Paediatric acute kidney injury induced by vancomycin monotherapy versus combined vancomycin and meropenem.

WHAT IS KNOWN AND OBJECTIVE: Increasing reports of the combined use of vancomycin (VAN) and piperacillin/tazobactam leading to higher nephrotoxicity have led to carbapenems being recommended as an alternative option to combine with VAN when nephrotoxicity is a major concern. However, whether carbapenems also increase the nephrotoxicity of VAN is unclear. This study aimed to determine whether meropenem is a suitable drug to combine with VAN based on whether meropenem enhances the nephrotoxicity of VAN. METHODS: This retrospective cohort study enrolled hospitalized children ranging in age from 1 month to 18 years at two tertiary hospitals from 1 February 2017 to 1 February 2018. Patients treated with either VAN or combined VAN and meropenem (VM) for more than 48 hours were eligible for inclusion. Those with underlying kidney diseases or abnormal age-adjusted baseline serum creatinine (SCr) at admission were excluded. Propensity score matching (PSM) was applied to the patients to balance factors associated with acute kidney injury (AKI). In addition, VAN trough concentrations were also compared. AKI was defined as an increase in SCr by ≥50% from baseline or by ≥0.3 mg/dL sustained over at least two consecutive measurements ranging from the time of initiation until 72 hours after the completion of VAN therapy. RESULTS AND DISCUSSION: The eligibility criteria were met by 183 of 243 identified patients: 101 patients received VAN alone and 82 received VM. PSM resulted in 154 hospitalized children being included (77 patients in each group). The incidence of AKI was 10.7% (8/77) in both of the compared groups, while the VAN trough concentration was significantly higher in the VM group (9.0 mg/L) than in the VAN group (6.6 mg/L, P = 0.007) after controlling for confounders. WHAT IS NEW AND CONCLUSION: Despite the elevated VAN trough concentration, meropenem did not increase the nephrotoxicity of VAN and might therefore be an acceptable antibiotic to combine with VAN when necessary.

Methotrexate and 5-aminoimidazole-4-carboxamide riboside exert synergistic anticancer action against human breast cancer and hepatocellular carcinoma.

AIM: To investigate the influences of methotrexate (MTX) on the anticancer actions and pharmacokinetics of 5-aminoimidazole-4-carboxamide riboside (AICA riboside) in human breast cancer and hepatocellular carcinoma. METHODS: Human breast cancer cell line MCF-7 and human hepatocellular carcinoma cell line HepG2 were examined. The cell proliferation was assessed using a sulforhodamine B assay. Western blotting and radioactivity assays were used to analyze the phosphorylation of AMPK. The DNA synthesis was analyzed with BrdU incorporation. Nude mice bearing MCF-7 cell xenografts were used to for in vivo study. MTX (50 mg/kg, ip, per week) and AICA riboside (200 mg/kg, ip, every other day) were administered the animals for 2 weeks. The concentrations of AICA riboside and its active metabolite AICA ribotide in the plasma and tumors were measured with HPLC. RESULTS: Synergistic cytotoxicity in vitro was observed with MTX (0.1, 0.5, and 1 µmol/L) combined with AICA riboside (0.25-1 mmol/L) in MCF-7 cells, and with MTX (0.5 and 1 µmol/L) combined with AICA riboside (0.5 and 1 mmol/L) in HepG2 cells. MTX (1 µmol/L) significantly enhanced the AICA riboside-induced AMPK activation and BrdU incorporation in both MCF-7 and HepG2 cells. Co-treatment with MTX and AICA riboside exerted more potent inhibition on the tumor growth in nude mice than either drug alone. After injection of AICA riboside (200 mg/kg, iv) in nude mice bearing MCF-7 xenografts, MTX (50 mg/kg, iv) significantly increased the concentrations of AICA riboside and its active metabolite AICA ribotide in tumors. CONCLUSION: MTX and AICA riboside exert synergistic anticancer action against MCF-7 and HepG2 cells in vitro and in vivo. MTX increases the concentration of AICA riboside and its active metabolite AICA ribotide in tumors in vivo.

Maximizing band gaps in two-dimensional photonic crystals in square lattices.

This paper is devoted to a numerical algorithm for the maximization of band gaps in two-dimensional photonic crystals in square lattices. We first apply the finite element method to solve the eigenvalue problem, then use the piecewise constant level set (PCLS) method to maximize the band gaps. The PCLS method is very powerful for representing and modeling regions of different structures. Extremely large gaps are realized with gallium arsenide material, for transverse magnetic field (TM), transverse electric field (TE), and for complete band gaps. When the mean gap frequency is below 1, the biggest gap is about 0.2922 for the TE.

Population pharmacokinetics of cyclosporine A based on NONMEM in Chinese allogeneic hematopoietic stem cell transplantation recipients.

To set up a population pharmacokinetic (PPK) model of cyclosporine A (CsA) in Chinese allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients to provide reference for individualized medication in clinical practice. 281 trough plasma concentrations of CsA and covariates such as demographics, clinical laboratory values and coadministration were retrospectively collected from 73 allo-HSCT patients. Population modeling was performed using general model of NONMEM expressed by differential equation. Hematocrit (HCT), plasma albumin (ALB) level, and coadministration of itraconazole (ITR) were found to significantly affect the clearance of CsA (CL, L/h). The final model formula was: CL = 28.2 × [1 - 0.0263 × (HCT - 26.62)] × [1 - 0.0289 × (ALB - 37.63)] × [1 - 0.146 × ITR] (L/h); V = 1,080 (L); K (a) = 1.28 (h⁻¹); F = 0.711. The interindividual variabilities for CL, V and F were 21.4, 41.5 and 6.07 %, respectively. The residual error was 0.00422 mg/L. The PPK model was validated to be effective and stable by bootstrap method. Clinical applications showed there was a good linear correlation between the predicted concentrations and the observed (y = 1.0095x + 0.0082, r = 0.9309, p < 0.0001). The PPK final model of CsA in Chinese allo-HSCT patients can be established using the NONMEM program which can be applied in clinical allo-HSCT practice when characteristics of patients fit in with those of subpopulation in the study.

Quantitative analysis and pharmacokinetic study of a novel diarylurea EGFR inhibitor (ZCJ14) in rat plasma using a validated LC-MS/MS method.

1-(4-(Pyrrolidin-1-yl-methyl)phenyl)-3-(4-((3-(trifluoromethyl) phenyl)amino)quinazolin-6-yl)urea (ZCJ14), a novel epidermal growth factor receptor (EGFR) inhibitor, with diarylurea moiety, displays anticancer effect. In the present study, an LCMS/MS method was established to determine the concentration of ZCJ14 in rat plasma. Furthermore, the method was applied to investigate the pharmacokinetic characteristics of ZCJ14. Chromatographic separation of ZCJ14 and internal standard (IS) [1-phenyl-3-(4-((3-(trifluoromethyl)phenyl)amino) quinazolin-6-yl)urea] was accomplished by gradient elution using the Kromasil C18 column. The selected reaction monitoring transitions were performed at m/z 507.24→436.18 and 424.13→330.96 for ZCJ14 and IS, resp. The established method was linear over the concentration range of 10-1000 ng mL-1. The intra- and inter-day precisions were < 11.0 % (except for LLOQ which was up to 14.3 %) and the respective accuracies were within the range of 87.5-99.0 %. The extraction recovery and matrix effect were within the range of 88.4-104.5 % and 87.3-109.9 %, resp. ZCJ14 was stable under all storage conditions. The validated method was successfully applied to the pharmacokinetic study of ZCJ14 in rats, and the pharmacokinetic parameters have been determined. The oral bioavailability of ZCJ14 was found to be 46.1 %. Overall, this accurate and reliable quantification method might be useful for other diarylurea moiety-containing drugs.

Catalytic dynamic spectrofluorimetry determination of trace antimony using new type arsenoxylphenylazo rhodanine.

A precise, simple, new spectrofluorimetry method is proposed for determination of trace antimony which is based on the reaction between potassium periodate and the new type fluorescent reagent 3-o-chlorophenyl-5-(2'- arsenoxylphenylazo) rhodanine (2ClRAAP). The possible mechanism is proposed. The fluorescence intensity is investigated to be sharply enhanced by the oxidation of 3-o-chlorophenyl-5-(2'-arsenoxylphenylazo) rhodanine by potassium periodate with antimony as catalyst in the buffer medium of potassium hydrogen phthalate-sodium hydroxide (pH 5.2). Under the optimum conditions the great increase of fluorescence intensity has a linear relationship against the concentration of antimony in the range of 0.2-10 microg L(-1) with a detection limit of 1.65 x 10(-10) g mL(-1). This proposed method led to the satisfied determination of antimony in environment water.

Paclitaxel-loaded trimethyl chitosan-based polymeric nanoparticle for the effective treatment of gastroenteric tumors.

Gastroenteric cancer is one of the most prevalent cancers and is responsible for most cancer-related deaths worldwide. Paclitaxel (PTX), a classical microtubule inhibitor, is indicated in the treatment of gastric/gastroenteric cancers. In the present study, trimethyl chitosan (TMC)-loaded PTX (TMC-PTX) was prepared and evaluated for its therapeutic effect in gastric cancers. A spherical shaped nanosized TMC-PTX particle was formed with high loading capacity (~30%) for PTX. The nanoparticles (NPs) showed a sustained release pattern (~70%) for up to 96 h of study period. The positively charged NPs were preferentially internalized by Caco-2 cells. TMC-PTX inhibited the gastric cell proliferation with an IC50 value of 0.6 µg in NCI-N87 cells while it was 1.26 µg in the SGC-7901 cell line after 24 h exposure. The apoptosis assay (Annexin V/PI) showed a large presence of cells in the early and late apoptosis chamber, while cell cycle analysis showed a marked G2/M phase arrest (50-60%) in NCI-N87 and SGC-7901 cell lines indicating its potent anti-proliferative effect. The in vivo antitumor study in NCI-N87 and SGC-7901 bearing xenograft model showed a superior chemotherapeutic efficacy for TMC-PTX NP. The NP group significantly reduced the tumor growth with no obvious sign of systemic side-effects (safety). Collectively, our results suggest that the microtubule inhibitory effect of PTX-loaded polymer NP could be a promising system for the treatment of gastroenteric cancers.

GRP78 mediates radiation resistance of a stem cell-like subpopulation within the MCF-7 breast cancer cell line.

Emerging evidence indicates that breast cancer-initiating cells (CICs) are relatively resistant to radiotherapy; however, the critical mechanisms determining breast CIC resistance to radiation remain elusive. In the present study, a subpopulation of cells displaying characteristics generally attributed to stem cells was identified within the breast cancer cell line MCF-7. This subpopulation displays cancer stem cell features characterized by overexpression of embryonic stem cell markers, high tumorigenic potential following transplantation into BALB/c-nu mice, self-renewal capacity and resistance to ionizing radiation (IR). Moreover, glucose­regulated protein 78KD (GRP78), which was found to play a crucial role in stem cell oncogenesis, was also shown to be overexpressed in this subpopulation. GRP78 is required for the cancer stem-like subpopulation cell resistance to IR, as knockdown of this gene augments the effects of IR, while overexpression of GRP78 increases the radiation resistance of the subpopulation to IR. These findings indicate that GRP78 acts as a potential therapeutic target aimed at tumor-generating subsets of breast cancer cells.