We have conducted synthetic studies of densely functionalized natural products. To complete total syntheses of these natural products in an efficient manner, we developed some new complexity-generating strategies. This review describes 2 novel synthetic routes to batrachotoxin, a steroidal alkaloid with potent neurotoxicity and puberuline C, a hexacyclic C₁₉-diterpenoid alkaloid. In batrachotoxin synthesis, the intermolecular coupling of AB-ring and D-ring fragments was realized at sterically congested positions by utilizing a palladium/silver (Pd/Ag)-promoted Suzuki–Miyaura coupling reaction. In the synthesis of puberuline C, the 2 rings and 5 contiguous stereocenters were simultaneously constructed by a radical cascade reaction, increasing the complexity of the molecule in a single step.

The introduction of rheology-based indices into pharmaceutical formulation design and evaluation is expected to enable the establishment of a theoretical framework based on physical principles, offering an alternative to conventional optimization strategies that have relied on empirical techniques and rules. Properties such as structural attributes, disintegration behavior, and process responsiveness involve complex mechanical responses—including time-dependent deformation and structural relaxation—that cannot be sufficiently characterized by viscosity measurements under steady shear conditions. Evaluating not only viscosity but also dynamic viscoelasticity enables quantitative assessment of the functional roles of drugs and excipients within the formulation. This review outlines studies that have evaluated the physicochemical properties and functional performance of pharmaceutical formulations based on rheological measurements. It first summarizes research investigating how the viscoelastic properties of pharmaceutical excipients affect formulation characteristics, and then describes approaches for developing rheology-based indices that reflect the functional behavior of thixotropic spray formulations and disintegrants. Through the establishment of a framework based on physicochemical principles, the rheological approach has the potential to support the development of a new paradigm in formulation design—one that enables mechanism-based optimization and enhances reproducibility across various pharmaceutical dosage forms.

Extracellular vesicles (EVs) are cell-derived membrane vsicles that contain biologically active molecules, such as proteins and nucleic acids, originating from EV-producing cells. Because EVs can deliver their contents to recipient cells, they exert biological effects via intercellular delivery. Accordingly, EVs derived from certain types of mammalian cells, particularly mesenchymal stem cells, can be used as therapeutic agents by utilizing their biological properties. Therefore, mammalian cell-derived EVs are considered the most promising EVs for therapeutic applications. However, several critical challenges must be addressed before EV-based therapies can be successfully implemented. These include elucidating the pharmacokinetics of EVs, and establishing robust methods for their large-scale production and validation. This review outlines the current progress in overcoming these challenges and discusses the remaining issues that need to be addressed to enable the practical application of EV-based therapies in clinical settings.

Extracellular vesicles (EVs), secreted by virtually all cell types, are instrumental in intercellular and intertissue communication; their membranes are characterized by a phospholipid bilayer that is structurally analogous to the cellular plasma membrane. They encapsulate diverse cargo, including nucleic acids, such as microRNAs and various proteins. Recent studies have highlighted the multifaceted biological functions of EVs phospholipid bilayers. For instance, certain lymphoma cells have been observed to exploit secretory phospholipase A2 (sPLA2) to generate lysophospholipids, thereby actively suppressing antitumor immune responses. In addition to highlighting the capacity of lysophospholipids to attenuate the rapid inflammatory reactions characteristic of cytokine storms. This lecture delves into the newly elucidated mechanisms that contribute to inflammation regulation. This presentation primarily focuses on the intricate interplay between EVs, phospholipids, and sPLA2, an enzyme crucial for phospholipid degradation, as the key components of this regulatory axis.

Plants have long supported human life as medicines and as sources of oxygen and food. Plant resources have played central roles in healthcare including traditional remedies and modern drugs such as aspirin. Recently, attention has shifted beyond small molecules to include higher-order biological structures such as extracellular vesicles (EVs). Plant-derived nanoparticles (pdNPs), obtained from edible plants by mechanical processing, are approximately 100 nm in size, biocompatible, and outperform mammalian EVs due to their safety, oral availability, stability, and low production cost. These features highlight the potential of pdNPs as platforms for drug delivery and therapeutic applications. Our group has focused on grains, legumes, and agro-industrial byproducts such as rice bran as sources of pdNPs. Corn-derived nanoparticles (cNPs) are abundant and enriched in carotenoids including lutein and zeaxanthin. We have demonstrated that cNPs could inhibit colon26 tumor cell growth by inducing G2 arrest and apoptosis, and also activate macrophages, suggesting dual antitumor and immunostimulatory effects. Furthermore, PEGylation improved pharmacokinetics, enhancing tumor accumulation, and therapeutic efficacy after intravenous administration. Rice bran-derived nanoparticles (rbNPs), prepared at high yield from low-value biomass, showed stronger tumor-specific growth inhibition than Doxil^®, a clinically used liposomal formulation of doxorubicin, inducing apoptosis in colon26 cells and suppressing peritoneal dissemination in vivo. These findings highlight the potential of rbNPs as sustainable nanomedicines with therapeutic activity and environmental value. In conclusion, pdNPs, particularly cNPs and rbNPs, are cost-effective, safe, and sustainable biomaterials with great potential for advancing cancer therapy, vaccine development, and drug delivery systems.

Mesenchymal stem cells (MSCs) have emerged as a leading cell source in regenerative medicine due to their multipotency and immunomodulatory capabilities. In recent years, extracellular vesicles (EVs) derived from MSCs have attracted increasing attention as a novel, cell-free therapeutic modality, exhibiting many of the biological effects similar to their parent cells. This review outlines the current status and future prospects of MSC-derived EVs, focusing on their therapeutic mechanisms, standardization efforts, and regulatory trends in Japan and overseas. We further discuss the challenges in the development of EV-based products, including scalable manufacturing, quality control strategies, viral safety, and impurity profiling. The application of Quality by Design (QbD) and single-particle analytics is also highlighted as a means to enhance product consistency and clinical reliability. MSC-EVs have the potential to revolutionize treatment paradigms for various refractory diseases, but their successful implementation will require harmonization of scientific, technical, and regulatory frameworks. This review provides a comprehensive overview of the translational pathway from basic research to clinical and commercial application of MSC-EV therapeutics.

Therapeutic extracellular vesicle (EV) products, including those containing exosomes (hereinafter referred to as EV products), are expected to have potential as a new therapeutic modality. Many EV products are currently under development in Japan or other countries; however, there are no guidelines specific to this product category and there is a need for establishing regulatory requirements that supports product development. EVs have an extremely complex structure and show high levels of heterogeneity, and their mechanisms of action remain unclear. Additionally, because therapeutic EV products are often manufactured using cells, and it is difficult to sufficiently remove product- or process- related impurities during the purification process, thus posing challenges for impurity control. To ensure the quality of EV products, it is necessary to conduct sufficient characterization of EV products and to identify critical quality attributes that require control to ensure efficacy and safety. Thus, establishing a strategy for controlling the critical quality attributes within the intended limits, ranges, and distributions is key. Furthermore, it is important to set specifications to confirm that EV products of the intended quality have been obtained. This article describes the current state of research on establishing characterization methods for EV products, and recent topics related to quality issues that need to be considered for the development of therapeutic EV products.

With advancements in the separation of medical and pharmaceutical practices, the roles of community pharmacists have become diversified, with their scope of professional activities expanded to include post-dispensing follow-up, aseptic preparation, and home care services. In the Ministry of Health, Labour and Welfare’s “Pharmacy Vision for Patients,” the concept of shifting from product-based to patient-centered services was introduced, emphasizing the role of pharmacists as personal health care providers. Enhancement of future pharmacy functions and pharmacist responsibilities, including the promotion of self-medication, task shifting, automated dispensing, outsourcing of dispensing operations, and so-called “original-package dispensing,” is gaining increased attention. This paper aims to examine the issues surrounding these developments and consider the future direction of pharmacies and community pharmacists in Japan.

There are approximately 60000 pharmacies in Japan. Effective utilization of this resource is a critical national public health issue. With the advent of work style reforms for physicians, pharmacists have a substantial scope to undertake initiatives to improve health literacy. However, if this is simply an extension of the current operations of pharmacies, significant added value cannot be expected. Instead, it is important to envision a future in which pharmacies function as community health stations, contributing to the health literacy of large numbers of people. To ensure that pharmacists have the necessary interpersonal resources, the government has announced policies aimed at streamlining dispensing operations, including outsourcing some of the preparation work involved in dispensing operations, introducing dispensing equipment, dispensing prescription-packaged medicines, and having non-pharmacists assist and support dispensing operations under pharmacist supervision. Considering the near-future vision of pharmacies and pharmacists from a backcasting perspective rather than a forecasting perspective is likely to lead to better outcomes in future.

The pharmacist’s responsibilities are shifting from product-based to patient-centered services. This review examines the current status and effectiveness of dispensing equipment and highlights the challenges to achieving efficient and high-precision pharmaceutical preparations. Automation, especially for powder medications, has reduced dispensing time and simplified workflows. However, full automation remains limited because manual intervention is still necessary to integrate processes. Unit-of-use dispensing, which is common in Europe, can improve efficiency but faces structural and systemic barriers in Japan. Three key challenges must be addressed to enable safe task delegation. First, dispensing instruction systems need equipment-based design changes, which restrict pharmacists to the dispensing room. Second, quality control systems lack adequate worker identification and traceability. Third, medication tracking relies on follow-up verification, which offers insufficient safety during distribution. This review proposes implementing real-time dispensing design systems, comprehensive quality control frameworks, and automated medication recording systems. These solutions are achievable with current technology, and phased implementation could allow pharmacists to focus more on patient care, improve safety, and expand their roles in community healthcare. Achieving true efficiency and precision requires integrated solutions that cover dispensing instructions, quality control, and medication follow-up.

This study aimed to clarify the current status of dispensing assistance and support tasks performed by nonpharmacists and to provide recommendations on quality assurance for these activities. The survey targeted Japanese pharmacists and nonpharmacist dispensing assistants/support staff, thereby collecting information on their demographics, workplaces, the content of dispensing assistance tasks at their facilities, and dispensing-related training. Pharmacists responded to 25 items, whereas nonpharmacist dispensing assistants/support staff responded to 21 items. Nonpharmacist dispensing assistants/support staff participated in dispensing-related tasks at 70% of the surveyed facilities, and only approximately 20–30% of them held registered sellers of OTC drug qualifications. With respect to training frequency, the most common response from pharmacists was “at employment and after near-miss incidents” (237 respondents, 41.4%), followed by “at employment only” (96 respondents, 16.8%). For nonpharmacist dispensing assistants/support staff, “at employment and after near-miss incidents” was also most common (110 respondents, 35.9%), followed by “at employment only” (77 respondents, 25.2%). Among the respondents, 423 pharmacists (73.8%) and 222 nonpharmacist dispensing assistants/support staff (72.5%) indicated that no regular training program existed. These findings suggest the need to review educational systems in various countries and to develop a structured training framework for nonpharmacist dispensing assistants/support staff in Japan that is tailored to local needs. Such efforts could support discussions on appropriate task delegation and ensure quality in dispensing support services.

The author retired from Iwate Medical University in March 2025 upon reaching mandatory retirement age. On this milestone occasion, I was given the opportunity to write a review article for Yakugaku Zasshi. This review primarily outlines research conducted under Professor Hiroshi Okamoto (now Professor Emeritus, Tohoku University) at the Department of Biochemistry, Graduate School of Medicine, Tohoku University, where I was affiliated before joining the Faculty of Pharmaceutical Sciences at Iwate Medical University. CD38 synthesizes cyclic adenosine diphosphate (ADP)-ribose using nicotinamide adenine dinucleotide (NAD) as a substrate, inducing insulin secretion from pancreatic β-cells via an increase in cytoplasmic calcium ion (Ca²⁺) concentration. Conversely, DNA damage to pancreatic β-cells activates poly (ADP-ribose) polymerase (PARP), promoting poly (ADP-ribosyl) ation. This depletes intracellular NAD, leading to pancreatic β-cell necrosis. Here, inhibiting PARP activity allows PARP to function as a transcription factor, enhancing the expression of the regeneration/proliferation factor RegI, leading to pancreatic β-cell regeneration and proliferation. Thus research findings from the Okamoto Laboratory suggest that in pancreatic β-cells, cell death, function, and regeneration/proliferation are closely interlinked, with NAD at the center. While NAD’s role as a coenzyme is well-established, its physiological significance as a substrate for proteins such as sirtuins, CD38, and PARP, and its link to aging, have also been proposed. The Okamoto Laboratory’s research on pancreatic β-cell function, death, and regeneration/proliferation centered on NAD represents pioneering work demonstrating NAD’s critical importance in the living organism.

This paper reviews enantioselective aldol-related reactions catalyzed by organic oxides (e.g., phenoxides, N-oxides, phosphine oxides, annulenones) developed in the author’s group. Chiral phenoxides catalyze the aldol-Tishchenko reaction, the 1,2-addition of an acetylide to a ketone, and various types of Michael addition. Chiral N-oxides or phosphine oxides catalyze aldehyde allylations and aldol reactions involving tetrachlorosilane as the silylating reagent, as well as α,α- and α,α′-double aldol reactions, which are used to realize the short syntheses of some biologically active compounds. The use of trichlorosilyl triflate as a silylating reagent was found to improve reactivity, thereby promoting the intramolecular aldol reactions of ketones as aldol acceptors. The ring opening of meso-epoxide, which generates a chiral chlorohydrin from an achiral starting material, is catalyzed by a chiral N-oxide, phosphine oxide or annulenone derivative.

As human pharmaceuticals are physiologically active substances, it is essential to assess their potential risk to ecosystems after being released into the environment. In Japan, the “Guidance on the Environmental Risk Assessment in New Pharmaceutical Development” (hereafter referred to as “the guidance”) was issued in 2016. The guidance includes the environmental risk assessment (ERA) workflow, in which novel pharmaceuticals subjected to ecotoxicity testing are selected based on n-octanol/water partition coefficient (log K_ow), action limit (0.01 µg/L), and predicted environmental concentration (PEC). However, for the ERA workflow, neither the action limit has been completely validated nor a method to calculate PEC has been sufficiently established. The objective of this study was to demonstrate the effectiveness and issues of the ERA workflow in the guidance. Using data accumulated from ecotoxicity studies and measured environmental concentration (MEC) data of human pharmaceuticals, we evaluated the validity of the action limit and PEC values. The action limit was found to be sufficiently on the safe side, and the PEC values (to median or 95th percentile MEC values) were generally on the safe side for the evaluated pharmaceuticals. Conversely, issues were also identified, which included a need to establish exemption rules for some specific pharmaceuticals with toxicological concerns at a concentration below the action limit and to refine the PEC calculation method based on the consideration of drug metabolism and environmental fate. The endeavor to address these issues will increase the reliability and effectiveness of the workflow.

Oral lichen planus (OLP) causes chronic pain and functional limitations. In a randomized, placebo-controlled crossover trial of ibuprofen gargle, short-term analgesia on the visual analog scale (VAS) was not statistically significant, although patient-perceived functional gains were suggested. This study aimed to characterize the long-term patient-centered response patterns to ibuprofen gargling using predefined responder definitions. We performed a secondary exploratory analysis of a single-center trial and its long-term extensions (jRCTs051220009 and jRCTs051220010). Twenty-four participants were followed up on day 176. Endpoints combined within-day analgesia on VAS at 0, 5, and 15 min (VAS₀, VAS₅, VAS₁₅) with multidimensional symptoms from the 10-item Patient-Reported Oral Mucositis Symptom (PROMS) scale. Time-to-first achievement (TFA) was summarized, and responses were evaluated descriptively and visually. Overall PROMS response (Definition C) occurred in 21/24 participants (median TFA, 5 d). Domain-level responders were frequent (e.g., pain domain D 20/24, eating domain F 18/24; both median 5 d). In contrast, fewer participants met VAS-based endpoints: A 16/24 (between-day VAS) and B 17/24 (within-day VAS) over the observation period. Visual summaries suggested that improvements tended to emerge early and were sustained or recurrent across subsequent weeks in some participants. Although immediate analgesia was modest, this exploratory analysis indicated that regular use of ibuprofen gargling may be associated with early and durable improvements in patient-reported symptoms and function in OLP. These exploratory findings suggest that patient-centered endpoints may be useful for evaluating topical NSAIDs, and should be examined in future studies with larger sample sizes.

Voriconazole (VRCZ) is a first-line agent for treating invasive fungal infections, but its pharmacokinetics vary widely, necessitating therapeutic drug monitoring (TDM) to maintain trough concentrations within the therapeutic range (1.0–4.0 µg/mL). C-reactive protein (CRP) is an inflammatory marker reportedly associated with VRCZ concentrations. However, its precise impact in machine learning models remains unclear because of missing values in previous studies. Thus, this study aimed to identify factors associated with supratherapeutic VRCZ concentrations using a classification and regression tree (CART) model incorporating CRP in Japanese patients. We retrospectively analyzed 121 patients who received VRCZ (2–4 mg/kg/dose) and underwent TDM. The patients were classified into a therapeutic range group (1.0–4.0 µg/mL; n=51) and a supratherapeutic group (>4.0 µg/mL; n=70). We excluded outpatients to ensure strict sampling timing, patients whose maintenance doses were changed before the first TDM, and patients with missing laboratory data immediately prior to administration. The CART analysis identified dose (threshold: 2.7 mg/kg/dose) as the primary predictor, followed by CRP (threshold: 5.0 mg/dL) and age (threshold: 74 years). The model demonstrated moderate performance in predicting the therapeutic range group, with an area under the curve of 0.770 [95% confidence interval (CI): 0.689–0.851], sensitivity of 78.4%, and specificity of 71.4%. Dose, CRP, and age were significant factors associated with supratherapeutic VRCZ concentrations. Our findings suggest that a decision-tree-based approach incorporating inflammatory status and age could provide valuable clinical insights for optimizing initial VRCZ dosing.

Risk management plan (RMP) utilization in clinical settings has been reported to be insufficient, particularly in community pharmacies. To facilitate the utilization of RMPs in pharmacists’ practice, we created an “RMP Pocket Edition” by summarizing the RMPs. This exploratory study conducted a questionnaire survey to evaluate the usefulness of the RMP Pocket Edition in pharmacists’ practice in community pharmacies within Iwate Prefecture. This study targeted managing pharmacists from 89 community pharmacies who intended to use the RMP Pocket Edition. Responses to specific survey items were measured using a five-point Likert scale (1=strongly disagree to 5=strongly agree). Of the 89 pharmacies, 56 responded (response rate: 62.9%), and 40 of them utilized the RMP Pocket Edition. The RMP Pocket Edition was most commonly utilized to check patient materials during counseling, assess drug risks while dispensing new medications, and for personal study. All median scores for the pocket book’s perceived usefulness across various aspects of pharmacists’ practice, including the understanding of RMPs, the identification of adverse drug reactions, and the facilitation of RMP utilization, were 4 or higher on a five-point scale. Further, the median score for the intention to continue utilizing the RMP Pocket Edition in the future was 5 (interquartile range, 4–5). In conclusion, the findings suggest that the RMP Pocket Edition contributes to facilitating the utilization of RMPs in pharmacists’ practice in community pharmacies.

Pembrolizumab is an immune checkpoint inhibitor that has been widely used in cancer treatment, and its approved indications have expanded rapidly in recent years. However, the effects of this increase on immune-related adverse events (irAEs) remain unclear. Using data from the Japanese Adverse Drug Event Report (JADER) database and the National Database of Health Insurance Claims and Specific Health Checkups (NDB Open Data), we analyzed trends in the number and characteristics of spontaneously reported adverse events associated with pembrolizumab from fiscal years 2016 to 2024. The number of adverse event reports in JADER generally increased in parallel with prescription volume. Following the expansion of indications for gynecological cancers (such as breast, uterus, and cervix cancers) around 2021, a marked increase in reports was observed from 2022. During this period, the demographic profile of reported patients shifted from predominantly older males to middle-aged females. Regarding cancer types, the proportion of reports on breast and uterus cancers increased significantly, whereas those on lung cancer declined. In addition to pulmonary disorders, endocrine disorders became increasingly reported and represented the most frequent category in fiscal year 2022. The distribution of irAEs by cancer type suggested potential associations; pulmonary toxicity was more frequent in lung cancer, whereas endocrine toxicity was predominant in breast, uterus, and cervix cancers. Our findings indicate that the expansion of pembrolizumab indications has substantially altered the profile of reported immune-related adverse events in Japan, highlighting the need for ongoing pharmacovigilance tailored to cancer type and patient demographics.