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Cyfuse Biomedical K.K. is a R&D venture company established in 2010 aiming at industrialization of its 3D cellular products for regenerative medicine based on innovative 3D cell stacking technology, and has newly listed on the Growth Market of the Tokyo Stock Exchange in December 2022. We are developing 3D cellular products consisted of only human cells through our unique platform technology created from the fusion of two disparate technologies; engineering and biology. Three pipelines aiming for approval as products for regenerative medicine have already advanced to the stage of human clinical trials, and are expected to implemented in society in the near future. In addition, we also have been developing functional cellular devices (FCD) using our core technology, the Kenzan method, and have begun marketing FCD as support tools that contribute to the development of new drugs. We will introduce in detail our contribution to the medical field that we are aiming for, with specific examples, also referring to the unique additive manufacturing (AM) technology that supports the realization of our cellular products as above. [ABSTRACT FROM AUTHOR]

In the current drug development process, most safety pharmacological tests are animal experiments optimized for low molecular weight compounds. However, development trends have shifted to new modality drugs such as human specific mRNA, antisense oligonucleotides, and siRNA, etc., indicating that now the importance of the human predictability in safety pharmacology is more important than ever. In parallel with that, in vitro use of human cells, such as human iPS cell-derived tissue cells and chimeric mice with human hepatocytes, has been studied strenuously. In this review, we will discuss about IVIVE in safety pharmacology to improve human predictability in this trend of drug development. [ABSTRACT FROM AUTHOR]

Chronic exposure to stress can lead to a variety of mental disorders such as depression. There are many treatment-resistant patients who do not respond adequately to the standard pharmacological treatments. Therefore, the development of novel therapeutic agents is highly expected. In rodents, socially defeated animals that were exposed to repeated physical aggression from other individuals are widely used in this field of research. The social defeat is considered as a stress that mimics human social stress. On the other hand, emotional stress, but not physical stress, is likely to contribute to the pathogenesis and etiology of depression in human. Therefore, there is a gap between the process of pathogenesis and the animal models, and this is one of the reasons why the development of new psychotropic drugs to treat depression has been difficult. Recently, a novel stress model has been introduced, in which mice are subjected to emotional stress without physical distress by witnessing social defeat scenes of their conspecifics. We have investigated the mechanisms by which emotional stress is transmitted by witnessing social defeat in mice, focusing on the insular cortex. In this article, we summarize and discuss the recent advancements in the neural basis of behavioral changes induced by emotional stress. [ABSTRACT FROM AUTHOR]

Copyright of Folia Pharmacologica Japonica is the property of Japanese Pharmacological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Folia Pharmacologica Japonica is the property of Japanese Pharmacological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Alzheimefs disease (AD) is a very serious problem and is a major health concern for elderly individuals. However, the development of pharmacological therapies for AD is not succeeded. Therefore, development of drugs and/or functional foods to prevent the onset of AD is highly expected. Accumulating evidence indicates that citrus-derived polymethoxylated flavones (PMFs), such as nobiletin and its analogue tangeretin, have influence on cognitive function. Several clinical and experimental studies indicate that these natural compounds improve cognitive impairment by exerting neuroprotective effects against their pathological features, including amyloid-β pathologies, tau hyperphosphorylation, neuroinflammation, oxidative stress, neurodegeneration, synaptic dysfunction and neuronal cell death in addition to its related mechanisms. This review provides recent evidence of the beneficial effects of PMF-rich citrus extracts on human cognitive function and several experimental animal models. [ABSTRACT FROM AUTHOR]

Recent virological researches using biophysical methods, termed as virus biophysics or virophysics, largely contribute to the development of anti-viral drugs and vaccines. In this review, examples of structural and physicochemical analyses for representative viruses to develop drug modalities such as small compounds, antibodies, and vaccines are explained, and future direction of biophysical research for virus research is also discussed. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is expected to be a promising next-generation cancer treatment. In 2020, Japan, which has led the research on this treatment modality, was the first country in the world to approve BNCT. The boron agents that have been clinically applied in BNCT include a caged boron compound (mercaptoundecahydrododecaborate: BSH) and a boron-containing amino acid (p-boronophenylalanine: BPA). In particular, the BPA preparation Steboronine ® is the only approved drug for BNCT. However, the problem with BPA is that it is poorly retained in the tumor and has very low solubility in water. This cannot be overlooked for BNCT, which requires large amounts of boron in the tumor. The high dosage volume, together with low tumor retention, leads to reduced therapeutic efficacy and increased physical burden on the patient. In the case of BSH, its insufficient penetration into the tumor is problematic. Based on drug delivery system (DDS) technology, we have developed a next-generation boron pharmaceutical superior to Steboronine ® . Our approach involves the redevelopment of BPA using innovative ionic liquid formulation technology. Here, we describe previous boron agents and introduce our recent efforts in the development of boron compounds.

Major depressive disorder (MDD) is a psychiatric disorder that affects more than 300 million people worldwide and has a serious impact on society. Conventional antidepressants targeting monoamines in the brain based on the monoamine hypothesis are known to take a prolonged time to be effective or less effective in 30% of MDD patients. Hence, there is a need to develop antidepressants that are effective against treatment-resistant depression and have a new mechanism different from the monoamine hypothesis. An increasing number of research groups including us have been establishing that pituitary adenylate cyclase-activating polypeptide (PACAP) and one of its receptors, PAC1 receptor, are closely related to the etiology of stress-related diseases such as MDD. Therefore, it is strongly suggested that the PAC1 receptor is a promising target in the treatment of psychiatric disorders. We developed a novel, non-peptidic, small-molecule, high-affinity PAC1 receptor antagonists and conducted behavioral pharmacology experiments in mice to characterize a novel PAC1 receptor antagonist as a new option for MDD therapy. The results show that our novel PAC1 receptor antagonist has the potential to be a new antidepressant with a high safety profile. In this review, we would like to present the background of developing our novel PAC1 receptor antagonist and its effects on mouse models of acute stress.

The 2019 Nobel Prize in Physiology or Medicine was awarded to Dr. William G. Kaelin Jr, Dr. Peter J. Ratcliffe, and Dr. Gregg L. Semenza for their elucidation of new physiological mechanisms "How cells sense and adapt to oxygen availability". Moreover, two different drugs, HIF-PH inhibitors and HIF-2 inhibitors were also developed based on the discovery. Interestingly, those three doctors have different backgrounds as a medical oncologist, a nephrologist, and a pediatrician, respectively. They have started the research based on their own unique perspectives and eventually merged as "the elucidation of the response mechanism of living organisms to hypoxic environments". In this review, we will explain how the translational research that has begun to solve unmet clinical needs successfully contributed to the development of innovative therapeutic drugs.

For nearly 40 years, combination therapy with cytarabine and anthracycline has been the standard of care for acute myeloid leukemia (AML). The cytogenetics and molecular biology of AML are now understood, and the treatment of AML has undergone dramatic changes in Japan with the launch of drugs such as FLT3 inhibitors, Bcl2 inhibitors, and hypomethylating agents since 2018. However, AML remains very difficult to cure, with a high relapse rate. Here, we review novel agents that have not yet been approved in Japan (CPX-351, IDH inhibitors, menin inhibitors, and oral azacitidine) as potential treatments for AML, as well as therapeutic antibodies (BiTEs, DARTs, immune checkpoint inhibitors) currently under investigation in clinical trials or in development. These novel agents are being investigated not only as monotherapy but also as combination therapy with intensive chemotherapy or azacitidine/venetoclax. The new era of AML treatment is expected to support a variety of goals, including leukemic cell elimination, long-term remission, and improved quality of life.

Transdermal drug delivery is a formulation in which the drug is absorbed through the skin for systemic action. Its advantages include avoidance of first-pass effects, sustained drug supply, and ease of administration and discontinuation. Drugs administered transdermally transfer into the blood circulation through the stratum corneum, epidermis, and dermis. The stratum corneum on the skin surface plays a barrier function in skin absorption. Therefore, developing of transdermal drug delivery systems requires innovations that overcome the barrier function of the stratum corneum and improve skin permeation. This review examines the usefulness of transdermal formulations based on solid nanoparticles using raloxifene. Milled raloxifene was gelled with (mRal-NPs) or without menthol (Ral-NPs) using Carbopol. The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. The inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted raloxifene nanoparticles to penetrate through the skin. Moreover, macropinocytosis relates to the formulation's skin penetration, including menthol (mRal-NPs). Applying mRal-NPs attenuated the decreases in calcium level and stiffness of bones of ovariectomized rats. This information can support future studies aimed at designing novel transdermal formulations.

Since 1993, the"R & D Promotion System for Orphan Drugs and Orphan Medical Devices"has been in operation to support the development of orphan drugs in Japan. Various supportive measures are in place for indications that target less than 50,000 patients, have high medical needs and high probability of successful development(which means regulatory approval). However, recently a trend was observed that the designation for orphan drugs occurred most often in late phase of development, because clinical data for late stage clinical studies were required to show the high probability of successful regulatory approval. The Ministry of Health, Labour and Welfare are trying to make efforts to expand the orphan drug designation, and have made the decision to include the related expenses will be included in the FY 2023 budget request. It is expected that the expansion of orphan drug designation will lead to promote drug development in rare disease area. On the other hand, fundamental reform is considered necessary for this system. Among the approved anti-cancer drugs that obtained orphan designation in the U. S. and EU as of 2020, there are 24 drugs that have not been approved in Japan. Of these, there are at least 16 drugs approved in either China, Taiwan, and South Korea. From viewpoint of development pathway of an orphan drug, participation in a multi-regional clinical trial(MRCT)is useful, but there are cases that Japan cannot join MRCT in time due to the requirement of Japanese safety data prior to the participation. In that case, it is impossible to conduct a separate clinical trial to obtain Japan regulatory approval due to very limited patients(eg several to several tens of Ultra-Orphan). A review system that allows earlier patient access is desired.

Medical big data is accumulated numerous medical related data day by day. These data may have tips for new approach for drug development. Authors tried to find drug-development-needs in children using medical big data analysis with prescription survey. Medical big data were provided from JMDC (Japan Medical Data Centre) Inc. about 3 million participants between January 2005 and June 2017. In these, we identified randomly identified 22787 participants from 466701 participants who are aged ≤11 years. In these participants, 9644 were administered "capsule," "tablet," "orally distegrating tablet," "controlled release tablet/capsule" or "enteric coated tablet" formula drugs. In these, 514 were administered these as powderization or decapsulation. Sixty components administered in 145 participants (28.2%) are not marketed for pediatric formula. On the other hands, 92 components administered in 369 participants (71.8%) are decapsulation or powderization, though pediatric formulas are marketed. These 152 components may have a development seeds for children. In conclusion, prescription survey using medical big data may partially resolve the drug-development-need in pediatrics because by using medical big data will leads low biased data depending each institution.

Chimeric mouse with humanized liver is an experimental animal which is produced by transplanting normal human hepatocytes into a host mouse having both of immunodeficient and liver-injured characters. PXB-mouse ® , which is developed and supplied by PhoenixBio group, is produced by utilizing cDNA-uPA/SCID mouse as a host animal and has a humanized liver containing over 70% of human hepatocytes. It has been utilized in the research fields of drug metabolism such as investigation of human-specific metabolites and pharmacokinetics, prediction of human DILI and development of anti-viral hepatitis drugs. Furthermore, it is expected that PXB-mouse will be valuable for the development of drugs of new modalities as the emerging technologies such as oligonucleotide medicine and gene therapy. Because it has an organ which consists almost entirely of human cells PXB-mouse is expected to be used in validation of efficacy or prediction of off-target effect caused by human specific nucleotide sequence. This paper introduces the character of PXB-mouse focusing on the successful achievements in these research fields.

The nuclear receptor superfamily comprises 48 members in humans. In various organs, nuclear receptors regulate a variety of physiological functions through transcription of target genes. They are associated with the development and progression of endocrine and metabolic disorders, as well as with cancer development. Therefore, agonists and antagonists targeting nuclear receptors are currently being developed as therapeutic drugs for these diseases. Nuclear receptors can be activated through ligand binding or phosphorylation, which is mediated by various cellular signaling pathways. Activation of a nuclear receptor necessitates significant structural modifications in each of its domains. My research has been focused on unraveling the intricate mechanisms underlying the activation of nuclear receptors using constitutive androstane receptor (CAR) and pregnane X receptor (PXR) as model nuclear receptor proteins. CAR and PXR are highly expressed in the liver and are activated by a wide range of xenobiotics. Given their crucial roles in the metabolism and disposition of xenobiotics, as well as their potential in mediating drug-drug interactions, it is imperative to extensively study the mechanisms of xenobiotic-induced activation of these receptors. Such studies are essential for advancements in drug development, as well as for ensuring food and chemical safety. In this review, I elucidate the molecular basis underlying the activation of xenobiotic-responsive nuclear receptors.

Blood brain barrier (BBB) is strong barrier specific to the brain vasculatures. BBB protects the brain from xenobiotics, while make it difficult to predict toxicokinetics/toxicodynamics, pharmacokinetics/pharmacodynamics, and efficiencies of new drugs in drug development. In this review, we will explain the physiological significance of BBB, the reason why the humanized BBB Micro Physiological System (MPS) is necessary, and the background technologies of BBB MPS. Because BBB MPS is the fusion of the engineering element technologies and the biological element technologies, we will explain the element technologies in both fields, respectively. We will also introduce the recent trends of BBB MPS to improve the human predictability: the shear stress in microfluidic models and the cellular architecture reproduction by three dimensional culture.

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.

Luliconazole (LLCZ), an imidazole derivative with a broad spectrum of potent antifungal activity especially for T. rubrum and T. mentagrophytes, is under development as a new drug for treatment of tinea unguium. It is well known that curative effect of an antifungal agent in dermatophytosis is affected by the pharmacokinetics of an agent at the infection loci as well as its antifungal activity, but there is no report about the affinity of LLCZ to nail keratin. We studied LLCZ affinity to keratin powder prepared from healthy human nail and porcine hoof. The LLCZ adsorbed to keratin preparations was washed with phosphate buffer, and its concentration in the buffer supernatant was measured by HPLC. Antifungal titer of the supernatant was also biologically confirmed by disk diffusion assay. Adsorption rate of LLCZ was 80% or more, and LLCZ was gradually liberated into washing buffer. Cumulative liberation rate in 10 times repeated washing against initially adsorbed drug amount was 47.4% for keratin from human nail and was either 52.5% or 50.8% (depending on the LLCZ concentration) for keratin from porcine hoof. The supernatant showed antifungal potential to T. rubrum. These results indicate that LLCZ applied to the nail surface is fully adsorbed to nail keratin and gradually liberated from it. The nail keratin could function as drug reservoir to supply biologically active LLCZ to the nail tissue region of infection loci. The LLCZ delivered to the loci would exert its antifungal potential on tinea unguium. This study also suggests the versatility of porcine hoof powder as an alternative to human nail keratin preparation for non-clinical study. [ABSTRACT FROM AUTHOR]

Extraordinary Measures is a 2010 film about parents who tried to develop a drug with a glycobiology scientist to save their children suffering from a milder subtype of infantile Pompe disease (non-classic infantile-onset form), which can be said as an intermediate type between infantile onset and late-onset types. This movie is based on a nonfiction book The Cure by Geeta Anand. Pompe disease (glycogen storage disease type 2) is a myopathy, that affects the diaphragm. Infantile Pompe disease presents cardiomyopathy and hepatomegaly. Enzyme replacement therapy for Pompe disease with Myozyme was approved by FDA in 2006. Activities of the patients and their families association, including fund-raising, were pictured in the film, as well as (1) negotiation with a venture capital firm, (2) management of a pharmaceutical company for an orphan drug development for a rare genetic disorder, and conflicts of the father who works for the pharmaceutical company and desperately wants to provide the products to his own children.

Protein-compound docking is a key technology in structure-guided drug development (SGDD), and some combinations of computational methods including the protein-compound docking have been used in the SGDD. Ligand-binding site prediction is the first step in the SGDD. The second step is the ensemble docking, in which compounds in a database are docked onto the protein surfaces of a structural ensemble of the target protein. The third step is the information analysis of the docking results. Finally, suitable docking results are selected for an assay experiment. Topics around the protein-compound docking and the SGDD are briefly explained. [ABSTRACT FROM AUTHOR]

In the post-genome era, with the availability of high-throughput data, our biological focus makes a shift from a behavior of individual components to their regulatory/causative/interactive relationships. Gene network, which is inferred from microarray data by using reverse engineering algorithms, gives valuable information about the regulation of genes in the living cells under the certain conditions. In particular, this technology is applied to the biomedical research fields, e.g. identification of drug targets and prognosis markers. In this short review, we summarize what gene network is and how it is inferred. We also show our work that identified new drug target of well-known compound in human endothelial cells by gene network analysis. [ABSTRACT FROM AUTHOR]

Astellas regards the situation where there still remain barriers for many people who have difficulty accessing the healthcare they need due to the lack of available treatments, poverty, healthcare system challenges and insufficient healthcare information. Astellas recognizes this problem as the Access to Health issue. To improve Access to Health, Astellas has identified four areas where we can leverage our strengths and technologies, and is working to solve issues, making full use of external partnerships. These areas are "creating innovation", "enhancing availability", "strengthening healthcare system" and "improving health literacy". In March 2018, Astellas participated in the Neglected Tropical Diseases Drug Discovery Booster, a consortium whose purpose is to identify lead compounds for leishmaniasis and Chagas disease, both of which are neglected tropical diseases (NTDs). Moreover, within the pediatric praziquantel consortium, involving pharmaceutical companies, research institutions and international non-profit organizations, Astellas has developed a pediatric formulation of praziquantel for the treatment of schistosomiasis. In this report, we will introduce concretely how Astellas has promoted new drug development projects for NTDs in collaboration with various external partners, giving the projects as examples.

The number of clinical trials investigating the use of nucleic acid drugs, including DNA/RNA-based vaccines, immunostimulatory/modulatory DNA/RNA and cyclic dinucleotides, for immuno-prophylaxis and -therapy has been increasing exponentially in recent years. These new drugs have revealed their therapeutic potential not only as vaccines or adjuvant therapies, but also as monotherapies for use in immuno-therapy of cancer and allergic disease. I will present an overview of their current R&D taking place in this field, then describe our recent progress, particularly regarding CpG oligodeoxynucleotides (ODNs), such as K3, K3-SPG, and D35 as either vaccine adjuvants or mono-immunotherapeutic agents for tropical diseases including malaria and leishmaniasis.

Drug-induced cardiotoxicity still remains a major cause of concern, and non-clinical integrated risk assessments from both functional and structural alterations in the cardiovascular system are strongly required in the creation of drugs with superior safety profiles. Although systemic blood pressure, heart rate, and electrocardiogram are the main items in safety pharmacology studies, direct cardiac function assessments such as cardiac output and ventricular contractility, mentioned in ICH S7A guideline, are also desirable. General toxicology studies are important to detect structural changes through clinical pathology and histopathological examination, and translational biomarkers and metabolomics analysis with high extrapolation to humans also provide useful insights. In this paper, we will introduce our basic research to investigate the cardiac effects of milrinone, a cAMP phosphodiesterase III inhibitor in cynomolgus monkeys, and share the importance of comprehensive risk assessment in non-clinical in vivo studies.

Cyclodextrins (CDs) are used not only as pharmaceutical excipients but also as active pharmaceutical ingredients. CDs can act as artificial carriers or shuttles to ameliorate lipid transport disorders. Niemann-Pick disease type C (NPC) is an inherited, progressive neurodegenerative disorder caused by mutations in NPC1 or NPC2 genes, in which unesterified cholesterol accumulates in lysosomes and the transport of cholesterol from lysosomes to the endoplasmic reticulum is impaired. 2-Hydroxypropyl-β-CD (HPBCD) has activity as a cholesterol shuttle and can attenuate NPC-related manifestations in model cells and animals. HPBCD can also be an effective treatment for NPC patients, but has produced lung damage and ototoxicity at therapeutic doses in clinical trials. Like HPBCD, 2-hydroxypropyl-γ-CD (HPGCD) can normalize disrupted cholesterol homeostasis in cells derived from NPC patients and NPC model mice. HPGCD interacts with unesterified cholesterol with a mode of interaction distinct from that of HPBCD and acts as a fine-tuned cholesterol shuttle for the treatment of NPC with a wider safety margin than HPBCD in terms of ototoxicity and pulmonary toxicity. By bridging clinical and basic research, it is hoped that progress will be made in the development of therapeutic agents against neurodegenerative lipid storage disorders that share common pathogenic mechanisms with NPC.

The modified Irwin's method and functional observational battery (FOB）used in non-clinical studies for predicting side effects that may appear in the central nervous system (CNS）in clinical studies consist of mainly macroscopic observation and largely depend on the observer's ability. Therefore, appropriate training for the observer and consistency of findings are extremely important, making it necessary for methods and judgment criteria to be standardized. In addition, because of concern for animal welfare as well as an increase in biopharmaceutical and anticancer drug development, there is increasing opportunity to incorporate safety pharmacological evaluation into general toxicity studies. While CNS evaluation can be incorporated into general toxicity studies relatively easily, studies need to be designed in such a way that reliable data can be obtained without reducing the ability to detect neurobehavioral abnormalities. It is therefore important to improve CNS evaluation techniques and to share these techniques with new observers in order to reliably detect the effects on the CNS during drug development.

The number of patients with exudative age-related macular degeneration, diabetic retinopathy and retinal vein occlusion is expected to rise in proportion with the aging of the population and increasing diabetes patients. Also, they are the most common diseases caused by intraocular neovascularization and are often difficult to treat. Currently, anti-vascular endothelial growth factor (VEGF) therapy has been developed and has demonstrated excellent results in treating macular edema, and many patients have avoided blindness. Unfortunately, there are problems with cases that do not respond to the anti-VEGF drugs and complications of administration. It is necessary to deepen the understanding of the physiological and pathological retinal roles of VEGF and to optimize the anti-VEGF therapy. There are also no drugs indicated for the regression of neovascularization itself. The solution to this problem is to develop novel therapies targeting other than VEGF. In this symposium review, we introduce the roles of VEGF in the ischemic retina and anti-angiogenic factors as promising therapeutic targets.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived immunostimulatory factor, which activates several immune cells such as dendritic cells, T cells, and mast cells. Recently, epithelial cell-derived TSLP has gained immense attention as a cytokine that induces allergic immune responses. Therefore, understanding the regulation of TSLP production is an important step in uncovering the pathophysiology of allergic diseases. Moreover, the compounds that regulate TSLP production can be used as therapeutic drugs for the treatment of allergic diseases. We aim to elucidate the detailed regulation of TSLP production from epithelial cells, and in doing so discovered new regulating factors and an inhibitor of TSLP production. This review article explains the role of TSLP in allergic diseases, its regulation, and our research results.

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.

The mission of regulatory science is to promote human longevity by providing safer and more effective drugs and ensuring human health. At present, various in vitro and in vivo evaluation methods are used for drug development, and no major problems have been observed. However, there is still room for improvement in terms of risk prediction in humans. Thus, new approaches and methodologies (NAMs) have recently been developed to predict adverse events in humans more accurately. Based on the animal alternative methods and the current COVID-19 pandemic, in vitro methods, such as human iPS cells, and computational approach are accelerated to improve the efficiency of drug development, ensure the patients' safety and speed up the review process. In this review, we would like to summarize the current status and future perspectives of pharmacological assay system using NAM in drug development.

Migraine is a common and debilitating neurological disorder characterized by recurrent attacks of moderate to severe throbbing headache accompanied by nausea, vomiting and photophobia/phonophobia. Because of its high prevalence, migraine causes a considerable financial burden on the society as well as impaired quality of life in individual patients. Scientific evidence shows that migraine is a quite complex neurological disorder that involves not only the trigeminovascular and autonomic systems but also the hypothalamus and cerebral cortex. Calcitonin gene-related peptide (CGRP) was originally discovered as a 37-amino acid neuropeptide derived from a calcitonin gene splicing variant. CGRP is found to be expressed in trigeminal ganglion neurons. Much attention has been attracted to this molecule since CGRP was found to be released from trigeminal terminals in animal migraine models. Subsequent studies demonstrated that CGRP administration induced migraine-like headache attacks specifically in migraineurs, thus highlighting a pivotal role of CGRP in the development of migraine attacks. Several CGRP receptor antagonists were shown to be efficacious for the treatment of acute migraine. Among them, telcagepant, was shown to exert a significant migraine prophylactic action as well. Nevertheless, the development of most of these agents were discontinued due to hepatotoxicity. Currently, newer CGRP receptor antagonists are being developed. On the other hand, monoclonal antibodies targeting CGRP and its receptor showed consistent efficacy for migraine prophylaxis with excellent safety profiles in Phase III clinical trials. Furthermore, emerging data support the long-term safety and efficacy of these antibodies. In this review article, the development and perspective of anti-migraine therapeutic strategies using CGRP-related antibodies are discussed.

We have developed a partial peptide of RANKL (receptor activator of NF-κB ligand) that suppresses TLR (toll-like receptor)-related inflammation via RANKL/RANK (receptor activator of nuclear factor-κB) signals in the acute phase of ischemic stroke. This peptide has been found to be a therapeutic agent for ischemic stroke that can be used in combination with tPA in a mouse model. Based on the findings, we are working on translational research to aim for clinical application of this peptide through collaboration with pharmacy companies. However, the problem is that the need for development of medication in the acute stage of ischemic stroke is currently low in pharmaceutical companies due to the failure of many investigational drugs in the past. To overcome the problem, we are examining the effects of this peptide in other diseases included in the company's priority areas and explaining the environmental changes in the clinical trials due to the development of endovascular treatment in the acute stage of ischemic stroke.

Natural products are useful sources in the search for biochemical probes and drug leads because of their unique biological activities. However, synthetic studies or functional analyses of polycyclic complex natural products or conjugated lipids (e.g., glycolipids) are often hampered because of their synthesis and handling are challenging. On the basis of rational designs, synthetic studies, and chemical modifications, natural products need to be optimized to more potent compounds with improved activities, selectivities and/or physical properties. We have been synthesizing natural products and their derivatives for the elucidation of their biological mechanisms and discovery of drug leads. This review describes three topics for developing functional compounds derived from natural products for prospective involvement in pharmaceutical research: 1) direct construction of the ergot alkaloid scaffold by palladium catalyzed domino cyclization of amino allenes; 2) identification of novel sphingosine kinase inhibitors through a structure-activity relationship study of jaspine B; and 3) design, synthesis and biological evaluation of novel CD1d glycolipid ligands containing modified lipid moieties.

Outcomes of treatment for malignant pediatric tumors including leukemia are improving by conventional multimodal treatment with strong chemotherapy, surgical resection, radiotherapy, and bone marrow transplantation. However, patients with advanced neuroblastoma, metastatic Ewing's sarcoma family of tumor (ESFT), and metastatic osteosarcoma continue to have an extremely poor prognosis. Therefore novel therapeutic strategies are urgently needed to improve their survival. Apoptotic cell death is a key mechanism for normal cellular homeostasis. Intact apoptotic mechanisms are pivotal for embryonic development, tissue remodeling, immune regulation, and tumor regression. Genetic aberrations disrupting programmed cell death often underpin tumorigenesis and drug resistance. Moreover, it has been suggested that apoptosis or cell differentiation proceeds to spontaneous regression in early stage neuroblastoma. Therefore apoptosis or cell differentiation is a critical event in this cancer. We extracted many compounds from natural plants (Angelica keiskei, Alpinia officiarum, Lycaria puchury-major, Brassica rapa) or synthesized cyclophane pyridine, indirubin derivatives, vitamin K3 derivatives, burchellin derivatives, and GANT61, and examined their effects on apoptosis, cell differentiation, and cell cycle in neuroblastoma and ESFT cell lines compared with normal cells. Some compounds were very effective against these tumor cells. These results suggest that they may be applicable as an efficacious and safe drug for the treatment of malignant pediatric tumors.

Because active-targeted liposomes are very complex formulations, quality characteristics of functional lipids have not been defined yet, and this is a major obstacle in clinical application of active targeted liposomes. We have developed high functionality and quality (HFQ) lipids, which define quality characteristics of functional lipids for clinical drug delivery system (DDS) applications. Because HFQ lipids are designed to enable facile and rapid functionalization of DDS carrier by simple and one-step mixing, we are expanding applications for not only liposomes but also exosomes and cells. Recently, we developed multi-color deep imaging by tissue clearing for analysis of spatial distribution of DDS in various tissues. Nanocarriers are usually non-uniformly distributed in solid tumors because of their heterogeneity. Especially, in refractory cancer such as pancreatic cancer, the presence of collagen and blood vessels greatly affects intra-tumor distribution of DDS carrier. Therefore information on spatial relations between the tissue structure and DDS carrier is important to regulate precisely intra-tumor distribution of DDS carrier. Recently, our group has established multi-color deep imaging to analyze spatial distribution of stromal collagen, liposomes, and blood vessels in pancreatic tumor tissue. In this review, we present recent research in developing HFQ lipids. Moreover, current status of research on DDS for pancreatic cancer treatment is reviewed.

Bioactive gas molecules, including oxygen, nitric oxide and carbon monoxide (CO), exhibit a variety of physiological activities, and are associated with the onset and progress of some disorders. These facts have led researchers to the development of bioactive gas donors for the treatment of intractable disorders. Hemoglobin is likely an ideal carrier of bioactive gases, since hemoglobin in red blood cells innately carries oxygen in the form of oxyhemoglobin, nitric oxide in the form of S-nitrosohemoglobin, and CO in the form of carbonylhemoglobin. In this study, we attempted to develop a biomimetic CO delivery system using a preparation of hemoglobin. Our strategy for the preparation of this hemoglobin-based CO carrier involves CO being exogenously bound to red blood cells or hemoglobin-encapsulated liposomes, called hemoglobin-vesicles (HbV), which mimic the structure and function of red blood cells. We accumulated evidence that the CO donors-CO-bound red blood cells and CO-bound HbV-showed therapeutic efficacy against intractable disorders in animal models. Here, we describe the potential of hemoglobin-based CO donors, especially CO-bound red blood cells and CO-bound HbV, for the treatment of certain disorders. Hemoglobin-based strategies for the delivery of other bioactive gases for novel drug development are also discussed.