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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 Kow), 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.
This study focuses on developing functional "molecules" and "reactions" aimed at controlling biomolecular functions. In the aspect of molecules, the asymmetric total syntheses of (-)-stemonamine and (-)-isostemonamine, which are stemona alkaloids isolated from Stemona japonica, were achieved. The strategy featured an intramolecular acylation to construct a seven-membered lactam and a tandem [2+2] cycloaddition/Dieckmann condensation to build the cyclopentenone ring, yielding the stemona alkaloids with high optical purity. Detailed kinetic analyses experimentally revealed, for the first time, the details of racemization and epimerization of/between stemonamine and isostemonamine. Biological assays demonstrated that (-)-isostemonamine exhibited potent antiproliferative activity against ERα-negative breast cancer cells. This synthetic methodology paves the way for the supply of stemona alkaloids whose biological activities are unknown and which have not yet been synthesized, and it is expected to greatly contribute to elucidating the biological functions hidden within their unique structures. In the aspect of reaction, a highly acid-sensitive Nazarov reaction proceeding under weakly acidic or even neutral conditions was developed. Key to this unprecedented reaction was the synergistic combination of (i) enhanced Lewis basicity of the carbonyl group, (ii) promotion of cyclization, and (iii) irreversible phenol elimination that shifts the reversible cyclization equilibrium toward the product. This system was further extended to a "molecular release reaction," enabling fluorescent dye liberation in aqueous media. While further development is still required, the methodology offers a basis for future exploration of biocompatible acid-responsive reactions and the establishment of new biochemical tools that releases molecules targeting the acidic environment within living systems.
Nanomaterials have unique functions due to their increased specific surface area compared to conventional materials. Various nanomaterials are already used in the production of many pharmaceuticals, cosmetics, and foods; however, this also means that, regardless of age or gender, it is now impossible to avoid exposure to these unique materials. Currently, there are concerns that nanomaterials may induce unexpected toxicities due to their small size. In addition, safety evaluations related to the exposure of pregnant women and fetuses, who are particularly vulnerable to the toxic effects of chemicals, are lacking globally; therefore, our understanding of the reproductive and developmental effects of nanomaterials is insufficient. Our group expects that understanding more about how the toxic effects of nanomaterials manifest not just in the mother and fetus but also in the placenta, an essential organ for maintaining pregnancy and fetal development, will be crucial for improving our understanding of the mechanisms that underly the reproductive and developmental toxicities of nanomaterials. Based on this, we have conducted a correlation analysis of the physicochemical properties, kinetics, and toxicities of nanomaterials, focusing on the placenta. In this review, we introduce the results of our research about effects of silica nanoparticles on trophoblast syncytial formation and placental kinetics of silica nanoparticles.
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.
In recent years, cancer chemotherapy has been administered in an outpatient setting; therefore, patient self-management of adverse events is an important issue. Pharmaceutical interventions were performed by pharmacists at the following 3 time points: before the physician consultation, after the physician consultation, and during multidisciplinary conferences at the Ibaraki Prefectural Central Hospital Cancer Chemotherapy Center. In this study, prescription proposals and their effectiveness for adverse events, were investigated. Of the 338 cases in which pharmaceutical interventions were performed, 280 were accepted by physicians, and the acceptance rates were 77% in conference, 89% before physician consultations, and 85% after physician consultations. Pharmaceutical interventions for the management of nausea and vomiting were most frequently accepted (96 cases), with improvement observed in 58 cases (60%). Improvement rates for hypertension and skin disorders were 76% and 56%, respectively, and improvement rates for peripheral neuropathy and dysgeusia were 33% and 22%, respectively. Of all interventions made by pharmacists, 68% were for the 1st 5 courses, with proposals continuing beyond the 6th course, suggesting that there is demand for long-term intervention. Pharmacists collecting patient information and implementing pharmaceutical interventions may contribute to the management of adverse events. As the degree of improvement varies according to the type of adverse event, it will be necessary to establish optimal pharmaceutical interventions in the future.
The development of innovative pharmaceuticals and their appropriate use is fundamental to the medical care that supports human health. Japan has made significant contributions to improving health standards through the production of a large number of pharmaceuticals. On the other hand, the declining share of Japan-developed drugs in the global market and the increasing import of foreign-origin medications have become more and more pronounced in recent years. Hence, the strengthening of drug discovery capabilities is recognized as an urgent issue. In this review, we introduce the outline, aims, and characteristics of the research-based six-year education system at the Faculty of Pharmaceutical Sciences, Osaka University, which is designed to foster human resources who will be responsible for drug discovery in Japan in the future.
Japan's pharmaceutical industry faces declining global competitiveness despite its historical strength in drug discovery. This paper examines the perspective of research-oriented pharmaceutical companies, focusing on the roles that pharmaceutical universities are expected to fulfill by the pharmaceutical industry. The diversification of therapeutic modalities-from small molecules to antibodies, middle-sized molecules, nucleic acids, and gene/cell therapies-requires new approaches to pharmaceutical research education. Using Chugai Pharmaceutical as a case study, we analyze the human resource composition across different functions, revealing an increasing demand for specialized researchers with Ph.D. degrees and diverse scientific backgrounds. Pharmaceutical companies seek three core qualities in researchers: scientific thinking capability, proactive collaboration skills, and patient-centered mindset. To develop these qualities, pharmaceutical universities should focus on cultivating strong scientific foundations through research experience; engaging in interdisciplinary collaboration with medical, engineering, and information sciences; and maintaining patient-centered perspectives through clinical training. The creation of a robust drug discovery ecosystem requires coordination between academia, pharmaceutical companies, startups, and regulatory authorities. Pharmaceutical universities play a crucial role in developing cutting-edge researchers and creating new drug discovery seeds and modality technologies. By strengthening both research and education in pharmaceutical universities, and fostering industry-academia collaboration, Japan can revitalize its pharmaceutical industry as a key economic sector and continue contributing to global healthcare through innovative medicines.
The field of epitranscriptomics, an area of genetics concerning the regulation of gene expression via post-transcriptional RNA modification, is currently attracting substantial research attention. In epitranscriptomics, proteins, collectively termed writers, erasers, and readers, enter into complex interactions that contribute to modifying RNA, thereby maintaining biological homeostasis. However, abnormalities in the expression or function of these proteins can lead to the onset and progression of cancers and neuropsychiatric disorders. Using prostate cancer clinical specimens, I cloned a novel gene, prostate cancer antigen-1 (PCA-1), containing a domain similar to the 2-oxoglutarate, iron(II) [Fe(II)]-dependent oxygenase domain of the Escherichia coli AlkB protein and characterized by enzymatic activity associated with the demethylation of methylated RNA. This was accordingly designated AlkB homolog 3 (ALKBH3). I demonstrate that ALKBH3 is highly expressed in tumor cells in prostate, pancreatic, lung, and other cancers, and its activity is correlated with a poor prognosis. In addition, I developed novel compounds that inhibit the RNA demethylase activity of ALKBH3, thereby providing a basis for developing a first-in-class cancer therapeutic. I also succeeded in cloning the ALKBH8 gene. High ALKBH8 expression was also observed in bladder cancer cells. Furthermore, abnormalities in development and behavior were noted in the generated Alkbh8 knockout mice. On the basis of the experience gained from ALKBH3 drug discovery research, I have established a foundation system for supporting academic drug discovery research. In this review, I describe the pathway followed in integrating the findings of basic pharmaceutical and drug discovery research and further developments.
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.
Antibodies are endogenous proteins that are involved in humoral immunity. Although various therapeutic monoclonal antibodies (mAbs) targeting cancer and immune diseases have been widely used, the development of mAbs for the treatment of infectious diseases has remained limited. During the coronavirus disease 2019 (COVID-19) pandemic, various mAbs targeting the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were developed, received Emergency Use Authorization (EUA), and were used for treating and preventing COVID-19. As successive SARS-CoV-2 variants emerged and the pandemic spread, mAbs with high target specificity proved less effective against these variants. Consequently, their EUAs were suspended within a short period, highlighting the limitations of antiviral mAbs developed against emerging infectious diseases. Since 2021, guidance documents on mAbs for prevention and treatment of COVID-19 have been issued by the WHO and US FDA, and efforts to prepare a regulatory environment supportive of drug development for future emerging and re-emerging infectious diseases have accelerated. The EMA published a concept paper on development of guidelines for non-clinical and clinical evaluation of mAbs for COVID-19. These trends indicate that the international regulatory landscape for mAbs against infectious diseases is entering a new era. We here provide an overview of the guidance documents issued by regulatory agencies, based on insights obtained from anti-SARS-CoV-2 mAbs during the COVID-19 pandemic. We also discuss the challenges and future prospects for the development of mAbs against infectious diseases, particularly in situations requiring rapid responses during pandemics.
Chemical substances are an indispensable part of the development of civilization; however, there are many known cases of health hazards induced by exposure to chemicals and their byproducts. In particular, the effects of exposure on the developing cerebral nervous system, even after a single exposure, may have lifelong effects; therefore, careful evaluation is required. In this paper, we provide examples of assessments conducted by our research group regarding the effects of exposure to chemicals in the environment during development, as well as the endpoints at which we were able to assess these effects. This will ultimately deepen our understanding of developmental neurotoxicity. Here, we demonstrate a case of late-onset abnormalities in female behavior and reproductive physiology due to developmental exposure to tris(2,6-dimethylphenyl)phosphate (TDMPP), a phosphorus-based flame retardant that exhibits typical estrogen-like effects. Also, we used IntelliCage, a fully automated behavioral measurement system for group-reared mice, to assess basal activity and adaptation to the social environment. An example of how IntelliCage can be used to assess behavior is dioxins, which are chemicals that are unintentionally produced. We focused on brominated dioxins and reported a case of abnormal exploratory behavior in a novel environment. Currently, there is growing public concern regarding substances and particle bodies that have not been adequately evaluated for use in the developing brain, such as PFAS and micro/nanoplastics. We believe that the establishment of more sophisticated evaluation methods and endpoints, including those introduced here, will continue to be necessary for building a foundation for a safe and secure society.
Early, high-quality resuscitation of patients experiencing sudden deterioration within medical facilities is a critical intervention directly influencing patient outcomes. To ensure rapid response, in-hospital emergency call systems have been established, enabling timely implementation of basic life support (BLS) and advanced cardiovascular life support (ACLS). As ACLS requires medications, the participation of a pharmacist is essential. At Kameda Medical Center, pharmacists receive BLS, ACLS, and departmental training and actively participate in emergency responses. The aim of this study was to clarify the effects of participation in emergency calls on professionalism and psychological stress of pharmacists. A hypothesis was developed and tested by surveying pharmacists who had participated in in-hospital emergency calls. The results suggest that emergency response provides pharmacists with opportunities to fulfill their professional roles, potentially enhancing professionalism. However, due to the high-pressure nature of these circumstances, pharmaceutical interventions do not always contribute to the development of professional identity. Pharmacists with >2 years of clinical experience reported greater confidence and a sense of accomplishment, indicating that early-career exposure is important for professional development. Additionally, 35% of respondents reported mental strain and 20% noted disruptions to routine duties, highlighting the requirement for improved training and psychological support systems.
We developed a symptom monitoring system that facilitates collaborations among physicians, hospital pharmacists, and community pharmacists using an electronic Patient-Reported Outcome (ePRO) application. The present study investigated the feasibility and acceptability of this system. Before and after the introduction of the system, participants completed a questionnaire assessing the burden, anxiety, and satisfaction using a 0-10 numeric rating scale. The rate of application input implementation, the number of times alert and free messages sent by patients, adherence, the incidence of adverse events (AEs), and admission due to AEs were assessed as secondary endpoints. Twenty-one patients with breast cancer initiating abemaciclib (300 mg/d), 10 community pharmacists, and 5 physicians participated in this study. Patients reported a reduced burden in both explaining their symptoms and having their symptoms confirmed (p<0.005), as well as a decrease in anxiety related to treatment (p<0.001). Healthcare professionals reported a reduced burden in symptom monitoring (p<0.05), and also experienced reduced anxiety about not knowing the status of patients (p<0.05). The rate of application input implementation was 94.3%. The total numbers of alert and free messages sent were 316 and 426, respectively. The median medication adherence rate based on pill counts and the medication possession ratio were 94.7% and 0.97, respectively. The rate of grade ≥2 diarrhea was 80.9%, with no emergency admissions due to AEs. The implementation of application input was well accepted and participants actively engaged with it. These results warrant further confirmation in large-scale studies.
Although still controversial in some aspects, the human papillomavirus (HPV) vaccine is widely recognized as a tool for preventing cervical cancer. However, Japan has historically struggled with vaccine hesitancy due to misinformation and public concerns about side effects. This cross-sectional preliminary study investigated an emerging social media trend, the "praise movement," in which users on X (formerly Twitter) commend individuals for receiving the HPV vaccine. Although the data collection period was short in 17 d and limited volume of posts were included in the analysis (n=70), we identified the movement when the term "HPV vaccination" appeared on Japan's trending list on X. Through sentiment analysis and content categorization of posts, we found that the majority of posts (91.4%) exhibited positive sentiment, whereas 5.7% were negative. While previous studies have documented negative reactions to HPV vaccination on social media, this study highlights a shift toward positive reinforcement. The praise movement may reflect a broader shift in public attitudes toward HPV vaccination, influenced by both grassroots advocacy and official efforts, including the catch-up vaccination program. Given this study is just a snapshot of a short period and a small volume of trend, a further in-depth study should be warranted. Nevertheless, our findings suggest that online communities can play a meaningful role in influencing public health behaviors, providing insights into potential strategies for improving vaccine uptake. This study offers valuable perspectives on digital health communication and its implications for addressing vaccine hesitancy in Japan and beyond.
A six-year pharmacy program began in 2006 focusing on medical pharmacy education. However, the importance of pharmaceutical health sciences remains universally unrecognized. Notably, the discussion about the positioning of pharmaceutical health sciences within pharmacy and pharmaceutical sciences as well as their relationship with the mission of pharmacists remains absent. In this review, I aimed to trace the historical development of pharmaceutical health sciences, examine the mission of pharmacists, and provide a historical perspective on the university education responsible for training pharmacists. The obtained results provide a basis to express expectations for the education of pharmaceutical professionals, particularly those with expertise in public health pharmacies.
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.
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.
Managing adverse events is important for optimizing cancer treatment and ensuring high patient satisfaction. Studies have assessed (1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody-induced skin toxicities, (2) development of severe neutropenia by renally excreted anticancer drugs in patients with renal impairment (RI), and (3) pharmaceutical care in the treatment of immune checkpoint inhibitors (ICIs). We identified liver metastasis as a risk factor and preemptive systemic antibiotic administration with anti-inflammatory effect as a preventive factor for grade ≥2 overall skin toxicities in anti-EGFR treatment for metastatic colorectal cancer (mCRC). Additional prophylactic topical steroids to systemic minocycline significantly prevented grade ≥2 rashes, but did not mitigate overall skin toxicities. Patients receiving trifluridine/tipiracil (FTD/TPI)-based chemotherapy for mCRC were assessed, resulting in significantly higher early severe neutropenia development among patients with RI. Additionally, we assessed the impact of RI on severe neutropenia development in carboplatin+pemetrexed-based chemotherapy for thoracic cancer. Consequently, severe neutropenia in the first cycle and all-treatment cycles was significantly more confirmed in patients with RI. We assessed the usefulness of pharmaceutical interventions in ICI treatment, which suggested that pharmaceutical care may improve quality of outpatient ICI treatment, and pharmaceutical intervention during the first three months after initiation of ICI treatment is crucial. Our studies have found clinically important outcomes that support the provision of less onerous chemotherapy.
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.
Although supernumerary ribs have been examined in regulatory developmental toxicity studies, their toxicological significance remains controversial because of the unclear etiology and strain-dependent background incidence of this condition. In the current study, we established a rat model of drug-induced supernumerary ribs by administering flucytosine to pregnant Sprague-Dawley rats, a strain with low natural occurrence of this skeletal anomaly. The results revealed that flucytosine exposure induced supernumerary ribs in a dose- and timing-dependent manner, accompanied by dysregulated expression of specific Hox genes. Altered expression was correlated with axial patterning defects and, in some cases, limb abnormalities. Comparative genetic analysis between Sprague-Dawley rats and BrlHan:WIST@GALAS rats, which exhibit high spontaneous incidence (~50%) of supernumerary ribs, revealed sequence variation in the upstream regulatory region of Hoxa9, particularly affecting miR-196b. These findings demonstrate that temporal dysregulation of Hox gene networks and micro RNA (miRNA)-mediated modulation are key factors in the pathogenesis of supernumerary ribs. Moreover, our results suggest that genetic background should be considered when interpreting skeletal variations in developmental toxicity studies. Mechanistic understanding of these findings may improve the relevance of endpoints in risk assessment and regulatory decision-making.