This review summarizes the contributions to the discovery, evaluation, and functional development of microbial and enzyme catalysts, as well as the rational design of pathways that synergistically integrate chemical and biochemical reactions. In the introduction, the author outlines his strategies and principles: 1) He avoided biosynthetic enzymes and pathways, opting instead for degradative enzymes that offer broader substrate flexibility and a wider range of applications. 2) He focused on commercially available enzymes, prioritizing their reproducibility and accessibility for widespread use. All the microorganisms he identified have been deposited in public institutions, making them available to researchers in both academic and corporate settings. 3) He developed methods to enhance reactivity and selectivity by optimizing reaction conditions and substrate structures, without altering the enzymes themselves. The main body of the review is divided into two parts. Part 1, titled “Chemo-enzymatic Synergistic Synthesis of Medicines,” covers the following topics: 1) the synthesis of dihydroxymethylepoxyquinomicin (DHMEQ); 2) the synthesis of sialic acids; 3) the utilization of epoxide hydrolase; and 4) the synthesis of (S)-azetidine-2-carboxylic acid. Part 2, titled “New Selective Reactions for Synthesis of Medicines,” includes: 1) the optimization of reaction conditions in lipase-catalyzed transesterification and aminolysis; 2) the conversion of racemates into single enantiomers using hydrolytic enzymes through novel pathways; 3) the use of carbonyl reductases in conjunction with substrate design; 4) nitrile hydratase and amidase in Rhodococcus species; 5) selective acylation and deacylation of alcohols and phenols; and 6) the use of oligosaccharides as protective groups in the synthesis of polyphenol glycosides.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive genetic disorder caused by loss-of-function mutations in the gene encoding adenosine deaminase (ADA) 2. This enzyme catalyzes the deamination reaction of adenosine/2′-deoxyadenosine to inosine/2′-deoxyinosine. DADA2 exhibits a complex clinical presentation, with systemic vasculitis with stroke, bone marrow failure, and immunodeficiency as the major pathologies. Since its discovery in 2014, more than 400 cases have been reported, and the phenotype has expanded significantly. DADA2 generally presents in childhood, although diagnosis in adulthood has also been reported, indicating the need to raise awareness of this disease beyond pediatrics. ADA2 is believed to be relevant in the regulation of the human immune system. Currently, knowledge is accumulating on the association between macrophage polarization into an inflammatory phenotype and systemic vasculitis, upregulation of the type I/II interferon pathway, and neutrophil function. The biochemical characteristics of ADA2 that differ from those of its isozyme ADA1 are a subject of significant research. One of these characteristics, N-glycosylation, plays a vital role in controlling the formation of the functional three-dimensional structure of ADA2. Moreover, with the accumulation of knowledge regarding the dysregulation of innate and adaptive immunity in DADA2 and the biochemical properties of ADA2, effective treatments and diagnostic methods are being established. This review provides an overview of ADA2 properties and DADA2.

Hypervalent iodine(III) compounds are known to be exceptionally good oxidizing reagents because they are generally highly reactive, can be used in various molecular designs, and are relatively easy to synthesize and handle. Although they are very useful reagents with a wide range of reactivity, some iodine(III) compounds are difficult to handle due to low solubility and stability issues. In earlier studies, it was found that iodine(III) reagents with an ether group introduced at the ortho-position have improved solubility and stability. Based on these results, new hypervalent iodine compounds were developed by utilizing coordinating properties of functional groups other than the ether group. In this paper, hypervalent iodine compounds with carboxyl or hydroxyl groups introduced into the aromatic ring attached to the iodine atom were successfully synthesized, and their structures were elucidated by X-ray structural analysis. In addition, the reactivity of these compounds is reported based on the successful development of several unique reactions.

Antigen-binding fragments (Fab) are a type of antibody fragment that contains an antigen-binding site in a therapeutic antibody format. To further improve their utility as therapeutic antibodies, this study aimed to enhance Fab functionality through protein engineering. A Fab expression system using the yeast Pichia pastoris was constructed, and recombinant Fabs were efficiently prepared. Second, a Fab mutant suitable for conjugation with polyethylene glycol (PEG) was generated to increase the serum half-life of the Fab. The interchain disulfide bond normally formed at the C-terminus (H: Cys224-L: Cys214) was shifted to a novel position (H: Cys177-L: Cys160), allowing a free cysteine residue at the C-terminus to be used for site-directed PEGylation without conformational destabilization of the Fab. The prepared PEGylated Fab displayed an increased serum half-life. Several additional sites for the introduction of interchain disulfide bonds, which contribute to conformational stability, have been identified in the Fab constant region, and a Fab with an N-glycosylation site introduced at position 178 of its heavy chain (H: L178N) was expressed in P. pastoris. The high-mannose type N-glycan attached to Fab showed the inhibited Fab aggregation under pH shift-induced stress, and the immunogenicity of the glycosylated Fab was lower than that of the wild-type Fab. These protein engineering results are expected to contribute to the design of Fab molecules with increased functional value and greater safety.

In the Model Core Curriculum for Pharmaceutical Education, revised in 2022, graduation research is mainly conducted in the later years of undergraduate studies and is designed to cultivate scientific inquiry. At pharmaceutical universities, graduation research spans diverse fields. Furthermore, there are two programs in the Faculty of Pharmacy: a 6-year and 4-year program, leading to different career paths for undergraduate students depending on the program taken. Some students aiming to become pharmacists may be unable to actively work on their graduation research because of the uncertainty of its relevance to their future careers. On the other hand, many Japanese university faculty members face challenges balancing teaching and research activities. To achieve the learning goals of graduation research, both faculty members and students must solve their own problems. In this symposium review, I would like to address the current situation of graduation research at pharmaceutical universities and consider how we should approach it in the future to make it meaningful for both the students who conduct graduation research and the faculty involved.

Organic chemistry in pharmaceutical education is indispensable for drug discovery and the understanding of biological phenomena and plays an important role in the identity formation of pharmacists. In the Model Core Curriculum for Pharmacy Education (2022 revision), organic chemistry is one of the most fundamental subjects in basic pharmaceutical sciences and plays an important role in the study of other fields. Based on basic pharmacy, the academic goal of pharmacological research is to develop problem-finding skills and foster the problem-solving abilities necessary for research that contributes to the development of pharmacy and medicine. The author devised ways for students to become interested in their research topics and to work on them independently. Specifically, the author adopted a teaching method that respects students’ independence in scheduling and selecting synthetic routes. For example, in research to determine the absolute configuration of metabolites of the antibiotic nabumetone, students managed their own schedules and became able to conduct research with a sense of conviction and responsibility. In addition, in research on the synthesis of thiophene derivatives, presenting multiple synthetic routes and allowing students to choose one enabled them to propose the direction of the experiment based on their own opinions. Therefore, it is necessary to devise and support research procedures tailored to individual students.

The work of pharmacists has shifted from object-centered based on dispensing to interpersonal work with a high degree of patient and local-resident interactions, while society has come to require advanced clinical practice skills. To cultivate clinical practice skills, improving themselves as a medical professional and enhancing their problem-solving skills is important, so graduation research is thought to play a major role. This paper introduces the daily laboratory activities of the Laboratory of Promotion of Pharmaceutical Education, with which I am affiliated. At one point, I realized that I was intervening too much in my graduation research guidance to students, which led me to drastically change my guidance methods. I engage with the students in dialog as we conduct the graduation research together, and I believe that trusting the students, entrusting them with the core of the research activities, and increasing their independence in the graduation research helps foster their scientific inquisitiveness.

In the 2022 version of the Model Core Curriculum for Pharmacy Education, scientific inquiry is highlighted as a crucial professional competency for pharmacists. Graduation research offers pharmacy students an excellent opportunity to develop an inquisitive and scientific perspective. While various types of pharmacy-related research exist, qualitative research is essential for understanding human psychology and behavior. At the laboratory where I am affiliated, students undertake qualitative research focused on the psychological aspects of patients and pharmacists as their graduation research themes. Students conducting qualitative research encounter various challenges. For instance, they might (1) rephrase text data using inappropriate terms when coding or (2) select unsuitable terms due to a lack of contextual understanding of the text data. My goal during graduate research supervision is to provide tailored guidance based on students’ common analytical errors. Furthermore, to support students’ independent research efforts, I engage in thorough discussions with them regarding the appropriateness of the coded terms they use. Even if these interventions seem inefficient, the persistent repetition of conversations with students is believed to enhance their scientific inquiry skills.

As the role of pharmacists expands from product-focused to patient-focused care, the development of pharmacist scientists with a balanced clinical and research mindset is expected in Pharmaceutical education. The 2022 revision of the Model Core Curriculum for Pharmacy Education emphasizes scientific inquiry as a fundamental competency for pharmacists. Although graduation research is crucial in promoting this exploration, the current approach to the 6-year pharmacy education program that began in 2006 needs to be re-evaluated. We surveyed undergraduate pharmacy students and practicing pharmacists to investigate their perspectives on graduation research. Those who value the cognitive and methodological skills gained through research have a positive view, whereas those who judge it based on its direct applicability to practice are more critical. The 2022 revision of the Model Core Curriculum for Pharmacy Education aims to develop the ability to identify and solve unknown problems through scientific thinking and appropriate research activities from a pharmaceutical perspective. Graduation research is the only opportunity in undergraduate education for students to experience the full research process—formulating clinical questions into research questions, planning studies, collecting and analyzing data, examining results, and presenting findings—thereby cultivating logical thinking skills and an understanding of research ethics. Universities are responsible for training pharmacists in the research capabilities needed to contribute to future healthcare. Hence, this issue requires collective consideration with clinical pharmacists. It is expected that all stakeholders will share a common understanding that the goal of graduation research is to cultivate a research mindset that pharmacists should naturally possess.

This review highlights the author’s research conducted at Mukogawa Women’s University from April 2002 to March 2024. The work is categorized into following three areas: (1) Evaluation of the bitterness of oral medications using a taste sensor, (2) Development of drug delivery systems utilizing poly(lactic-co-glycolic acid) (PLGA), and (3) Clinical pharmaceutical evaluation of various injectable formulations. In section (1), the bitterness of oral medications, both alone and in combination with food or beverages, was quantitatively assessed. The taste sensor demonstrated high predictive accuracy, with a significant correlation observed between the sensor’s bitter-sensitive outputs and the human taste receptor hT2R14, as documented in BitterDB. Recently, an innovative taste sensor featuring lipid/polymer membranes modified with 2,6-dihydroxybenzoic acid (2,6-DHBA), based on an allosteric mechanism, was developed to improve the detection of bitterness in non-charged compounds. In section (2), PLGA microspheres were engineered for the sustained release of prostaglandin derivatives over one month. Furthermore, polymeric micelles under 100 nm in diameter, composed of PLGA and LL-12 (a mutated fragment of human cathelicidin peptide), exhibited potent antibacterial activity and inhibited the proliferation of various cancer cells. Section (3) focuses on injectable formulations, including the development of a quantitative predictive system to evaluate the risk of insoluble particle formation when mixing ceftriaxone with calcium-containing injections. Additionally, the use of minimum inhibitory concentration (MIC) values and nomograms was explored to predict the clinical efficacy of imipenem derivatives. This research significantly contributes to enhancing the safety and efficacy of clinical treatments for patients.

The adult ureter is a delicate structure with an approximate internal diameter of 5 mm located deep within the lower abdomen and surrounded by various tissues. Therefore, due to its positioning, visual identification of the ureter is challenging. Iatrogenic ureteral injuries, which can lead to severe illness, occur during both open and laparoscopic abdominal surgeries, posing a serious clinical concern. Reliable intraoperative identification of the ureters is essential to prevent inadvertent injuries. Ureteral stenting or catheter placement, commonly used procedure for ureteral identification, involve insertion via the urethra and bladder. However, these techniques have limitations, including prolonged surgery time, risk of urinary tract complications, limited diagnostic capability for ureteral injury, and higher medical costs. Optical imaging has the potential to assist in surgeries involving invisible tissues. Recently, novel fluorescent compounds, ASP5354, ZW800-1, and IS-001, has entered phase 3 clinical trials for intravenous use in intraoperative ureteral identification and injury diagnosis. These compounds possess a heptamethine cyanine skeleton that generates near-infrared fluorescence (700–900 nm), exhibit excellent tissue permeability, enable ureteral visualization throughout minimally invasive laparoscopic procedures, and are safe and well tolerated. Notably, no adverse events have been reported in clinical trials to date. This review provides an overview of these promising compounds and their potential effect in improving surgical outcomes.

Durotep^®MT Patch (DMTP) (Janssen Pharmaceutical K.K., Tokyo) is a systemically acting narcotic patch containing fentanyl. It is applied transdermally and removed 72 h after applying. The range of effective serum fentanyl concentrations is very narrow (0.3–3 ng/mL). Therefore, analysis of the absorption kinetics (ABK) is especially important. We studied ABK for fentanyl from DMTP 16.8 mg. There are 5 analytical methods to obtain ABK: The estimated mean absorbed rate at steady state (EMARSS) obtained using the residual method (standard value), absolute bioavailability method, Wagner–Nelson method, 3-compartment model Loo–Riegelman method (3LR), and SPLINE–Deconvolution method (SDecon), yielding results of 0.104, 0.119, 0.114, 0.109, and 0.103 mg/h respectively. EMARSS for 3LR and SDecon were nearly equal to the standard value. The absorbed rate for fentanyl with elapsed time by SDecon indicated an amplitude of 3 times with about a 20 h period at 10.7–72 h and the increase in the absorption rate began before the increase in the serum concentration when DMTP was applied transdermally. This phenomenon indicates that the mean absorption rate was constant; thus, an absorption steady state was reached. The actual mean absorption rate during this period was 0.0924 mg/h (range: 0.0594–0.131). The cumulative absorption ratio increased gradually with only a small amplitude, and bioavailability was 44.2%. From our results, SPLINE–Deconvolution is the most suitable method to assess fentanyl absorption kinetics of DMTP.

In Japan, the use of organomercury compounds is regulated in textile products (diapers, diaper covers, bibs, underwear, sanitary pads, sanitary panties, gloves, hosiery), adhesive, paint, wax, and shoe polish buffers. This is stated in Act No. 112 of 1973, ‘Act on Control of Household Products Containing Harmful Substances’. In this study, we modified the currently used official method. The modified method uses cyclohexane/ethyl acetate (3 : 1) as the extraction solvent instead of carbon tetrachloride. The phenyl mercuric acetate as the organomercury compounds was quantified by a direct thermal decomposition mercury analyzer accurately, precisely, and safely. The calibration curves for determining the level of phenyl mercuric acetate were shown to be linear in the range of 0.12–6.0 ng mercury (Hg). The quantitation limit (Hg: 4.7 ng/g) was adequately low relative to the regulation value (Hg: 1 µg/g). The modified method exhibited a recovery rate of phenyl mercuric acetate in various household products of 38–87% with relative standard deviations of 1.5–19.5% when the standard solution (60 ng Hg) was added to the samples (1.0 g). In addition, we found that the use of suction filtration during the extraction from textile products such as thick socks provided high recovery. Thus, the modified method would be applicable for measuring levels of the organomercury compounds in various controlled household products.