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Inhibitors of phosphodiesterase-4 (PDE4) are efficacious for allergic asthma in animal models and have shown some efficacy in human asthma. Regulation of PDE4 in allergy and asthma has been widely investigated in blood leukocytes, with discrepant results. This study investigated PDE4 regulation in the lung in a rat model of allergic asthma. Ovalbumin sensitization and challenge significantly increased pulmonary resistance and lung interleukin (IL)-4 production. The increases in pulmonary resistance and IL-4 production were both suppressed by the PDE4-selective inhibitor rolipram or the corticosteroid drug dexamethasone. Furthermore, cAMP-PDE enzyme activity in the lung was also significantly increased by the sensitization and challenge. mRNA analysis confirmed that PDE4 gene expression was increased in the lung of the allergic rats. A highly significant correlation was observed between the increases in PDE activity and IL-4 production. Our data suggest, for the first time, that PDE4 may be upregulated in the lung and play a role in the pathogenesis of allergic asthma.

This study presents a rapid, specific and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay for determination of risperidone (RIS) in human serum using paroxetine as an internal standard (IS). An Alltima-C18 column (2.1 mm×100 mm, 3 μm) and a mobile phase consisting of 0.1% formic acid-acetonitrile (40:60, v/v) were used for separation. The analysis was performed by selected reaction monitoring (SRM) method, and the peak area of the m/z 411.3→191.1 transition for RIS was measured versus that of the m/z 330.1→192.1 transition for IS to generate the standard curves. The assay linearity of RIS was confirmed over the range 0.25~50.00 ng/ml and the limit of quantitation was 0.05 ng/ml. The linear range corresponds well with the serum concentrations of the analytes obtained in clinical pharmacokinetic studies. Intraday and interday relative standard deviations were 1.85%~9.09% and 1.56%~4.38%, respectively. The recovery of RIS from serum was in the range of 70.20%~84.50%. The method was successfully applied to investigate the bioequivalence between two kinds of tablets (test versus reference products) in 18 healthy male Chinese volunteers. The result suggests that two formulations are bioequivalent.

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Abstract:In order to comply with the requirements for a drug listed in China, the study was developed to compare the pharmacokinetics and relative bioavailability of two different enteric formulations of omeprazole (OPZ) in healthy Chinese subjects. A total of 32 volunteers participated in the study. Plasma concentrations were analyzed by nonstereospecific liquid chromatography/tandem mass spectrometric (LC-MS/MS) method. After administration of a single 40-mg dose of the two OPZ formulations, the comparative bioavailability was assessed by calculating individual AUC 0-t (the area under the concentration-time curve from time zero to the last measurable concentration), AUC 0-∞ (the area under the concentration-time curve extrapolated to infinity), C max (the maximum observed concentration), and T peak (the time to C max ) values of OPZ, 5-hydroxyomeprazole (OH-OPZ), and omeprazole sulfone (OPZ-SFN), respectively. The 90% confidence intervals (CIs) of AUC 0-t , AUC 0-∞ , and C max were 85

A simple, robust LC-MS/MS assay for quantifying cefuroxime in human plasma was developed. Cefuroxime and tazobactam, as internal standard (IS), were extracted from human plasma by methanol to precipitate protein. Separation was achieved on a Zorbax SB-Aq (4.6 × 250 mm, 5 μm) column under isocratic conditions. The calibration curve was linear in the concentration range of 0.0525–21.0 μg/mL (r = 0.9998). The accuracy was higher than 90.92%, while the intra- and interday precision were less than 6.26%. The extraction procedure provides recovery ranged from 89.44% to 92.32%, for both analyte and IS. Finally, the method was successfully applied to a bioequivalence study of a single 500 mg dose of cefuroxime axetil in 22 healthy Chinese male subjects under fasting condition. Bioequivalence was determined by calculating 90% Cls for the ratios of C max, AUC0−t, and AUC0−∞ values for the test and reference products, using logarithmic transformed data. The 90% Cls for the ratios of C max (91.4%~104.2%), AUC0−t (97.4%~110.9%), and AUC0−∞ (97.6%~111.1%) values were within the predetermined range. It was concluded that the two formulations (test for capsule, reference for tablet) analyzed were bioequivalent in terms of rate and extent of absorption and the method met the principle of quick and easy clinical analysis.