ABSTRACT
OBJECTIVE Lapachol is a natural naphthoquinone compound that possesses extensive biological activities. The aim of this study is to investigate the inhibitory effects of lapachol on rat C6 glioma both in vitro and in vivo, as well as the potential mechanisms. METHODS The antitumor effect of lapachol was firstly evaluated in the C6 glioma model in Wistar rats. The effects of lapachol on C6 cell proliferation, apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)/ phenazinemethosulfate (PMS) assay, hoechst 33358 staining, annexinⅤ-FITC/PI staining, and comet assay. Effects of lapachol on topoisomerase I (TOP I) and topoi?somerase Ⅱ (TOP Ⅱ) activities were detected by TOP Ⅰ and TOP Ⅱ mediated supercoiled pBR322 DNA relaxation assays and molecular docking. TOPⅠ and TOPⅡ expression levels in C6 cells were also determined. RESULTS High dose lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats (P<0.05). It was showed that lapachol could inhibit proliferation, induce apoptosis and DNA damage of C6 cells in dose dependent manners. Lapachol could inhibit the activities of both TOPⅠ and Ⅱ. Lapachol-TOPⅠ showed relatively stronger interaction than that of lapachol-TOPⅡ in molecular docking study. Also, lapachol could inhibit TOPⅡ expression levels, but not TOPⅠ expression levels. CONCLUSION These results showed that lapachol could significantly inhibit C6 glioma both in vivo and in vitro, which might be related with inhibiting TOPⅠ and TOPⅡ activities, as well as TOPⅡ expression.
ABSTRACT
OBJECTIVE The aim of the study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) profile of cisatracurium in 0-2 years and 2-5 years old children patients with cheilopalatognathus, to find if there are some connections between the different muscle relaxation action and different PK procedure . METHODS 14 children patients were divided into two groups, ≤2 years and 2-5 years group, venous samples were taken before injection of a 0.15 mg·kg- 1 dose of cisatracurium and then at 2, 5, 10, 30, 60, 90, and 120 min. Cisatracurium plasma concentrations were determined by ultra- performance liquid chromatography/electrospray ionization/triple quadrupole tandem mass spectrometer system (UPLC/MS/MS). The degree of neuromuscular block was measured by train of four (TOF) testing. An indirect PK-PD link model with a sigmoid Emax model was established using Win Nonlin software. The model were applied to PK and PD data analysis, respectively. RESULTS The TOF monitor parameters showed that cisatracurium works very quickly, the onset time were (2.64± 0.93) min and (2.59 ± 0.90) min for ≤2 years and 2- 5 years group respectively. Young children ≤2 years have longer muscle blocking duration time (62.5 ± 6.01 min vs 53.86 ± 12.18 min) and slower recovery index (32.14±7.10 min and 27.43±10.63 min) than those children in group of 2-5 years. More children ≤2 years have postoperative complication than that in 2-5 children. PK parameters showed that there were no statistical differences in blood concentration and pharmacokinetic parameters. While the concentration of cisatracurium in muscle site calculated by using PK/PD model were higher and longer for ≤2 year children than that of 2-5 year children. This means that cisatracurium could stay at high concentration for a longer time in younger children' muscle tissue. CONCLUSION As a result young children tend to have postoperative complications related to slower muscle recovery action and increased concentration in skeletal muscle. So more careful observation and monitor are needed for younger children, our study could be of use in clinical practice for the administration of cisatracurium to children patients.