Hideki Hayashi

Background: Pemetrexed (PEM) is an antimetabolite antineoplastic agent that has been available in generic form in Japan since June 2021. As a hazardous drug (HD), the use of a closed-system transfer device (CSTD) is recommended. Some generics, including 800-mg vials, are not available for the original product; however, changes in prescribing patterns following the introduction of generics remain unclear. This study examined the prescription volume and drug costs of PEM before and after the launch of generics. Methods: Clinical data were analyzed using the MDV analyzer ^® (Medical Data Vision Co., Ltd.). Patients who received PEM between June 2020 and May 2023 were enrolled. Study outcomes included the number of prescriptions, dose per prescription, drug costs (yen), and vials used. Data were categorized into original PEM, generics without 800-mg vials, and generics with 800-mg vials. Results: A total of 89,078 prescriptions were analyzed. In the last 3 months of the study, prescription counts (proportions) were 966 (14.8%) for original PEM, 404 (6.2%) for generics without 800-mg vials, and 5,155 (79.0%) for generics with 800-mg vials. The mean prescribed doses were 773.2 mg, 789.6 mg, and 777.8 mg, respectively. The mean drug costs were 193,683 yen, 84,583 yen, and 78,770 yen, respectively. The average numbers of vials per prescription, calculated from the total number of vials and prescriptions, were 3.4, 3.5, and 2.3, respectively, indicating that generics with 800-mg vials were associated with approximately one fewer vial per prescription compared to other groups. Conclusions: After the introduction of generics, a shift in prescription patterns was observed, with an increasing proportion of products with 800-mg vials. Although mean prescribed doses were similar across groups, generics with 800-mg vials appeared to be more cost-effective and utilized fewer vials per prescription within this study population. The reduction in the number of vials suggests a potential decrease in CSTD use, which could contribute to lowering material costs. These results provide important insight for future drug development and for strategies aimed at reducing healthcare expenditures, including material costs.

Background: This study examined pharmaceutical needs in the subacute phase following the 2024 Noto Peninsula Earthquake, using dispensed prescriptions as a proxy. We described demand patterns, the dispensing timeline amid early shortages, and the alignment between observed requirements and four disaster medicine lists. Methods: We conducted a retrospective cross-sectional analysis of prescriptions dispensed in disaster-affected areas of Japan (primarily Suzu City) between January 7 and 13, 2024. A total of 236 prescriptions were included and categorized into major therapeutic classes. We separated regular prescriptions from as-needed (pro re nata, PRN) prescriptions. The dispensing interval was defined as the number of days from prescription issuance to dispensing. Coverage was calculated by comparing dispensed medicines against four disaster medicine lists, including the Japanese Medical Association Team (JMAT) Carry-on Medicine List. Results: Cardiovascular, central nervous system, and gastrointestinal drugs were the most commonly prescribed medicines. Early shortages delayed dispensing until wholesale supplies resumed on January 11. Regular and PRN prescriptions accounted for 41.9% and 53.8% of all prescriptions, respectively. However, PRN prescriptions were dispensed in fewer days. Coverage of the four disaster medicine lists ranged from 41.8% to 65.9%, with the highest coverage for the JMAT Carry-on Medicine List. Conclusions: This study clarified the characteristics of pharmaceutical needs in Suzu City during the subacute phase, albeit within a limited scope based on the activities of specific medical support teams. Observed pharmaceutical requirements only partially overlapped with existing lists. Portable medicine lists, regional stockpiles, and local formularies tailored to community needs could improve responsiveness. Interim measures, such as temporary services and mobile support, helped bridge the gap in medicine access before supply chain recovery. In this setting, mobile pharmacy vehicles potentially played a central role until normal distribution resumed. These data can inform future disaster medicine planning.

Glucocorticoid-induced osteoporosis (GIOP) is a side effect of glucocorticoid (GC) treatment; however, despite established prevention guidelines in various countries, a gap persists between these guidelines and clinical practice. To address this gap, we implemented a collaborative intervention between hospitals and community pharmacists, aiming to assess its effectiveness. Pharmacists recommended to the prescribing doctor osteoporosis treatment for patients who did not undergo osteoporosis treatment with a fracture risk score of ≥3 via tracing reports (TRs), between 15 December 2021, and 21 January 2022. Data were extracted from electronic medical records, including prescriptions, concomitant medications, reasons for not pursuing osteoporosis treatment, and TR contents. Of 391 evaluated patients, 45 were eligible for TRs, with 34 (75.6%) being males. Prednisolone was the most common GCs administered, and urology was the predominant treatment department. Among the 45 patients who received TRs, prescription suggestions were accepted for 19 (42.2%). After undertaking the intervention, guideline adherence significantly increased from 87% to 92.5%. This improvement indicates that TRs effectively bridged the evidence–practice gap in GIOP prevention among GC patients, suggesting their potential utility. Expansion of this initiative is warranted to further prevent GIOP.

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor commonly used in Japan. This study aims to develop a simultaneous rapid assay for gefitinib, erlotinib, afatinib, and osimertinib using liquid chromatography-tandem mass spectrometry (LC-MS/MS). These drugs in plasma samples were purified by liquid-liquid extraction with tert-butyl methyl ether, a simple and inexpensive method. The purified drugs were rapidly separated in less than 5 min by isocratic elution using an XBridge Shield RP18 column as the separation column and were sensitively quantified by MS/MS in the electrospray ionization positive mode. The quantification range in plasma for the four drugs was 5–200 nM with a linearity of >0.994 and a lower limit of quantification of 5 nM. The developed method was applied to therapeutic drug monitoring of patients with non–small cell lung cancer treated with oral osimertinib preparation and demonstrated its usefulness.

Background/Aim: Osimertinib is the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The present study aimed to determine the previously unclarified association of osimertinib plasma trough concentrations with efficacy, adverse events, and genetic polymorphisms in Japanese patients with NSCLC harboring EGFR mutations. Patients and Methods: In this prospective study, blood samples of 25 patients who received osimertinib were collected to measure plasma osimertinib concentrations and to genotypically characterize ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2 polymorphisms. Plasma osimertinib concentrations were analyzed using validated multiple reaction monitoring mode-based liquid chromatography-tandem mass spectrometry. Osimertinib concentration necessary to achieve optimal median progression-free survival (PFS) was determined using receiver operating characteristic curve analysis. PFS and overall survival were analyzed using the Kaplan–Meier method, and between-group differences were compared using the log-rank test. Plasma osimertinib concentrations between different patient groups were compared using the Mann–Whitney U-test. Results: Patients were divided into high and low concentration groups based on a plasma osimertinib cut-off concentration of 211 ng/ml. Median PFS was longer in the high trough concentration group than that in the low trough concentration group (46.3 vs. 16.8 months, p=0.029). Plasma osimertinib concentrations adjusted for dose and body weight did not differ between the patients with and without variant polymorphisms. Conclusion: Monitoring plasma trough concentrations during maintenance might improve osimertinib treatment efficacy in patients with NSCLC harboring EGFR mutations.

The stratum corneum (SC) of the epidermis acts as a skin permeability barrier, and abnormalities in SC formation lead to several skin disorders. Lipids, especially the epidermis‐specific ceramide classes ω‐O‐acylceramides (acylceramides) and protein‐bound ceramides, are essential for skin barrier formation. Ceramide synthase 3 (CERS3) is involved in the synthesis of acylceramides and protein‐bound ceramides, and CERS3 mutations cause autosomal recessive congenital ichthyosis. In the present study, we measured ceramide synthase activity and performed comprehensive SC ceramide profiling in an ichthyosis patient with compound heterozygous CERS3 mutations: nonsense mutation p.Arg75* and missense mutation p.Arg229His. The activity of p.Arg75* and p.Arg229His mutant CERS3 proteins was reduced to 4% and 56%, respectively, of the wild‐type protein. In the patient’s SC, acylceramide levels were greatly reduced, but the levels of protein‐bound ceramides remained almost unchanged. Non‐acylated ceramide levels were also affected in the patient; in particular, the levels of ceramides composed of sphingosine and non‐hydroxy or α‐hydroxy fatty acid were substantially higher than in healthy controls. These results suggest that a reduction in acylceramide levels alone leads to ichthyosis. Although protein‐bound ceramides are synthesized from acylceramides, levels of acylceramides and protein‐bound ceramides are not necessarily correlated.

This study presents a simple, accurate, and selective bioanalytical method of bevacizumab detection from plasma samples based on aptamer affinity purification–high-temperature reversed-phased liquid chromatography (HT-RPLC) with fluorescence detection. Bevacizumab in plasma samples was purified using magnetic beads immobilized with an anti-idiotype DNA aptamer for bevacizumab. The purified bevacizumab was separated with HT-RPLC and detected with its native fluorescence. Using aptamer affinity beads, bevacizumab was selectively purified and detected as a single peak in the chromatogram. HT-RPLC achieved good separation for bevacizumab with a sharp peak within 10 min. The calibration curves of the two monoclonal antibodies ranged from 1 to 50 μg/mL and showed good correlation coefficients (r² > 0.999). The limit of detection (LOD) and lower limit of quantification (LLOQ) values for bevacizumab were 0.15 and 0.51 μg/mL, respectively. The proposed method was successfully applied to the bioanalysis of the plasma samples obtained from the patients with lung cancer and may be extended to plan optimal therapeutic programs and for the evaluation of biological equivalencies in the development of biosimilars.

Metformin-associated lactic acidosis is a well-known life-threatening complication of metformin. We here report the case of a patient who developed metformin-associated lactic acidosis without organ manifestations, due to the simultaneous ingestion of an overdose of metformin and alcohol, and who recovered with high-flow high-volume intermittent hemodiafiltration. A 44-year-old Asian woman with type 2 diabetes attempted suicide by ingesting 10 tablets of metformin 500 mg and drinking approximately 600 mL of Japanese sake containing 15% alcohol. She was transferred to our emergency department because of disturbed consciousness. Continuous intravenous administration of noradrenalin (0.13 μg/kg per minute) was given because she was in shock. Laboratory findings included a lactate level of 119 mg/dL (13.2 mmol/L), bicarbonate of 14.5 mmol/L, and serum metformin concentration of 1138 ng/mL. She was diagnosed as having metformin-associated lactic acidosis worsened by alcohol. After 4560 mL of bicarbonate ringer (Na+ 135 mEq/L, K+ 4 mEq/L, Cl− 113 mEq/L, HCO3− 25 mEq/L) was administered, high-flow high-volume intermittent hemodiafiltration. (dialysate flow rate: 500 mL/min, substitution flow rate: 3.6 L/h) was carried out for 6 h to treat metabolic acidosis and remove lactic acid and metformin. Consequently, serum metformin concentration decreased to 136 ng/mL and noradrenalin administration became unnecessary to maintain normal vital signs. On hospital day 12, she was moved to the psychiatry ward. HFHV-iHDF may be able to remove metformin and lactic acid efficiently and may improve the condition of hemodynamically unstable patients with metformin-associated lactic acidosis.

In recent years, the popularity of LED lighting has rapidly increased, owing to its many advantages, including economic benefits. We examined the change in the quality of drugs during storage under LED and fluorescent lighting and found that some medicines exhibited a different degree of color change depending on the light source. The purpose of this study was to investigate the effects of different plastic storage bags on the color change over time when various medicines were stored under LED and fluorescent lighting conditions. Photostability tests were conducted on several types of target drugs. Subsequently, subjective evaluation by ten evaluators and objective evaluation by image analysis software were carried out regarding color change. A similar change in color tone was observed after all types of illumination. Subjective evaluation by 10 evaluators revealed that “change in color tone” occurred in the order of bulb-color LED lighting < daylight-color LED lighting < fluorescent lighting, regardless of the type of plastic bags. A similar tendency was observed also in objective evaluation. In this study, it was considered that a brown light-shielding plastic bag was more effective than a normal plastic bag for the prevention of the color change of medicines stored under LED lighting. The above results suggested that the most appropriate combination of plastic bag and light source for medicine storage was a brown light-shielding plastic bag and bulb-color LED lighting.