The present investigation demonstrates that NO, but not prostacyclin, is essential for flow-mediated dilatation of large human arteries. Hence, this response can be used as a test for the L-arginine/NO pathway in clinical studies.

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One in 11 primary care patients had frequent difficulties in swallowing tablets and capsules while GPs grossly underestimated these problems. Therefore, physicians should rule out swallowing difficulties regularly to avoid non-adherence and inappropriate drug modifications. Special attention should be paid to specific patient groups (e.g. women and patients with dysphagia, dysphagia indicators, or mental illness).

Pharmacokinetic drug-drug interactions often occur at the level of P-glycoprotein (Pgp). To study possible interactions caused by the newer antidepressants we investigated citalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, and venlafaxine and their major metabolites desmethylcitalopram, norfluoxetine, paroxetine-metabolite (paroxetine-M), desmethylsertraline, N-desmethylvenlafaxine, and O-desmethylvenlafaxine for their ability to inhibit Pgp. Pgp inhibition was studied by a fluorometric assay using calcein-acetoxymethylester as Pgp substrate and two different cell systems: L-MDR1 cells (model for human Pgp) and primary porcine brain capillary endothelial cells (pBCECs, model for the blood-brain barrier). Both cell systems proved to be suitable for the evaluation of Pgp inhibitory potency of drugs. All antidepressants tested except O-desmethylvenlafaxine showed Pgp inhibitory activity with sertraline, desmethylsertraline, and paroxetine being the most potent, comparable with the well known Pgp inhibitor quinidine. In L-MDR1 cells fluoxetine, norfluoxetine, fluvoxamine, reboxetine, and paroxetine-M revealed intermediate Pgp inhibition and citalopram, desmethylcitalopram, venlafaxine, and N-desmethylvenlafaxine were only weak inhibitors. The ranking order was similar in pBCECs. The fact that some of the compounds tested exert Pgp inhibitor effects at similar concentrations as quinidine suggests that pharmacokinetic drugdrug interactions between the newer antidepressants and Pgp substrates should now be thoroughly studied in vivo.P-glycoprotein (Pgp) is a member of the ATP-binding cassette superfamily of membrane transport proteins, responsible for the efflux of many drugs. It represents a major component of the blood-brain barrier (Schinkel et al., 1994) and the intestinal barrier (van Asperen et al., 1998), and it contributes to renal and biliary elimination of drugs (Kusuhara et al., 1998;Chiou et al., 2000). At the blood-brain barrier Pgp is localized in the apical membrane of brain capillary endothelial cells and transports substrates toward the blood compartment (Cordon-Cardo et al., 1989;van Asperen et al., 1997). Therefore, Pgp can limit the penetration into and retention within the brain and thus modulate effectiveness and central nervous system toxicity of numerous compounds. In contrast, the absence of active Pgp as observed in mdr-1 knockout mice lacking Pgp and thus exhibiting unrestricted access of Pgp substrates to the brain yields significantly increased central nervous system concentrations often exceeding those observed in wild-type mice by orders of magnitude (Schinkel et al., 1994(Schinkel et al., , 1996. Pgp is also highly expressed in the apical membrane of epithelial cells in the small and large intestine, where it transports drugs out of the cells into the intestinal lumen (Cordon-Cardo et al., 1989;van Asperen et al., 1998), thus limiting bioavailability of compounds such as paclitaxel and human immunodeficiency virus protease inhibitors (Sparreboom et al., 1997...

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