A variety of new methods are being tried in education of pharmacology for medical students, to make pharmacology be directly oriented to practical medical treatment. Among them, thinking that the method of “selection of personal drug (P-drug)” is suitable for learning “evidence-based medicine (EBM)”, I have been engaged in “P-drug education” in Kyushu university for many years. If doctors carefully select medicines that are indispensable for their medical treatment based on clinical evidence, are made familiar with how to use them, and in principle perform daily medical treatment using only those medicines, EBM can be really practiced. And moreover, it may also lead to the suppression of medical errors and adverse drug reactions. Such essential medicines for an individual doctor are called P-drug. Since 2003, I have adopted “P-drug selection” in the education of pharmacology for upper grade medical students. After more than 15 years of trial and error, I have been able to create an educational model using “P-drug selection” that I think could be easily adopted at any medical school. At this symposium, I talked about the relationship between “P-drug selection” and EBM and demonstrate the “P-drug education” model.

Active learning in pharmacology education “pharmacology role-play,” in which students pretend to be health professionals and patients and explain diseases and drug treatments. Because pharmacology role-play is based on cases presented in advance and active learning through communication, named Case & Communication based approach (C&C approach). Pharmacology role-play was started in 2010 at the University of Miyazaki, it has been shared by 28 schools in 4 faculties of medicine, pharmacy, dentistry, and nursing (23 medical schools, 1 pharmaceutical school, 2 dental schools, and 2 nursing universities) over the 13 years until 2022. Although it is a common program, it is implemented with diversity while devoting various ingenuity according to the characteristics of the University. Pharmacology role-play is effective in (1) understanding of medical treatment, (2) understanding patient’s feelings, (3) improvement of mental attitude and motivation as health professionals (4) positive influence upon study attitude, regardless of universities that conducted the pharmacology role-play. Various efforts include combining with Personal Drugs, developing interprofessional education through joint role-playing by medical students and nursing students, and developing Oriental medicine education through the cases including Kampo medicine. In addition, there are online lectures in response to the Covid-19, and a joint implementation of two universities, all of which are highly effective. The advantage of the multi-institution common program is that a lot of information can be obtained at once, and it is easy to quickly reflect successful ideas. The flexibility and high resilience that can flexibly change the implementation method (face-to-face/remote) according to the situation are also great strengths.

Pharmacology role-play works well for students playing the role of the medical doctor or patient, but students without any roles behave just like observers, resulting in a relatively low learning effectiveness. To improve this issue, a personal drug (P-drug) report was introduced to the role-play program. To examine to what extent the P-drug report affected the learning effectiveness of role-play, we performed questionnaire surveys for players and audiences and subsequent nominal logistic regression analysis. The questionnaire topics were (1) understanding of medical treatment, (2) understanding patient’s feelings, (3) improvement of awareness and motivation as a medical doctor, and (4) positive influence upon study attitude. In the topics (1) and (2), the statistical analyses in audiences showed significant relationship between the introduction of the report and observer’s recognition of the learning effectiveness, indicating the improvement of learning effectiveness after the introduction of the P-drug report. In players, the percentage of high marks was higher than that in audiences, and no significant differences were found between before and after the introduction of the report. In addition, in the free description, many students realized the importance of selection of therapeutic drugs based on P-drug methods. These results suggest that the introduction of the P-drug report seems useful to make all students participate in the activity of role-play with understanding the selection process of therapeutic drugs, and improves the learning effectiveness of role-play especially in observers. It may be useful to combine P-drug with pharmacology role-play in practical pharmacotherapy education.

The pharmacology role-play, in which students impersonate medical personnel and patients to explain illness and drug treatment, is one of the active learning of pharmacology. However, until now, it has been carried out only within one facility, and has not been carried out between different multi-facility facilities with a larger scale. However, the spread of COVID-19 infection in 2020 was a turning point that drastically changed the way of medical school education centered on traditional face-to-face lectures. Above all, remote real-time lessons using Zoom etc. have the advantage that about 300 students can be conducted at multiple facilities without having to gather them in one place at the same time. With the Korona-ka as a strange currency, the infrastructure has been set up to carry out joint education in pharmacological role-playing between different multi-institutions. We are the first in Japan to conduct a pharmacology role-play jointly by Fujita Medical University and Aichi Medical University, so we would like to introduce the contents.

The symptoms and behavioral abnormalities of brain diseases are thought to be caused by the dysfunction of neural circuits formed by numerous neurons. Virtual reality (VR) is used for behavioral tasks under head fixation and has the advantage of precise control of experimental conditions. In this review, we first overview the application of VR in rodent neuroscience, introduce our research on two-photon calcium imaging of the hippocampus of autism spectrum disorder (ASD) model mice navigating a VR environment, and then discuss how hippocampal dysfunction can relate to ASD phenotypes. By combining a VR system with two-photon microscopy, we clarified the formation of hippocampal CA1 place cell maps in mice undergoing spatial learning in VR. As mice learned, the number of place cells increased, and the density of cells that responded to places with behaviorally relevant features such as rewards and landmarks increased more than cells active elsewhere. Furthermore, many stable place cells responded at landmark and reward locations. Shank2-deficient ASD model mice spent more time running and received more rewards. In their hippocampal maps, the proportion of cells active at landmarks did not increase, whereas the proportion of cells active at rewards excessively increased. Individuals with ASD are known to show unique tendencies in their perception and cognition of the world around them, but the detailed brain mechanisms remain unclear. It is thus possible that some ASD cases involve cognitive mapping abnormalities, such as the distortion of hippocampal information representation that our study revealed.

Alzheimer’s disease (AD) patients cause cognitive impairment in time and space as early symptoms, in which the hippocampus plays an essential role. In the hippocampus, place cells play an important role in processing spatial information. The hippocampus recognizes space and guides creatures to their destinations using these place cells. In AD patients, the hippocampal neuronal network that place cells form could malfunction with age. However, it has remained unknown how the disruption of the neural circuits progresses at a single-cell resolution in AD. Conventional methods such as electrophysiology experiments could only record the same cells in the hippocampal neural circuit of awake mice for a few days. To clear the detail of neuronal circuit disruption in AD, it is necessary to observe brains of the same individuals over several months. Therefore, we performed chronic two-photon calcium imaging using AD model mice expressing the fluorescent calcium sensor protein G-CaMP7 to monitor spatiotemporal representation in a virtual reality environment. The activity of hundreds of hippocampal CA1 pyramidal neurons was detected over months from the same neuronal populations. In AD mice, amyloid (Aβ) plaque-like aggregates in the stratum oriens layer of hippocampal CA1 start to develop at 2.5 months of age, increase in both number and size with age, and neurons with hyperactivity increase near Aβ plaque-like aggregates. In addition, place cells observed during VR navigation showed abnormalities in the stability of activity within the place field at 4 months old, and then the stability was further deteriorated and the number of place cells decreased at 7 months old. Thus, we demonstrated that the activity patterns of various neurons, including place cells, in the neural circuitry of the hippocampal CA1 region in AD have different failure modes, and this finding is expected to be applied to the effective drug evaluation for AD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral abnormalities such as poor social communication and stereotyped/repetitive behaviors. Functional dynamics among multiple cortical areas are associated with processing sensory information and planning and executing behavioral expressions. However, the reconfiguration of large-scale functional network dynamics during behaviors remains to be elucidated in ASD. In this review, we describe our virtual reality (VR) based real-time imaging system which allowed us to investigate wide-field cortical activity in voluntarily behaving mice. We previously generated a mouse model of ASD with chromosome 15q11-13 duplication (15q dup), one of the most frequent genomic abnormalities, and reported that 15q dup mice display ASD-like behaviors. Using this system, we examined the functional cortical network during behaviors in 15q dup mice. Pair-wise correlation of cortical area activity on a time scale of a second was calculated to represent the dynamic state of cortical functional connectivity (FC). A graph theoretical network analysis was then conducted to illustrate rapid and robust behavior-state-dependent cortical network reconfiguration. Our VR-based real-time imaging system provides invaluable information to understand FC dynamics linked to a behavioral abnormality of neuropsychiatric disorders.

In this review, I will present that focusing on global brain state dynamics could bring unique insights into the biological understanding of autism. To this end, I will first introduce energy landscape analysis and a novel brain stimulation method called brain-state-driven neural stimulation. Then, this article will discuss the results of the applications of these methods to autism. Finally, I will also state what such an approach reveals about the brain mechanisms underpinning ADHD.

Dendrites receive excitatory synaptic inputs from upstream cell ensembles to trigger action potentials at the cell body. The efficiency of excitatory synaptic inputs on neuronal output depends on the spatiotemporal pattern of synaptic inputs. However, technical limitations still make it unclear how synaptic inputs are organized along dendrites in both space and time. Spine calcium imaging, which records synaptic inputs as calcium transients at individual spines using calcium ion-sensitive fluorophores, is a unique method for studying the spatiotemporal patterns of synaptic input. We developed a functional multiple-spine calcium imaging (fMsCI) that combines whole-cell patch-clamp recording and spinning-disk confocal imaging to observe hundreds of synaptic inputs simultaneously. Using this method, we discovered sequential synaptic inputs that accompanied sharp wave ripple oscillations. In this review, I will discuss the function of sequential synaptic inputs and the potential uses of fMsCI to better understand neurological disorders.

Postprandial glucose concentration is dependent on the time of day and its concentration in the morning is lower than in the evening. The circadian rhythm of glucose metabolism is regulated by the central circadian pacemaker in the suprachiasmatic nucleus (SCN). Both the SCN circadian clock and the pancreatic clock play important role in generating and maintaining the circadian rhythm of glucose metabolism. Also, short sleep duration and circadian misalignment are closely associated with a decrease in insulin sensitivity and an increase in type2 diabetes. Increased frequency of mastication and/or thorough chewing has been reported to alter the secretion of hormones related to appetite and energy metabolism. Furthermore, we have reported that the effect of mastication on postprandial glucose metabolism is dependent on the time of day and frequency of mastication. Morning mastication but not evening decreases postprandial blood glucose concentrations and increases insulin secretion at 30 min and so-called the insulinogenic index as a marker of early-phase β-cell function. This novel finding may aid in reducing the incidence of obesity and type 2 diabetes mellitus. This review covers the basic concept of the mammalian human circadian system, the underlying mechanism causing phase adjustment of the circadian rhythms in the SCN and peripheral organs, and the effect of eating behavior (e.g., chewing frequency) on the circadian rhythm of glucose metabolism.

Insulin-regulated glucose transport is dependent on glucose transporter GLUT4 translocation to the plasma membrane, which incorporates glucose into the cells, mainly in adipose tissue and skeletal muscle. Insulin receptor signaling can stimulate GLUT4 vesicle transport from perinuclear pool to the plasma membrane via the vesicle transport machinery. At first, insulin signaling is divided to the multiple pathways, such as Akt/PKB and PKC-zeta/lambda. Subsequently, PKC-zeta/lambda activates KIF3, motor protein based on microtubules, and sequentially Akt/PKB activates Myosin-Va, motor protein based on actin filaments. KIF3 motor moves GLUT4 vesicles from perinuclear pool to the end of microtubules, and Myosin-Va transports GLUT4 vesicles from the end of microtubules to the plasma membrane. Here we indicate the machinery of insulin-regulated GLUT4 vesicle translocation, showing that these motor proteins are the destinations of insulin receptor signaling to regulate glucose transport into the cells.

Skin-related complications of insulin therapy have long been a problem as a factor interfering with insulin therapy. Among the traditional skin-related complications, lipoatrophy and insulin allergy have decreased markedly with the development of insulin preparations, but lipohypertrophy is still common in insulin-treated patients. Recently, there have been more reports of a skin-related complication called insulin-derived amyloidosis or insulin ball. Insulin-derived amyloidosis is a condition in which injected insulin becomes amyloid protein and is deposited at the injection site. Insulin-derived amyloidosis causes poor glycemic control and increased insulin dose requirements, which are caused by decreased insulin absorption. Lipohypertrophy also decreases insulin absorption, but insulin-derived amyloidosis causes a more significant decrease in insulin absorption and has a greater clinical impact. Therefore, it is important to make a differential diagnosis between insulin-derived amyloidosis and lipohypertrophy, but sometimes it is difficult to distinguish the two and imaging studies are required. The diagnosis of insulin-derived amyloidosis is often difficult in the general practice, and its pathogenesis and prevalence have not been fully clarified. Recently, it has been reported that insulin-derived amyloidosis can be toxic, suggesting an association with minocycline use. The treatment of insulin-derived amyloidosis and lipohypertrophy is to avoid the site of amyloidosis or lipohypertrophy and inject insulin, but the dose of insulin injection should be reduced. Prevention of both insulin-derived amyloidosis and lipohypertrophy is important, and for this purpose, observations of the insulin injection site and instruction on appropriate insulin injection techniques are necessary, and multidisciplinary cooperation is extremely important.

Japanese Academy of Nursing Science (JANS) and the Japanese Pharmacological Society (JPS) have been conducting human interaction at each other’s scientific meeting symposia in a home-and-away fashion since 2018. JANS and JPS have been working on a joint scientific project, “Scoping Review: Insulin Balls” since 2021. At the 95th Annual Meeting of the JPS held in 2022, we reported from a nursing perspective on the theme of “Assessment and preventive care of insulin balls from a scoping review”. Subcutaneous injection into insulin balls has been reported to cause poor blood glucose control. Therefore, it is important to prevent insulin balls. In this study, we had the research questions, “What methods are available for assessment of the insulin injection site?” and “What is the care to prevent induration and how effective is it?” and conducted a scoping review. Regarding methods of injection site assessment, most of the literature identified the injection site by palpation, visual examination, and ultrasonography. About the preventive care, there were some reports of insulin balls occurring because patients have been injecting insulin at the same site, even though healthcare professionals instructed them to avoid the same site. Some of the literature had specific teaching methods such as hand site rotation and calendar injection method, and they were reported effective. In the future, we plan to proceed with the review including care after the development of insulin balls.

In life science and medicine, we have been conducting research using laboratory animals such as mice, rats and monkeys. However, it is impossible for humans to fully understand the feelings and conditions of experimental animals with whom we cannot communicate. In particular, investigators have recently focused on brain function and have created animal models to mimic human depression, pain, and dementia through behavioral tests such as tail suspension and mazes. These methods allow for some evaluation of the animal’s condition. However, we cannot detect trivial behavioral changes that reflect the state of mind and body of the animals reproducibly and objectively. With improvements in imaging and information processing technology, it is now possible to photograph animals for extended periods of time and perform sophisticated analysis. Artificial intelligence (AI) can also perform learning and inference, or intelligent work (machine learning), for extended periods of time by processing higher levels of information and can find interpretations that humans are unaware of. To bring innovation to life science research using animals, it is necessary to integrate and utilize these technologies to digitize and extensively and deeply evaluate biological information and emotions of experimental animals. We have been developing some basic technologies for experimental animals by applying image analysis technology, AI, and mathematical analysis. In this review, we introduce the technologies we have developed, including the latest reports.

In the environment surrounding the pharma industries (1) declining productivity in research and development in pharma industries, (2) spreading of 3Rs in animal testing, and (3) diversifying of modalities, the regulatory authorities and pharmaceutical companies in US and EU are paying attention to the microphysiological system (MPS) to actively incorporate cutting-edge technologies into the evaluation assays used for approval applications for drug research and development. MPS generally refers to an in vitro culture system in which a culture environment close to that of a living body (in vivo) is reconstructed in a created minute space using a microfluidic device. Currently, many products have been put into practical use by US and EU companies and are sold all over the world. This time, the trends of MPS as a drug development tool, especially case of safety assessment, issues for implementation to pharma, and future perspectives are described in this article.

Imeglimin hydrochloride (imeglimin) is an orally drug for type 2 diabetes mellitus, which was approved in Japan for the first in the world, with dual mode of actions: pancreatic action means amplifying glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and extrapancreatic action means improving insulin sensitivity by which gluconeogenesis suppresses in hepatocytes and glucose uptake increases in skeletal muscles. Although the molecular target of imeglimin is still unknown, imeglimin exerts some of its actions through modulation of the mitochondrial function. In pancreatic islets, imeglimin enhanced adenosine triphosphate and Ca²⁺ under high-glucose conditions. Furthermore, imeglimin induced the synthesis of oxidized form nicotinamide adenine dinucleotide (NAD⁺) via the ‘salvage pathway’, and NAD⁺ metabolites may contribute to the increase in intracellular Ca²⁺. The in vivo studies indicated that imeglimin enhanced the sensitivity to insulin and modulated the mitochondrial function (restoring the deficient Complex III activity, decreasing Complex I activity and reactive oxygen species production), which contribute to the improvement of glucose metabolism in hepatocytes and skeletal muscles. In clinical trials, imeglimin’s dual effects were demonstrated in foreign type 2 diabetic patients who received 1500 mg bid, which is different from the domestic approved dose. Imeglimin has been shown to evidence of statistically significant glucose lowering, a generally favorable safety and tolerability profile in patients with type 2 diabetes by monotherapy and combination therapy with 1,000 mg bid in four Japanese trials. Since imeglimin has dual effects, it may have shown a newly effective option, regardless of the pathophysiology of type 2 diabetic patients.

Carotegrast-methyl (brand name: CAROGRA^® Tablets) is a new chemical entity created by Ajinomoto Pharmaceuticals Co., Ltd. (currently EA Pharma Co., Ltd.) as an α4 integrin inhibitor. In vivo, it exerts an anti-inflammatory effect by inhibiting the functions of both α4β1 integrin and α4β7 integrin expressed on the surface of inflammatory cells such as lymphocytes. Under the joint development of EA Pharma Co., Ltd. and Kissei Pharmaceutical Co., Ltd., the efficacy and safety of carotegrast methyl were confirmed in patients with moderate active ulcerative colitis. Carotegrast-methyl, the Japan-originated, world-first orally available α4 integrin antagonist, was approved in March and launched in May 2022 in Japan. Patients who had inadequate response or intolerance to the basic treatment with 5-ASA preparations for ulcerative colitis, have widely desired an orally available treatment with the new mechanism of actions. Carotegrast methyl can be a treatment option that meets that unmet medical need and has the potential to greatly contribute to the treatment of ulcerative colitis based on the thorough practice of proper use. This article mainly introduces the pharmacological properties and clinical trial results of carotegrast methyl.