Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan最新文献

This study utilized real-world data from the "Setsuyaku-Bag Campaign" conducted by the Hokkaido Pharmaceutical Association to investigate the actual status of leftover medications among patients with diabetes and identify factors associated with pharmacists' pharmaceutical care interventions aimed at addressing this issue. The primary analysis focused on patients who brought their antidiabetic medications,a examining factors related to the implementation of pharmaceutical care. In addition, a supplementary analysis including all patients was performed. The implementation rate of pharmaceutical care activities in the Setsuyaku-Bag Campaign (3.5%-67.0%) substantially exceeded national statistics. Patients who brought antidiabetic medications had a significantly greater number of medications (p = 0.015) and higher dosing frequency (p < 0.001). Multivariate analysis revealed that, in addition to hypoglycemia-risk drugs such as sulfonylureas and glinides, the use of biguanides and α-glucosidase inhibitors was associated with pharmaceutical care activities. These findings suggest that pharmacists provide support and assess medication adherence based on the pharmacological characteristics of drugs. Furthermore, regarding the pharmaceutical care of patients with diabetes, interventions tend to depend on factors such as collaboration with related medical institutions and the establishment of information-sharing systems as opposed to the outcomes of prescription inquiries. Through these frameworks, pharmacies notify prescribing physicians of patients' leftover medications, and under such collaboration, measures against polypharmacy and adjustments of medication regimens are carried out. To realize more effective pharmaceutical care in the future, a comprehensive management system that includes collaboration between physicians and pharmacists needs to be constructed.

In recent years, chemistry education using gamification has been introduced. Although many studies have been conducted in various countries, there have been few reports evaluating the characteristics of students that lead to higher learning outcomes. This study aimed to identify the factors influencing learning outcomes in gamified education of organic chemistry for pharmacy students. We implemented Game-ed., which is a four-stage online learning program that covers key topics in organic chemistry, including nomenclature, aromaticity, and acidity/basicity of organic compounds, simultaneously with regular coursework for pharmacy students at a private university in Japan. A questionnaire was administered to assess the perceptions of the students for organic chemistry and gaming. Cluster analysis was used to classify students based on their responses, and final examination scores in organic chemistry were compared between the Game-ed. intervention, and non-intervention groups. In addition, the relationships between final examination scores in organic chemistry and 12 explanatory variables were determined using partial least squares regression analysis. Students who reported frequent gaming habits and those who completed a greater number of stages in Game-ed. tended to achieve higher final exam scores. Conversely, game preference and baseline total test scores were negatively associated with performance. Notably, students with a self-reported lack of confidence in organic chemistry still achieved score improvements when expressing a positive impression toward the game. Chemistry education using gamification effect is moderated by learner characteristics, with habitual gaming and the number of stages completed emerging as key contributors to improved performance.

Idiosyncratic drug-induced liver injury (iDILI) is a rare but serious adverse reaction that occurs only in a small subset of individuals. Traditionally, drug-induced liver injury has been studied primarily through the lens of hepatocellular toxicity; however, this approach fails to explain the unpredictable nature of iDILI, which often evades detection in preclinical models. Recent studies have shifted the paradigm toward an immune-mediated mechanism, with CD8⁺ T cell activation restricted by specific human leukocyte antigen (HLA) class I alleles playing a central role. Nevertheless, the presence of a risk HLA allele alone is insufficient to induce disease, underscoring the importance of additional host-specific factors that regulate immune responsiveness. Among these, breakdowns in immune tolerance-such as impaired regulatory T cell function or immune checkpoint failure-appear critical in unleashing pathological T cell activity. Importantly, effective CD8⁺ T cell activation also requires more than antigen recognition. While HLA-mediated antigen presentation (signal 1) provides specificity, co-stimulatory signals (signal 2) from activated antigen-presenting cells are necessary to drive full activation. The convergence of these two signals, in the context of a permissive immune environment, initiates tissue-damaging immune responses. This stepwise framework offers a more accurate understanding of iDILI as an immunologically orchestrated process rather than a purely toxicological phenomenon. Although HLA-transgenic mouse models seldom reproduce overt liver injury, they serve as valuable platforms for investigating HLA-restricted immune responses in vivo and lay the foundation for improved risk prediction, mechanistic modeling, and safer therapeutic strategies.

Fluoropyrimidine anticancer agents, exemplified by 5-fluorouracil (5-FU), induce severe adverse effects-such as myelosuppression, emesis, diarrhea, and hand-foot syndrome-in approximately 10-30% of patients. As such toxicities can result in delays or discontinuation of therapy, accurate prediction of drug response prior to treatment initiation is of critical importance. The metabolic degradation of 5-FU is primarily mediated by the drug-metabolizing enzymes dihydropyrimidine dehydrogenase (DPD) and dihydropyrimidinase (DHPase). These enzymes are encoded by the DPYD and DPYS genes, respectively; polymorphisms in these genes that reduce or abolish enzymatic activity lead to elevated systemic concentrations of 5-FU, thereby increasing the risk of severe toxicity. In Caucasian populations, four DPYD polymorphisms have been identified as predictive markers of adverse drug reactions. However, these variants are rarely observed in Japanese individuals, and reliable pharmacogenomic biomarkers remain largely unreported in this population. To address this gap, we conducted a comprehensive in vitro functional analysis of DPD and DHPase activity of DPYD and DPYS variants identified through large-scale whole-genome sequencing databases. This review summarizes our findings and elucidates the underlying mechanisms affecting the function of 5-FU-metabolizing enzymes, as revealed by our prior research.

Idiosyncratic drug-induced liver injury (IDILI) is particularly problematic due to its severity and unpredictability. Various pathogenic mechanisms have been proposed for IDILI; however, these mechanisms have yet to be comprehensively elucidated. Although the hapten hypothesis has long been posited as a possible pathogenic mechanism, it is believed that other mechanisms may also elicit a strong immune response. We hypothesized that reactive metabolites generated by drug metabolism cause cellular stress and release damage-associated molecular patterns (DAMPs) that may activate antigen-presenting cells (APCs). We have shown that the metabolites of drugs such as acetaminophen, flutamide, and bicartamide activate the inflammasome response in APCs. Moreover, we confirmed that these reactions are suppressed by steroids. Meanwhile, we are also investigating drugs that are suspected to have an immune-mediated mechanism of action based on basic studies using real-world data. If the pathogenic mechanism of IDILI is indeed immune-mediated, it may be suppressed by steroid administration or activated by the concomitant use of immune checkpoint inhibitors. Additionally, we are analyzing the relative risk rates of these drugs in combination. In this review, we present the findings of our previous studies on the pathogenesis of IDILI, including those on reactive metabolites and immune activation. We also present the results of the real-world data analysis which validated the pathogenic mechanism of IDILI that was previously elucidated through basic research, showcasing our efforts to integrate basic and clinical research.

Resolvins are endogenous polyunsaturated fatty acids that show strong anti-inflammatory activity and are therefore expected to be promising new anti-inflammatory drug candidates. However, resolvins have many problems, including instability. This article reviews efforts to improve the stability of resolvin E2 (RvE2) and develop chemical probes to elucidate its anti-inflammatory mechanism. First, to improve the oxidative stability of RvE2, α- and β-CP-RvE2 were designed and synthesized by introducing cyclopropanes (CP) to C11-C12 of RvE2, and the oxidative stability of RvE2 was significantly improved. Next, 5-, 18-, and 20-AP-β-CP-RvE2 were designed and synthesized by introducing azidopropyl (AP) groups to C5, C18, and C20 of β-CP-RvE2 so as to determine the position of introduction of functional groups. The anti-inflammatory activity and phagocytosis of macrophages were evaluated, and it was revealed that 5-AP-β-CP-RvE2 has the same activity as RvE2 and β-CP-RvE2. In addition, to simplify the structure of RvE2, o-, m-, and p-BZ-RvE2 were designed and synthesized by introducing a benzene (BZ) ring into C9-C14 of RvE2. It was found that the metabolic stability of o-BZ-RvE2 was improved compared with RvE2, and the anti-inflammatory activity of o-BZ-RvE2 was equal to or greater than that of RvE2.

Chronic liver disease causes approximately 2 million deaths annually worldwide, accounting for nearly 4% of global mortality. Liver fibrosis is a central pathological feature driving the progression of chronic liver disease (CLD), irrespective of the underlying etiology-be it hepatitis viruses, alcohol consumption, or the increasingly prevalent metabolic dysfunction-associated steatosis. Liver fibrosis arises from a dysregulated wound-healing response following sustained liver injury and inflammation, leading to excessive extracellular matrix deposition that intersects normal liver architecture and function. Despite the significance of fibrosis in CLD progression, effective antifibrotic therapies have not been deduced. A limited subset of metabolic dysfunction-associated steatotic liver disease (MASLD) patients progresses to metabolic dysfunction-associated steatohepatitis (MASH) characterized by inflammation and fibrosis, which indicates that this progression involves specific triggering mechanisms or factors. Hepatic stellate cells (HSCs), located in the space of Disse as quiescent vitamin A-storing cells, are the key mediators of fibrosis. The activation and transdifferentiation of HSCs into myofibroblast-like cells following liver injury results in markedly increased collagen production. Our recent research has indicated that altered adenosine metabolism in hepatocytes leads to increased extracellular adenosine, which in turn drives the activation of HSCs, promoting the progression from MASLD to MASH. The regulatory mechanisms involving prostaglandin E₂ and adenosine signaling in the activation of HSCs are complex and have not been fully elucidated. Further detailed investigations that would uncover the complete pathways controlling the activation of HSCs and enable the development of novel therapeutic strategies targeting liver fibrosis in CLD are warranted.

The biological clock system regulates gene transcription in approximately 24 h cycles, creating circadian rhythms with respect to drug pharmacokinetics and pharmacological efficacy. My research focuses on clinical applications of clock systems and the elucidation of pathophysiological mechanisms involving clock genes. In the present study, I aimed to identify the optimal timing of methylprednisolone (mPSL) administration to pediatric patients undergoing liver transplantation. A randomized clinical trial of 60 such patients demonstrated that evening administration (20:00) was associated with significantly fewer episodes of acute rejection and lower histological damage scores than morning administration (08:00). Notably, in patients who were not undergoing pretreatment with rituximab, mPSL administration in the evening completely prevented acute rejection within 14 d of transplantation. Pathophysiological studies revealed low clock gene expression rhythms in the adipose tissue of obese diabetic (ob/ob) mice, mediated through low histone H3K9 acetylation of the Dbp gene. Pharmacological correction of the abnormal histone acetylation increased the circulating adiponectin concentration and insulin sensitivity through peroxisome proliferator-activated receptor (PPAR)-γ mediated adipocyte differentiation. Importantly, low Dbp and PPAR-γ expression was also identified in human omental adipose tissue samples from patients with diabetes. I also discovered that diabetic microvascular complications can result from circadian clock dysfunction, with low zonula occludens-1 expression causing greater vascular permeability in the liver. Currently, I am evaluating the utility of microRNAs in extracellular vesicles as non-invasive biomarkers of intracellular clock gene expression. These findings should contribute to the optimization of chronotherapy and the identification of novel therapeutic targets.

The innovation patterns and institutional environments of software as a medical device (SaMD) were empirically, comparatively, and institutionally analyzed as SaMD is attracting attention as innovative medical technology. Data were collected on SaMD products approved by the U.S. Food and Drug Administration (FDA) and medical providers (n=581 and 268, respectively). The relationships among SaMD use, the interaction of SaMD with existing medical devices, and company characteristics were structurally evaluated. The use of the current SaMDs as highly concentrated in the medical image processing field, with emerging information and communication technology companies producing many products. The relationship between SaMDs and hardware-type medical devices varied with their use purpose, based on which an innovation regime map for SaMDs was constructed. Next, the differences in reimbursement systems in Japan, the U.S., and Europe were comparatively analyzed, considering the policy implications for high-uncertainty technologies, such as SaMD and orphan drugs. We specifically focused on the cost-effectiveness-oriented reimbursement decision in Europe, the approval-for-reimbursement structure in Japan, and the range of individual decisions by payers in the United States. We summarized the actual state of price setting and payment models in each region (e.g., performance-based payments, price caps, and rebates). A framework for risk allocation between manufacturers and insurers is required when the value of medical technology is uncertain, suggesting a need for flexible and data-linked evaluations in future system designs.

Benign prostatic hyperplasia (BPH) and overactive bladder (OAB) are common conditions in adult men and women. The use of Epilobium angustifolium extract has garnered attention, especially in Europe. Clinical trials have revealed that E. angustifolium extract may improve symptoms of BPH and OAB. Additionally, this extract contains Oenothein B, an ellagitannin, and has been reported to have anti-inflammatory, antioxidant and anti-ageing effects. The mechanism of Oenothein B's anti-inflammatory and antioxidant effects is unclear. Therefore, this study evaluated the autophagy activity of Oenothein B to determine if E. angustifolium extract containing Oenothein B activates autophagy. To evaluate the autophagy activity of E. angustifolium extract containing Oenothein B, we used the tfLC3 assay, which evaluates the formation of autolysosomes. E. angustifolium extract containing Oenothein B activates autophagy starting at 0.01 mg/mL. The results suggest that E. angustifolium extract containing Oenothein B activates autophagy, potentially exerting anti-inflammatory and antioxidant effects through this activation.