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Amoxicillin, a broad-spectrum [beta]-lactam antibiotic, is widely used for treatment of neonatal infections. Despite the unmet need in neonates, an adapted analytical method is still missing in clinical practice. The purpose of this study was to develop and test an easy and credible high performance liquid chromatography-UV (HPLC-UV) method to determine amoxicillin in small volumes of human plasma and use it in routine therapeutic drug monitoring (TDM) of neonates. After a protein precipitation, amoxicillin for standards, quality control samples, and patient samples were separated by LC and measured by UV detection, and tinidazole was used as the internal standard. The calibration range was 0.50-20.0 [micro]g/mL. Intra- and inter-day precisions were less than 4.7%. The acceptance criteria of accuracy (between 85-115%) were met in all cases. A plasma volume of 50 [micro]L was required to achieve the limit of quantification of 0.50 [micro]g/mL. Thus, a simple, rapid, and accurate HPLC-UV method has been developed to detect the concentration of amoxicillin in human plasma. This method was adapted to do TDM of amoxicillin in neonates., Amoxicillin ([C.sub.16][H.sub.19][N.sub.3][O.sub.5]S, Figure 1) is one of the most commonly prescribed antimicrobial drugs in the world (1,2). Amoxicillin is prescribed for various infections including nose, ear, throat, and skin infections, [...]

Summary: Colorectal cancer is one of the most serious tumors and berberine can inhibit the recurrence and transformation of colorectal adenoma into colorectal cancer. However, the direct binding target proteins of berberine in inhibiting colorectal cancer remain unclear. In this study, the chemical proteomics method was used and demonstrated that berberine is directly bound to pyruvate kinase isozyme type M2 (PKM2) in colorectal cancer cells. The triangular N-O-O triangular structure of berberine contributed to hydrophobic interaction with I119 amino acid residues and π-π interaction with F244 amino acid residues of PKM2 protein. Moreover, berberine was shown to inhibit the reprogramming of glucose metabolism and the phosphorylation of STAT3, down regulate the expression of Bcl-2 and Cyclin D1 genes, ultimately inhibiting the progression of colorectal cancer. This study uncovered the direct binding target protein and mechanism of berberine to improve metabolic reprogramming in colorectal cancer, which is helpful to guide the optimization of berberine.

Comprehensive Summary: A new family of trinuclear windwheel complexes with molecular formula [MII3(tpa)3(μ‐ttc)](ClO4)3·n(sol) (ttc = 1,3,5‐triazine‐2,4,6‐trithiol; tpa = tris(2‐pyridylmethyl)amine; M = Mn, n = 2, sol = CH3CN, 1; M = Co, n = 1, sol = CH3CN, 2; M = Ni, n = 0, 3) were synthesized and characterized. Single‐crystal X‐ray diffraction revealed that three metal centers in 1—3 are connected by ttc bridge, forming a regular triangular MII3 core. Each metal center is bonded by chelating S, N atoms from ttc and by N atoms from tpa. Magnetic studies showed that 1—3 displayed antiferromagnetic behavior and further gave the easy‐axis anisotropy (D = −0.77 cm−1 for 1 and −8.13 cm−1 for 2) and easy‐plane anisotropy (D = 5.08 cm−1 for 3). Moreover, 2 exhibited field‐induced slow magnetic relaxation behavior and their effective energy barriers were roughly evaluated Ueff = 6.9 K. [ABSTRACT FROM AUTHOR]

The objective of this study was to establish a nomogram model to predict SI in patients with cancer and further evaluate its performance. This study was performed among 390 patients in oncology departments of Affiliated Hospital of Nantong University from April 2020 to January 2021. Of these, eligible patients who were diagnosed with cancer were split into training and validation cohorts according the ratio of 2:1 randomly. In the training cohort, multivariate regression was performed to determine the independent variables related to SI. A nomogram was built incorporating these variables. The model performance was evaluated by an independent validation cohort. The prevalence of SI in patients with cancer was 22.31% and 19.23% in training and validation cohorts, respectively. The nomogram model suggested independent variables for SI, including depression, emotional function, time after diagnosis, family function and educational status. The area under the curve (AUC) was 0.93 (95%CI, 0.90–0.97) and 0.82 (95%CI, 0.74–0.90) in training and validation cohorts respectively, which indicated good discrimination of the nomogram in predicting SI in cancer patients. The p-value of the goodness of fit (GOF) test was 0.197 and 0.974 in training and validation cohorts respectively, suggesting our nomogram model has acceptable calibration power, and the calibration curves further indicated good calibration power. In conclusion, the nomogram model for predicting individualized probability of SI could help clinical caregivers estimate the risk of SI in patients with cancer and provide appropriate management. [ABSTRACT FROM AUTHOR]

A high-salt diet often leads to a local intrarenal increase in renal hypoxia and oxidative stress, which are responsible for an excess production of pathogenic substances. Here, Wistar Kyoto/spontaneous hypertensive (WKY/SHR) rats fed a high-salt diet developed severe proteinuria, resulting from pronounced renal inflammation, fibrosis and tubular epithelial cell apoptosis. All these were mainly non-pressure-related effects. Hsp90β, TGF-β, HIF-1α, TNF-α, IL-6 and MCP-1 were shown to be highly expressed in response to salt loading. Next, we found that Hsp90β might play the key role in non-pressure-related effects of salt loading through a series of cellular signalling events, including the NF-κB, p38 activation and Bcl-2 inactivation. Hsp90β was previously proven to regulate the upstream mediators in multiple cellular signalling cascades through stabilizing and maintaining their activities. In our study, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) or Hsp90β knockdown dramatically alleviated the high-salt-diet-induced proteinuria and renal damage without altering blood pressure significantly, when it reversed activations of NF-κB, mTOR and p38 signalling cascades. Meanwhile, Co-IP results demonstrated that Hsp90β could interact with and stabilize TAK1, AMPKα, IKKα/β, HIF-1α and Raptor, whereas Hsp90β inhibition disrupted this process. In addition, Hsp90β inhibition-mediated renal improvements also accompanied the reduction of renal oxidative stress. In conclusion, salt loading indeed exhibited non-pressure-related impacts on proteinuria and renal dysfunction in WKY/SHR rats. Hsp90β inhibition caused the destabilization of upstream mediators in various pathogenic signalling events, thereby effectively ameliorating this nephropathy owing to renal hypoxia and oxidative stress.

Five novel trinuclear nickel(II) clusters were successfully synthesized, namely Ni3(fshz)2(L)4·n(sol) (H3fshz = N-formylsalicylhydrazide; L = pyridine, n = 0, 1; L = 4-methylpyridine, n = 1, sol = CH3CN, 2; L = 4-ethylpyridine, n = 2, sol = CH3OH, 3; L = 4-vinylpyridine, n = 1, sol = CH3OH, 4; and L = 2,6-pyridinedimethanol, n = 2, sol = CH3OH, 5). Single-crystal X-ray diffraction revealed that the metallic skeletons of 1–5 were built by three Ni(II) ions, two fshz3− units, and four auxiliary ligands. The coordination geometry of the Ni(II) ions in 1–5 are followed in two modes: square-planar and/or octahedral. Magnetic studies showed that 1–5 displayed intermolecular antiferromagnetic behavior and all the square-planar Ni(II) ions were diamagnetic as certified. Moreover, 1–4 presented easy-axis anisotropy with D = −4.02, −5.31, −4.82, and −3.65 cm−1, respectively, while 5 presented easy-plane anisotropy (D = 11.06 cm−1) due to the different coordination mode. [ABSTRACT FROM AUTHOR]

Aims: Meropenem is increasingly used to treat neonatal sepsis. There are several guidelines recommending different dosing regimens of meropenem in neonates. Furthermore, deviations from these guidelines regularly occur in daily clinical practice. Therefore, the current study aimed to evaluate the variations of meropenem dosing guidelines and compare the difference between guideline and clinical practice in terms of the probability of target attainment. Methods: This study is based on a population pharmacokinetic model. After defining the predictive performance of the model, Monte Carlo simulations were used to calculate the probability of target attainment of the currently existing dosing guidelines of meropenem and their use in daily clinical practice. Results: Two guidelines and two labels were included in the Monte Carlo simulations. For 70% fT>MIC (fraction of time when the free meropenem concentration exceeded the minimum inhibitory concentration during the dosing interval), the probability of target attainment of four recommended doses ranged from 59% to 88% (MIC = 2 mg·L−1) and from 17% to 47% (MIC = 8 mg·L−1). At the clinical practice evaluation, only 20% of patients attained target exposure for the MIC of 8 mg·L−1 with 70% fT>MIC, which was much less than those found in the Food and Drug Administration labels (40%). Conclusion: This model‐based population pharmacokinetics simulation showed that improper guidelines and/or clinical practice deviations will result in low probability of target attainment for patients infected with resistant bacteria and critically ill patients. It is important to develop and adhere to evidence‐based and clinically pragmatic guidelines. [ABSTRACT FROM AUTHOR]

Severe burn shock remains an unresolved clinical problem with an urgent need to explore novel therapeutic treatments. Intracellular β-catenin, through interaction with other proteins, has been reported to be able to regulate the size of cutaneous wounds. Higher expression of β-catenin is associated with larger sized wounds. However, the identification of serum β-catenin complex is difficult and has been rarely reported. The exploitation of more binding partners can contribute to uncovering the exact mechanisms behind serum β-catenin mediated biological effects. Here, we describe a method that consists of immunoprecipitation, SDS-PAGE, in-gel digestion, and nanoLC coupled to LCMS-IT-TOF for the investigation of serum β-catenin complex in mice scald model. Among selected gel bands obtained from the protein gels, a total of 31 peptides were identified and sequenced with high statistical significance (p

Aims: Early‐onset sepsis (EOS) is a common disease in neonates with a high morbidity and mortality rate. Piperacillin/tazobactam has been used extensively and empirically for EOS treatment without clinically validated dosing regimens, although the population pharmacokinetics (PPK) of piperacillin in neonates has been reported. Therefore, we wanted to study the effectiveness and tolerance of a PPK model‐based dosing regimen of piperacillin/tazobactam in EOS patients. Methods: A prospective, single‐centre, phase II clinical study of piperacillin/tazobactam in neonates with EOS was conducted. The dosing regimen (90 mg·kg−1, q8h) was determined based on a previous piperacillin PPK model in young infants using NONMEM v7.4. The pharmacodynamics (PD) target (70%fT > MIC, free drug concentration above MIC during 70% of the dosing interval) attainment was calculated using NONMEM combined with an opportunistic sampling design. The clinical treatment data were collected. Results: A total of 52 neonates were screened and 49 neonates completed their piperacillin/tazobactam treatment course and were included in this analysis. The median (range) values of postmenstrual age were 33.57 (range 26.14–41.29) weeks. Forty‐seven (96%) neonates reached their PD target. Eight (16%) neonates experienced treatment failure clinically. The mean (SD, range) duration of treatment and length of hospitalization were 100.1 (62.2, 36.2–305.8) hours and 31 (30, 5–123) days. There were no obvious adverse events and no infection‐related deaths occurred in the first month of life. Conclusions: A model‐based dosing regimen of piperacillin/tazobactam was evaluated clinically, was tolerated well and was determined to be effective for EOS treatment. [ABSTRACT FROM AUTHOR]

Two pairs of pure enantiomers of high-nuclearity chiral lanthanide–oxo clusters with the formulas [Y14(L)16(μ3-OH)16(H2O)20]·(ClO4)10·xH2O (x ≈ 55; L = L -L− for L -Y14; L = D -L− for D -Y14) and [Dy14(L)16(μ3-OH)16(H2O)20]·(ClO4)10·xH2O (x ≈ 67; L = L -L− for L -Dy14; L = D -L− for D -Dy14) were prepared in the presence of chiral ligands N-acetyl- L -alanine (L -HL) and N-acetyl- D -alanine (D -HL). Structural analysis showed that four cubane-like units as building blocks sharing vertices formed the lanthanide–oxo cluster unit {(ClO4)2@[Y12(μ3-OH)16]}18+ with two ClO4− as anion templates. The remaining Y3+ ions were connected to the opposite position of {(ClO4)2@[Y12(μ3-OH)16]}18+ through four L -L−, respectively. High-resolution electrospray ionization mass spectrometry (HRESI-MS) captured the signals of the cluster fragment {Y12(OH)16−x(O)x} (x = 4, 5, 6, 7, 8) and the unbroken dimer of {Y12(L -L)12(OH)16−x(O)x}2 (x = 4, 5, 12) from L -Y14 in a mixed solution of methanol and dichloromethane, suggesting that {Ln12(OH)16−x(O)x} is a stable cluster unit that could be further assembled into higher-nuclearity lanthanide–oxo clusters in solution. The solid-state circular dichroism (CD) spectra of compounds L -Y14/ D -Y14 and L -Dy14/ D -Dy14 displayed mirror symmetry effects in the range of 220–250 nm. The study of magnetic properties showed that L -Dy14 had a weak antiferromagnetic interaction and displayed SMM-like behavior in the absence of a dc field. [ABSTRACT FROM AUTHOR]

Aims: This open‐label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony‐stimulating factor (PEG‐rhG‐CSF) for the treatment of chemotherapy‐induced neutropenia in children with acute leukaemia. Methods: PEG‐rhG‐CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG‐rhG‐CSF. PEG‐rhG‐CSF serum concentrations were determined by an enzyme‐linked immunosorbent assay. Population pharmacokinetic (PPK) analysis was implemented using the nonlinear mixed‐effects model. Short‐term safety was evaluated through adverse events collection (registered at clinicaltrials.gov identifier: 03844360). Results: A total of 16 acute leukaemia patients (1.8–13.6 years) were included, of whom two (12.5%) had grade 3 neutropenia, six (37.5%) had grade 4 neutropenia, and eight (50.0%) had severe neutropenia. For PPK modelling, 64 PEG‐rhG‐CSF serum concentrations were obtainable. A one‐compartment model with first‐order elimination was used for pharmacokinetic data modelling. The current weight was a significant covariate. The median (range) of clearance (CL) and area under the serum concentration–time curve (AUC) were 5.65 (1.49–14.45) mL/h/kg and 16514.75 (6632.45–54423.30) ng·h/mL, respectively. Bone pain, pyrexia, anaphylaxis and nephrotoxicity were not observed. One patient died 13 days after administration, and the objective assessment of causality was that an association with PEG‐rhG‐CSF was "possible". Conclusions: The AUC of PEG‐rhG‐CSF (100 mcg/kg, 3 mg maximum dose) in paediatric patients with acute leukaemia were similar to those of PEG‐rhG‐CSF (100 mcg/kg) in children with sarcoma. PEG‐rhG‐CSF is safe, representing an important therapeutic option for chemotherapy‐induced neutropenia in paediatric patients with acute leukaemia. [ABSTRACT FROM AUTHOR]

Objective: The elucidation of CYP2D6 developmental pharmacogenetics in children has improved, however, these findings have been largely limited to studies of Caucasian children. Given the clear differences in CYP2D6 pharmacogenetic profiles in people of different ancestries, there remains an unmet need to better understand the developmental pharmacogenetics in populations of different ancestries. We sought to use loratadine as a substrate drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese pediatric patients. Methods: Chinese children receiving loratadine treatment were enrolled in the present study. The metabolite-to-parent ratio (M/P ratio), defined as the molar ratio of desloratadine to loratadine of trough concentrations samples at steady-state condition, was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method. Variants of CYP2D6 were genotyped by polymerase chain reaction for CYP2D6 *4, *10, *41 and long polymerase chain reaction for CYP2D6 *5. Results: A total of 40 patients were available for final analysis. The mean age was 4.50 (range 0.50–9.00) years and the mean weight was 19.64 (range 7.00–42.00) kg. The M/P ratio was significantly lower in intermediate metabolizers (IMs) compared to normal metabolizers (NMs) (10.18 ± 7.97 vs. 18.80 ± 15.83, p = 0.03). Weight was also found to be significantly associated with M/P ratio (p = 0.03). Conclusion: The developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a substrate drug. This study emphasizes the importance of evaluating the developmental pharmacogenetics in populations of different ancestries. [ABSTRACT FROM AUTHOR]

Purpose: Considering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL. Subjects and Methods: ALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Results: Plasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway. Conclusion: Inflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments. [ABSTRACT FROM AUTHOR]