritaka Ariyoshi, Takashi Nakayama, Yoshihide Fujimoto, Kazumasa Sugimoto, Shinichi Wakabayashi, Hideki Hanaoka, Yoshio Kobayashi

    Journal of cardiology   69 ( 5 )   752 - 755   2017.5

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    BACKGROUND: The impact of chronic kidney disease (CKD) on the antiplatelet effect of clopidogrel and low-dose (3.75mg) prasugrel in Japanese patients is largely unknown. METHODS: A total of 53 consecutive Japanese patients with stable coronary artery disease who received aspirin and clopidogrel were enrolled, and categorized by estimated glomerular filtration rate (eGFR): CKD group (n=15, eGFR<60ml/min/1.73m2) and non-CKD group (n=38, eGFR≥60ml/min/1.73m2). Clopidogrel was switched to 3.75mg prasugrel. Platelet reactivity measurement using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA, USA) was performed at baseline (on clopidogrel) and day 14 (on prasugrel). RESULTS: The VerifyNow P2Y12 reaction units (PRU) during clopidogrel therapy was significantly higher in the CKD group than that in the non-CKD group (185.2±51.1 PRU vs. 224.3±57.0 PRU, p=0.02), whereas, the PRU with the prasugrel therapy in the CKD group and non-CKD group were not significantly different (149.9±51.1 PRU vs. 165.3±61.8 PRU, p=0.36). The PRU was significantly lower with the prasugrel therapy compared to that with the clopidogrel therapy both in the CKD group and in the non-CKD group. CONCLUSIONS: Antiplatelet effect of clopidogrel but not prasugrel is attenuated in patients with CKD. Prasugrel achieves a consistently lower platelet reactivity compared with clopidogrel regardless of the presence of mild to moderate CKD.

    DOI: 10.1016/j.jjcc.2016.07.017

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  • プロトコルに基づく外来処方の問い合わせの効率化とその効果

    内田 雅士, 新井 さやか, 山崎 香織, 竹田 真理子, 鈴木 貴明, 中村 貴子, 有吉 範高, 石井 伊都子

    日本病院薬剤師会雑誌   53 ( 4 )   417 - 422   2017.4

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    千葉大学医学部附属病院では院外処方せんに関する問い合わせは薬剤部医薬品情報(DI)室を介して実施している。保険薬局からの問い合わせのうち約90%は医師に照会を行っているが、形式的に医師に確認をとる程度の軽微な内容も多く、医師・患者・保険薬局の負担となっていた。そこで、11項目の問い合わせ内容について問い合わせの受付時に医師に照会を行わず薬剤師の判断で対応するプロトコルを作成し、医師の合意の下、運用を開始した。プロトコル導入後、医師に照会することなく対応した問い合わせは全体の31.1%であり医師に照会した件数は11件/日減少した。医師への疑義照会の所要時間は中央値3.5分(値域1〜237分)であり、保険薬局・患者の待ち時間が短縮される事例があると考えられた。よってプロトコルに基づく運用は有用だと考えられた。(著者抄録)

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  • 院内処方せんに導入した医薬品別検査値表示方式とその有用性 Reviewed

    横山 威一郎, 橋本 杏里, 山口 洪樹, 山崎 香織, 松島 徹, 中村 貴子, 鈴木 貴明, 有吉 範高, 石井 伊都子

    医療薬学   42 ( 11 )   738 - 745   2016.11

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    本邦で承認されている全ての医療用医薬品の警告・禁忌・原則禁忌(禁忌等)を内容ごとに分類し、処方鑑査での確認可能項目を調査した。医療用医薬品17756品目について添付文書に記載されている禁忌等は51804件で、内容ごとに分類すると14種類となった。禁忌等分類は、疾患・症状の件数が最も多く、半数を占めた。直接臨床検査値と結びつく、肝障害、臨床検査値、腎障害、透析の件数は5291件であり、全体の10.2%であった。確認可能項目は、処方せんに検査値を表示する前は7種類16483件であったのが、検査値表示開始後は11種類21774件となった。処方せんで確認できない項目は3種類30030件あり、全体の58.0%を占めた。採用薬2122品目のうち、禁忌等に該当は287品目505件、「腎」マークの表示に該当は75品目であった。臨床検査値関連の疑義照会によって処方変更に至った事例のうち禁忌に該当する事例は、医薬品別検査値表示開始前は6ヵ月間で0件であったが、表示開始直後は4件、最近の6ヵ月間では20件であった。

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  • Beta-migrating very low-density lipoprotein conjugates with acrolein in high-cholesterol diet-fed rabbits and localizes to atherosclerotic lesions with macrophages Reviewed

    Kanogawa, Yuri, Fujiyoshi, Masachika, Nakazato, Yuki, Watanabe, Kenta, Kurihara, Mizuki, Takezawa, Akari, Uchida, Masashi, Igarashi, Kazuei, Suzuki, Takaaki, Ariyoshi, Noritaka, Ishii, Itsuko

    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY   9 ( 11 )   11149 - 11158   2016

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    Protein-conjugated acrolein (PC-Acro) is detected in atherosclerotic lesions, and we demonstrated previously that acrolein-conjugated low-density lipoproteins induce macrophage foam cell formation. Although it has been suggested that beta-migrating very low-density lipoprotein (beta VLDL) is taken up by macrophages during atherogenesis, the modification of beta VLDL with acrolein and its localization on lesions are still unclear. The purpose of this study was to clarify the localization of PC-Acro in atherosclerotic lesions and to determine the role of acrolein-conjugated beta VLDL in atherogenesis. Male New Zealand white rabbits were fed 0.5% cholesterol-containing rabbit chow for 8 weeks, and used as an animal model of atherosclerosis. PC-Acro and malondialdehyde (MDA)-conjugated protein levels, which has been used widely as a means to detect oxidized low-density lipoprotein (LDL), in plasma were increased in the 0.5% cholesterol-containing diet-induced animal model of atherosclerosis, whereas their level was unchanged in the control diet fed rabbit. PC-Acro was detected in beta VLDL by western blot analysis, and acrolein-conjugated beta VLDL was effectively taken up by THP-1 macrophages. By immunohistochemical analysis, PC-Acro and macrophages were detected at the internal elastic lamina of the aorta, which was the initial lesion of atherosclerosis. These results suggest that acrolein-conjugated beta VLDL has an important role in the initiation of atherosclerosis via the induction of macrophage foam cell formation in the atherosclerotic lesion.

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  • Organic anion transporting polypeptide 2B1 expression correlates with uptake of estrone-3-sulfate and cell proliferation in estrogen receptor-positive breast cancer cells Reviewed

    Jun Matsumoto, Noritaka Ariyoshi, Masahiro Sakakibara, Takeo Nakanishi, Yoshiyuki Okubo, Nobumitsu Shiina, Kaoru Fujisaki, Takeshi Nagashima, Yukio Nakatani, Ikumi Tamai, Harumi Yamada, Hiroshi Takeda, Itsuko Ishii

    Drug Metab Pharmacokinet .   30 ( 2 )   133 - 141   2015.4

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  • Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in Japanese patients with stable coronary artery disease. Reviewed

    Takeshi Nishi, Noritaka Ariyoshi, Takashi Nakayama, Yoshihide Fujimoto, Kazumasa Sugimoto, Masayuki Takahara, Shinichi Wakabayashi, Masaya Koshizaka, Hideki Hanaoka, Yoshio Kobayashi

    Circulation journal : official journal of the Japanese Circulation Society   79 ( 11 )   2439 - 44   2015

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    BACKGROUND: The pharmacodynamic effects of changing from standard-dose clopidogrel to low-dose (3.75 mg) prasugrel in Japanese patients are largely unknown. METHODS AND RESULTS: A total of 53 consecutive Japanese patients with stable coronary artery disease (CAD) who received aspirin and clopidogrel were enrolled. Clopidogrel was switched to 3.75 mg prasugrel. At day 14, prasugrel was switched to 75 mg clopidogrel. Platelet reactivity was measured using the VerifyNow assay at baseline, day 14, and day 28. VerifyNow P2Y12 reaction units (PRU) >208 was defined as high on-treatment platelet reactivity (HPR). The prevalence of HPR (18.9% vs. 41.5% vs. 44.2%, P<0.001) and the PRU level (154.3±54.2 vs. 196.2±55.5 vs. 194.6±55.8, P<0.001) were significantly lower on prasugrel maintenance therapy compared with the clopidogrel therapy before and after switching. The CYP2C19 genotypes that account for the 3 phenotypes (ie, extensive metabolizer, intermediate metabolizer, and poor metabolizer) had a significant impact on platelet reactivity with clopidogrel (174.9±54.0 vs. 193.1±56.5 vs. 240.6±25.4 PRU, P<0.001) but not prasugrel (147.0±51.9 vs. 147.5±58.3 vs. 184.4±38.3 PRU, P=0.15). CONCLUSIONS: Low-dose prasugrel achieves stronger platelet inhibition than clopidogrel in Japanese patients with stable CAD.

    DOI: 10.1253/circj.CJ-15-0546

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  • Pharmacogenetic-guided algorithms to estimate personalized dose or individual responses to anti-thrombotic drugs. Reviewed

    Ariyoshi, N

    Pers Med Univers.   4   13 - 22   2015

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  • 薬剤師と医師による定期処方協働入力の試みとその評価

    山口 洪樹, 三浦 剛, 石井 晃, 石田 敬一, 鈴木 貴明, 有吉 範高, 松宮 護郎, 石井 伊都子

    日本病院薬剤師会雑誌   50 ( 11 )   1303 - 1307   2014.11

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    千葉大学医学部附属病院において毎週1週間分処方される定期処方は、処方入力自体なされていない例(処方もれ)や経過中に変更された投与量が反映されていない例(処方ミス)が散見された。そこで、医療安全の確保を目的として、心臓血管外科病棟において薬剤師と医師が病棟で協議しながら定期処方を決定し入力する「協働入力」を開始した。取り組み開始後に処方もれはみられなくなり、処方ミスによる処方修正件数は開始前45件(22.4%)に対し開始後9件(3.4%)と有意な減少(p<0.01)がみられた。さらに、医師へのアンケート結果からも協働入力に対して好意的な回答が多く得られ、処方入力の際に患者の病態や服薬状況を理解している病棟薬剤師がその場で提案・情報提供できていることが、医師からの高い評価につながったと考えられた。以上により、本取り組みはチーム医療の推進につながり、医療安全および処方の適正化に貢献したと考えられた。(著者抄録)

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  • Genetic and non-genetic factors responsible for antiplatelet effects of clopidogrel in Japanese patients undergoing coronary stent implantation: an algorithm to predict on-clopidogrel platelet reactivity. Reviewed International journal

    Go Miura, Noritaka Ariyoshi, Yasunori Sato, Hiroki Yamaguchi, Yo Iwata, Yoshihide Fujimoto, Yoshio Kobayashi, Itsuko Ishii

    Thrombosis research   134 ( 4 )   877 - 83   2014.10

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    INTRODUCTION: Antiplatelet effects of clopidogrel appear to be affected by various factors including genetic polymorphism. So far, there has been little information about the response of clopidogrel in Asians, whose prevalence of a CYP2C19 loss-of-function (LOF) allele is high. METHODS AND RESULTS: We investigated background and clinical factors affecting on-clopidogrel platelet reactivity in Japanese patients undergoing coronary stent implantation (n=114). In univariate analysis, antiplatelet effects of clopidogrel in a steady state were associated with not only CYP2C19 genotypes but also several factors including dyslipidemia. In addition, we developed an algorithm that can estimate P2Y12 Reaction Units (PRU) in a steady state by multiple regression analysis and evaluated the adequacy of the algorithm by the Akaike Information Criterion. CONCLUSIONS: We revealed several factors influencing on-clopidogrel platelet reactivity in Japanese patients. We also succeeded in developing an algorithm that estimates PRU in a steady state, although it is uncertain whether the algorithm can be applied to other populations.

    DOI: 10.1016/j.thromres.2014.07.018

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  • バンコマイシン血中濃度コントロールに難渋した難治性腹水患者の1例 Reviewed

    高塚 博一, 山崎 伸吾, 對田 尚, 清野 宗一郎, 竹田 真理子, 鈴木 達也, 関本 匡, 丸山 紀史, 鈴木 貴明, 有吉 範高, 横須賀 收, 石井 伊都子

    TDM研究   31 ( 3 )   166 - 166   2014.5

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  • ボリコナゾールの胸腔内投与が血中濃度に与える影響 Reviewed

    山崎 伸吾, 渡邉 哲, 高塚 博一, 横山 威一郎, 亀井 克彦, 田川 哲三, 溝渕 輝明, 鈴木 貴明, 有吉 範高, 石井 伊都子

    日本化学療法学会雑誌   62 ( Suppl.A )   284 - 284   2014.5

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  • Functional characterization of seven single-nucleotide polymorphisms of the steroid sulfatase gene found in a Japanese population Reviewed

    MATSUMOTO Jun, ARIYOSHI Noritaka, ISHII Itsuko, KITADA Mitsukazu

    Journal of human genetics   58 ( 5 )   267 - 272   2013.5

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  • 遺伝子検査と薬物治療

    有吉 範高

    日本病院薬剤師会雑誌   49 ( 4 )   351 - 357   2013.4

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    分子生物学の進展によるヒト化技術の成功により多数の抗体医薬品が発売され、低分子の医薬品開発においても、癌の領域を中心に分子標的薬が次々に開発・上市されている。体細胞変異および遺伝子多型の両者が薬物応答性と関連していることが明らかになった今、これらの情報を無視して医薬品の適正使用を行うことは困難になりつつある。分子標的薬の投与適格性にかかわる遺伝子検出、遺伝子増幅確認、薬物応答性と関連する体細胞変異について述べた。

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  • 簡易遺伝子診断法の開発・実臨床への適用による医薬品適正使用の推進

    有吉 範高

    医療薬学   39 ( 2 )   61 - 76   2013.2

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    薬物応答性の個体差をもたらす原因に関する研究は、分子レベルから遺伝子レベルへの時代に突入した。2000年から開始されたミレニアム・ゲノム・プロジェクトや、ファルマスニップコンソーシアムによる研究を皮切りに、今日まで多数の大型プロジェクトが実施されている。大型プロジェクトがもたらしたもの、研究成果が医療現場でなかなか活かせない理由、医療現場における遺伝子多型診断の実際、薬物応答性の個体差をもたらす多型以外の遺伝子情報、遺伝子診断を取り入れた臨床研究について述べた。

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  • Development of a simple method for detection of the HLA-A*31:01 allele Reviewed

    Kazuki Uchiyama, Fumika Kubota, Noritaka Ariyoshi, Jun Matsumoto, Itsuko Ishii, Mitsukazu Kitada

    Drug Metab Pharmacokinet .   28 ( 5 )   435 - 438   2013

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  • 眼科クリニカルパスにおける点眼手技評価方法の統一化に向けた取り組み

    山口 洪樹, 三浦 剛, 舩本 智津子, 加藤 陽子, 加瀬 千鶴, 石井 晃, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌   48 ( 11 )   1366 - 1370   2012.11

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    千葉大学医学部附属病院では眼科白内障および硝子体手術のクリニカルパスに薬剤管理指導を導入し、薬剤師と看護師が協働して点眼指導を行ってきた。しかし、患者の点眼手技を評価する際に、評価者側に個人差があることが問題となっていた。新評価法では点眼手順に沿って6項目(手をふく、瞼をふく、目と点眼容器の距離、的外れ、滴下量、涙嚢部圧迫)評価を行うこととし、各項目の達成基準を設定した。達成した度合いに応じて各項目にA〜Dのスコアをつけ看護師と評価を共有した。新評価法導入後の評価を行った結果、評価者側の個人差は減少していることが示唆された。また、眼科看護師へのアンケート結果から新規評価法は抵抗感なく受け入れられており、運用面からも高い評価を得ていると考えられた。以上により、今回作成した点眼手技の新評価法でクリニカルパスにおける点眼指導の標準化と質的向上に貢献することができたと考えられる。(著者抄録)

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  • FPIA法を用いた薬物モニタリングへの蛍光眼底造影剤の干渉 Reviewed

    三浦 剛, 中村 裕義, 山形 真一, 山崎 伸吾, 仲佐 啓詳, 有吉 範高, 山本 修一, 北田 光一

    TDM研究   29 ( 4 )   83 - 88   2012.9

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    我々は、蛍光眼底造影検査(FAG)後の患者の蛍光偏光免疫測定(FPIA)法による血中シクロスポリン(CYA)濃度測定において、バックグラウンドの異常高値により測定不能となった症例を経験した。その原因として、FAGの際に投与された蛍光眼底造影剤フルオレセイン(F)による影響が疑われたため、FPIA法によるCYA、カルバマゼピン(CBZ)および酵素免疫測定法(MEIA法)によるジゴキシン(DIG)濃度測定に及ぼすFの影響について検討を行った。その結果、CYAでは全血液中F濃度が31.25ng/mLまで、CBZでは血清中F濃度は0.5μg/mLまでは薬物の測定値に影響することなく測定可能であったが、この濃度を超過すると測定不能となった。一方、DIGではF濃度が100μg/mLにおいても測定が可能であった。FPIA法による薬物血中濃度測定をFAG実施当日に行う場合には、FAG実施前に採血する必要があると考えられた。(著者抄録)

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  • スナップ・ショットを用いた抗菌薬の適正使用推進の試み 感染制御チームとの連携

    三浦 剛, 中村 裕義, 千葉 均, 井上 智香子, 瀬川 俊介, 渡辺 正治, 渡辺 哲, 石和田 稔彦, 佐藤 武幸, 仲佐 啓詳, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌   48 ( 8 )   977 - 980   2012.8

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    使用において特に注意を要する抗菌薬(以下、特定抗菌薬)の院内における適正使用の推進を目的として、感染制御チーム(以下、ICT)と連携して定点状況調査(以下、スナップ・ショット)を用いた使用状況の把握と病棟担当薬剤師による問題症例に対する介入を試みた。本取り組み開始前後1年間における特定抗菌薬の平均使用件数および14日以上の長期投与件数を比較したところ、いずれも開始後有意な減少が認められた。また、問題症例に対するICTの提言内容は、薬剤の選択と用法・用量の変更を要するものが半数以上を占め、これらの提言に対する遵守率は96%であった。以上、スナップ・ショットを用いた問題症例の抽出と、それに続く病棟担当薬剤師とICTの連携による指導等の取り組みにより、院内における特定抗菌薬の適正使用が推進されたと考えられた。(著者抄録)

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  • 使用実態からみたTPNの適正使用に関する検討

    新井 健一, 山本 晃平, 竹田 真理子, 鍋谷 圭宏, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌   48 ( 7 )   853 - 856   2012.7

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    中心静脈カテーテルを用いた高カロリー輸液(以下、TPN)は、経腸栄養療法に比べ、その使用頻度は減少傾向であるが、消化管を使用できない患者に対しては必要な栄養療法である。本研究では、千葉大学医学部附属病院におけるTPNの使用実態を調査し、問題点を具体化し、適正使用にいかに寄与すべきかを検討した。本調査より、TPN投与期間の短い症例、糖質の投与速度超過、脂肪乳剤の併用不足、投与熱量不足などの実態が明らかとなった。TPNを有益な栄養療法とするために、TPN投与における当該患者の適応症の確認、投与速度、必要熱量を体重より算出し、指示が適切でない場合は、適正な情報を提供することが必要であると考えられた。本結果を基に今後医師への医薬品情報(DI)提供、薬剤管理指導、栄養サポートチーム(NST)による院内講習会などを通してTPNの適正使用を推進する必要があると考えられた。(著者抄録)

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  • シクロスポリン細粒の分包調剤後の光安定性に関する検討 Reviewed

    山崎 伸吾, 中村 裕義, 山形 真一, 仲佐 啓詳, 有吉 範高, 北田 光一

    医薬品情報学   14 ( 1 )   35 - 39   2012.5

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    シクロスポリン(CsA)細粒の分包調剤後の光安定性について検討した。700ルクスの白色蛍光灯による光照射を1日12時間行う条件下において3種の保存形態、分包紙のみで被覆のない状態(曝光保存)、外面がパルプで内面をポリエチレンコーティングされた薬袋内に保管(薬袋内保存)、遮光ポリエチレン袋に保管(遮光袋内保存)で実施した。薬袋内あるいは遮光袋内で保管した場合には3ヵ月までは安定であったが、曝光群においては同様の条件下でCsAの外観が白色に変化し、12週後においてわずかながら規格値である残存率(95%)を下回った。3種の保管環境での溶出パターンの変化について検討し、残存率の低下を反映した溶出率の低下は認めたが、溶出パターンには変化は認めなかった。

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  • Correlation between antizyme 1 and differentiation of vascular smooth muscle cells cultured in honeycomb-like type-I collagen matrix Reviewed

    Itsuko Ishii, Takaaki Suzuki, Hiromi Kaneko, Masashi Uchida, Yukari Suzuki, Kyohei Higashi, Satoko Yagi, Noritaka Ariyoshi, Kazuei Igarashi, Mitsukazu Kitada

    Amino Acids   42 ( 2-3 )   565 - 575   2012.2

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    Vascular smooth muscle cells (SMC) are able to proliferate when cultured on plates, but become differentiated when maintained in three-dimensional type I collagen matrices (honeycombs). SMC grown in honeycombs contained a low level of polyamines due to the presence of antizyme 1 (AZ1), a negative regulator of ornithine decarboxylase (ODC) and of polyamine uptake. To clarify the role of AZ1 in differentiation of SMC in honeycombs, an ODC gene was stably transfected into SMC (ODCSMC). Although proliferation of ODC-SMC on plates was accelerated together with an increase in phosphorylated focal adhesion kinase (FAK) and a decrease in a-actin and myosin, maker proteins of differentiation, growth of ODCSMC ceased in honeycombs similarly to normal SMC with a low level of phosphorylated FAK and a high level of a-actin and myosin. AZ1 expression in ODC-SMC on plates was low, but that in honeycombs was high. Antizyme in ODC-SMC in honeycombs not only decreased the level of ODC but also inhibited polyamine uptake activity. These results taken together suggest that low levels of polyamines caused by AZ1 in SMC in honeycombs inhibit phosphorylation of FAK and enhance expression of a-actin and myosin, resulting in differentiation through inhibition of focal adhesions. © Springer-Verlag 2011.

    DOI: 10.1007/s00726-011-1034-8

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  • Q172H Replacement Overcomes Effects on the Metabolism of Cyclophosphamide and Efavirenz Caused by CYP2B6 Variant with Arg262 Reviewed

    Noritaka Ariyoshi, Miyuki Ohara, Mayumi Kaneko, Sakino Afuso, Takuya Kumamoto, Hiroyoshi Nakamura, Itsuko Ishii, Tsutomu Ishikawa, Mitsukazu Kitada

    DRUG METABOLISM AND DISPOSITION   39 ( 11 )   2045 - 2048   2011.11

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    There are a number of reports indicating that CYP2B6*6 (c.516G &gt; T and c.785A &gt; G) is responsible for decreased clearance of efavirenz (EFV), although increased disposition of cyclophosphamide (CPA) in individuals with this polymorphism was observed. Thus, we hypothesized that the effects of the two single nucleotide polymorphisms (SNPs) of CYP2B6*6 on the metabolism of drugs might be considerably different between these two agents. To clarify this possibility, we expressed two major variants of this enzyme, CYP2B6.6 (Q172H and K262R) and CYP2B6.4 (K262R), and investigated metabolic activities of these variants toward EFV and CPA. Kinetic analyses clearly indicated that CYP2B6.4 possessed enhanced metabolic activity toward EFV compared with that of the wild-type enzyme (CYP2B6.1), whereas CPA was metabolized less efficiently by CYP2B6.4 than by CYP2B6.1. On the other hand, CYP2B6.6 showed a completely opposite character, suggesting that Q172H gives inverse effects on metabolic activities of CYP2B6 affected by K262R. Although it is recognized that effects of amino acid change in cytochrome P450 on the metabolic activity depend on substrates, this study revealed SNPs giving an opposite effect on the metabolism of two clinically important drugs currently used. Furthermore, this study provides the first evidence that Q172H can reverse the direction of the effect caused by K262R in CYP2B6 on the metabolism of certain drugs.

    DOI: 10.1124/dmd.111.039586

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  • Degradation of filamin induces contraction of vascular smooth muscle cells in type-I collagen matrix honeycombs Reviewed

    Masashi Uchida, Itsuko Ishii, Kaori Hirata, Fumiko Yamamoto, Kaori Tashiro, Takayoshi Suzuki, Yuji Nakayama, Noritaka Ariyoshi, Mitsukazu Kitada

    Cellular Physiology and Biochemistry   27 ( 6 )   669 - 680   2011

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    Background: Dedifferentiated rabbit vascular smooth muscle cells (SMCs) exhibit similar features to differentiated SMCs when cultured in three-dimensional matrices of type-I collagen called "honeycombs," but the mechanism is unknown. The role of filamin, an actin-binding protein that links actin filaments in SMCs, was investigated. Methods: Filamin and other related proteins were detected by western blot analysis and immunofluorescence staining. Honeycomb size was measured to confirm the contraction of SMCs. Results: Full-length filamin was expressed in subconfluent SMCs cultured on plates
    however, degradation of filamin, which might be regulated by calpain, was observed in confluent SMCs cultured on plates and in honeycombs. While filamin was co-localized with β-actin in subconfluent SMCs grown on plates, filamin was detected in the cytoplasm in SMCs cultured in honeycombs, and degraded filamin was mainly detected in the cytoplasmic fraction of these cells. In addition, β-actin expression was low in the cytoskeletal fraction of SMCs cultured in honeycombs compared with cells cultured on plates, and the size of the honeycombs used for culturing SMCs was significantly reduced. Conclusion: These data suggest that degradation of filamin in SMCs cultured in honeycombs induces structural weakness of β-non-muscle actin filaments, thereby permitting SMCs in honeycombs to achieve contractility. Copyright © 2011 S. Karger AG, Basel.

    DOI: 10.1159/000330076

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  • 薬剤師の観点から見たNutrition Support Team活動の現状と問題点

    新井 健一, 山本 晃平, 鍋谷 圭宏, 櫻井 健一, 古川 勝規, 野本 尚子, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌   46 ( 12 )   1657 - 1660   2010.12

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    千葉大学医学部附属病院では2006年4月よりnutrition support team(以下、NST)活動を開始した。今回我々は、これまでに介入した症例を基に、薬剤師の観点から活動の問題点と今後の課題を検討した。NSTへの依頼内容は、栄養状態の改善と食欲不振対策が全体の60%以上を占め、その患者の多くは悪性腫瘍であった。悪性腫瘍である患者の多くは病態により栄養状態が悪化しており、またがん化学療法を施行している場合には嘔気・嘔吐などの副作用により食欲不振に陥るため介入依頼となっていた。NSTが介入するも、血清アルブミン値(血清ALB値)が低下した症例について検討した結果、がん化学療法による栄養状態悪化が最も多かった。がん化学療法による嘔気・嘔吐対策、食事・経腸栄養剤との相互作用対策など医薬品に関する事例が介入内容に多く認められたため、NSTに属する薬剤師として医薬品の適正使用を推進し、患者の栄養改善に向けた取り組みが必要と考えられた。(著者抄録)

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  • 医薬品の服用時期および最大投与量の設定根拠を迅速に検索できるデータベースの構築と疑義照会への活用

    新井 さやか, 大久保 正人, 石島 彩子, 長谷川 敦, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    医薬品情報学   12 ( 2 )   69 - 76   2010.11

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    添付文書に記載された服用時期および最大投与量の設定根拠となる情報を迅速に検索可能なデータベース(DB)を構築し、その有用性について評価した。採用の内服薬(723品目)のうち、服用時期として、「起床時」「食前」「食直前」「食直後」「食間」「空腹時」の規定のある医薬品38品目、および最大投与量の規定のある184品目を対象とした。服用時期および最大投与量ともに、日常業務において比較的容易に検索可能である添付文書やIFから得られた割合は少なく、50%以上の医薬品で製薬企業への問い合わせが必要であった。設定根拠が不明な医薬品も服用時期で3品目、最大投与量で25品目存在した。服用時・期では二重盲検比較試験の結果に基づいて設定されている医薬品が38品目中17品目ある一方で、販売開始後に出版された雑誌の総説や症例報告などを設定根拠としている医薬品も存在した。稼動当初のDBのレコード数は313件であった。

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  • Kefiran reduces atherosclerosis in rabbits fed a high cholesterol diet. Reviewed

    Masashi Uchida, Itsuko Ishii, Chika Inoue, Yoshie Akisato, Kenta Watanabe, Saori Hosoyama, Toshihiko Toida, Noritaka Ariyoshi, Mitsukazu Kitada

    Journal of atherosclerosis and thrombosis   17 ( 9 )   980 - 8   2010.9

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    AIM: Kefiran is an exopolysaccharide produced by Lactobacillus kefiranofaciens, and has been proposed to have many health-promoting properties. We investigated the antiatherogenic effect of kefiran on rabbits fed a high-cholesterol diet. METHODS: Male New Zealand White rabbits were fed a 0.5% cholesterol diet without (control group, n = 7) or with kefiran (kefiran group, n = 8) for eight weeks. The aorta was analyzed by histochemistry and atherosclerotic lesions were quantified. Lipids and sugars in serum were measured. Foam cell formation of RAW264.7 by βVLDL derived from both groups of rabbits was also investigated. RESULTS: Cholesterol, triglyceride and phospholipids levels of serum and lipoprotein fractions were not significantly different between these groups. Atherosclerotic lesions of the aorta in the kefiran group were statistically lower than those of the control group, with marked differences in the abdominal aorta. T-lymphocytes were not detectable in the aorta of the kefiran group. Cholesterol contents in stools were almost identical in both groups. Cholesterol content in the liver of the kefiran group was statistically lower than in the control group. Galactose content of βVLDL derived from the kefiran group was higher, and the lipid peroxidation level was much lower than in the control group. RAW264.7 macrophages treated with βVLDL from the kefiran group showed a more spherical shape and accumulated statistically lower cholesterol than macrophages treated with βVLDL from the control group. CONCLUSION: Orally derived kefiran is absorbed in the blood. Kefiran prevents the onset and development of atherosclerosis in hypercholesterolemic rabbits by anti-inflammatory and anti-oxidant actions.

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  • Application of Akaike information criterion to evaluate warfarin dosing algorithm. Reviewed International journal

    Takumi Harada, Noritaka Ariyoshi, Hitoshi Shimura, Yasunori Sato, Iichiro Yokoyama, Kaori Takahashi, Shin-ichi Yamagata, Mizuho Imamaki, Yoshio Kobayashi, Itsuko Ishii, Masaru Miyazaki, Mitsukazu Kitada

    Thrombosis research   126 ( 3 )   183 - 90   2010.9

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    INTRODUCTION: Several factors responsible for inter-individual differences in response to warfarin have been confirmed; however, unidentified factors appear to remain. The purpose of this study was to examine a simple method to evaluate whether optional variables are appropriate as factors to improve dosing algorithms. MATERIALS AND METHODS: All patients were Japanese. Genotyping of selected genes was conducted, and other information was obtained from medical record. Dosing algorithms were constructed by multivariate linear regression analyses and were evaluated by the Akaike Information Criterion (AIC). RESULTS AND CONCLUSIONS: Multivariate analysis showed that white blood-cell count (WBC), concomitant use of allopurinol, and CYP4F2 genotype are apparently involved in warfarin dose variation, in addition to well-known factors, such as age and VKORC1 genotype. We evaluated the adequacy of these variables as factors to improve the dosing algorithm using the AIC. Addition of WBC, allopurinol administration and CYP4F2 genotype to the basal algorithm resulted in decreased AIC, suggesting that these factor candidates may contribute to improving the prediction of warfarin maintenance dose. This study is the first to evaluate the warfarin dosing algorithm by AIC. To further improve the dosing algorithm, AIC may be a simple and useful tool to evaluate both the model itself and factors to be incorporated into the algorithm.

    DOI: 10.1016/j.thromres.2010.05.016

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  • Super-acute onset of tumor lysis syndrome accompanied by hypercytokinemia during treatment of Hodgkin's lymphoma with ABVD chemotherapy. Reviewed International journal

    Takaaki Suzuki, Masahiro Takeuchi, Hiromi Saeki, Shingo Yamazaki, Hitomi Koga, Daijiro Abe, Miki Nishimura, Chiaki Nakaseko, Hiromitsu Nakasa, Hiroyoshi Nakamura, Noritaka Ariyoshi, Mitsukazu Kitada

    Clinical therapeutics   32 ( 3 )   527 - 31   2010.3

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    BACKGROUND: Tumor lysis syndrome (TLS) is a group of life-threatening metabolic complications that can occur after initiation of cancer chemotherapy. Onset of TLS in the middle of chemotherapy, however, has not been reported previously in patients with hematologic malignancies. OBJECTIVE: We report a case of a patient who experienced TLS of super-acute onset accompanied by hypercytokinemia during chemotherapy treatment with a combination of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD). CASE SUMMARY: A 36-year-old Japanese man (height, 182 cm; weight, 83 kg; body surface area, 2.04 m(2)) was admitted to the hospital for the treatment of malignant lymphoma (clinical stage IVB Hodgkin's lymphoma). Chemotherapy was initiated using the ABVD regimen (doxorubicin [Adriamycin] 25 mg/m(2) by 30-minute infusion, bleomycin 9 mg/m(2) by 30-minute infusion, vinblastine 6 mg/m(2) by bolus injection, and dacarbazine 375 mg/m(2) by 2-hour infusion). During the dacarbazine infusion, the patient's body temperature rose from 36.5 degrees C to 42 degrees C; he experienced a convulsion and then lost consciousness. The convulsion was not suppressed despite the use of diazepam (5 mg IV twice) and phenytoin (500 mg IV). The patient was then transferred to the intensive care unit and sedated using a continuous infusion of midazolam (10 mg/h). Levels of serum lactate dehydrogenase, aspartate aminotransferase, uric acid, blood urea nitrogen, and creatinine evaluated shortly after the ABVD regimen were outside normal limits. In addition, interleukin-6 (IL-6) concentrations were elevated to 54,220 pg/mL. Continuous hemodiafiltration was immediately performed to lower the elevated levels of IL-6. The next day, IL-6 concentrations decreased to 97 pg/mL, and the patient was weaned from ventilator support and sedation. The patient had no adverse effects after the event. According to the results of an assessment using the Naranjo adverse drug reaction probability scale (score = 3), the development of TLS in this patient was possibly related to the chemotherapy regimen. CONCLUSIONS: ABVD chemotherapy was possibly associated with the super-acute onset of TLS in this patient. In addition, hypercytokinemia occurred with TLS, which led to pyrexia, convulsion, and loss of consciousness.

    DOI: 10.1016/j.clinthera.2010.03.010

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  • Six novel single nucleotide polymorphisms of the steroid sulfatase gene in a Japanese population. Reviewed International journal

    Jun Matsumoto, Noritaka Ariyoshi, Itsuko Ishii, Mitsukazu Kitada

    Drug metabolism and pharmacokinetics   25 ( 4 )   403 - 7   2010

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    Steroid sulfatase (STS) is a microsomal enzyme responsible for the formation of 3beta-hydroxysteroid from the corresponding sulfate conjugates. Screening of all exons, exon-intron boundaries and the 5'-flanking region of the STS gene in 93 healthy Japanese individuals was carried out. Among seven single nucleotide polymorphisms (SNPs) identified in this study, six were novel, including one in the untranslated region of exon 1, one in exon 10, and four in the 5'-flanking region. The nonsynonymous SNP (1647G>A) in exon 10 caused amino-acid replacement, Val476Met, with a frequency of 0.014. The allele frequencies of the other SNPs were 0.071 for 155G>A, 0.007 for -21G>A, 0.014 for -1117T>C, 0.106 for -1588G>A, 0.007 for -2427G>A and 0.007 for -2837T>C.

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  • Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese. Reviewed International journal

    Noritaka Ariyoshi, Yukako Iga, Koji Hirata, Yasunori Sato, Go Miura, Itsuko Ishii, Seiji Nagamori, Mitsukazu Kitada

    Drug metabolism and pharmacokinetics   25 ( 3 )   298 - 306   2010

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    Hepatotoxicity is the most frequent adverse drug reaction (ADR) in Japanese treated with ticlopidine (TP). We investigated the relationship between CYP2B6 haplotype and incidence of TP-induced hepatotoxicity in 114 Japanese patients. Although 4 haplotypes (*1A, *1H, *1J and *6B) accounted for more than 80% of the inferred haplotypes in both control (n=81) and case (n=22) subjects, the prevalence was apparently different: control, *1A>*6B>*1H>*1J and case, *1J>*1H>*1A>*6B. The reporter gene assay for the two SNPs, which comprise the *1H or *1J haplotype, suggested that the *1H and *1J haplotypes may be associated with the increased expression of CYP2B6, probably due to g.-2320T>C. Combination analysis of CYP2B6 and human leukocyte antigen (HLA) haplotypes revealed that individuals possessing CYP2B6*1H or *1J with HLA-A*3303 have the highest susceptibility to TP-induced hepatotoxicity (odds ratio, 38.82; 95%CI, 8.08-196.0, P<0.001). Although this is a preliminary case-control study with some limitations, it is the first example that HLA-induced idiosyncratic ADR may be modified by individual variation in CYP activities.

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  • Unexpected serum level of vancomycin after oral administration in a patient with severe colitis and renal insufficiency. Reviewed International journal

    S Yamazaki, H Nakamura, S Yamagata, G Miura, N Hattori, K Shinozaki, T Sadahiro, A Toyoda, H Nakasa, N Ariyoshi, S Oda, K Harigaya, M Kitada

    International journal of clinical pharmacology and therapeutics   47 ( 11 )   701 - 6   2009.11

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    OBJECTIVE: To report a case in which the serum concentration of vancomycin (VCM) reached the supratherapeutic range following oral administration in a patient with severe pseudomembranous colitis and renal insufficiency. CASE SUMMARY: A 65-year-old, 70 kg weighing man with severe acute pancreatitis and acute renal failure was subjected to continuous hemodiafiltration (CHDF). CHDF could only be performed intermittently because of the unstable circulation dynamic of this patient. After admission, intravenous VCM therapy was initiated. Thereafter, oral VCM administration was begun (0.5 g every 6 h). Despite the discontinuation of intravenous VCM after the first 2 days of oral VCM, the serum VCM concentration increased gradually to 49.8 mg/l over a period of 2 weeks from the initiation of oral administration (34.4 mg/l). Based on pharmacokinetic analysis, the bioavailability of VCM was estimated to over 33%. Autopsy findings indicated broadly distributed necrosis on the lamina propria of the mucosa throughout all parts of the intestine below the duodenum. DISCUSSION: This case indicates necessity of the careful monitoring after oral high-dose VCM administration in a patient with a broadly distributed necrosis and renal insufficiency. CONCLUSIONS: TDM should be considered according to renal function, the severity of enteritis and the total dosage of oral VCM administration.

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  • ワルファリン治療個別化に利用可能な簡易・同時遺伝子診断法の確立

    有吉 範高, 中澤 一純, 北田 光一

    医療薬学   35 ( 8 )   551 - 557   2009.8

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    ワルファリン(Wf)による抗凝固療法はその投与量に個体差が大きく、Wf治療個別化及び医療現場におけるルーチンな遺伝子診断への応用を視野に入れ、遺伝子診断が必須となることが想定されるVKORC1とCYP2C9の簡便な同時遺伝子多型診断法の確立を試みた。その結果、本研究では採血することなく、低侵襲な方法で良質なDNAを得て、その試料で実施できる遺伝子診断を行う新規多型診断法を確立した。本遺伝子診断法ではコスト面や迅速性に問題のあった従来法に比べ、1回のPCRと電気泳動で同時にVKORC1とCYP2C9の遺伝子型の判定結果を正確・簡便・低コストで迅速に得ることが可能である。しかし、Wf感受性は遺伝的要因のみならず患者の生理的要因や食事・併用薬物などの環境要因によっても著しい影響を受けるため、VKORC1やCYP2C9の遺伝子多型情報だけでは患者の維持投与量の正確な事前予測は困難であり、今後さらなる研究が必要と考えられた。

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  • 上皮成長因子受容体(EGFR)体細胞変異の簡易遺伝子診断法開発と臨床応用

    有吉 範高, 伊豫田 明, 廣島 健三, 渋谷 潔, 滝口 裕一, 中谷 行雄, 北田 光一

    医療薬学   35 ( 7 )   468 - 477   2009.7

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    比較的迅速で、コストが安く、感度も満足しうる簡便な上皮成長因子受容体(EGFR)遺伝子変異診断法を開発した。構築した診断法は欠失領域と相補的なプライマーが結合できなくなるため、そのいずれの欠失パターンであっても診断可能である。更にエクソン21のL861Qは、その頻度はL858Rに比べ1/10以下と少ないが、L858R診断のために増幅したPCR産物を別の制限酵素で切断するだけで判定可能である。しかも両エクソン由来の増幅断片は同じPCR条件下で増幅できるように設計してあるため、一度のPCRで3種類の変異箇所の診断に必要な増幅産物を全て知ることができる。PCRのサイクル数は試料から回収されるDNA量によって多少変更が必要であるが十分な品質と量のDNAが得られる試料の場合は30サイクル、FFPE薄切標本を試料とした場合は35〜40サイクルで十分であった。

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  • Growth inhibition and differentiation of cultured smooth muscle cells depend on cellular crossbridges across the tubular lumen of type I collagen matrix honeycombs. Reviewed International journal

    Takaaki Suzuki, Itsuko Ishii, Akira Kotani, Michi Masuda, Kaori Hirata, Madoka Ueda, Takahiro Ogata, Takanori Sakai, Noritaka Ariyoshi, Mitsukazu Kitada

    Microvascular research   77 ( 2 )   143 - 9   2009.3

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    Although rabbit vascular smooth muscle cells (SMCs) showed a differentiated phenotype in three-dimensional type I collagen matrices (honeycombs, diameter of pores=200-500 microm), mouse vascular SMCs proliferated in honeycombs having the same pore size. Here we investigated the relationship between pore sizes of honeycombs and differentiation of SMCs using various pore sizes of honeycombs. Rabbit SMCs (length: 200+/-32 microm) and mouse SMCs (49+/-10 microm) formed crossbridges in honeycombs with 200-300 microm and less than 200 microm of pores, respectively. Both SMCs spread on the inner wall but did not form crossbridges in honeycombs with larger pores. [(3)H]Thymidine incorporation and cell number of both SMCs were decreased when the crossbridges were formed in honeycombs. Because proliferation inhibition and crossbridge formation were observed in the culture of rabbit and mouse SMCs using 200-300 microm and less than 200 microm pore sized honeycombs, respectively, these data suggested that forming crossbridges was important for the inhibition of proliferation of SMCs. Rabbit SMCs differentiation was accompanied by the expression of caldesmon heavy chain when cultured in honeycombs having less than 300 microm pores. Proliferation of mouse SMCs stopped in honeycombs having less than 200 microm pores, but caldesmon heavy chain was not detected despite the expression of its mRNA. Proliferation of SMCs stopped on plates when cells reached confluent state, however, caldesmon heavy chain was not expressed. These data suggested that an appropriate structure and suitable honeycomb pore size are important for the differentiation of SMCs.

    DOI: 10.1016/j.mvr.2008.08.006

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  • 粉砕調剤後の安定性の情報に関する調査・検討

    増田 和司, 今関 美智子, 高橋 香, 大久保 正人, 長谷川 敦, 中村 貴子, 中澤 一純, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    医薬品情報学   10 ( 4 )   291 - 297   2009.3

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    錠剤の粉砕後の安定性に関して、現場の薬剤師が得られる情報について調査し、一定の基準を設定し粉砕後の保存可能期間や保存時の注意事項について検討し、粉砕調剤の可否を検討する上での問題点について考察した。粉砕調剤の可否を判断する上で製剤学的に問題がある医薬品(徐放性製剤、腸溶性製剤、舌下錠)や粉砕調剤の必要性が低いと考えられる医薬品(速崩壊性製剤など)を除外した364成分406品目を対象とした。製薬企業からの情報提供や文献検索により錠剤の粉砕後の安定性試験の情報を得ることができた医薬品は、257成分269品目であった。このうち226品目の粉砕後の安定性情報は、製薬企業の有する非公表の情報からのみ入手可能であった。安定性を評価するうえで最低限必要と考えられる性状と有効成分含量の両項目が検討されていた医薬品は248成分259品目であった。

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  • 病院薬剤部における調剤インシデントレポート内容の分析に基づいた対策とその効果

    高橋 香, 中澤 一純, 長谷川 敦, 中村 貴子, 中村 裕義, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌   44 ( 12 )   1761 - 1764   2008.12

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    千葉大学医学部附属病院薬剤部調剤室では、調剤薬の最終鑑査で発見されたレベル0のインシデント事例について収集を行ってきた。今回その事例を分析し、調剤ミスを回避するための対策を実施することで、ミスの発生がどのように変化したか調査した。平成14,15および17年度においてレベル0のインシデント事例を基に採用薬の見直し、医薬品の配置変更や処方せんへの印字工夫などの対策を行った。その結果、調剤ミス発生率は経年的に低下し、診療科別でもほとんどの診療科で低下傾向を認めた。また曜日別では、どの年度においても月曜日に高く水曜日に低い傾向を示したが、平成17年度はすべての曜日において低値であった。以上のことより、レベル0のインシデント事例を収集・分析し対策を講じることにより、調剤ミスをより一層減少させることが可能であることが示された。(著者抄録)

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  • レトロスペクティブ調査からAnti-Methiciliin-Resistant Staphylococcus aureus Agentsの適正使用を考える 起炎菌・検査値・therapeutic drug monitoringを用いた薬剤使用前後における検討

    中村 安孝, 横山 威一郎, 橋本 典子, 長谷川 敦, 仲佐 啓詳, 中村 裕義, 渡辺 正治, 野村 文夫, 渡邊 哲, 猪狩 英俊, 佐藤 武幸, 中澤 一純, 有吉 範高, 北田 光一

    薬学雑誌   128 ( 7 )   1073 - 1079   2008.7

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    千葉大学医学部附属病院における抗メチシリン抵抗性S.aureus剤(抗MRSA剤)の2001〜2005年迄の5年間の使用記録から、4日以上使用した症例を集めた。それぞれの症例について抗MRSA剤投与前後の細菌検査、臨床検査データとTDMが行われたかどうかを調べた。抗MRSA剤のうちで硫酸アルベカシンを除いて、塩酸バンコマイシンとテイコプラニンを投与した患者数と薬剤量が年ごとに増加する傾向が認められた。抗MRSA剤投与によって体温、C反応性蛋白質、白血球数が有意に低下した。抗MRSA剤投与患者の75.6%で細菌検査が行われ、そのうち72.4%でMRSAが検出された。TDMが行われた患者の割合は60%で、他の検査に比べて僅かしか検査されていなかった。抗MRSA薬がMRSA以外の起炎菌にも使用され、一部治療終了後も保菌状態であることが確認された。TDMにより適正な治療域へ早期に導く必要性があると推察された。

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  • Probable interaction between warfarin and antitumor agents used in R-ESHAP chemotherapy. Reviewed International journal

    Takaaki Suzuki, Hitomi Koga, Shingo Yamazaki, Hiromi Saeki, Hiroaki Tanaka, Miki Nishimura, Chiaki Nakaseko, Hiromitsu Nakasa, Hiroyoshi Nakamura, Noritaka Ariyoshi, Mitsukazu Kitada

    Clinical therapeutics   30 ( 6 )   1155 - 9   2008.6

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    BACKGROUND: The pharmacologic effects of warfarin might be altered by various factors, including drug-drug interaction. CASE SUMMARY: A 49-year-old Japanese man (height, 174 cm; weight, 68 kg) presented with a 20-month history of malignant lymphoma (diffuse large B cell lymphoma, clinical stage IV). He was treated with a combination of rituximab chemotherapy and etoposide, cisplatin, high-dose cytarabine, and methyl-prednisolone (R-ESHAP). He had been receiving warfarin for the secondary prevention of pulmonary embolism with deep venous thrombosis. When R-ESHAP was started, international normalized ratio (INR) increased from 1 to 5. This phenomenon was observed again in the second R-ESHAP. The INR was increased from 2.44 to 4.71 during chemotherapy but was returned to within the normal range (1.05; normal range: 0.81-1.009) 5 days after chemotherapy was completed. CONCLUSION: In this patient, R-ESHAP chemotherapy might have affected warfarin anticoagulation sensitivity; thus, careful monitoring of INR is essential, particularly in patients receiving warfarin who undergo R-ESHAP chemotherapy.

    DOI: 10.1016/j.clinthera.2008.06.008

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  • 当院における術後感染予防薬の使用状況と本邦ガイドラインとの比較検討

    橋本 典子, 中村 安孝, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    医薬品情報学   10 ( 1 )   48 - 52   2008.5

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    当院における術後感染予防のための抗菌薬使用状況を調査し、日本感染症学会「抗菌薬使用のガイドライン」(GL)と比較した。対象期間の手術5111件のうち、4060件で抗菌薬が使用され、第一世代セフェム系が32.4%と最も多かった。使用状況の評価で、薬剤種類については70.2%がGLの推奨範囲内であったが、使用期間は23.5%が推奨範囲内であった。手術の種類別にみると、使用薬剤・期間ともGLの推奨範囲内であった割合が高かったのは乳腺・甲状腺外科97.9%、食道・胃腸外科の胃切除術83.9%であった。一方、使用薬剤が推奨範囲外であった割合が50%以上は食道・胃腸外科(食道手術)と呼吸器外科(胸腔鏡下・開胸手術)で、食道手術では推奨よりもスペクトルの広いフロモキセフが、呼吸器外科では推奨にないアンピシリン/スルバクタムが使用されていた。使用期間については眼科、心臓血管外科、循環器内科、周産期・母性科、呼吸器外科(胸腔鏡下・開胸手術)で推奨範囲外が多かった。

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  • Population pharmacokinetics of oral busulfan in young Japanese children before hematopoietic stem cell transplantation. Reviewed International journal

    Hiroyoshi Nakamura, Takeyuki Sato, Kenji Okada, Go Miura, Noritaka Ariyoshi, Kazuyoshi Nakazawa, Mitsukazu Kitada

    Therapeutic drug monitoring   30 ( 1 )   75 - 83   2008.2

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    The objectives of this study were to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of busulfan in Japanese pediatric patients who received high-dose oral busulfan as a conditioning regimen before hematopoietic stem cell transplantation. Population analysis was performed using retrospective therapeutic drug monitoring data (including test dose data) from 103 children. Their ages ranged from 2 months to 11 years old (mean age, 30 months; median age, 18 months). The plasma concentration of busulfan in all 1028 samples was measured with the same high-performance liquid chromatography method. Maximum likelihood estimates were sought for pharmacokinetic parameters with the NONMEM program. The best structural covariate-free model for busulfan was a one-compartment model with an exponential error model to account for intersubject variability and a proportional error model to account for intrasubject variability. The apparent oral clearance was found to be correlated with age, aspartate transaminase, and type of disease (malignant disease or other). The apparent volume of distribution was related to body weight. The busulfan formulation (1% powder form or crystal form) and dose (milligrams per kilogram) influenced the absorption rate constant. It was estimated that oral clearance expressed per kilogram of body weight is low at early infancy, then increases to a maximum at approximately 2 years of age and, thereafter, decreases. In conclusion, we have developed a population pharmacokinetic model of oral busulfan in children, particularly for those younger than 4 years old, that takes into consideration not only body size, but also several other covariates.

    DOI: 10.1097/FTD.0b013e3181621cde

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  • 医薬品数量管理システム構築と医薬品購入費および業務効率に対する効果

    大久保 正人, 増田 和司, 長谷川 敦, 中村 貴子, 野口 昇, 中村 裕義, 中澤 一純, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌   44 ( 2 )   233 - 236   2008.2

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    医薬分業の進展により院内で調剤される医薬品数量は減少したが、投与日数制限が原則撤廃されたために一度に処方される数量は増加しており、調剤室に置く医薬品数量の調整が新たな課題となっている。そこで、本研究では調剤室の医薬品数量の適正化を目的として、病院情報システムのデータを利用した医薬品請求システムの構築を試みた。まず、処方オーダリングシステムのデータから対象医薬品の処方量を医薬品別・月別に集計し、適正な一回請求量の設定と不動医薬品の選別化を行った。次に、処方が低頻度な高額医薬品の管理のために、患者の次回来院予定日を電子カルテから検索するシステムを構築した。これらのシステム稼動前後で、年度末棚卸金額は40.4%減少、特に外用剤では54.8%と著しく減少した。一方で、臨時発注件数には顕著な増加は認められず、今回の取り組みが在庫適正化に寄与したと考えられた。(著者抄録)

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  • Relationship between Kaposi's varicelliform eruption in Japanese patients with atopic dermatitis treated with tacrolimus ointment and genetic polymorphisms in the IL-18 gene promoter region. Reviewed International journal

    Kouji Osawa, Takafumi Etoh, Noritaka Ariyoshi, Itsuko Ishii, Michteru Ohtani, Satoru Kariya, Katsuyoshi Uchino, Mitsukazu Kitada

    The Journal of dermatology   34 ( 8 )   531 - 6   2007.8

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    Kaposi's varicelliform eruption is the most important problem in treating patients with atopic dermatitis (AD) with tacrolimus ointment. It has been considered that Kaposi's varicelliform eruption occurs due to decreased levels of interleukin (IL)-18. The aim of this study was to examine the relationship between Kaposi's varicelliform eruption and genetic polymorphisms in the IL-18 gene. IL-18 gene promoter polymorphisms were analyzed in 21 AD patients treated with tacrolimus ointment and in 100 healthy volunteers. Six AD patients with Kaposi's varicelliform eruption during the treatment with tacrolimus ointment showed significantly higher frequency in G-to-C mutations at the IL-18 gene promoter region -137 compared with 15 AD patients without Kaposi's varicelliform eruption. The 15 AD patients without Kaposi's varicelliform eruption as well as 100 healthy volunteers did not have mutations of G-to-C at the IL-18 gene promoter region -137. These results suggest that the onset of Kaposi's varicelliform eruption following the treatment with tacrolimus ointment is associated with the mutation of G-to-C in the IL-18 gene promoter region -137, and that caution is required when using tacrolimus ointment for treating AD patients with this mutation.

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  • 院外処方内容に関するチェックシート機能の利用とデータベース構築

    長谷川 敦, 小林 えり, 近藤 夏未, 木村 真春, 松島 徹, 中村 貴子, 中澤 一純, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌   43 ( 8 )   1087 - 1089   2007.8

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    千葉大学医学部附属病院(以下、当院)薬剤部では、当院における院内・院外処方せんについて相互作用の可能性のある医薬品が併用された場合や複数の診療科から重複して薬が処方された場合に、チェックシートが出力されるシステムを利用している。しかし、このチェックシートに基づいて疑義照会を行う際、過去に問い合わせた内容であるか否かが判断できないため、処方鑑査の質は向上したものの、業務の効率化という点では問題を残していた。そこで今回、院外処方に対するチェックシートに関する照会事項をデータベース化した。その結果、データベースを利用することで同一内容の疑義照会を回避でき、問い合わせを行うか否かの判断も容易となった。また、チェックシートを基に疑義照会を行うことで処方内容に変更が生じ、その後のチェックシートの出力枚数が減少し、さらには保険薬局からの問い合わせの減少にもつながり、業務の効率化に貢献できることがわかった。(著者抄録)

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  • Identification and partial characterization of a novel CYP2C9 splicing variant encoding a protein lacking eight amino acid residues. Reviewed International journal

    Noritaka Ariyoshi, Yoko Shimizu, Yukari Kobayashi, Hiroyoshi Nakamura, Hiromitsu Nakasa, Kazuyoshi Nakazawa, Itsuko Ishii, Mitsukazu Kitada

    Drug metabolism and pharmacokinetics   22 ( 3 )   187 - 94   2007.6

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    CYP2C9 is known as an enzyme responsible for the metabolism of various clinically important drugs. Recently, we cloned a cDNA corresponding to a CYP2C9 splicing variant (SV), which seemed to have an open reading frame of a protein with 482 amino acid residues. To investigate whether or not the SV can be translated as a functionally active protein, we expressed the CYP2C9SV in insect cells, and spectrophotometric and enzymatic properties were characterized. The CYP2C9SV protein showed a typical reduced CO-difference spectrum, indicating that the translated protein binds a heme moiety. However, CYP2C9SV did not metabolize tolbutamide or diclofenac at all, suggesting that the SV protein appeared to lack the ability to catalyze reactions mediated by CYP2C9. Although the CYP2C9SV mRNA was detected in all human liver samples examined in this study by real-time PCR, the level was generally low, ranging between 0.7 and 9.6% of the normal CYP2C9 mRNA. These results suggest that the CYP2C9SV protein is unlikely to contribute to CYP2C9 activities, although it appears to be expressed in most individuals.

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  • Helices F-G are important for the substrate specificities of CYP3A7 Reviewed

    Nao Torimoto, Itsuko Ishii, Ken-Ichi Toyama, Masayuki Hata, Kanako Tanaka, Hitoshi Shimomura, Hiroyoshi Nakamura, Noritaka Ariyoshi, Shigeru Ohmori, Mitsukazu Kitada

    DRUG METABOLISM AND DISPOSITION   35 ( 3 )   484 - 492   2007.3

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    CYP3A7 is a member of the human CYP3A family and a major form of P450 expressed in human fetal livers. Although CYP3A7 shares nearly 90% base sequence with CYP3A4, CYP3A7 shows striking functional differences in the catalytic preference for several substrates, such as dehydroepiandrosterone ( DHEA) or dehydroepiandrosterone 3-sulfate (DHEA-3S). First, to clarify the reason for the differences between CYP3A7 and CYP3A4, a homology model of CYP3A7 was constructed using the CYP3A4 crystal structure. Because these two structures were similar, four kinds of chimeric enzymes were constructed to determine which sequences are important for exhibiting the characteristics of CYP3A7. The results of kinetic analysis of DHEA and DHEA-3S 16 alpha-hydroxylations by CYP3A7, CYP3A4, and CYP3A chimeras suggested that the amino acid residues from Leu210 to Glu279 were important to express the specificity for substrates as CYP3A7. This region was on the F and G helices of the modeled CYP3A7. Furthermore, to assess which amino acid in this sequence is important for the substrate specificity of CYP3A7, a one-point mutation of CYP3A7 to CYP3A4 was made by site-directed mutagenesis. The mutants of K224T and K244E had lost DHEA and DHEA-3S 16 alpha-hydroxylation activities. The mutants also greatly decreased the metabolism of testosterone, erythromycin, nevirapine, and triazolam relative to those activities of CYP3A7 wild-type enzyme. From these results, it is expected that CYP3A7 can recognize specific substrates using the lysines in F-G loops.

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  • Theoretical calculation of triazolam hydroxylation and endogenous steroid inhibition in the active site of CYP3A4. Reviewed International journal

    Nao Torimoto, Itsuko Ishii, Masayuki Hata, Yukari Kobayashi, Hiroyoshi Nakamura, Noritaka Ariyoshi, Mitsukazu Kitada

    Biochimica et biophysica acta   1774 ( 2 )   223 - 32   2007.2

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    CYP3A4 has unusual kinetic characteristics because it has a large active site. CYP3A4 produced more 4-hydroxytriazolam than alpha-hydroxytriazolam at concentrations of more than 60 muM triazolam, and different steroids had different inhibitory effects on the system. To clarify these interesting observations, the interactions between substrate and substrate/steroid were investigated by theoretical calculations. When two triazolam molecules were docked into the active site, the distance between the O-atom and the 4-hydroxylated site was less than the distance to the alpha-hydroxylated site because of interaction between the two triazolam molecules. Estradiol inhibited both alpha- and 4-hydroxytriazolam formation by 50%. Dehydroepiandrosterone (DHEA) inhibited alpha-hydroxylation more than 4-hydroxytriazolam formation, whereas aldosterone had no effect. When one triazolam molecule and one steroid molecule were simultaneously docked, estradiol increased the distance between the O-atom and the two hydroxylated sites, DHEA only increased the distance between the O-atom and alpha-hydroxylated site, and aldosterone did not change the distances. The relevant angles of Fe-O-C in the hydroxylated site of triazolam also widened, together with increased distance. These findings indicate that formation of a substrate and substrate/effector complex in the active site may be a factor for determining the enzyme kinetic parameters of CYP3A4.

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  • 資料に基づく後発医薬品の評価 プラバスタチンナトリウムおよびシンバスタチン製剤の比較

    久保 さやか, 中澤 一純, 長谷川 敦, 岡田 賢二, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌   42 ( 2 )   219 - 223   2006.2

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    資料に基づく後発医薬品の評価としてHMG-CoA還元酵素阻害剤のプラバスタチンナトリウムとシンバスタチン製剤を比較した.方法は,プラバスタチンナトリウム製剤22製品およびシンバスタチン製剤12製品の添付文書,インタビューフォームを用いて情報の評価を行なった.1)添付文書,インタビューフォーム記載事項はいずれも製剤間で異なっており,先発品は全ての調査項目について記載されていたが,後発品では吸収速度定数(Ka),消失速度定数(Ke),クリアランス(CL),分布容積(Vd)が記載されているのはプラバスタチンナトリウムで4割以下,シンバスタチンで5割以下であった.2)添加物では,両製剤とも9割以上の後発品で記載があったが,記載のないもの,製剤により添加物が違うものを認めた.3)安全性では,先発品ほど詳細な検討が行われていない後発品が過半数を占め,条件設定も製剤間で異なり,資料請求電話番号なしが7割を占めていた.4)単回投与での血中濃度推移は製剤間で大きなばらつきを認めた.以上,先発品も含め,情報提供のあり方に課題があると考えられた

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  • CYP1A1 is a major enzyme responsible for the metabolism of granisetron in human liver microsomes Reviewed

    H Nakamura, N Ariyoshi, K Okada, H Nakasa, K Nakazawa, M Kitada

    CURRENT DRUG METABOLISM   6 ( 5 )   469 - 480   2005.10

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    Granisetron, a potent 5-HT3 receptor antagonist, has been reported to be mainly metabolized to 7-hydroxygranisetron and a lesser extent to 9'-desmethylgranisetron in humans. A previous study indicated that cytochrome P450 (CYP)3A4 is a major catalyst of 9'-demethylation, although the major CYP isoform(s) responsible for 7-hydroxylation are unknown. To clarify granisetron 7-hydroxylase, the in vitro metabolism of granisetron using expressed human CYPs and human liver microsomes was investigated. 7-Hydroxygranisetron was produced almost exclusively by CYP1A1, while, apparently, 9'-desmethylgranisetron was preferentially produced by CYP3A4. Marked inter-individual differences in the ratio of the formation of 7-hydroxygranisetron and 9'-desmethylgranisetron in human liver microsomes was observed. Granisetron 7-hydroxylase activity was strongly correlated with benzo[a]pyrene 3-hydroxylase activity (p &lt; 0.0001), but not with testosterone 6 beta-hydroxylase activity in human liver microsomes. Furthermore, an anti-human CYP I A I antibody completely inhibited 7-hydroxylation in human liver microsomes, however, the reaction was not inhibited at all by an anti-CYP3A4 antibody. On the other hand, granisetron 9'-demethylase activity correlated significantly not only with testosterone 6 beta-hydroxylase activity (p &lt; 0.0001) but also with benzo[a]pyrene 3-hydroxylase activity (p &lt; 0.01). Consistent with this, both the anti-CYP1A1 and anti-human CYP3A4 antibodies inhibited the 9'-demethylase activity. These data indicate that CYP1A1 is a major enzyme responsible for the metabolism of granisetron via a main 7-hydroxylation pathway and an alternative 9'-demethylation route. This is the first report demonstrating the substantial contribution of CYP1A1 to the metabolism of a drug, although its role in the metabolism of environmental compounds is well established.

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  • 造血幹細胞移植施行患者におけるフルコナゾール血中濃度モニタリングの有用性に関する検討

    鈴木 貴詞, 岡田 賢二, 中村 裕義, 有吉 範高, 中澤 一純, 北田 光一

    TDM研究   22 ( 4 )   322 - 327   2005.10

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    造血幹細胞移植(HSCT)施行患者に対し,フルコナゾール(FLCZ)は深在性真菌症予防の目的で高用量が長期間投与される.HSCT施行患者では免疫抑制剤など腎毒性の高い薬物が投与されるため,腎排泄型薬物であるFLCZの血中濃度の上昇を来し,副作用を生じる恐れがある.そこで,HSCT施行患者を対象として血漿中FLCZ濃度の測定を行い,FLCZ血中濃度モニタリングの有用性について検討を行った.今回対象とした7名の患者のいずれにおいても,腎機能低下に伴うと考えられる血漿中FLCZ濃度の上昇が認められたが,その上昇の程度は患者間で大きく異なっていた.現在FLCZの添付文書には,クレアチニンクリアランスが50ml/min以下の患者には投与量を半減するように記載されているが,本方法では,患者個々に対する至適投与量の設定は困難と推察された.したがって,腎機能の低下が頻発するHSCT施行患者におけるFLCZ血中濃度モニタリングの施行は適正使用の観点から望ましいと考えられた(著者抄録)

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  • Inhibitory effects of nicardipine to cytochrome P450 (CYP) in human liver microsomes. Reviewed

    Katsunori Nakamura, Noritaka Ariyoshi, Takafumi Iwatsubo, Yasuhisa Fukunaga, Saburou Higuchi, Kunio Itoh, Noriaki Shimada, Kazuo Nagashima, Tsuyoshi Yokoi, Koujirou Yamamoto, Ryuya Horiuchi, Tetsuya Kamataki

    Biological & pharmaceutical bulletin   28 ( 5 )   882 - 5   2005.5

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    To anticipate drug-drug interactions by nicardipine in vivo, cytochrome P450 (CYP) forms responsible for the metabolism of nicardipine and inhibition of CYP-dependent drug metabolism by nicardipine were investigated. Microsomes of human B-lymphoblastoid cells expressing each human CYP form were used for the metabolism of nicardipine. Inhibitory effects of nicardipine on drug metabolism were studied using human liver microsomes. CYP2C8, CYP2D6 and CYP3A4 were identified as major CYP forms for the metabolism of nicardipine in human liver microsomes. Nicardipine strongly inhibited two-pathways of triazolam hydroxylation both catalyzed by CYP3A4. Comparison of three Ca(2+) antagonists, nicardipine, nifedipine, and diltiazem revealed that only nicardipine showed such a strong inhibitory potency on the typical CYP2D6-catalyzed drug metabolism. Furthermore, nicardipine inhibited other reactions catalyzed by CYP1A, CYP2A6, CYP2C8, CYP2C9 and CYP2C19 with K(i) values ranging from 1.1 to 29.4 microM. In conclusion, nicardipine was a relatively potent inhibitor of human CYP2D6, CYP3A4 and CYP2C (especially for CYP2C8 and CYP2C19) in vitro, suggesting that drug-drug interactions between nicardipine and other drugs metabolized mainly by these CYP forms appear to occur in vivo.

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  • 血液透析患者におけるアルベカシンの投与設計

    岡田 賢二, 鈴木 貴詞, 中村 裕義, 石川 耕, 有吉 範高, 中澤 一純, 齋藤 康, 北田 光一

    TDM研究   22 ( 1 )   27 - 33   2005.1

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    45歳男.2型糖尿病,慢性腎不全,右下腿潰瘍,MRSA骨髄炎であった.慢性腎不全による浮腫を軽減する目的で,週3回,1回4時間の血液透析(HD)を施行した.右下腿潰瘍部よりMRSAおよびP.aeruginosaを検出した.HDスケジュールを考慮したアルベカシン(ABK)の投与設計を試みた.HD施行3時間前にABKを投与することによって,ピーク濃度を約9〜10μg/mlで数時間持続させ,かつトラフ濃度を2μg/ml付近まで低下させることを可能にした.しかし,体温とCRPの低下は認めたが,MRSAの消失には至らなかった

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  • 心臓血管外科手術後患者に対するアンジオテンシン変換酵素阻害薬およびアンジオテンシンII受容体拮抗薬使用成績

    公手 妙, 中村 貴子, 仲佐 啓詳, 石井 晃, 中澤 一純, 有吉 範高, 今牧 瑞浦, 宮崎 勝, 北田 光一

    日本病院薬剤師会雑誌   40 ( 11 )   1425 - 1427   2004.11

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    アンジオテンシン変換酵素阻害薬(ACEI)およびアンジオテンシンII受容体拮抗薬(ARB)は,高カリウム(K)血症をひき起こすことが知られ,K保持性利尿薬との併用や腎機能低下患者に対する使用では,高K血症を助長させる危険性があり注意が必要である.今回,心臓血管外科手術後の患者におけるACEIあるいはARBの使用と高K血症との関連性について検討した.ACEIおよびARB使用による明らかなK値上昇傾向は認めず,電解質変動への影響が少ない薬剤であることが示唆された.しかし,高K値を示した患者を個々に評価すると,これら薬剤による高K血症の発現が疑われる症例もあり,使用時には十分な注意が必要であると考えられた

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  • Identification of deletion-junction site of CYP2A6*4B allele lacking entire coding region of CYP2A6 in Japanese Reviewed

    N Ariyoshi, H Sekine, K Nakayama, K Saito, A Miyamoto, T Kamataki

    PHARMACOGENETICS   14 ( 10 )   701 - 705   2004.10

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  • Effects of Continuous Ingestion of Green Tea or Grape Seed Extracts on the Pharmacokinetics of Midazolam Reviewed

    NISHIKAWA Masataka, ARIYOSHI Noritaka, KOTANI Akira, ISHII Itsuko, NAKAMURA Hiroyoshi, NAKASA Hiromitsu, IDA Mayuri, NAKAMURA Hideo, KIMURA Nobuhito, KIMURA Maharu, HASEGAWA Atsushi, KUSU Fumiyo, OHMORI Shigeru, NAKAZAWA Kazuyoshi, KITADA Mitsukazu

    Drug Metabolism and Pharmacokinetics   19 ( 4 )   280 - 289   2004.8

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    Limited systematic data on herb-drug interaction are available, despite many opportunities to concomitant use of herb with prescribed drugs. We investigated the effects of 15 herbal extracts in dietary supplements on CYP2C9, CYP2D6 and CYP3A4 activities in human liver microsomes. Strong inhibition of these CYP activities was found by the addition of green tea extracts (GTE) or grape seed extracts (GSE) in vitro. To examine the effects of these extracts on CYP3A activities in vivo, the pharmacokinetics of midazolam (MDZ) was analyzed in rats. Although single treatments with these extracts had negligible effects, 1 week of treatment with them resulted in a significant increase in the ke of intravenously administered MDZ, indicating the induction of CYP3A in the liver. In contrast, 1 week of treatment with GTE, but not GSE, caused a significant increase in the Cmax and AUC0-∞ of orally administered MDZ without change in the t1/2, suggesting a reduction in CYP3A activity in the small intestines. These studies indicate that subchronic ingestion of GTE or GSE may alter the pharmacokinetics of MDZ, and the effects of GTE on CYP3A activity appear opposite between liver and small intestine, which could not be predicted from in vitro experiments.<br>

    DOI: 10.2133/dmpk.19.280

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    Other Link: http://search.jamas.or.jp/link/ui/2006149345

  • The use of urine to clarify the genotype of a patient with toxic phenytoin concentrations who had undergone peripheral blood stem cell transplantation. Reviewed International journal

    Noritaka Ariyoshi, Katsuhiro Sho-no, Miki Nishimura, Michihiro Ito, Hiroyoshi Nakamura, Takayoshi Asai, Yasushi Saitoh, Takashi Ishizaki, Mitsukazu Kitada

    British journal of clinical pharmacology   58 ( 2 )   225 - 6   2004.8

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  • 【健康食品・植物成分の薬物療法への影響】健康食品の薬物動態への影響

    有吉 範高

    日本病院薬剤師会雑誌   40 ( 8 )   955 - 957   2004.8

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  • Direct interaction between substrates and endogenous steroids in the active site may change the activity of cytochrome P450 3A4 Reviewed

    N Torimoto, Ishii, I, M Hata, H Nakamura, H Imada, N Ariyoshi, S Ohmori, T Igarashi, M Kitada

    BIOCHEMISTRY   42 ( 51 )   15068 - 15077   2003.12

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    CYP3A4 exhibits unusual kinetic characteristics that result from the metabolism of multiple substrate including endogenous steroids and some drugs that coexist at the active site. To clarify the mechanism of the effect of endogenous steroids on the drug metabolism, the interaction between substrates, nevirapine (NVP) and carbamazepine (CBZ), and endogenous steroids was investigated by theoretical calculations. When the activities of NVP 2-hydroxylation and CBZ 10,11-epoxidation by expressed CYP3A4 were measured in the presence of steroids, NVP 2-hydroxylation was found to be remarkably increased by aldosterone and inhibited by estradiol. CBZ 10,11-epoxidation was increased by androstenedione. Three-dimensional computer modeling has shown that the active site of CYP3A4 is especially large, permitting access of two substrate molecules. The interactions between NVP and aldosterone and between CBZ and androstenedione were estimated by theoretical calculations assuming the substrate and steroids to be present in the active site at the same time. It was shown that NVP or CBZ would be stably fixed close to the oxygen atom at the sixth ligand of heme by interaction with steroids, suggesting that NVP and CBZ may be hydroxylated more easily due to the interaction with steroids. Estradiol was also expected to interact with NVP via a pi/pi interaction between a benzene ring, in which the NVP hydroxylation site is located, and a benzene ring of estradiol, suggested to inhibit the reaction. From these results, interactions between the substrate and endogenous steroids in the active site may change the activity of CYP3A4.

    DOI: 10.1021/bi034409n

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  • 病院薬剤師と薬局薬剤師の連携 実習型調剤技術懇話会の参加者の評価

    中村 安孝, 仲佐 啓詳, 長谷川 敦, 松島 徹, 木村 真春, 柴田 みづほ, 三浦 剛, 稲野 祥宗, 大塚 知子, 明石 利恵子, 丹野 恵子, 有吉 範高, 中澤 一純, 中村 均, 大森 栄, 北田 光一

    薬学雑誌   123 ( 6 )   463 - 468   2003.6

  • CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids Reviewed

    H Nakamura, N Torimoto, Ishii, I, N Ariyoshi, H Nakasa, S Ohmori, M Kitada

    DRUG METABOLISM AND DISPOSITION   31 ( 4 )   432 - 438   2003.4

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    Recently, we reported that several endogenous steroids affect CYP3A4-mediated drug metabolism, using human adult liver microsomes as an enzyme source. Especially, carbamazepine (CBZ) 10,11-epoxidation is activated by androstenedione (AND). In the present studies, we investigated the effects of endogenous steroids on the activity of CBZ 10,11-epoxidation by expressed CYP3A4 and CYP3A7. When expressed CYP3A4 was used as an enzyme source, the addition of AND to the reaction mixture also caused a drastic increase in the activity of CBZ 10,11-epoxidase, and resulted in a change in the kinetics from sigmoid to Michaelis-Menten type. On the other hand, expressed CYP3A7-mediated CBZ 10,11-epoxidation was activated by sulfate conjugate steroids, such as pregnenolone 3-sulfate, 17alpha-hydroxypregnenolone 3-sulfate, and dehydroepiandrosterone 3-sulfate (DHEA-S), whereas the unconjugated form corresponding to these three steroids did not activate the reaction. Especially, DHEA-S was found to be a potent activator of CBZ 10,11-epoxidation by expressed CYP3A7. The kinetic character of CBZ 10,11-epoxidation by CYP3A7 is Michaelis-Menten type regardless of the presence of DHEA-S. The presence of DHEA-S caused a decrease in K-m and increase in V-max for CYP3A7-mediated CBZ 10,11-epoxidation, whereas DHEA-S 16alpha-hydroxylation was not affected by the coexistence of CBZ. In conclusion, CYP3A4 and CYP3A7-mediated CBZ 10,11-epoxidations are activated by different types of endogenous steroids. This is the first report regarding CYP3A7 cooperativity.

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  • Association of CYP2A6 gene deletion with cigarette smoking status in Japanese adults Reviewed

    Masahiko Ando, Nobuyuki Hamajima, Noritaka Ariyoshi, Tetsuya Kamataki, Keitaro Matsuo, Yoshiyuki Ohno

    Journal of Epidemiology   13 ( 3 )   176 - 181   2003

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    BACKGROUND: Genetic variation of CYP2A6 is shown to alter nicotine metabolism. This study was developed to investigate the genetic influence of the whole deletion-allele of CYP2A6 on active and passive smoking behavior. METHODS: Two hundred and forty Japanese adults, who visited Aichi Cancer Center as outpatients, were genotyped for the wild-type (CYP2A6*1A, CYP2A6*1B) and the whole deletion-type (CYP2A6*4C) polymorphism of CYP2A6. Information about active and passive smoking status was obtained by a self-administered questionnaire. Genetic influence of CYP2A6 polymorphism on smoking behavior was evaluated using the Mantel extension test. RESULTS: The frequency of the deletion allele was 18%. All 8 subjects carrying two deletion alleles had no smoking habit, and the homozygous deletion genotype showed a tendency to correlate with active smoking status after adjustment for sex and age (p=0.054). However, the proportion of never smokers among heterozygous subjects was almost the same as among subjects carrying no deletion allele (54% and 58%, respectively). Furthermore, CYP2A6 genotypes were correlated neither with the number of cigarettes smoked per day nor with the age at starting smoking (p=0.364 and 0.880, respectively). Among never smokers, CYP2A6 genotypes were not correlated with exposure to passive smoking at home or in the workplace (p=0.623 and 0.484, respectively). CONCLUSION: Despite the possible protection against active smoking behavior in subjects homozygous for the deletion allele, the CYP2A6 polymorphism has only a limited impact on public health because no protective effect was found in heterozygous subjects.

    DOI: 10.2188/jea.13.176

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  • New allelic arrangement CYP2D6*36x2 found in a Japanese poor metabolizer of debrisoquine Reviewed

    M Chida, N Ariyoshi, T Yokoi, N Nemoto, M Inaba, M Kinoshita, T Kamataki

    PHARMACOGENETICS   12 ( 8 )   659 - 662   2002.11

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    DOI: 10.1097/00008571-200211000-00011

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  • Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers Reviewed

    N Ariyoshi, M Miyamoto, Y Umetsu, H Kunitoh, H Dosaka-Akita, Y Sawamura, J Yokota, N Nemoto, K Sato, T Kamataki

    CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION   11 ( 9 )   890 - 894   2002.9

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    Cytochrome P450 2A6 (CYP2A6) is the principal enzyme involved in the metabolic activation of tobacco-specific nitrosamines to their ultimate carcinogenic forms and metabolism of nicotine. We investigated the effects of the CYP2A6*4, an entire CYP2A6 gene deletion-type polymorphism, on lung cancer risk and daily cigarette consumption in Japanese male smokers via a hospital-based case control study. The frequency of the CYP2A6*4 variant was compared in 370 lung cancer patients and 380 control smokers. A markedly reduced adjusted odds ratio for lung cancer risk, 0.23 [95 % confidence interval, 0.08-0.67], was seen in the group with homozygous deletion (*4/*4) when the odds ratio for a group with homozygous wild (*1A/*1A) was defined to be 1.00 by logistic regression. The subjects with lung cancer were additionally divided into three groups according to the histological classification of the cancer and examined for an association with the CYP2A6 polymorphism. The *4/ *4 genotype was not found in patients with squamous cell carcinoma (0 of 105) or small cell carcinoma (0 of 44), indicating that subjects with the *4/*4 genotype have low risk for lung cancers, particularly those caused by tobacco smoke. Furthermore, a significant reduction of daily cigarette consumption was observed in smokers with the *4/*4 genotype, suggesting a possibility that complete lack of CYP2A6 appeared to affect the smoking behavior. These data suggest that male smokers possessing the *1A/*1A genotype have higher risk for tobacco-induced lung cancers.

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  • Characterization of a genotype previously designated as CYP2A6 D-type: CYP2A6*4B, another entire gene deletion allele of the CYP2A6 gene in Japanese Reviewed

    N Ariyoshi, H Sekine, K Saito, T Kamataki

    PHARMACOGENETICS   12 ( 6 )   501 - 504   2002.8

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    CYP2A6 is known as an enzyme responsible for the metabolism of several clincally used drugs such as tegafur. Previously, we found two novel genotypes of the CYP2A6 gene, D-type and E-type, and the E-type was clarified to be homozygous for the CYP2A6* 4A allele. On the other hand, since the D-type was reported to lack regions from at least intron 5 to a part of exon 9 of the CYP2A6 gene, it caused a misunderstanding that the D-type would be a partial CYP2A6 gene-deleted allele. In this paper, we demonstrate that the D-type is a genotype heterozygous for the CYP2A6*4A and another novel entire CYP2A6 gene-deleted allele, CYP2A6*4B, by analyzing a Japanese family including parents genotyped as the CYP2A6*4A/4A and CYP2A6* 1A/*4B, respectively.

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  • A novel mutant allele of the CYP2A6 gene (CYP2A6*11) found in a cancer patient who showed poor metabolic phenotype towards tegafur Reviewed

    S Daigo, Y Takahashi, M Fujieda, N Ariyoshi, H Yamazaki, W Koizumi, S Tanabe, K Saigenji, S Nagayama, K Ikeda, Y Nishioka, T Kamataki

    PHARMACOGENETICS   12 ( 4 )   299 - 306   2002.6

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    In a clinical study, a newly developed anticancer drug, TS-1 capsule, which contained tegafur (FT) and 5-chloro-2,4-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase, was orally administered to five gastric cancer patients (patients 1-5). The total area under the plasma FT concentration-time curve in patient 1 was fourfold higher than in other patients. Since cytochrome P450 2A6 (CYP2A6) has been reported to metabolize FT to yield 5-fluorouracil (5-FU), it was postulated that the poor metabolic phenotype of patient 1 was caused by mutations of the CYP2A6 gene. Thus, alleles for the CYP2A6 genes derived from patient 1 were completely sequenced. It was found that one allele was CYP2A6*4C, which was a whole deleted allele for the human CYP2A6 gene. The other allele was a novel mutant allele (CYP2A6*11) in which thymine at nucleotide 670 was changed to cytosine. The nucleotide change caused an amino acid change from serine at residue 224 to proline. To examine whether or not the amino acid change affected CYP2A6 activity, we expressed an intact or mutant CYP2A6 together with NADPH-P450 oxidoreductase in Escherichia coli, and compared the capacity of the wild and mutant enzymes to metabolize FT to 5-FU. The V-max value for FT metabolism by the mutant CYP2A6 was approximately one-half of the value of the intact CYP2A6, although the K-m values were nearly the same. From these results, we conclude that the poor metabolic phenotype of patient 1 was caused by the existence of the two mutant alleles, CYP2A6*4C and the new variant CYP2A6*11.

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  • Activation of microsomal epoxide hydrolase by interaction with cytochromes P450: kinetic analysis of the association and substrate-specific activation of epoxide hydrolase function Reviewed

    K Taura, H Yamada, E Naito, N Ariyoshi, M Mori, K Oguri

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   402 ( 2 )   275 - 280   2002.6

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    The kinetics of the association between cytochrome P450 (P450) and microsomal epoxide hydrolase (mEH) was studied by means of resonant mirror based on the principle of surface plasmon resonance. The dissociation equilibrium constants (KD) for the affinity of P450 enzymes for mEH were estimated by resonant mirror using an optical biosensor cell covalently bound to rat mEH. Comparable KD values were obtained for CYP1A1 and 2131, and these were greater by one order of magnitude than that for the CYP2C11. To clarify the influences of P450 enzymes on the catalytic activity of mEH, the hydrolyzing activity for styrene oxide and benzo(a)pyrene-7,8-oxide [B(a)P-oxide] was analyzed in the presence or absence of P450s. Styrene oxide hydrolysis was activated by all P450s including the CYP1A, 2B, 2C, and 3A subfamilies. In agreement with the association affinity determined by resonant mirror, CYP2C11 tends to have enhanced activity for styrene oxide hydrolysis. On the other hand, B(a)P-oxide hydrolysis was enhanced by only CYP2C11 while CYP1A1 and CYP2B1 had no effect. These results suggest that (1) many P450 enzymes associate nonspecifically with mEH, (2) the CYP2C11 plays a greater role in the association/activation of mEH and (3) the P450-mediated activation of mEH depends upon the substrate of mEH. (C) 2002 Elsevier Science (USA). All rights reserved.

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  • Effects of endogenous steroids on CYP3A4-mediated drug metabolism by human liver microsomes Reviewed

    H Nakamura, H Nakasa, Ishii, I, N Ariyoshi, T Igarashi, S Ohmori, M Kitada

    DRUG METABOLISM AND DISPOSITION   30 ( 5 )   534 - 540   2002.5

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    In the present study, we investigated the effects of 14 endogenous steroids on the CYP3A4-mediated drug metabolism by human liver microsomes in vitro. Nevirapine (NVP) 2-, 12-hydroxylations, carbamazepine (CBZ) 10,11-epoxidation, triazolam (TZM) 1'-, 4-hydroxylations, erythromycin (EM) N-demethylation, and 2-sulphamoylacetylphenol (SMAP) formation from zonisamide (ZNS) were investigated. The activities of the NVP 2-, 12-hydroxylations, the CBZ 10,11-epoxidation, and the TZM 4-hydroxylation were activated by endogenous androgens, such as androstenedione (AND), testosterone, and dehydroepiandrosterone. However, these androgens inhibited EM N-demethylation, TZM 1'-hydroxylation, and SMAP formation. To understand the mechanisms of these effects of androgens on CYP3A4 activities, we performed a kinetic analysis of the metabolism of CBZ and ZNS in the presence or absence of AND using the modified two-site equation model. The addition of AND to the reaction mixture caused a drastic increase in the activity of CBZ 10,11-epoxidase, especially at a low substrate concentration, and resulted in a change in the kinetics from the sigmoid to Michaelis-Menten type. On the other hand, the metabolism of ZNS was strongly inhibited by AND, although no allosteric change was observed in this case. These data demonstrate that endogenous steroids, especially androgens, strongly affect CYP3A4-mediated drug metabolism in vitro. The postulated mechanisms of the interactions between AND and CBZ or ZNS are discussed.

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  • CYP2D6.10 present in human liver microsomes shows low catalytic activity and thermal stability Reviewed

    K Nakamura, N Ariyoshi, T Yokoi, S Ohgiya, M Chida, K Nagashima, K Inoue, T Kodama, N Shimada, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   293 ( 3 )   969 - 973   2002.5

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    Comparing bufuralol 1'-hydroxylase activity among liver microsomes prepared from individuals whose CYP2D6 genotypes had been determined, we found that the activity tended to decrease depending on the number of the CYP2D6*10 allele. Pre-incubation of liver microsomes from individuals homozygous for the CYP2D6*10 allele resulted in a decrease in the enzyme activity more rapidly than those from individuals homozygous for the CYP2D6*1, suggesting that not only the catalytic activity but also the thermal stability of the enzyme appeared to be affected by the genetic polymorphism. To confirm this hypothesis, the kinetic parameters of CYP2D6.1 and CYP2D6.10 were compared for bufuralol 1'-hydroxylation and dextromethorphan O-demethylation using microsomes prepared from yeast transformed with plasmids carrying CYP2D6 cDNAs (*1A and *10B). Kinetic studies of these CYP2D6 forms indicated clear differences in the metabolic activities between the wild (CYP2D6.1) and the mutant enzymes (CYP2D6.10). Bufuralol 1'-hydroxylase activity in microsomes of yeast expressing CYP2D6.10 was rapidly decreased by heat treatment. supporting the idea that the thermal stability of the enzyme was reduced by amino acid replacement from Pro (CYP2D6.1) to Ser (CYP2D6.10). These data strongly suggest that the thermal instability together with the reduced intrinsic clearance of CYP2D6.10 is one of the causes responsible for the known fact that Orientals show lower metabolic activities than Caucasians for drugs metabolized mainly by CYP2D6, because of a high frequency of CYP2D6*10 in Orientals. (C) 2002 Elsevier Science (USA). All rights reserved.

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  • Variation in coumarin 7-hydroxylase activity associated with genetic polymorphism of cytochrome P450 2A6 and the body status of iron stores in adult Thai males and females. Reviewed International journal

    Pailin Ujjin, Soisungwan Satarug, Yuvaree Vanavanitkun, Satoshi Daigo, Noritaka Ariyoshi, Hiroshi Yamazaki, Paul E B Reilly, Michael R Moore, Tetsuya Kamataki

    Pharmacogenetics   12 ( 3 )   241 - 9   2002.4

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    The relationships between catalytic activity of cytochrome P450 2A6 (CYP2A6), polymorphism of CYP2A6 gene, gender and levels of body iron stores were analysed in a sample group of 202 apparently healthy Thais, aged 19-47 years. Eleven individuals were found to have high activity of CYP2A6, judged by the relatively large amounts (11.2-14.6 mg) of 7-hydroyxcoumarin (7-OHC) excreted 3 h following administration of 15 mg of coumarin. Ten individuals, however, did not excrete any 7-OHC. Of these 10, four were found to have no CYP2A6 gene (whole gene deletion; CYP2A6*4 allele). The frequency of the CYP2A6 alleles; *1A, *1B and *4 in the whole sample group was 52, 40 and 8% while the frequency of the CYP2A6 gene types; *1A/*1A, *1A/*1B, *1B/*1B, *1A/*4, *1B/*4, *4/*4 was 29, 41, 16, 7, 5 and 2%. Subjects having CYP2A6*1A/*1B gene-type group were found to have higher rates of coumarin 7-hydroxylation compared with those of the CYP2A6*1B/*1B and CYP2A6*1A/*4 gene types. The inter-individual variability in CYP2A6 catalytic activity was therefore attributed in part to the CYP2A6 genetic polymorphism. Variation in CYP2A6 activity in this sample group was not associated with gender but, interestingly, it did show an inverse association with plasma ferritin; an indicator of body iron stores. Higher rates of coumarin 7-hydroxylation were found in individuals with low body iron stores (plasma ferritin < 20 microg/l) compared with subjects having normal body iron store status. Subjects (n = 16) with iron overload (plasma ferritin > 300 microg/l) also tended to have elevated rates of coumarin 7-hydroxylation. These results suggest an increased CYP2A6 expression in subjects who have excessive body iron stores. Further investigations into the underlying factors that may lead to increased expression of CYP2A6 in association with abnormal body iron stores are currently in progress in our laboratory.

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  • CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka Reviewed

    Z Topcu, Chiba, I, M Fujieda, T Shibata, N Ariyoshi, H Yamazaki, F Sevgican, M Muthumala, H Kobayashi, T Kamataki

    CARCINOGENESIS   23 ( 4 )   595 - 598   2002.4

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    We investigated the relationship between inter-individual difference in CYP2A6 genotype and susceptibility to oral cancer among habitual betel quid chewers in a Sri Lanka population. A total of 286 subjects showing oral malignant or premalignant lesions and 135 control subjects with no lesions were analyzed. The frequency of homozygotes for CYP2A6*4C mutation, a gene deletion type of polymorphism, was significantly lower in the case subjects than the controls. The odds ratio (OR) of the group homozygous for the deletion was significantly lower and calculated to be 0.14 (95% CI; 0.03-0.72). In the allelic base analysis, there was also a significant decrease in the OR of the deletion allele. Our data suggest that deficient CYP2A6 activity due to genetic polymorphism reduces oral cancer risk in betel quid chewers.

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  • Role of human cytochrome P450 (CYP) in the metabolic activation of nitrosamine derivatives: Application of genetically engineered Salmonella expressing human CYP

    T Kamataki, K Fujita, K Nakayama, Y Yamazaki, M Miyamoto, N Ariyoshi

    DRUG METABOLISM REVIEWS   34 ( 3 )   667 - 676   2002

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    The role of human cytochrome P450 (CYP) in the metabolic activation of tobacco-related N-nitrosamines was examined by Salmonella mutation test using a series of genetically engineered Salmonella typhimurium YG7108 strains each co-expressing a form of CYP (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) together with human NADPH-cytochrome P450 reductase. Seven tobacco-related N-nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N-nitrosodiethylamine, N-nitrosopyrrolidine, N-nitrosopiperidine, N-nitrosonornicotine, N-nitrosoanabasine, and N-nitrosoanatabine were used. The CYP2A6 was found to be responsible for the mutagenic activation of essentially all tobacco-related N-nitrosamines examined. On the basis of the evidence, genetic polymorphism of the CYP2A6 gene appeared to be one of the factors determining cancer susceptibility caused by smoking. Previously, we found the whole deletion of the CYP2A6 gene (CYP2A6*4C) as a type of genetic polymorphism in Japanese. We hypothesized that individuals possessing the gene homozygous for CYP2A6*4C were incapable of activating tobacco-related N-nitrosamines and showed lower susceptibility to lung cancer induced by tobacco smoke. Thus, the relationship between the CYP2A6*4C and the susceptibility to the lung cancer was evaluated. The frequency of the CYP2A6*4C was significantly lower in the lung cancer patients than healthy volunteers, suggesting that the subjects carrying the CYP2A6*4C alleles are resistant to carcinogenesis caused by N-nitrosamines because of the poor metabolic activation capacity.
    Taking these results into account, CYP2A6 is an enzyme enhancing lung cancer risk.

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  • The relationship between CYP2A6 gene deletion and susceptibility to oral cancer

    Z Topcu, Chiba, I, M Fujieda, T Shibata, N Ariyoshi, H Yamazaki, F Sevgican, M Muthumala, H Kobayashi, T Kamataki

    DRUG METABOLISM REVIEWS   34   154 - 154   2002

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  • Role of the dioxin-like toxic compound coplanar polychlorinated biphenyl, 3,3 ',4,4 ',5-pentachlorobiphenyl in reducing hepatic alcohol dehydrogenase levels in rats in vivo

    Y Ishii, H Kato, M Hatsumura, T Ishida, N Ariyoshi, H Yamada, K Oguri

    JOURNAL OF HEALTH SCIENCE   47 ( 6 )   575 - 578   2001.12

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    The ability of a dioxin-like toxic compound, coplanar polychlorinated biphenyl, 3,3',4,4',5-pentachlorobiphenyl (PCB126) to reduce the protein level of hepatic class 1 alcohol dehydrogenase (ADH), which plays an important role in the metabolism of ethanol, was studied. Male Wistar rats received PCB126 25 mg/kg i.p. At this dose the compound induces a wasting syndrome. PCB126 administration resulted in a significant suppression of the protein level of class 1 ADH, whereas the difference between free- and pair-fed controls was slight. These results suggest that dioxins also reduce class 1 ADH without involvement of decreased food consumption. These data offer new insights into the toxicity of dioxins via a marked decrease in the level of class 1 ADH.

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  • Relationships between non-occupational cadmium exposure and expression of nine cytochrome P450 forms in human liver and kidney cortex samples Reviewed

    Baker, JR, S Satarug, PEB Reilly, RJ Edwards, N Ariyoshi, T Kamataki, MR Moore, DJ Williams

    BIOCHEMICAL PHARMACOLOGY   62 ( 6 )   713 - 721   2001.9

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    This study was undertaken to assess associations between age, gender, cigarette smoke and non-workplace cadmium exposure, and liver pathology and inter-individual variation in cytochrome P450 (CYP) expression in human tissues. Autopsy specimens of twenty-eight Queensland residents whose ages ranged from 3 to 89 years were analyzed for the presence of nine CYP protein isoforms by immunoblotting. All subjects were Caucasians and their liver cadmium contents ranged from 0.11 to 3.95 kg/g wet weight, while their kidney cadmium contents were in the range of 2 to 63 mug/g wet weight. CYP1A2, CYP2A6, CYP2D6, CYP3A4, and CYP3A5 were detected in liver but not in kidney, and CYP1A1 and CYP1B1 were not found in liver or kidney. Lowered liver CYP2C8/19 protein contents were found to be associated with liver pathology. Importantly, we show elevated levels of CYP2C9 protein to be associated with cadmium accumulation in liver. No mechanism that explains this association is apparent, but there are two possibilities that require further study. One is that variation in CYP2C9 protein levels may be, in part, attributed to an individual's non-workplace exposure to cadmium, or an individual's CYP2C9 genotype may be a risk factor for cadmium accumulation. A positive correlation was found between liver CYP3A4 protein and subject age. Levels of liver CYPIA2 protein, but not other CYP forms, were increased in people more exposed to cigarette smoke, but there was no association between CYPIA2 protein and cadmium. CYP2A6 protein was found in all liver samples and CYP2A6 gene typing indicated the absence of CYP2A6 null allele (CYP2A6(D)) in this sample group, confirming very low prevalence of homozygous CYP2A6(D) in Caucasians. CYP2A6 gene types W/W, WIC, and CIC were not associated with variations in liver microsomal CYP2A6 protein. CYP2D6 protein was absent in all twenty-five kidney samples tested but was detectable in liver samples of all but two subjects, indicating the prevalence of the CYP2D6 null allele (CYP2D6(D)) in this sample group to be about 7%, typical of Caucasian populations. (C) 2001 Elsevier Science Inc. All rights reserved.

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  • Comparison of the levels of enzymes involved in drug metabolism between transgenic or gene-knockout and the parental mice Reviewed

    N Ariyoshi, S Imaoka, K Nakayama, Y Takahashi, K Fujita, Y Funae, T Kamataki

    TOXICOLOGIC PATHOLOGY   29   161 - 172   2001.9

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    Drug-metabolizing enzymes are involved in the metabolic activation or detoxification of carcinogens. To evaluate animals developed as models for alternative carcinogenicity testing, we investigated whether or not a gene manipulation including the transgene of ras and the knocking out of a tumor suppressor gene such as p53 or XPA could alter the expression of representative drug-metabolizing enzymes directly or indirectly. Expression of several isoforms of cytochrome P450 (CYP) in the liver of rasH2, p53 (+/-), Tg. AC, and XPA (-/-) mice with or without treatment of prototype inducer, phenobarbital or 3-methylcholanthrene, was analyzed by Western immunoblotting in comparison with their parental strains of mice. In addition, the activities of 3 major phase II enzymes, UDP-glucronosyltransferase, sulfotransferase, and glutathione S-transferase, were compared between the gene-manipulated and the corresponding parental strains of mice. Results demonstrate that XPA gene knockout appeared to increase constitutive expression of CYP2B and CYP3A isoforms. Overexpression of human c-Ha-ras gene or p53 gene knockout appeared to increase constitutive UGT activity toward 4-nitrophenol. The content or activities of almost all other enzymes examined in the present study do not appear to be affected by the gene manipulation.

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  • 代謝研究は創薬にどう活かされるか レトロスペクティブな評価とプロスペクティブな活用 Cytochrome P450とmEH及びUGTとの蛋白質間相互作用

    田浦 健一郎, 山田 英之, 内藤 絵里, 竹田 修三, 石井 祐次, 有吉 範高, 森 正明, 小栗 一太

    薬物動態   16 ( Suppl. )   S94 - S95   2001.9

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    ラット肝を用いて異種薬物代謝酵素間における蛋白-蛋白相互作用の有無を検討した.その結果,小胞体膜上のcytochrome P450はmEH(microsomal epoxide hydrolase)やUGT(UDP-glucuronosyltransferase)等の異種薬物代謝酵素と相互作用することで多段階の薬物代謝反応を効率的に実行している可能性が示唆された

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  • Relationships between non-occupational cadmium exposure and expression of nine cytochrome P450 forms

    Baker, JR, S Satarug, PEB Reilly, RJ Edwards, N Ariyoshi, T Kamataki, DJ Williams, MR Moore

    TOXICOLOGY   164 ( 1-3 )   61 - 62   2001.7

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  • CYP遺伝子多型解析の病棟業務への応用

    斉藤 嘉津彦, 清水 瓊子, 岡崎 正子, 伊林 至洋, 端 和夫, 前野 康次郎, 石井 清二, 土橋 和文, 島本 和明, 戸田 貴大, 黒澤 菜穂子, 大和田 栄治, 加藤 芳伸, 大山 徹, 梅津 有理, 千田 道洋, 有吉 範高, 鎌滝 哲也, 板谷 幸一

    医療薬学   27 ( 3 )   228 - 234   2001.6

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    脳神経外科で初めて多型解析を利用した例として,脳動静脈奇形の術後に痙攣発作予防の目的で投与されたフェニトインのTDMを行った32歳女の例を提示し,経過及び薬物代謝酵素遺伝子解析後の服薬指導内容を述べた.また薬物代謝酵素遺伝子解析を希望した患者に対する情報提供として使用している「解析結果報告書」及び「解析結果の説明書」を紹介した

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  • コプラナーPCBによる中間代謝への影響 ラット肝サイトソルのトリオースリン酸含量の低下について(Effects of a Highly Toxic Coplanar Polychlorinated Biphenyl, 3,3',4,4',5-Pentachlorobiphenyl on Intermediary Metabolism: Reduced Triose Phosphate Content in Rat Liver Cytosol)

    石井 祐次, 加藤 晴敏, 初村 恵, 石田 卓巳, 有吉 範高, 山田 英之, 小栗 一太

    福岡医学雑誌   92 ( 5 )   190 - 200   2001.5

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    トリオースリン酸代謝酵素群(グリセルアルデヒド-3-リン酸デヒドロゲナーゼ,トリオースリン酸イソメラーゼ,グリセロキナーゼ,トランスアルドラーゼ,及びトランスケトラーゼ)に及ぼす3,3',4,4',5-pentachlorobiphenyl(PenCB)の影響を調べた.又,PenCBによるアルコール脱水素酵素(ADH)の発現抑制が,どの程度トリオースリン酸代謝に影響を及ぼしているかを検討した.PenCB処理により,これら酵素群の活性はいずれも50%程度まで有意に低下していた.ピラゾールで阻害される活性をADH由来とした場合,ADHは約30%の寄与があることが分かり,特にこの部分への抑制が顕著であった.摂餌対照群とPenCB処理群では肝臓中のトリオースリン酸の含量が,自由摂餌群に比べて著しく低かった.PenCB処理によってトリオースリン酸代謝の回転が落ち,栄養を補給してもエネルギーとして利用されにくいシステムが出来ている可能性がある

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  • A novel single nucleotide polymorphism altering stability and activity of CYP2A6

    N Ariyoshi, Y Sawamura, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   281 ( 3 )   810 - 814   2001.3

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    CYP2A6 is known as a major cytochrome P450 (CYP) responsible for the oxidation of nicotine and coumarin in humans. In this study, we explored genetic polymorphisms, which reduce CYP2A6 activity in Japanese. Two novel mutations in exon 9 of the CYP2A6 gene were found. A single nucleotide polymorphism of T1412C and G1454T resulted in Ile471Thr and Arg485Leu substitution, respectively. The frequency of the former variant allele was considerably high (15.7%), while the latter variant appeared to be a rare polymorphism. Heterologous expression of CYP2A6 using a cDNA possessing C instead of T-base at codon 471 in Escherichia coli caused remarkable reduction of the stability of holoenzyme at 37 degreesC. Furthermore, this variant enzyme almost lacked nicotine C-oxidase activity, although coumarin 7-hydroxylase activity was still observed. These data suggest that individuals homozygous for the T1412C variant allele or heterozygous for this and a defect allele such as the CYP2A6*4 may be poor metabolizer of nicotine, but not coumarin. (C) 2001 Academic Press.

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  • A single nucleotide polymorphism of CYP2B6 found in Japanese enhances catalytic activity by autoactivation

    N Ariyoshi, M Miyazaki, K Toide, Y Sawamura, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   281 ( 5 )   1256 - 1260   2001.3

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    A single nucleotide polymorphism (SNP) resulting in a substitution from Gin to His was found in exon 4 of the CYP2B6 gene in Japanese. The frequency of the variant allele was found to be 19.9%. The mutant- and the wild-type enzymes were expressed in Escherichia coli, and the effects of the single amino acid substitution on the catalytic activity were examined by investigating the kinetic profiles of 7-ethoxycoumarin O-deethylase activity. The wild-type enzyme showed typical Michaelis-Menten kinetics, while the mutant-type enzyme represented the sigmoidal kinetics with a higher V-max value compared to that of the wild-type enzyme. Eadie-Hofstee plots further revealed an existence of allosteric effects for the reaction catalyzed by the variant. This is the first evidence demonstrating that only one amino acid substitution, Gln172His, caused by natural SNP enhances the catalytic activity of CYP by obtaining the character of homotropic cooperativity. stool Academic Press.

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  • Genetic polymorphisms of cytochrome P450 2A6 in a case-control study on lung cancer in a French population

    MA Loriot, S Rebuissou, M Oscarson, S Cenee, M Miyamoto, N Ariyoshi, T Kamataki, D Hemon, P Beaune, Stucker, I

    PHARMACOGENETICS   11 ( 1 )   39 - 44   2001.2

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    Cytochrome P450 2A6 (CYP2A6) is involved in the C-oxidation of nicotine and in the metabolic activation of tobacco nitrosamines. Recent data have suggested that CYP2A6 genetic polymorphisms might play a role in tobacco dependence and consumption as well as in lung cancer risk, However, the previously published studies were based on a genotyping method that overestimated the frequencies of deficient alleles, leading to misclassification for the CYP2A6 genotype, In this study, we genotyped DNA from 244 lung cancer patients and from 250 control subjects for CYP2A6 (wild-type allele CYP2A6*1, and two deficient alleles: CYP2A6*2, and CYP2A6*4, the latter corresponding to a deletion of the gene) using a more specific procedure. In this Caucasian population, we found neither a relation between genetically impaired nicotine metabolism and cigarette consumption, nor any modification of lung cancer risk related to the presence of defective CYP2A6 alleles (odds ratio = 1.1, 95% confidence interval = 0.7-1.9). Pharmacogenetics 11:39-44 (C) 2001 Lippincott Williams & Wilkins.

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  • Accumulation of the 1-methyl-4-phenylpyridinium ion in suncus (Suncus murinus) brain: Implication for flavin-containing monooxygenase activity in brain microvessels

    T Mushiroda, N Ariyoshi, T Yokoi, E Takahara, O Nagata, H Kato, T Kamataki

    CHEMICAL RESEARCH IN TOXICOLOGY   14 ( 2 )   228 - 232   2001.2

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    The metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was examined in an effort to evaluate the role of flavin-containing monooxygenase (FMO) expressed in the brain of suncus (Suncus murinus) and rats. MPTP was metabolized to generate both 1-methyl-4-phenylpyridinium ion (MPP+) and MPTP N-oxide by brain homogenates from rats. Although the level of MPP+-producing activity was similar in suncus and rats, a remarkable difference was found between the animal species in MPTP N-oxygenase activity, which was not detectable in brain homogenates from suncus, The concentrations of MPP+ in suncus brain after a single ip administration of MPTP were markedly higher than that in rats, probably because of the lack of FMO activity in the suncus brain. The MPTP N-oxygenase activity of microvessel homogenates of rat brain was 21-fold greater than that of whole brain homogenates. These results suggest that FMO(s) plays a significant role in the detoxification of MPTP in cerebral endothelial cells.

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  • Structural characterization of a new variant of the CYP2A6 gene (CYP2A6*1B) apparently diagnosed as heterozygotes of CYP2A6*1A and CYP2A6*4C

    N Ariyoshi, Y Takahashi, M Miyamoto, Y Umetsu, S Daigo, T Tateishi, S Kobayashi, Y Mizorogi, MA Loriot, Stucker, I, P Beaune, M Kinoshita, T Kamataki

    PHARMACOGENETICS   10 ( 8 )   687 - 693   2000.11

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    During the course of investigating the frequency of a CYP2A6 whole deletion-type polymorphism (CYP2A6*4C) in Japanese, an unexpectedly large population of heterozygotes for CYP2A6*4C and the wild-type (CYP2A6*1A) was found. Cloning of a cDNA encoding CYP2A6 from the liver of individuals judged as heterozygotes for CYP2A6*4C and the CYP2A6*1A was carried out to identify the causal allele(s) responsible for a possible overestimation. A clone isolated from the liver cDNA library possessed 58 bp sequences in the 3'-untranslated region, which was replaced with the corresponding region of the CYP2A7 gene. The same gene conversion existed in the genomic DNA, indicating that the replacement was not a cloning artifact. Based on the gene structure of the allele (CYP2A6*1B), this variant was thought to be one of the causal alleles responsible for overestimation of heterozygotes for CYP2A6*4C and CYP2A6*1A. To investigate this further, we developed a genotyping method which could distinguish the CYP2A6*1A, CYP2A6*1B and CYP2A6*4C alleles from each other. The results clearly showed that CYP2A6*1B was the sole allele responsible for the overestimation. We conclude that the new genotyping method allows determination of six genotypes of the CYP2A6 gene, simultaneously and precisely, in both Oriental and Caucasian populations. Pharmacogenetics 10:687-693 (C) 2000 Lippincott Williams & Wilkins.

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  • A high-level expression of CYP2A in the lung of the suncus (Suncus murinus) and its role in the activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

    T Mushiroda, N Ariyoshi, K Kimura, E Takahara, O Nagata, H Kato, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   269 ( 2 )   393 - 396   2000.3

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    Northern blot analysis of mRNA prepared from the lung of Suncus murinus (suncus), which was classified as an ancestor of primates, revealed that the expression level of cytochrome P450 2A (CYP2A) mRNA was about 100-fold higher than in the lung from rats and mice. To confirm that the pulmonary CYP2A of the suncus had a catalytic activity, the metabolism of a specific substrate for CYP2A6, (+)-cis-3,5-dimethyl-2-(3-pyridyl) thiazolidin-4-one hydrochloride (SM-12502), was determined. The intrinsic clearance for SM-12502 S-oxidation by the suncus lung microsomes was calculated to be 99-fold higher than that by rat liver microsomes. The mutagen-producing activity of a 9000g supernatant fraction prepared from suncus lung was examined using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as a promutagen. The results showed that the suncus lung possessed 82-fold higher mutagen-producing activity than the rat lung, indicating that NNK was efficiently activated by the CYP2A isoform expressed in the suncus lung and that the suncus was a sensitive animal species to the genotoxicity of NNK contained in tobacco smoke. (C) 2000 Academic Press.

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  • A highly toxic coplanar polychlorinated biphenyl compound suppresses Delta 5 and Delta 6 desaturase activities which play key roles in arachidonic acid synthesis in rat liver Reviewed

    K Matsusue, Y Ishii, N Ariyoshi, K Oguri

    CHEMICAL RESEARCH IN TOXICOLOGY   12 ( 12 )   1158 - 1165   1999.12

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    The effect of 3,3',4,4',5-pentacklorobiphenyl (PenCB) on the synthesis of unsaturated fatty acids was studied in male Wistar rats. The arachidonic acid (20:4) content in the total lipids of liver homogenates was significantly reduced on day 5 of PenCB administration, while those of linoleic acid (18:2) and bishomo-gamma-linolenic acid (20:3) were increased. These changes in the total lipids of liver homogenates were observed following doses of PenCB ranging from 0.5 to 25 mg/kg of body weight. The same changes in these fatty acids were seen with four subtypes of microsomal glycerophospholipids in the liver. The marked reduction in the molar ratio of 20:4 to 18:2 in the lipids suggests alteration of the activity of the enzymes responsible for the synthesis of unsaturated fatty acids. The activity of Delta 5 and Delta 6 desaturases (arachidonic acid synthetase) in the liver microsomes was 17 and 13% of that of pair-fed control animals, whereas the activity of 1-acylglycerophosphorylcholine or 1-acylglycerophosphate acyltransferase, which transfers 20:4 or 18:2 to phospholipids, was not affected by the treatment. Thus, the reduction in the level of 20:4 that was observed can be explained by a reduction in desaturase activity. These results are evidence that the coplanar PenCB has a significant effect on the reduced synthesis of physiologically essential long-chain unsaturated fatty acids.

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  • Analysis of the CYP2D6 gene in relation to dextromethorphan O-demethylation capacity in a Japanese population (vol 65, pg 570, 1999)

    T Tateishi, M Chida, N Ariyoshi, Y Mizorogi, T Kamataki, S Kobayashi

    CLINICAL PHARMACOLOGY & THERAPEUTICS   66 ( 6 )   581 - 581   1999.12

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  • CYP2A6 gene deletion reduces susceptibility to lung cancer

    M Miyamoto, Y Umetsu, H Dosaka-Akita, Y Sawamura, J Yokota, H Kunitoh, N Nemoto, K Sato, N Ariyoshi, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   261 ( 3 )   658 - 660   1999.8

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    CYP2A6 is an enzyme with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogen. In the present study, we investigated the relationship between genetic polymorphism of CYP2A6 and lung cancer risk in a case-control study of Japanese subjects. Genotyping of the CYP2A6 gene in both healthy volunteers and lung cancer patients was conducted. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion-type mutation (deletion), which causes lack of the enzyme activity, was lower in the lung cancer patients than in the healthy control subjects. The odds ratio (OR) of the group homozygous for the deletion was significantly lower and calculated to be 0.25 (95% CI; 0.08-0.83) when the OR for the population with homozygotes of the CYP2A6 wild-type gene was defined as 1.00, In the allelic-base analysis, there was also a significant decrease in the OR for the deletion allele, These data suggest that deficient CYP2A6 activity due to genetic polymorphism reduces lung cancer risk. (C) 1999 Academic Press.

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  • Metabolism of 2,3 ',4 ',5-tetrachlorobiphenyl by cytochrome P450 from rats, guinea pigs and hamsters Reviewed

    N Koga, N Kikuichi, T Kanamaru, H Kuroki, K Matsusue, C Ishida, N Ariyoshi, K Oguri, H Yoshimura

    CHEMOSPHERE   37 ( 9-12 )   1895 - 1904   1998.10

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    The metabolism of 2,3',4',5-tetrachlorobiphenyl (TCB) was compared using liver microsomes and six isoforms of cytochrome P450 purified from rats, guinea pigs and hamsters. In microsomal study, the following species differences were observed: 1) Untreated guinea pigs and hamsters but not rats can metabolize this TCB to 3-hydroxy- or 4-hydroxy-2,3',4',5-TCB, 2) Guinea pig microsomes showed only 3-hydroxylating activity, whereas hamster microsomes showed higher activity of 4-hydroxylation than that of 3-hydroxylation. In common with three species, the 3-hydroxylation was accelerated by phenobarbital. The 4-hydroxylation in rats and hamsters was increased by pretreatment with 3-methylcholanthrene and 3,3',4,4',5-pentachlorobiphenyl. The hydroxylation activities of liver microsomes from the three species could be explained by an involvement of different isoforms of cytochrome P450. In addition, it is apparent that hamster CYP1A2 as well as hamster CYP2A8 is involved in the 4-hydroxylation of 2,3',4',5-TCB although it has no activity for 2,2',5,5'-TCB. (C) 1998 Elsevier Science Ltd. All rights reserved.

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  • Highly toxic coplanar PCB126 reduces liver peroxisomal enzyme activities in rats

    N Ariyoshi, M Iwasaki, H Kato, S Tsusaki, M Hamamura, T Ichiki, K Oguri

    ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY   5 ( 3 )   219 - 225   1998.5

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    The effect of the highly toxic coplanar PCB congener, 3,4,5,3',4'-pentachlorobiphenyl (PCB126) on hepatic peroxisomes was studied in rats. The aim of this study was to investigate whether a toxic dose of the dioxin-like coplanar PCB modifies enzyme activities in peroxisomes where plays an important role in lipid metabolism. Treatment with PCB126, at a single i.p. administration of 25 mg/kg which evokes clear suppression of body weight gain, resulted in marked reduction (to about 40-50%) of catalase activity and peroxisomal fatty acyl-CoA beta-oxidizing system. Immunoblotting showed that expression of catalase was greatly reduced by the treatment in parallel with the activity. Light microscopy revealed a drastic reduction in granules possessing peroxidase activity, while electron microscopy demonstrated that no apparent morphological changes had taken place. Thus the reduction in catalase activity caused by PCB126 could be attributable to suppression of protein expression. The marked reduction of these peroxisomal enzyme activities might be related to hyperlipidemia caused by dioxin-related compounds in rats and humans. (C) 1998 Elsevier Science B.V. All rights reserved.

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  • Characterization of the rat Star gene that encodes the predominant 3.5-kilobase pair mRNA - ACTH stimulation of adrenal steroids in vivo precedes elevation of Star mRNA and protein Reviewed

    N Ariyoshi, YC Kim, Artemenko, I, KK Bhattacharyya, CR Jefcoate

    JOURNAL OF BIOLOGICAL CHEMISTRY   273 ( 13 )   7610 - 7619   1998.3

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    The steroidogenic acute regulatory protein (STAR) participates in steroidogenesis through the mitochondrial transfer of cholesterol to cytochrome P450scc. The rat adrenal Star gene is transcribed as a 3.5-kilobase pair (kb) and 1.6 kb mRNA with the larger mRNA predominating (similar to 85% of total) in. vivo, Hypophysectomy (HPX) produced a 3-5-fold decrease in Star mRNA along with a loss of adrenal steroids, whereas P450scc mRNA decreased by less than 2-fold, Adrenocorticotropic hormone (ACTH) treatment of HPX rats maximally stimulated steroidogenesis rates within 5 min with over 10-fold elevation of steady state blood levels occurring within 10 min. For intact rats there was a 5-10-fold larger increase, paralleling previously observed elevations of cholesterol-cytochrome P450scc association and metabolism in subsequently isolated adrenal mitochondria, ACTH did not increase either total STAR protein or a group of modified forms until at least 30 min after completion of acute stimulation, indicating that elevated translation of STAR protein cannot alone mediate this acute stimulation. Parallel slow changes in STAR protein and corticosterone formation after ACTH treatment are consistent with participation of STAR forms as co-regulators of these hormonal responses, ACTH stimulation of HPX rats increased Star mRNA by 2.5-fold within 20 min and by 4.5-fold after 1 h, thus preceding the rise in the STAR protein, A 3.5-kb Star cDNA clone isolated from a rat adrenal cDNA library exhibited a 0.9-kb open reading frame and a 2.5-kb 3'-untranslated region (3'-UTR). The open reading frame sequence differed at only 12 amino acids from that of the mouse Star. The rat Star gene seven exons with exon 7 encoding the entire 2.5 kb of 3'-UTR of the 3,5-kb mRNA. The 3'-UTR sequence suggests that 1.6- and 3,5-kb mRNA are formed by an alternative usage of different polyadenylation signals, Multiple UUAUUUA(U/A)(U/A) motifs also suggest additional regulation through this extended 3'-UTR, Although elevation of STAR protein by ACTH does not cause the acute increase in adrenal cholesterol metabolism, changes in the turnover or distribution of an active STAR subfraction cannot be excluded.

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  • Species-specific alteration of hepatic glucose 6-phosphate dehydrogenase activity with coplanar polychlorinated biphenyl: Evidence for an Ah-receptor-linked mechanism

    M Hori, H Kondo, N Ariyoshi, H Yamada, K Oguri

    CHEMOSPHERE   35 ( 5 )   951 - 958   1997.9

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    We examined the in vivo effect of a highly toxic coplanar polychlorinated biphenyl (PCB) on the hepatic activity of glucose 6-phosphate dehydrogenase (G6PDH) in aryl hydrocarbon (Ah)-responsive (C57/BL) and -less-responsive (DBA) strains of mice. The activity in the C57BL strain was moderately increased by 3,3',4,4',5-pentachlorobiphenyl (PCB 126) in a dose dependent manner. However, this was not observed in DBA mice although greater doses were injected. 2,2',5,5'-Tetrachlorobiphenyl (PCB 52) with a non-planar structure did not increase G6PDH activity, The increase in G6PDH activity with PCB 126 was also seen in rats, but not in guinea pigs. The activity in the latter species was decreased rather than increased. These results suggest that the induction of hepatic G6PDH by coplanar PCB is mediated by a mechanism involving the Ah receptor, and the response was highly species-specific. (C) 1997 Elsevier Science Ltd.

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  • Changes in the hepatic glutathione peroxidase redox system produced by coplanar polychlorinated biphenyls in Ah-responsive and -less-responsive strains of mice: mechanism and implications for toxicity

    M Hori, H Kondo, N Ariyoshi, H Yamada, A Hiratsuka, T Watabe, K Oguri

    ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY   3 ( 4 )   267 - 275   1997.9

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    The alteration in hepatic glutathione peroxidase (GPx) produced by polychlorinated biphenyls (PCBs) was studied in vivo in aryl hydrocarbon (Ah)-responsive C57BL and -less-responsive DBA strains of mice. 3,3',4,4',5-Pentachlorobiphenyl (PCB 126), one of the high-affinity ligands for the Ah receptor, significantly reduced Se-dependent GPx activity in C57BL mice, but not in DBA mice. A reduction in activity in C57BL mice was also observed following treatment with a high dose of 3,3',4,4'-tetrachlorobiphenyl with lesser affinity for the Ah receptor than PCB 126, but not by 2,2',5,5'-tetrachlorobiphenyl, a low-affinity ligand. To assess the effects on GPx in the liver, the content of reduced glutathione (GSH), an obligate co-factor for GPx, and the activity of two enzymes, gamma-glutamyl transpeptidase (gamma-GTP) and glutathione reductase (GR), which play a role in supplying GSH were determined after PCB treatment. The results showed that although the hepatic activity of gamma-GTP and GR was affected differently by PCB 126, the content of GSH was slightly increased rather than reduced in both strains of mice. The activity of non-Se-dependent GPx, which is due to the catalysis by some isozymes of glutathione S-transferase (GST), was significantly increased only in C57BL mice by PCB 126 treatment. Immunoblot analysis demonstrated that the induction of the class theta GST, which is a potent reducer of peroxides (Hiratsuka et al., 1995. Biochem. Biophys. Res. Commun. 212, 743) reflects the enhancement of the above activity. These results suggest that (i) the PCB-induced reduction in Se-dependent GPx activity is mediated by a mechanism involving the Ah receptor; and (ii) a concomitant increase in the class theta GST partially rescues the Ah-responsive mice from coplanar PCB-induced oxidative stress. (C) 1997 Elsevier Science B.V.

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  • Co-planar PCBの肝glutathione peroxidase-redox systemに対する影響 ラット及びモルモットでの検討

    堀 美穂, 有吉 範高, 山田 英之

    福岡医学雑誌   88 ( 5 )   144 - 148   1997.5

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    活性酸素消去系の損傷とそれに基づく酸化的ストレスの役割について検討した.この目的の為,本研究ではラットとモルモットのcoplanar PCBに対する感受性の違いに注目した.即ち活性酸素消去系の障害が動物種を越えた共通の毒性発現機構なら,感受性動物のモルモットの方が感受性の低いラットよりも障害の程度が顕著なはずであるとの作業仮説を立てて検討を行ったが,上記の推定を支持する結果は得られなかった.即ち,PCB 126処理ラットでは主要な活性酸素消去系の一つであるGPx活性が有意に低下したが,感受性の高いモルモットではむしろ活性増加した.肝GSH含量並びにこの供給に働くGR及びγ-GTP活性の変動もラットでのみ障害の発生が観察された

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  • A highly toxic PCB produces unusual changes in the fatty acid composition of rat liver

    K Matsusue, Y Ishii, N Ariyoshi, K Oguri

    TOXICOLOGY LETTERS   91 ( 2 )   99 - 104   1997.4

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    The changes in lipid metabolism produced by a coplanar PCB were studied in rats. Male Wistar rats were given a single intraperitoneal injection of 3,3',4,4',5-pentachlorobiphenyl at a dose of 25 mg/kg. After 5 days of administration, total hepatic lipids were treated with 1 M KOH in methanol at 75 degrees C and the liberated fatty acids were analyzed by HPLC after conversion to fluorescent derivatives. In comparison with free-fed and pair-fed control groups, the proportion of arachidonic acid in the PenCB-treated rats was reduced by about 50%, while oleic and linoleic acids increased significantly. We also examined the individual glycerophospholipids, separated by TLC,to see if they were affected by alteration in the fatty acid composition of the whole liver. In all glycerophospholipids, the proportion of arachidonic acid was reduced significantly to the same degree while linoleic acid increased. Changes in the activity of desaturase isozymes have been postulated to explain this unusual lipid metabolism following administration of a toxic PCB and this may contribute to its toxicity. (C) 1997 Elsevier Science Ireland Ltd.

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  • Effect of highly toxic 3,3',4,4',5-pentachlorobiphenyl on the synthesis of unsaturated fatty acids Reviewed

    K Matsusue, N Ariyoshi, M Inoue, Y Ishii, K Oguri

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH   43 ( 1 )   P19 - P19   1997.2

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  • Significant suppression of aldolase B, carbonic anhydrase III and alcohol dehydrogenase in liver cytosol of rats treated with a highly toxic coplanar PCB Reviewed

    H Kato, Y Ishii, M Hatsumura, T Ishida, Nakayama, I, N Ariyoshi, K Oguri

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH   43 ( 1 )   P20 - P20   1997.2

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  • Significant suppression of rat liver aldolase B by a toxic coplanar polychlorinated biphenyl, 3,3',4,4',5-pentachlorobiphenyl

    Y Ishii, H Kato, M Hatsumura, T Ishida, N Ariyoshi, K Oguri

    TOXICOLOGY   116 ( 1-3 )   193 - 199   1997.1

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    A toxic coplanar polychlorinated biphenyl, 3,3',4,4',5-pentachlorobiphenyl (PenCB), significantly suppresses the expression of liver aldolase B in rats, Hepatic aldolase activity in PenCB-treated rats was significantly reduced to about 50% of that in free- and pair-fed control groups. The reduced aldolase activity following PenCB-treatment was due to the marked suppression of the expression of aldolase B shown by immunoblot analysis after SDS-polyacrylamide gel electrophoresis and two-dimensional gel electrophoresis. The suppression of rat liver aldolase B could be a key biochemical lesion caused by PenCB. Copyright (C) 1997 Elsevier Science Ireland Ltd.

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  • Cytochrome P450scc in rat adrenal cells mediated by regulation of the steroidogenic acute regulatory protein

    YC Kim, N Ariyoshi, Artemenko, I, ME Elliott, KK Bhattacharyya, CR Jefcoate

    STEROIDS   62 ( 1 )   10 - 20   1997.1

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    Cholesterol conversion to pregnenolone by cytochrome P450scc in steroidogenic cells, including those of the adrenal cortex is determined by hormonal control of cholesterol availability. Intramitochondrial cholesterol movement to P450scc, which retains hormonal activation in isolated mitochondria, is apparently dependent an peripheral benzodiazepine receptor and the recently cloned steroidogenic acute regulatory (SrARJ protein. In rat adrenal cells, StAR is formed as a 37-kDa precursor that is transferred to the mitochondrial inner membrane following phosphorylation by hormonally activated protein kinase A, and processed to multiple forms, some of which turn over very rapidly. In bovine cells, StAR undergoes three modifications for ming a set of eight proteins seen in both glomerulosa and fasciculata cells. In the former, cyclic AMP and angiotensin ii each decrease two forms and elevate six forms. Significantly, the major change seen after activation may not involve phosphorylation of StAR. Cholesterol transfer across mitochondrial membranes is also activated in isolated mitochondria by GTP and low concentrations of Ca2+, apparently prior to activation by StAR. Depletion of StAR by cyclohexmide inhibits cholesterol transfer but is overcome by uptake of Ca2+ into the matrix. This activation of cellular- cholesterol transport is sustained in adrenal cells pereabilized by Streptolysin 0. In rat adrenal cells cAMP elevates 3.5- and 1.6-kb mRNA, hybridized by a 1.O-kb StAR cDNA. A 3.5-kb rat adrenal cDNA that encodes all except the 5' end of the longest StAR mRNA has been characterized. The corresponding gene sequence is distributed across seven exons. The shorter mRNA may arise from polyadeylation signals early in exon 7. However, the 3.5-kb mRNA comprises 80-90% of untreated rat adrenal StAR mRNA and may therefore provide the prime source for in vivo translation of StAR protein. (C) 1997 by Elsevier Science, Inc.

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  • Effect of co-planar polychlorinated biphenyl on the hepatic glutathione peroxidase redox system in rats and guinea pigs

    M. Hori, N. Ariyoshi, H. Yamada, K. Oguri

    Fukuoka Acta Medica   88 ( 5 )   12 - 16   1997

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    The effect of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) on hepatic glutathione peroxidase (GPx) redox system was studied in vivo in rats and guinea pigs. PCB 126 treatment caused significant reduction of Se-dependent and -non-dependent GPx activity in rats. In agreement with this, the content of glutathione (GSH) and the activities of GSH reductase (GR) and γ-glutamyl transpeptidase (γ-GTP) were also decreased in this species. On the contrary, guinea pig liver Se-non-dependent GPx activity was significantly enhanced by PCB 126 treatment, while no effect on Se-dependent activity was observed. Neither the content of GSH nor the enzyme activities responsible for GSH supply in guinea pig liver was affected by PCB 126. These result suggested that the damage on GPx redox system is, at least, one of mechanisms by which co-planar PCB induces the toxicity in rats. However, in guinea pigs, this is not the case, and different mechanism from the damage on active oxygen quenching system is likely to be involved.

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  • Metabolism of 2,4,5,2',4',5'-hexachlorobiphenyl (PCB153) in guinea pig Reviewed

    N. Ariyoshi, N. Koga, H. Yoshimura, K. Oguri

    Xenobiotica   27 ( 9 )   973 - 983   1997

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    1. The in vitro and vivo metabolism of 2,4,5,2',4',5'-hexachlorobiphenyl (PCB153) in guinea pig has been studied. 2. Seven metabolites were detected in the faeces of PCB153-treated animals and three were identical to those produced by dog liver microsomes. The detection of a metabolite where a chlorine atom was shifted from the 2- to 3-position strongly suggested the involvement of 2,3-arene oxide intermediate, and evidence for the concomitant formation of a 3,4-arene oxide intermediate was provided by identifying other two minor metabolites which were dechlorinated at the 4-position. 3. In vitro studies using liver microsomes from guinea pigs revealed that the 2,3-arene oxide and 5-hydroxylation pathways are the predominant metabolic routes compared with the 3,4-arene oxide pathway. Although the guinea pig is an another species that can metabolize PCB153 mainly to the 2,3-arene oxide intermediate, the rate of formation was only about one-tenth of the dog. 4. These results indicate that the ability to form this unusual 2,3-arene oxide intermediate may not be responsible for high excretion rate of this congener. Our data also suggest that the cytochrome P450-catalysed metabolism of PCB153 in the guinea pig and dog are similar, whereas for post-cytochrome P450 metabolism, the guinea pig resembles the rabbit.

    DOI: 10.1080/004982597240136

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  • Production of antibody against cytosolic 54kDa protein in rat liver evidence of the significant induction by a highly toxic coplanar polychlorinated biphenyl

    T. Ishida, Y. Ishii, K. Tasaki, N. Ariyoshi, K. Oguri

    Fukuoka Acta Medica   88 ( 5 )   3 - 11   1997

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    We have reported that a 54kDa protein in rat liver cytosol is highly inducible by treatment with 3,3',4,4',5-pentachlorobiphenyl (PenCB) or 3- methylcholanthrene (MC) using SDS-polyacrylamide gel electrophoresis. Internal amino acid sequences of this protein in the rat liver were highly homologous to those of selenium binding protein (SeBP) or acetaminophen binding protein (APBP) in mouse liver cytosol. In this paper, the purification and characterization of this protein were demonstrated MC was given at a dose of 20 mg/kg for 3 consecutive days. The liver cytosolic 54kDa protein was purified twice from the MC-treated male Wistar rats by Rotofore Cell(TM) procedure to apparent single on SDS-polyacrylamide gel electrophoresis, and the rabbit antiserum against this protein was obtained. Male Wistar rats were given PenCB in corn oil at a single dose of 25 mg/kg i.p. The liver cytosol was prepared on the 5th day after the treatment and subjected to immunoblot analysis. The 54kDa protein was markedly induced in the liver cytosol of PenCB-treated rats. Immunoblot analysis after two- dimensional gel electrophoresis suggested that there could be isoforms of 54kDa protein. The induction of the 54kDa protein with PenCB was assumed to be mediated through Ah-receptor. The physiological role of the 54kDa protein was discussed together with SeBP and APBP, the role of which has not yet been elucidated.

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  • Significant induction of a 54-kDa protein in rat liver with homologous alignment to mouse selenium binding protein by a coplanar polychlorinated biphenyl, 3,4,5,3',4'-pentachlorobiphenyl and 3-methylcholanthrene

    Y Ishii, M Hatsumura, T Ishida, N Ariyoshi, K Oguri

    TOXICOLOGY LETTERS   87 ( 1 )   1 - 9   1996.9

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    A 54-kDa protein in rat liver cytosol was significantly induced by treatment with 3,4,5,3',4'-pentachlorobiphenyl (25 mg/kg, single i.p.) and 3-methylcholanthrene (20 mg/kg, once a day for 3 days, i.p.). The protein exhibited pi of 6.8 on two-dimensional gel electrophoresis. The amino acid sequences of peptide fragments from the protein digested in situ were highly similar to a selenium binding protein in mice and to the isoform acetaminophen binding protein in mice. The present result clearly demonstrates that a coplanar polychlorinated biphenyl and 3-methylcholanthrene are responsible for induction of selenium binding protein homologues. The physiological role of the mouse proteins, however, is not yet elucidated.

    DOI: 10.1016/0378-4274(96)03668-5

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  • Hamster liver cytochrome P450 (CYP2A8) as a 4-hydroxylase for 2,5,2',5'-tetrachlorabiphenyl Reviewed

    N Koga, N Kikuichi, T Kanamaru, N Ariyoshi, K Oguri, H Yoshimura

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   225 ( 2 )   685 - 688   1996.8

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    Metabolism of 2,5,2',5'-tetrachlorobiphenyl (TCB) was studied using liver microsomes of hamsters and two hamster P450 isoforms, CYP1A2 and 2A8. CYP2A8 catalyzed selectively 4-hydroxylation of 2,5,2',5-TCB at a rate of 21.7 pmol/min/nmol P450. In contrast, CYP1A2 showed no activity for hydroxylation of 2,5,2',5'-TCB. Immunological study revealed that rabbit antiserum against CYP2A8 almost completely inhibited the microsomal 4-hydroxylation but that against CYP1A2 did not. It was also shown that the induction pattern of CYP2A8 protein by P450 inducer was similar to that of the 4-hydroxylase activity in hamster liver microsomes. These results suggest that CYP2A8 plays a major role in the 4-hydroxylation of 2,5,2',5'-TCB in hamster liver. (C) 1996 Academic Press, Inc.

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  • A coplanar PCB induces a selenium binding protein as a major cytosolic protein in rat liver

    Y Ishii, M Hatsumura, T Ishida, N Ariyoshi, K Oguri

    CHEMOSPHERE   32 ( 3 )   509 - 515   1996.2

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    We obtained evidence that a toxic coplanar polychlorinated biphenyl (PCB) induces a counterpart of murine 56kDa selenium binding protein in rat liver cytosol. A 54kDa protein in the liver cytosol was significantly induced by 3,3',4,4',5-pentachlorobiphenyl and proved to be a major cytosolic protein in the rat liver. The protein exhibited pi of 6.8 on two-dimensional gel electrophoresis. The amino acid sequence of peptide fragments from the protein digested in situ, was highly similar to a 56kDa selenium binding protein and similar to an acetaminophen binding protein in mice.

    DOI: 10.1016/0045-6535(95)00316-9

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  • Involvement of cytochrome b(5) in the metabolism of tetrachlorobiphenyls catalyzed by CYP2B1 and CYP1A1

    K Matsusue, N Ariyoshi, K Oguri, N Koga, H Yoshimura

    CHEMOSPHERE   32 ( 3 )   517 - 523   1996.2

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    The role of cytochrome b(5) in the cytochrome P450 (CYP)-dependent hydroxylation of tetrachlorobiphenyl (TCB) isomers was examined using a reconstituted mixed function oxygenase (MFO) system containing purified CYP2B1 or 1A1, and rat liver microsomes. Hydroxylations of 2,2',5,5'- and 3,3',4,4'-TCBs were catalyzed mainly by CYP2B1 and 1A1, respectively, in the reconstituted MFO system and those of 2,3',4',5- and 2,3',4,4'-TCBs were mediated by both cytochrome P450 systems. The activity toward 2,2',5,5'- and 2,3',4',5-TCB was significantly increased 6.5- and 5.5-fold, respectively, by addition of cytochrome b, in the reconstituted MFO system containing of CY2B1. Either hydroxylation activity toward 2,3',4,4'-TCB with the CYP2B1 system was very low or decreased by addition of cytochrome b(5). These results suggest that the involvement of cytochrome b(5) to the hydroxylation of TCBs is dependent on the TCB congener being metabolized, and the cytochrome P450 isoform involved in its metabolism.

    DOI: 10.1016/0045-6535(95)00318-5

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  • METABOLISM OF HIGHLY PERSISTENT PCB CONGENER, 2,4,5,2',4',5'-HEXACHLOROBIPHENYL, BY HUMAN CYP2B6

    N ARIYOSHI, K OGURI, N KOGA, H YOSHIMURA, Y FUNAE

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   212 ( 2 )   455 - 460   1995.7

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    Metabolism of 2,4,5,2',4',5'-hexachlorobiphenyl was studied with cDNA-expressed human P450 2B isoform, CYP2B6. 3-Hydroxy-2,4,5,2',4',5'-hexachlorobiphenyl was identified as a major metabolite, and the formation activity was compared with that of dog CYP2B11 and guinea pig P450(GP-1). The activity of 3-hydroxylation was comparable with that of P450(GP-1), but one-tenth of CYP2B11. These results indicate that P450 2B in humans as well as other animal species can metabolize 2,4,5,2',4',5'-hexachlorobiphenyl, and the reason why this PCB congener remained most abundantly in human bodies is discussed. (C) 1995 Academic Press, Inc.

    DOI: 10.1006/bbrc.1995.1991

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  • EFFECT OF HIGHLY TOXIC COPLANAR PCB ON PEROXISOMAL ENZYME-ACTIVITY - THE SPECIES-DIFFERENCE BETWEEN RATS AND GUINEA-PIGS Reviewed

    M IWASAKI, H KATO, N ARIYOSHI, K OGURI

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH   41 ( 1 )   P32 - P32   1995.2

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  • Effect of a coplanar PCB on lipid metabolism ; The remarkable difference between rats and Guinea pigs(共著)

    Fukuoka Acta Media   86 ( 5 )   135   1995

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  • Alteration of perixosomal enzyme activities in the liver of guinea pigs caused by coplanar PCB

    M. Iwasaki, H. Kato, N. Ariyoshi, K. Oguri

    Fukuoka Acta Medica   86 ( 5 )   12 - 20   1995

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    The hyperlipidemia is a well-known typical symptom in Yusho patients and experimental animals treated with PCBs. We have found a significant induction of CYP4A1, which catalyzes ω-hydroxylation of fatty acids, in guinea pigs by the treatment with a coplanar PCB, 3,4,5,3',4'-pentachlorobiphenyl (PenCB), though the P450 is reduced in the treated rats. Peroxisome has β-oxidation enzymes distinct from mitochondrial enzymes, and also play an important role in lipid metabolism. Peroxisome proliferators have been shown to regulate the expression of CYP4A1 and peroxisomal enzymes by the same mechanism in the rat. In the present study, we examined the effect of PenCB treatment on peroxisomal enzymes in the liver of guinea pigs. As a result, the enzyme activities of hepatic peroxisome, e.g. fatty acid oxidizing system, catalase and urate oxidase, had a rising tendency by the treatment with PenCB in the animal. The results suggest that the regulation of peroxisomal enzymes and CYP4A1 is also associated in guinea pigs, and PenCB provides a similar effect of peroxisomal proliferators to the animal. The possible toxicity through the peroxisomal alteration was discussed.

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  • Studies on PCB toxicity involving 2C subfamily cytochrome P450

    N. Ariyoshi, S. Ito, A. Okudaira, M. Mise, K. Matsusue, H. Yamada, K. Oguri

    Fukuoka Acta Medica   86 ( 5 )   21 - 30   1995

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    It has been demonstrated that PCB metabolism is mainly catalyzed by 1A and 2B subfamily cytochrome P450s, CYP 1A1/2 and CYP 2B1/2. These studies were conducted mostly with hepatic enzymes in rodents. The 1A and 2B subfamily P450s are constitutively expressed little, but markedly induced by xenobiotics such as 3-methylcholanthrene and phenobarbital in rodents. On the other hand, the recent studies showed that cytochrome P450s in human liver are remarkably different from isoform of rodents in constitution and enzyme activities. In the present study, we first tried to metabolize some PCBs with 2C subfamily cytochrome P450 (CYP2C) purified from dog liver microsomes. The data suggested that CYP2C may not be involved in PCB metabolism. Since CYP2C is the same most abundant enzyme as 3A subfamily P450 in human liver and plays a major role for metabolism of many drugs used clinically, and may also play an important role for metabolism of some steroid hormones, we further studied the inhibition of CYP2C-catalyzed steroid metabolism by typical PCB congeners. CYP2C-mediated steroid metabolism is greatly inhibited by 2,4,5,2',4',5'-hexachlorobiphenyl, but not by 3,4,5,3',4'-pentachlorobiphenyl. On the contrary, 3,4,5,3',4'-pentachlorobiphenyl markedly suppressed CYP2C expression in the dog liver. These results suggest that residual PCBs may affect the current situation of steroid hormones in Yusho patients, and may cause PCB-drug interactions.

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  • PURIFICATION AND CHARACTERIZATION OF DOG LIVER MICROSOMAL EPOXIDE HYDROLASE Reviewed

    N ARIYOSHI, M TANAKA, Y ISHII, K OGURI

    JOURNAL OF BIOCHEMISTRY   115 ( 5 )   985 - 990   1994.5

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    An epoxide hydrolase (mEH) in liver microsomes was purified to apparent homogeneity from a dog treated with phenobarbital. The purified enzyme had a minimum molecular weight of 47,000 as determined by SDS-PAGE. The dog mEH activity was characterized by use of a substrate, 7-glycidoxycoumarin (GOC), and some effecters of this enzyme. In vitro activators, metyrapone, and isoquinoline, stimulated the microsomal activity, but the former had no such effect on the purified enzyme in case of this substrate. All mEH inhibitors, 1,1,1-trichloropropene 2,3-oxide (TCPO), cyclohexene oxide, and 2-bromo-4'-nitroacetophenone (BrNAP), suppressed hydrolase activity. The NH2-terminal amino acid sequence of the purified enzyme was highly homologous (90%) to the sequences deduced from a cDNA clone of rat enzyme. Antiserum to the purified enzyme raised in rabbits cross-reacted with rat and guinea pig epoxide hydrolases. No gender-difference in this enzyme in liver microsomes was observed in dogs.

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  • EFFECT OF COPLANAR PCB ON GLUCONEOGENESIS AND LIPID-METABOLISM - COMPARISON BETWEEN RATS AND GUINEA-PIGS Reviewed

    M HATSUMURA, T ISHIDA, Y ISHII, N ARIYOSHI, Y KOGA, K OGURI, H YOSHIMURA

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH   40 ( 1 )   P27 - P27   1994.2

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  • INDUCTION OF BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE AND CYP4A1 P450 BY COPLANAR PCBS - DIFFERENT RESPONSIVENESS OF GUINEA-PIGS AND RATS

    Y KOGA, M TSUDA, N ARIYOSHI, Y ISHII, H YAMADA, K OGURI, Y FUNAE, H YOSHIMURA

    CHEMOSPHERE   28 ( 3 )   639 - 645   1994.2

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    Induction of hepatic microsomal bilirubin UDP-glucuronyltransferase and CYP4A1 P450 by 3,4,3',4'-tetrachlorobiphenyl (TCB) and 3,4,5,3',4'-pentachlorobiphenyl (PenCB) was studied in guinea pigs and rats. Both enzyme activities in guinea pigs were increased 4-fold or more over the control by PenCB treatment, while by treatment with a less toxic congener, TCB, these were increased to a lesser extent. On the contrary, the rat enzymes were significantly decreased by treatment with these co-planar polychlorinated biphenyls. These results suggest that the alterations of both bilirubin UDP-glucuronyltransferase and CYP4A P450 are the characteristic indices for the toxicities of polychlorinated hydrocarbons.

    DOI: 10.1016/0045-6535(94)90305-0

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  • MODIFICATION OF THE GLUCONEOGENESIS IS NOT INVOLVED IN THE COPLANAR PCB TOXICITY IN HIGHLY SENSITIVE GUINEA-PIGS Reviewed

    K OGURI, M HATSUMURA, Y ISHII, Y KOGA, N ARIYOSHI, H YOSHIMURA

    CHEMOSPHERE   27 ( 11 )   2295 - 2303   1993.12

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    Effect of a co-planar PCB, 3,4,5,3',4'-pentachlorobiphenyl (PenCB) on gluconeogenesis in guinea pigs was compared with that in rats. The key enzyme of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), in liver cytosol of rats was reduced by PenCB treatment to about 50% of control level. Hypoglycemia was also seen in the rat. On the contrary, the liver cytosol PEPCK activity in guinea pigs was slightly increased by PenCB treatment. Plasma levels of alanine and tryptophan were increased in the rat treated with PenCB, but the level of glycogenic amino acid, alanine, was not raised significantly-in the guinea pig. Thus the modification of the gluconeogenesis was not involved in the PenCB toxicity in highly sensitive guinea pigs.

    DOI: 10.1016/0045-6535(93)90140-Z

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  • IDENTIFICATION OF IN-VITRO METABOLITES OF 2,4,6,2',4',6'-HEXACHLOROBIPHENYL FROM PHENOBARBITAL-TREATED DOG LIVER-MICROSOMES Reviewed

    N ARIYOSHI, H YOSHIMURA, K OGURI

    BIOLOGICAL & PHARMACEUTICAL BULLETIN   16 ( 9 )   852 - 857   1993.9

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    We studied in vitro metabolites of 2,4,6,2',4',6'-hexachlorobiphenyl (HCB, IUPAC PCB No. 155) produced by liver microsomes of a phenobarbital (PB)-treated beagle dog. The major metabolites were 3-hydroxy-2,4,6,2',4',6'-HCB (M-1), 4-hydroxy-2,6,2',4',6'-pentachlorobiphenyl (PenCB, M-2) and 3,4-dihydroxy-2,6,2',4',6'-PenCB (M-3). Furthermore, 4-hydroxy-2,3,6,2',4',6'-HCB (M4), which could be formed via the 3,4-epoxidation and the subsequent NIH-shift of the chlorine from the 4 to the 3 position, was also detected. We found that M-3 is a common secondary metabolite of the two major monohydroxy metabolites, M-1 and M-2. These results indicate that the dog seems to metabolize and eliminate this congener not only by a mechanism involving direct insertion of a hydroxyl group but also via an arene oxide intermediate.

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  • INDUCTION OF BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE AND P-450-4A SUBFAMILY IN GUINEA-PIGS BY TREATMENT WITH COPLANAR PCB Reviewed

    Y KOGA, M TSUDA, N ARIYOSHI, Y ISHII, H YAMADA, K OGURI, H YOSHIMURA, Y FUNAE

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH   39 ( 1 )   P23 - P23   1993.2

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  • Induction of Bilirubin UDP-Glucuronyltransferase and P-450 4A Subfamily in Guinea Pigs Reviewed

    Yoshiko Koga, Yoshihiko Funaec, Hidetoshi Yoshimura, Noritaka Ariyoshi, Yuji Ishii, Hideyuki Yamada, Kazuta Oguri, Minoru Tsuda

    Eisei kagaku   39 ( 1 )   1993

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    DOI: 10.1248/jhs1956.39.P23

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  • Inducing Ability of Co-planar PCBs toward Bilirubin UDP-glucuronyltransferase of Liver Microsomes : The Remarkable Difference between Guinea Pigs and Rats. Reviewed

    Fukuoka Acta Medica   84 ( 5 )   175   1993

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  • METABOLISM OF 2,4,5,2',4',5'-HEXACHLOROBIPHENYL WITH LIVER-MICROSOMES OF PHENOBARBITAL-TREATED DOG - THE POSSIBLE FORMATION OF PCB 2,3-ARENE OXIDE INTERMEDIATE Reviewed

    N ARIYOSHI, N KOGA, K OGURI, H YOSHIMURA

    XENOBIOTICA   22 ( 11 )   1275 - 1290   1992.11

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    1. Metabolism of 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) was investigated in vitro using liver microsomes of one male beagle dog after phenobarbital treatment.
    2. Three major metabolites were isolated and identified as 3-hydroxy-2,4,5,2',4',5'-HCB, 2-hydroxy-4,5,2',4',5'-pentachlorobiphenyl (PenCB), and 2-hydroxy-3,4,5,2',4',5'-HCB, by comparison of g.l.c.-mass spectrometry and H-1-n.m.r. data with those of authentic samples.
    3. 2-Hydroxy-3,4,5,2',4',5'-HCB was found as a metabolite of 2,4,5,2',4',5'-HCB for the first time using dog liver microsomes. Present results indicate that this metabolite and the dechlorinated PenCB are derived from a metabolic intermediate, namely, 2,3-epoxy-2,4,5,2',4',5'-HCB. 2,3-Epoxide formation is a new metabolic pathway of PCB.

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  • PURIFICATION AND CHARACTERIZATION OF 2 FORMS OF 2,3,4,7,8-PENTACHLORODIBENZOFURAN INDUCIBLE CYTOCHROME-P-450 IN HAMSTER LIVER Reviewed

    N KOGA, N ARIYOSHI, H NAKASHIMA, H YOSHIMURA

    JOURNAL OF BIOCHEMISTRY   107 ( 6 )   826 - 833   1990.6

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    Golden SyrianハムスターにPenCDF (0.5 mg/kg)を膜腔内1回投与し,投与後5日目に屠殺し肝ミクロゾームを調製した.1.0%コール酸で可溶化後,ω-aminooctyl-Sepharose 4B, DE-52およびHydroxylapatiteの各カラムにて精製し,電気泳動的に単一で分子量52kDaのhamster P-450H(比含量12.8 nmol/mg protein)と分子量50 kDaのhamster P-450L(比含量7.73 nmol/mg protein)の2種を得た.いずれのP-450もCO-還元差スペクトルの吸収極大を446 nmに示し,それぞれ混合(高スピン+低スピン)型と低スピン型であった.なおhamster P-450H標品はhamster P-450Lの約27倍ものPenCDFを含有していた(0.107 nmol/nmol of P-450).両P-450に対する抗体を用いて未処理およびPenCDF処理ハムスター肝ミクロゾーム中の両P-450を定量したところ,hamster P-450Hは未処理ミクロゾーム全P-450量の約15%を占めること,およびPenCDF処理ではhamster P-450Hが60%,hamster P-450Lが30%を占めることが判明し,いずれの分子種もPenCDF誘導性であることが明らかとなった

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    医薬品情報・評価学 第3版・南江堂  2011 

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    薬物代謝学 第3版・東京化学同人  2009 

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  • 薬物代謝 第3版

    廣川書店  2009 

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  • ゲノムと遺伝子解析情報

    医薬情報評価学・医学書院  2009 

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    乳がん標準化学療法の実際 第2版・金原出版  2007 

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  • 薬物代謝の遺伝的多型と遺伝子診断による予知

    薬物療法学・南江堂  2003 

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  • くすりの効き方は人によって違うの?

    日本薬学会編・丸善  2003 

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  • Carcinogenesisにおける個体差

    Annual Review 呼吸器2002  2002 

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  • 薬物代謝からみた肝・腎・心疾患患者への医薬品投与時の注意 薬物代謝酵素

    医薬ジャーナル社  2001 

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  • 薬物動態・作用と遺伝子多型 薬物治療の患者個別化を目指した21世紀の新展開 CYP遺伝子多型と発現調節

    医薬ジャーナル社  2001 

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  • 7.薬物相互作用/9.2遺伝的多型の遺伝子診断/11.6内分泌撹乱物質と薬物代謝

    薬物代謝学 第2版  2000 

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  • 肝胆系における薬物代謝と肝障害-薬物代謝関連酵素の遺伝的多型

    消化器疾患-State of arts(Ver.2)  1999 

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  • 呼吸器疾患における分子生物学の基礎とその臨床応用34,P450と多型

    呼吸器疾患の分子生物学  1998 

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  • 環境要因感受性を支配する遺伝的要因 異物代謝の個人差と環境要因感受性

    環境と健康II  1998 

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  • 正常血圧を超えた方に対するピペリン含有食品の血圧改善に関する臨床研究

    薗田 晴香、有吉 範高、森 舞華、松本 准、藤吉 正哉

    第60回日本薬学会・日本薬剤師会・日本病院薬剤師会;中国四国支部学術大会 講演要旨集   182 - 182   2021.10

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  • 腎がん患者におけるCYP3A5の発現と患者予後との関連性

    松本 准, 小寺 佑実, 和田里 章悟, 竹内 虎一, 植木 英雄, 小山 敏広, 和田 耕一郎, 藤吉 正哉, 那須 保友, 有吉 範高

    第60回日本薬学会・日本薬剤師会・日本病院薬剤師会;中国四国支部学術大会 講演要旨集   146 - 146   2021.10

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  • UGT1A8遺伝子におけるメチル化DNA検出方法の確立

    中村 美沙樹, 米田 紗英, 渡辺 紗羅, 塩飽 力也, 松本 准, 藤吉 正哉, 有吉 範高, 埴岡 伸光, 須野 学

    日本薬学会年会要旨集   140年会   28P - am043   2020.3

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究(第2報):難消化性デキストリンの効果

    鎌田早紀、有吉範高、利根淳仁、松本 准、藤吉正哉

    第58回日本薬学会・日本薬剤師会・日本病院薬剤師会;中国四国支部学術大会 講演要旨集   237 - 237   2019.11

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究(第3報):豆乳の効果

    篠山泰子、有吉範高、利根淳仁、松本 准、藤吉正哉

    第58回日本薬学会・日本薬剤師会・日本病院薬剤師会;中国四国支部学術大会 講演要旨集   271 - 271   2019.11

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究(第4報):桑の葉茶の効果

    濱田浩司、有吉範高、利根淳仁、松本 准、藤吉正哉

    第58回日本薬学会・日本薬剤師会・日本病院薬剤師会;中国四国支部学術大会 講演要旨集   272 - 272   2019.11

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究(第5報):サラシアの効果

    山本弥生、有吉範高、利根淳仁、松本 准、藤吉正哉

    第58回日本薬学会・日本薬剤師会・日本病院薬剤師会;中国四国支部学術大会 講演要旨集   236 - 236   2019.11

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究(第1報)

    有吉範高、鎌田早紀、篠山泰子、濱田浩司、山本弥生、利根淳仁、松本 准、藤吉正哉

    医療薬学フォーラム2019/第27回クリニカルファーマシーシンポジウム 講演要旨集   226 - 226   2019.7

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  • 肺移植患者における血中ミコフェノール酸トラフ濃度/投与量比に与えるUGT1A8の影響について

    須野 学, 内嶺 陽平, 伊藤 明花, 松本 潤, 藤吉 正哉, 有吉 範高, 大谷 真二, 大藤 剛宏

    日本薬学会年会要旨集   138年会 ( 4 )   175 - 175   2018.3

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  • 実臨床下における第二世代Bcr-Abl TKIの効果・副作用と薬物動態評価に基づく治療最適化の検討

    有吉 範高

    薬学研究の進歩   ( 33 )   73 - 79   2017.3

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  • メマンチン塩酸塩投与後に洞不全症候群を呈した高度腎障害の1症例

    藤井 聡, 山口 洪樹, 江口 紀子, 高岡 浩之, 中村 貴子, 鈴木 貴明, 有吉 範高, 小林 欣夫, 石井 伊都子

    日本腎臓病薬物療法学会誌   5 ( 2 )   S118 - S118   2016.10

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  • バンコマイシンクリアランスが著しく変動した敗血症性ショックの1症例

    鈴木 達也, 山崎 伸吾, 渡邉 栄三, 鈴木 貴明, 有吉 範高, 織田 成人, 石井 伊都子

    TDM研究   33 ( 2 )   145 - 145   2016.5

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  • 持続的血液濾過透析施行中におけるバンコマイシンのクリアランスの評価と体内動態に与える影響因子の検討

    建部 泉希, 山崎 伸吾, 鈴木 達也, 高塚 博一, 藤吉 正哉, 鈴木 貴明, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   136年会 ( 4 )   79 - 79   2016.3

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  • I型コラーゲン3次元培養系における血管平滑筋細胞増殖抑制におけるPI3Kの関与

    三浦 寄子, 内田 雅士, 藤吉 正哉, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   136年会 ( 3 )   93 - 93   2016.3

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  • 機能的ポリマーを用いた浮遊培養法における血管平滑筋細胞の増殖抑制

    名取 知美, 内田 雅士, 金木 達朗, 安部 菜月, 藤吉 正哉, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   136年会 ( 3 )   92 - 92   2016.3

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  • マクロファージ特異的なCES2A1の導入によるapolipoprotein Eヘテロ欠損マウスの肥厚形成抑制

    竹澤 明香里, 渡辺 健太, 藤吉 正哉, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   136年会 ( 3 )   106 - 106   2016.3

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  • アクロレイン化LDL中apoBのアクロレイン化部位の解析

    栗原 瑞季, 藤吉 正哉, 渡辺 健太, 本泉 昌子, 鈴木 健裕, 堂前 直, 五十嵐 一衛, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   136年会 ( 3 )   106 - 106   2016.3

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  • 小児苺状血管腫に対するプロプラノロールゲルの製剤学的検討

    吉澤 なぎ, 高塚 博一, 中澤 孝文, 力久 直昭, 鈴木 貴明, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   136年会 ( 4 )   103 - 103   2016.3

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  • 透析導入中にB型肝硬変を併発したHIV感染者にツルバダ配合錠の投与をテノホビル血中濃度に基づいて検討した症例

    築地 茉莉子, 山崎 伸吾, 中村 貴子, 鈴木 貴明, 有吉 範高, 猪狩 英俊, 石井 伊都子

    日本エイズ学会誌   17 ( 4 )   450 - 450   2015.11

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  • 慢性骨髄性白血病患者におけるダサチニブによる血小板減少の原因探求

    有吉 範高, 後藤 優理, 今井 千晶, 中世古 知昭, 石井 伊都子

    Personalized Medicine Universe. Japanese Edition   4 ( Suppl.2 )   62 - 62   2015.10

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  • CH1.0Nを用いた持続的血液濾過透析施行患者におけるバンコマイシンの全身クリアランスに関する評価と影響因子の検討

    山崎 伸吾, 鈴木 達也, 高塚 博一, 建部 泉希, 服部 憲幸, 藤吉 正哉, 渡邉 栄三, 鈴木 貴明, 有吉 範高, 織田 成人, 石井 伊都子

    日本急性血液浄化学会雑誌   6 ( Suppl. )   82 - 82   2015.9

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  • CH1.0N膜での持続的血液濾過透析施行患者のバンコマイシンクリアランスと投与設計に関する検討

    山崎 伸吾, 鈴木 達也, 高塚 博一, 建部 泉希, 服部 憲幸, 竹田 真理子, 藤吉 正哉, 渡邉 栄三, 鈴木 貴明, 有吉 範高, 織田 成人, 石井 伊都子

    TDM研究   32 ( 2 )   162 - 162   2015.5

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  • 持続的血液濾過透析施行患者におけるテイコプラニンクリアランスの評価方法に関する検討

    鈴木 達也, 山崎 伸吾, 高塚 博一, 建部 泉希, 竹田 真理子, 服部 憲幸, 藤吉 正哉, 渡邉 栄三, 鈴木 貴明, 有吉 範高, 織田 成人, 石井 伊都子

    TDM研究   32 ( 2 )   172 - 172   2015.5

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  • マクロファージにおけるCES2A1の泡沫化抑制機序の解析

    竹澤 明香里, 渡辺 健太, 藤吉 正哉, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   135年会 ( 3 )   105 - 105   2015.3

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  • トブラマイシン投与経過中に血清シスタチンCと血清クレアチニンの時間的乖離を認めた1症例

    高塚 博一, 山崎 伸吾, 鈴木 達也, 石井 伊都子, 鈴木 貴明, 有吉 範高

    日本化学療法学会雑誌   63 ( 2 )   242 - 243   2015.3

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  • 新規三次元培養基材を用いた浮遊培養法における血管平滑筋細胞の性質の変化

    名取 知美, 内田 雅士, 金木 達朗, 北原 真樹, 藤吉 正哉, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   135年会 ( 3 )   156 - 156   2015.3

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  • アクロレイン化LDL負荷マクロファージにおけるコレステロール及びapoB代謝の解析

    栗原 瑞季, 渡辺 健太, 藤吉 正哉, 有吉 範高, 五十嵐 一衛, 石井 伊都子

    日本薬学会年会要旨集   135年会 ( 3 )   106 - 106   2015.3

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  • 乳幼児の苺状血管腫に対する院内製剤チモロールゲルの製剤学的検討

    高塚 博一, 山崎 伸吾, 鈴木 達也, 竹田 真理子, 岸本 路子, 力久 直昭, 鈴木 貴明, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   135年会 ( 4 )   138 - 138   2015.3

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  • 高コレステロール食給餌が脳におけるTNFαの発現量と脳機能に与える影響

    叶川 友里, 渡辺 健太, 須藤 知子, 藤吉 正哉, 橋本 謙二, 藤田 有子, 安部 寛子, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   135年会 ( 3 )   88 - 88   2015.3

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  • 栄養摂取方法と栄養摂取量が褥瘡改善に与える影響

    新井 健一, 山本 晃平, 佐藤 由美, 熱海 雪絵, 外川 八英, 三川 信之, 村田 淳, 中村 貴子, 鈴木 貴明, 有吉 範高, 石井 伊都子

    日本静脈経腸栄養学会雑誌   30 ( 1 )   303 - 303   2015.1

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  • 散剤調剤における乳糖賦形量の減量とその評価

    築地 茉莉子, 増田 和司, 鈴木 貴明, 有吉 範高, 石井 伊都子

    千葉医学雑誌   90 ( 6 )   205 - 210   2014.12

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    千葉大学医学部附属病院薬剤部では従来,秤量する散剤の1包あたりの分包重量が0.3gを下回る場合に,散剤調製上の取扱いをしやすくするためにそれ自身薬理作用を有しない散剤(賦形剤)として乳糖を加え,1包量が0.3gになるように調剤することを内規としてきた。しかし,散剤を必要とする小児にとって散剤重量0.3gはしばしば飲み込みが困難な量である。また小児および成人ともに,多剤を同時に経管投与する場合には1回の投与量が多過ぎることによるチューブの閉塞を引き起こす場合がある。一方,近年における散剤分包器ならびに周辺機器の開発進展により,分包後の散剤重量のばらつきは減少していることが予測される。そこで調剤した散剤の分包重量および回収重量のばらつきを許容範囲内に維持しながら乳糖賦形量を減らすことが可能か,複数種類の薬剤を用いて検討した。その結果,1包量が0.2gあるいは0.3gになるように賦形した場合において,分包による薬剤の紛失を含む分包重量のばらつきや,分包紙から取り出す際の薬剤の損失はすべて許容範囲内であり,1包あたりの散剤重量を0.2gとしても現在の調剤方法と変わらない品質で患者に薬剤提供できることが示された。また賦形する散剤の1包量を0.3gから0.2gに変更することによって,散剤調剤時に賦形剤を加える作業を約1割削減することができることが明らかとなった。(著者抄録)

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  • 抗血小板薬応答性を規定する新規因子の究明

    有吉 範高

    上原記念生命科学財団研究報告集   28   1 - 6   2014.12

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    抗血小板薬応答性を規定する新規因子について検討した。経皮的冠動脈形成術(PCI)を施行後、少なくとも1ヵ月以上維持用量のクロピドグレルを内服中で、抗血小板効果が定常状態に到達している114例を対象とした。クロピドグレルの薬物動態との関連性が証明されているか、あるいは関連性が指摘されている遺伝的因子として、薬物代謝酵素5遺伝子7多型、薬物トランスポーター1遺伝子3多型を検討し、クロピドグレルによる血小板応答性と有意な関連性を認めた因子はCYP2C19遺伝子多型のみであった。非遺伝的要因において、PRUと有意な関連性を認めた因子は、性別、脂質異常症であった。ABCB1(MDR1)のアミノ酸置換を伴う多型が定常状態におけるクロピドグレルの効果を予測するのに重要な遺伝的因子である可能性が示唆された。

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  • LC-MSによる新世代Bcr-Ablチロシンキナーゼ阻害薬の血中濃度測定

    後藤 優理, 有吉 範高, 中世古 知昭, 今井 千晶, 石井 伊都子

    JSBMS Letters   39 ( Suppl. )   96 - 96   2014.9

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  • 持続的血液濾過透析によるトブラマイシンの投与期間短縮化が治療効果に寄与したと考えられる1症例

    鈴木 達也, 山崎 伸吾, 高塚 博一, 竹田 真理子, 岸本 路子, 大網 毅彦, 渡邉 栄三, 鈴木 貴明, 有吉 範高, 織田 成人, 石井 伊都子

    日本急性血液浄化学会雑誌   5 ( Suppl. )   81 - 81   2014.9

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  • 緩徐式血漿交換施行中のバンコマイシンの薬物動態を評価した1症例

    山崎 伸吾, 鈴木 達也, 高塚 博一, 服部 憲幸, 大網 毅彦, 内田 雅士, 竹田 真理子, 岸本 路子, 三島 敬, 渡邉 栄三, 大塚 将之, 鈴木 貴明, 有吉 範高, 織田 成人, 宮崎 勝, 石井 伊都子

    日本急性血液浄化学会雑誌   5 ( Suppl. )   87 - 87   2014.9

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  • 28-P1PM-008 処方オーダデータを利用した医薬品管理システムによる自動請求の構築とその効果(医薬品管理,一般演題(ポスター),新時代を拓く医療薬学フロンティア)

    山本 晃平, 川口 真由子, 宮本 仁, 増田 和司, 横山 威一郎, 中村 貴子, 鈴木 貴明, 有吉 範高, 石井 伊都子

    日本医療薬学会年会講演要旨集   24   416 - 416   2014.8

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  • 28-P4PM-086 携帯型持続注入ポンプの流速に関する製品間比較(がん薬物療法(無菌調製・曝露対策),一般演題(ポスター),新時代を拓く医療薬学フロンティア)

    宮本 仁, 山崎 伸吾, 鈴木 達也, 仲佐 啓詳, 中村 貴子, 鈴木 貴明, 有吉 範高, 石井 伊都子

    日本医療薬学会年会講演要旨集   24   441 - 441   2014.8

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  • 28-P4PM-064 アセトニトリル処理によるリネゾリドHPLC測定法の改善(TDM・投与設計2,一般演題(ポスター),新時代を拓く医療薬学フロンティア)

    三浦 剛, 山崎 伸吾, 中村 貴子, 鈴木 貴明, 有吉 範高, 石井 伊都子

    日本医療薬学会年会講演要旨集   24   438 - 438   2014.8

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  • 28-O2AM-09 小児細菌性髄膜炎患者に対するバンコマイシン投与設計において多面的視点が要求された一症例(TDM・投与設計(抗生剤・免疫抑制剤),一般演題(口頭),新時代を拓く医療薬学フロンティア)

    竹田 真理子, 山崎 伸吾, 鈴木 達也, 高塚 博一, 鈴木 貴明, 岸本 路子, 中村 貴子, 有吉 範高, 石井 伊都子

    日本医療薬学会年会講演要旨集   24   231 - 231   2014.8

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  • 28-P2AM-021 手術部において薬剤師の介入により改善された業務とその評価(ハイケアユニット業務,一般演題(ポスター),新時代を拓く医療薬学フロンティア)

    柴田 みづほ, 川口 真由子, 橋本 杏里, 渡辺 健太, 石川 雅之, 新部 陽子, 中村 貴子, 鈴木 貴明, 有吉 範高, 石井 伊都子

    日本医療薬学会年会講演要旨集   24   366 - 366   2014.8

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  • 新規創薬ターゲットおよびバイオマーカーの確立を目指した乳がんにおけるestrogen前駆体の取り込み機構の解明

    松本 准, 有吉 範高, 榊原 雅裕, 中西 猛夫, 石井 伊都子, 山田 治美, 武田 弘志

    国際医療福祉大学学会誌   19 ( 抄録号 )   59 - 59   2014.8

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  • パロキセチンの長期使用に関する遡及的調査

    築地 茉莉子, 橋本 佐, 鈴木 貴明, 有吉 範高, 伊豫 雅臣, 石井 伊都子

    日本医薬品情報学会総会・学術大会講演要旨集   17回   130 - 130   2014.7

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  • 明日から役立つ個別化医療 抗凝固薬・抗血小板薬 個別化医療への挑戦

    有吉 範高

    Personalized Medicine Universe. Japanese Edition   3 ( Suppl.1 )   28 - 28   2014.6

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  • 第二世代Bcr-Abl TKI治療実態下における血中濃度測定の試験的運用と課題

    有吉 範高, 後藤 優理, 今井 千晶, 中世古 知昭, 石井 伊都子

    TDM研究   31 ( 3 )   173 - 173   2014.5

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  • バンコマイシンの極めて高いバイオアベイラビリティーを示した重症消化管疾患症例とその考察

    山崎 伸吾, 鈴木 達也, 高塚 博一, 大網 毅彦, 藤城 健, 石川 雅之, 竹田 真理子, 岸本 路子, 服部 憲幸, 宮内 英聡, 鈴木 貴明, 有吉 範高, 松原 久裕, 織田 成人, 石井 伊都子

    TDM研究   31 ( 3 )   128 - 128   2014.5

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  • 【徹底理解!点眼剤 眼科領域の薬物治療に活かすポイント】点眼剤を実践活用するためのポイント 眼科クリニカルパスにおける点眼剤の手技の評価

    山口 洪樹, 有吉 範高

    薬局   65 ( 5 )   1840 - 1843   2014.4

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    <Key Points>千葉大学医学部附属病院では眼科クリニカルパスにおける点眼指導は薬剤師と看護師が協働して行っている。点眼手技の評価は、評価者間で差が生じていることが問題となっていた。薬剤師と看護師が協議して、共通で用いる点眼手技評価法を作成した。構築した評価法により評価者間における個人差は減少し、点眼手技の把握や指導が必要な患者の抽出、薬剤師と看護師の連携に役立っている。構築した評価法は実際に使用する医療スタッフの合意のもとで作成されたため、日常業務に容易に受け入れられる方法である。(著者抄録)

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  • 難治性口内炎に対するインドメタシンスプレー使用後のQOL評価

    金谷 典子, 新井 健一, 山崎 香織, 増田 和司, 鈴木 貴明, 田口 奈津子, 首藤 潔彦, 中世古 知昭, 仲佐 啓詳, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌   50 ( 3 )   275 - 279   2014.3

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    がん化学療法や放射線療法を施行した患者は難治性の口内炎を発症することが多く、その疼痛のために、摂食不良、不眠、会話困難などのquality of life(以下、QOL)が低下することが多い。口内炎の疼痛に対し、インドメタシンスプレーが使用され、その有用性が各施設より報告されているが、QOLについて詳細な評価がなされていない。そこで、本研究では、千葉大学医学部附属病院において、インドメタシンスプレーを使用した患者に対して薬剤師がアンケート調査を行い、QOLに及ぼす効果を評価することを目的とした。患者アンケートの結果、疼痛の軽減、QOLの向上が示唆された。(著者抄録)

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  • 経皮的冠動脈形成術施行患者におけるクロピドグレルの抗血小板効果予測アルゴリズムの構築

    三浦 剛, 有吉 範高, 佐藤 泰憲, 山口 洪樹, 岩田 曜, 藤本 善英, 小林 欣夫, 石井 伊都子

    日本薬学会年会要旨集   134年会 ( 4 )   60 - 60   2014.3

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  • 3次元培養における血管平滑筋細胞の増殖抑制におけるp21CIP1の役割

    鈴木 佐季, 内田 雅士, 渡辺 健太, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   134年会 ( 3 )   125 - 125   2014.3

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  • 腎臓由来培養細胞におけるβ-VLDL負荷の影響

    竹内 美穂, 渡辺 健太, 内田 雅士, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   134年会 ( 3 )   71 - 71   2014.3

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  • 薬剤師による処方設計 心房細動に対する抗血栓療法における処方設計支援

    山口 洪樹, 三浦 剛, 鈴木 貴明, 仲佐 啓詳, 有吉 範高, 石井 伊都子

    医薬ジャーナル   50 ( 1 )   164 - 169   2014.1

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    抗凝固薬は「ハイリスク薬」に分類され、薬剤師は患者への指導だけでなく、医療スタッフへの情報提供や処方設計について積極的に関与していくことが求められている。近年、心房細動に対する抗血栓療法は新規抗凝固薬の登場により、患者に応じた選択が可能となった。一方で、既に服用されていた抗凝固薬が、さまざまな理由により他の抗凝固薬へ変更されるケースも散見されるようになった。本稿では、千葉大学医学部附属病院において、ダビガトランからワルファリンへの切り替えを行った症例および、ワルファリンからダビガトランへの切り替えを検討した症例について、薬剤師が介入し、処方設計支援を行ったので報告する。(著者抄録)

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  • Fcγ受容体多型と抗EGFR抗体を含む化学療法の効果に関する後方視的解析

    有吉 範高, 佐藤 彩, 宮内 英聡, 吉留 博之, 多田 素久, 山崎 香織, 佐藤 泰憲, 山本 晃平, 松原 久裕, 宮崎 勝, 横須賀 收, 石井 伊都子

    臨床薬理   44 ( Suppl. )   S258 - S258   2013.11

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  • 経口栄養摂取率が食道癌化学療法・化学放射線療法による口内炎に及ぼす影響

    山本 晃平, 新井 健一, 山崎 香織, 竹田 真理子, 川口 真由子, 佐藤 由美, 鍋谷 圭宏, 古川 勝規, 鈴木 貴明, 仲佐 啓詳, 有吉 範高, 石井 伊都子

    外科と代謝・栄養   47 ( 3 )   116 - 116   2013.6

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  • リウマチ疾患モデルマウスにおいてsynbiotics投与が病態および腸管免疫に及ぼす影響

    竹田 真理子, 渡辺 健太, 八木 聡子, 内田 雅士, 中里 有希, 鈴木 佐季, 竹内 美穂, 福本 泰典, 新井 健一, 山本 晃平, 増田 和司, 古川 勝規, 中村 裕義, 鈴木 貴明, 仲佐 啓詳, 有吉 範高, 北田 光一, 石井 伊都子

    外科と代謝・栄養   47 ( 3 )   118 - 118   2013.6

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  • 生体部分肝移植術後の門脈狭窄に対するステント挿入処置によるタクロリムス薬物動態の変化

    宮崎 宏史, 山形 真一, 大塚 将之, 山崎 伸吾, 堀越 光子, 丸山 紀史, 鈴木 貴明, 仲佐 啓詳, 有吉 範高, 横須賀 收, 宮崎 勝, 北田 光一, 石井 伊都子

    TDM研究   30 ( 3 )   186 - 186   2013.5

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  • I型コラーゲン三次元培養系における血管平滑筋細胞のタンパク分解機構

    八木 聡子, 内田 雅士, 渡辺 健太, 有吉 範高, 石井 伊都子

    日本薬学会年会要旨集   133年会 ( 3 )   100 - 100   2013.3

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  • Analysis of Risk Factors Influencing Development of Renal Failure with Cyclosporin A in Hematopoietic Stem Cell Transplantation Recipients

    Miyamoto Jin, Nakaseko Chiaki, Kitada Mitsukazu, Suzuki Takaaki, Yamazaki Shingo, Imai Chiaki, Koga Hitomi, Takeda Mariko, Nakasa Hiromitsu, Nakamura Hiroyoshi, Ariyoshi Noritaka

    Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences)   39 ( 1 )   45 - 51   2013.1

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    Renal failure induced by cyclosporin A(CyA) in hematopoietic stem cell transplantation recipients is frequently observed as a major side effect. However, it is difficult to compare the frequency or severity among the reports because of differences in the method of administering CyA. In addition, there is little analysis of risk factors influencing the development of renal failure. Therefore, in this study, we tried to analyze risk factors influencing the development of renal failure induced by CyA in hematopoietic stem cell transplantation recipients at Chiba University Hospital using patient records. Among 50 patients in our study, 26 (52%) developed renal failure (grade 2 &lt;), and serum creatinine reached maximum 32.7 days after the initiation of CyA administration on average. The mean blood CyA concentration was not correlated with the variance of serum creatinine (r = 0.12). In univariate analysis, the frequency of renal failure was significantly higher in females than that in males (&lt;i&gt;P&lt;/i&gt; = 0.02). In addition, female and myeloablative conditioning were shown to be significant risk factors by multivariate analysis. These findings suggest that it is necessary to observe changes in clinical examination data such as BUN, uric acid, and serum creatinine more carefully because the risk of renal failure increases in patients with such risk factors.

    DOI: 10.5649/jjphcs.39.45

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  • Synbiotics投与がリウマチ疾患モデルマウスにおける病態に及ぼす影響

    竹田 真理子, 渡辺 健太, 八木 聡子, 内田 雅士, 中里 有希, 鈴木 佐季, 竹内 美穂, 新井 健一, 山本 晃平, 増田 和司, 古川 勝規, 仲佐 啓詳, 有吉 範高, 石井 伊都子, 北田 光一

    静脈経腸栄養   28 ( 1 )   195 - 195   2013.1

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  • 当院における経腸栄養マニュアルの評価と今後の展望

    新井 健一, 山本 晃平, 竹田 真理子, 花澤 豊行, 古川 勝規, 佐藤 由美, 烏 祐佳里, 前田 芙美, 吉田 由香, 鍋谷 圭宏, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    静脈経腸栄養   27 ( 6 )   1403 - 1403   2012.11

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  • P2-039 薬剤師と医師による定期処方協働入力の試み(薬剤管理指導・病棟薬剤業務,ポスター,一般演題,岐路に立つ医療〜千年紀の目覚め〜よみがえれ!ニッポン!薬の改革は我らが手で!)

    山口 洪樹, 三浦 剛, 石井 晃, 石田 敬一, 仲佐 啓詳, 中村 裕義, 松宮 護郎, 有吉 範高, 北田 光一

    日本医療薬学会年会講演要旨集   22   385 - 385   2012.10

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  • 薬物治療とpharmacogenetics

    有吉 範高

    アレルギー   61 ( 7 )   941 - 947   2012.7

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    pharmacogeneticsとは薬理学と遺伝学からなる造語である。pharmacogeneticsが対象とするのは、薬物応答性に関連する遺伝的な要因であり、主として薬物動態に関与するタンパク質或いは薬理効果に関与する標的タンパク質などの遺伝子多型を対象とする。アレルギー疾患領域におけるpharmacogenetics研究において、現在、最も注目されているロイコトリエン受容体拮抗薬の応答性予測などについて述べた。

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  • 分包調剤したシクロスポリン細粒製剤の光安定性に関する検討

    山崎 伸吾, 中村 裕義, 山形 真一, 仲佐 啓詳, 有吉 範高, 北田 光一

    日本医薬品情報学会総会・学術大会講演要旨集   15回   68 - 68   2012.6

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  • 【個別化薬物療法-始まっている臨床応用】薬剤師が始める臨床現場での遺伝子診断

    有吉 範高

    薬事   54 ( 6 )   975 - 978   2012.6

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    薬物応答性の個体差の一部は、遺伝的要因によって決定されているため、遺伝子多型診断の実施がその個体の薬物応答性を推測する際に有益な場合があり、今後増えていくことが期待されている。現時点において国が保険適用としているものは、イリノテカン塩酸塩による重篤な副作用と関連するUGT1A1遺伝子多型の診断のみであるが、遺伝子多型診断を行うことで、副作用の原因を推定したり、投与量の変更による薬物療法是正の根拠を得られる場合はほかにもある。本稿では、薬剤師が関わることが望ましいと考えられる遺伝子診断の特徴や始め方、遺伝子診断結果の取り扱いなどについて解説する。(著者抄録)

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  • カルバマゼピン誘発SCARsのリスク因子HLA-A*3101の簡易迅速診断法の開発

    内山 数貴, 久保田 史佳, 有吉 範高, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   132年会 ( 4 )   198 - 198   2012.3

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  • ApoEヘテロ欠損マウスへのCES2A1導入による動脈硬化抑制作用

    藤内 真実, 渡辺 健太, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   132年会 ( 3 )   105 - 105   2012.3

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  • オーラプテンによるTHP-1細胞の細胞増殖抑制

    前田 悠佑, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   132年会 ( 3 )   89 - 89   2012.3

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  • I型コラーゲン3次元培養系における血管平滑筋細胞の増殖停止と翻訳因子に関する解析

    内田 雅士, 石井 伊都子, 有吉 範高, 五十嵐 一衛, 北田 光一

    日本薬学会年会要旨集   132年会 ( 3 )   96 - 96   2012.3

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  • 細胞増殖制御における血管平滑筋細胞とNIH3T3細胞の比較

    八木 聡子, 石井 伊都子, 内田 雅士, 有吉 範高, 五十嵐 一衛, 北田 光一

    日本薬学会年会要旨集   132年会 ( 3 )   95 - 95   2012.3

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  • 感染制御チームによるスナップ・ショットを用いた抗菌薬適正使用への試み

    三浦 剛, 中村 裕義, 千葉 均, 井上 智香子, 瀬川 俊介, 渡辺 正治, 渡辺 哲, 石和田 稔彦, 佐藤 武幸, 仲佐 啓詳, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   132年会 ( 4 )   192 - 192   2012.3

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  • エストロゲン前駆体の取り込みがホルモン依存性乳がんの増殖に及ぼす影響

    松本 准, 有吉 範高, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   132年会 ( 3 )   111 - 111   2012.3

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  • NSTによる経腸栄養マニュアル作成とその評価

    新井 健一, 山本 晃平, 竹田 真理子, 花澤 豊行, 古川 勝規, 佐藤 由実, 烏 祐佳里, 前田 芙美, 吉田 由香, 鍋谷 圭宏, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    静脈経腸栄養   27 ( 1 )   519 - 519   2012.1

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  • Drug therapy and pharmacogenetics

    Noritaka Ariyoshi

    Japanese Journal of Allergology   61 ( 7 )   941 - 947   2012

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    Scopus

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  • I型コラーゲン3次元培養系における血管平滑筋細胞の増殖停止と翻訳開始因子の関わり

    内田 雅士, 石井 伊都子, 有吉 範高, 五十嵐 一衛, 北田 光一

    日本生化学会大会プログラム・講演要旨集   84回   4T16p - 17   2011.9

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  • 日本人における3種類のCYP3A4遺伝子多型がタクロリムスの主代謝反応に及ぼす影響

    有吉 範高, 佐々木 達也, 竹田 真理子, 島田 誠, 山形 真一, 中村 裕義, 仲佐 啓詳, 石井 伊都子, 北田 光一

    TDM研究   28 ( 3 )   s181 - s181   2011.6

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  • 生体部分肝移植患者におけるバンコマイシンの薬物動態

    山崎 伸吾, 山形 真一, 代市 拓也, 中村 安孝, 大塚 将之, 仲佐 啓詳, 中村 裕義, 有吉 範高, 宮崎 勝, 北田 光一

    日本化学療法学会雑誌   59 ( Suppl.A )   250 - 250   2011.6

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  • 薬物治療とpharmacogenetics

    有吉 範高

    アレルギー   60 ( 3-4 )   329 - 329   2011.4

  • 妊婦への子宮頸管熟化薬投与における胎児突然死の原因究明に関する研究

    松本 准, 有吉 範高, 粕谷 優子, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   131年会 ( 4 )   193 - 193   2011.3

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  • 抗EGFR抗体薬応答性予測の簡易診断法

    岩崎 裕佳里, 石井 伊都子, 糸賀 栄, 松下 一之, 野村 文夫, 松原 久裕, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   131年会 ( 4 )   193 - 193   2011.3

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  • 食餌性高コレステロール血症がマウス腎臓に及ぼす影響

    野村 里香, 石井 伊都子, 富澤 宏之, 藤内 真実, Rumiana Bakalova, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   131年会 ( 3 )   84 - 84   2011.3

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  • アクロレイン化LDLにおけるアポBへの影響とマクロファージの泡沫化

    渡辺 健太, 石井 伊都子, 五十嵐 一衛, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   131年会 ( 3 )   84 - 84   2011.3

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  • 柑橘類由来オーラプテンによるTHP-1細胞のG1-S期移行遅延

    前田 悠佑, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   131年会 ( 3 )   92 - 92   2011.3

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  • CES2A1導入によるマウスにおける動脈硬化病巣の変化

    藤内 真実, 渡辺 健太, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   131年会 ( 3 )   84 - 84   2011.3

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  • RAW264.7細胞の泡沫化に対するケフィランの効果

    篠塚 晴子, 石井 伊都子, 戸井田 敏彦, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   131年会 ( 3 )   84 - 84   2011.3

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  • 抗血小板薬誘発肝障害との関連性が疑われるHLA型遺伝子診断法の開発

    内山 数貴, 有吉 範高, 久保田 史佳, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   131年会 ( 4 )   193 - 193   2011.3

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  • 経口摂食の有無が食道癌化学療法・化学放射線療法による口内炎に及ぼす影響

    山本 晃平, 新井 健一, 金谷 典子, 山崎 香織, 竹田 真理子, 鍋谷 圭宏, 古川 勝規, 佐藤 由美, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    静脈経腸栄養   26 ( 1 )   312 - 312   2011.1

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  • I型コラーゲン3次元培養系における血管平滑筋細胞の増殖停止

    内田 雅士, 石井 伊都子, 前田 悠佑, 有吉 範高, 北田 光一

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   2P - 0396   2010.12

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  • タウリンクロラミンによるマクロファージのコレステロール蓄積抑制作用

    加藤 淳平, 石井 伊都子, 有吉 範高, 北田 光一

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   1P - 0013   2010.12

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  • 眼科クリニカルパスにおける点眼手技評価方法の統一化に向けた取り組み

    山口 洪樹, 三浦 剛, 舩本 智津子, 加藤 陽子, 加瀬 千鶴, 石井 晃, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    日本クリニカルパス学会誌   12 ( 4 )   608 - 608   2010.11

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  • 造血幹細胞移植後のシクロスポリンによる腎障害の危険因子の解析

    宮本仁, 鈴木貴明, 今井千晶, 古賀ひとみ, 竹田真理子, 山崎伸吾, 仲佐啓詳, 中村裕義, 有吉範高, 中世古知昭, 北田光一

    日本医療薬学会年会講演要旨集   20th   415   2010.10

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    J-GLOBAL

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  • 【体内動態における薬物相互作用を評価する】代謝酵素が関係した相互作用 イトラコナゾールとCYP3A4代謝薬剤

    長谷川 敦, 有吉 範高

    薬局   61 ( 8 )   2810 - 2815   2010.7

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    <Key Points>イトラコナゾール代謝物も強力なCYP3A4阻害作用を有する。イトラコナゾール200mgとケトコナゾール400mgは同程度の阻害強度を示す。(著者抄録)

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  • 持続血液ろ過透析施行患者におけるバンコマイシンの薬物動態と投与設計方法

    山形 真一, 山崎 伸吾, 三浦 剛, 林 彰子, 貞広 智仁, 仲佐 啓詳, 中村 裕義, 有吉 範高, 織田 成人, 北田 光一

    TDM研究   27 ( 3 )   s151 - s151   2010.6

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  • 統計学的解析及び動物実験による新規ワルファリン投与量予測因子の探索

    原田 匠, 有吉 範高, 志村 仁史, 佐藤 泰憲, 横山 威一郎, 高橋 香, 伊勢川 直久, 山形 真一, 今牧 瑞浦, 小林 欣夫, 石井 伊都子, 宮崎 勝, 北田 光一

    日本薬学会年会要旨集   130年会 ( 4 )   174 - 174   2010.3

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  • 柑橘類中オーラプテンはcAMP-PKA経路を介してTHP-1細胞増殖を阻害する可能性がある(Citrus auraptene can inhibit THP-1 cell proliferation through cAMP-PKA pathway)

    Parajuli Paudel Ramila, 石井 伊都子, 村上 茂, 佐々木 貴生, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   130年会 ( 3 )   151 - 151   2010.3

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  • アクロレイン化LDLがマクロファージの泡沫化に与える影響

    渡辺 健太, 石井 伊都子, 斎木 遼太郎, 五十嵐 一衛, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   130年会 ( 3 )   88 - 88   2010.3

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  • 妊婦への子宮頸管熟化薬投与における胎児突然死の原因究明に関する研究

    松本 准, 有吉 範高, 粕谷 優子, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   130年会 ( 4 )   174 - 174   2010.3

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  • 抗ヒトEGFR抗体適正使用に向けたがん細胞における複数の体細胞変異の同時診断

    岩崎 裕佳里, 有吉 範高, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   130年会 ( 4 )   174 - 174   2010.3

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  • 血管平滑筋細胞の増殖および分化に対するアンチザイムの役割

    金子 裕美, 石井 伊都子, 東 恭平, 五十嵐 一衛, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   130年会 ( 3 )   77 - 77   2010.3

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  • TPNのglucose投与速度が肝機能に与える影響

    新井 健一, 宮崎 宏史, 山本 晃平, 竹田 真理子, 仲佐 啓詳, 中村 裕義, 有吉 範高, 鍋谷 圭宏, 松原 久裕, 北田 光一

    静脈経腸栄養   25 ( 1 )   473 - 473   2010.1

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  • GCP改正に伴う治験審査委員会の記録の概要公表への対応と今後の課題についての検討

    青柳 玲子, 花岡 英紀, 加藤 えり子, 山崎 敦美, 貞光 美幸, 近藤 夏美, 小林 えり, 渡辺 千穂, 谷岡 恭子, 椎名 貴美江, 有吉 範高, 北田 光一

    臨床薬理   40 ( Suppl. )   S248 - S248   2009.11

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  • ゲノム創薬の最新動向と展望 薬物治療個別適正化に遺伝子診断が有用であった例と病院でのエビデンス構築の試み

    有吉 範高

    臨床薬理   40 ( Suppl. )   S110 - S110   2009.11

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  • 添付文書中の相互作用に関する記載の問題点とその改善策の検討

    山崎 香織, 和田 早也乃, 鈴木 貴明, 土屋 晃三, 松島 徹, 木村 真春, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    千葉県薬剤師会雑誌   55 ( 11 )   1022 - 1022   2009.11

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  • UGT1A1*28、*6とイリノテカン副作用および治療効果との関連の検討

    佐藤 麻美, 宮内 英聡, 坂田 治人, 大平 学, 森田 絢子, 有吉 範高, 北田 光一, 松原 久裕

    日本癌治療学会誌   44 ( 2 )   641 - 641   2009.9

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  • 中性コレステロールエステラーゼが示す基質の至適条件と泡沫化抑制作用

    渡辺 健太, 石井 伊都子, 有吉 範高, 北田 光一

    日本生化学会大会プログラム・講演要旨集   82回   2T18a - 1   2009.9

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  • 薬効制御因子の遺伝子情報を活用した個別化薬物治療戦略の確立を目指した臨床研究

    有吉 範高

    臨床薬理の進歩   ( 30 )   29 - 41   2009.7

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    薬効制御因子(主として上皮成長因子受容体(EGFR)とワルファリン標的分子(VKOR)C1)の遺伝子情報を活用した薬物治療個別適正化の戦略に関する検討結果について報告した。肺癌組織からのEGER遺伝子変異診断は、変異をもたない癌組織、あるいは正常組織の混入が避けられないことから、それら変異陰性の組織の混入割合により変異の存在率が連続的に変化する。維持用量がすでに確定している患者の検体を入手できるのであれば、VKORC1やCYP2C9以外に、ワルファリン維持用量と関連する未同定の薬効制御因子を探索することも重要と考えた。WBCは、ワルファリン維持投与量と関連する、これまでに報告されていない新規の独立した非遺伝的因子である可能性が示唆された。予測精度向上に寄与する因子として、アロプリノールとWBCを見出し、それらを変数として追加した独自の投与量予測アルゴリズムを構築した。

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  • CYP3A5はコルチゾール代謝に関与しない

    有吉 範高, 高崎 由樹子, 中村 裕義, 石井 伊都子, 北田 光一

    TDM研究   26 ( 3 )   s207 - s207   2009.6

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  • 千葉大学病院における遺伝カウンセリングの現状 遺伝カウンセリング室から遺伝子診療部へ

    野村 文夫, 宇津野 恵美, 石井 拓磨, 長田 久夫, 金井 数明, 梅村 啓史, 松下 一之, 木原 真紀, 西村 基, 澤井 摂, 浦尾 充子, 難波江 玲子, 葛田 衣重, 大町 和美, 峯尾 アヤ, 有吉 範高, 市川 智彦, 羽田 明

    日本遺伝カウンセリング学会誌   30 ( 1 )   64 - 64   2009.4

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  • ウサギの動脈硬化形成に対する米ケフィランの抑制効果

    井上 千嘉, 内田 雅士, 石井 伊都子, 渡辺 健太, 細山 沙織, 戸井田 敏彦, 朱 霞, 加藤 久宜, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   129年会 ( 3 )   64 - 64   2009.3

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  • 医薬品代謝におけるCYP1A1の寄与

    玉造 竜郎, 有吉 範高, 中村 裕義, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   129年会 ( 3 )   95 - 95   2009.3

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  • 日本人に認められるCYP3A4多型が示す薬物代謝酵素活性

    佐々木 達也, 竹田 真理子, 有吉 範高, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   129年会 ( 3 )   95 - 95   2009.3

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  • 特定HLA-Aハプロタイプの簡易診断法の開発と評価

    久保田 史佳, 有吉 範高, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   129年会 ( 4 )   162 - 162   2009.3

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  • タウリンクロラミンのコレステロール蓄積抑制作用

    宮崎 宏史, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   129年会 ( 3 )   64 - 64   2009.3

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  • 当院における入院患者の経腸栄養剤使用経過と問題点の検討

    山本 晃平, 新井 健一, 竹田 真理子, 鍋谷 圭宏, 櫻井 健一, 鮫田 真理子, 野本 尚子, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    静脈経腸栄養   24 ( 1 )   459 - 459   2009.1

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  • 千葉大学医学部附属病院における高カロリー輸液使用実態調査 現状の問題点と今後の課題

    新井 健一, 山本 晃平, 竹田 真理子, 鍋谷 圭宏, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    静脈経腸栄養   24 ( 1 )   255 - 255   2009.1

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  • IRB審査での自主臨床試験プロトコール指摘事項の検討 IRB審査および事前検討会の目指すもの

    青柳 玲子, 花岡 英紀, 山崎 淳美, 有吉 範高, 北田 光一

    臨床薬理   39 ( Suppl. )   S300 - S300   2008.11

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  • 白内障手術患者に対する薬剤管理指導の評価と質的向上への試み

    山口 洪樹, 山本 晃平, 佐伯 宏美, 大久保 正人, 高橋 香, 鈴木 貴明, 三浦 剛, 加藤 三枝, 石井 晃, 仲佐 啓詳, 中村 裕義, 有吉 範高, 北田 光一

    千葉県薬剤師会雑誌   54 ( 11 )   932 - 932   2008.11

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  • Warfarin投与量推定アルゴリズムの予測精度向上に寄与する因子の探索的検討

    原田 匠, 志村 仁史, 有吉 範高, 横山 威一郎, 高橋 香, 山崎 伸吾, 三浦 剛, 山形 真一, 宮崎 勝, 北田 光一

    臨床薬理   39 ( Suppl. )   S174 - S174   2008.11

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  • Warfarin維持用量予測におけるcalumenin R4Q多型と用量推定アルゴリズムの有用性評価

    原田 匠, 志村 仁史, 有吉 範高, 高橋 香, 横山 威一郎, 山崎 伸吾, 三浦 剛, 山形 真一, 今牧 瑞浦, 宮崎 勝, 北田 光一

    TDM研究   25 ( 3 )   s235 - s235   2008.6

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  • 静注用ブスルファン添付文書記載の小児投与量の妥当性に関する検討

    中村 裕義, 佐藤 武幸, 高塚 博一, 山崎 伸吾, 三浦 剛, 山形 真一, 仲佐 啓詳, 有吉 範高, 北田 光一

    TDM研究   25 ( 3 )   s197 - s197   2008.6

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  • ブスルファン代謝におけるGST isozymeと遺伝子多型の影響の検討

    原田 匠, 有吉 範高, 三浦 剛, 長谷川 敦, 山形 真一, 中村 裕義, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   128年会 ( 3 )   3 - 3   2008.3

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  • CYP3A4およびCYP3A5によるcortisol 6β-水酸化酵素活性の比較

    高崎 由樹子, 有吉 範高, 中村 裕義, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   128年会 ( 3 )   3 - 3   2008.3

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  • 日本人に認められるCYP1A1多型がアゼラスチン代謝に及ぼす影響

    有吉 範高, 小笠原 瞳, 加藤 恵介, 石井 伊都子, 秋田 弘幸, 北田 光一

    日本薬学会年会要旨集   128年会 ( 3 )   3 - 3   2008.3

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  • 千葉大学医学部附属病院におけるNST活動の現状と問題点 薬剤師の観点から

    新井 健一, 山本 晃平, 鍋谷 圭宏, 櫻井 健一, 古川 勝規, 烏 祐佳里, 二川 真理子, 小川 常子, 野本 尚子, 田村 道子, 中村 裕義, 有吉 範高, 北田 光一

    静脈経腸栄養   23 ( 増刊 )   243 - 243   2008.1

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  • 自主臨床試験の試験デザインと試験の信頼性について

    青柳 玲子, 花岡 英紀, 金子 洋子, 近藤 夏未, 小林 えり, 加藤 えり子, 有吉 範高, 北田 光一

    臨床薬理   38 ( Suppl. )   S172 - S172   2007.11

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  • CYP2B6遺伝子多型がエファビレンツ代謝酵素活性に及ぼす影響

    小原 美由紀, 金子 真弓, 有吉 範高, 中村 裕義, 石井 伊都子, 北田 光一

    臨床薬理   38 ( Suppl. )   S183 - S183   2007.11

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  • CYP1A1多型がグラニセトロン代謝酵素活性に及ぼす影響

    有吉 範高, 小笠原 瞳, 中村 裕義, 石井 伊都子, 北田 光一

    臨床薬理   38 ( Suppl. )   S181 - S181   2007.11

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  • 【薬学的視点から薬をみる力 薬物動態パラメータをどう読むか?】各種パラメータが意味するものと生体の変動要因 薬物代謝の変動要因と医薬品使用上の注意点

    山形 真一, 有吉 範高

    薬事   49 ( 9 )   1299 - 1306   2007.9

  • 個別化医療と医薬品適正使用

    有吉 範高

    薬事新報   ( 2485 )   9 - 16   2007.8

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  • 次世代の動脈硬化研究を担う若者たちの集い 領域を超えた交流による新たな展開 マクロファージのコレステロール代謝におけるpitavastatinの影響

    秋里 圭恵, 石井 伊都子, 北原 真樹, 玉木 太郎, 斉藤 康, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   127年会 ( 1 )   281 - 281   2007.3

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  • 【薬学6年制 10年後を見据えて】大学病院の立場から 医療現場で求められる質の高い薬剤師を育てるために

    有吉 範高

    医薬ジャーナル   43 ( 1 )   89 - 93   2007.1

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    実地医療の現場で活躍できる"質の高い薬剤師"を育成するための薬学6年制が始まり、いよいよその一期生が入学してきた。薬剤師に限らず、一般に質の高い人材を育成するためには少数精鋭主義が取られるべきである。だが、それに逆行するように次々と大学や学部が新設され、また長期実務実習を含めた教育のあり方に関しては統一的方針も定まらぬまま、混沌とした状況が今後もしばらく続くものと考えられる。今回、本企画の立案に関わられた先生のお一人から、「10年後を見据えた薬学6年制への思いのたけをぶつけて欲しい」とのご依頼をいただき、現場経験が浅い筆者で本当に良いのかという戸惑いはあったが、学部での在職期間が長かったため、今後6年制教育において先導的立場をとるべき薬学部の事情も比較的よく理解しているという立場から何か提言できることもあるのではないかと考え、ご依頼を引き受けた。本稿では、6年制の学部教育に必要なものとして筆者が感じている点について、持論を書かせていただくことにした。(著者抄録)

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  • 血液を用いた遺伝子多型診断が誤判定をもたらした一症例

    有吉 範高, 鈴木 貴明, 三浦 剛, 中澤 一純, 北田 光一

    臨床薬理   37 ( Suppl. )   S230 - S230   2006.11

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  • 脂肪肝がCYP2C9活性に及ぼす影響

    小原 美由紀, 清水 洋子, 有吉 範高, 中村 裕義, 石井 伊都子, 中澤 一純, 北田 光一

    臨床薬理   37 ( Suppl. )   S134 - S134   2006.11

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  • 自主臨床試験における試験薬管理について

    高見 真理子, 花岡 英紀, 青柳 玲子, 万代 千尋, 仲佐 啓詳, 中村 貴子, 藤村 光子, 有吉 範高, 北田 光一, 齋藤 康

    臨床薬理   37 ( Suppl. )   S236 - S236   2006.11

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  • 【薬剤師による臨床研究の進め方 日常業務から医療薬学研究のシーズを育てる】臨床研究の実際 臨床研究の種類と手法 臨床事例から研究への展開

    中村 裕義, 有吉 範高, 北田 光一

    薬事   48 ( 8 )   1181 - 1187   2006.7

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  • 薬物血中モニタリングの現状と課題 遺伝子多型診断の臨床適用に関する私見

    有吉 範高

    Drug Metabolism and Pharmacokinetics   21 ( 3 )   9 - 13   2006.6

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  • 外来化学療法の取り組み 千葉大学医学部附属病院における外来化学療法への薬剤師の関与 外来注射オーダリングシステムを利用した薬剤師による注射剤ミキシング

    仲佐 啓詳, 中澤 一純, 有吉 範高, 北田 光一

    薬事新報   ( 2426 )   31 - 36   2006.6

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  • 薬剤師による処方支援(16)TDMによる抗生物質の処方支援

    三浦 剛, 中村 裕義, 有吉 範高

    医薬ジャ-ナル   42 ( 5 )   140 - 148   2006.5

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    Other Link: http://search.jamas.or.jp/link/ui/2006161758

  • 薬剤師による処方支援 TDMによる抗生物質の処方支援

    三浦 剛, 中村 裕義, 有吉 範高, 中澤 一純, 北田 光一

    医薬ジャーナル   42 ( 5 )   1490 - 1498   2006.5

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    薬剤師がTDM(therapeutic drug monitoring)を実施し,チーム医療の一員として医師の処方設計に対し支援を行うことは,個別化医療を意識した医薬品の有効かつ安全な使用に大きく貢献している良い例の一つであると言える.千葉大学医学部附属病院では,現在20数種類の薬物のTDMを行っており,本稿ではその中でも抗MRSA(メチシリン耐性黄色ブドウ球菌)薬を中心とした抗生物質のTDMを,薬剤師による処方支援の例として紹介する(著者抄録)

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  • 加齢がマクロファージコレステロール代謝に及ぼす影響

    清水 香奈子, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   126年会 ( 3 )   37 - 37   2006.3

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  • 血管平滑筋細胞の分化過程と発現蛋白の変化

    平田 香織, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   126年会 ( 3 )   93 - 93   2006.3

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  • 【小児の薬物療法とTDM】小児の薬物動態の基礎を学ぶ 肝薬物代謝酵素の発育による変化を理解する

    有吉 範高

    薬局   57 ( 2 )   175 - 190   2006.2

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  • WEBを用いた治験ネットワーク臨床試験支援システムCANVASについて

    花岡 英紀, 青柳 玲子, 山口 千穂, 並木 一枝, 桜井 千尋, 黄野 麻子, 飯沼 君子, 有吉 範高, 北田 光一, 齋藤 康

    臨床薬理   36 ( Suppl. )   S227 - S227   2005.11

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  • 造血幹細胞移植前処置における小児のブスルファン母集団薬物動態解析

    中村 裕義, 佐藤 武幸, 三浦 剛, 中澤 一純, 有吉 範高, 北田 光一

    臨床薬理   36 ( Suppl. )   S151 - S151   2005.11

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  • IRB機能強化のための治験事前審査への取り組みについて

    青柳 玲子, 花岡 英紀, 高見 真理子, 桜井 千尋, 大野 洋子, 成田 陽子, 岡本 尚子, 有吉 範高, 北田 光一, 齋藤 康

    臨床薬理   36 ( Suppl. )   S300 - S300   2005.11

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  • 【ファーマコジェノミクスと薬剤感受性】基礎 薬物の代謝多型と薬剤応答性

    有吉 範高, 北田 光一

    最新医学   60 ( 9 )   1809 - 1818   2005.9

  • 造血幹細胞移植施行患者におけるフルコナゾール血中濃度モニタリングの有用性の検討

    鈴木 貴詞, 岡田 賢二, 中村 裕義, 有吉 範高, 中澤 一純, 北田 光一

    TDM研究   22 ( 2 )   143 - 144   2005.4

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  • シトクロムP450およびミクロゾーマルエポキシドヒドロラーゼがヒトUGTlAlの活性に及ぼす影響

    西村 嘉雄, 石井 祐次, 竹田 修三, 有吉 範高, 山田 英之

    日本薬学会年会要旨集   125年会 ( 3 )   121 - 121   2005.3

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  • ヒトマクロファージにおける2種類の中性コレステロールエステラーゼ

    岩田 大, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   125年会 ( 3 )   29 - 29   2005.3

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  • ゲフィチニブ応答性を規定する遺伝子変異診断法の確立

    有吉 範高, 中澤 一純, 北田 光一

    日本薬学会年会要旨集   125年会 ( 2 )   195 - 195   2005.3

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  • CYP2C9 splicing variantの同定と機能解析

    清水 洋子, 小林 由香, 有吉 範高, 中村 裕義, 石井 伊都子, 中澤 一純, 北田 光一

    日本薬学会年会要旨集   125年会 ( 3 )   117 - 117   2005.3

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  • 遺伝子多型解析の成果による臨床応用の新展開 遺伝子多型診断の臨床応用における問題点 病院薬剤部の立場から

    有吉 範高

    臨床薬理   36 ( 1 )   65S - 66S   2005.1

  • Polymorphismと薬剤感受性

    有吉 範高

    循環器科   56 ( 5 )   522 - 534   2004.11

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  • 遺伝子多型解析の成果による臨床応用の新展開 遺伝子多型診断の臨床応用における問題点 病院薬剤部の立場から

    有吉 範高

    臨床薬理   35 ( Suppl. )   S93 - S93   2004.8

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  • PXR遺伝子上流多型とCYP3A4 basal activityとの関連性評価(第2報)

    有吉 範高, 中村 裕義, 仲佐 啓詳, 中澤 一純, 北田 光一

    臨床薬理   35 ( Suppl. )   S180 - S180   2004.8

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  • 千葉大学におけるIRBの安全性の審議について

    青柳 玲子, 花岡 英紀, 岡本 尚子, 有吉 範高, 櫻井 千尋, 並木 一枝, 山口 千穂, 大野 洋子, 黄野 麻子, 金澤 薫, 北田 光一, 齋藤 康

    臨床薬理   35 ( Suppl. )   S158 - S158   2004.8

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  • 血液透析スケジュールを考慮したアルベカシンの投与設計

    岡田 賢二, 鈴木 貴詞, 中村 裕義, 石川 耕, 有吉 範高, 中澤 一純, 齋藤 康, 北田 光一

    TDM研究   21 ( 2 )   121 - 122   2004.4

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  • 血管平滑筋細胞の分化における細胞骨格の重要性

    田代 佳織, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   124年会 ( 3 )   139 - 139   2004.3

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  • 【抗がん剤の適正使用へのポイント】抗がん剤の薬物間相互作用

    有吉 範高, 北田 光一

    薬局   55 ( 3 )   1468 - 1480   2004.3

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  • 日本人に多いCYP2B6多型がシクロホスファミドの代謝的活性化に及ぼす影響 発現系での検証

    安富祖 咲乃, 有吉 範高, 中村 裕義, 石井 伊都子, 仲佐 啓詳, 中澤 一純, 舩江 良彦, 北田 光一

    日本薬学会年会要旨集   124年会 ( 4 )   26 - 26   2004.3

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  • p27kip1ノックアウトマウス由来血管平滑筋細胞における細胞周期の変化

    石井 エリカ五月, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   124年会 ( 3 )   136 - 136   2004.3

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  • カルボキシルエステラーゼ(CES)/HU3過剰発現マウス由来マクロファージにおけるコレステロール蓄積

    増田 和司, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   124年会 ( 3 )   82 - 82   2004.3

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  • アジア人で見出されたCYP3A4遺伝子多型の薬物代謝に及ぼす影響

    島田 誠, 有吉 範高, 中村 裕義, 石井 伊都子, 中佐 啓詳, 中澤 一純, 北田 光一

    日本薬学会年会要旨集   124年会 ( 4 )   26 - 26   2004.3

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  • 【薬物代謝酵素の遺伝的多型-特に個別化薬物治療を目ざして】新しい遺伝子診断法の方法論と機器

    有吉 範高, 北田 光一

    臨床検査   48 ( 2 )   149 - 156   2004.2

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    近年の遺伝子診断技術の進歩は目覚しく,遺伝子解析の革命的技術であった遺伝子増幅さえもPCR以外の方法論が登場し,さらには増幅を行わずとも少量のゲノムDNAで遺伝子多型が判定できる方法も現れた.これらにより,疾患感受性や,薬物応答性などを規定する遺伝的要因の解明が飛躍的に進展するものと期待されている.そこで,日進月歩の遺伝子診断技術のうち,遺伝子多型診断に焦点を当て,近年汎用されている比較的新しい方法論と機器について概説した

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  • PXR遺伝子上流多型とCYP3A4 basal activityとの関連性評価

    有吉 範高, 中村 裕義, 仲佐 啓詳, 中澤 一純, 北田 光一

    臨床薬理   35 ( 1 )   212S - 212S   2004.1

  • 千葉大学における事前審査の取り組みについて

    花岡 英紀, 青柳 玲子, 岡本 尚子, 有吉 範高, 山口 千穂, 並木 一枝, 大野 洋子, 池上 靖子, 村松 美英, 金澤 薫, 北田 光一, 齋藤 康

    臨床薬理   35 ( 1 )   138S - 138S   2004.1

  • 【チトクロムP450・トランスポーターと臨床上重要な相互作用】CYPが関係した相互作用のメカニズム

    岡田 賢二, 有吉 範高

    薬局   54 ( 11 )   2757 - 2766   2003.11

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  • 抗がん剤適正使用を支える医薬品プロフィール

    政田 幹夫, 菅原 満, 有吉 範高, 森田 邦彦, 川上 純一, 後藤 伸之, 中村 敏明, 栄田 敏之, 直良 浩司, 井関 健, 黒崎 勇二, 谷川原 祐介, 向山 雄人

    日本癌治療学会誌   38 ( 2 )   202 - 202   2003.9

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  • 注射薬の投与ルートに関する考察 臨床における投与ルートと添付文書上の投与ルートの相違

    新井 健一, 仲佐 啓詳, 田中 良子, 佐久間 敦子, 中村 安孝, 中澤 一純, 有吉 範高, 北田 光一

    医薬品情報学   5 ( 1 )   A52 - A52   2003.6

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  • 発現CYP3A7とCYP3A4の基質特異性の差異

    中村 裕義, 有吉 範高, 石井 伊都子, 鈴木 貴詞, 岡田 賢二, 中澤 一純, 北田 光一

    日本薬学会年会要旨集   123年会 ( 4 )   40 - 40   2003.3

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  • 健康食品中に含まれる天然物エキスがミダゾラムの体内動態に及ぼす影響

    西川 征孝, 有吉 範高, 中村 裕義, 長谷川 敦, 石井 伊都子, 木村 宜仁, 中村 英雄, 中澤 一純, 北田 光一

    日本薬学会年会要旨集   123年会 ( 4 )   171 - 171   2003.3

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  • 調製対象TPN処方の自動集計による業務の効率化と対応の拡大

    仲佐 啓詳, 中村 安孝, 新井 健一, 野口 昇, 中澤 一純, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   123年会 ( 4 )   116 - 116   2003.3

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  • Invader AssayによるNAT2遺伝子多型診断法の開発と臨床応用

    有吉 範高, 釼持 一美, 猪狩 英俊, 江頭 徹, 鈴木 貴詞, 岡田 賢二, 中村 裕義, 仲佐 啓詳, 近藤 雅敏, 中澤 一純, 栗山 喬之, 北田 光一

    臨床薬理   34 ( 1 )   119S - 120S   2003.1

  • 移植された肝臓のCYP2D6活性は臓器提供者の活性を反映しないのか

    DRUG METABOLISM AND PHARMACOKINETICS   18 ( 3 )   8 - 9   2003

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  • CYPが関係した相互作用のメカニズム

    薬局   54 ( 11 )   3 - 12   2003

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  • 臨床におけるCYP研究とその意義

    有吉 範高, 北田 光一

    Jpn J Clin Pharmacol Ther   34 ( 4 )   141 - 148   2003

  • 後発医薬品に係わる諸問題

    中澤 一純, 櫻井 千尋, 有吉 範高, 北田 光一

    薬事新報   ( 2236 )   15,25 - 30   2002.10

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  • CYP2A6遺伝子欠損と発がんリスク:噛みタバコと口腔がん

    山崎 浩史, 千葉 逸朗, Topcu Zeki, 藤枝 正輝, 柴田 敏之, 有吉 範高, 小林 博, 鎌滝 哲也

    日本癌学会総会記事   61回   48 - 48   2002.10

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  • PXRの遺伝子多型こそがCYP3A4活性個体差の原因か?

    有吉 範高

    ファルマシア   38 ( 8 )   786 - 787   2002.8

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  • 薬理遺伝学の臨床応用に向けて テーラーメディケーションへの道程

    有吉 範高

    薬事新報   ( 2228 )   27 - 32   2002.8

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  • 薬剤師教育における薬系大学と病院薬剤部の人的交流

    有吉 範高

    日本医療薬学会会報   6 ( 1 )   8 - 10   2002.4

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  • 異常なテガフールの体内動態を示した患者のCYP2A6遺伝子の解析

    藤枝 正輝, 醍醐 聡, 高橋 芳樹, 有吉 範高, 小泉 和三郎, 田辺 聡, 西元寺 克禮, 永山 績夫, 池田 和正, 西岡 安彦

    臨床薬理   33 ( 2 )   239S - 240S   2002.3

  • 医薬品適正使用とセイフティマネージメント(2)

    中澤 一純, 新井 健一, 三浦 剛, 木村 真春, 有吉 範高, 北田 光一

    薬事新報   ( 2206 )   9 - 13   2002.3

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  • 内因性ステロイドによる発現CYP3A4およびCYP3A7の活性変化

    鳥本 奈緒, 中村 裕義, 有吉 範高, 中澤 一純, 大森 栄, 畑 晶之, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   122年会 ( 4 )   101 - 101   2002.3

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  • CYP3A7の機能制御アミノ酸残基の解析

    下村 斉, 外山 賢一, 大森 栄, 有吉 範高, 石井 伊都子, 北田 光一

    日本薬学会年会要旨集   122年会 ( 4 )   101 - 101   2002.3

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  • 健康食品に含まれる天然物エキスのヒトCYP活性に及ぼす影響

    西川 征孝, 有吉 範高, 中村 裕義, 長谷川 敦, 石井 伊都子, 大森 栄, 中村 英雄, 中澤 一純, 北田 光一

    日本薬学会年会要旨集   122年会 ( 4 )   102 - 102   2002.3

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  • CYP2A6遺伝子多型と口腔がんリスクとの関連について

    Topcu Zeki, 山崎 浩史, 千葉 逸朗, 藤枝 正輝, 有吉 範高, 柴田 敏之, Figen Sevgican, Malsantha Muthumala, 小林 博, 鎌滝 哲也

    日本薬学会年会要旨集   122年会 ( 4 )   46 - 46   2002.3

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  • 注射処方鑑査の向上を指向した注射薬処方オーダリングシステムの運用と問題点

    仲佐 啓詳, 野口 昇, 中村 安孝, 新井 健一, 中澤 一純, 有吉 範高, 鈴木 隆弘, 本多 正幸, 里村 洋一, 北田 光一

    日本薬学会年会要旨集   122年会 ( 4 )   97 - 97   2002.3

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  • CYP2A6*7と喫煙による肺がんリスクとの関連について

    藤枝 正輝, 山崎 浩史, 有吉 範高, 宮本 昌美, 梅津 有理, 國頭 英夫, 秋田 弘俊, 澤村 祐一, 横田 淳, 根本 信雄, 佐藤 邦雄, 鎌滝 哲也

    日本薬学会年会要旨集   122年会 ( 4 )   46 - 46   2002.3

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  • 注射薬処方オーダリングシステム導入後の注射処方入力ミスの解析

    並木 千秋, 鈴木 貴詞, 明石 利恵子, 仲佐 啓詳, 中澤 一純, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   122年会 ( 4 )   117 - 117   2002.3

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  • 骨髄性白血病治療における薬物代謝酵素の遺伝子多型診断の臨床的意義

    水野 路子, 有吉 範高, 岡田 賢二, 中村 裕義, 仲佐 啓詳, 小野田 昌弘, 伊勢 美樹子, 西村 美樹, 斎藤 康, 中澤 一純, 北田 光一

    日本薬学会年会要旨集   122年会 ( 4 )   102 - 102   2002.3

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  • 管腔内培養における血管平滑筋細胞の増殖停止とポアサイズの関係

    増田 通, 石井 伊都子, 有吉 範高, 北田 光一

    日本薬学会年会要旨集   122年会 ( 3 )   126 - 126   2002.3

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  • 医薬品適正使用とセイフティマネージメント(1)

    中澤 一純, 新井 健一, 三浦 剛, 木村 真春, 有吉 範高, 北田 光一

    薬事新報   ( 2204 )   9 - 14   2002.3

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  • 肺癌の診断と治療 –最新の研究動向― 遺伝子多型と肺癌リスクとの関連性

    日本臨床 別冊   60 ( 5 )   46 - 49   2002

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  • Perspectives on application of genetic polymorphisms for cancer chemotherapy

    N Ariyoshi, T Kamataki, M Kitada

    JAPANESE JOURNAL OF PHARMACOLOGY   88   46P - 46P   2002

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  • ゲノム情報の活用と服薬のタイミングを考える テーラーメイド医療を目指した研究・治療の現状:薬理遺伝学的視点から

    薬局   53 ( 10 )   2 - 13   2002

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  • Clinical pharmacogenetics and future prospects in drug therapy

    Noritaka Ariyoshi

    Folia Pharmacologica Japonica   120 ( 3 )   181 - 186   2002

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    The human genome project has a large impact on various drug-related fields including drug discovery and clinical medication. Although clinical pharmacogenetics introduced the importance of studying genetic factors determining inter-individual variation on drug response for establishing a personalized medicine, which will be achieved in this century, recent strategies for exploring the genetic factors drastically differ from those of classical pharmacogenetics. The usefulness of an application of findings obtained from basic researches to a medication is uncertain at present because of limited in vivo evidence on the significance of genetic polymorphism to ensure an efficacy or to avoid adverse reactions of the drugs. In this review, a brief history of pharmacogenetics and the current status of the research are summarized. A number of problems that make it difficult to do clinical trials to clarify the significance of genetic polymorphism are discussed. Finally, it is expected in the near future that information on genetic variation with in silico technologies may predict the response toward drugs in each patient with various physiological and therapeutic conditions.

    DOI: 10.1254/fpj.120.181

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  • 【肺癌に対する新たな分子標的治療 21世紀はこう変わる】喫煙による肺癌発生と遺伝子多型

    鎌滝 哲也, 有吉 範高

    内科   88 ( 5 )   883 - 885   2001.11

  • 【チトクロームP450遺伝子多型】チトクロームP450の遺伝子多型 CYP2A,2B,2C及び3A

    有吉 範高, 鎌滝 哲也, 北田 光一

    細胞   33 ( 12 )   457 - 461   2001.11

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  • ヒト肝薬物代謝酵素活性に及ぼす内因性ステロイドの影響

    中村 裕義, 今田 洋司, 鳥本 奈緒, 石井 伊都子, 有吉 範高, 中澤 一純, 大森 栄, 畑 晶之, 北田 光一

    薬物動態   16 ( Suppl. )   S305 - S305   2001.9

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  • 内因性ステロイドによるCYP3A4活性変化の密度汎関数理論的解析

    鳥本 奈緒, 今田 洋司, 中村 裕義, 有吉 範高, 中澤 一純, 大森 栄, 畑 晶之, 石井 伊都子, 北田 光一

    薬物動態   16 ( Suppl. )   S227 - S227   2001.9

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  • 癌治療の個別化と展望 癌化学療法におけるPharmacogenetics 基礎の立場から

    有吉 範高

    臨床医薬   17 ( 8 )   1116 - 1120   2001.8

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  • 薬物代謝酵素の遺伝的多型の変異原活性化における意義

    鎌滝 哲也, 藤田 健一, 串田 浩孝, 梅津 有理, 宮本 昌美, 有吉 範高

    環境変異原研究   23 ( 1 )   33 - 37   2001.6

  • 癌治療の個別化と展望 癌化学療法におけるPharmacogenetics 基礎の立場から

    有吉 範高, 藤田 健一, 醍醐 聡, 高橋 芳樹, 池田 和正, 西岡 安彦, 永山 績夫, 小泉 和三郎, 田辺 聡, 西元寺 克禮, 鎌滝 哲也

    臨床薬理   32 ( 3 )   477S - 478S   2001.5

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    抗癌薬の代謝或いは代謝的活性化に関与する薬物代謝酵素の同定を行うと共に,進行性胃癌治療の為S-1投与を受けていた患者のうち,テガフールの血中濃度が異常高値を示した1名と正常血中動態を示した5名を対象にCYP2A6多型の遺伝子診断を行った.正常動態を示した患者は野生型遺伝子のホモ接合体であったのに対し,異常動態を示した患者は片側アリルに遺伝子全欠損型多型を有し,他方のアリルは見掛け上野生型に判定された.その全翻訳領域の塩基配列を調べたところ,野生型と判定されたアリルのエクソン5領域に新規の1塩基多型(SNP)を見出した.このSNPにより,野生型ではセリンであるアミノ酸残基がプロリンに置換していることが推定された.この変異型酵素を発現し,テガフールから5-FUへの代謝活性化反応の速度論的解析を行った結果,Km値は殆ど違いがなかったのに対し,Vmax値は1/2に低下しており,このことがテフガールの血中濃度上昇の原因と推定した

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  • ヒトCYP2A6遺伝子の新規欠損型変異の同定と遺伝子診断法の開発

    関根 宏美, 高橋 芳樹, 有吉 範高, 斎藤 嘉津彦, 鎌滝 哲也

    日本薬学会年会要旨集   121年会 ( 3 )   41 - 41   2001.3

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  • CYP2A6の新規遺伝子多型とその活性への影響

    有吉 範高, 澤村 祐一, 鎌滝 哲也

    日本薬学会年会要旨集   121年会 ( 3 )   41 - 41   2001.3

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  • 異常なテガフールの体内動態を示した患者より見いだしたCYP2A6遺伝子の新規遺伝子変異の解析

    醍醐 聡, 高橋 芳樹, 有吉 範高, 小泉 和三郎, 田辺 聡, 西元寺 克禮, 永山 績夫, 池田 和正, 西岡 安彦, 鎌滝 哲也

    日本薬学会年会要旨集   121年会 ( 3 )   41 - 41   2001.3

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  • ヒトCYP2A6の新規な変異型遺伝子であるCYP2A6*4Bの遺伝子構造の解析

    高橋 芳樹, 関根 宏美, 有吉 範高, 斎藤 嘉津彦, 鎌滝 哲也

    臨床薬理   32 ( 2 )   337S - 338S   2001.3

  • 薬物代謝酵素CYP2A6の遺伝的多型とその人種差

    鎌滝 哲也, 醍醐 聡, 有吉 範高, 宮本 昌美, 澤村 祐一, Ujjin Pailin, Satarug Soisungwan

    治療   83 ( 2 )   362 - 363   2001.2

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  • Pharmacogenetics

    42 ( 2 )   176 - 185   2001

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  • 薬物代謝における遺伝多型と薬物療法 -CYP1A2-

    医薬ジャーナル   37 ( 10 )   79 - 85   2001

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  • チトクロームP450遺伝子多型 2A-2Cおよび3AサブファミリーCYPの遺伝的多型

    細胞   33 ( 12 )   9 - 13   2001

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  • 分子疫学と発癌リスク-遺伝子多型解析の現状と将来-

    Medical Practice   19 ( 1 )   58   2001

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  • 喫煙による肺発癌と遺伝子多型

    分子呼吸器病   5 ( 4 )   13 - 20   2001

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  • Application of the polymorphism of the CYP genes to the therapeutic management and counseling of patients

    Jpn. J. Pharm. Health Care Sci.   27 ( 3 )   228 - 234   2001

  • CYP2Aと遺伝子多型

    月刊薬事臨時増刊号   43 ( 3 )   86 - 93   2001

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  • CYP2B6の日本人における遺伝的多型

    有吉 範高, 宮崎 雅史, 藤田 健一, 鎌滝 哲也

    薬物動態   15 ( Suppl. )   S210 - S210   2000.9

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  • CYP2A6の遺伝的多型と肺がんリスクとの関連性

    有吉 範高, 宮本 昌美, 梅津 有理, 國頭 英夫, 秋田 弘俊, 澤村 祐一, 横田 淳, 根本 信雄, 佐藤 邦雄, 鎌滝 哲也

    日本癌学会総会記事   59回   412 - 412   2000.9

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  • 集団から個人の癌予防 CYP2A6の遺伝的多型を例として

    鎌滝 哲也, 有吉 範高, 藤田 健一, 國頭 英夫

    日本癌学会総会記事   59回   50 - 50   2000.9

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  • CYP2A6の新しい変異型遺伝子であるCYP2A6*4Bの遺伝子構造の解析

    関根 宏美, 高橋 芳樹, 有吉 範高, 斉藤 嘉津彦, 鎌滝 哲也

    薬物動態   15 ( Suppl. )   S306 - S306   2000.9

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  • 異常なテガフール体内動態を示した患者のCYP2A6遺伝子多型の解析

    醍醐 聡, 高橋 芳樹, 有吉 範高, 池田 和正, 西岡 安彦, 小泉 和三郎, 田辺 聡, 西元寺 克禮, 鎌滝 哲也

    薬物動態   15 ( Suppl. )   S209 - S209   2000.9

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  • CYP2A6の日本人とタイ人における遺伝子多型頻度に関する研究

    醍醐 聡, Ujjin Pailin, Satarug Soisungwan, 宮本 昌美, 澤村 祐一, 有吉 範高, 鎌滝 哲也

    日本薬学会年会要旨集   120年会 ( 4 )   7 - 7   2000.3

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  • LA-PCRによるCYP2D6*5の判定時に出現する短い増幅産物の解析

    千田 道洋, 有吉 範高, 鎌滝 哲也

    臨床薬理   31 ( 2 )   433 - 434   2000.3

  • CYP2A6の遺伝子多型に関する研究

    有吉 範高, 布谷 憲一, 高橋 由紀, 宮本 昌美, 醍醐 聡, 梅津 有理, 横井 毅, 木村 寛三, Beaune Philippe, 鎌滝 哲也

    薬物動態   15 ( 1 )   57 - 61   2000.2

  • 薬物代謝酵素の遺伝的多型と薬物動態-CYP2D

    月刊薬事臨時増刊号   42 ( 4 )   219 - 226   2000

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  • 前立腺癌における代謝酵素遺伝子多型の関与

    村田 万里子, 渡辺 正俊, 林 宣男, 有馬 公伸, 柳川 真, 千田 道洋, 有吉 範高, 窪田 吉信, 伊藤 晴夫, 鎌滝 哲也

    日本癌治療学会誌   34 ( 2 )   375 - 375   1999.10

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  • タモキシフェンの活性代謝物生成に関与するCYP分子種

    宮崎 雅史, 有吉 範高, 鎌滝 哲也

    薬物動態   14 ( Suppl. )   S201 - S201   1999.9

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  • 代謝 基質特異性と種差,遺伝子多形 CYP2A6の遺伝子多型に関する研究

    有吉 範高, 布谷 憲一, 高橋 由紀, 梅津 有理, 宮本 昌美, 醍醐 聡, 横井 毅, Kwon Jun-Tack, Kadlubar Fred F., Sinha Rashimi

    薬物動態   14 ( Suppl. )   S100 - S101   1999.9

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  • CYP2A6及びGSTM1遺伝的多型と発がんリスクとの関連

    宮本 昌美, 梅津 有理, 秋田 弘俊, 澤村 祐一, 横田 淳, 國頭 英夫, 根本 信雄, 有吉 範高, 鎌滝 哲也

    日本癌学会総会記事   58回   131 - 131   1999.8

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  • タモキシフェンの活性代謝物生成に関与するCYP分子種の検討

    宮崎 雅史, 有吉 範高, 鎌滝 哲也

    日本癌学会総会記事   58回   282 - 282   1999.8

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  • DRHラットにおける肝発がん低感受性に寄与する遺伝子の探索

    関根 宏美, 有吉 範高, 鎌滝 哲也

    日本癌学会総会記事   58回   130 - 130   1999.8

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  • Pharmacogenetics

    鎌滝 哲也, 有吉 範高

    Cancer Frontier   1 ( 1 )   57 - 63   1999.6

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  • Analysis of the C Upsilon P2D6 gene in relation to dextromethorphan O-demethylation capacity in a Japanese population

    T Tateishi, M Chida, N Ariyoshi, Y Mizorogi, T Kamataki, S Kobayashi

    CLINICAL PHARMACOLOGY & THERAPEUTICS   65 ( 5 )   570 - 575   1999.5

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    Objective: To analyze the CYP2D6 allele frequencies in a Japanese population and to evaluate the effects of CYP2D6 variants on in vivo CYP2D6 activity as measured by the dextromethorphan metabolic ratio (MR).
    Methods: Ninety-eight unrelated, healthy Japanese men were phenotyped with dextromethorphan and genotyped by the polymerase chain reaction amplification method for 7 CYP2D6 alleles.
    Results:The CYP2D6*1, CYP2D6*10 CYP2D6*2 CYP2D6*5, CYP2D6*4, and CYP2D6*21 allele frequencies in our Japanese subjects were 0.423, 0.408, 0.092, 0.061, 0.020, and 0.010, respectively. Thirty-three subjects (33.7%) were heterozygous for *10/*1, and 18 (18.4%) and 17 (17.3%) subjects were homozygous for *1 and *10 respectively. Subjects who were homozygous for *10 showed the highest dextromethorphan MR among these 3 genotypes. Eighteen subjects (18.3%) were heterozygous for *2 but their dextromethorphan MR values were not greater than the MR values of subjects who were homozygous for *1. One subject was a poor metabolizer phenotypically, and he was homozygous for *5.
    Conclusions The CYP2D6 allele frequencies in our Japanese subjects differed from those determined in previous studies of white subjects or mainland Chinese subjects. Individuals homozygous for *10 who have relatively low in vivo CYP2D6 activity represent almost 20% of the Japanese population. In addition, we did not identify any subjects with amplified *2 among our 98 Japanese men.

    DOI: 10.1016/S0009-9236(99)70077-9

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  • カルシウム拮抗薬ニカルジピンの薬物相互作用の検討

    中村 克徳, 有吉 範高, 岩坪 隆史, 福永 泰久, 樋口 三朗, 島田 典招, 横井 毅, 鎌滝 哲也

    臨床薬理   30 ( 1 )   85 - 86   1999.1

  • 日本人におけるCYP2D6遺伝子診断とフェノタイピングとの関連

    千田 道洋, 有吉 範高, 名倉 弘哲, 立石 智則, 小林 真一, 溝呂木 能浩, 鎌滝 哲也

    臨床薬理   30 ( 1 )   81 - 82   1999.1

  • カルシウム拮抗薬塩酸ニカルジピンのin vitro及びin vivo薬物相互作用の検討

    岩坪 隆史, 福永 泰久, 橋本 匡, 渡辺 隆, 樋口 三朗, 中村 克徳, 有吉 範高, 鎌滝 哲也

    臨床薬理   30 ( 1 )   359 - 360   1999.1

  • ヒトCYP2D6Ch/P450還元酵素同時発現酵母の樹立

    中村 克徳, 有吉 範高, 千田 道洋, 扇谷 悟, 島田 典招, 鎌滝 哲也

    薬物動態   13 ( Suppl. )   S190 - S190   1998.10

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  • 日本人におけるCYP2A6遺伝子全欠損型の判定法の開発

    梅津 有理, 高橋 由紀, 有吉 範高, 木下 盛敏, 名倉 弘哲, 立石 智則, 小林 真一, 溝呂木 能浩, 清水 瓊子, 鎌滝 哲也

    薬物動態   13 ( Suppl. )   S193 - S193   1998.10

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  • 化学発がん抵抗性ラット肝に特異的に認められるmRNA発現のDifferential Display法を用いた探索

    有吉 範高, 東 監, 鎌滝 哲也

    日本癌学会総会記事   57回   275 - 275   1998.8

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  • HMG-CoA reductase阻害薬fluvastatinのLDL酸化変性に対する保護作用

    田浦 健一郎, 有吉 範高, 山田 英之, 小栗 一太

    生化学   70 ( 8 )   962 - 962   1998.8

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  • 残留性有機汚染物質と生物の存亡-物質文明の最果てに-

    道薬誌   15 ( 5 )   5 - 8   1998

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  • Role of cytochrome b(5) in the oxidative metabolism of polychlorinated biphenyls catalyzed by cytochrome P450

    K Matsusue, N Ariyoshi, K Oguri, N Koga, H Yoshimura

    XENOBIOTICA   26 ( 4 )   405 - 414   1996.4

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    1. The role of cytochrome b(5) in the cytochrome P450-dependent hydroxylation of tetrachlorobiphenyl (TCB) isomers was examined using a reconstituted system consisting of CYP2B1 and CYP1A1 and rat liver microsomes.
    2. By addition of cytochrome b(5) to the reconstituted system containing CYP2B1, the 3-hydroxylation of 2,5,2,'5'- and 2,5,3',4'-TCB was increased about six-ford, but the 3- and 5-hydroxylation of 2,4,3',4'-TCB was decreased by about 50%.
    3. All hydroxylations of 3,4,3',4'-, 2,5,3',4'- and 2,4,3',4'-TCBs were decreased by addition of cytochrome b(5) to the reconstituted system containing CYP1A1.
    4. In stoichiometry measurements, changes in NADPH oxidation and coupling efficiency by addition of cytochrome b(5) was observed and these differed according to the position of chlorine atoms of TCBs and cytochrome P450 isoforms used in the systems.

    DOI: 10.3109/00498259609046719

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  • Role of cytochrome b(5) in the oxidative metabolism of polychlorinated biphenyls catalyzed by cytochrome P450

    K Matsusue, N Ariyoshi, K Oguri, N Koga, H Yoshimura

    XENOBIOTICA   26 ( 4 )   405 - 414   1996.4

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    1. The role of cytochrome b(5) in the cytochrome P450-dependent hydroxylation of tetrachlorobiphenyl (TCB) isomers was examined using a reconstituted system consisting of CYP2B1 and CYP1A1 and rat liver microsomes.
    2. By addition of cytochrome b(5) to the reconstituted system containing CYP2B1, the 3-hydroxylation of 2,5,2,'5'- and 2,5,3',4'-TCB was increased about six-ford, but the 3- and 5-hydroxylation of 2,4,3',4'-TCB was decreased by about 50%.
    3. All hydroxylations of 3,4,3',4'-, 2,5,3',4'- and 2,4,3',4'-TCBs were decreased by addition of cytochrome b(5) to the reconstituted system containing CYP1A1.
    4. In stoichiometry measurements, changes in NADPH oxidation and coupling efficiency by addition of cytochrome b(5) was observed and these differed according to the position of chlorine atoms of TCBs and cytochrome P450 isoforms used in the systems.

    DOI: 10.3109/00498259609046719

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  • 高毒性3、3'、4、4'、5-pentachlorobiphenylによるラット肝トリグリセリド脂肪酸組成の影響について

    松末 公彦, 井上 晴美, 石井 祐次, 有吉 範高, 小栗 一太

    日本薬学会年会要旨集   116年会 ( 3 )   191 - 191   1996.3

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  • コプラナーPCBによるモルモット肝ペルオキシソーム酵素活性の変化

    岩崎 優, 加藤 晴敏, 有吉 範高

    福岡医学雑誌   86 ( 5 )   144 - 152   1995.5

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    PenCB処理により,ペルオキシソームの脂肪酸β-酸化(FAOS)活性は上昇の傾向を示したが,本動物種ではPPsによっても誘導がかかりにくいことから,上昇傾向がPenCB処理に由来するものであるか否かは判断出来なかった.尿酸酸化酵素はPenCB処理で上昇し,この変化はモルモットにとっては酸化的ストレス生起への毒性的変化と考えられた.これに対し,カタラーゼ活性はPenCB処理によって不変であるか,むしろ上昇すると考えられた.モルモットではPenCB処理時でもなお抗酸化能力が上回っていると考えられた.今回の検討で,PenCB処理によってモルモット肝ペルオキシソーム酵素活性はいずれも上昇(傾向)した.この事実と,モルモットではCYP4A1が誘導される事実から,少なくともモルモットにおいてはPCB処理による両現象が関連していることが示された

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=1995&ichushi_jid=J01325&link_issn=&doc_id=19950904450002&doc_link_id=%2Fdk5fukuo%2F1995%2F008605%2F003%2F0144-0152%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdk5fukuo%2F1995%2F008605%2F003%2F0144-0152%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • 2CサブファミリーP450を介したPCBの毒性作用発現に関する研究

    有吉 範高, 伊藤 正一, 奥平 章子

    福岡医学雑誌   86 ( 5 )   153 - 162   1995.5

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    著者等は残留性が高く現在の患者体内に最も高濃度に蓄積されている2,4,5,2',4',5'-HCBの体内消失に関する研究を行っている.しかし,本congenerは従来蓄積性は高いが毒性は低いと考えられており,軽視されがちであった.2,4,5,2',4',5'-HCBは混合物として投与した場合,他のcongenerの毒性を相乗的に高めること等から,今後毒性学的にも無視できない化合物と思われる.前述したように2,4,5,2',4',5'-HCBの毒性作用についてはまだ未知であるが,今回,見出されたCYP2C酵素活性の抑制作用は2,4,5,2',4',5'-HCB単独での毒性として明確に提示された最初の例であると考えられる

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=1995&ichushi_jid=J01325&link_issn=&doc_id=19950904450003&doc_link_id=%2Fdk5fukuo%2F1995%2F008605%2F004%2F0153-0162%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdk5fukuo%2F1995%2F008605%2F004%2F0153-0162%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • CoplanarPCBによる脂質代謝への影響:ラットとモルモット間の顕著な相違

    福岡医学雑誌   86 ( 5 )   135   1995

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  • 2,4,6,2′,4′,6′-Hexachlorobiphenylのイヌにおけるin vivo代謝とそれに関与するCytochrome P-450分子種の予備的検討

    有吉 範高, 重藤 真千, 小栗 一太

    福岡医学雑誌   84 ( 5 )   181 - 188   1993.5

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    1) 2,4,6,2′,4′,6′-HCBは経口投与では吸収されにくいと考えられ,未変化体および代謝物は尿中にはまったく排泄されず,糞中にのみ検出された。2)糞中に少なくとも3種の主代謝物が検出され,その構造は3-hydroxy-2,4,6,2′,4′,6′-HCB (M-1), 4-hydroxy-2,6,2′,4′,6′-PenCB (M-2)および3,4-dihydroxy-2,6,2′,4′,6′-PenCB (M-3)と同定された。3) Cytochrome P-450分子種の特異的誘導剤および阻害剤を用いたin vitro研究によって2,4,6,2′,4′,6′-HCBの代謝に関わる分子種は2,4,5,2′,4′,5′-HCBを主に代謝する分子種とは異なる可能性が示唆された

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=1993&ichushi_jid=J01325&link_issn=&doc_id=19950044270002&doc_link_id=%2Fdk5fukuo%2F1993%2F008405%2F003%2F0181-0188%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdk5fukuo%2F1993%2F008405%2F003%2F0181-0188%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • Co-planar PCBによる肝ビリルビンUDP-グルクロン酸転移酵素の誘導:モルモットとラット間の顕著な相違(共著)

    福岡医学雑誌   84 ( 5 )   175   1993

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  • Metabolism In Vivo of 2,4,6,2',4',6'-hexachlorobiphenyl in Dog and Partial Characterization of Cytochrome P450 lsozyme Responsible for Biotransformation of the Congener.

    Fukuoka Acta Medica   84 ( 5 )   181   1993

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  • 2,3,4,7,8-Pentachlorodibenzofuran (Pen CDF)処理ハムスター肝シトクロムP-450精製とその諸性質

    有吉 範高

    日本薬学会年会要旨集   109年会 ( 4 )   104 - 104   1989.3

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    Language:Japanese   Publisher:(公社)日本薬学会  

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Presentations

  • Derivation of Novel Scoring System Predicting High Platelet Reactivity on Prasugrel in Patients With Coronary Artery Disease

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    Event date: 2022.3.11 - 2022.3.13

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  • 正常血圧を超えた方に対するピペリン含有食品の 血圧改善に関する臨床研究

    薗田晴香、有吉範高 他

    第60回日本薬学会・日本薬剤師会・日本病院薬剤師会 中国四国支部学術大会  2021.11.8 

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    Event date: 2021.10.23 - 2021.11.21

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  • 腎がん患者におけるCYP3A5の発現と患者予後との関連性

    松本 准, 小寺 佑実, 和田里 章悟, 竹内 虎一, 植木 英雄, 小山 敏広, 和田 耕一郎, 藤吉 正哉, 那須 保友, 有吉 範高

    第60回日本薬学会・日本薬剤師会・日本病院薬剤師会 中国四国支部学術大会  2021.11.8 

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    Event date: 2021.10.23 - 2021.11.21

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究(第2報):難消化性デキストリンの効果

    鎌田早紀、有吉範高 他

    第58回日本薬学会・日本薬剤師会・日本病院薬剤師会;中国四国支部学術大会  2019.11.10 

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    Event date: 2019.11.9 - 2019.11.10

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究 (第5報):サラシアの効果

    山本弥生、有吉範高 他

    第58回日本薬学会・日本薬剤師会・日本病院薬剤師会 中国四国支部学術大会  2019.11.10 

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    Event date: 2019.11.9 - 2019.11.10

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究 (第4報) : 桑の葉茶の効果

    濱田浩司、有吉範高 他

    第58回日本薬学会・日本薬剤師会・日本病院薬剤師会;中国四国支部学術大会  2019.11.9 

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    Event date: 2019.11.9 - 2019.11.10

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究(第3報):豆乳の効果

    篠山泰子、有吉範高 他

    第58回日本薬学会・日本薬剤師会・日本病院薬剤師会;中国四国支部学術大会  2019.11.9 

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    Event date: 2019.11.9 - 2019.11.10

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  • 機能性食品等によるリアルワールドでの食後血糖抑制効果に関する検証的研究(第1報)

    有吉範高 他

    医療薬学フォーラム2019/第27回クリニカルファーマシーシンポジウム  2019.7.13 

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    Event date: 2019.7.13 - 2019.7.14

    Presentation type:Poster presentation  

    Venue:広島  

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  • Minor contribution of cytochrome P450 3A5 to the in vitro metabolism of hepatitis C NS5B inhibitor beclabuvir

    The 28th Annual Meeting of the Japanese Society of Pharmaceutical Health Care and Sciences 

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    Event date: 2018.11.23 - 2018.11.25

    Presentation type:Poster presentation  

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  • Contribution of CYP3A5 to the metabolism of direct acting anti-hepatitis C virus drugs asunaprevir, daclatasvir, and beclabuvir (Ximency) in vitro International conference

    Matsumoto J et al.

    The 25th International Congress of Personalized Medicine 

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    Event date: 2018.11.18

    Presentation type:Poster presentation  

    Venue:東京  

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  • Minor contribution of human cytochrome 3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro International conference

    San SN et al.

    日本薬物動態学会 第33回年会/第22回MDOシンポジウム合同国際学会 

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    Event date: 2018.10.1 - 2018.10.5

    Language:English   Presentation type:Poster presentation  

    Venue:金沢  

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  • Exertion to precision medicine for anti-thrombotic drugs with using information of germline mutations International conference

    The 31st Annual Meeting of the Japanese Society for the Study of Xenobiotics 

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    Event date: 2016.10.13 - 2016.10.15

    Presentation type:Symposium, workshop panel (nominated)  

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Awards

  • 日本医療薬学会 学術貢献賞

    2011  

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  • 日本医療薬学会 論文賞

    2010  

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  • 第17回 日本医療薬学会年会 優秀発表賞

    2007  

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  • 医療薬学フォーラム2002/第10回クリニカルファーマシー シンポジウム優秀ポスター賞

    2002  

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Research Projects

  • 薬効制御蛋白質の遺伝的多型,医薬品適正使用

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    Grant type:Competitive

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  • Genetic Polymorphisms of Proteins controling drug efficacy

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    Grant type:Competitive

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  • 遺伝子多型解析の臨床現場への応用

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    Grant type:Competitive

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  • Clinical preparation education I (2020academic year) 1st and 2nd semester  - 金1,金2

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