Aim The aim of this study was to examine the pharmacokinetics of donepezil HCl and ketoconazole separately, and in combination, following administration of single and multiple oral doses. Methods This was an open-label, randomized, three-period crossover study in healthy volunteers (n=21). During each treatment period, subjects received single daily doses of either donepezil HCl (5 mg ), ketoconazole (200 mg), or a combination of both drugs for 7 consecutive days. Pharmacokinetic comparisons were made between treatment groups for the day 1 and day 7 profiles. Each treatment period was followed by a 3-week, drug-free washout period. Results On both day 1 and day 7, a statistically significant difference was observed between the donepezil and the donepezil+ketoconazole treatment groups in terms of C max and AUC (0-24) of donepezil. The concurrent administration of both drugs resulted in a 12% greater C max (9.5 ng ml −1 versus 8.4 ng ml −1 ; P=0.01) and a 12% greater AUC (0-24) (135.2 ng h ml −1 versus 118.7 ng h ml −1 ; P=0.001) than donepezil alone on day 1, and a 26.8% greater C max (37.7 ng ml −1 versus 27.6 ng ml −1 ; P<0.0001) and a 26.4% greater AUC (0-24) (680.9 ng h ml −1 versus 501.0 ng h ml −1 ; P<0.0001) than donepezil alone on day 7.In contrast, ketoconazole plasma concentrations were unaffected by the concurrent administration of donepezil, and there were no statistically significant differences in ketoconazole pharmacokinetics when ketoconazole administered alone was compared with ketoconazole administered with donepezil. Conclusions The concurrent administration of ketoconazole and donepezil produces no change in ketoconazole plasma concentrations, but a statistically significant change in donepezil plasma concentrations. These observed changes, which are smaller than those produced by ketoconazole for other agents sharing the CYP-3A4 pathway, are most likely the result of donepezil also being metabolized by CYP-2D6, as well as its slow rate of clearance from plasma.

The objective of this research was to study the effects of cathodic protection at coating holidays and associated areas of disbondment through simultaneous determination of the electro-chemical reactions and chemical changes taking place in the environment adjacent to the steel substrate. Primary parameters of interest were applied potential, solution conductivity, pH oxygen in solution. The experimental plan was comprised of six interrelated studies involving both laboratory simulations and modeling. It was found that an effective CP system provides sufficient current flow at the exposed steel surface to modify the ground water in the immediate environment by lowering soluble oxygen levels and increasing its alkalinity. Further, corrosion protection is achieved in the shielded areas under the disbonded coating where current flow is minimal, through this chemical modification of the aqueous environment, and it is not necessary that current flow into all of the disbonded region. Three conditions of import to pipeline corrosion protection were also simulated in this investigation. Chemical environment and electric potential distribution within disbond regions were measured for the affects of interruption and reapplication of current; the occurrence of wet/dry cycles at the holiday and the presence of prior corrosion products.