Folia Pharmacologica Japonica最新文献

The global spread of antimicrobial resistance (AMR) is a threat to the international community, but few new antimicrobials are in the development stage and there are few options to treat AMR infections. In light of this situation, AMR has been continuously featured on the G7 agenda since 2015, and the 2023 G7 Hiroshima Leaders' Communiqué also states that in recognition of the global and rapid spread of AMR, push and pull incentives will be explored and implemented. In addition, the World Health Assembly adopted the Global Action Plan on AMR in 2015, and Japan developed its first AMR action plan in 2016. An updated version has been released in 2023. It is hoped that the attractiveness of the antibiotic market will be improved, and the new antibiotic development will be revitalized by further expansion and enhancement of the pull incentive systems. Cefiderocol, a novel siderophore cephalosporin, demonstrates potent antibacterial activity against carbapenem-resistant Gram-negative bacteria, which are considered to be particularly high-priority pathogens by the World Health Organization (WHO) and other organizations. A partnership between the SHIONOGI, the Global Antibiotic Research and Development Partnership (GARDP) and the Clinton Health Access Initiative (CHAI) formed to improve access to cefiderocol in countries around the world, including low- and middle-income countries. In order to bring these efforts to fruition in the fight against AMR, it is important to have further understanding and cooperation from people around the world, regardless of country or field.

Age-related macular degeneration (AMD) is one of the most common neuroinflammatory diseases that is the leading cause of blindness worldwide. AMD is caused by not only mutations in immune-related genes such as Cfh (complement factor H) but also the accumulation of environmental factors such as obesity and other inflammatory triggers with age. Our study found that the past histories of obesity can lead to immunological reprogramming in the innate immune system and affect the development of AMD in later life. This reveals a new link in the role of innate immune memory in neuroinflammatory diseases such as AMD, and intervention in innate immune memory may be a new therapeutic strategy.

The delay and loss of drugs are serious problems in Japan. To overcome this issue, it is important to strengthen drug development capabilities. For drug development, the establishment and advancement of non-clinical testing methods are necessary for safe and effective clinical trials. Recently, the movement toward alternatives to animal testing has accelerated internationally. New Approach Methodologies (NAMs), such as human inducible pluripotent stem cell (hiPSC) technology and in silico modeling & simulation, are considered valuable for drug development. It has been demonstrated that hiPSC-derived cardiomyocytes (hiPSC-CMs) are useful tools to assess drug-induced cardiotoxicity, including arrhythmia and cardiac contractile dysfunction, leading to the use of hiPSC-CMs in the drug review process. Advancing hiPSC technologies have enabled the generation of mature hiPSC-CMs and engineered heart tissues, which are expected to provide novel information in drug safety and efficacy evaluation. Furthermore, it would be possible to establish the non-clinical evaluation that takes into account individual differences by developing hiPSCs bearing characteristics specific to certain populations, such as pediatrics or rare disease patients. Here, we present the recent findings and future perspectives on non-clinical evaluation using hiPSC technology.

The prevalence of allergic diseases is increasing worldwide, with approximately one in two individuals in Japan affected by some form of allergic condition, making it a common disease. While most allergic diseases are multifactorial, involving a complex interplay between genetic predispositions and environmental factors, a subset of cases is attributed to monogenic disorders, which have been increasingly reported in recent years. This article focuses on JAK1 gain-of-function (GOF) variants, highlighting their clinical features, therapeutic potential, and the future prospects of research on monogenic disorders in allergic diseases. JAK1-GOF variants are characterized by early onset and severe atopic dermatitis that does not respond to conventional therapies. They are also frequently associated with other allergic diseases, such as food allergies and asthma, as well as autoimmune diseases and growth impairments. JAK inhibitors represent a promising therapeutic option for JAK1-GOF mutations, with previous reports suggesting their efficacy. Predicting drug efficacy through in vitro studies could enable the selection of tailored treatments for individual patients, potentially leading to significant clinical improvements. It is hypothesized that undiagnosed patients with such monogenic disorders may exist. Accurate diagnosis of these patients could facilitate effective treatments. Moreover, research on monogenic disorders has the potential to lead to the development of novel molecular-targeted therapies through the elucidation of disease pathophysiology, benefiting not only patients with rare genetic disorders but ultimately a broader population.

Glaucoma is the leading cause of blindness worldwide. Vision loss in glaucoma is caused by damage to retinal ganglion cells (RGCs), which are responsible for transmitting visual information from the retina to the brain. Glaucoma is a multifactorial disease with multiple risk factors, among which elevated intraocular pressure (IOP) is the most well-established. Currently, lowering IOP is the mainstay of glaucoma treatment. However, disease progression is frequently observed even in patients whose IOP is well controlled. Notably, the majority of Japanese glaucoma patients are diagnosed with normal-tension glaucoma (NTG). These observations highlight the urgent need to elucidate IOP-independent mechanisms contributing to glaucoma pathogenesis. In this context, increasing attention has been directed toward the potential role of glial cells in the development and progression of glaucoma. Glial cells are known to play critical roles in various neurodegenerative diseases. In glaucoma, glial activation and dysfunction have been documented in the ocular tissue of human patients, as well as in primate and rodent models. Importantly, glial activation is observed at early stages of glaucoma, even before detectable RGC loss occurs. This raises the possibility that glial dysfunction is not merely a secondary response to neuronal injury but may serve as a primary driver of disease onset. For example, deletion of glial cell-specific genes has been shown to induce NTG-like phenotypes. This article provides an overview of recent advances in our understanding of the role of glial cells in glaucoma pathogenesis, with a focus on insights gained from our own research.

Over the years, research has accumulated a vast amount of knowledge about the pathogenesis of dementia, including Alzheimer's disease (AD). However, fundamental treatments for AD have not yet been established. In this article, we discuss an Aβ receptor, paired immunoglobulin like receptor B (PirB) and its endogenous regulator lateral olfactory tract usher substance (LOTUS), which are completely different novel drug target from existing drugs, and the possibility of endogenous inhibitors of PirB. PirB expressed in neurons is a negative regulator of neuronal plasticity, as loss or inhibition of PirB increases neuronal plasticity, leading to increased spine density and improved cognitive function. Furthermore, PirB is known to function as a receptor for Aβ, leading to reduced neuronal plasticity and cell death. These findingss suggest that PirB can be positioned as a novel drug target for the treatment of AD. The neuronal circuit-forming factor LOTUS, which binds to PirB and functions as an endogenous antagonist, has been shown to inhibit the neurotoxic effects of Aβ mediated by PirB. Namely, LOTUS is an endogenous molecule that inhibits Aβ receptor function of PirB and may have medicinal effects against Aβ pathology.

In recent years, the rapid development of generative AI has given rise to a variety of services such as machine translation, sentence summarization, and programming code generation. In drug discovery, generative AI and chemoinformatics have been used for seed/lead compound generation and optimization, and several successful cases were reported. The use of AI technology in drug discovery is expected to solve previously difficult problems and dramatically improve success rate in drug discovery. ITM, Inc. is a venture company established in 2004 to support drug discovery in silico using original chemoinformatics technology. Currently, ITM is developing a drug discovery support system that combines state-of-the-art AI technology and chemoinformatics technology. This paper introduces ITM's technology with a focus on the use of generative AI.