Shoji SERA

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.

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

The quantitative determination of serum fentanyl (FT), urinary FT and its main metabolite, Nor-FT was examined to ascertain the individual variation in the elimination process of FT among 17 patients. The pharmacokinetics of FT was solved from the obtained data using 2-compartment model including the metabolic process. Furthermore, we compared Nor-FT excretion with CYP3A4 activity based on urinary 6&beta;-hydroxycortisol (6&beta;-OHF) and cortisol (F) excretion ratio.<BR> FT and Nor-FT were determined by isotope dilution analysis using deuterium labeled FT (FT-²H₁₉) or Nor-FT (Nor-FT-²H₁₀) as internal standards. The isotopic fractionation was achieved by a capillary gas chromatograph equipped with a surface ionization detector. The pharmacokinetic parameters were calculated from serum FT concentration time profiles and excreted amount of FT and Nor-FT in urine, using the pharmacokinetic data analysis software, WinNonlin standard Ver. 1.5 (Scientific Consulting). Urinary F and 6&beta;-OHF concentrations were determined by HPLC using fludrocortisone as an internal standard after conversion to fluorescence derivative using 1, 2-diamino-4, 5-methylenedioxybenzene.<BR> The obtained pharmacokinetic parameters showed considerable difference between individuals. The predicted time course for FT and Nor-FT was adapted to FT kinetics. The predicted final excretion rates of FT and Nor-FT were 0.14-15.77% (mean 4.30%) and 7.36-99.38% (mean 55.12%), respectively. The CYP3A4 activity obtained from steroid excretion was not reflected by FT elimination in this study for a low dose of FT (5&mu;g/kg).

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

Isotope dilution analysis was applied to determine urinary excretion of fentanyl (FT) and its main metabolite, norfentanyl (Nor-FT), by isotopic fractionation using a capillary gas chromatograph equipped with a surface ionization detector (SID) . Urinary FT was determined quantitatively in the range of 0.4-40 ng/ml using deuterium labeled FT (FT-²H₁₉), as an internal standard.<BR>We also performed isotope dilution analysis of Nor-FT in urine. NV Alkylation was necessary to sensitively detect Nor-FT with SID. Methyl derivative was selected from 3 kinds of NV alkyl derivatives to increase sensitivity and peak resolution, and to prevent interference with urinary compound. Nor-FT concentration was quantitatively determined in the range of 10-400 ng/ml using deuterium labeled Nor-FT (Nor-FT-²H₁₀) . No endogenous compounds or concomitant drugs interfered with the detection of FT and Nor-FT in the urine of patients. The present method will be useful for pharmacokinetic studies and the evaluation of drug interactions in FT metabolism.

Isotopic fractionation of benzoic acid (BA) and hippuric acid (HA) from their deuterated analogues (BA-d₅ and HA-d₅) were examined by high performance liquid chromatography (HPLC) . Reversed-phase HPLC was used with C₁₈column and McOH-phosphoric acid solution mixture as mobile phase. The resolution coefficients between protio-and deutero forms were 1.22 for BA and 1.05 for HA respectively<BR>The present isotopic fractionation procedure was applied to the isotopic dilution analysis of BA and HA. Measurement of the samples contained known amount of protio-and deutero-forms allowed observation of linear relationship between peak area ratio and added amount ratio in the case of both compounds. The correlation coefficients obtained by regression analysis were 0.9995 for BA and 0.9999 for HA, respectively. The present method was applied to determine the urinary excretion of HA-d₅in man after oral administration of BA-d₅. Two methods were examined for determination of HA-d₅. One was the measurement of BA-d₅after hydrolysis of HA-d₅, and another was direct measurement of HA-d₅. Former method is superior to latter method in the separation of protio-and deutero-forms, while, requires the complex procedures, conversion, extraction and evaporation. These isotopic fractionation of BA from BA-d₅and HA from HA-d₅by HPLC are simple and specific methods for determination of exogenous HA without the interference of endogenous HA.