Nemonoxacin Enhances Antibacterial Activity and Anti-Resistance Mutation Ability of Vancomycin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Dynamic Pharmacokinetic/Pharmacodynamic Model.

Reduced susceptibility and emergence of resistance to vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) have led to the development of various vancomycin-based combinations. Nemonoxacin is a novel nonfluorinated quinolone with antibacterial activity against MRSA. The present study aimed to investigate the effects of nemonoxacin on antibacterial activity and the anti-resistant mutation ability of vancomycin for MRSA and explore whether quinolone resistance genes are associated with a reduction in the vancomycin MIC and mutant prevention concentration (MPC) when combined with nemonoxacin. Four isolates, all with vancomycin MICs of 2 µg/mL, were used in a modified in vitro dynamic pharmacokinetic/pharmacodynamic model to investigate the effects of nemonoxacin on antibacterial activity (isolates M04, M23, and M24) and anti-resistant mutation ability (isolates M04, M23, and M25, all with MPCs of ≥19.2 µg/mL) of vancomycin. The mutation sites of gyrA, gyrB, parC, and parE of 55 clinical MRSA isolates were sequenced. We observed that in M04 and M23, the combination of vancomycin (1 g given every 12 h [q12h]) and nemonoxacin (0.5 g once daily [qd]) showed a synergistic bactericidal activity and resistance enrichment suppression. All clinical isolates resistant to nemonoxacin harbored gyrA (S84→L) mutation; gyrA (S84→L) and parC (E84→K) mutations were the two independent risk factors for the unchanged vancomycin MPC in combination. Nemonoxacin enhances the bactericidal activity and suppresses resistance enrichment ability of vancomycin against MRSA, with an MIC of 2 µg/mL. Our in vitro data support the combination of nemonoxacin and vancomycin for the treatment of MRSA infection with a high MIC.

A sensitive and high-throughput LC-ESI-MS/MS method to detect budesonide in human plasma: application to an evaluation of pharmacokinetics of budesonide intranasal formulations with and without charcoal-block in healthy volunteers.

Budesonide is one of the intranasal corticosteroids, referred as first-line therapy for allergic rhinitis. Its determination is a challenging task due to its extremely low plasma levels, which limits the progress in the investigation of pharmacokinetics and quality control of preparations. In this study, a sensitive and high-throughput method to determine budesonide in human plasma using budesonide-d8 as the internal standard was developed and validated. A small volume of plasma sample (0.2 mL) was diluted with 0.2 mL water, followed by a solid-phase extraction using Cleanert PEP-2 products. Extracted samples were analyzed by liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Chromatographic separation of analytes was performed on an InertSustain AQ-C18 HP column (3 µm, 2.1 × 50 mm) under the reversed-phase condition with gradient elution. With the assay, linear calibration curves were obtained over the concentration range of 10-1200 pg/mL for budesonide, with considerable extraction recoveries (84.7-89.4%), and negligible matrix effects (<4.1). Moreover, the newly developed method was successfully applied to the evaluation of pharmacokinetics of two budesonide intranasal formulations with and without charcoal block in healthy volunteers.

Transport Properties of CO2 in Different Reactivity Coke Solution Loss Reaction Based on Stefan Flow Theory.

In this paper, the influence of Stefan flow on different reactivity coke solution loss reaction (Ccoke + CO2 = 2CO) at different temperatures were analyzed and compared to deeply understand the mechanism of the coke solution loss reaction. Isothermal experiments of carbon dioxide gasification with Coke A (low reactivity), Coke B (medium reactivity), and Coke C (high reactivity), respectively, were carried out at 1100-1300 °C. After calculation, it is concluded that the external diffusion coefficients and the mass transfer coefficients with Stefan flow of three kinds of coke were decreased, and their minimum average deviations with and without Stefan flow were 44.57/43.27/43.23 and 42.57/39.47/39.15%, respectively. As the coke reactivity increased, the diffusion and mass transfer capacity of carbon dioxide with Stefan flow in the boundary layer decreased. The carbon dioxide concentration on the outer surface of three kinds of coke with Stefan flow was less than that without Stefan flow. The influence of Stefan flow on carbon dioxide concentration on the outer surface of coke was increased with the increase of coke reactivity. The area of carbon dioxide concentration region in the three kinds of coke declined after modification, and the deviations of the carbon dioxide concentration region area before and after modification of three kinds of coke ranged from 6.62 to 22.85%, 7.74 to 25.17%, and 8.62 to 26.74%. The influence of Stefan flow on the carbon dioxide concentration region increased as coke reactivity increased.

Development and validation of a LC-MS/MS method for simultaneous determination of TQ-A3326 and its major metabolites in human plasma, urine and feces: application to pharmacokinetic assay.

TQ-A3326 has been developed as a new drug by modifying the structure of daclatasvir with deuterium. The pharmacokinetics (PK) of TQ-A3326 in human remains unclear. The aim of the present study was to establish a LC-MS/MS method to investigate preliminarily the PK characteristics of TQ-A3326 and its major metabolites in healthy Chinese volunteers. All volunteers were administrated TQ-A3326 (60 mg). Plasma, feces and urine samples were extracted through protein precipitation. A rapid and sensitive LC-MS/MS method was successfully developed and applied to assess the PK properties of TQ-A3326. The AUC0-t and Cmax were 39516.3 ± 10778.5, 1034.6 ± 452.9 and 71.0 ± 49.5 ng·h·mL-1, and 1411.2 ± 325.4, 52.9 ± 16.4 and 1.8 ± 0.5 ng·mL-1, respectively, for TQ-A3326, M2-D and M4-D. Feces were the predominant route of elimination of TQ-A3326. M2-D was an abundant metabolite in feces and urine, representing 23.72% and 0.24% of the dose, respectively. The measurements of TQ-A3326 and its active metabolites would help to better understand the predominant route of elimination of the prototype drug, and provide meaningful information for further investigation of the bioactive mechanism of TQ-A3326 and its clinical applications.