Discovery of Potent and Isoform-selective Histone Deacetylase Inhibitors Using Structure-based Virtual Screening and Biological Evaluation.

Histone deacetylases (HDACs) are key enzymes in epigenetics and promising targets for anticancer therapy. Although several drugs targeting HDAC have been approved for the treatment of tumors, their clinical use has been limited by their deleterious side effects and poor efficacy. Herein, we discover four potent HDAC inhibitors through pharmacophore model screening and molecular docking. These compounds are able to bind HDACs 1, 3, and 6 with nanomolar affinity. Among them, compound 3 shows greater inhibitory effect on HDACs 1, 3, and 6 than that of vorinostat (SAHA). Evaluation of anticancer activity indicates that compound 3 significantly inhibits the growth of solid cancer cells including HGC-27, AGS, MDA-MB-231, A549, MCF-7, and H460 cells. In vivo anticancer study suggests that compound 3 can also markedly inhibit the growth of HGC-27 cells-derived xenograft, with no observable toxicity. These findings suggest that compound 3 may be as a potential HDAC-targeting inhibitor for solid tumor therapy.

Effect of CYP2C19 polymorphism on the plasma voriconazole concentration and voriconazole-to-voriconazole-N-oxide concentration ratio in elderly patients.

BACKGROUND: Effects of CYP2C19 polymorphism on voriconazole concentration (C0 ), dose-adjusted trough concentrations (C0 /dose) and voriconazole-to-voriconazole-N-oxide concentration ratio (C0 /CN ) have not been fully investigated. OBJECTIVES: To investigate correlations of CYP2C19 polymorphisms with plasma concentrations of voriconazole and the major metabolite voriconazole-N-oxide in elderly patients. METHODS: A prospective, multi-centre, non-intervention, open clinical study was conducted within Southwestern Chinese patients clinically diagnosed with invasive fungal infections, to investigate the associations of CYP2C19∗2 (681G > A), CYP2C19∗3 (636G > A) and CYP2C19∗17 (-806C > T) genetic polymorphisms with voriconazole C0 , C0 /dose and C0 /CN . RESULTS: The study included 131 adult patients, of which 72 were elderly (≥60 years) and 59 were adults (<60 years). The allele frequencies of CYP2C19∗2, ∗3 and ∗17 in the elderly cohort were 61.1%, 29.9% and 7.6%, respectively, which were similar to those in the adult cohort (66.9%, 29.7% and 2.5%, respectively; P > .05). The median voriconazole C0 (C0 ), C0 /dose and C0 /CN ratio in patients with the CYP2C19∗1/∗2 and CYP2C19∗2/∗2 genotypes were significantly higher than those in patients with the CYP2C19∗1/∗1 genotype in the adult cohort (P < .05). The C0 and C0 /dose in patients with the CYP2C19∗1/∗3 and CYP2C19∗2/∗2 genotypes, and the C0 /CN ratio for patients with the CYP2C19∗1/∗2 genotype were numerically higher than those in patients with the CYP2C19∗1/∗1 genotype in the elderly cohort, but this difference was not statistically significant (P > 0.05). The C0 , C0 /dose and C0 /CN in patients with poor metaboliser phenotypes were higher than in those with normal metaboliser phenotypes and C0 in patients with intermediate metaboliser phenotypes were significantly higher than in those with normal metaboliser phenotypes in the adult cohort (P < .05). However, there were no significant differences in the C0 , C0 /dose and C0 /CN among different CYP2C19-predicted metabolic phenotypes in the elderly cohort. CONCLUSIONS: Voriconazole C0 , C0 /dose and C0 /CN ratio are not significantly affected by the CYP2C19∗2/∗3 polymorphisms in the elderly patients.

Therapeutic drug monitoring and safety of voriconazole in elderly patients.

BACKGROUND: Data on therapeutic drug monitoring of voriconazole in elderly patients are limited. Impaired liver function and an inflammatory state in elderly individuals are hypothesized to impact the voriconazole serum level. METHODS: A total of 166 adult patients (317 trough concentrations) who underwent voriconazole therapeutic drug monitoring were enrolled. The voriconazole trough concentration, its associated covariates, and its correlation with adverse effects in 73 elderly (≥60 years) patients (116 trough concentrations) were analyzed and compared to those in 93 adult (<60 years) patients. RESULTS: The voriconazole trough concentration was 4.31 ± 3.03 µg/mL (range, 0.4-15.5 µg/mL) in the elderly patients, which was significantly higher than the 3.11 ± 2.13 µg/mL (range, 0.4-14.3 µg/mL) in the adult patients (P = 0.001). The proportion of voriconazole trough concentrations higher than 5 µg/mL was 35.3% in the elderly patients, which was also significantly higher than the 15.4% in the adult patients (P < 0.001). A stepwise multivariable linear regression model showed that procalcitonin and gamma-glutamyl transpeptidase were independently associated factors in the elderly patients (OR = 2.590, 95% confidence interval [CI] = 1.506-3.673, P = 0.001; OR = -0.016, 95% CI = -0.027 to -0.006, P = 0.005). Receiver operating characteristic (ROC) curve analysis indicated that procalcitonin concentrations of ≥1.31 ng/mL increased the incidence of a voriconazole trough concentration higher than 5 µg/mL (95% CI = 0.53-0.87 µg/mL) (P = 0.03). The incidence of decreased albumin concentrations was higher in the elderly cohort than that in the adult cohort independent of the voriconazole trough concentration (P < 0.05). CONCLUSIONS: The voriconazole trough concentrations in the elderly patients were significantly higher than those in the adult patients who received voriconazole therapy and were significantly affected by severe inflammation as evaluated by the procalcitonin concentration. Frequent monitoring of the voriconazole serum concentration and procalcitonin concentration during and after severe inflammation is critical to maintain the voriconazole serum concentration within the therapeutic range.

Population pharmacokinetics of zonisamide after oral administration in healthy Chinese volunteers.

To develop a population-based pharmacokinetic model for the oral antiepileptic drug zonisamide using a cohort of healthy (nonepileptic) subjects and evaluate the effect of individual factors on the pharmacokinetics of zonisamide. 30 young adults (21-39 years) in good health were randomly assigned to 3 equal groups (1:1 sex ratio) for single-dose administration of zonisamide at 200 mg, 300 mg, or 400 mg. An additional 9 subjects (22-24 years) were administered once daily zonisamide at 300 mg for 14 days, and comprised the multiple dosing group. Venous blood samples were collected for analysis prior to (baseline, 0 hours) and after (1-300 hours) drug administration, providing 607 total samples used to build the pharmacokinetic model. The population pharmacokinetic analysis was performed by ICON's nonlinear mixed-effect modeling (NONMEM) software. Validation of the final model was carried out by nonparametric bootstrapping and visual predictive check. The zonisamide pharmacokinetics was best described by a two-compartment model with first-order elimination. In the final model, the estimated value of clearance (CL) was 23.25 L/h, the volume of distribution of the central compartment (Vc) was 34.50 L, the intercompartmental clearance (Q) was 20.22 L/h, and the Ka was 0.026 h(-1). The peripheral volume of distribution (Vp) was 1,429 L for single dose and 1,003 L for multiple doses. Body weight was the significant covariate affecting CL, Vc, Vp, and Q. Otherwise, female subjects had a lower Q than male subjects. The pharmacokinetics of zonisamide after oral administration could be described using a linear first-order elimination two-compartment model, which may provide a reference for clinical use of zonisamide in Chinese adults.

[Determination of ifenprodil in human plasma using liquid chromatography with electrospray tandem mass spectrometry].

A method for the determination of ifenprodil levels in human plasma was established. Ifenprodil and the internal standard (IS), ketoconazole, were extracted from the plasma with ethyl acetate using liquid-liquid extraction. The extracts were separated by high performance liquid chromatography (HPLC) using methanol-6 mmol/L ammonium acetate (pH value was adjusted to 7.40) (90 : 10, v/v) as the mobile phase, and were then detected using mass spectrometry (MS). Electrospray source was applied and operated in positive ion mode. Selected reaction monitoring (SRM) mode with the transition of m/z 326.1 --> 308.2 was used to quantify ifenprodil, and m/z 531.0 --> 82.1 for IS. The excellent sensitivity and selectivity of the HPLC-MS/MS method allowed quantitation and identification of ifenprodil at low levels with a run time of 6.0 min. The assay was linear over the range from 0.25 to 50 microg/L. The intra-day and inter-day precisions measured as relative standard deviations (RSDs) were less than 2.7% and less than 6.5%, respectively. The average recoveries varied between 101.3% and 105.0%, and the detection limit was 0.08 microg/L. Due to its simplicity and accuracy, the established method is suitable for the application in a pharmaceutical study of the intervenous drop infusion of ifenprodil tartrate.