I worked in a hospital pharmacy department, where I was responsible for managing drug safety information within the hospital, providing patient-specific drug information to physicians and other healthcare professionals, and offering medication guidance to patients. Through these responsibilities, I became keenly aware of the need to develop methodologies for predicting drug–drug interactions (DDIs) and to improve the communication of such information. To address these challenges, we have been working over the past 20 years on a pharmacokinetic drug interaction significance classification system (PISCS), designed for clinical use. We were the first to develop the PISCS as an alert system that can easily and comprehensively predict changes in drug clearance caused by cytochrome P450-mediated interactions on the basis of the contribution ratio of target metabolizing enzyme to the oral clearance of substrates (CR) and the inhibition ratio of inhibitors (IR) (the CR–IR method). Leveraging these research findings, I have actively promoted DDI management through academic conferences, committee work, lectures, and publications. Moreover, I have contributed to the development of guidelines based on PISCS concepts for evaluating DDIs and disseminating information related to drug development. Notably, in July 2018, the Ministry of Health, Labour and Welfare of Japan issued the Guideline on drug interaction for drug development and appropriate provision of information, which is currently internationally harmonized as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M12 guideline. Consequently, DDI evaluations in drug development are being conducted in accordance with this guideline, and the descriptions of DDIs in drug package inserts have been significantly improved.

Although clinical questions regarding treatment and disease mechanisms frequently arise in clinical practice, clear answers may not always be available. Investigating these issues could lead to new therapeutic strategies and further advancements in clinical pharmacies. This review presents three examples in which meta-analysis was used as a link between basic and clinical studies to resolve clinical questions. First, the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of cisplatin-induced nephrotoxicity (CIN) was examined. A meta-analysis indicated that NSAID use was a risk factor (odds ratio: 1.88; 95% confidence interval: 1.44–2.45). Based on these results, basic studies that used rat kidney cells revealed that 17 NSAIDs have varying effects on CIN. Second, the dose-dependency of magnesium sulfate, a known preventive agent for CIN, was evaluated. Although a basic study suggested dose dependency, clinical evidence is limited. A meta-regression analysis demonstrated a dose-dependent preventive effect of magnesium sulfate within 5–20 mEq, supporting a rational dose setting in clinical practice. Third, we assessed the effect of acid suppressants (ASs) on the efficacy of immune checkpoint inhibitors (ICIs). A meta-analysis showed that AS use was associated with reduced overall survival in patients treated with ICIs. Subgroup analysis revealed that, although proton pump inhibitors (PPIs) negatively affected survival, histamine-2 receptor antagonists (H2RAs) did not, suggesting that H2RAs are potential alternatives to PPIs in ICI-treated patients. These studies suggest that meta-analyses based on reverse translational research are useful in resolving clinical questions and are expected to contribute to further advances in clinical pharmacies.

Bioactive molecules are mostly chiral, and their enantiomers often exhibit different biological properties, including pharmacological effects and toxicity. Recent biochemical studies have revealed that certain trace-level chiral metabolites are associated with specific pathological conditions, including chronic kidney disease and metabolic disorders. This finding highlights the importance of enantioselective imaging techniques that can help visualize the spatial distribution and dynamic behavior of individual enantiomers. Although enantioselective biochemical analyses, such as those based on chromatography or electrophoresis, have proven effective in separating enantiomers, progress in enantioselective imaging methods has been limited. Ion mobility spectrometry/mass spectrometry imaging (IMS/MSI) has emerged as a powerful tool with the potential to enable the enantioselective imaging of minor chiral metabolites. However, suitable chemical structures that can achieve both sufficient resolving power for the target enantiomer in IMS and high ionization efficiency in MSI remain unclear. This review highlights the development of enantioselective imaging methods based on on-tissue chiral derivatization and IMS/MSI. After exploring suitable chiral derivatization reagents, we designed a new charged chiral tag that enabled complete separation of a pair of enantiomers by IMS, sensitive detection of D,L-2-hydroxyglutaric acid by mass spectrometry, and the visualization of their distribution in the mouse testis by IMS/MSI. This approach can be further expanded to analyze other chiral molecules and has great potential for unveiling the enantioselective distribution and dynamics of minor chiral metabolites in biological tissues.

Cells are involved in various biological events by transporting message substances such as proteins and nucleic acids to target cells. Recently, it was revealed that extracellular vesicles (EVs), which are cell-secreted membrane particles, function as intercellular delivery vehicles. As EVs reflect the characteristics of their parent cells, the development of novel EV-based therapies is expected. Moreover, it has become clear that microorganisms also secrete EVs. Probiotics are live microorganisms that confer a health benefit on the host and known to secret EVs. However, the information about the characteristics of probiotic-derived EVs is not fully understood. Furthermore, there were no technologies to modify the functionality of probiotic-derived EVs, such as formulation and drug loading, which are essential for their practical application. Therefore, we aimed at elucidation of the usefulness of probiotic-derived EVs and development of technologies for their functionalization. First, as an evaluation of the usefulness of probiotic-derived EVs, we evaluated the effects on the innate immune response, which is the initial immune response of the host. Next, we elucidated the pharmacokinetics and immunostimulatory effects of EVs when administered to the mice. Furthermore, we developed a novel functional modification technology of EVs by combining the amino acid metabolism mechanism and the bio-orthogonal reaction, aiming at the application of probiotic-derived EVs to immunotherapy. These findings will be helpful for the development of immunotherapy based on probiotic-derived EVs with superior safety and efficacy.

Nitriles are important organic compounds that are frequently found in pharmaceuticals, natural products, agrichemicals, and functional materials. In addition, nitriles serve as versatile building blocks in synthetic chemistry, as the nitrile moiety can be readily transformed into a variety of valuable functional groups, such as carbonyl derivatives, amines, and heterocycles. However, conventional methods for nitrile synthesis often rely on highly toxic metal cyanides, such as copper(I) cyanide (CuCN) and potassium cyanide (KCN). In this review, I introduce our recent works on a cyanide- and transition metal-free approach for the synthesis of (hetero)aromatic and aliphatic nitriles from N-acyl (2-nitrophenyl)sulfonamides via a base-promoted desulfonylative Smiles rearrangement. The reactions proceeded under operationally simple conditions using potassium acetate as a base and 1,3-dimethyl-2-imidazolidinone as a solvent. This method enables the efficient preparation of a wide range of nitriles, including those bearing primary, secondary, and tertiary carbon centers, with broad functional group compatibility and in good to excellent yields.

Although the primary effects of most drugs have been well verified, their secondary effects remain less understood. Therefore, concomitant medications used to prevent side effects may attenuate the efficacy of the primary therapeutic agent. In this study, we investigated whether concomitant medications that maximize therapeutic efficacy can be used to reduce the effectiveness of the main therapeutic agent. In particular, we focused on anti-vascular endothelial growth factor (anti-VEGF) drugs, which are essential for cancer treatment. We demonstrated that the therapeutic outcome of anti-VEGF drugs can be changed by the concomitant use of gastric acid secretion inhibitors and identified a potential involvement of estrogen receptors in the mechanism underlying this interaction. Therefore, we are examining the mechanism in detail and conducting further studies, including the exploration of drugs that may exert stimulatory or inhibitory effects on estrogen receptors as a secondary action, through omics data analysis. This approach can be applied to a wide variety of drugs and is expected to improve therapeutic outcomes of various drug treatments.

Dysmenorrhea refers to pathological symptoms that occur in association with menstruation during the menstrual period. Treatment options for dysmenorrhea include nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose estrogen–progestin combination pills. However, some patients do not respond to these treatments, and long-term use can lead to adverse reactions, raising additional problems. To overcome these issues, Kampo (traditional Japanese herbal) medicines are often used, with prescriptions based on Kampo medicine diagnoses. In this study, we investigated the analgesic effects of Kamishoyosan, a Kampo medicine frequently used to treat this disease, using a mouse primary dysmenorrhea (PD) model. Since Kamishoyosan is typically administered over a long term in clinical settings, we also evaluated its effects on PD after single-dose or repeated long-term administration. Oxytocin administration to continuously estradiol-treated mice significantly increased the number of writhing responses (an index of pain), uterine tissue level of prostaglandin F2α (PGF2α), and calcium ion (Ca²⁺) level, while uterine blood flow significantly decreased. In contrast, repeated administration of Kamishoyosan decreased the number of writhing responses. The uterine tissue PGF2α and Ca²⁺ levels reduced after single-dose administration at a high dose and regardless of dosage after repeated administration. Uterine blood flow was improved by single-dose administration regardless of dosage. These results showed that continuous administration of Kamishoyosan exerted analgesic effects on PD symptoms even at non-high doses. Furthermore, Kamishoyosan may reduce PD-related pain by acting on uterine contraction factor (including PG)-producing pathways and uterine blood flow.

Direct involvement of community pharmacists in the sale of OTC medicines is expected to help prevent adverse drug reactions (ADRs) and enhance treatment efficacy. However, the extent of their actual involvement in OTC medicine sales remains insufficiently investigated. To address this, we retrospectively analyzed OTC medicine sales survey forms to assess the involvement of community pharmacists in OTC medicine sales, and identify drug-related problems (DRPs) requiring pharmaceutical decisions. All customers who visited the Yokohama Nishiguchi branch of WinPharma Co., Ltd. to purchase OTC medicines were included in the study. Community pharmacists were involved in all OTC medicine sales. Among the 821 customers who sought specific OTC medicines, product choice was changed based on pharmacist recommendation in 124 cases (15.1%), including cases recommended to visit a doctor. Frequency of product change was highest for second-class OTC medicine sales. In addition, contraindications (21.0%) were the most common DRPs, with second-class OTC medicines accounting for 80.8% of all these cases. Furthermore, when including the 666 cases in which community pharmacists were consulted directly about purchasing OTC medicines, 790 of the 1487 cases (53.1%) required pharmacist involvement. These findings highlight the crucial role of community pharmacists preventing ADRs and enhancing treatment efficacy based on OTC medicines characteristics and conditions and lifestyles of users regardless of the risk classification of OTC medicines. Proactive involvement by community pharmacists can improve self-medication safety and efficacy by ensuring the proper use of OTC medicines.