Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity and impulsivity. Psychostimulants such as methylphenidate are first-line treatments, but carry risks of severe side effects and addiction. Therefore, further research and the discovery of non-psychostimulant medications with novel mechanisms are urgently needed. We previously reported that juvenile stroke-prone spontaneously hypertensive rats (SHRSP/Ezo) are a suitable animal model of ADHD, and we identified N-methyl-D-aspartate (NMDA) receptor dysfunction in the prefrontal cortex of SHRSP/Ezo. D-Serine, a co-agonist for the glycine binding site of NMDA receptors, is synthesized from L-serine by serine racemase (SR) and degraded by D-amino acid oxidase (DAAO). Although D-serine dysregulation is implicated in psychiatric disorders, its pathophysiological role in ADHD is unclear. We measured D-serine in the medial prefrontal cortex (mPFC) of SHRSP/Ezo and addressed SR and DAAO expression. Additionally, we assessed cognitive function following DAAO inhibitor microinjection into the mPFC. SHRSP/Ezo showed a reduced D-serine/total serine (DL) ratio in the mPFC compared with the genetic control, Wistar Kyoto rat/Ezo (WKY/Ezo). DAAO expression in the mPFC was higher in SHRSP/Ezo rats compared with WKY/Ezo, however there was no difference in SR expression. The microinjection of a DAAO inhibitor into the mPFC of SHRSP/Ezo rats increased the DL ratio and ameliorated ADHD-like behaviors in the Y-maze test. These results suggest an association between abnormal D-serine metabolism and ADHD-like behaviors based on NMDA receptor dysfunction in the mPFC. Our findings provide insight into ADHD pathogenesis and should advance the development of new therapeutic approaches for the disorder.

Bronchial asthma is primarily caused by sensitization to specific antigens that activate type 2 helper T cells (Th2) through acquired immunity, leading to chronic inflammation due to eosinophilic infiltration. Consequently, inhaled steroids have become an established standard treatment. However, refractory cases that do not respond to this treatment pose a challenge. Recent studies have revealed that neutrophils and type-2 innate lymphoid cells (ILC2) are steroid-resistant. The association between these cells and refractory severe asthma has garnered considerable attention. Therefore, my research focused on investigating the interplay among neuro-endocrine, -immune, and -epithelial cells to understand the pathology of refractory asthma, particularly steroid resistance, and to develop therapeutic medications. So far, I have elucidated the mechanism of the onset of neutrophilic airway inflammation due to stress and discovered the role of interleukin-1β, which could be a therapeutic target. Additionally, I have investigated the activation of ILC2 by pulmonary neuroendocrine cells, the release of calcitonin gene-related peptide (CGRP), and the efficacy of treatments for this condition. In this review, I outline treatment targets and approaches from a novel perspective to address severe refractory asthma focusing on my research findings.

Transporters are critical for maintaining the homeostasis of metabolites within cells, organelles, and extracellular fluids. Various transporters have been targeted for development as pharmaceutical therapies, including glucose transporter (SLC5A2/SGLT2) and urate transporter (SLC22A12/URAT1). The solute carrier transporter family includes many orphan transporters with unknown physiological functions and substrates, largely because of the difficulties in optimizing the transporter probes and constructing convenient evaluation systems for functional analysis. However, the analysis of these transporters is important as they may be potential candidates for pharmaceutical therapies or drug targets. This review focuses on the analysis of the SLC16A family, which encodes monocarboxylate transporters (MCTs), as it contains orphan transporters known to be associated with several disease pathologies. We successfully identified taurine, cephradine, and 5-carboxyfluorescein as new substrates for rat Slc16a6/MCT7, SLC16A13/MCT13, and SLC16A5/MCT6, respectively. These substrates enabled the functional analysis of the transporters in mammalian cells. We found that the co-expression of ancillary proteins, such as ancillary protein basigin/CD147 and embigin/GP70, enhanced the transport functions of these transporters. Interestingly, the functions of MCT6 and MCT13 were affected by extracellular chloride and potassium ions, respectively, but MCT7 was unaffected. These findings are helpful for elucidating the pathophysiological roles and substrates of orphan and uncharacterized MCTs.

Chemical phototoxicity is elicited after exposure of skin to photosensitive chemicals, followed by exposure to sunlight. The intensity of ultraviolet light has increased due to ozone layer destruction; therefore, interest in avoidance of the phototoxicity risk of chemicals has increased in drug discovery and product development. Based on the mechanism of chemical phototoxicity, a photosafety screening strategy focusing on the photoreactivity of chemicals and skin exposure to chemicals was proposed. In an initially-developed photosafety screening system, a reactive oxygen species (ROS) assay and an in vivo cassette-dosing pharmacokinetic study were employed to evaluate the photoreactivity of chemicals and skin exposure to chemicals, respectively, and previous investigations yielded reliable photosafety predictions. On the other hand, the tools in the photosafety screening system have some issues, such as low applicability to poorly water-soluble chemicals in the ROS assay and unsatisfactory animal welfare in in vivo cassette-dosing pharmacokinetic studies. The present study aimed to overcome these issues. A micellar ROS (mROS) assay was newly developed to evaluate photoreactivity of poorly water-soluble chemicals, resulting in an increase in the number of evaluable chemicals by ROS assay systems. An in vitro permeation test was applied to the proposed photosafety screening strategy as an alternative to the in vivo pharmacokinetic study for evaluating chemical exposure of the skin. Combined use of the ROS assay system and in vitro permeation test provided reliable photosafety evaluations. These findings would contribute to drug discovery and product development with high photosafety and improved animal welfare.

Liquid chromatography tandem mass spectrometry (LC-MS/MS) is an essential tool for drug discovery that enables simple and rapid identification and quantification of chemical substances. A combination of a mobile phase and column makes it possible to analyze a wide range of target substances from low-molecular weight high-polar substances, such as amino acids and peptides, to low-polar substances such as lipids, and even macromolecular substances such as proteins. In this paper, we describe the results of applying LC-MS/MS to the analysis of phospholipids and related substances in biological samples and the analysis of photoproducts of pharmaceuticals. First, MS conditions were optimization using several standards, and a system that enables measurement of a vast number of molecular species with different carbon chain lengths and degrees of unsaturation. Its application to the lipid profiling of influenza A virus-infected cells suggested that viral infection triggered the increase of intracellular levels of diacylglycerols and ceramides at the later stages of infection concomitant with viral replication. In addition, the analysis of lysophospholipids in several cell lines revealed partial functions of several types of glycerophosphodiester phosphodiesterase, which metabolize lysophospholipids. Next, the chemical structures of several photoproducts of pharmaceuticals were elucidated. Novel photoproducts of photo-exposed pharmaceuticals were identified, and the photodegradation pathways were suggested. Based on the photodegradation mechanism, the photodegradability of naproxen was regulated by the addition of several additives such as polyphenols.

Tacrolimus is widely recognized as an anti-rejection agent due to its immunosuppressive characteristics. It binds to the immunophilin FK506-binding protein (FKBP) and thus to calcineurin, and inhibits its activity. Tacrolimus’ therapeutic concentration range in blood is narrow, and its pharmacokinetics are highly variable among individuals. First, because tacrolimus primarily distributes to red blood cells (RBCs), anemia and blood transfusions can cause fluctuations in tacrolimus blood concentrations. Variations in blood tacrolimus concentration significantly correlated with variations in RBC count, hemoglobin level, and hematocrit value, but not with variations in white blood cell or platelet counts. Interestingly, FKBP played an important role in tacrolimus distribution to RBCs. The effects of intracellular and extracellular FKBP levels on RBC distribution of tacrolimus in circulating blood were substantial. Secondly, proteins affecting pharmacokinetics can differ at the genetic level in their expression and functional potency. Genetic polymorphisms that influence tacrolimus pharmacokinetics have been reported. A polymorphism in the gene encoding the metabolic enzyme cytochrome P450 (CYP) 3A5 is a particularly influential factor affecting tacrolimus pharmacokinetics in Japanese patients. CYP3A5 polymorphisms correlated with individual differences in tacrolimus blood concentration changes after starting continuous infusion in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In addition, CYP3A5*3 polymorphism also correlated with differences in the frequency of acute graft-versus-host disease (GVHD) development in allogeneic HSCT recipients.

Three years have passed since the Science Council of Japan issued its recommendations entitled “Profession and lifelong learning of pharmacists responsible for sustainable medical care.” These recommendations include active involvement in community medicine, securing patient information necessary for pharmaceutical management, harmonizing undergraduate and post-graduate education, reform of the certification system for specialty-credentialed pharmacists, and development of the pharmacist resident system. This paper provides an overview of recent trends and future prospects for pharmacists and pharmacies in Japan.

With the increasing separation of dispensing and prescribing, Japanese pharmacists have changed over the past 50 years. Changes affecting pharmacists include the bashing of the separation of dispensing and prescribing, the formulation of the “Vision for Patient-centered Pharmacies” and the implementation of the Action Plan to realize this vision, and the amendment of the “Pharmaceuticals and Medical Devices Act.” By 2025, when many baby boomers will be 75 years of age and older, the construction of the “Integrated Community Care System” is being promoted in various regions, and pharmacists are expected to be involved in community healthcare as members of community support networks based on multidisciplinary cooperation. In Nagasaki City, Japan, a regional medical cooperation system centered on the “Nagasaki Home Doctor Net” has been established, and a multidisciplinary network supports the region. In 2007, volunteers, mainly pharmacy managers, established the “Nagasaki Pharmaceutical Care Net (P-net)” to provide home medical care. To date, these volunteers have been involved in community healthcare while continuing their studies through the group. At the symposium, I introduced my active involvement in community healthcare as a pharmacist and as a member of P-net. I hope this symposium will help pharmacists’ involvement and collaboration in community healthcare.

Although there have been appeals for regional cooperation for a considerable time, are hospitals and local communities really working together? Hospitals typically permit a variety of professionals to work together, share information via medical records, and directly discuss patients. A problem with treating patients at home in local communities is that doctors and pharmacists do not share the same workplace; hospitals, clinics, and pharmacies do not have a common information source equivalent to medical records. Prescriptions and medical notes are the only things that connect health provision to the community. We have added laboratory data to prescriptions for outpatients to eliminate confusion. This has improved efficacy and made it easier to avoid serious side effects. It has also prevented economic losses to some extent. An important goal of medicine is to provide individualized care. This current endeavor may be a small but steady step towards this goal.

The six-year pharmacy university education program that began in 2006 was guided by the Model Core Curriculum for Pharmacy Education which started as process-based education. It was first revised in 2013 and further revised in 2023 to provide outcome-based education. There remains a need to develop a consistent six-year curriculum spanning basic science to clinical pharmacy. The overall goal is to develop problem-solving abilities; however, there are still many challenges to overcome. There has also been little progress in incorporating the basic qualities required of pharmacists into pharmacy education programs. In conjunction with the revision, guidelines have been established for practical pharmacy training, and the promotion of participatory, experiential training. However, the results are still insufficient. This article examines changes in pharmaceutical university education over the past 15 years and proposes future pharmacy education solutions.

This is a personal review of my chemistry research on retirement from Teikyo University. Under the guidance of Prof. Masaji Ohno of the Faculty of Pharmaceutical Sciences, The University of Tokyo, my research career started with the synthesis of water-soluble basic natural compounds, including the first artificial bleomycin showing potent molecular-oxygen activation effects and DNA binding abilities. While studying abroad at Eidgenössische Technische Hochschule (ETH) under the guidance of Prof. Albert Eschenmoser, I studied the formation of ribose under prebiotic conditions. The condensation reaction between formaldehyde and glycolaldehyde phosphate produced ribose in far greater yield than the formose reaction. In the School of Pharmacy, Showa University, I conducted research in nucleic acid chemistry to synthesize, for example, anomeric spiro-nucleosides using radical chemistry and oligonucleotides that interacted with the κB motif. After moving to Teikyo University in 1999, I engaged in studies on the synthesis of vitamin D derivatives, included in fat-soluble vitamins, with selective biological activities without calcemic side-effects, and discovered, for example, 2α-(3-hydroxypropyl)-19-nor-1α,25-dihydroxyvitamin D₃ (MART-10), which exhibits potent anticancer activity in vivo, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D₃ (AH-1), which shows greater bone-forming effects than natural active vitamin D₃ in vivo, and the A-ring-converted vitamin D derivative KK-052, which is an in vivo selective inhibitor of sterol regulatory-element binding protein (SREBP), a master transcription factor of lipogenesis, independent of the vitamin D canonical activity through a vitamin D receptor.

Intentional overdose (OD) of over-the-counter (OTC) and prescription drugs is becoming a significant social issue all over the world. While previous research has focused on drug misuse, there has been limited analysis using social networking service data. This study aims to analyze posts related to a drug overdose on Twitter^® (X^®) to understand the characteristics and trends of drug misuse, and to examine the applicability of social media in understanding the current situation of OD through natural language processing techniques. We collected posts in Japanese containing the term “OD” from January 10 to February 8, 2023, and analyzed 30203 posts. Using a pre-trained, fine-tuned bidirectional encoder representations from transformers (BERT) model, we classified the posts into categories, including direct mentions of OD. We examined the content for drug types and emotional context. Among the 5283 posts categorized as “Posts describing ODing,” about one-third included specific drug names or related terms. The most frequently mentioned OTC drugs included active ingredients such as codeine, dextromethorphan, ephedrine, and diphenhydramine. Prescription drugs, particularly benzodiazepines and pregabalin, were also common. Tweets peaked at midnight, suggesting a link between negative emotions and potential OD incidents. Our classifier showed high accuracy in distinguishing OD-related posts. Analyzing Twitter^® posts provides valuable insights into the patterns and emotional contexts of drug misuse. Monitoring social networking services for OD-related content could help identify high-risk individuals and inform prevention strategies. Enhanced monitoring and public awareness are crucial to reducing the risks associated with both OTC and prescription drug misuse.