Folia Pharmacologica Japonica最新文献

Currently, a variety of anticancer agents are used in the treatment of cancer. Since anticancer agents are used continuously over a long time, they carry the risk of side effects. One of the major side effects is cardiac dysfunction. For example, doxorubicin, an anthracycline-type anticancer agent, is clinically restricted because of its dose-dependent cardiotoxicity. Cardiotoxicity includes decreased ejection fraction, arrhythmias, and congestive heart failure, all of which are associated with high mortality rates. Therefore, it is important to assess the risk of cardiotoxicity of anticancer agents in advance. Cardiomyocytes require energy to beat and retain an abundance of mitochondria. We established quantitative measurements of mitochondrial length and respiratory activities using cardiomyocytes. We found that exposure of human iPS cell-derived cardiomyocytes (hiPSC-CMs) to anticancer agents with reported cardiotoxicity enhanced mitochondrial hyperfission and the oxygen consumption rate was significantly reduced. Knockdown of dynamin-related protein 1 (Drp1), mitochondrial fission-accelerating GTP-binding protein, suppressed mitochondrial hyperfission in hiPSC-CMs. This indicates that visualizing mitochondrial functions in hiPSC-CMs will be helpful in assessing the risk of cardiotoxicity caused by anticancer agents and that maintaining mitochondrial quality will become a new strategy to reduce anticancer agents-induced cardiotoxicity. In this review, we present the evaluation of cardiotoxicity targeting mitochondrial quality in anticancer agents, using osimertinib, a non-small cell lung cancer drug, as an example.

Approximately 80% of all the information we receive about the world comes through the visual pathways and visual function deterioration causes severe decline in QOL. Glaucoma is the leading cause of blindness in the world, in which visual field deficit deteriorates as the optic nerve degeneration progresses. Hence, the development of fundamental cure is needed. Our research focuses on the signaling of brain-derived neurotrophic factor (BDNF), one neurotrophic factor reduced with aging and glaucoma patients. We generated modified tropomyosin receptor kinase B (TrkB) which can be constitutively activated in the absence of its ligand BDNF. The active site of TrkB is localized to the plasma membrane, allowing for constitutive activation of intracellular signaling. Gene therapy with the modified TrkB in a mouse model of glaucoma was proven to be protective. In addition, our group reported that apoptosis signal-regulating kinase 1 (ASK1), one of the stress response factors, is related to the severity of optic neuritis and myelitis in model mice of multiple sclerosis. We generated four lines of cell type specific ASK1 conditional knockout mice and found that ASK1 in glial cells increased the severity of neuroinflammation while ASK1 deficiency in immune cells had no significant effects. Further, we found that ASK1 is required in microglia and astrocytes to cause and maintain neuroinflammation by a feedback loop between these two cell types. Our results suggest that ASK1 might be a promising therapeutic target for reducing neuroinflammation including optic neuritis.

MPS is already being utilized in various aspects of drug development. This paper introduces MPS from a different viewpoint in previous reviews. First, I will introduce how the term "microphysiological systems" came to be used based on the results of the PubMed search, and show the results of an abstract analysis at the MPS World Summit 2023 held in Berlin, which quantified the organs of interest in MPS and the needs of pharmaceutical companies. Next, the author's activities in the AMED-MPS2 (the identification and experimental validation of device or cell considerations as MPS evaluation systems) and MPS-RS (the development of CoUs suitable for guidelines) projects as MPS projects in Japan will be introduced. I am also engaged in the construction of an evaluation system using cardiac MPS. The features and results of several cardiac MPS devices that have been developed for the contraction evaluation will be introduced, including the author's own efforts. Evaluation systems using MPS are attracting attention not only in drug discovery but also in the food and chemical industries, and while social implementation is gradually advancing, discussion groups are being created around the world to discuss how MPS should truly be utilized in society and in regulations. Countries seem to be focusing on acquiring data using useful devices that have survived the race for survival. For Japan to lead the world, it will be necessary to quickly identify useful devices and acquire enough data to discuss them.

Distal myopathy with rimmed vacuoles (GNE myopathy) is an incurable disease that develops after the late teens, progresses slowly, and has no effective treatment. It is inherited in an autosomal recessive manner, and the number of patients in Japan is estimated to be around 400. The causative gene was revealed to be GNE, the rate-limiting enzyme in the sialic acid biosynthesis pathway, and non-clinical studies demonstrated the effectiveness of sialic acid. Tohoku University Hospital conducted an investigator-initiated phase I trial with aceneuraminic acid in 2010. After that, trials were conducted overseas, and a phase II trial using acenoiraminic acid sustained-release tablets confirmed that muscle strength in the upper limbs had recovered, and the drug progressed to a phase III trial. In Japan, a Phase II/III study was conducted at five domestic facilities using the same protocol as the overseas Phase III study, and efficacy and safety were confirmed. However, Phase III trials overseas failed to show efficacy and development was discontinued. An additional confirmation study was conducted in Japan, and as a result of confirming reproducibility, the product was approved for manufacturing and sales in March 2024, ahead of the rest of the world. This is a successful example of the development of a therapeutic drug for an ultra-orphan disease, which is said to be difficult to develop, and is expected to lead to early treatment for patients.

In the overall Japanese population, the prevalence of perennial allergic rhinitis (AR) increased from 18.7% to 24.5% from 1998 to 2019. For Japanese cedar pollen (JCP) induced AR, the prevalence in the same period increased from 16.2% to 38.8% in the general population and from 7.2% to 30.1% in children (5-9 years), indicating a serious problem especially in younger age groups. Allergy immunotherapy (AIT) is an AR treatment modality that induces immune tolerance to allergens by repeated allergen administration and is the only treatment form that reduces symptoms and medication use and provides sustained effect after treatment completion. In Japan, AIT is available primarily as sublingual immunotherapy (SLIT) tablets. Two tablets based on a freeze-dried formulation (a JCP SLIT-tablet, approved 2018, and a house dust mite (HDM) SLIT-tablet, approved 2015), and one tablet based on a compressed formulation (HDM, approved 2015) are available. For SLIT to be effective, the concentration of allergen when solubilized in saliva must be as high as possible for as long as possible within the recommended sublingual holding time (1-2 minutes), parameters that must be supported by the tablet formulation. The characteristics of the freeze-dried and compressed formulations were compared using the HDM SLIT-tablets. Freeze-dried tablets disintegrated immediately and displayed fast and complete HDM allergen release in solvent, while compressed tablets disintegrated more slowly and provided only incomplete allergen release. Freeze-dried SLIT-tablets are believed to provide full mucosal availability of the allergen content during the sublingual holding time, and a low medication burden.