Day: December 6, 2022

Yang, Yilei published the artcileCYP3A5 genotype-dependent drug-drug interaction between tacrolimus and nifedipine in Chinese renal transplant patients, Category: pyridine-derivatives, the main research area is tacrolimus nifedipine human renal transplant CYP3A5 genotype drug interaction; CYP3A5; drug-drug interaction; nifedipine; renal transplantation; tacrolimus.

The drug-drug interactions (DDIs) of tacrolimus greatly contributed to pharmacokinetic variability. Nifedipine, frequently prescribed for hypertension, is a competitive CYP3A5 inhibitor which can inhibit tacrolimus metabolism The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimusnifedipine DDI in Chinese renal transplant patients. All renal transplant patients were divided into CYP3A5*3/*3 homozygotes (group I) and CYP3A5*1 allele carriers (CYP3A5*1/*1 + CYP3A5*1/*3) (group II). Each group was subdivided into patients taking tacrolimus co-administered with nifedipine (CONF) and that administrated with tacrolimus alone (Controls). Tacrolimus trough concentrations (C0) were measured using high performance liquid chromatog. A retrospective anal. compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between CONF and Controls in group I and II, resp. At the same time, a multivariate line regression anal. was made to evaluate the effect of variates on C0/D. In this study, a significant DDI between tacrolimus and nifedipine with respect to the CYP3A5*3 polymorphism was confirmed. In group I (n = 43), the C0/D of CONF was significantly higher than in Controls [225.2 ± 66.3 vs. 155.1 ± 34.6 ng/mL/(mg/kg); p = 0.002]. However, this difference was not detected in group II (n = 27) (p = 0.216). The coadministrated nifedipine and CYP3A5*3/*3 homozygotes significantly increased tacrolimus concentrations in multivariate line regression anal. A CYP3A5 genotype-dependent DDI was found between tacrolimus and nifedipine. Therefore, personalized therapy accounting for CYP3A5 genotype detection as well as therapeutic drug monitoring are necessary for renal transplant patients when treating with tacrolimus and nifedipine.

Frontiers in Pharmacology published new progress about Allele frequency. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Category: pyridine-derivatives.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Lee, Fei Yee published the artcileAdverse drug reactions of antihypertensives and CYP3A5*3 polymorphism among chronic kidney disease patients, Computed Properties of 72509-76-3, the main research area is cytochrome polymorphism chronic kidney disease human antihypertensive drug reaction; CYP3A5; adverse drug reaction; antihypertensive drugs; chronic kidney disease; pharmacogenetics.

Chronic kidney disease (CKD) patients may be more susceptible to adverse drug reactions (ADRs), given their complex medication regimen and altered physiol. state driven by a decline in kidney function. This study aimed to describe the relationship between CYP3A5*3 polymorphism and the ADR of antihypertensive drugs in CKD patients. This retrospective, multi-center, observational cohort study was performed among adult CKD patients with a follow-up period of up to 3 years. ADRs were detected through medical records. CYP3A5*3 genotyping was performed using the direct sequencing method. From the 200 patients recruited in this study, 33 (16.5%) were found to have ADRs related to antihypertensive drugs, with 40 ADRs reported. The most frequent ADR recorded was hyperkalemia (n = 8, 20.0%), followed by bradycardia, hypotension, and dizziness, with 6 cases (15.0%) each. The most common suspected agents were angiotensin II receptor blockers (n = 11, 27.5%), followed by angiotensin-converting enzyme inhibitors (n = 9, 22.5%). The CYP3A5*3 polymorphism was not found to be associated with antihypertensive-related ADR across the genetic models tested, despite adjustment for other possible factors through multiple logistic regression (p > 0.05). After adjusting for possible confounding factors, the factors associated with antihypertensive-related ADR were anemia (adjusted odds ratio [aOR] 5.438, 95% confidence interval [CI]: 2.002, 14.288) and poor medication adherence (aOR 3.512, 95% CI: 1.470, 8.388). In conclusion, the CYP3A5*3 polymorphism was not found to be associated with ADRs related to antihypertensives in CKD patients, which requires further verification by larger studies.

Frontiers in Pharmacology published new progress about Allele frequency. 72509-76-3 belongs to class pyridine-derivatives, name is 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C18H19Cl2NO4, Computed Properties of 72509-76-3.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Giantin, Mery published the artcileFunctional impact of cytochrome P450 3A (CYP3A) missense variants in cattle, Formula: C17H18N2O6, the main research area is CYPA missense mutation testosterone nifedipine mol docking.

Cytochrome P 450 3A is the most important CYP subfamily in humans, and CYP3A4/CYP3A5 genetic variants contribute to inter-individual variability in drug metabolism However, no information is available for bovine CYP3A (bCYP3A). Here we described bCYP3A missense single nucleotide variants (SNVs) and evaluated their functional effects. CYP3A28, CYP3A38 and CYP3A48 missense SNVs were identified in 300 bulls of Piedmontese breed through targeted sequencing. Wild-type and mutant bCYP3A cDNAs were cloned and expressed in V79 cells. CYP3A-dependent oxidative metabolism of testosterone (TST) and nifedipine (NIF) was assessed by LC-MS/MS. Finally, SNVs functional impact on TST hydroxylation was measured ex vivo in liver microsomes from individually genotyped animals. Thirteen missense SNVs were identified and validated. Five variants showed differences in CYP3A catalytic activity: three CYP3A28 SNVs reduced TST 6β-hydroxylation; one CYP3A38 variant increased TST 16β-hydroxylation, while a CYP3A48 SNV showed enhanced NIF oxidation Individuals homozygous for rs384467435 SNV showed a reduced TST 6β-hydroxylation. Mol. modeling showed that most of SNVs were distal to CYP3A active site, suggesting indirect effects on the catalytic activity. Collectively, these findings demonstrate the importance of pharmacogenetics studies in veterinary species and suggest bCYP3A genotype variation might affect the fate of xenobiotics in food-producing species such as cattle.

Scientific Reports published new progress about Allele frequency. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Formula: C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Mao, Junjun published the artcileIncorporating nonlinear kinetics to improve predictive performance of population pharmacokinetic models for ciclosporin in adult renal transplant recipients: A comparison of modelling strategies, Related Products of pyridine-derivatives, the main research area is ciclosporin renoprotectant pharmacokinetic renal transplantation; Ciclosporin; Modelling strategies; Nonlinear kinetics; Population pharmacokinetics.

Ciclosporin has been shown to follow nonlinear pharmacokinetics (PK) in renal transplant recipients who received ciclosporin (Neoral, Novartis)-based triple immunosuppressive therapy. Some of these nonlinear properties have not been fully considered in population PK (popPK) anal. Therefore, the aim of this study was to determine the potential influence of nonlinearity and the functional forms of covariates on model predictability as well as to analyze multiple nonlinear factors in the in vivo process. A total of 2969 ciclosporin whole-blood measurements, including 1328 pre-dose and 1641 2-h post-dose concentrations, were collected from 173 patients who underwent their first renal transplantation. Four popPK models based on different modeling strategies were developed to investigate the discrepancy between empirical and theory-based, linear and nonlinear compartmental kinetic models and empirical formulas on model predictability. Prediction and simulation-based diagnostics (prediction-corrected visual predictive checks) were performed to determine the stability and predictive performance of these four models. Model predictability improved when nonlinearity was considered. The theory-based nonlinear model which incorporated nonlinear property based on known theor. relationships performed better than the other two compartmental models. The nonlinear Michaelis-Menten model showed a remarkable improvement in predictive performance compared to the other three compartmental models. The saturated binding of ciclosporin to erythrocytes, auto-inhibition induced by the inhibitory effects of ciclosporin on cytochrome P 450 3A4/P-glycoprotein may have contributed to the nonlinearity. Ciclosporin-prednisolone drug interaction should be given serious consideration in clin. settings. Incorporation of nonlinear properties is likely to be a promising approach for improving ciclosporin model predictability. Theory-based modeling is helpful to improve model predictability. However, ciclosporin nonlinear kinetics resources need further investigation.

European Journal of Pharmaceutical Sciences published new progress about Adult, mammalian. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Related Products of pyridine-derivatives.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Mao, Junjun published the artcileIncorporating nonlinear kinetics to improve predictive performance of population pharmacokinetic models for ciclosporin in adult renal transplant recipients: A comparison of modelling strategies, COA of Formula: C18H19Cl2NO4, the main research area is ciclosporin renoprotectant pharmacokinetic renal transplantation; Ciclosporin; Modelling strategies; Nonlinear kinetics; Population pharmacokinetics.

Ciclosporin has been shown to follow nonlinear pharmacokinetics (PK) in renal transplant recipients who received ciclosporin (Neoral, Novartis)-based triple immunosuppressive therapy. Some of these nonlinear properties have not been fully considered in population PK (popPK) anal. Therefore, the aim of this study was to determine the potential influence of nonlinearity and the functional forms of covariates on model predictability as well as to analyze multiple nonlinear factors in the in vivo process. A total of 2969 ciclosporin whole-blood measurements, including 1328 pre-dose and 1641 2-h post-dose concentrations, were collected from 173 patients who underwent their first renal transplantation. Four popPK models based on different modeling strategies were developed to investigate the discrepancy between empirical and theory-based, linear and nonlinear compartmental kinetic models and empirical formulas on model predictability. Prediction and simulation-based diagnostics (prediction-corrected visual predictive checks) were performed to determine the stability and predictive performance of these four models. Model predictability improved when nonlinearity was considered. The theory-based nonlinear model which incorporated nonlinear property based on known theor. relationships performed better than the other two compartmental models. The nonlinear Michaelis-Menten model showed a remarkable improvement in predictive performance compared to the other three compartmental models. The saturated binding of ciclosporin to erythrocytes, auto-inhibition induced by the inhibitory effects of ciclosporin on cytochrome P 450 3A4/P-glycoprotein may have contributed to the nonlinearity. Ciclosporin-prednisolone drug interaction should be given serious consideration in clin. settings. Incorporation of nonlinear properties is likely to be a promising approach for improving ciclosporin model predictability. Theory-based modeling is helpful to improve model predictability. However, ciclosporin nonlinear kinetics resources need further investigation.

European Journal of Pharmaceutical Sciences published new progress about Adult, mammalian. 72509-76-3 belongs to class pyridine-derivatives, name is 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C18H19Cl2NO4, COA of Formula: C18H19Cl2NO4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Garcia-Marin, Luis M. published the artcileLarge-scale genetic investigation reveals genetic liability to multiple complex traits influencing a higher risk of ADHD, Safety of 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, the main research area is genetic liability attention deficit hyperactivity disorder child adult.

Attention Deficit-Hyperactivity Disorder (ADHD) is a complex psychiatric and neurodevelopmental disorder that develops during childhood and spans into adulthood. ADHD’s etiol. is complex, and evidence about its cause and risk factors is limited. We leveraged genetic data from genome-wide association studies (GWAS) and performed latent causal variable analyses using a hypothesis-free approach to infer causal associations between 1387 complex traits and ADHD. We identified 37 inferred potential causal associations with ADHD risk. Our results reveal that genetic variants associated with iron deficiency anemia (ICD10), obesity, type 2 diabetes, synovitis and tenosynovitis (ICD10), polyarthritis (ICD10), neck or shoulder pain, and substance use in adults display partial genetic causality on ADHD risk in children. Genetic variants associated with ADHD have a partial genetic causality increasing the risk for chronic obstructive pulmonary disease and carpal tunnel syndrome. Protective factors for ADHD risk included genetic variants associated with the likelihood of participating in socially supportive and interactive activities. Our results show that genetic liability to multiple complex traits influences a higher risk for ADHD, highlighting the potential role of cardiometabolic phenotypes and phys. pain in ADHD’s etiol. These findings have the potential to inform future clin. studies and development of interventions.

Scientific Reports published new progress about Adult, mammalian. 72509-76-3 belongs to class pyridine-derivatives, name is 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C18H19Cl2NO4, Safety of 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Andrews, L. M. published the artcileA population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients, Related Products of pyridine-derivatives, the main research area is tacrolimus renoprotectant CYP3A4 albumin kidney transplantation adult; cytochrome P450 enzymes; genetics and pharmacogenetics; immunosuppression Immunology; pharmacokinetics; population analysis; renal transplantation.

To describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clin. tool for selecting the best starting dose for each patient. Data on tacrolimus exposure were collected for the first 3 mo following renal transplantation. A population pharmacokinetic anal. was conducted using nonlinear mixed-effects modeling. Demog., clin. and genetic parameters were evaluated as covariates. A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two-compartment model. The mean absorption rate was 3.6 h-1, clearance was 23.0 l h-1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P 450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: Dosemg=222nghml-1*22.5lh-1*1.0ifCYP3A5*3/*3or1.62ifCYP3A5*1/*3orCYP3A5*1/*1*1.0ifCYP3A4*1or unknownor0.814ifCYP3A4*22*Age56-0.50*BSA1.930.72/1000 Both models were successfully internally and externally validated. A clin. trial was simulated to demonstrate the added value of the starting dose model. For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation.

British Journal of Clinical Pharmacology published new progress about Adult, mammalian. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Related Products of pyridine-derivatives.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Hayes, Heather B. published the artcileNovel method for action potential measurements from intact cardiac monolayers with multiwell microelectrode array technology, COA of Formula: C17H18N2O6, the main research area is cardiac monolayer action potential multiwell microelectrode array.

The cardiac action potential (AP) is vital for understanding healthy and diseased cardiac biol. and drug safety testing. However, techniques for high throughput cardiac AP measurements have been limited. Here, we introduce a novel technique for reliably increasing the coupling of cardiomyocyte syncytium to planar multiwell microelectrode arrays, resulting in a stable, label-free local extracellular action potential (LEAP). We characterized the reliability and stability of LEAP, its relationship to the field potential, and its efficacy for quantifying AP morphol. of human induced pluripotent stem cell derived and primary rodent cardiomyocytes. Rise time, action potential duration, beat period, and triangulation were used to quantify compound responses and AP morphol. changes induced by genetic modification. LEAP is the first high throughput, non-invasive, label-free, stable method to capture AP morphol. from an intact cardiomyocyte syncytium. LEAP can accelerate our understanding of stem cell models, while improving the automation and accuracy of drug testing.

Scientific Reports published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, COA of Formula: C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Kernik, Divya C. published the artcileA computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources, Application In Synthesis of 21829-25-4, the main research area is Pluripotent stem cell cardiomyocyte electrophysiol; computer modelling; iPSC-CMs; variability.

A promising in vitro method to address patient-specific proclivity to cardiac disease utilizes induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We postulated, however, that cell-to-cell variability may constitute a strength when appropriately utilized in a computational framework to build cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in exptl. data across multiple laboratories to develop a computational framework for investigating subcellular phenotypic mechanisms. We have developed a whole-cell model of iPSC-CMs composed of simple model components comprising ion channel models with single exponential voltage-dependent gating variable rate constants, parameterized to fit exptl. iPSC-CM data for all major ionic currents. By optimizing ionic current model parameters to multiple exptl. datasets, we incorporate exptl.-observed variability in the ionic currents. The resulting population of cellular models predicts robust inter-subject variability in iPSC-CMs. This approach links mol. mechanisms to known cellular-level iPSC-CM phenotypes, as shown by comparing immature and mature subpopulations of models to analyze the contributing factors underlying each phenotype. In the future, the presented models can be readily expanded to include genetic mutations and pharmacol. interventions for studying the mechanisms of rare events, such as arrhythmia triggers.

Journal of Physiology (Oxford, United Kingdom) published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Application In Synthesis of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Chang, Yun published the artcilehERG-deficient human embryonic stem cell-derived cardiomyocytes for modelling QT prolongation, Synthetic Route of 21829-25-4, the main research area is cardiomyocyte embryonic stem cell hERG QT prolongation; CRISPR/Cas9; Human ether-a-go-go-related gene; KCNH2; QT prolongation; hESCs.

Long-QT syndrome type 2 (LQT2) is a common malignant hereditary arrhythmia. Due to the lack of suitable animal and human models, the pathogenesis of LQT2 caused by human ether-a-go-go-related gene (hERG) deficiency is still unclear. In this study, we generated an hERG-deficient human cardiomyocyte (CM) model that simulates ′human homozygous hERG mutations′ to explore the underlying impact of hERG dysfunction and the genotype-phenotype relationship of hERG deficiency. The KCNH2 was knocked out in the human embryonic stem cell (hESC) H9 line using the CRISPR/Cas9 system. Using a chem. defined differentiation protocol, we obtained and verified hERG-deficient CMs. Subsequently, high-throughput microelectrode array (MEA) assays and drug interventions were performed to characterize the electrophysiol. signatures of hERG-deficient cell lines. Our results showed that KCNH2 knockout did not affect the pluripotency or differentiation efficiency of H9 cells. Using high-throughput MEA assays, we found that the elec. field potential duration and action potential duration of hERG-deficient CMs were significantly longer than those of normal CMs. The hERG-deficient lines also exhibited irregular rhythm and some early afterdepolarisations. Moreover, we used the hERG-deficient human CM model to evaluate the potency of agents (nifedipine and magnesium chloride) that may ameliorate the phenotype. We established an hERG-deficient human CM model that exhibited QT prolongation, irregular rhythm and sensitivity to other ion channel blockers.

Stem Cell Research & Therapy published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Synthetic Route of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem