Association Between the Development of Sensorineural Hearing Loss and Blood NAD Levels.

Background: Hearing loss prevalence increases with age, affecting over 25% of the global population aged 60 years or older. The aim of the study was to investigate the association between the development of sensorineural hearing loss (SNHL) and the blood levels of nicotinamide adenine dinucleotide (NAD).

Methods: A single-center, observational study was conducted at Kawagoe Otology Institute in Japan.

An integrated population pharmacokinetic model of febuxostat in pediatric patients with hyperuricemia including gout and adult population of healthy subjects and patients with renal dysfunction.

The study objective was to validate febuxostat dosage and administration in pediatric patients with hyperuricemia including gout, using an integrated population pharmacokinetic (PopPK) analysis in the Japanese population. Integrated PopPK analysis of febuxostat used a nonlinear mixed-effects modeling (NONMEM) program on plasma febuxostat concentration data for 2611 samples from Japanese pediatric patients with hyperuricemia including gout (n = 29) and from adult subjects who are healthy or have renal dysfunction (n = 113). We described febuxostat pharmacokinetics using an integrated PopPK model applicable both to pediatric patients and to the adult population.

A Practical Method for Predicting Compound Brain Concentration-Time Profiles: Combination of PK Modeling and Machine Learning.

Given the aging populations in advanced countries globally, many pharmaceutical companies have focused on developing central nervous system (CNS) drugs. However, due to the blood-brain barrier, drugs do not easily reach the target area in the brain. Although conventional screening methods for drug discovery involve the measurement of (unbound fraction of drug) brain-to-plasma partition coefficients, it is difficult to consider nonequilibrium between plasma and brain compound concentration-time profiles.

Prediction of Inhibitory Activity against the MATE1 Transporter via Combined Fingerprint- and Physics-Based Machine Learning Models.

Renal secretion plays an important role in excretion of drug from the kidney. Two major transporters known to be highly involved in renal secretion are MATE1/2 K and OCT2, the former of which is highly related to drug-drug interactions. Among published in silico models for MATE inhibitors, a previous model obtained a ROC-AUC value of 0.

Efficacy and safety of febuxostat in Japanese paediatric patients with hyperuricaemia including gout: Phase 2, single arm, open‒label, multicentre studies.

Objectives: Urate-lowering efficacy and safety of febuxostat was evaluated in paediatric patients with hyperuricaemia including gout.

Methods: A Phase 2 study of febuxostat in paediatric patients aged 6-18 years with hyperuricaemia including gout was conducted. We evaluated the proportion of patients achieving serum uric acid (sUA) level ≤6.

Effect of photobiomodulation on lower urinary tract dysfunction in rat cystitis model.

Objective: Photobiomodulation selectively controls the activity of the sensory nervous system associated with A-delta and C fibers. Hypersensitivity involving the afferent A-delta and C fibers occurs in cystitis and decreases urinary function. This study aimed to investigate the effect of photobiomodulation on urinary storage dysfunction and voiding functions in cystitis model rats.

Photobiomodulation transiently increases the spontaneous firing in the superficial layer of the rat spinal dorsal horn.

The therapeutic benefits of photobiomodulation (PBM) in pain management, although well documented, are accompanied by concerns about potential risks, including pain, particularly at higher laser intensities. This study investigated the effects of laser intensity on pain perception using behavioral and electrophysiological evaluations in rats. Our results show that direct laser irradiation of 1000 mW/cm to the sciatic nerve transiently increases the frequency of spontaneous firing in the superficial layer without affecting the deep layer of the spinal dorsal horn, and this effect reverses to pre-irradiation levels after irradiation.

Photobiomodulation improves acute restraint stress-induced visceral hyperalgesia in rats.

The purpose of this study is to explore the potential application of photobiomodulation to irritable bowel syndrome. We established the following experimental groups: the Non-Stress + Sham group, which consisted of rats that were not restrained and were only subjected to sham irradiation; the Stress + Sham group, which underwent 1 hour of restraint stress followed by sham irradiation; and the Stress + Laser group, which was subjected to restraint stress and percutaneous laser irradiation bilaterally on the L6 dorsal root ganglia for 5 minutes each. The experiment was conducted twice, with three and two laser conditions examined.

Development of a Novel In Silico Classification Model to Assess Reactive Metabolite Formation in the Cysteine Trapping Assay and Investigation of Important Substructures.

Predicting whether a compound can cause drug-induced liver injury (DILI) is difficult due to the complexity of drug mechanism. The cysteine trapping assay is a method for detecting reactive metabolites that bind to microsomes covalently. However, it is cumbersome to use 35S isotope-labeled cysteine for this assay.

Elevated Serum Xanthine Oxidase and Its Correlation with Antioxidant Status in Patients with Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder associated with a loss of dopamine neurons in the substantia nigra. The diagnosis of PD is sensitive since it shows clinical features that are common with other neurodegenerative diseases. In addition, most symptoms arise at the late stage of the disease, where most dopaminergic neurons are already damaged.

Development of Novel Methods for QSAR Modeling by Machine Learning Repeatedly: A Case Study on Drug Distribution to Each Tissue.

Artificial intelligence is expected to help identify excellent candidates in drug discovery. However, we face a lack of data, as it is time-consuming and expensive to acquire raw data perfectly for many compounds. Hence, we tried to develop a novel quantitative structure-activity relationship (QSAR) method to predict a parameter more precisely from an incomplete data set via optimizing data handling by making use of predicted explanatory variables.

CDK4/6 inhibitor-induced bone marrow micronuclei might be caused by cell cycle arrest during erythropoiesis.

Background: A micronucleus test is generally used to evaluate the genotoxic potential of chemicals. Exaggerated erythropoiesis, as occurs following bleeding, may induce an unexpected increase in micronucleus frequency. This false positive result would be typical in a genotoxicity study due to the enhanced progression of the cell cycle that restores decreased blood cells.

Synthesis of (22)-, (22)-22-Fluoro-, and 22,22-Difluoro-25-hydroxyvitamin D and Effects of Side-Chain Fluorination on Biological Activity and CYP24A1-Dependent Metabolism.

Three novel analogues of C22-fluoro-25-hydroxyvitamin D (-) were synthesized and evaluated to investigate the effects of side-chain fluorination on biological activity and metabolism of vitamin D. These novel analogues were constructed by convergent synthesis applying the Wittig-Horner coupling reaction between CD-ring ketones (,,) and A-ring phosphine oxide (). The introduction of C22-fluoro units was achieved by stereoselective deoxy-fluorination for synthesizing and or two-step cationic fluorination for .

Relationship between Laser Intensity at the Peripheral Nerve and Inhibitory Effect of Percutaneous Photobiomodulation on Neuronal Firing in a Rat Spinal Dorsal Horn.

Photobiomodulation is an effective treatment for pain. We previously reported that the direct laser irradiation of the exposed sciatic nerve inhibited firing in the rat spinal dorsal horn evoked by mechanical stimulation, corresponding to the noxious stimulus. However, percutaneous laser irradiation is used in clinical practice, and it is unclear whether it can inhibit the firing of the dorsal horn.

Synthesis of New 26,27-Difluoro- and 26,26,27,27-Tetrafluoro-25-hydroxyvitamin D: Effects of Terminal Fluorine Atoms on Biological Activity and Half-life.

As an extension of our research on providing a chemical library of side-chain fluorinated vitamin D analogues, we newly designed and synthesized 26,27-difluoro-25-hydroxyvitamin D (1) and 26,26,27,27-tetrafluoro-25-hydroxyvitamin D (2) using a convergent method applying the Wittig-Horner coupling reaction between CD-ring ketones (13, 14) and A-ring phosphine oxide (5). The basic biological activities of analogues, 1, 2, and 26,26,26,27,27,27-hexafluoro-25-hydroxyvitamin D [HF-25(OH)D] were examined. Although the tetrafluorinated new compound 2 exhibited higher binding affinity for vitamin D receptor (VDR) and resistance to CYP24A1-dependent metabolism compared with the difluorinated 1 and its non-fluorinated counterpart 25-hydroxyvitamin D [25(OH)D], HF-25(OH)D showed the highest activity among these compounds.

Development of a 2D-QSAR Model for Tissue-to-Plasma Partition Coefficient Value with High Accuracy Using Machine Learning Method, Minimum Required Experimental Values, and Physicochemical Descriptors.

Background: The demand for physiologically based pharmacokinetic (PBPK) model is increasing currently. New drug application (NDA) of many compounds is submitted with PBPK models for efficient drug development. Tissue-to-plasma partition coefficient (K) is a key parameter for the PBPK model to describe differential equations.

Prediction of Compound Plasma Concentration-Time Profiles in Mice Using Random Forest.

Pharmacokinetic (PK) parameters such as clearance (CL) and volume of distribution (Vd) have been the subject of previous predictive models. However, having information of the concentration over time profile explicitly can provide additional value like time above MIC or AUC, etc., to understand both the efficacy and safety-related aspects of a compound.

Near-Infrared Photobiomodulation of the Peripheral Nerve Inhibits the Neuronal Firing in a Rat Spinal Dorsal Horn Evoked by Mechanical Stimulation.

Photobiomodulation has analgesic effects via inhibition of nerve activity, but few reports have examined the effects on the spinal dorsal horn, the entry point for nociceptive information in the central nervous system. In this study, we evaluated the effects of laser irradiation of peripheral nerve axons, which are conduction pathways for nociceptive stimuli, on the neuronal firing in lamina II of the spinal dorsal horn of a rat evoked by mechanical stimulation with von Frey filaments (vFF). In order to record neuronal firing, electrodes were inserted into lamina II of the exposed rat spinal dorsal horn.

Stabilization and quantitative measurement of nicotinamide adenine dinucleotide in human whole blood using dried blood spot sampling.

Nicotinamide adenine dinucleotide (NAD) is a coenzyme essential for energy production. Recently, associations between NAD and aging-related diseases have been reported, and NAD precursors that increase NAD concentration in the body have been acknowledged as anti-aging supplements. However, there have been only a few studies on the link between aging or aging-related diseases and human blood NAD concentration because NAD and its precursors are unstable in blood and difficult to measure.

QSAR model to predict K with a small dataset, incorporating predicted values of related parameter.

The unbound brain-to-plasma concentration ratio (K) is a parameter that indicates the extent of central nervous system penetration. Pharmaceutical companies build prediction models because many experiments are required to obtain K. However, the lack of data hinders the design of an accurate prediction model.

Predicting Total Drug Clearance and Volumes of Distribution Using the Machine Learning-Mediated Multimodal Method through the Imputation of Various Nonclinical Data.

Pharmacokinetic research plays an important role in the development of new drugs. Accurate predictions of human pharmacokinetic parameters are essential for the success of clinical trials. Clearance (CL) and volume of distribution (Vd) are important factors for evaluating pharmacokinetic properties, and many previous studies have attempted to use computational methods to extrapolate these values from nonclinical laboratory animal models to human subjects.

Water molecule-mediated selective inhibition of bacterial zinc metalloproteinases by non-hydroxamate compounds: Ab initio molecular simulations.

UDP-3-O-acyl-N acetylglucosamine deacetylase (LpxC), Zn metalloenzyme for Gram-negative bacteria is an attractive target for developing novel therapeutic agents. Since LpxC has the similar binding pocket as the human matrix metalloproteinases (MMPs), LpxC inhibitors might also inhibit MMP functions producing side effects in human bodies. Here, we investigated specific interactions between LpxC/MMP and their inhibitors using ab initio molecular simulations to elucidate the reason of selective inhibition for LpxC by non-hydroxamate compounds.