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Efficient copper-catalyzed [3 + 2] cycloadditions of ethynyl indoloxazolidones with 1,3-cyclohexanediones to access functionalized furan derivatives under mild conditions.

The visible-light-promoted difunctionalization of alkenyl ketones has been developed for easy access of various tetralones, cyclopropane, or alkenyl migration compounds. With

An acid-catalyzed formal [3 + 2] cyclization/N,O-ketalization of in situ formed ortho-alkynyl quinone methides (o-AQMs) and tryptophol derivatives was developed.

Herein, we present a palladium-catalyzed tandem [4+1] cyclo­addition of 4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones with ­N-tosyl­hydrazones. The reaction is accomplished by merging the in situ generated aza-ortho-quinone methides (aza-o-QMs) with nucleophilic carbenes. This method enables the construction of diverse indolines with broad functional group compatibility in good yields with high levels of diastereoselectivity under mild conditions.

The aim of this study was to establish the population pharmacokinetics (PK) model of Vancomycin for Chinese pediatric patients which can extrapolate to whole age periods by bridging the published adult population PK model and the established pediatric population PK model. The final consolidated population PK model was used to explore the correlation of pharmacokinetics/pharmacodynamics (PK/PD) indices and efficacy of vancomycin and to provide evidence for the optimized regimen of vancomycin in Chinese pediatric patients with Gram-positive bacterial infection. 108 pediatric patients with Gram-positive infections from 2 pediatric hospitals in China in the first period of the prospective multi-center vancomycin clinical observational study were enrolled to establish the population PK model. A one-compartment population PK model was established and validated. The correlation between vancomycin PK/PD indices [trough concentration (Cmin), peak concentration (Cmax), 0–24 h area under the curve (AUC0–24) and the area under the curve to minimum inhibitory concentration ratio (AUC0–24/MIC)] and the overall clinical outcomes (clinical efficacy and microbiological efficacy) in Chinese pediatric patients were evaluated. There is no significant correlation between PK/PD indices and clinical efficacy or microbiological efficacy. Considering the high clinical effective rate (>90%) and median AUC0–24/MIC values of 200–300, Chinese pediatric patients with Gram-positive bacterial infection may be suitable for lower AUC0–24/MIC target value compared to the target value of 400–600 recommended by IDSA guideline. Different optimal dose regimen of vancomycin for Chinese pediatric patients should be considered. Further evaluation in more prospective studies will be needed.

To evaluate the effects of component contents in different colistin methanesulfonate (CMS) formulas on their clinical pharmacokinetics of the prodrug CMS and the formed colistin.Two CMS formulas (CTTQ and Parkedale) were investigated in a single dose, randomized, open-label, crossover study conducted in 18 healthy Chinese subjects. Both CMS formulas met the requirements of European Pharmacopoeia 9.2 with 12.1% difference in the two major active components (CMS A and CMS B). The PK parameters after a single intravenous infusion of CMS at 2.5 mg/kg were calculated and the steady-state plasma colistin concentrations (CThe systemic exposure (AUCThe difference in component content in the two CMS formulas had a significant (P 0.001) impact on the systemic exposure of colistin in human, thus, warranted essential considerations in clinical applications.

A novel Lewis base-catalyzed [4 + 3] annulation process for the construction of benzo[b]oxepine scaffolds has been developed. 1,4-Diazabicyclo[2.2.2]octane (DABCO) promotes the union of o-QMs and Morita–Baylis–Hillman carbonates in reasonable to excellent yields and good stereoselectivities (dr > 20:1). This straightforward, catalytic approach offers access to a variety of synthetically useful benzo[b]oxepine derivatives bearing oxindole scaffolds containing all-carbon spiro-quaternary stereocenters.

A rapid ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay method was developed for determination of CMS and formed colistin in human plasma and urine. After extraction on a 96-well SPE Supra-Clean Weak Cation Exchange (WCX) plate, the eluents were mixed and injected into the UHPLC-MS/MS system directly. A Phonomenex Kinetex XB-C18 analytical column was employed with a mobile phase consisting of solution "A" (acetonitrile:methanol, 1:1, v/v) and solution "B" (0.1% formic acid in water, v/v). The flow rate was 0.4 mL/min with gradient elution over 3.5 min. Ions were detected in ESI positive ion mode and the precursor-product ion pairs were m/z 390.7/101.3 for colistin A, m/z 386.0/101.2 for colistin B, and m/z 402.3/101.2 for polymyxin B1 (IS), respectively. The lower limit of quantification (LLOQ) was 0.0130 and 0.0251 mg/L for colistin A and colistin B in both plasma and urine with accuracy (relative error, %)

The high prevalence of extensively drug-resistant Gram-negative pathogens has forced clinicians to use colistin as a last-line therapy. Knowledge on the pharmacokinetics of colistin methanesulfonate (CMS), an inactive prodrug, and colistin has increased substantially; however, the pharmacokinetics in the Chinese population is still unknown due to lack of a CMS product in China. This study aimed to evaluate the pharmacokinetics of a new CMS product developed in China in order to optimise dosing regimens. A total of 24 healthy subjects (12 female, 12 male) were enrolled in single- and multiple-dose pharmacokinetic (PK) studies. Concentrations of CMS and formed colistin in plasma and urine were measured, and PK analysis was conducted using a non-compartmental approach. Following a single CMS dose [2.36 mg colistin base activity (CBA) per kg, 1 h infusion], peak concentrations ( C max ) of CMS and formed colistin were 18.0 mg/L and 0.661 mg/L, respectively. The estimated half-life ( t 1/2 ) of CMS and colistin were 1.38 h and 4.49 h, respectively. Approximately 62.5% of the CMS dose was excreted via urine within 24 h after dosing, whilst only 1.28% was present in the form of colistin. Following multiple CMS doses, colistin reached steady-state within 24 h; there was no accumulation of CMS, but colistin accumulated slightly ( R AUC = 1.33). This study provides the first PK data in the Chinese population and is essential for designing CMS dosing regimens for use in Chinese hospitals. The urinary PK data strongly support the use of intravenous CMS for serious urinary tract infections.

Ovarian cancer is the leading cause of death among all gynecological cancers. This is mainly attributed to its frequent presentation at an advanced stage (International Federation of Gynecology and Obstetrics stage III-IV). Nuclear factor-kappaB (NF-κB) is critically involved in the carcinogenesis and development of ovarian cancer. A functional insertion/deletion polymorphism (-94 ins/del ATTG) in the promoter region of the NFKB1 gene, which encodes the p50 subunit of the NF-κB protein, has been recently identified and shown to increase the susceptibility to many diseases. The purpose of this study was to explore the association between this polymorphism and the risk of advanced ovarian cancer in a Chinese population. A total of 179 advanced ovarian cancer patients and 223 healthy controls were recruited into this study. Genotypes were determined using polymerase chain reaction-capillary electrophoresis method. The insertion increased the risk of advanced ovarian cancer (odds ratio = 2.111, 95% confidence intervals = 1.125-3.961, p = 0.019 for heterozygote insertion, and odds ratio = 2.656, 95% confidence intervals = 1.397-5.051, p = 0.002 for homozygote insertion) compared with homozygote deletion. Similar results were seen in age-adjusted analyses (p 0.05). Our preliminary results suggest that NFKB1-94 ins/del ATTG promoter polymorphism may be associated with increased susceptibility to advanced ovarian cancer.

Studies on how acute stress and the stress-related hormones affect learning and memory have yielded inconsistent findings, which might be due to some variables such as the properties of stressors, the nature of memory, the protocols for behavioral tasks and the characteristics of the subjects. However, the impacts of acute stress on different memory components have not been clearly demonstrated within one single experiment. The aim of present study was to evaluate the effects of 1-h restraint stress and the stress-induced plasma corticosterone elevation on memory acquisition, consolidation, and retrieval in mice, using object-recognition task (ORT) and object-location task (OLT) with a 4-h or 24-h intertrial interval (ITI). The results showed that, regardless of ITI, the recognition memory retrieval was significantly disrupted by acute restraint stress exposure, which started 75 min before the test session of both ORT and OLT. Acute restraint stress performed immediately after memory acquisition interrupted the consolidation of short-term recognition memories (4-h ITI) into long-term ones (24-h ITI). Moreover, the disrupted memory retrieval or consolidation was strongly related to the stress-induced plasma corticosterone elevation in a negative manner. These preliminary results clarified that acute restraint stress differently impacts three memory components, and the enhanced plasma corticosterone level under stressful situation plays critical roles in the information processing of memory under the stressful situation.