著者

竹内 裕紀 市田 公美 虎石 竜典 岩本 整 中村 有紀 今野 理 木原 優 横山 卓剛 池田 千絵 奥山 清 川口 崇 河地 茂行 尾田 高志 平野 俊彦 畝崎 榮

出版者

一般社団法人 日本痛風・核酸代謝学会

雑誌

痛風と核酸代謝 (ISSN:13449796)

巻号頁・発行日

vol.41, no.2, pp.191-198, 2017-12-20 (Released:2017-12-20)

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背景:腎移植で使用される免疫抑制薬のアザチオプリンと高尿酸血症治療薬である尿酸合成阻害薬の併用は,アザチオプリンの活性代謝物6-メルカプトプリン(6-MP)の代謝酵素であるキサンチンオキシダーゼを阻害することにより,6-MPの血中濃度が上昇し,重篤な骨髄抑制を起こす体内動態学的相互作用がある.しかし,添付文書の記載では,フェブキソスタットとトピロキソスタットは併用禁忌だが,アロプリノールは併用注意である.方法:アザチオプリンとアロプリノールの相互作用を起こした自験例や過去の報告により,併用の危険性を示し,添付文書におけるアザチオプリンと各尿酸合成阻害薬間における相互作用の記載内容の整合性について調査し,さらに文献値から求めた各尿酸合成阻害薬の臨床用量におけるキサンチオキシダーゼ阻害作用の効力比を比較することで,添付文書における尿酸合成阻害薬間の併用禁忌と併用注意記載の理論的な裏付けが存在するかも調べた.症例:生体腎移植後20年の女性患者で血清尿酸値が13mg/dLとなったためアロプリノールを開始することになった症例で,高度の腎機能低下患者(eGFR7.7mL/min)であったため,アロプリノールを50mg/ 日と減量して開始した.またアザチオプリンも75mg/ 日を服用していたため,,同時に50mg/ 日へ減量して併用を開始した.しかし,服用後に顕著な汎血球減少症が認められたため,即時アロプリノールを中止し,中止後は回復した.結果・考察:添付文書におけるフェブキソスタットとトピロキソスタットのアザチオプリンとの併用禁忌の理由は,「6-MPの血中濃度が上昇することがアロプリノール(類薬)で知られている.」からであり,実際のエビデンスはなかった.一方で,両剤の併用禁忌の理由の根拠薬であるアロプリノ-ルが併用禁忌となっていないことには矛盾があると考えられた.そこで,文献値から臨床用量におけるキサンチンオキシダーゼの阻害作用の相対効力比を算出した結果では,アロプリノールで弱く,相互作用は小さいことが推定された.しかし,5-FUとソリブジンの相互作用のように核 酸代謝拮抗薬の血中濃度を上げる相互作用は,骨髄抑制を起こす極めて危険な併用であり,本自験例や他の報告のように重篤な副作用を誘発する危険な相互作用であるため,併用注意のままでは問題があると考えられた.さらに,本症例を含め腎機能低下患者ではオキシプリノールの蓄積も加わり,6-MPの血中濃度が上昇しやすくなり,極めて危険な相互作用を起こす可能性が高くなると考えられ,少なくとも腎機能低下患者には併用禁忌とすべきと考えられた.

著者

本間 真人 平野 俊彦 湯沢 賢治 大河内 信弘 剣持 敬

出版者

一般社団法人 日本臓器保存生物医学会

雑誌

Organ Biology (ISSN:13405152)

巻号頁・発行日

vol.24, no.1, pp.76-80, 2017 (Released:2017-03-31)

参考文献数

7

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Questionnaire survey concerning practical use of generic immunosuppressive agents and the European Society for Organ Transplantation (ESOT) guideline was conducted in 130 clinical institutions including transplant hospitals where the members of The Japan Society for Organ Preservation and Biology were working. Forty five institutions answered the questionnaire survey (the recovery rate: 34.6%). Use of generic immunosuppressive agents in the institutions has been different among the agents; tacrolimus (6.7%), cyclosporin (8.9%) and mycophenorate mofetil (8.9%) and corticosteroid injection (51.1%). The results indicated that use of generic immunosuppressive agents, especially in the agents that require therapeutic drug monitoring (TDM) for dose adjustment, have not been spread in Japan. The most of the institutions (greater than 62%) agreed with the ESOT guideline for generic substitution of immunosuppressive agents. It is considered that the Japanese guideline is also required to prepare according to ESOT guideline, though the use of generic products have not been popular yet Japan.

著者

袁 博 高木 教夫 岡崎 真理 平野 俊彦

雑誌

日本薬学会第141年会(広島)

巻号頁・発行日

2021-02-01

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Arsenic and its compounds are widely distributed in the environment and exist in organic and inorganic forms. Although as a well-known poison, arsenic has been used medicinally for over 2,000 years. Notably, administration of trivalent arsenic derivatives (arsenite, AsIII) such as arsenic trioxide (ATO) has demonstrated a remarkable efficacy in the treatment of acute promyelocytic leukemia (APL), the vast majority of which is characterized by the promyelocytic leukemia (PML)-retinoic acid receptors (RARα) fusion caused by the t(15;17) translocation. Differentiation associated with the degradation of fusion protein PML-RARα, apoptosis induction, cell cycle arrest as well as autophagy induction have been shown to be linked to the therapeutic effects of ATO against APL. Several research groups including us have conducted detailed pharmacokinetic studies of ATO in APL by using biological samples such as peripheral blood, cerebrospinal fluid, bone marrow from patients. Aquaporin 9 and multidrug resistance-associated proteins (MRP1/MRP2/MRP4) have been reported to play pivotal roles in the uptake/efflux of arsenic, respectively. Here, we are going to introduce the mechanisms underlying the antitumor activity of AsIII and provide new insights into its potential novel application in terms of combinational treatment. Despite organic arsenicals mainly contained in seafood are known to be harmless, a novel organic arsenical, S-dimethylarsino-glutathione (darinaparsin, Dar), synthesized by conjugating dimethylarsenic to glutathione, has shown promising anticancer activity and is currently in use in human clinical trials in cancer patients. It has been demonstrated that Dar has overlapping, but distinct, signaling mechanisms of cell death induced by AsIII. We also provide some recent evidence of the cytocidal effect of Dar on several leukemia cell lines for understanding the arsenic compound in comparison to AsIII.

著者

杉山 健太郎 磯貝 和也 坂爪 重明 外山 聡 佐藤 博 齋藤 和英 中川 由紀 田﨑 正行 高橋 公太 平野 俊彦

出版者

一般社団法人 日本臓器保存生物医学会

雑誌

Organ Biology (ISSN:13405152)

巻号頁・発行日

vol.18, no.1, pp.47-51, 2011-06-10 (Released:2014-11-26)

参考文献数

10

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Renal transplant recipients are administered immunosuppressive therapy to prevent acute rejection. In particular, new immunosuppressive agents have helped to improve the allograft survival rate and reduce the rate of rejection in renal transplant recipients. The optimal dose of calcineurin inhibitors is determined by therapeutic drug monitoring. However, the pharmacological efficacy of cyclosporine and tacrolimus should be estimated using both pharmacokinetics and pharmacodynamic parameters. We therefore employed the lymphocyte immunosuppressant sensitivity test(LIST) with the 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide(MTT)assay procedure to evaluate renal transplant recipients. The LIST with the MTT assay procedure can predict the pharmacological efficacy of immunosuppressive drugs using peripheral blood mononuclear cellsMoreover, renal transplant recipients must be correctly treated with immunosuppressive agents and another medicines. Therefore, the pharmacist must provide instructions for all medications to maintain adherence in renal transplantation. Therefore, transplantation therapy must be based on the pharmaceutical care given by pharmacists.

著者

竹内 裕紀 岩本 整 中村 有紀 河地 茂行 島津 元秀 畝崎 榮 平野 俊彦

出版者

一般社団法人 日本臓器保存生物医学会

雑誌

Organ Biology (ISSN:13405152)

巻号頁・発行日

vol.22, no.1, pp.7-22, 2015 (Released:2015-09-10)

参考文献数

59

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Corticosteroids or steroids are useful drug in clinical renal transplantation because of multiple effects in immunosuppression. There are not a few renal transplant recipients who need steroid therapy, although various new immunosuppressive drugs have developed. However, steroid dosage should be kept as low as possible and preferably withdrawn, because adverse effects of steroids are the most problematical in immunosuppressive drugs. The individual difference of efficacy and adverse effects of steroids depends on pharmacodynamics factor. We have been tried to resolve the dual nature of steroid therapy by steroid sensitivities test using peripheral blood mononuclear cell(PBMC). We clarified significant relationship in steroid sensitivity and clinical outcome, relative immunosuppressive efficacy of steroid, availability of methylprednisolone as immunosuppressive drug, utility for selecting patients who can sustain steroid withdrawal, and pharmacodynamic interaction of calcineurin inhibitors and steroids. We describe here not only results of pharmacodynamic research of steroid sensitivity test, but also comprehensive issues, i. e., history of steroid therapy in renal transplantation, action mechanism of steroid and factor of individual difference of steroid sensitivity, pharmacokinetics of steroid, suppression of hypothalamic-pituitary-adrenal system and immune system, adverse effects of steroid, and practice toward optimal steroid therapy for individual renal recipients.