[Biomimetic electrochemical synthesis of quinol-thioether conjugates: their implication in the serotonergic neurotoxicity of amphetamine derivatives]. / Synthèse électrochimique biomimétique de conjugués quinol-thioéthers: leur implication dans la neurotoxicité sérotoninergique de dérivés de l'amphétamine.

Injection of 3,4-methylenedioxyamphetamine (MDA) or 3,4-methylenedioxymethylamphetamine (MDMA or ecstasy) directly into the brain fails to reproduce the long-term effects observed after peripheral administration, implying an essential role for systemic metabolites in the development of toxicity. However, the precise identity of the metabolites participating in MDA and MDMA-mediated serotonergic neurotoxicity remains unclear: neither 3,4-alpha-methyldopamine, nor N-methyl-alpha-methyldopamine, major metabolites, produce neurotoxicity following peripheral administration. In vivo, these metabolites are oxidized to the corresponding orthoquinones, that readily react with protein and nonprotein sulphydryls including glutathione (GSH). The resulting quinol-thioether conjugates exhibit a variety of toxicological activities, which can be regulated by intramolecular cyclisation reactions that occur subsequent to oxidation. The ability of quinol-thioether conjugates to redox cycle and produce reactive oxygen species provides a rationale for the potential role of these metabolites in MDA and MDMA neurotoxicity. A biomimetic one-pot synthesis of 5-(GSH-S-yl)-N-Me-alpha-Me-DA involving addition of GSH to the electrogenerated orthoquinone species, is reported to evaluate its in vivo potential neurotoxicity.

Microassay of propranolol enantiomers and conjugates in human plasma and urine by high-performance liquid chromatography after chiral derivatization for pharmacokinetic study.

A microdetermination of propranolol enantiomers and of their glucuronide and sulphate conjugates in human plasma and urine by reversed-phase HPLC after chiral derivatization is described. After extraction from 100 microliters of plasma or urine with racemic 4-methylpropranolol as internal standard (I.S.), the enantiomers are derivatized with R(+)-phenylethylisocyanate as chiral derivatization reagent. Chromatography is performed on Novapak C18 column with fluorescence detection. Glucuronide and sulphate conjugates are cleaved prior to extraction by incubating, respectively, the samples with glucuronidase-arylsulphatase and saccharic acid 1-4 lactone as specific glucuronidase inhibitor. The retention times of propranolol and I.S. enantiomer derivatives are short (tR = 5.5-6.2 min and 8.8-10.1 min, respectively). The diastereomeric derivatives are very stable and show good peak symmetry and resolutions (RS = 2 and 2.2). The use of 4-methylpropranolol as I.S. improves significantly relative standard deviations (RSD: 1.7-5.1). Sensitivity is about 1 ng ml-1 per enantiomer. The method is applied to pharmacokinetic studies of racemic propranolol in human plasma and urine. S-propranolol and its conjugates show higher concentrations than R-propranolol and its conjugates in plasma and urine.

Separation and determination of warfarin enantiomers in human plasma samples by capillary zone electrophoresis using a methylated beta-cyclodextrin-containing electrolyte.

A methyl beta-cyclodextrin with a degree of substitution of 1.8 proved to be an effective chiral selector, among other cyclodextrins tested, for the separation of warfarin enantiomers by capillary electrophoresis. The operating conditions were optimized with respect to electrolyte composition (buffer pH, ionic strength, cyclodextrin concentration, methanol content) and applied voltage. The influence of a high ionic strength on the resolution was clearly shown. A baseline separation can be obtained in less than 15 min with an efficiency of ca. 250,000 theoretical plates. These conditions were applied to the determination of warfarin enantiomers in the plasma of patients under warfarin therapy. The limit of detection for the whole procedure (dichloromethane extraction followed by evaporation to dryness and capillary electrophoresis) was of the order of 0.2 mg/l (6.5.10(-7) M) of each enantiomer.