Ti Meng

Pharmacokinetic/pharmacodynamic adequacy of echinocandins against Candida spp. in intensive care unit patients and general patient populations

This study evaluated whether contemporary echinocandin regimens achieved pharmacokinetic/pharmacodynamic targets in ICU patients and general patient populations (GPPs) and assessed caspofungin (CAS) regimens in hepatic impairment (HI) patients. A Monte Carlo simulation was performed using previously published data. Recommended dosing regimens of echinocandins in ICU patients, GPPs and healthy volunteers were evaluated: 70mg loading dose then 50mg maintenance dose (70/50mg) for CAS; 100mg q24h for micafungin (MCF); and 200/100mg for anidulafungin (ANF). Moreover, CAS 70mg and 100mg q24h in GPPs, and CAS 70/50mg and 70/35mg in mild and moderate HI patients, respectively, were evaluated. Cumulative fraction of response (CFR) was calculated for each dosing regimen. For Candida albicans, CFRs for the recommended doses of CAS, MCF and ANF were 95.8%, 13.5% and 50.5% in ICU patients and 96.3%, 42.4% and 61.6% in GPPs, respectively; for Candida glabrata, CFRs were 99.4%, 90.6% and 44.6% in ICU patients and 99.5%, 97.1% and 59.8% in GPPs. For Candida parapsilosis, CFRs of echinocandins for standard regimens were <70%; only CAS 100mg q24h achieved the target CFR. CAS 70/50mg and 70/35mg in mild and moderate HI patients were appropriate. Considerable interindividual variability was observed. For C. albicans and C. glabrata, CAS is good choice both for ICU and other patient populations, but for C. parapsilosis an increased dose should be considered. For MCF and ANF, administering higher doses with longer dosing intervals achieves better target attainment and should be investigated in clinical trials.

Transgelin-2: A potential oncogenic factor

Actin-binding proteins are proteins that could bind to actin or actin fibers. As a member of actin-binding proteins, Transgelin-2 is expressed in smooth muscle cells and non-smooth muscle cells, and its gene, TAGLN2, is differently expressed in all cells and tissues. The deregulation of Transgelin-2 is considered to be correlated with progression of many kinds of diseases, especially the development of malignant tumors, such as invasion, metastasis, and resistance, yet the function and mechanism of action of Transgelin-2 remain elusive. Therefore, we reviewed the basic characteristics and function of Transgelin-2 and its biological role in various types of diseases in order to provide the theoretical basis for further research and new perspectives on cancer development.

SET protein overexpression contributes to paclitaxel resistance in MCF-7/S cells through PI3K/Akt pathway

Abstract Patient SE translation (SET) is a carcinogen in facilitating cellular growth and proliferation, and promoting tumorigenesis and metastasis. The present study was to investigate the resistance mechanisms associated with SET in paclitaxel-induced human breast cancer cells. The different expressions of SET, ATP-binding cassette (ABC) transporters and PI3K/Akt pathway between paclitaxel sensitive MCF-7/S and paclitaxel resistant MCF-7/PTX cells were identified using western blotting. We adopted plasmid transfection to upregulate SET in MCF-7/S cells and a novel SET antagonist COG112 to decrease SET in MCF-7/PTX cells. Subsequently, cell viability to paclitaxel was assessed by MTT assay and cell apoptosis was analyzed by flow cytometry. We found that levels of SET, ABC transporters and PI3K/Akt pathway were elevated in MCF-7/PTX. Upregulation of SET in MCF-7/S cells expressed resistant to paclitaxel and decreased cell apoptosis. Moreover, overexpression of SET promoted the mRNA and protein level of ABC transporters and PI3K/Akt signal pathway in MCF-7/S cells. Conversely, decreased level of SET by COG112 not only significantly sensitized MCF-7/PTX cells to paclitaxel, but also enhanced paclitaxel-induced cell apoptosis. Additionally, the levels of the ABC transporters and PI3K/Akt signal pathway were also reduced in the COG112-treated MCF-7/PTX cells. The above results demonstrated that SET was associated with paclitaxel resistance in MCF-7/PTX cells.

SB-T-121205, a next-generation taxane, enhances apoptosis and inhibits migration/invasion in MCF-7/PTX cells

Breast cancer is the leading cause of cancer death among women. Paclitaxel, a mitotic inhibitor, is highly effective in the treatment of breast cancer. However, development of resistance to paclitaxel limits its clinical use. Identifying new compounds and new strategies that are effective against breast cancer, in particular drug-resistant cancer, is of great importance. The aim of the present study was to explore the potential of a next-generation taxoid, SB-T-121205, in modulating the proliferation, migration and invasion of paclitaxel-resistant human breast cancer cells (MCF-7/PTX) and further evaluate the underlying molecular mechanisms. The results of MTT assay showed that SB-T-121205 has much higher potency to human breast cancer cells (MCF-7/S, MCF-7/PTX and MDA-MB-453 cells) than paclitaxel, while that the non-tumorigenic human bronchial epithelial cells (BEAS-2B) were slightly less sensitive to SB-T-121205 than paclitaxel. Flow cytometry and western blot methods revealed that SB-T-121205 induced cell cycle arrest at the G2/M phase and apoptosis in MCF-7/PTX cells through accelerating mitochondrial apoptotic pathway, resulting in reduction of Bcl-2/Bax ratio, as well as elevation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP) levels. Moreover, SB-T-121205 changed epithelial-mesenchymal transition (EMT) property, and suppressed migration and invasion abilities of MCF-7/PTX cells. Additionally, SB-T-121205 exerted antitumor activity by inhibiting the transgelin 2 and PI3K/Akt pathway. These findings indicate that SB-T-121205 is a potent antitumor agent that promotes apoptosis and also recedes migration/invasion abilities of MCF-7/PTX cells by restraining the activity of transgelin 2 and PI3K/Akt, as well as mitochondrial apoptotic pathway. Such results suggest a potential clinical value of SB-T-121205 in breast cancer treatment.

Uptake and efflux kinetics, and intracellular activity of voriconazole against Aspergillus fumigatus in human pulmonary epithelial cells: a new application for the prophylaxis and early treatment of invasive pulmonary aspergillosis

Invasive pulmonary aspergillosis (IPA), most caused by Aspergillus fumigatus, is a serious life‐threatening infection in immunocompromised patients. Voriconazole is used to prevent and treat IPA. However, little is known about the pharmacological characteristics of voriconazole in pulmonary epithelial cells, which are the target site for the prophylaxis and early treatment of IPA. The aim of the study was to evaluate the kinetics and activity of voriconazole against A. fumigatus in A549 cells. High‐performance liquid chromatography/tandem mass spectrometry and time‐kill method were used to study the cellular pharmacokinetic and pharmacodynamics of voriconazole. Voriconazole exerted a concentration‐dependent toxic effect on A549 cells and could penetrate into cells, reaching plateau concentrations of 1.14 ± 0.64, 3.72 ± 1.38 and 6.36 ± 0.95 ng/mg protein after A549 cells were exposed to voriconazole at extracellular concentrations of 2, 8 and 16 mg/L for 2 h, respectively. The efflux of voriconazole was rapid, with a half‐life of 10.2 min. Voriconazole can decrease the A. fumigatus conidia invade cells, and the number of viable A. fumigatus conidia in cells can be decreased 2.1‐ to 20.6‐fold when A549 cells were cultured in medium containing voriconazole. After 24‐h incubation, 75.6% and 80.5% of intracellular A. fumigatus were killed when extracellular voriconazole concentration was 8 and 16 mg/L, respectively. This study illustrated a new application for the prophylaxis and early treatment of IPA from the cellular pharmacokinetics and pharmacodynamics and emphasized the importance of monitoring concentrations of voriconazole in epithelial lining fluid in immunocompromised patients receiving voriconazole therapy.

Meta-analysis of effects of ABCB1 polymorphisms on clopidogrel response among patients with coronary artery disease

PurposeThe substantial variability in the antiplatelet efficacy of clopidogrel has raised major concerns. Molecular epidemiological research suggests that ABCB1 C3435T polymorphism may be associated with clopidogrel response, but results remain controversial. To derive a more precise evaluation of the associations between ABCB1 C3435T polymorphism and the clinical efficacy of clopidogrel, we have conducted a PRISMA-compliant meta-analysis.MethodsThe PubMed and EMBASE databases were searched for eligible studies up to 25 October 2016. The odds ratio (OR), the standard mean difference (SMD) and 95% confidence interval (CI) were applied to assess the strength of the relationship.ResultsOverall, 28 related studies involving 23,243 patients were analyzed. No association was found between the ABCB1 polymorphisms and the primary outcome. In the subgroup analysis, the C3435T mutation significantly reduced platelet activity as tested by the LTA assay in the dominant (SMD −0.140, 95% CI −0.272 to −0.009, P = 0.036) and heterozygous (SMD −0.154, 95% CI −0.290 to −0.017, P = 0.027) models, but the result lacked robustness in the sensitivity analysis. A significant association between the C3435T polymorphism and bleeding risk was also observed with low heterogeneity in the dominant (OR 1.805, 95% CI1.124–2.900, P =0.015, I2 = 0%), homozygous (OR 1.952, 95% CI 1.055–3.611, P = 0.033, I2 = 13.2%) and heterozygous (OR 1.793, 95% CI 1.091–2.946, P = 0.021, I2 = 0%) models in Asian patients.ConclusionsThe results of the meta-analysis suggest that ABCB1 C3435T polymorphism may increase the risk of bleeding in Asian patients treated with clopidogrel. The implied relationship needs to be verified in future basic genetic pharmacology studies.

Choosing Optimal Antifungal Agents To Prevent Fungal Infections in Nonneutropenic Critically Ill Patients: Trial Sequential Analysis, Network Meta-analysis, and Pharmacoeconomic Analysis

ABSTRACT The use of antifungal interventions in critically ill patients prior to invasive fungal infection (IFI) being microbiologically confirmed and the preferred drug are still controversial. A systematic literature search was performed to identify randomized controlled trials (RCTs) that compared untargeted antifungal treatments applied to nonneutropenic critically ill patients. The primary outcomes were all-cause mortality and proven IFI rates. A random-effects model was used with trial sequential analyses (TSA), a network meta-analysis (NMA) was conducted to obtain indirect evidence, and a cost-effectiveness analysis using a decision-analytic model was completed from the patient perspective over a lifetime horizon. In total, 19 RCTs involving 2,556 patients (7 interventions) were included. Untargeted antifungal treatment did not significantly decrease the incidence of all-cause mortality (odds ratio [OR] = 0.89, 95% confidence interval [95%CI] = 0.70 to 1.14), but it did reduce the incidence of proven IFI (OR = 0.45, 95%CI = 0.29 to 0.71) relative to placebo/no intervention. The TSA showed that there was sufficient evidence supporting these findings. In the NMA, the only significant difference found for both primary outcomes was between fluconazole and placebo/no intervention in preventing proven IFI (OR = 0.35, 95%CI = 0.19 to 0.65). Based on drug and hospital costs in China, the incremental cost-effectiveness ratios per life-year saved for fluconazole, caspofungin, and micafungin relative to placebo/no intervention corresponded to US

Determination and Characterization of the Uptake of Voriconazole in Human Lung Epithelial Cells by High-Performance Liquid Chromatography–Tandem Mass Spectrometry

889, US

HDACI regulates the PI3K/Akt signaling pathway to reverse MCF-7/PTX resistance by inhibiting SET

9,994, and US

Fluconazole versus mould-active triazoles for primary antifungal prophylaxis in adult patients with acute lymphoblastic leukemia: clinical outcome and cost-effectiveness analysis

10,351, respectively. Untargeted antifungal treatment significantly reduced proven IFI rates in nonneutropenic critically ill patients but with no mortality benefits relative to placebo/no intervention. Among the well-tolerated antifungals, fluconazole remains the only one that is effective for IFI prevention and significantly cheaper than echinocandins.