Effects of CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy subjects.

Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone.

Physiologically based pharmacokinetic (PBPK) modeling of flurbiprofen in different CYP2C9 genotypes.

The aim of this study was to establish the physiologically based pharmacokinetic (PBPK) model of flurbiprofen related to CYP2C9 genetic polymorphism and describe the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes. PK-Sim® software was used for the model development and validation. A total of 16 clinical pharmacokinetic data for flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups were used for the PBPK modeling.

Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease.

Globoid cell leukodystrophy (Krabbe disease) is a fatal neurodegenerative, demyelinating disease caused by dysfunctional activity of galactosylceramidase (GALC), leading to the accumulation of glycosphingolipids including psychosine. While oligodendrocytes have been extensively studied due to their high levels of GALC, the contribution of astrocytes to disease pathogenesis remains to be fully elucidated. In the current study, we generated induced pluripotent stem cells (iPSCs) from two donors with infantile onset Krabbe disease and differentiated them into cultures of astrocytes.

Physiologically based pharmacokinetic modelling to predict the pharmacokinetics of metoprolol in different CYP2D6 genotypes.

Metoprolol, a selective β-adrenoreceptor blocking agent used in the treatment of hypertension, angina, and heart failure, is primarily metabolized by the CYP2D6 enzyme, which catalyzes α-hydroxylation and O-desmethylation. As CYP2D6 is genetically highly polymorphic and the enzymatic activity differs greatly depending on the presence of the mutant allele(s), the pharmacokinetic profile of metoprolol is highly variable depending on the genotype of CYP2D6. The aim of study was to develop the physiologically based pharmacokinetic (PBPK) model of metoprolol related to CYP2D6 genetic polymorphism for personalized therapy with metoprolol.

Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease.

A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3.

Physiologically based pharmacokinetic (PBPK) modeling of piroxicam with regard to CYP2C9 genetic polymorphism.

Piroxicam is a non-steroidal anti-inflammatory drug used to alleviate symptoms of osteoarthritis and rheumatoid arthritis. CYP2C9 genetic polymorphism significantly influences the pharmacokinetics of piroxicam. The objective of this study was to develop and validate the piroxicam physiologically based pharmacokinetic (PBPK) model related to CYP2C9 genetic polymorphism.

A novel brain-penetrant oral UGT8 inhibitor decreases in vivo galactosphingolipid biosynthesis in murine Krabbe disease.

Krabbe disease is a rare, inherited neurodegenerative disease due to impaired lysosomal β-galactosylceramidase (GALC) activity and formation of neurotoxic β-galactosylsphingosine ('psychosine'). We investigated substrate reduction therapy with a novel brain-penetrant inhibitor of galactosylceramide biosynthesis, RA 5557, in twitcher mice that lack GALC activity and model Krabbe disease. This thienopyridine derivative selectively inhibits uridine diphosphate-galactose glycosyltransferase 8 (UGT8), the final step in the generation of galactosylceramides which are precursors of sulphatide and, in the pathological lysosome, the immediate source of psychosine.

Association between the presence of delirium during intensive care unit admission and cognitive impairment or psychiatric problems: the Korean ICU National Data Study.

Objective: Delirium in the intensive care unit (ICU) may be a preventable risk factor for cognitive impairment or psychiatric problems. We aimed to evaluate the association between the presence of delirium during hospitalization involving ICU care and post-discharge cognitive impairment or psychiatric problems.

Design: A retrospective cohort study.

Effects of CYP2C9*3 and *13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects.

Glipizide is a second-generation sulfonylurea antidiabetic drug. It is principally metabolized to inactive metabolites by genetically polymorphic CYP2C9 enzyme. In this study, we investigated the effects of CYP2C9*3 and *13 variant alleles on the pharmacokinetics and pharmacodynamics of glipizide.

The multiplicative effect of stress and sleep on academic cognitions in Latino college students.

Latino students are increasingly represented in higher education within the United States, but remain one of the groups least likely to graduate from a four-year institution. Stress and sleep are factors that have been implicated in students' academic success. This study examined concurrent and longitudinal interactive effects of stress and sleep on academic cognitions in a sample of 196 Latino students (= 18.

Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients.

Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces.

Physiologically based pharmacokinetic (PBPK) modeling of meloxicam in different CYP2C9 genotypes.

Meloxicam, a non-steroidal anti-inflammatory drug, is used for the treatment of rheumatoid arthritis and osteoarthritis. Cytochrome P450 (CYP) 2C9 and CYP3A4 are major and minor enzymes involved in the metabolism of meloxicam. Impaired enzyme activity of CYP2C9 variants increases the plasma exposures of meloxicam and the risk of adverse events.

Physiologically based pharmacokinetic (PBPK) modelling of tamsulosin related to CYP2D6*10 allele.

Tamsulosin, a selective [Formula: see text]-adrenoceptor blocker, is commonly used for alleviation of lower urinary tract symptoms related to benign prostatic hyperplasia. Tamsulosin is predominantly metabolized by CYP3A4 and CYP2D6 enzymes, and several studies reported the effects of CYP2D6 genetic polymorphism on the pharmacokinetics of tamsulosin. This study aims to develop and validate the physiologically based pharmacokinetic (PBPK) model of tamsulosin in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 genotypes, using Simcyp® simulator.

Long-Term Prognosis of Asthma-Bronchiectasis Overlapped Patients: A Nationwide Population-Based Cohort Study.

Purpose: Asthma and bronchiectasis are common chronic respiratory diseases, and their coexistence is frequently observed but not well investigated. Our aim was to study the effect of comorbid bronchiectasis on asthma.

Methods: A propensity score-matched cohort study was conducted using the National Health Insurance Service-Health Screening Cohort database.

Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model.

Mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson's disease (PD). Additionally, PD patients harboring a mutant GBA allele present with an earlier disease onset and an accelerated disease progression of both motor and non-motor symptoms. Preclinical studies in mouse models of synucleinopathy suggest that modulation of the sphingolipid metabolism pathway via inhibition of glucosylceramide synthase (GCS) using a CNS-penetrant small molecule may be a potential treatment for synucleinopathies.

Latino Adolescents' Academic Trajectories over the Transition to Higher Education: Variation by School and Neighborhood Contexts and Familism.

Latino college graduation rates continue to fall behind rates of other racial/ethnic groups, highlighting the importance of understanding risk and protective processes across the transition into higher education. The current study examined changes in socio-cultural contexts (i.e.

Forecasting the Walking Assistance Rehabilitation Level of Stroke Patients Using Artificial Intelligence.

Cerebrovascular accidents (CVA) cause a range of impairments in coordination, such as a spectrum of walking impairments ranging from mild gait imbalance to complete loss of mobility. Patients with CVA need personalized approaches tailored to their degree of walking impairment for effective rehabilitation. This paper aims to evaluate the validity of using various machine learning (ML) and deep learning (DL) classification models (support vector machine, Decision Tree, Perceptron, Light Gradient Boosting Machine, AutoGluon, SuperTML, and TabNet) for automated classification of walking assistant devices for CVA patients.

Promoter engineering-mediated Tuning of esterase and transaminase expression for the chemoenzymatic synthesis of sitagliptin phosphate at the kilogram-scale.

Here, we report a bienzymatic cascade to produce β-amino acids as an intermediate for the synthesis of the leading oral antidiabetic drug, sitagliptin. A whole-cell biotransformation using recombinant Escherichia coli coexpressing a esterase and transaminase were developed, wherein the desired expression level of each enzyme was achieved by promotor engineering. The small-scale reactions (30 ml) performed under optimized conditions at varying amounts of substrate (100-300 mM) resulted in excellent conversions of 82%-95% for the desired product.

The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PD.

Background: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PD ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement.

Objective: To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI).

Methods: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PD patients compared to PD patients.

Comparison of Antioxidant Properties of Evening Primrose Seeds by Different Processing Methods, and Physiological Properties of Evening Primrose Seed Powder.

This study proposes the processing method that could maximize the functional properties of evening primrose seeds (EPS) and its various nutritional components. EPS can be prepared by different methods, such as being left raw, roasting, steaming, and powdering. Processing of EPS to create EPS powder (EPSP) resulted in higher levels of vitamin E, fatty acids, total phenolic contents, and antioxidant activity, compared with the other processing methods.

The role of United States identity in adjustment among Veterans.

Given over 2.77 million US service members have been deployed in the past 20 years and the intense process of reintegration to civilian life, understanding factors that contribute to Veterans' mental health and substance use is critical. This study sought to understand the effects of US identity exploration, US identity commitment, US identity affirmation, and US identity centrality on substance use and symptoms of depression and anxiety.

Daily Family Connection and Objective Sleep in Latinx Adolescents: The Moderating Role of Familism Values and Family Communication.

Spending time with family ("family connection") is a salient aspect of adolescents' daily lives linked with healthy sleep. Less is known regarding the unique effects of parent and sibling connection on sleep. This study examined daily and average associations between parent/sibling connection and objective sleep (duration, efficiency) in a sample of Latinx adolescents (N = 195; M = 18.

Substrate reduction therapy using Genz-667161 reduces levels of pathogenic components in a mouse model of neuronopathic forms of Gaucher disease.

Most lysosomal storage diseases (LSDs) have a significant neurological component, including types 2 and 3 Gaucher disease (neuronal forms of Gaucher disease; nGD). No therapies are currently available for nGD since the recombinant enzymes used in the systemic form of Gaucher disease do not cross the blood-brain barrier (BBB). However, a number of promising approaches are currently being tested, including substrate reduction therapy (SRT), in which partial inhibition of the synthesis of the glycosphingolipids (GSLs) that accumulate in nGD lowers their accumulation.

Correction of cilia structure and function alleviates multi-organ pathology in Bardet-Biedl syndrome mice.

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy affecting multiple organs. The development of potential disease-modifying therapy for BBS will require concurrent targeting of multi-systemic manifestations. Here, we show for the first time that monosialodihexosylganglioside accumulates in Bbs2-/- cilia, indicating impairment of glycosphingolipid (GSL) metabolism in BBS.