Publications by authors named "Takahito Ito"

Article Synopsis
  • There is an increasing demand for specialized drug delivery systems focused on treating liver diseases, particularly by targeting the asialoglycoprotein receptor found in the liver.
  • Researchers designed helical peptides that showed improved liver selectivity and uptake compared to traditional delivery systems, indicating they might be more effective for drug delivery.
  • The study also explored the potential of these peptides in targeting lysosomes and highlighted their versatility for both therapeutic and diagnostic purposes in liver disease treatment.
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  • * To address these problems, site-specific conjugation methods have been developed, aiming for more uniform ADCs with clearer effects on performance and safety based on specific linker structures and conjugation sites.
  • * This study created 30 homogeneous site-specific ADCs and found that the characteristics, such as linker stability and cytotoxicity, were influenced by both the chosen conjugation site and linker structure, indicating that optimizing these factors is crucial for enhancing ADC performance.
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The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical products. Contamination by N-nitrosamines diverts resources and time from research and development or pharmaceutical production, representing a bottleneck in drug development. Therefore, predicting the risk of N-nitrosamine contamination is an important step in preventing pharmaceutical contamination by DNA-reactive impurities for the production of high-quality pharmaceuticals.

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Antimicrobial peptides (AMPs) are promising therapeutic agents against bacteria. We have previously reported an amphipathic AMP Stripe composed of cationic L-Lys and hydrophobic L-Leu/L-Ala residues, and Stripe exhibited potent antimicrobial activity against Gram-positive and Gram-negative bacteria. Gramicidin A (GA), composed of repeating sequences of L- and D-amino acids, has a unique β-helix structure and exhibits broad antimicrobial activity.

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Purpose: We developed a method to measure the extracellular and intracellular fluid volumes using the kinetics of uric acid in the bodies of Japanese patients undergoing dialysis. In this research, we aimed to assess the prognosis of vascular events using this uric acid kinetic model method.

Methods: We conducted a retrospective cohort study of 1,298 patients who were undergoing hemodialysis or predilution online hemodiafiltration at the end of December 2019 at 13 institutions in Japan.

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We have previously reported that (l-Leu-d-Leu-Aib-l-Leu-d-Leu-Aib) (), a cyclic hexapeptide consisting of heterochiral l-Leu and d-Leu (l-Leu-d-Leu) residues with achiral 2-aminoisobutyric acid (Aib) residues, forms a figure-8 conformation. In this study, we newly designed (l-Leu-d-Leu-Aib-d-Leu-l-Leu-Aib)+ (), an epimer of , and examined the conformational differences between and by X-ray crystallographic analysis. Peptide formed a planar cyclic conformation with an antiparallel β-sheet hydrogen-bonding pattern.

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Multidrug-resistant bacteria (MDRB) remain a significant threat to humanity, resulting in over 1.2 million deaths per year. To combat this problem effectively, the development of therapeutic agents with diverse mechanisms of action is crucial.

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Helical amphipathic peptides containing cationic and hydrophobic amino acid residues can possess potent antimicrobial activity against both Gram-positive and Gram-negative bacteria. In this study, several amphipathic peptides with enhanced helical structures containing nonproteinogenic amino acids were designed, and the relationships between the antimicrobial activity, hemolytic activity, and cytotoxicity were evaluated. In particular, the effect on the antimicrobial activity and cytotoxicity of the number and position of stapling structures introduced into the sequence was investigated.

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An increasing number of research reports are describing modifications of the E3 ligand, in particular, cereblon (CRBN) ligands, to improve the chemical and metabolic stabilities as well as the physical properties of PROTACs. In this study, phenyl-glutarimide (PG) and 6-fluoropomalidomide (6-F-POM), recently used as CRBN ligands for PROTAC design, were applied to hematopoietic prostaglandin D synthase (H-PGDS)-targeted PROTACs. Both PROTAC-5 containing PG and PROTAC-6 containing 6-F-POM were found to have potent activities to induce H-PGDS degradation.

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The Japanese Pharmacopoeia (JP) is an official normative publication for establishing the authenticity and properties and maintaining the quality of pharmaceutical products in Japan. The JP is revised every five years and partially revised in order to respond to the progress of science and technology, the demand for medical care, and international harmonization. Thus, "Internationalization of the JP" is one of the most important issues to address for the revision of the JP, which is also referred to the basic principles for the preparation of the JP 19th edition.

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Antimicrobial peptides (AMPs) have received considerable attention as next-generation drugs for infectious diseases. Amphipathicity and the formation of a stabilized secondary structure are required to exert their antimicrobial activity by insertion into the microbial membrane, resulting in lysis of the bacteria. We previously reported the development of a novel antimicrobial peptide, 17KKV, based on the Magainin 2 sequence.

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The vitamin D receptor (VDR) is a nuclear receptor, which is involved in several physiological processes, including differentiation and bone homeostasis. The VDR is a promising target for the development of drugs against cancer and bone-related diseases. To date, several VDR antagonists, which bind to the ligand binding domain of the VDR and compete with the endogenous agonist 1α,25(OH)D, have been reported.

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Degradation of hematopoietic prostaglandin D synthase (H-PGDS) by proteolysis-targeting chimeras (PROTACs) is expected to be important in the treatment of allergic diseases and Duchenne's muscular dystrophy. We recently reported that 7 (1), which is composed of H-PGDS inhibitor (TFC-007) and cereblon (CRBN) E3 ligase ligand (pomalidomide), showed potent H-PGDS degradation activity. Here, we investigated the structure-activity relationships of 1, focusing on the C4- or C5-conjugation of pomalidomide, in addition, the H-PGDS ligand exchanging from TFC-007 with the biaryl ether to TAS-205 with the pyrrole.

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Introduction: The bioimpedance spectroscopy (BIS) method is used in individual patients requiring body fluid volume measurement. In a hemodialysis facility, however, regular screening of body fluid volumes is also necessary. Such screening, by kinetic modeling, may become possible by calculating distribution volumes of urea and uric acid from regular blood test results.

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Targeted protein degradation by proteolysis-targeting chimera (PROTAC) is one of the exciting modalities for drug discovery and biological discovery. It is important to select an appropriate linker, an E3 ligase ligand, and a target protein ligand in the development; however, it is necessary to synthesize a large number of PROTACs through trial and error. Herein, using a docking simulation of the ternary complex of a hematopoietic prostaglandin D synthase (H-PGDS) degrader, H-PGDS, and cereblon, we have succeeded in developing (), which showed potent and selective degradation activity (DC = 17.

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Norgestomet is a synthetic progesterone derivative applied in veterinary medicine to control estrus and ovulation in cattle. Norgestomet has been widely used in the livestock industry to promote the synchronization of estrus in cattle and increase pregnancy rates. However, highly reproducible synthetic methods for Norgestomet have been rarely reported.

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Peptide-based target protein degradation inducers called PROTACs/SNIPERs have low cell penetrability and poor intracellular stability as drawbacks. These shortcomings can be overcome by easily modifying these peptides by conjugation with cell penetrating peptides and side-chain stapling. In this study, we succeeded in developing the stapled peptide stPERML-R7, which is based on the estrogen receptor alpha (ERα)-binding peptide PERML and composed of natural amino acids.

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The Japanese Pharmacopoeia (JP) is an official normative publication that is referred to, for establishing the authenticity and properties and maintaining the quality of pharmaceutics in Japan. Partial amendments are periodically made to these guidelines to keep up with the progress of science and technology, and the international harmonization is revised every 5 years. Thus, "Internationalization of the JP" is one of the more important issues to address for the revision of the JP.

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Ciclesonide is an inhaled corticosteroid used to treat asthma and is currently undergoing clinical trials for treatment of coronavirus disease 2019 (COVID-19). An active metabolite of ciclesonide, Cic2, was recently reported to repress severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genomic RNA replication. Herein, we designed and synthesized a few types of ciclesonide analogues.

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Article Synopsis
  • The Japanese Pharmacopoeia (JP) serves as Japan's official guide that ensures the quality and authenticity of medicines, with updates every 5 years and amendments as needed to align with scientific advancements and international standards.
  • The current study focuses on removing toxic reagents from the JP, highlighting the need for modern quality improvements and international integration in the revision process.
  • Clonidine hydrochloride is being examined, using a method of potentiometric titration for JP while contrasting it with HPLC methods used by other pharmacopoeias like the USP and EP, alongside synthesizing impurities for thorough analysis.
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Although hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for treatment of a variety of diseases, including allergic diseases and Duchenne muscular dystrophy, no H-PGDS inhibitors have yet been approved for treatment of these diseases. Therefore, the development of novel agents having other modes of action to modulate the activity of H-PGDS is required. In this study, a chimeric small molecule that degrades H-PGDS via the ubiquitin-proteasome system, , was developed.

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Introduction: Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used in patients with type 2 diabetes mellitus (T2DM) on maintenance hemodialysis (HD), but the efficacy of the once-weekly DPP4 inhibitor omarigliptin is not known.

Methods: This prospective, randomized, open-label, parallel-group, non-inferiority/superiority, once-daily DPP4 inhibitor linagliptin-controlled, multicenter study examined glycemic control and safety of omarigliptin (UMIN000024284). Sample size was calculated to confirm non-inferiority in terms of changes in glycated hemoglobin (HbA1c).

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Background: Vascular calcification is a prominent feature in chronic kidney disease (CKD) and diabetes mellitus. A recent report suggests that angiotensin II is protective to vascular calcification. Therefore, we investigated the relationship between vascular calcification and use of angiotensin-converting-enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB) from a cross-sectional view.

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Background: Several reports indicate that extracellular volume predicted by bioimpedance analysis method is associated with hydration status of hemodialysis patients.

Theory: Fundamentally, uric acid does not cross cell membranes by simple diffusion, either by facilitated diffusion or by active transport. In addition, uric acid cannot move through cell membranes in most tissues other than those involved in uric acid excretion.

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The enzymes responsible for acceleration of ferulic acid and ethyl ferulate formation in sake mash were studied. Ferulic acid and ethyl ferulate are formed during the sake brewing process from feruloylated glucuronoarabinoxylan. Cellulase reagent from genus Trichoderma was used instead of rice koji, because rice koji for sake brewing produces extremely low levels of xylan-degrading enzymes.

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