29 research outputs found
Carbamazepine-Valnoctamide Interaction in Epileptic Patients: In Vitro/In Vivo Correlation
Six patients stabilized with carbamazepine (CBZ) therapy received an 8-day "add-on" supplement of valnoctamide (VCD), a tranquilizer available over the counter (OTC) in several European countries that exhibits promising anticonvulsant activity in animal models. During VCD intake, serum levels of the active CBZ metabolite, carbamazepine-10,11-epoxide (CBZ-E), increased fivefold from 1.5 +/- 0.7 micrograms/ml at baseline to 7.4 +/- 4.4 micrograms/ml after 4 days of VCD therapy and 7.7 +/- 3.1 micrograms/ml after 7 days of VCD therapy (means +/- SD, p < 0.01). In 4 patients, the increase in serum CBZ-E levels was associated with clinical signs of CBZ intoxication. CBZ-E levels returned to baseline after VCD therapy was discontinued. Serum CBZ levels remained stable throughout the study. The interaction observed in this study is similar to that described in patients treated with CBZ and valpromide (VPD, an isomer of VCD). In a mechanistic study, therapeutic concentrations of VCD inhibited hydrolysis of styrene oxide in human liver microsome preparations. Thus, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC50 15 microM). There was a striking similarity between in vitro and in vivo inhibition potencies. In this study, VCD clearance was higher in epileptic patients (treated with CBZ) than in healthy subjects
Studies toward the Development of New Silicon-Containing Building Blocks for the Direct <sup>18</sup>F‑Labeling of Peptides
Silicon-containing
prosthetic groups have been conjugated to peptides to allow for a
single-step labeling with <sup>18</sup>F radioisotope. The fairly
lipophilic di-<i>tert</i>-butylphenylsilane building block
contributes unfavorably to the pharmacokinetic profile of bombesin conjugates. In this article, theoretical and experimental studies
toward the development of more hydrophilic silicon-based building
blocks are presented. Density functional theory calculations were
used to predict the hydrolytic stability of di-<i>tert</i>-butylfluorosilanes <b>2</b>–<b>23</b> with the
aim to improve the in vivo properties of <sup>18</sup>F-labeled silicon-containing
biomolecules. As a further step toward improving the pharmacokinetic
profile, hydrophilic linkers were introduced between the lipophilic
di-<i>tert</i>-butylphenylsilane building block and the
bombesin congeners. Increased tumor uptake was shown with two of these
peptides in xenograft-bearing mice using positron emission tomography
and biodistribution studies. The introduction of a hydrophilic linker
is thus a viable approach to improve the tumor uptake of <sup>18</sup>F-labeled silicon–bombesin conjugates