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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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