世良 庄司

Background/Objectives: Anticoagulant therapy, particularly the use of direct oral anticoagulant agents (DOACs), is recommended for patients with nonvalvular atrial fibrillation (NVAF). This multicenter observational retrospective cohort study aimed to assess the efficacy and safety of DOACs compared to warfarin in Japanese patients aged 75 years and older with NVAF. Methods: Data from the Mie-Life Innovation Promotion Center Database were used to collect medical information on the patients. The cumulative incidences of clinically significant bleeding events and systemic embolic events (SEEs) were analyzed. Results: This study included 1787 older adult patients, of whom 1321 received DOACs (edoxaban: 428; apixaban: 586; dabigatran: 105; rivaroxaban: 202) and 466 receiving warfarin. There were no statistically significant differences in the cumulative incidence of bleeding events between the DOAC- and warfarin-treated groups. However, a statistically significant difference was observed for SEEs, with dabigatran showing a significantly lower incidence compared to warfarin. Conclusions: The incidence rates of bleeding events for individual DOACs were comparable to those for warfarin. Additionally, a history of vascular disorders was identified as a risk factor for bleeding events in the DOAC-treated group (hazard ratio (HR): 1.83, 95% confidence interval (CI): 1.16–2.88, p < 0.01) and warfarin-treated group (HR: 1.80, 95% CI: 1.15–2.84, p < 0.01). Based on real-world data, the overall efficacy and safety of DOACs were generally comparable to warfarin.

OBJECTIVES: Theophylline is used in the treatment of chronic obstructive pulmonary disease but readily causes symptoms of intoxication and exhibits high risks in elderly patients. However, there have only been a few recent reports on the significance of therapeutic drug monitoring (TDM) implementation, especially in elderly patients. To examine the usefulness of theophylline TDM, we evaluated the current status of prescriptions containing theophylline and its side effects and assessed the influence of aging, sex, drug formulation, and concurrent drugs use on theophylline exposure using data from various nationwide databases and a pharmacokinetic modeling approach. METHODS: We utilized sampling data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Using the data of patients aged ≥80 years, we conducted an association analysis of theophylline and concurrent drugs. The transition in plasma theophylline concentration levels of elderly patients was estimated based on a previously reported physiological-based pharmacokinetic model. RESULTS: Altogether, 3973 patients using theophylline were registered in our dataset, and about 50% were over 70 years old and used theophylline. Therapeutic drug monitoring implementation was confirmed in only 1.13% of patients. The association analysis confirmed a frequent co-occurrence with allopurinol and famotidine, which increase theophylline exposure, in elderly patients aged ≥80 years. The physiologically based pharmacokinetic model indicated that theophylline trough concentrations were 1.65-fold higher in elderly patients aged 80 years compared to those aged 30 years and 1.35-fold higher in females compared to males. CONCLUSION: This study effectively combined information on the nationwide health care database and modeling approach, indicating the importance of proactive TDM and dose justification for female and elderly patients.

Introduction: Lipid emulsion preparations, known for their clinical utility, are associated with various adverse events related to lipid metabolism. In this study, we analyzed the safety profile of lipid emulsions in clinical practice, using a real-world database.Methods: The U.S. Food and Drug Administration Adverse Event Reporting System database was used to retrieve adverse events associated with lipid emulsion use. The risk of adverse events was evaluated based on the reported odds ratio and time-to-onset analysis.Results: A total of 4,430 relevant adverse event reports were identified. Hepatic dysfunction tended to occur in the early stages after administration, regardless of the lipid emulsion type. The incidence of hepatic dysfunction varies depending on the triglyceride content of the administered lipid emulsion. Infection tended to occur in the early stages of lipid emulsion administration; however, the incidence did not significantly differ depending on triglyceride content.Conclusion: Our study revealed adverse lipid emulsion events, indicating the need for comprehensive safety management, particularly in the early stages, for clinical use. Particularly, patients receiving parenteral nutrition, irrespective of lipid emulsion administration, necessitate thorough monitoring of liver function and triglyceride levels and reassessment of infusion rates.

国立成育医療研究センターへの問合せが多い薬効群について、2019年より始まった新記載要領による添付文書の改訂前後で、各医薬品の妊婦・授乳婦に関する内容を調査、投与における判断基準や記載文言の変更状況とともに、情報提供内容がどのように変化したのかについて分析・検討した。

Objectives To examine the incidence of stroke or systemic embolic events (SSEs) and bleeding events in untreated patients with non-valvular atrial fibrillation (NVAF) after widespread use of direct oral anticoagulant agents (DOACs). Design Multicentre, non-interventional, observational, retrospective cohort study using real-world data in Japan (2016-2018). Setting The Mie, Musashino University study of NVAF, which used the Mie-Life Innovation Promotion Center Database. This is a regional clinical database involving one university hospital and eight general hospitals in Mie Prefecture in Japan. Participants Japanese patients with NVAF (n=7001). Primary and secondary outcome The incidence of SSEs and bleeding events. Results A total of 7001 patients with NAVF were registered, and 53.0% were treated with DOACs, 10.6% were treated with warfarin and 36.4% had no treatment. Additionally, 29.5% of patients with a CHADS2 (congestive heart failure, hypertension, age≥75 years, diabetes, previous stroke or transient ischemic attack) score of 3–6 were untreated. In the no treatment group, the SSE rates by the CHADS2 score (0, 1, 2 and 3–6) were 1.4%, 1.4%, 3.2% and 8.0%, respectively. The rates of bleeding events by the CHADS2 score (0, 1, 2 and 3–6) in the no treatment group were 0.7%, 1.0%, 1.2% and 2.9%, respectively. A multivariate analysis of SSEs in components of the CHADS2 showed that the adjusted HRs were 2.32 for heart failure, 1.66 for an age ≥75 years, 1.81 for diabetes mellitus and 5.84 for prior stroke or transient ischaemic attack. Conclusions Approximately one-third of the patients do not receive any anticoagulation in the modern DOAC era in Japan. The SSE rate increases by the CHADS2 score. The SSE rate is low in patients with a CHADS2 score <1, supporting no indication of anticoagulation in current guidelines. In patients with a CHADS2 score >1, the use of anticoagulant drug therapy is recommended because of a higher risk of stroke.

医療系学生を対象にした情報リテラシー教育支援システム(Wed-ED)を開発した.Wed-EDは教員と学生全員に1台ずつの専用パーソナルコンピュータが用意できれば,各種アンケート,試験,提出ファイルの収集等を容易に行なうことができる.これらは全てWedサーバ上のデータベースに登録され,その内容や状況を随時監視することができる.Wed-EDのソフトは全て無料で利用でき,その構築方法,スクリプトをページ上で公開し,システム構築方法も解説しているため,各自の環境に合わせたシステム構築が可能である.実際に薬学部情報処理の講義に使用し,小テストを行なったが,十分な実用性を認めた

合成麻薬性鎮痛薬フェンタニル投与患者の未変化体および主代謝物の血中／尿中濃度推移から、その体内動態パラメータをパーソナルコンピュータにより解析、代謝過程を組み込んだ2-コンパートメントモデルに適合することを示し、変動要因について分析、本医薬品の適正使用に役立つ情報（体内動態パラメータ）を報告した。

同位体分離法によるフェンタニルの同位体希釈分析法について、同化合物標識体の合成から分析法の確立、測定精度の限界、代謝物への適用まで、その有用性を含めて解説し、体内動態解析結果を示した。

安定同位体希釈分析により,麻薬性鎮痛薬フェンタニル(FT)の血清中濃度を測定した.19個の重水素を標識したFT-2H19とFTは,表面電離型イオン化検出器装備キャピラリGCにより15分以内で分離測定可能であった.ヒト血清1mlに対してFTを0.2-40ng,FT-2H19を20ng添加し抽出後GC測定したところ,ピーク面積比と重量比の間には優れた直線関係が認められた(r=0.999).FTの構造類似物質を内部標準に用いた場合と本方法を比較検討し,本方法の有用性を示した.外科手術時にFT投与を受けた患者の血清中濃度を測定したところ,生体内物質や併用薬物の影響を受けず正確な測定が可能であり,FTの体内動態解析に有用である

安定同位体希釈分析により, 麻薬性鎮痛薬フェンタニル (FT) とその主代謝物であるNor-FTの尿中濃度を測定した。19個の重水素を標識したFT-²H₁₉とFTは, 表面電離型イオン化検出器 (SID) 装備キャピラリGCにより分離測定可能であり, 尿中FTを0.4-40 ng/mlの範囲で再現性よく測定できた。Nor-FTは二級アミンでありSIDでは高感度検出ができないが, N-アルキル誘導体化により三級アミンとすることで高感度検出を試みた。3種類の誘導体を用い分離, 感度, 再現性から検討したところ, N-メチル誘導体が最適であった。尿中のNor-FTを10-400 ng/mlの範囲でNor-FT-²H₁₀を用い誘導体化後測定したところ, 優れた直線性と良好な再現性が得られた。FT投与患者尿中のFTおよびNor-FTの測定を行ったところ, 生体内物質や併用薬物の影響を受けず正確な測定が可能であり, FTの体内動態解析に有用であると考えられる。

ガスクロマトグラフィによる同位体分離法による同位体希釈分析を、合成麻薬性鎮痛薬フェンタニルの高感度分析に応用するため、7種類の重水素標識体を合成、熱力学的な解析を元に最適な条件について考察した。

高速液体クロマトグラフィ (HPLC) による安息香酸 (BA) および馬尿酸 (HA) とその重水素標識体 (d₅) の分離測定を試みたところ, 通常のカラムを用いて分離測定が可能であることを確認した。本方法を利用して, 重水素標識安息香酸服用後の重水素標識馬尿酸の尿中排泄速度を同位体二重希釈法により容易に測定でき, グリシン抱合能の評価に応用可能であることを認めた。

クロマトグラフィにおける平衡過程の同位体効果の報告例を紹介し、同法による安定同位体標識化合物と非標識化合物の分離測定が、臨床診断を含めたトレーサ研究に有用であることを示した。