589 results on '"DRUG development"'
Search Results
2. [Current Status and Issues in Drug Development for Rare Cancers].
- Author
-
Kashitani Y, Takayama H, Hamada N, Go S, Tagami M, and Sugihara T
- Subjects
- Humans, Orphan Drug Production, Rare Diseases drug therapy, Drug Development, Drug Approval, Neoplasms drug therapy, Antineoplastic Agents therapeutic use
- Abstract
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.
- Published
- 2023
3. [Drug Development Based on PPAR-ligand Structural Studies].
- Author
-
Ishii I
- Subjects
- Ligands, Peroxisome Proliferator-Activated Receptors, Drug Development
- Published
- 2022
- Full Text
- View/download PDF
4. [Chimeric mouse with humanized liver, an emerging tool for the drug development].
- Author
-
Shimada T
- Subjects
- Mice, Humans, Animals, Mice, SCID, Drug Development, Liver, Hepatocytes
- Abstract
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.- Published
- 2023
- Full Text
- View/download PDF
5. [The Charm of Protein for Drug Development].
- Author
-
Ishima Y and Taguchi K
- Subjects
- Animals, Humans, Drug Development methods, Drug Development trends, Proteins
- Published
- 2020
- Full Text
- View/download PDF
6. [Strategy of Drug Development Based on the Bioactive Gas-carrying Capacity of Hemoglobin].
- Author
-
Taguchi K, Matsumoto K, Maruyama T, and Otagiri M
- Subjects
- Erythrocytes metabolism, Humans, Carbon Monoxide metabolism, Drug Development, Hemoglobins metabolism, Nitric Oxide metabolism, Oxygen metabolism
- Abstract
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.
- Published
- 2020
- Full Text
- View/download PDF
7. [Challenges in Drug Development Targeting Anti-atherosclerotic Proteins].
- Author
-
Okuhira K
- Subjects
- Apolipoprotein A-I physiology, Cardiovascular Diseases etiology, Cardiovascular Diseases prevention & control, Humans, Protein Binding, ATP-Binding Cassette Transporters physiology, Atherosclerosis prevention & control, Cholesterol, HDL metabolism, Drug Development
- Abstract
Atherosclerosis is a vascular disease responsible for acute heart attacks and stroke, which are leading causes of death not only in industrialized countries but also worldwide, and the number of patients afflicted by this disease has been increasing in Japan. High-density lipoprotein (HDL) is the plasma lipoprotein that carries what is often called your "good cholesterol" through the blood. This good cholesterol moniker is associated with HDL because higher circulating levels of this lipoprotein are associated with a well-known reduction in the risk of arteriosclerosis. Moreover, many protective mechanisms by which HDL could reduce atherosclerosis are described, including reverse cholesterol transport, along with anti-oxidant, anti-inflammatory and anti-thrombosis activities. However, HDL-modulating therapies to lower cardiovascular risk are not yet available. It has recently been proposed that apolipoprotein A-I (apoA-I) binding protein (AIBP) enhances HDL function by accelerating lipid release from cells and reducing associated inflammatory processes. In this context, our research is focused on the function of HDL-related proteins, such as proteins that regulate HDL production (ATP-binding cassette transporters), and HDL-binding proteins. We expect that these studies could eventually help in the development of HDL-related prognostic and therapeutic strategies to reduce the burden of cardiovascular disease in the future.
- Published
- 2020
- Full Text
- View/download PDF
8. [Drug Development Based on Intracellular Pharmacokinetic Analysis of Molecular Target Drug in Mice Bearing Patient-derived Xenograft Model].
- Author
-
Hamada A
- Subjects
- Animals, Disease Models, Animal, Heterografts, Humans, Mice, Tissue Distribution, Tumor Microenvironment, Antineoplastic Agents pharmacokinetics, Drug Development, Molecular Targeted Therapy, Neoplasm Transplantation, Neoplasms drug therapy
- Abstract
Traditionally, anticancer drug discovery research has been conducted based on immortalized cancer cell lines, either cultured in vitro or grown in vivo. In the USA and Europe, patient derived xenograft (PDX) model is rapidly expelling traditional in vitro and in vivo models due to the good predictability of clinical outcome and its nature of retaining characteristics and heterogeneity in the original tumor. Furthermore, a significant association was also reported between drug responses in patient and corresponding PDX as high as 87%. We are preparing a PDX model for Japanese cancer patients including drug resistance examples and rare cancers. Using the established PDX model, we confirmed the possibility that the tumor microenvironment might affect the efficacy and distribution of drugs even if the target receptor is expressed in tumor sites as compared to the cell line (CDX) model, which has been widely used in drug discovery. Interestingly, although expressing a target receptor in viable tumor cells, we also have found a PDX model with a lower distribution of molecular target drug. Therefore we will evaluate the usefulness of the PDX model in drug development by exploring new biomarkers and elucidating the mechanisms of drug resistance in target tumors. Moreover, pharmaco-imaging system will allow us to visualize the exposure and distribution of drugs in tumors at macro and micro levels. Finally, we evaluate relations between distribution of drugs in the tumor microenvironment including target tumor cells, neovessels, stromal cells, immune cells, and fibroblasts.
- Published
- 2020
- Full Text
- View/download PDF
9. [Progressing Basic Immunology for Development of New Therapeutic Medicines].
- Author
-
Kashiwakura JI and Nishida K
- Subjects
- Humans, Animals, Allergy and Immunology, Drug Development
- Published
- 2024
- Full Text
- View/download PDF
10. [Approach for Producing New 3,3,3-Trifluoropropenylation Reagents: Introduction of a 3,3,3-Trifluoroprop-1-enyl Group for Drug Development].
- Author
-
Ikeda A
- Subjects
- Acetylene chemistry, Cyclization, Drug Design, Halogenation, Indoles chemistry, Molecular Conformation, Allyl Compounds chemistry, Drug Development, Indicators and Reagents chemical synthesis, Indomethacin analogs & derivatives, Indomethacin chemical synthesis
- Abstract
The chemistry of the 3,3,3-trifluoroprop-1-enyl (TFPE) group has attractive characteristics in medicinal chemistry as a new fluorine motif. However, there are no reports on the properties of this group because it is difficult to construct molecules with it. For the convenient construction of the TFPE group, a new fluorination reagent, CF
3 CH=CHTMS (1), was developed from commercially available chemicals with easy purification processes and excellent yields. The utility of 1 as a trifluoropropenylation reagent was exhibited in several types of reaction such as the Sonogashira cross-coupling reaction. Furthermore an indometacin analogue bearing a TFPE group showed greater pharmaceutical activity than the original indometacin. This review describes the details of these research studies under three topics: 1) synthesis of 1; 2) Sonogashira cross-coupling reaction of 1 with acetylene, followed by cyclization into an indole ring; and 3) synthesis of an indometacin analogue with a TFPE group.- Published
- 2019
- Full Text
- View/download PDF
11. [Toward precision medicine new modalities for challenging targets in drug development as a protein degradation mediated by chemical knockdown].
- Author
-
Miyamoto-Sato E
- Subjects
- Drug Development, Precision Medicine, Proteolysis
- Published
- 2019
- Full Text
- View/download PDF
12. [Ⅳ. Current Understanding of Mechanism of BCG Failure, and the Status of Drug Development Using BCG Cell Wall Components].
- Author
-
Shiga M and Nishiyama H
- Subjects
- Cell Wall, Drug Development, Humans, BCG Vaccine adverse effects, Urinary Bladder Neoplasms
- Published
- 2022
13. [In vivo integrated safety assessment of the cardiovascular system in drug development].
- Author
-
Chiba K
- Subjects
- Drug Development, Drug Evaluation, Preclinical, Electrocardiography, Heart, Cardiovascular System
- Abstract
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.
- Published
- 2022
- Full Text
- View/download PDF
14. [Inclusion Solves Insolubility -Translational Research Cycle from Bedside to Bench and Bench to Bedside for Drug Development Targeting Niemann-Pick Disease Type C].
- Author
-
Irie T
- Subjects
- 2-Hydroxypropyl-beta-cyclodextrin, Animals, Drug Development, Humans, Mice, Translational Research, Biomedical, Niemann-Pick Disease, Type C drug therapy, Niemann-Pick Disease, Type C genetics, beta-Cyclodextrins
- Abstract
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.
- Published
- 2022
- Full Text
- View/download PDF
15. [PMDA's Initiatives to Encourage the New Drug Development for Rare Cancers].
- Author
-
Takahashi H and Yaginuma H
- Subjects
- Humans, United States, Orphan Drug Production, Drug Approval, Neoplasms drug therapy, Antineoplastic Agents therapeutic use, Hematologic Neoplasms drug therapy
- Abstract
Rare cancers, estimated to account for 15% of all cancers, have many unmet medical needs, but at the same time, developing treatments for these cancers is fraught with difficulties. PMDA's efforts to promote and support the development of treatments for rare cancers include the development consultation to meet the needs of emerging biopharma(EBP), promotion of development through multi-regional clinical trials, and development support for investigator-initiated clinical trials. In addition, the development environment for rare cancers and rare subtypes has been improved through the revision of clinical evaluation guidelines, consultation programs and guidance publication for the utilization of RWDs, and the accumulation of tissue-agnostic cancer drug approvals. Regarding the Orphan Drug Designation System, about one-third of the 267 drugs designated during the 15-year period from 2004-2018 were anti-cancer drugs. Looking at the approvals of anti-cancer drugs during the past 10 years(2013-2022), 26%(53/203)of drugs for solid tumors and 60%(62/104)of drugs for hematologic tumors received orphan drug designation. Regulatory measures that support the development for rare cancers include not only the Orphan Drug Designation but also the Conditional Accelerated Approval, which facilitates the development of drugs for diseases where timely conduct of a confirmatory clinical trial is difficult, and the Sakigake Designation that allows the accelerated approval of innovative new drugs. PMDA will continue its efforts to promote drug development in response to changes of the circumstances surrounding drug development as well as developer's need and will make further efforts to disseminate information of those measures both domestically and internationally.
- Published
- 2023
16. [Latest information about drug development of hepatitis B and future prospect].
- Author
-
Kato N
- Subjects
- Hepatitis B virus, Humans, Antiviral Agents therapeutic use, Drug Development, Hepatitis B drug therapy
- Published
- 2018
- Full Text
- View/download PDF
17. [Ⅲ. Early Phase Drug Development and Precision Medicine for Osteosarcoma].
- Author
-
Iwata S
- Subjects
- Cell Line, Tumor, Drug Development, Humans, Precision Medicine, Bone Neoplasms drug therapy, Osteosarcoma drug therapy
- Published
- 2021
18. [Exploring for Drug Development Seeds for Children Using a Large Claims Data-Survey for Powderization or Decapsulation of Oral Tablets or Capsule Formula in Children].
- Author
-
Momo K, Kobayashi M, and Sasaki T
- Subjects
- Humans, Child, Tablets, Japan, Prescriptions
- Abstract
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.
- Published
- 2023
- Full Text
- View/download PDF
19. [Chemical Approaches for RNAi Drug Development].
- Author
-
Saito-Tarashima N
- Subjects
- DNA, Immunity, Innate, Oligonucleotides chemistry, Protein Interaction Domains and Motifs, RNA, Small Interfering chemistry, RNAi Therapeutics, Tubercidin chemistry, Drug Development methods, RNA Interference, RNA, Small Interfering chemical synthesis
- Abstract
RNA interference (RNAi) is the standard method of suppressing gene expression because of its target specificity, potency, and ability to silence the expression of virtually any gene. Using 21-mer small interfering RNA (siRNA) is the general approach for inducing RNAi, as siRNA can be easily prepared using a DNA/RNA synthesizer. Synthetic siRNA can be chemically modified to increase the potency of RNAi activity and abrogate innate immune stimulation. However, designing chemically modified siRNA requires substantial experimentation. A practical method for understanding the interaction of siRNA and RNAi-related proteins and how modifications affect RNA-protein interactions is therefore needed. Plasmid DNA (pDNA) expressing short hairpin RNA (shRNA) can also be used to induce RNAi. pDNA produces numerous shRNAs that induce RNAi with potent and longterm RNAi activity, even if only one pDNA molecule is delivered to the nucleus. However, this approach has some drawbacks with regard to its therapeutic application, such as a low pDNA transfection efficiency due to its huge molecular size and innate immune responses induced by extra genes, such as CpG motifs. To overcome these issues with RNAi inducers (siRNA and pDNA), our group developed some chemical approaches using chemically modified oligonucleotides. This article focuses on our two original approaches. The first involves the groove modification of siRNA duplexes to understand siRNA-protein interactions using 7-bromo-7-deazaadenosine and 3-bromo-3-deazaadenosine as chemical probes, while the second involves the generation of RNAi medicine using chemically modified DNA, known as an intelligent shRNA expression device (iRed).
- Published
- 2020
- Full Text
- View/download PDF
20. History and Current status of antibacterial drug development-Fighting drug-resistant bacteria-
- Author
-
Saeki, Kozo
- Subjects
antibacterial ,薬剤耐性 ,コリスチン ,drug resistance ,deep-sea ,actinomycetes ,抗菌薬 ,放線菌 ,colistin ,深海 - Abstract
抗菌薬の登場により感染症治療は大きく進歩し,これまでに多様な抗菌薬が開発されてきたが同時に薬剤耐性菌の発生という問題も生じた。薬剤耐性菌は多剤耐性菌も含めて世界中で蔓延し最後の砦であるコリスチンへの耐性化も危惧される一方で,抗菌薬開発の採算性の低さや創薬ターゲットの枯渇から抗菌薬の承認数は1980年代をピークに2010年まで顕著に低下している。しかし抗菌薬開発を促進するプログラムや法律が施行され近年では抗菌薬開発は持ち直しつつあり,創薬ターゲットについても,深海放線菌からメシチリン耐性黄色ブドウ球菌に抗菌活性を示す新たな物質が見出されるなど,未知の環境の微生物が期待されている。, With the advent of antibacterial drugs, the treatment of infectious diseases has made great progress, and various antibacterial drugs have been developed so far, but the problem of drug-resistant bacteria has arisen. Drug-resistant bacteria, including multidrug-resistant bacteria, are widespread all over the world and there is concern that they will become resistant to colistin, which is the last fort antibacterial drug. Antibacterial drug development is not profitable and drug discovery targets are depleted. The number of approvals peaked in the 1980s and has declined significantly until 2010. However, antibacterial drug development has been picking up in recent years due to the enforcement of programs and laws that promote antibacterial drug development, and new substances showing antibacterial activity from deep-sea actinomycetes to methicillin-resistant Staphylococcus aureus have been found. Microorganisms in an unknown environment are expected as new drug discovery targets.
- Published
- 2022
21. [Current progress of research and use of microminipigs in drug development].
- Author
-
Nakamura K and Otake M
- Subjects
- Animals, Female, Humans, Pregnancy, Swine, Swine, Miniature, Drug Development trends, Models, Animal, Research trends
- Abstract
The use of minipigs has been increasing in the areas of pharmacology researches and drug development. The microminipig developed by Fuji Micra Inc. (Shizuoka, Japan) inherits characteristics of other pig strains showing several similarities to humans in anatomy, physiology, omnivorousness and diurnal, but at the same time has several advantages over other pig strains because of its small size which allows easy keeping, handling and dosing, and saving of test substances. The microminipig weighs about 10 kg at the age of 6 months. Canine cages can be used to keep the animal. Swine leukocyte antigens (SLA) are defined in each individual animal which is useful for testing immunological reactions. As there are many similarities in metabolic enzymes and transporters to those in humans, the microminipig is a powerful animal model for toxicokinetic studies. Unfortunately as in other minipigs the microminipig is not appropriate for embryo-fetal development studies of antibody drugs due to its poor placental transfer, but can be used for other reproductive and developmental studies. Repeat dose toxicity, safety pharmacology, immunotoxicity and local tolerance studies should be also other arenas of this animal model.
- Published
- 2018
- Full Text
- View/download PDF
22. Pathophysiological functions of macrophages in sensory ganglia and a perspective of drug development against skeletal pain
- Author
-
Iori, Takashi, Sato, Takanori, Lee, Jiwon, Kitagawa, Yoshimasa, and Iimura, Tadahiro
- Published
- 2022
23. Prospects for antifungal drug development by drug repurposing
- Published
- 2021
24. Current Status of Drug Development and Legal Issues of Generic Medicine: Focusing on Patent Linkage
- Abstract
Article, 【論説/Articles】
- Published
- 2021
25. [Prospects and Challenges of Anti-VEGF Drug Treatment for Pathological Angiogenesis of the Retina].
- Author
-
Nakamura S and Hara H
- Subjects
- Animals, Diabetic Retinopathy etiology, Diabetic Retinopathy pathology, Humans, Macular Degeneration etiology, Macular Degeneration pathology, Mice, Molecular Targeted Therapy, Retinal Vein Occlusion etiology, Retinal Vein Occlusion pathology, Vascular Endothelial Growth Factor A physiology, Angiogenesis Inhibitors therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Aptamers, Nucleotide therapeutic use, Diabetic Retinopathy drug therapy, Drug Development, Macular Degeneration drug therapy, Neovascularization, Pathologic, Ranibizumab therapeutic use, Receptors, Vascular Endothelial Growth Factor therapeutic use, Recombinant Fusion Proteins therapeutic use, Retina pathology, Retinal Vein Occlusion drug therapy, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
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.
- Published
- 2021
- Full Text
- View/download PDF
26. Proposal for orphan drug development based on a survey on recent re-examination reports of approved products in Japan
- Published
- 2020
27. [Current status and perspectives in the development of therapeutic agents targeting post-ischemic inflammation in the acute stage of stroke].
- Author
-
Shimamura M, Nakagami H, Sasaki T, Morishita R, and Mochizuki H
- Subjects
- Animals, Haplorhini, Humans, Molecular Targeted Therapy, Receptor Activator of Nuclear Factor-kappa B, Toll-Like Receptors, Drug Development, Stroke drug therapy, Stroke etiology, Translational Research, Biomedical
- Abstract
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.
- Published
- 2020
- Full Text
- View/download PDF
28. [Research on Analysis of Final Diagnosis and Prognostic Factors, and Development of New Therapeutic Drugs for Malignant Tumors (Especially Malignant Pediatric Tumors)].
- Author
-
Suzuki T
- Subjects
- Apoptosis, Cell Differentiation, Child, Child, Preschool, Genes, Tumor Suppressor, Humans, Infant, Leukemia drug therapy, Leukemia pathology, Neoplasms pathology, Plant Extracts, Prognosis, Drug Development, Neoplasms diagnosis, Neoplasms drug therapy
- Abstract
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.
- Published
- 2020
- Full Text
- View/download PDF
29. [Development of Nano-DDS Carriers for Control of Spatial Distribution Using Multi-color Deep Imaging].
- Author
-
Kawakami S and Suga T
- Subjects
- Humans, Pancreatic Neoplasms metabolism, Drug Carriers, Drug Delivery Systems methods, Drug Development, Liposomes, Molecular Imaging methods, Nanoparticles, Tissue Distribution
- Abstract
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.
- Published
- 2020
- Full Text
- View/download PDF
30. [Development of New Neurotrophic Compounds Based on Talaumidin].
- Author
-
Harada K
- Subjects
- Animals, Humans, Nerve Regeneration drug effects, Neuronal Outgrowth drug effects, Optic Nerve physiology, Rats, Structure-Activity Relationship, Drug Development, Furans pharmacology
- Abstract
(-)-2S,3S,4S,5S-Talaumidin (1) exhibits potent neurotrophic activities such as neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in nerve growth factor (NGF)-differentiated PC12 cells. To examine the stereochemistry-activity relationship of 1, systematic syntheses of seven stereoisomers of 1 were accomplished via Evans aldol reaction, diastereoselective hydroboration, and Mitsunobu reaction. All stereoisomers showed moderate-to-potent neurite-outgrowth promotion in NGF-differentiated PC12 cells. In particular, (-)-2S,3R,4S,5R-1e having all-cis-substituted configuration exhibited the most significant neurite-outgrowth promotion. Subsequently, we developed a short-step synthetic route for talaumidin derivatives so as to explore new neurotrophic compounds that could be obtained on a large scale. First, we synthesized derivative 2a, which is a racemic compound of (-)-1e, and compared its neurotrophic activity with (-)-1e. It was found that the neurotrophic activity of racemic 2a was similar to that of (-)-1e. Using the same synthetic route, several talaumidin derivatives were synthesized to optimize the oxy-functionality on aromatic rings. Thereby, bis(methylenedioxybenzene) derivative 2b was found to exhibit the highest neurotrophic activity. In addition, examination of the structure-activity relationship of 2b indicated that the 2,5-diphenyl structure was crucial moiety, and the two methyl groups on the tetrahydrofuran (THF) ring could enhance the neurotrophic activity. Furthermore, 2a and 2b were found to induce mouse optic nerve regeneration in vivo.
- Published
- 2020
- Full Text
- View/download PDF
31. [Mechanism of Taurohyodeoxycholate-induced Biliary Phospholipid Efflux -Understanding the Function of the ABCB4 Enhancer for Developing Therapeutic Agents against Bile Salt-induced Liver Injury].
- Author
-
Ikeda Y
- Subjects
- Animals, Chemical and Drug Induced Liver Injury, Chronic drug therapy, Cholesterol pharmacology, HEK293 Cells, Hepatocytes metabolism, Humans, Mice, Knockout, Phosphatidylcholines metabolism, Taurodeoxycholic Acid pharmacology, ATP Binding Cassette Transporter, Subfamily B physiology, Bile metabolism, Bile Acids and Salts adverse effects, Chemical and Drug Induced Liver Injury, Chronic etiology, Chemical and Drug Induced Liver Injury, Chronic genetics, Drug Development, Phosphatidylcholines pharmacology, Phospholipids metabolism, Taurodeoxycholic Acid analogs & derivatives
- Abstract
Biliary lipids primarily consist of bile salts, phospholipids, and cholesterol. Bile salts have potent detergent properties and deleterious effects on the cell membrane and are cytotoxic to hepatocytes. We have previously reported that phosphatidylcholine (PC), the predominant bile phospholipid, protects hepatocytes from the cytotoxicity of bile salts, whereas cholesterol reverses the cytoprotective effects of PC against bile salts. ABCB4, a member of the ATP-binding cassette transporter family, secretes biliary phospholipids, especially PC, from the hepatocytes into the bile. Using Abcb4 knockout mice and HEK293 cells that stably expressed ABCB4, we examined the effects of taurine- or glycine-conjugated cholate, ursodeoxycholate, and hyodeoxycholate on the ABCB4-mediated efflux of PC. We observed that the biliary secretion of PC in wild-type mice significantly increased following infusion of all the tested bile salts, especially taurohyodeoxycholate. On the other hand, the biliary secretion of PC in Abcb4 knockout mice was not affected by the bile salt infusions. The results also demonstrated that the efflux of PC from ABCB4-expressing HEK293 cells was significantly stimulated by taurohyodeoxycholate, which has a strong potential to form mixed micelles with PC. Furthermore, the results of our study emphasized the possibility that the specific interactions of bile salts with ABCB4 are necessary for the release of PC molecules from the binding pocket of ABCB4 into the aqueous environment. Further understanding of this mechanism will aid in the development of novel therapeutic agents for cholestatic liver diseases.
- Published
- 2020
- Full Text
- View/download PDF
32. [Membrane Transporters and Their Regulatory Mechanisms at the Brain and Retinal Barriers to Establish Therapies for Refractory Central Nervous System Diseases].
- Author
-
Akanuma SI
- Subjects
- Animals, Central Nervous System Diseases drug therapy, Connexin 43 metabolism, Dinoprostone metabolism, Excitatory Amino Acid Transporter 1 metabolism, Glutamic Acid metabolism, Humans, Mice, Molecular Targeted Therapy, Multidrug Resistance-Associated Proteins metabolism, Organic Anion Transporters, Sodium-Independent metabolism, Biological Transport, Blood-Brain Barrier metabolism, Blood-Retinal Barrier metabolism, Brain metabolism, Central Nervous System Diseases etiology, Central Nervous System Diseases metabolism, Drug Development, Membrane Transport Proteins metabolism, Retina metabolism
- Abstract
The central nervous system (CNS) is segregated from the circulating blood and peripheral tissues by endothelial and epithelial barriers. To overcome refractory CNS diseases, it is important to understand the membrane transport systems of drugs and the endogenous compounds that relate to the pathogenesis of CNS diseases at these barriers. The endothelial barrier in the brain is the blood-brain barrier (BBB). Our studies clarified the efflux transport of prostaglandin E
2 (PGE2 ), a modulator of neural excitation and inflammatory responses, across the BBB via plasma membrane transporters such as organic anion transporter 3 (Oat3) and multidrug resistance-associated protein 4 (Mrp4). This efflux transport was attenuated by peripheral inflammation or cerebral treatment with neuroexcitatory l-glutamate, suggesting that BBB-mediated PGE2 elimination was altered under several pathological conditions. We also examined excitatory amino acid transporter (EAAT) 1 and 3 as l-glutamate efflux transporters of the inner blood-retinal barrier (BRB) and blood-cerebrospinal barrier. It was considered that these efflux membrane transporters participated in the homeostasis of neuroexcitatory and neuroinflammatory responses in the brain and retina. Moreover, we identified connexin 43 (Cx43) hemichannels as a new membrane transport system that is activated under pathological conditions and recognizes several monocarboxylate drugs, such as valproate. As it is expected that the action of these membrane transporters across the CNS barriers is of great importance in understanding the pathology of various neuroexcitatory diseases, our studies should contribute to the establishment of therapeutic strategies for refractory CNS diseases.- Published
- 2020
- Full Text
- View/download PDF
33. [Development of DDS Actively to Overcome the Blood-brain Barrier in the Region of Ischemic Stroke].
- Author
-
Fukuta T and Kogure K
- Subjects
- Humans, Permeability, Protein Transport, Reperfusion Injury drug therapy, Reperfusion Injury metabolism, Blood-Brain Barrier metabolism, Drug Delivery Systems, Drug Development, Leukocytes, Liposomes metabolism, Membrane Proteins metabolism, Neuroprotective Agents administration & dosage, Stroke drug therapy, Stroke metabolism
- Abstract
We previously showed that increased permeability of the blood-brain barrier (BBB) after ischemic stroke enables extravasation of nano-sized liposomes and accumulation in the ischemic region, and that delivery of neuroprotective agents using liposomal drug delivery systems (DDS) is applicable for treating cerebral ischemia/reperfusion (I/R) injury. However, entry of liposomes into the brain parenchyma was limited in the early stages after I/R possibly due to microvascular dysfunction induced by pathological progression. As such, new approaches to overcome the BBB are needed. Leukocytes can pass through inflamed BBB in I/R region due to membrane proteins displayed on their surface. We thus hypothesized that incorporation of leukocyte membrane proteins onto liposomal membranes would impart leukocyte-mimicking functions to liposomes and that leukocyte-mimetic liposomes (LM-Lipo) may pass through inflamed endothelial cells and BBB, similar to leukocytes. LM-Lipo prepared using intermembrane protein transfer from human leukemia cells showed significantly increased association to inflamed human umbilical vein endothelial cells relative to plain liposomes. Moreover, LM-Lipo passed through inflamed endothelial cell layer by regulating intercellular junctions. These results suggest that imparting leukocyte-like properties to liposomes via intermembrane protein transfer would be an effective strategy to overcome inflamed endothelial barriers. In this review, we describe our findings on ischemic stroke treatment using liposomal DDS and the potential of LM-Lipo to overcome inflamed endothelial barriers.
- Published
- 2020
- Full Text
- View/download PDF
34. [Medicinal Chemical Studies Based on the Theoretical Design of Bioactive Compounds].
- Author
-
Shuto S
- Subjects
- Calcium metabolism, Cyclopropanes chemical synthesis, Enzyme Inhibitors, Glucose chemistry, Ligands, Molecular Conformation, Organic Chemistry Phenomena, Peptides, Cyclic chemistry, Peptidomimetics, Stereoisomerism, Cyclic ADP-Ribose chemistry, Cyclopropanes chemistry, Drug Design, Drug Development, Inositol 1,4,5-Trisphosphate chemistry
- Abstract
I have engaged in medicinal chemical studies based on the theoretical design of bioactive compounds. First, I present a three-dimensional structural diversity-oriented conformational restriction strategy for developing bioactive compounds based on the characteristic steric and stereoelectronic features of cyclopropane. Using this strategy, various biologically active small molecule compounds, such as receptor agonists/antagonists and enzyme inhibitors, were effectively developed. The strategy was also applied to develop versatile peptidomimetics and membrane-permeable cyclic peptides. Next, studies on Ca
2+ -mobilizing second messengers, cyclic ADP-ribose (cADPR) and myo-inositol trisphosphates (IP3 ), are described. In these studies, stable equivalents of cADPR were developed, since biological studies of cADPR have been limited due to its instability. Various potent IP3 receptor ligands, which were designed using the d-glucose structure as a bioisostere of the myo-inositol moiety of IP3 , have been identified. Organic chemistry studies have also been extensively performed, because excellent organic chemistry is essential for promoting high-level medicinal chemical studies. For examples, new methods for the synthesis of chiral cyclopropanes, new radical reactions with silicon tethers, and kinetic anomeric effect-dependent stereoselective glycosidations have been developed.- Published
- 2020
- Full Text
- View/download PDF
35. [Development of Vaccines with Self-assembled Carriers That Deliver Drugs to Target Organs].
- Author
-
Kurosaki T
- Subjects
- Animals, Humans, Mice, Nanoparticles, Polymers, Cancer Vaccines, Drug Carriers, Drug Development, Gene Transfer Techniques, Polyglutamic Acid analogs & derivatives, Vaccines, DNA
- Abstract
I have developed novel ternary complexes of various vaccines with cationic materials and anionic polymers. Plasmid DNA (pDNA) encoding firefly luciferase was used as a model drug to form adequate ternary complexes. Cationic binary complexes were constructed using pDNA and polyethylenimine, and these binary complexes were coated with various anionic polymers to form ternary complexes. These ternary complexes significantly improved cytotoxicity and aggregation with erythrocytes in comparison to the binary complexes. On the other hand, most of those ternary complexes showed little in vitro transgene efficiency because of their anionic surface charge. γ-Polyglutamic acid (γ-PGA)-ternary complexes, however, demonstrated high in vitro transgene efficiency. After the intravenous administration of γ-PGA-ternary complexes to mice, extremely high gene expression was detected in the marginal zone of the spleen, which is rich in antigen-presenting cells. This spleen-specific phenomenon of γ-PGA-ternary complexes appeared to be suited to DNA vaccines against cancer. I therefore examined the preventive effect of γ-PGA-ternary complexes containing pUb-M, a pDNA encoding melanoma surface antigen, against melanoma-bearing mice. Vaccinations of γ-PGA-ternary complexes into mice significantly suppressed the tumor growth of B16-F10 melanoma cells subcutaneously injected into the mice. In the same manner, vaccinations of γ-PGA-ternary complexes containing ovalbumin (OVA) completely suppressed the growth of E.G7-OVA cells expressing OVA. These results strongly suggest that γ-PGA-ternary complexes are useful in the manufacture of specific tumor vaccines.
- Published
- 2020
- Full Text
- View/download PDF
36. [Semi-rational Design of Target-binding Small Proteins for Cancer Treatment].
- Author
-
Kadonosono T and Kizaka-Kondoh S
- Subjects
- Antibodies, Monoclonal, Humanized, Humans, Molecular Targeted Therapy, Protein Binding, Receptor, ErbB-2, Trastuzumab, Antibodies, Monoclonal, Antineoplastic Agents, Drug Development, Molecular Dynamics Simulation
- Abstract
Small proteins that have a high affinity for cancer cell surface markers can be promising cheap alternatives to antibodies (antibody mimetics). Various types of antibody mimetics have thus been extensively developed. We recently found that a target-binding peptide binds to its target molecule more strongly when it is structurally constrained. To apply this finding to the development of chemically synthesizable small antibody mimetics, we have established an efficient method of creating such proteins, named fluctuation-regulated affinity proteins (FLAPs). To identify desirable scaffolds, first, 13 human proteins (46-104 aa) were selected from the Protein Data Bank. Then, thirteen graft acceptor (GA) sites that efficiently immobilize the grafted peptide structure were identified from six small protein scaffolds using molecular dynamics simulation. To assess the designed antibody mimetics in vitro, human epidermal growth factor receptor 2 (HER2)-binding peptides were selected from the anti-HER2 antibody drugs trastuzumab and pertuzumab by calculating the binding energy, and these were then grafted into the GA sites of scaffolds to create 65 FLAP candidates. The FLAP candidates were expressed in bacteria as fusion proteins with Renilla luciferase (Rluc), and their relative binding affinity to HER2 was easily determined by measuring the Rluc bioluminescence intensity without protein purification. Finally, four out of the 65 showed specific binding to HER2 with a dissociation constant (K
D ) of 24-65 nM, and these were used for the detection of HER2-expressing cancer cells. Our design strategy will promote the development of antibody mimetics for the effective treatment of cancers and other diseases.- Published
- 2020
- Full Text
- View/download PDF
37. [Study of the Mechanisms of Maintaining the Transparency of the Lens and Treatment of Its Related Diseases for Making Anti-cataract and/or Anti-presbyopia Drugs].
- Author
-
Nakazawa Y
- Subjects
- Hydrostatic Pressure, Lens, Crystalline metabolism, Oxidation-Reduction, Presbyopia etiology, Sodium-Potassium-Exchanging ATPase metabolism, Sodium-Potassium-Exchanging ATPase physiology, TRPV Cation Channels physiology, Aquaporins physiology, Cataract drug therapy, Cataract etiology, Drug Development, Eye Proteins physiology
- Abstract
The lens of the eye is an avascular and anuclear tissue that serves to focus objects on the retina. Cataract is opacity within the clear lens that changes the transparency and refractive index of the lens causing significant visual impairments. These impairments can severely restrict the ability to carry out daily activities. Cataracts is common among elderly person occurring in more than 80% of patients aged 80 or older. Notably, we have recently identified key compounds that are effective against cataract formation. Presbyopia is also an ocular disease that typically develops in people over the age of 45 while affecting almost 100% of people over the age of 65. Recent research suggests that age-related changes in hydrostatic pressure of the lens controlled by Na/K ATPase contribute to the development of presbyopia. In the lens, Na/K ATPase has been shown to be regulated by transient receptor potential cation channels, vanilloid 1 (TRPV1) and 4, thus suggesting the potential role of TRPV1 and TRPV4 in the development of presbyopia. This review article summarizes data obtained from our laboratory with my colleagues highlighting the critical role of aquaporin 0 (AQP0) in maintaining a healthy lens redox environment, key molecules that delay the onset of cataract in vivo, as well as potential mechanisms of lens hydrostatic pressure control that may be associated with presbyopia.
- Published
- 2020
- Full Text
- View/download PDF
38. [Development of Medicines for Infectious Diseases -Malaria].
- Author
-
Kita K
- Subjects
- Animals, Antiparasitic Agents, Antiviral Agents, Helminthiasis, Hemorrhagic Fever, Ebola, Humans, Neglected Diseases, Trypanosomiasis, Antimalarials, Drug Development, Malaria
- Abstract
In developed countries, it is said that "threats of infectious diseases are already thought as things of the past". However, as you can see in the case of Ebola hemorrhagic fever that occurred in West Africa, this is a big mistake. Among infectious diseases, only smallpox has been successfully eradicated worldwide. In addition to the three major infectious diseases of HIV/AIDS, tuberculosis, and malaria, there is another group called emerging and reemerging infectious diseases. Recently, neglected tropical diseases (NTDs) have been listed as threats by the WHO, as have drug-resistant bacteria. The spread of these pathogens is increasing due to an increase in global travel. Malaria and more than half of the NTDs are parasitic diseases, such as trypanosomiasis and soil-borne helminthiasis. These are caused by parasites, with eukaryotes similar to their host mammals. In the case of these NTDs, protective immune responses induced by differences between a pathogen and host do not work well, and there is no vaccine against parasites. As for drugs developed to treat these diseases, because the properties of enzymes and target receptors are very similar, and effective drugs simultaneously show efficacy against both the disease and the host, severe side effects often occur. Therefore, the search for targets specifically present in parasites, and screening for drugs that inhibit their physiological functions, is extremely important. Here, as an example of the development of antiparasitic drugs, I will introduce a study on malaria.
- Published
- 2020
- Full Text
- View/download PDF
39. [Unraveling the Pathogenesis of Inflammatory Bowel Disease and Search for New Therapeutic Medicines].
- Author
-
Hayashi S
- Subjects
- Humans, Inflammatory Bowel Diseases immunology, Interleukin-10 immunology, Interleukin-10 metabolism, Intestinal Mucosa immunology, Macrophages immunology, Drug Development, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases etiology
- Abstract
The breakdown of the intestinal mucosal barrier has been shown to play a key role in the pathogenesis of intestinal immune-related disorders such as inflammatory bowel disease (IBD). IBD is a chronic inflammatory disorder with intermittent episodes of remission and relapse, and the incidence of IBD in Japan has risen dramatically in recent decades. Although sustained clinical remission has recently been recognized as an important goal of IBD therapy, there are not many treatment options to maintain long-term remission. Intestinal macrophages play pivotal roles in the regulation of immune homeostasis and inflammation in the intestine. Resident intestinal macrophages can regulate themselves and other immune cells, primarily through the spontaneous secretion of interleukin-10 (IL-10). We reported that the enhancement of IL-10 production by intestinal macrophages has the potential to be a novel therapeutic mechanism for maintaining the remission of IBD. Thus, to develop new therapeutic medicines for IBD, we screened the Wakanyaku Library derived from medicinal herbs for the ability to enhance IL-10 production by intestinal macrophages. Some compounds were identified with the potential to enhance IL-10 production by intestinal macrophages and thereby maintain long-term remission in IBD. This review focuses on our recent findings on the role of intestinal macrophages in the pathogenesis of IBD and developing a novel therapeutic strategy aimed at maintaining remission in IBD.
- Published
- 2020
- Full Text
- View/download PDF
40. [Development of Cancer-targeted Theranostics Probes Based on the Physicochemical Properties of Water-soluble Macromolecules].
- Author
-
Sano K
- Subjects
- Drug Delivery Systems, Solubility, Antineoplastic Agents, Chemical Phenomena, Drug Development, Macromolecular Substances chemistry, Theranostic Nanomedicine, Water
- Abstract
Water-soluble macromolecules, such as polymers and monoclonal antibodies, have some advantages, including high water solubility, high biocompatibility, a wide range of molecular weights, and amenability to easy modification through the terminal attachment of functional groups. Although there are many instances in which water-soluble polymers are used as solubilizers and stabilizing agents in the medical sciences, the possibility of water-soluble polymers themselves serving as drug carriers in cancer-targeting theranostics (therapeutic+diagnostic) remains to be elucidated. We developed water-soluble polymers labeled with radioisotopes and fluorescence dyes, and elucidated their usefulness as cancer-targeting imaging probes by evaluating their biodistribution with in vivo molecular imaging techniques including nuclear medicine, fluorescence imaging, and photoacoustic imaging. Many water-soluble polymers have some physicochemical properties, such as lower critical solution temperature (LCST), which must be considered as well. We developed cancer-targeting therapeutic compounds by controlling the tumor accumulation of water-soluble polymers based on these physicochemical properties. In this paper, details of the development of cancer-targeting theranostics probes will be discussed.
- Published
- 2020
- Full Text
- View/download PDF
41. [Chasing New Cancer Treatments: Current Status and Future Development of Boron Neutron Capture Therapy].
- Author
-
Shirakawa M
- Subjects
- Humans, Sulfhydryl Compounds, Drug Development, Boron Neutron Capture Therapy methods, Neoplasms radiotherapy, Neoplasms therapy, Neoplasms drug therapy, Boron Compounds administration & dosage, Phenylalanine analogs & derivatives, Borohydrides, Drug Delivery Systems
- Abstract
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.- Published
- 2024
- Full Text
- View/download PDF
42. [Strategy for the development of small-molecule antidepressant targeting PAC1 receptor].
- Author
-
Takasaki I, Hayata-Takano A, Shintani Y, Kurihara T, and Hashimoto H
- Subjects
- Animals, Humans, Drug Development, Depressive Disorder, Major drug therapy, Depressive Disorder, Major metabolism, Molecular Targeted Therapy, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I metabolism
- Abstract
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.
- Published
- 2024
- Full Text
- View/download PDF
43. [The development of innovative therapeutic drugs targeting hypoxia responses].
- Author
-
Yoshikawa K, Hagimoto H, and Nakamura E
- Subjects
- Humans, Animals, Drug Development, Molecular Targeted Therapy, Basic Helix-Loop-Helix Transcription Factors metabolism, Hypoxia drug therapy, Hypoxia metabolism
- Abstract
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.
- Published
- 2024
- Full Text
- View/download PDF
44. [Future prospects for the development of novel agents for acute myeloid leukemia].
- Author
-
Hosono N
- Subjects
- Humans, Antineoplastic Agents therapeutic use, Drug Development, Molecular Targeted Therapy, Leukemia, Myeloid, Acute drug therapy
- Abstract
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.
- Published
- 2024
- Full Text
- View/download PDF
45. [Development of Transdermal Formulation Based on Nanotechnology and Elucidation of Its Drug Delivery Pathways].
- Author
-
Otake H and Nagai N
- Subjects
- Animals, Rats, Humans, Skin metabolism, Nanotechnology, Drug Liberation, Osteoporosis drug therapy, Female, Drug Development, Administration, Cutaneous, Skin Absorption, Raloxifene Hydrochloride administration & dosage, Raloxifene Hydrochloride pharmacokinetics, Menthol administration & dosage, Nanoparticles administration & dosage, Drug Delivery Systems
- Abstract
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.
- Published
- 2024
- Full Text
- View/download PDF
46. 創薬ツールとしてのヒト肝細胞キメラマウス.
- Author
-
島田 卓
- Abstract
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.)
- Published
- 2023
- Full Text
- View/download PDF
47. In vitro in vivo extrapolation (IVIVE) in safety pharmacology to improve human predictability --new evaluation systems for new drug modalities--.
- Author
-
Daiju Yamazaki and Kaoru Sato
- Subjects
EXTRAPOLATION ,PHARMACOLOGY ,MOLECULES ,DRUG development ,MOLECULAR weights - Abstract
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]
- Published
- 2023
- Full Text
- View/download PDF
48. [Verification of Pharmacokinetic Approaches in Prior Drug Development].
- Author
-
Iga K
- Subjects
- Cytochrome P-450 Enzyme System, Drug Design, Drug Interactions, Humans, Metabolic Clearance Rate, Models, Biological, Drug Discovery methods, Pharmacokinetics
- Abstract
In this review, 9 compounds with insufficient absorption characteristics, safety or efficacy were selected from among the compounds for which the author was in charge of development between 2000 and 2005, in order to evaluate the pharmacokinetic (PK) approaches used to develop these compounds. Optimization of the PK characteristics of a compound at the early stage of chemical design was found to be the most important factor for successful development. For example, (i) selecting class I or II drugs in the biopharmaceutical classification system, while avoiding efflux transporters, and introducing an appropriate dissociation moiety into a compound to make it soluble lead to sufficient drug absorption; (ii) designing compounds whose production of reactive metabolites, such as acyl glucuronide, does not largely affect total metabolism, yet helps to prevent abnormal PK caused by reactive metabolites. Other factors include (i) selection of a drug efficacy evaluation system based on the correct understanding of the relationship between PK and pharmacodynamics (PD) helps to solve species differences in PD; (ii) the establishment of a nonclinical study based on the identification of the involvement of specific cytochrome P450 molecules in the total metabolic clearance of a drug (f
m,CYP s) helps to solve species differences in PK; and (iii) PK analysis using the tube model for hepatic extraction kinetics, and knowledge of the fm,CYP s of the victim drug, lead to successful drug-drug interaction (DDI) prediction. I hope that this review aids in future drug discovery or development.- Published
- 2019
- Full Text
- View/download PDF
49. [Elucidation of Disease Mechanisms Based on Transport Function at Tissue Barriers and Challenges in Drug Development].
- Author
-
Ito S
- Subjects
- Alzheimer Disease etiology, Amyloid beta-Peptides metabolism, Animals, Brain Diseases, Metabolic, Inborn etiology, Brain Diseases, Metabolic, Inborn genetics, Cholecalciferol pharmacology, Creatine deficiency, Creatine genetics, Glycosylation, Humans, Loss of Function Mutation, Membrane Transport Proteins genetics, Mental Retardation, X-Linked etiology, Mental Retardation, X-Linked genetics, Plasma Membrane Neurotransmitter Transport Proteins deficiency, Plasma Membrane Neurotransmitter Transport Proteins genetics, Blood-Brain Barrier metabolism, Drug Delivery Systems, Drug Discovery
- Abstract
Tissue barriers contribute to the maintenance of homeostasis in the body, and tissue barrier dysfunction presents a risk factor for a variety of diseases. The blood-brain barrier (BBB) is a major tissue barrier acting as a static barrier and dynamic interface that plays an important role in the maintenance of central nervous system homeostasis. We show the functional characterization of the brain-to-blood efflux transport system of amyloid-β peptide (Aβ) across the BBB. We found that activated vitamin D3 may be a candidate agent for modulating the Aβ clearance across the BBB. Cerebral creatine deficiency syndromes are caused by loss-of-function mutations in the creatine transporter (CRT; SLC6A8), which transports creatine at the BBB. We found that functional impairment of CRT due to a G561R mutation resulted in incomplete N-linked glycosylation due to misfolding during protein maturation, leading to impaired creatine transport activity at the BBB. To develop a delivery system for biomedicine across the tissue barrier, we established a screening system to identify cell-penetrating peptides by a combination of in vitro cell permeability screening assays and phage display technology. Using this system, we identified cyclic hepta-peptides that are able to facilitate intestinal absorption of phages in vitro and in vivo, which are promising candidates as a carrier for macromolecular biomedicines. In conclusion, these studies focusing on the dynamic interface of tissue barriers will contribute to knowledge on disease pathogenesis as well as the development of a targeted biomedicine delivery system.
- Published
- 2019
- Full Text
- View/download PDF
50. Study on Natural Products for Drug Development
- Author
-
Sachiko, Tsukamoto
- Subjects
natural product ,enantiomer ,fungus ,499.39 ,ubiquitin-proteasome system ,indole alkaloid ,drug development - Abstract
The ubiquitin-proteasome system (UPS) plays a major role in selective protein degradation and regulates various cellular events. Approval of bortezomib for the treatment of multiple myeloma validated the proteasome as an anticancer target. In order to find drug candidates targeting the ubiquitin-dependent protein degradation, we paid an attention to inhibitors against three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), which are required for polyubiquitination of proteins and prerequisite to proteasome-mediated protein degradation. We succeeded in isolating various compounds with three distinct inhibitory activities against an E1 enzyme reaction, Ubc13 (E2)-Uev1A interaction, and p53-HDM2 (E3) interaction as well as the proteasome inhibitors. We also isolated new alkaloids, notoamides, from a marine-derived Aspergillus sp. Among them, notoamide B and stephacidin A contain a bicyclo[2.2.2]diazaoctane ring in their structures. We proposed this ring is constructed from notoamide E by the intramolecular Diels-Alder (IMDA) reaction. Recently, the isolation of the antipodes of notoamides from the terrestrial Aspergillus has been reported. We propose that each enantiomer is generated by a distinct face-selective IMDA.
- Published
- 2010
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.