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.

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.

Approximately 7000 rare diseases have been identified globally; however, effective treatments are available for only 5% of them, highlighting substantial unmet medical needs worldwide. In Japan, drug loss—the lack of domestic approval or development of drugs already approved overseas—has become a pressing public health issue. We analyzed orphan drugs (ODs) approved in the United States (U.S.) between 2005 and 2021 to examine trends in OD development in the U.S., drug loss and associated research and development (R&D) models, with the aim of identifying factors that could facilitate more seamless OD development in Japan. Despite a marked increase in OD approvals in the U.S. since 2018, the number of ODs not approved in Japan have increased rapidly, reaching 120 drugs (49%), of which approximately 70% had not entered development, indicating greater OD loss in Japan. U.S./Europe-based startups have become key players in rare disease drug R&D, significantly contributing to this drug loss trend. They successfully develop drugs in the U.S. by combining in-licensing with in-house drug discovery. Out-licensing to Japanese companies or large pharma is critical for expansion into Japan, with successes attributed to drug innovation, target indications, and transactional capabilities. Underlying this trend were Japan’s perceived low market potential, its complex clinical trial environment and regulatory requirements, and the financial limitations of startups. These findings highlight the need to foster partnerships with startups and cultivate an ecosystem in Japan that nurtures local startups, to address drug loss and ensure access to promising drugs.

Patients with rare diseases worldwide face substantial unmet therapeutic needs. In Japan, drug lag—delays in drug approval compared to other countries—has resurfaced as a pressing public health issue. This study analyzes orphan drugs (ODs) approved in the United States (U.S.) from 2005 to 2021, examining OD lag trends, and research and development (R&D) models to streamline OD development in Japan. Despite increased OD approval in the U.S. since 2018, the number of unapproved ODs in Japan has substantially increased. Although OD lag had once decreased, it has shown a tendency to resurge since 2017. This is largely due to changes in the R&D strategies of pharmaceutical companies, which are driven by the growing presence of U.S.- and Europe-based small- to mid-sized enterprises (SMEs) and the evolving industry landscape. Large foreign pharmaceutical companies have shifted toward a global development strategy for Japan, aiming for more efficient development and competitive advantage. This has been propelled by a move toward in-licensing earlier-stage drug candidates with global exclusivity from SMEs. Japanese pharmaceutical companies have focused on in-licensing late-stage drug candidates for the Japanese market from SMEs without a business presence in Japan, which have not been developed locally, thereby employing a bridging strategy for Japan. With the increase in ODs developed in the U.S. by these SMEs, this practice has substantially exacerbated the OD lag. As these SMEs are unlikely to enter the Japanese market, it is crucial for Japanese pharmaceutical companies to proactively pursue earlier, more proactive global partnerships with SMEs.

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.

Our early study showed the vasoactive effects of soybean lecithin-derived lysophosphatidic acid (LPA). The finding indicates that the oral administration of LPA-rich supplements is beneficial to human health. Our studies have showed five beneficial effects of LPA in the upper digestive systems. First, we detected LPA at high levels in various herbs used in Chinese traditional medicine for the treatment of gastric ulcers, as well as other foods, including various vegetables. Second, we found human mixed saliva to be an LPA-rich biological fluid, suggesting its protective effect on human oral mucosa. Third, LPA levels in gingival crevicular fluid from patients with periodontitis was lower than that in healthy subjects, reinforcing the protective quality of LPA. Fourth, daily topical injections of LPA in rat buccal gingiva reduced the degree of alveolar bone absorption induced by oral bacteria in rats with experimental periodontitis. Fifth, repeated intragastric administration of LPA-rich herb reduced the degrees of gastric ulcer induced by stress (rats) or medication (mouse). Previous findings on the beneficial effects of LPA acting on the lumen side of the lower digestive tracts in mammals are well documented, although results on the harmful effects of LPA on mouse and rats with genetically easy to progress colon cancer are noted. Our studies also showed a novel pathway of LPA generation by lysophospholipase D activity of glycerophosphodiesterase 7 on the lumen side of digestive tracts. These findings suggest that additional research into creative food supplements focusing on LPA as a food factor could be beneficial.

While drugs affecting stroke rehabilitation outcomes have been studied in the context of convalescent hospitals, data on acute stroke patients remain insufficient. This retrospective single-center study aimed to evaluate the impact of medications on functional outcomes during rehabilitation in acute stroke patients. The study included stroke patients who received rehabilitation between April 2017 and March 2018. A total of 144 patients (mean age: 70.6±12.3 years; male/female: 86/58) were analyzed, including 101 with cerebral infarction (mean age: 72.3±12.1 years; male/female: 65/36) and 43 with cerebral haemorrhage (mean age: 66.7±12.1 years; male/female: 21/22). Multiple regression analysis was used to identify associations between drug use and recovery of activities of daily living (ADL). Multiple regression analysis of the overall data identified the use of non-steroidal anti-inflammatory drugs (NSAIDs) as a promoting factor for ADL recovery [partial regression coefficient (PRC): 34.52, p<0.01] and the use of angiotensin-converting enzyme inhibitors (ACE-Is) as an inhibiting factor (PRC: −36.33, p<0.01). In the cerebral infarction group, only ACE-I use was identified as an inhibiting factor (PRC: −28.85, p<0.01). In the cerebral haemorrhage group, NSAID use was identified as a promoting factor (PRC: 51.27, p=0.01), while the use of diabetes drugs was identified as an inhibiting factor (PRC: −39.82, p=0.046). Our results suggest that certain drugs influence functional recovery after stroke. However, further research is needed to understand the underlying mechanisms.

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.

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.

Although zinc oxide ointment is commonly used to treat diaper dermatitis in infants, there exists limited evidence of pharmacists suspecting hyperzincemia due to zinc oxide ointment and early intervention for mitigation of severity. This case study is female infant who was born at 27 weeks and 1 d of gestation and weighing 542 g. On postnatal 49 d, the serum zinc concentration was 65 µg/dL. Thereafter, treatment with oral zinc acetate hydrate (2 mg/kg/d) began on 56 d for ameliorating hypozincemia. Zinc oxide ointment was administered on 86 d as a treatment for diaper dermatitis. Despite of attaining hyperzincemia (427 µg/dL), treatment with zinc acetate hydrate and zinc oxide ointment continued because diarrhea and nausea had not developed. On 105 d, the serum zinc concentration was 199 µg/dL and the dermatitis conditions showed a marked improvement. Consequently, the pharmacist considered that zinc oxide ointment might have contributed to the hyperzincemia and consulted with the physician. Subsequently, both the zinc acetate hydrate and zinc oxide ointment were discontinued. Although zinc acetate hydrate was restarted on 114 d, serum zinc concentration was 101 µg/dL on 128 d. The Naranjo Adverse Drug Reaction Probability Scale score was 9 points, which is categorized as “definitive.” Administration of zinc oxide ointment to diaper dermatitis with decrease skin barrier may have increased percutaneous absorption of zinc, resulting hyperzincemia. The pharmacist may be able to conduct early intervention for hyperzincemia by monitoring not only serum zinc concentration but also changes in the dermatitis conditions in infant patients.