Eva McCaskey Hadašová

Links among paroxetine-induced sexual dysfunctions, gender, and CYP2D6 activity.

The aim of the study was to compare the distribution of therapeutic efficacy and sexual dysfunction during maintenance paroxetine treatment in 17 males and 38 females genotyped and phenotyped to determine their CYP2D6 metabolic status. Clinical results were monitored on scales Clinical Global Impression-Severity of Illness Scale (CGIS) and Arizona Sexual Experience Scale (ASEX). The phenotype procedure showed 7 males and 12 females with extensive metabolic status (EM) and 10 males and 26 females with poor metabolic status (PM). No variation in therapeutic efficacy between male and female subjects classified as PM and those marked as EM was found. A significantly higher rate of sexual dysfunction (p = 0.01) was recorded among females with a PM phenotype.

Relationship between CYP 2D6 metabolic status and sexual dysfunction in paroxetine treatment.

This article describes the incidence of sexual dysfunction in 30 patients subjected to long-term treatment by paroxetine in dependence on the P 450 CYP 2D6 isoenzyme metabolic status. Measured on the Arizona Sexual Experience Scale (ASEX; McGahuey, Delgado, & Gelenberg, 1999), the incidence of sexual dysfunction in patients converted to CYP 2D6 poor metabolizers was markedly higher compared with patients who had no history of such conversion, a difference that reached the level of statistical significance. Our article discusses the incidence of sexual dysfunction in connection with reduced CYP 2D6 capacity.

Direct determination of procainamide and N-acetylprocainamide by capillary zone electrophoresis in pharmaceutical formulations and urine

In this work a new sensitive capillary zone electrophoresis method for the direct determination of procainamide (PA) and N-acetylprocainamide (NAPA) in pharmaceutical formulations and urine samples without any extraction and/or preconcentration steps has been developed. The determination was carried out in a fused-silica capillary of 43.5 cm (35.9 cm length to the detector) x 0.75 micron J.D. Phosphate 0.05 M buffer was used as the background electrolyte and 10 kV separation voltage was applied. The separation of PA and NAPA is possible in a wide range of pH from 1.7 to 9.7. However, in order to avoid the effect of the urine matrix, it is optimal to work at pH 7.7. The determination of PA and NAPA takes less than 5 min while high resolution is achieved. The detection limits obtained, 1.235 micrograms/ml and 0.359 microgram/ml for PA and NAPA respectively, are lower than those for GC method normally reported.

Drug oxidation and N-acetylation in rats pretreated with subtoxic doses of streptolysin O

SLO in sublytic doses (100 HU/kg body wt) depressed the hepatic microsomal cytochrome P450 and aminopyrine-N-demethylase but increased significantly the cytosolic N-acetyltransferase after acute and subacute (5 days) pretreatment of male Wistar rats. Aniline hydroxylase was reduced after acute and unchanged after subacute pretreatment. The effects of SLO on the oxidative enzymes and drug N-acetylation might have been caused by the membranal and immunological properties of the toxin.

Effect of methamphetamine on the pharmacokinetics of dextromethorphan and midazolam in rats.

SummaryMethamphetamine is the fourth most frequently reported compound associated with drug abuse on admission of patients to treatment centres after cocaine, heroin and marijuana. It is metabolized in the organism with a reaction that is catalyzed by cytochrome P450, mainly by the CYP2D and CYP3A subfamily, 4-hydroxyamphetamine and amphetamine being dominant metabolites. The present pharmacokinetic study was undertaken to investigate the possible influence of methamphetamine (10 mg/kg, i.p., once daily for six days) on the pharmacokinetics of dextromethorphane as a model substrate for rat cytochrome P-4502D2 and midazolam as a model substrate for CYP3A1/2. Animals received a single injection of dextromethorphane (10 mg/kg) or midazolam (5 mg/kg) in the tail vein 24 h after the last dose of methamphetamine or administration of placebo. The results of pharmacokinetic analysis showed a significantly increased rate of dextrorphane and 3-hydroxymorphinan formation, and a marked stimulatory effect of methamphetamine on CYP2D2 metabolic activity. Similarly, the kinetics of midazolam’s metabolic conversion to hydroxy derivates of midazolam indicated a significant increase in CYP3A1/2 activity. The results showed that the administration of methamphetamine significantly stimulated the metabolic activity of CYP2D2 as well as that of CYP3A1/2. With regard to the high level of homology between human and rat CYP isoforms studied, the results may have a clinical impact on future pharmacotherapy for methamphetamine abuse.

Solid-Phase Extraction of Perphenazine from Blood Serum for High Performance Liquid Chromatographic Analysis

Abstract A solid-phase extraction (SPE) process has been developed with the aim of replacing multistage liquid-liquid extraction that is currently used for sample clean-up before the chromatographic determination of perphenazine (PPZ) in serum. The method comprises the trapping of PPZ from 2 mL of serum by 100 mg of silica gel with polymeric C18 phase, followed by rinsing of the endogenous compounds with water and acetonitrile. The drug is eluted with 0.7 mL of methanol and the eluate is evaporated to dryness under stream of air. The residue is dissolved in 100 μL of methanol and 20–μ aliquot is injected onto an HPLC column packed with silica gel modified with cyanopropyl groups. To control the retention and separation of PPZ from the other compounds, ammonium acetate concentration in the mobile phase consisting of 90% v/v methanol has been varied from 10 to 40 mmol/L. The SPE method enabled 86.2+5.0% of PPZ to be recovered which is 12% to 22% more than by liquid-liquid extraction procedure. The repeatabi...

Effects of streptolysin O, picibanil (OK 432) and interferon α2A on cytochrome P-450-dependent monooxygenases and arylamine N-acetyltransferase in rat liver

Streptolysin O, a thiol-activated exotoxin from group A beta-haemolytic streptococci, caused a dose-dependent depression of aniline hydroxylase, aminopyrine N-demethylase and ethylmorphine N-demethylase activities when added into the hepatic microsomal mixtures from male rats at concentrations 0.02-0.4 HU/mL in vitro. The activities of 7-ethoxycoumarin O-deethylase, 7-ethylresorufin O-deethylase and 7-pentylresorufin O-depentylase were not altered with the used concentrations of the toxin. Specific antibody against haemolytic action of streptolysin O added to incubation mixtures in vitro was not able to protect streptolysin-sensitive monooxygenases from the inhibition. The addition of streptolysin O (0.01-0.8 HU/mL) into the cytosol-containing medium did not significantly influence the activity of procainamide N-acetyltransferase. Immunomodulators picibanil (OK 432) and human recombinant interferon alpha 2A which are known to suppress oxidative metabolism in vivo in humans and animals, were without effect either on the cytochrome P-450-dependent monooxygenases or on the N-acetyltransferase activity when administered in vitro at the doses real in their clinical application (0.001-0.1 KE/mL of picibanil and 10-500 U/mL of alpha-interferon).

Effects of psychopharmacotherapy on phenotypic expression of cytochrome P450 2D6 in patients genotyped for CYP2D6 mutations.

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