Faculty Profiles - ARIYOSHI Noritaka

Papers - ARIYOSHI Noritaka

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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

Language：Japanese Publisher：(一社)日本医薬品情報学会

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

There are a number of reports indicating that CYP2B6*6 (c.516G > T and c.785A > 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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：Japanese Publisher：(一社)日本病院薬剤師会

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)

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

Language：Japanese Publisher：(一社)日本医薬品情報学会

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

Language：English Publishing type：Research paper (scientific journal)

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.

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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.

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

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

Language：English Publishing type：Research paper (scientific journal)

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.

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

Language：Japanese Publisher：(一社)日本医療薬学会

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

Language：Japanese Publisher：(一社)日本医療薬学会

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：Japanese Publisher：(一社)日本医薬品情報学会

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。

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

Language：Japanese Publisher：(一社)日本病院薬剤師会

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)

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

Language：Japanese Publisher：(公社)日本薬学会

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。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J01459&link_issn=&doc_id=20080708380011&doc_link_id=110006792638&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F110006792638&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：Japanese Publisher：(一社)日本医薬品情報学会

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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