Spectrophotometric methods as a novel screening approach for analysis of dihydropyrimidine dehydrogenase activity before treatment with 5-fluorouracil chemotherapy.

5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutics in the treatment of malignancies originating from breast, prostate, ovarian, skin and gastrointestinal tissues. Around 80% of administered dose of 5-FU is catabolized by dihydropirymidine dehydrogenase (DPD). Patients, in whom a deficiency or insufficient activity of this enzyme is observed, are at great risk of development of severe, even lethal, 5-FU toxicity. According to recent studies, so far over 30 mutations of DPYD gene, which are associated with DPD deficiency/insufficiency, have already been discovered. Currently, there are several analytical methods used for measurements of DPD activity. However, in this paper we report a novel, simple, economical and more accessible spectrophotometric method for measurements of DPD activity in the peripheral blood mononuclear cells (PBMCs) that was developed and validated on analysis of 200 generally healthy volunteers aged 22-63. We present two spectrophotometric protocols in this study, and as a reference method we used already described reverse phase high-performance liquid chromatography (RP HPLC) analysis. Basing on our findings, we conclude that spectrophotometric methods may be used as a screening protocol preceding 5-FU-based chemotherapy. Nevertheless, before introduction into clinical reality, our results should be confirmed in further larger studies.

[Effect of therapeutic drug monitoring of amitriptyline and genotyping on efficacy and safety of depression therapy]. / Przydatnosc terapii monitorowanej stezeniem leku we krwi oraz badan farmakogenetycznych w ocenie skutecznosci i bezpieczenstwa leczenia depresji amitryptylina.

Modern pharmacotherapy is based on precise adjustment of a dosage schedule to individual requirements of patient. Therapeutic drug monitoring is a method that allows for a more effective treatment approach, especially in the case of a narrow therapeutic index of a drug. Tricyclic antidepressant drugs are characterised by narrow therapeutic index as well as relationship between serum drug concentration and side effects. It was demonstrated that interindividual variability of blood concentrations of tricyclic antidepressant drugs is related to genetic polymorphism of oxidating enzymes participating in metabolism of these drugs. The aim of the study was to estimate the impact of therapeutic drug monitoring of tricyclic antidepressant drugs as well as genotyping on efficacy and safety of endogenous depression therapy. The study included 9 patients with established diagnosis of endogenous depression. Blood serum concentrations of amitryptyline was measured by fluorescence polarisation immune assay (FPIA, Abbott system). Genotype of cytochrome P450 isoenzyme CYP2D6 was determined using PCR-RFLP method. It was demonstrated that monitoring therapy of tricyclic antidepressant drugs in combination with determination of the genotype seems to be more safe and effective. Monitoring therapy and genotyping may be less expensive than the costs of prolonged hospitalisation and risk of side effects.

Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and Susceptibility to idiopathic generalized epilepsy.

Several interacting genetic factors are likely to be involved in the epileptogenesis of idiopathic generalized epilepsies (IGE). Neurotransmitter transporters play a central role in the fine tuning of neurotransmission by removal of released neurotransmitters from the synaptic cleft. The present association study tested the hypotheses that variation of the genes encoding neurotransmitter transporters confers susceptibility to IGE. The genotypes of 133 German IGE subjects and 223 ethnically matched controls were assessed for DNA polymorphisms of genes encoding the glutamate (EAAT2), the serotonin (SERT), and dopamine (DAT) transporters. To increase genetic homogeneity, a subgroup of 76 patients with idiopathic absence epilepsy (IAE) was analyzed separately. We found no evidence for an allelic association of either the silent G603A substitution polymorphism in exon 5 of the EAAT2 gene or the regulatory promoter polymorphism of the SERT gene with either IGE or IAE. The frequency of the nine-copy allele of the 40 base pair repeat polymorphism in the 3' un pop popd region of the DAT gene was significantly increased in the IGE patients (chi2 = 4.11, degrees of freedom (d.f.) = 1, P = 0.043) and, in particular, in the IAE patients (chi2 = 7.81, d.f. = 1, P = 0.005) compared with the controls. The present findings strengthen previous evidence that genetic variation of the DAT gene modulates neuronal network excitability and contributes to the epileptogenesis of IAE.

Genetic variation of the glutamate transporter EAAT2 gene and vulnerability to alcohol dependence.

Glutamate-mediated excitatory pathways play an important role in the pathogenesis of alcohol dependence. The present association study tested the candidate gene hypothesis that variation of the gene encoding the astroglial glutamate transporter EAAT2 confers vulnerability to alcohol dependence. Genotypes of a silent G603A nucleotide exchange in exon 5 of the EAAT2 gene were assessed in 565 subjects of German descent, comprising 342 alcohol-dependent subjects and 223 control subjects. Two more homogeneous subgroups of alcoholics were selected: (1) 112 alcoholics with a history of alcohol withdrawal seizure or delirium; and (2) 54 alcoholics with an antisocial personality disorder. The Tridimensional Personality Questionnaire was applied to assess personality dimensions in 106 alcohol-dependent males. The allele frequencies of the G603A polymorphism did not differ significantly between the control subjects and either the entire sample of alcoholics or the alcoholics with severe physiological withdrawal symptoms. Without correction for multiple testing, there was a significant increase of the frequency of the A603 allele in the antisocial alcoholics compared with either the control subjects [chi2 = 4.587, 1 degree of freedom (df), P = 0.032] or the alcoholics without ASPD (chi2 = 4.968, 1 df, P = 0.026). The personality trait of Harm Avoidance was significantly lower in alcoholics carrying the A603 allele compared with those lacking it (U-test; P = 0.009). These two consistent lines of evidence suggest that genetic variation of the EAAT2 gene confers vulnerability to risk-taking behavior in alcoholics.

Evaluation of an allelic association of the serotonin 5-HT1B G681C polymorphism with antisocial alcoholism in the German population.

Our study tested whether an association of the 861C allele of the serotonin 5-HT1B gene (HTR1B) with antisocial alcoholism exists in the German population. The HTR1B G861C polymorphism was genotyped in 588 subjects of German descent, comprising 250 non-alcoholic controls and 338 alcohol-dependent subjects, of whom 56 exhibited a dissocial personality disorder (DSPD). The Tridimensional Personality Questionnaire was assessed in 109 alcohol-dependent males to explore an effect of the 861C allele to risk-taking behaviour. Our results revealed no evidence for an association of the 861C allele with antisocial alcoholism (p > 0.63). There were no significant differences in the personality traits, novelty-seeking, harm avoidance and reward dependence between 46 male alcoholics carrying the 861C allele compared to those 63 alcoholics lacking it (p > 0.52). Our results do not provide evidence that the 861C allele contributes a substantial vulnerability effect to antisocial behavior in German alcohol-dependent subjects.

[Mianserin efficacy in the treatment of depression]. / Skutecznosc mianseryny w leczeniu zespolów depresyjnych.

Fifty patients suffering from depression were treated wigh mianserin in monotherapy. ICD-9 and DSM-III criteria for depression were used. Patients were divided into four groups--with monopolar depression (28 patients), bipolar depression (8 patients), organic depression (10 patients), neurotic depression (4 patients). The intensity of psychopathological symptoms of depression was established using the Hamilton Depression Rating Scale (HDS) on the 7th, 14th and 28th day of the treatment. The antidepressant action of mainserin was evident already on the 14th day of treatment. Mianserin proved to be most effective in endogenous bipolar depression group and neurotic depression group (70% reduction in the score obtained on the HDRS). Mianserin was well tolerated by most patients. Most frequent side effects observed were: hypertension (8 patients), feeling of anxiety (10 patients), constipation (8 patients), tachycardia (6 patients), dry mouth (3 patients).