Pharmacokinetics and metabolism of ulixertinib in rat by liquid chromatography combined with electrospray ionization tandem mass spectrometry.

The purpose of this study was to develop and validate a simple and sensitive liquid chromatography tandem mass spectrometry method for the determination of ulixertinib in rat plasma. The plasma samples were precipitated with acetonitrile and then separated on a C18 column with water containing 0.1% formic acid and acetonitrile as mobile phase at a flow rate of 0.3 mL/min. Analytes were monitored on a TSQ Vantage triple quadrupole tandem mass spectrometer operated in positive electrospray ionization mode. Selected reaction monitoring transitions were m/z 433.1→262.1 for ulixertinib and m/z 450.1→260.1 for internal standard. The assay achieved good linearity over the concentration range of 0.1-1000 ng/mL with correlation coefficient > 0.9991. The validated assay has been successfully applied to pharmacokinetic study of ulixertinib in rat after oral and intravenous administration. The results revealed that ulixertinib showed high exposure in rat plasma, low clearance, moderate oral bioavailability (45.13%), and dose-independent pharmacokinetic profiles over the oral dose range of 1-15 mg/kg. In addition, six metabolites from rat plasma and hepatocytes were detected and structurally identified by ultra-high performance liquid chromatography combined with high-resolution mass spectrometry. The metabolic pathways of ulixertinib referred to hydroxylation and dealkylation and glucuronidation.

A reversible proton relay process mediated by hydrogen-bonding interactions in [FeFe]hydrogenase modeling.

A reversible and temperature-dependent proton-relay process is demonstrated for a Fe2 complex possessing a terminal thiolate in the presence of nitrogen-based acids. The terminal sulfur site (S(t) ) of the complex forms a hydrogen-bond interaction with N,N-dimethylanilinium acid at 183 K. The Fe2 core, instead, is protonated to generate a bridging hydride at 298 K. Reversibility is observed for the tautomerization between the hydrogen-bonded pair and the Fe-hydride species. X-ray structural analysis of the hydrogen-bonded species at 193 K reveals a short N(H)⋅⋅⋅S(t) contact. Employment of pyridinium acid also results in similar behavior, with reversible proton-hydride interconversion. DFT investigation of the proton-transfer pathways indicates that the pKa value of the hydrogen-bonded species is enhanced by 3.2 pKa units when the temperature is decreased from 298 K to 183 K.

Redox communication within multinuclear iron-sulfur complexes related to electronic interplay in the active site of [FeFe]hydrogenase.

The one-electron oxidations of a Fe2 complex lead to the formation of a persistent metal-stabilized thiyl radical Fe2 species, mixed-valent Fe4, and Fe8 complexes. The unpaired spin in the Fe2 radical species delocalizes over the Fe2 and the aromatic dithiolate, mostly on the terminal sulfur. The subsequent dimerization of the singly oxidized Fe2 to the Fe4 retains the partial thiyl radical character. For an analogue with less steric hindrance, the π-π stacking interaction between the dithiolato aromatic rings induces generation of the Fe8, in which process electronic structures of the species are modulated through reducing the thiyl radical to the thiolate. Electronic reorganization repeats when the Fe8 is converted to Fe4. Electronic interplay in the complexes decreases the energy gap of frontier MOs and buffers electronic impacts upon redox events. Easier accessible redox potentials and increased stability of the species are facilitated. The results demonstrate that electronic versatility of the benzenedithiolate exerts pronounced influences on electronic and coordination structure of the metal complexes.

Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis.

PURPOSE: To assess the efficacy and safety of the novel sodium glucose co-transporter 2 (SGLT2) inhibitor-canagliflozin for type 2 diabetes (T2DM). METHODS: A search of Medline (1946-January 2014), Embase (1950-January 2014), and The Cochrane Library for randomized controlled trials of canagliflozin compared to placebo or active comparator in T2DM was performed. Clinical Trials website and unpublished U.S. Food and Drug Administration data were also searched. RESULTS: Ten trials including 6,701 patients were analyzed. Compared with placebo, canagliflozin produced absolute reductions in glycated hemoglobin A1c levels when used as monotherapy (weighted mean difference (WMD) -1.08%, 95% confidence interval (CI) [-1.25 to -0.90], p < 0.00001) or add-on treatment (WMD -0.73%, 95%CI [-0.84 to -0.61], p < 0.00001). When compared with other active comparators, canagliflozin significantly reduced HbA1c by -0.21% (WMD, 95%CI [-0.33 to -0.08], p = 0.001). Canagliflozin led to greater body weight loss (vs. placebo, WMD -2.81 kg, 95%CI [-3.26 to -2.37]; vs. active comparators, WMD -3.49 kg, 95%CI [-4.86 to -2.12]). Hypoglycemia with canagliflozin was similar to placebo or sitagliptin, and was lower than glimepiride (risk ratio (RR) 0.15, 95%CI [0.10 to 0.22]). Genital tract infections were more common with canagliflozin (vs. placebo, RR 3.76, 95%CI [2.23 to 6.35]; vs. active comparators, RR 4.95, 95%CI [3.25 to 7.52]). Similar incidences of urinary tract infections were noted with canagliflozin compared with control groups. CONCLUSION: Canagliflozin led to improvements in reducing glycated hemoglobin A1c levels and body weight with low risk of hypoglycemia in patients with T2DM. Common adverse effects including genital tract infections and osmotic diuresis-related AEs were identified and reviewed. Risks of cardiovascular events are even less certain, and more data on long-term effects are needed.

[Reserach on Raman spectra of organic ingredients on colored pearls].

Based on the visible spectra and Raman spectra test of a variety of colored pearls samples to study the relationship between the organic component and the pearl's color was studied. The study results show that both the freshwater and seawater pearls exhibit strong characteristic peaks in 1121-1132 and 1506-1524 cm(-1) range, which is respectively attributed to the C-C and C=C stretching vibration; the peak intensity in 1117-1132, 1502-1524 and 2000-3500 cm(-1) range increases as the color deepens, which is closely related to the pearl's color; The peak in the 1475-1575 cm(-1) range is divided into 8-10 secondary peaks of purple freshwater pearl and deep orange seawater pearl. The number of C=C double bonds is N=9 approximately 27 and N=7 approximately 27 respectively after calculation. Polyene compound of different varieties and content could be the reason for the pearls' color.

Chemical analysis of selected harmful and potentially harmful constituents and in vitro toxicological evaluation of leading flavoured e-cigarette aerosols in the Chinese market.

Use of electronic cigarettes (e-cigarettes) has increased significantly over the past decade due to consumer perception that these products represent a less risky alternative to combustible cigarettes. E-liquids generally contain a simple mix of vegetable glycerin, propylene glycerol, nicotine, organic acids, and flavourings. Regulators require that harmful and potentially harmful constituents (HPHCs) that might cause harm to the consumer must be monitored in the aerosol generated by e-cigarettes and in cigarette smoke (CS). To quantify HPHCs in aerosols from commercial flavoured e-cigarettes in Chinese market, this study has systematically compared levels of HPHCs, including eight carbonyls, five volatile organic compounds, four tobacco-specific nitrosamines, 16 polycyclic aromatic hydrocarbons, and seven heavy metals, in the aerosols of four market-leading flavoured e-cigarettes and mainstream CS, alongside in vitro cytotoxicity and mutagenicity assays. The vast majority of HPHCs were either undetected or significantly lower in the e-cigarette aerosols than in commercial CS or reference CS (3R4F). Where HPHCs were detected, there were small variations among the different flavoured e-cigarettes. In the neutral red uptake and Ames assays, aqueous extracts of the e-cigarette aerosols did not induce obvious cytotoxicity or mutagenicity, whereas CS aqueous extract showed dose-related cytotoxicity and mutagenicity. Collectively, these results indicate that use of e-cigarettes might potentially lead to a significant reduction in exposure to harmful substances, with fewer cytotoxic and mutagenic effects, as compared with conventional smoking. Further studies based on human puffing conditions and longer evaluation periods will be needed to substantiate this potential.

An unexpected cause of a subcutaneous nodule: a case report of dirofilaria infection.

Humans are not natural hosts of Dirofilaria; however, pulmonary or subcutaneous infections may occur through mosquitoes transmission. Patients presenting with simple subcutaneous nodules may not seek early medical attention, and hence systemic involvement through hematogenous spread may occur. Definitive diagnosis of Dirofilaria infection is made by histopathological examinations of the infected tissues. We report a patient with an incidental diagnosis of Dirofilaria infection confirmed by histopathological findings of a subcutaneous nodule on the right thigh. The source of infection remains unknown.