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Background: Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored. Methods: The cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts' tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate's efflux were analyzed through the vanadate-sensitive ATPase assay, [125I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence. Results: We found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-driven MDR cells. Importantly, the mice vivo combination study has verified that BI-2865 effectively improved the anti-tumor action of paclitaxel without toxic injury. In mechanism, BI-2865 prompted doxorubicin accumulating in carcinoma cells by directly blocking the efflux function of P-gp, which more specifically, was achieved by BI-2865 competitively binding to the drug-binding sites of P-gp. What's more, at the effective MDR reversal concentrations, BI-2865 neither varied the expression and location of P-gp nor reduced its downstream AKT or ERK1/2 signaling activity. Conclusions: This study uncovered a new application of BI-2865 as a MDR modulator, which might be used to effectively, safely and specifically improve chemotherapeutic efficacy in the clinical P-gp mediated MDR refractory cancers. [ABSTRACT FROM AUTHOR]

Purpose: Hemodialysis (HD)-induced myocardial ischemia may lead to left ventricular (LV) dysfunction after normal perfusion returns. This study aimed to assess the short-term influence of predilution hemodiafiltration (HDF) and high-flux hemodialysis (HD) on intradialytic LV systolic function, and hematologic and biochemical risk factors. Methods: This cross-over clinical trial enrolled 38 dialysis patients who were randomized equally into one of two treatment sequences: 1-week predilution HDF treatment followed by 1-week high-flux HD, and vice versa. LV systolic function was assessed by echocardiography before and after the mid-week dialysis session. Hematologic and biochemical parameters were also measured. Replacement fluid volume for all patients was 24.2 ± 1.3 L/session. Results: Subjects' mean age was 53.3 ± 11.8 years and 24 were males. LV ejection fraction (LVEF) decreased from 61.31 ± 9.96 to 59.03 ± 10.37% after HDF (P = 0.016), and increased from 61.69 ± 11.08 to 62.72 ± 11.26% after high-flux HD (P = 0.190). Average of peak LV systolic tissue velocity increased from 6.74 ± 1.23 to 6.98 ± 1.56 cm/s after HDF (P = 0.246), and increased from 6.71 ± 1.34 to 7.44 ± 2.18 cm/s (P = 0.039) after high-flux HD. The ratio between peak LV early diastolic mitral inflow velocity and peak LV early diastolic tissue velocity (E/E′) at the septal mitral annulus decreased to 18 ± 9 from 21 ± 11 (P = 0.147) after HDF, and to 17 ± 8 from 20 ± 8 (P = 0.037) after high-flux HD. β2-microglobulin was reduced more during HDF than during high-flux HD (70.7 ± 5.3 vs. 67.7 ± 3.9%, P < 0.001). Conclusion: Predilution HDF decreases intradialytic LV systolic function more than high-flux HD. Randomized controlled trials with a larger multi-center sample and long-term follow-up are required to demonstrate the potential mechanisms of predilution HDF effecting on ventricular function. [ABSTRACT FROM AUTHOR]

Presents information on several studies about liver to be presented at the 65th Scientific Sessions of the American Diabetes Association at the San Diego Convention Center in California from June 10 to 14, 2005. Insufficiency of reduction in liver fructose 1, 6 bisphosphatase1 to lower fasting blood glucose levels in mice; Enhancement of glucagon-induced hepatic gluconeogenesis by adiponectin; Effects of metformin diabetic agent on insulin sensitivity and intracellular lipid contents in muscle and liver in insulin-resistant overweight subjects.

A sensitive and simple high-performance liquid chromatography method with UV detection was developed and validated for determining picroside II in dog plasma. Paeoniflorin was employed as internal standard and the sample pre-treatment procedure consists of deproteinization by addition of acetonitrile. Chromatographic separations were performed on a Shimadzu VP-ODS column (250 × 4.6 mm i.d., 5 µm). The mobile phase consisted of acetonitrile-0.1% acetic acid aqueous (v/v), 23:77, v/v, at a rate of 1 mL/min. Detection was carried out at a wavelength of 266 nm. Calibration standards ranged from 0.25 to 500 µg/mL in dog plasma and the mean correlation coefficient of 0.9981 was found for the linear calibration curves ( n = 6). The limit of quantification (LOQ) was 0.25 µg/mL. Intra- and inter-assay RSD ranged from 0.70 to 7.5%. Accuracy (%bias) ranged from −6.3 to 6.0%. This method was applied to the pharmacokinetic study of picroside II in dogs. The study demonstrated the plasma picroside II concentration-time curves were fitted to the two-compartment open model and showed linear pharmacokinetics. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]