The Model Core Curriculum for Pharmacy Education was revised in 2013 and has been applied to all pharmaceutical universities throughout Japan since 2015. Based on this revised core curriculum for pharmaceutical education, Pharmacy Practice Experiences began in February 2019. This Model Core Curriculum focuses on application of outcome-based education in order to achieve “professional competencies for pharmacists”. The Model Core Curriculum for Pharmacy Practice Experiences addressed two main points: the eight common diseases that trainees should learn about, and collaboration between universities, pharmacies, and hospitals to conduct effective training for students. In Hokkaido, the Pharmacy Education Council Hokkaido District Coordination Agency, organized by the Hokkaido Pharmaceutical Association, the Hokkaido Society of Hospital Pharmacists, Hokkaido University, and Hokkaido University of Science, and Health Sciences University of Hokkaido has worked to improve practical pharmacy education since four-year pharmacy education programs. Additionally, the agency is central to coordinating and responding to various issues and working toward the implementation of practical pharmacy training. I contributed as chair of the working group to implement pharmacy practice experiences based on revisions of the core curriculum. In particular, we formulated evaluation standards based on sample evaluations presented at a liaison conference on the practical aspects of pharmacy. In addition, in order to convey the changes in pharmacy practice experiences based on this revised core curriculum for pharmacists, I contributed to the implementation of new pharmacy practices as an instructor at seminars in Hokkaido.

Several direct asymmetric Michael additions to α,β-unsaturated carboxylic acids with integrated catalysts comprising chiral bifunctional thiourea and arylboronic acid were developed. First, the asymmetric aza-Michael addition of hydroxylamine derivatives efficiently afforded a variety of optically active β-amino acid derivatives. Furthermore, upon detailed investigation of the reaction, tetrahedral borate complexes, comprising two carboxylate molecules, were found to serve as reaction intermediates. Based on this observation, a drastic improvement in product enantioselectivity was achieved upon benzoic acid addition. Second, on merely changing the solvent, the asymmetric thia-Michael addition of arylthiols afforded both enantiomers of the adducts, which are important building blocks for biologically active compounds.

The interaction between transition metals and ligands is important for catalytic reactions. The ligands are largely dominated by the covalent X-type (hydride, alkyl and halogen) and/or dative L-type ligands (e.g., P, N, CO, olefin, etc.). Therefore, the interaction of the Z-type ligands (B, Al and Si, etc.) with transition metals is emerging as a new concept for the reactivity of the metal center. Recently, we developed the synthesis of the gold complex Au(DPB)X (DPB=diphosphine-borane) featuring the Z-type ligand, and their catalytic reaction. The gold catalysts showed a high activity compared to the general catalysts (without Z-ligand) for the various cyclization reactions due to the electron-withdrawing effect of the Z-ligand on the coordinating gold center. In this review, first the structure analysis of the synthesized Au→Z complex is introduced in detail, and second, the catalytic reactions based on the alkyne activation are described.

Gold compounds have been employed throughout history to treat various types of disease, from ancient times to the present day. In the year 1985, auranofin, a gold-containing compound, was approved by U.S. Food and Drug Administration (FDA) as a therapeutic agent to target rheumatoid arthritis that would facilitate easy oral drug administration as opposed to conventional intramuscular injection used in treatments. Furthermore, auranofin demonstrates promising results for the treatment of various diseases beyond rheumatoid arthritis, including cancer, neurodegenerative diseases, acquired immune deficiency syndrome, and bacterial and parasitic infections. Various potential novel applications for auranofin have been proposed for treating human diseases. Auranofin has previously been demonstrated to inhibit thioredoxin reductase (TrxR) involved within the thioredoxin (Trx) system that comprises one of the critical cellular redox systems within the body. TrxR comprises the sole known enzyme that catalyzes Trx reduction. With cancers in particular, TrxR inhibition facilitates an increase in cellular oxidative stress and suppresses tumor growth. In this review, we describe the potential of auranofin to serve as an anticancer agent and further drug repurposing to utilize this as a strategy for further appropriate drug developments.

Nanomedicine is a new medical field involving the use of nanoparticles. Early examples of biocompatible nanomedicines include liposomes (Doxil^®) and albumin nanoparticles (Abraxane^®), and promising new nanomedicines include nanocarriers such as nanomicelles and nanoemulsions. A new trend towards the use of metal-based nanoparticles, including gold nanoparticles, has led to global clinical trials. These particles exhibit novel properties compared to conventional nanomedicines such as liposomes and albumin nanoparticles. These properties hold promise for nanomedicines, and thus the biodistribution and pharmacokinetics of metal-based nanoparticles should be carefully investigated. This had led to an increasing number of clinical trials investigating metal nanoparticles and inorganic nanoparticles. The present review evaluates multi-functional gold nanoparticles described in recent articles and shows that the unique properties of gold nanoparticles are applicable for not only drug delivery, but also for imaging. The combined therapeutic modality between therapeutics and diagnostics is called “theranostics” and is promising for future personalized cancer therapy. This review also introduces recent research from our laboratory involving the use of various kinds of molecules [polyethylene glycol (PEG), drug/cyclodextrin inclusion complexes, biosimilars and small interfering (siRNAs)] loaded onto and/or conjugated with gold nanoparticles.

Controlled drug release in response to light irradiation is an important technique for focusing drug elution to specific sites and reducing the side effects of drugs in normal tissue. In one example, we used double-stranded DNA to modify gold nanorods. When the gold nanorods were heated by irradiation with near-infrared light, single-stranded DNA was released. Thus, we successfully prepared a controlled release system that responds to near-infrared irradiation by combining heat-labile linkers such as double-stranded DNA. However, the drug-loading capacity on the surface of the nanoparticles was limited. To improve the loading efficiency, we encapsulated gold nanorods in poly(lactic-co-glycolic acid) (PLGA) nanoparticles, where PLGA acted as a drug payload. When the gold nanorod-containing PLGA nanoparticles were irradiated with a near-infrared laser, the PLGA nanoparticles were destroyed and significant drug release was observed. In another example, silver nanoplates were used as a near-infrared responsive photothermal nanodevice. Silver nanoparticles show antimicrobial activity that we expected could be controlled by light irradiation. First, we coated the silver nanoplates with gold atoms to mask the antimicrobial activity. When the gold-coated silver nanoplates were irradiated with a near-infrared pulsed laser, the shape of the silver nanoplates changed from plate-like to spherical, and silver ions were released. As a result, the antibacterial activity of the silver nanoplates was recovered. In this review, we outline examples of controlled release systems that respond to light irradiation. We believe that this review will contribute to improving the efficiency and safety of chemotherapy.

Blood vessels including arteries, veins, and capillaries, are densely spread throughout the body. One round of systemic blood circulation through these blood vessels occurs approximately every minute, and blood sent by the heart transports oxygen, nutrients, and fluid to cells throughout the body. This nourishes cells, tissues, and organs and maintains homeostasis. The relatively simple structure of blood vessels consists of endothelial cells surrounded by a basal lamina and pericytes covering the outer layer. However, blood vessels patterning markedly varies among tissues. The diversity and plasticity of vascular networks are considered vital for this system to facilitate distinct functions for each tissue. Recent studies revealed that blood vessels create a tissue-specific niche, thus attracting attention as biologically active sites for tissue development. This vascular niche establishes specialized microenvironments through both direct physical contact and secreted-soluble factors. Here, we review advances in our understanding of how the vascular niche is utilized by neural stem and progenitor cells during neocortical development, and describe future perspectives regarding new treatment strategies for neural diseases utilizing this vascular niche.

We have been investigating the physiological and pathological roles of stem cells and progenitor cells in the central nervous system using multimodal imaging methods, including positron emission tomography (PET), in vivo optical imaging, and light as well as electron microscopy. Furthermore, we generated transgenic rats for selective ablation of these cells. Imaging studies have demonstrated the proliferation and dynamics of neural stem cells in neurogenic regions and glial progenitor cells expressing a chondroitin sulfate proteoglycan (neuron-glial antigen 2; NG2) in the brain of adult rodents. Glial progenitor cells change their direction of differentiation into mature oligodendrocytes or astrocytes by neural activity following their proliferation. This phenomenon was thought to control the local tissue structure for maintenance of moderate neural activity. Furthermore, selective ablation of glial progenitor cells in the brain induced defects of neurons via neuroinflammation with microglial activation and proinflammatory cytokine production in the region. Thus, we have proposed a novel concept that glial progenitor cells regulate the neuro-immune system in the central nervous system, in addition to their role as germinal cells, giving rise to mature glial cells. Neuroinflammation is associated with the onset and progression of depression, chronic fatigue syndrome, and neurodegenerative diseases, including Alzheimer's disease. Anti-inflammatory effects of glial progenitor cells might bring about the possibility of these cells as the new therapeutic targets for such neurological disorders.

Folds of the cerebral cortex, which are called gyri and sulci, are one of the most prominent features of the mammalian brain. However, the mechanisms underlying the development and malformation of cortical folds are largely unknown, mainly because they are difficult to investigate in mice, whose brain do not have cortical folds. To investigate the mechanisms underlying the development and malformation of cortical folds, we developed a genetic manipulation technique for the cerebral cortex of gyrencephalic carnivore ferrets. Genes-of-interest can be expressed in the ferret cortex rapidly and efficiently. We also demonstrated that genes-of-interest can be knocked out in the ferret cortex by combining in utero electroporation and the CRISPR/Cas9 system. Using our technique, we found that fibroblast growth factor (FGF) signaling and sonic hedgehog (Shh) signaling are crucial for cortical folding. In addition, we found that FGF signaling and Shh signaling preferentially increased outer radial glial cells and the thickness of upper layers of the cerebral cortex. Furthermore, over-activation of FGF signaling and Shh signaling resulted in polymicrogyria. Our findings provide in vivo data about the mechanisms of cortical folding in gyrencephalic mammals. Our technique for the ferret cerebral cortex should be useful for investigating the mechanisms underlying the development and diseases of the cerebral cortex that cannot be investigated using mice.

Microglia are immune cells resident in the central nervous system (CNS). It has been gradually clarified that microglia play various roles at the developmental stage of the CNS. From embryonic to early postnatal age, microglia remove apoptotic cells by phagocytosis and refine the neural circuits by synaptic pruning. In addition, microglia promote the proliferation and differentiation of neural stem cells by releasing physiologically active substances. Our group has focused on the physiological actions of microglia via cytokines and chemokines at the early postnatal developmental stage. We found that a large number of activated microglia accumulate in the early postnatal subventricular zone (SVZ). We demonstrated that the these SVZ microglia facilitate neurogenesis and oligodendrogenesis via inflammatory cytokines including IL-1β, TNFα, IL-6, IFNγ. We have also found that microglia regulate the functional maturation of the blood brain barrier (BBB) and identified the cytokines and chemokines involved in the effects of microglia. These findings indicate that microglia are physiologically more important than ever thought to reveal robust brain functions. Furthermore, the new mode of microglial action may lead to the discovery of drug targets of the incurable CNS diseases.

Developmental retardation of the brain with reduced cortical neurogenesis is observed in Ts1Cje mice, a model of Down syndrome (DS) as it is in people with DS; however, the mechanisms and the responsible gene(s) remain unknown. The goal of the present study is to establish a therapeutic approach for treating the delayed brain development in DS. To achieve this, we have utilized multiple OMICS analyses, including proteomics and transcriptomics, to uncover the molecular alterations in the brains of DS model mice. Furthermore, we have elucidated that a transcriptional factor, the Erg gene, which is coded in the trisomic region, contributed to reduced cortical neurogenesis in the embryo of a DS mouse model by a molecular genetic technique, the “in vivo gene subtraction method”. In the current review, I will introduce our recent work, the identification of the gene responsible for delayed brain development in the DS mouse model and will discuss the possibility that blood vessel dysfunction may be associated with reduced embryonic neurogenesis in DS.

Nowadays, approximately 90 percent of the general population in Japan uses the internet and many of them look for health-related information. However, there have been serious concerns about the contents and credibility of these information. Among “mixture of wheat and chaff”, information provided by the public domains are expected as accurate and reliable ones. This article reviews five public websites that provide health or health care information for users including the general population: Minds by the Japan Council for Quality Health Care, e-health net, evidence-based Japanese Integrative Medicine (eJIM), Cancer Information Service by the National Cancer Center, Center for Cancer Control and Information Services, Information system on safety and effectiveness for health foods (HF net) by National Institute of Health and Nutrition. These websites show their running policy transparently and have constructed collaborative relationships with each domain experts, and from the people who are not related with the healthcare field including patients in some cases. Each of them is content-rich and well-organized as an individual unit. The organizations that run these websites share the common goal that provides the general population with quality health-related information, however, cooperation have been limited. To increase awareness among the public, it is worthy considering joint efforts of these organizations in future.

When taking a drug one must keep in mind certain risks and benefits based on the safety and efficacy information. One of the most reliable sources of information that enables patients to use drugs properly is package inserts, which are regulated under the law and therefore should include valid and accurate contents. With the recent revision of the Pharmaceutical and Medical Device Act, the information contained in the package insert, which was provided together with the drug, will now also be provided electronically and separately from the drug itself. In addition, a digital code will be displayed on the product packaging so that the latest information of the drug can be obtained from outside the package by scanning the code. The more drug information gets shared among healthcare professionals, patients and the public, the less the asymmetry in drug information among them will exist. It is necessary now more than ever to establish a framework and a system to ensure that sufficient information is provided to patients and the public to encourage their proper use of drugs. I believe that it is important for patients and the public to strive for a better understanding of drug information. It is also crucial for all relevant parties involved in drug information to work together on how best to utilize the information. In this way they would keep trying so that therapeutic effects could be maximized and the risks of side effects are minimized.

Health literacy is defined as the ability to obtain, evaluate, and scrutinize health information and make appropriate decisions and actions. The spread of the Internet means that medical and drug information is becoming increasingly accessible to patients. However, there is also a large amount of inappropriate and biased medical- and drug-related information on the Internet. Therefore, patients require a high level of health literacy to ensure the effectiveness and safety of pharmacotherapy. In particular, outpatients need a high level of health literacy because they use their own medications without the supervision of healthcare professionals. In this article, I discuss the situation of health literacy and access to pharmaceutical information on the Internet in Japan. Furthermore, issues related to providing drug information to specific populations are explained using the example of chronic kidney disease. It is essential for all pharmaceutical information stakeholders to work together to solve these problems.

With the progress of medical treatment, information on drugs, etc. is overflowing on the media and the Internet, and some of them are leading to uncertain information for the purpose of profit, and some of them are wrong information or inaccurate information, and the effect on the patient is regarded as a problem. In Japan, information on public pharmaceuticals for patients and consumers is provided on the Internet, but its utilization is not sufficient. In the Pharmaceuticals and Medical Devices Act, it is stated that “Citizens shall endeavor to use pharmaceuticals, etc., properly and deepen their knowledge and understanding of their efficacy and safety”. On the other hand, there is a variety of information available on the Internet, and simply searching does not necessarily lead to reliable information. It is necessary to provide information with a mechanism to ensure that the information is reliable so that it can lead to appropriate medical care. Overseas, medical information infrastructure systems, including highly reliable public pharmaceuticals based on evidence, have been developed. Examples include National Health Service (NHS) in the United Kingdom, MedlinePlus in the United States, and National Prescribing Service (NPS) MedicineWise in Australia. In the era of digital health, it is necessary to discuss issues and prospects for the construction and dissemination of information provision infrastructure that meets the needs of patients and consumers from the perspective of industry, government, academia, and patients.

Pharmacists began preparing drug solutions intraoperatively for postoperative analgesia in the Department of Surgery at Chiba University Hospital from May 2014. To verify the usefulness of pharmacists preparing these drug solutions, we conducted a questionnaire survey among 51 anesthesiologists and received 44 responses (recovery rate 86.3%). Burden on the anesthesiologists was significantly reduced both temporally and mentally when the pharmacists prepared the drug solutions compared with when the anesthesiologists did (p<0.01). The anesthesiologists' degree of anxiety about sometimes having to prepare drug solutions alone without any confirmation was also significantly reduced when pharmacists prepared them (p<0.01), which implies the need for a double-check system. In addition, 88.6% of anesthesiologists said that they were reassured with preparations done by the pharmacists under a sterile environment using a clean bench. Overall, 88.6% of anesthesiologists responded that they were satisfied with the preparation of drug solutions by pharmacists. Based on the results of this survey, pharmacists' preparation of drug solutions for postoperative analgesia is considered to be useful in ensuring the quality and safety of medical care because it reduced anesthesiologists' work to prepare the drug solutions, allowing them to concentrate on anesthesia and related work, it established a double-check system between the two staff teams, and it was done under a sterile environment.

Doxorubicin (DOX) is currently one of the most widely used and effective drugs for the treatment of breast cancer, but drug resistance in breast cancer often leads to poor efficacy. MicroRNAs (miRNAs) are involved in the development and progression of various tumors and increasing number of studies have confirmed that abnormal miR-520b expression is closely associated breast cancer. We analyzed the clinical features, including miR-520b, of 30 patients with breast cancer. Further, we analyzed the interaction between miR-520b and insulin-like growth factor 1 receptor (IGF-1R) in breast cancer cell. miR-520b expression was significantly increased in chemotherapy-sensitive patients and was positively correlated with the chemotherapeutic efficacy in breast cancer. Cell proliferation assay confirmed that miR-520b promotes DOX-induced breast cancer cell apoptosis by regulating the PI3K/AKT signaling pathway. Moreover, bioinformatics method and dual luciferase reporter assay demonstrated that miR-520b negatively regulates IGF-1R, and IGF-1R overexpression and enhanced activity are closely associated with tumor development, progression, metastasis, and chemotherapy resistance. Similarly, cell proliferation assay showed that IGF-1R is negatively correlated with the efficacy of DOX chemotherapy and affects cell apoptosis mediated by the PI3K/AKT signaling pathway. On the contrary, miR-520b can downregulate the expression of IGF-1R. miR-520b increases DOX sensitivity and promotes cell apoptosis in breast cancer by inhibiting IGF-1R expression by the PI3K/AKT signaling pathway.

Daptomycin (DAP) has a completely different mechanism of action compared with conventional drugs for methicillin-resistant Staphylococcus aureus (MRSA) and is widely used as the first-line drug for treatment of dermal soft tissue infection and sepsis caused by MRSA infection in clinical practice. However, DAP has serious side effects, including renal dysfunction and rhabdomyolysis, and thus therapeutic drug monitoring of DAP is recommended. The purpose of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for DAP that is simpler and more sensitive compared with existing assay methods and can be used in pharmacokinetic studies. Anti-DAP antibody was obtained by immunizing mice with an antigen conjugated with mercaptosuccinyl bovine serum albumin using N-(4-maleimidobutyryloxy) succinimide as a heterobifunctional coupling agent. Enzyme labeling of DAP with horseradish peroxidase was performed using pyromellitic dianhydride. The generated antibody and enzyme conjugate were used to develop a highly sensitive and specific ELISA for DAP in human serum. This ELISA shows a linear range of detection from 0.3 to 72.9 ng/mL, and a limit of quantification of approximately 0.3 ng/mL. The developed ELISA should be a valuable tool for pharmacokinetic studies and therapeutic drug monitoring of DAP.

Currently, various hyperphosphatemia drugs are administered orally to hemodialysis patients in order to lower serum phosphorus levels. However, it is known that medication adherence is poor, possibly due to greater pill burden taken each time and their complicated schedules. Therefore, large amounts of unused hyperphosphatemia drugs are likely to be leftover. The increase in leftover prescribed drugs leads to the unnecessary elevation of medical care costs. To date, however, the available information on leftover hyperphosphatemia drugs in hemodialysis outpatients is limited. In this study, we performed an interview survey of medication adherence to hyperphosphatemia drugs among 60 hemodialysis outpatients and evaluated the cost of the leftover drugs. Thirty-four patients showed good adherence. On the other hand, 19 patients self-adjusted to take hyperphosphatemia drugs according to their daily diet. When assessing the serum phosphorus levels for these patients over the past year, the values often exceeded the targeted range (3.5-6.0 mg/mL). Furthermore, 35 patients kept hyperphosphatemia drugs at their home. When estimating the cost derived from leftover drugs using the bootstrap method, main distribution of drug cost was shown to be in the range of 2000 to 2500 yen. This drug cost seemed to in part reflect preparation for an emergency. A serious problem was that 14 patients had previous experience in discarding hyperphosphatemia drugs. This study suggested that more appropriate pharmaceutical care according to each patient's situation is essential in improving phosphorus control in hemodialysis outpatients and in reducing the waste of medical resources.

Herein, we describe a case of an elderly patient with muscular dystrophy for whom control of the plasma vancomycin (VCM) concentration proved difficult when he developed a catheter-related bloodstream infection. The pharmacist initially carried out therapeutic drug monitoring using an estimate of the creatinine clearance (CL_cr) level, which was based on the serum creatinine (SCr) and serum cystatin-C (CysC) levels, but was ultimately unable to control the plasma VCM concentration. Therefore, the plasma VCM concentration was predicted ex post facto using population pharmacokinetic parameters as a covariate; that is, directly including the glomerular filtration rate (GFR_CysC) estimated from the CysC level, which is not affected by the muscle mass. As a result, the estimated VCM concentration was closer to the actual concentration than that predicted using CL_cr. Furthermore, the results of examining the predictive accuracy according to the assessment of renal function at the time of initial VCM administration suggested that estimation of the trough concentration using GFR_CysC might be useful in elderly patients with muscular dystrophy.