To clarify the roles of claudins in endometrial tumorigenesis, we determined levels of protein and messengerRNA (mRNA) expression of claudin-3 and claudin-4 in human endometrial tissue (proliferative phase [PE, n= 25]; secretory phase [SE, n= 25]; simple hyperplasia [SH, n= 20]; complex hyperplasia [CH, n= 12]; atypical hyperplasia [AH, n= 15]; endometrioid adenocarcinoma [EEC, n= 30]) using immunohistochemistry, western blotting, and real-time polymerase chain reaction, respectively. Morphologic changes of tight junctions (TJs) were also observed in normal, hyperplastic, and malignant endometrial tissue. Absence or weak staining for claudin-3 and claudin-4 was observed in PE, SE, SH, and CH, while medium to intense staining was detected in AH and EEC. Staining of claudin-3 and claudin-4 was predominantly localized to the glandular epithelial cell membrane. Expression of claudin-3 and claudin-4 was significantly increased in the groups of AH and EEC in comparison with the groups of CH, SH, and normal cyclic endometrium at both protein and mRNA levels. The highest expression was observed in EEC. Although no relevance was found with regard to FIGO stage and histologic grade, overexpression of claudin-3 and claudin-4, especially claudin-4, significantly correlated with myometrial invasion. Transmission electron microscopy analysis indicated morphologic disruptions of TJs may lag behind the increase of claudins expression. These results demonstrate that claudin-3 and claudin-4 are strongly expressed in AH and EEC, but less frequently in normal endometrium. The upregulation of claudins expression during endometrial carcinogenesis suggests their potential utility as diagnostic and prognostic biomarkers.

Arsenic trioxide (As(2)O(3)), has been used for centuries in traditional Chinese medicine; it has considerable efficacy in the treatment of relapsed acute promyelocytic leukemia, inducing partial differentiation and promoting apoptosis of malignant promyelocytes. Although a number of studies have demonstrated that As(2)O(3) has potent activity against cell growth in a series of leukemia cell lines, little information is available regarding this compound's effect on cell growth in solid tumor cell lines. In this study, we investigated the effects of As(2)O(3)in vitro on ovarian cancer cell lines sensitive (3AO) and resistant (3AO/CDDP) to cisplatin. The 3-(4,5-dimethy-thiazoyl-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to evaluate cytotoxicity. Flow cytometric analysis was used to determine the apoptosis, cell cycle distribution. We clearly demonstrated that As(2)O(3) induced cell apoptosis and inhibition of cell growth in both the cell lines. Furthermore, we identified that As(2)O(3)-induced apoptosis involved Fas pathway. As(2)O(3) is an active agent against ovarian cancer cells and could be effective in the clinical treatment of ovarian cancer.

A sensitive and selective liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of domperidone (CAS number: 57808-66-9) in human plasma using paracetamol (CAS number: 103-90-2) as an internal standard (IS). Domperidone and paracetamol in plasma were extracted with ethyl acetate, separated on a C18 reversed phase column, eluted with mobile phase of acetonitrile-glacial acetic acid (0.3%) (40:60, v/v), ionized by positive ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor→product ions of m/z 426.2→175.1 for domperidone and 152→110 for the IS, respectively. The calibration curve was linear (r2≥0.99, n=5) over the concentration range of 0.2-80 ng/mL and with lower limit of detection and quantitation of 0.05 and 0.2 ng/mL. The specificity, matrix effect, recovery, sensitivity, linearity, accuracy, precision, and stabilities were validated for domperidone in human plasma. In conclusion, the validation results showed that this method was sensitive, economical and less toxic and it can successfully fulfill the requirement of clinical pharmacokinetic study of domperidone oral preparation in Chinese healthy volunteers.

A more rapid, sensitive and specific high-performance liquid chromatography coupled to ?tandem mass spectrometry (HPLC-MS/MS) was developed and validated for the quantification of nifedipine in human plasma, and applied to the pharmacokinetic study of nifedipine in Chinese healthy volunteers. Nifedipine and internal standard (IS) acetaminophen in plasma were extracted with ethyl acetate, separated on a C18 (150?mm?4.6?mm, 5??m) reversed-phase column, eluted with acetonitrile mixed with 5?mM ammonium acetate solution (pH=6.62) (60:40, v/v), ionized by negative ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor?product ions of m/z 354.1?222.2 for nifedipine and 150.1?107.1 for the IS. A single oral dose of 20?mg nifedipine sustained release tablets and blood samples (4?mL) was collected before and 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, and 36?h after administration. The main pharmacokinetic parameters of nifedipine, as Tmax, t1/2?, t1/2?, t1/2z, Cmax, AUC0~36, AUC0~? were 2.80?0.50?h, 6.78?2.52?h, 6.82?2.53?h, 6.69?2.22?h, 76.69?19.51 (ng/mL), 546.49?162.28 (ng???h/mL) and 564.05?176.74 (ng???h/mL), respectively. The calibration curve was linear over the concentration range of 0.17?102?ng/mL (r2>0.99, n=5) with a lower limit of quantification (LLOQ) of 0.17?ng/mL. The intra- and inter-day precision was less than 15% for all quality control samples at concentrations of 0.42, 6.53 and 81.60?ng/mL and the accuracy (relative error, RE) was ???3.92% to 7.31% at 3 quality control levels. The specificity, matrix effect, recovery, sensitivity, linearity, accuracy, precision and stabilities were validated, and can fulfill the requirement of pharmacokinetic study of nifedipine sustained release tablets in Chinese volunteers.

No abstract

We aim to identify the effects of food on the pharmacokinetics (PK) of amlodipine, losartan and losartan's active metabolite (EXP3174) after oral administration of the Compound Amlodipine Tablets with single dose in healthy Chinese subjects. 12 subjects took the compounds (10 mg/100 mg, amlodipine/losartan) at the conditions of a high-fat breakfast and an overnight fast with a washout period of 14 days. Plasma samples were obtained at scheduled time, and determined by HPLC-MS/MS for the concentrations of amlodipine and HPLC-MS for the concentrations of losartan and EXP3174, respectively. PK parameters were calculated using Software Drug and Statistics (Version 2.0). When tablets were co-administered with food, there was no significant difference of AUC for amlodipine and losartan, but the AUC of EXP3174 was reduced by 19.1%. Meanwhile, the Cmax of amlodipine, losartan and EXP3174 were reduced by 11.4%, 20.0% and 41.4%, and the Tmax of losartan and EXP3174 were 1.3 and 1.8 h longer, respectively. No significant difference was found at t1/2 following food intake. In conclusion, the Compound Amlodipine Tablets, are affected by food administration by reducing the AUC of EXP3174. It is thus suggested that the Compound Amlodipine Tablets should be administered 1 h before or 2 h after meal.

In this small study, a single 250-mg oral dose of an acipimox tablet (test formulation) is bioequivalent to the established reference formulation.

This single-dose study in healthy Chinese fasted volunteers was shown that the ibuprofen test and reference met the requirement of the State Food and Drug Administration, and the test and reference were bioequivalent.