Rainer Burger

Effect of lipoic acid on redox state of coenzyme Q in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and diethyldithiocarbamate

We investigated the effects of a combined treatment of male C57Bl/6 mice with diethyldithiocarbamate and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the absence or presence of different forms of lipoic acid (Thioctacid TR; commonly used for treatment of diabetic polyneuropathies) on levels and redox states of alpha-tocopherol and coenzyme Q in vivo and on activities of various enzymes of energy metabolism ex vivo. Treatment of mice with diethyldithiocarbamate plus MPTP resulted in a decrease in dopamine (67%) and its major metabolites dihydroxyphenylacetic acid (38%) and homovanillic acid (37%) in striatum. alpha-Tocopherol levels were unaltered in striatum; however, the reduced forms of coenzyme Q were decreased in frontal cortex and hippocampus following diethyldithiocarbamate plus MPTP. In frontal cortex activity of NADH dehydrogenase was significantly inhibited by diethyldithiocarbamate plus MPTP ex vivo, suggesting that the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium ion, is acting in brain regions other than striatum as well. Lipoic acid, administered 6 times, each at 90 min prior to MPTP, could not restore dopamine in striatum but in contrast maintained a normal ratio of the reduced form to the oxidized form of coenzyme Q, suggesting an interaction of lipoic acid with energy metabolism which seems, however, not only to be due to an activation of pyruvate dehydrogenase.

Therapeutic drug monitoring of tricyclic antidepressants in everyday clinical practice

Data about therapeutic drug monitoring (TDM) of psychotropic medications are often obtained from samples of highly selected individuals, who may not be representative for the average psychiatric patient. These data therefore may have limitations with regard to their transferability to everyday clinical practice. Therefore studies under naturalistic conditions are important to clarify the full clinical relevance of TDM. We retrospectively evaluated all TDM-analyses of the tricyclic antidepressants (TCA) amitriptyline and clomipramine during a 12-month period in an unselected sample of patients in a standard clinical setting. We especially examined the relationship between serum levels on one hand and clinical response and adverse effects on the other hand. In patients with amitriptyline, responders showed a significantly higher serum level than non-responders, whereas in patients with clomipramine a serum level within the recommended therapeutic range was associated with clinical response. We also found significantly higher serum concentrations in patients with adverse effects compared to patients without adverse effects in the clomipramine group. No such relationship could be shown in patients treated with amitriptyline. Our results suggest that therapeutic ranges in naturalistic settings in some ways differ from those obtained in controlled clinical settings and that TDM studies in everyday clinical practice are necessary and beneficial.

Brain aging phenomena in migrating sockeye salmon Oncorhynchus nerka nerka

Summary.Aging, a process occuring in all vertebrates, is closely related to a loss in physical and functional abilities. There is widespread interest in clarifying the relevance of environmental, metabolic, and genetic factors for vertebrate aging. In the Pacific salmon a dramatic example of aging is known. Looking for changes in the salmon brain, perhaps even in the role of initiating the aging processes, we investigated several biochemical parameters that should reflect brain functional activity and stress response such as the neurotransmitters dopamine, and serotonin, and two of their respective metabolites 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindole acetic acid, as well as glutathione, glutathione disulfide, and the extent of terminal deoxynucleotidyltransferase-mediated dUTP nick end-labelling. The aging of migrating sockeye salmon (Oncorhynchus nerka nerka) is accompanied by gradual increase in dopamine and serotonin turnover and a gradual decrease of brain total protein and glutathione levels. There appears to be an increased need for detoxification of reactive biological intermediates since activities of superoxide dismutase and catalase increase with age. However, our data do not support a major increase in apoptotic cell death during late aging but rather implicate an age related downward regulation of protein and glutathione synthesis and proteolysis increasing the need for autophagocytosis or heterophagocytosis in the course of cell death.

Determination of glutathione, glutathione disulphide, ascorbic acid and dehydroascorbic acid in tissues by reversed-phase liquid chromatography with electrochemical detection

SummaryHigh-performance liquid chromatography with electrochemical detection was applied to the estimation of glutathione, glutathione disulphide, ascorbic acid and dehydroascorbic acid in various tissues of man, animal, and plant. The simultaneous determination of glutathione and ascorbic acid in tissues was done by a coulometric method. Separation of glutathione and ascorbic acid and unequivocal substance identifications were performed on a 100×4.6 mm RP-18 Spheri 5 column. As mobile phase 0.015 mol/l o-phosphoric acid, pH 2.3 was used. Retention time of ascorbic acid was 5.0 min and of glutathione 10.0 min. Dehydroascorbic acid was determined after reduction to ascorbic acid with dithiothreitol. Glutathione disulphide was reduced at pH 7.5 by β-nicotinamide-dinucleotide phosphate and glutathione reductase, EC 1.6.4.2., to regenerate glutathione. To exclude interfering substances, several other compounds present in tissues and foods were investigated. This coulometric method is highly sensitive, specific and simple. Very low concentrations of ascorbic acid, glutathione, dehydroascorbic acid, and glutathione disulphide (<500 pg/injection) could be analysed using this HPLC-ECD method.

The relation between dosage, serum concentrations, and clinical outcome in children and adolescents treated with sertraline: a naturalistic study.

Objective:This naturalistic therapeutic drug monitoring (TDM) study aimed to evaluate the relationship between dosage, serum concentration, and clinical outcome in children and adolescents treated with the serotonin reuptake inhibitor sertraline for different indications. Methods:Steady-state trough serum concentrations were analyzed in 90 subjects, treated with 25–200 mg sertraline per day. Therapeutic efficacy was assessed by the Clinical Global Impression Improvement subscale and side effects by the Udvalg for Kliniske Undersogelser-Side Effect Rating Scale. Results:In the study population, children were administered higher body weight normalized daily doses than adolescents. The relationships between sertraline daily dosage and serum concentrations (rs = 0.67, P < 0.0001) as well as between body weight normalized daily doses and serum concentrations (r = 0.62, P < 0.0001) were linear. In the whole patient group, no correlation between serum concentrations and either the therapeutic effect or side effects could be observed, neither significant effects of gender, age, concomitant medications, or smoking habits. When analyzing just the patients with depression, those with side effects had significantly higher sertraline serum concentrations than those without (44.8 ng/mL versus 22.3 ng/mL, P = 0.01). In general, occurrence of side effects was significantly more frequent in patients with psychiatric comedication (37.9%) than those without (11.5%, P = 0.002). Discussion:As this study has the typical limitations of naturalistic studies, the results should be interpreted cautiously. From the data, it is not possible to suggest an age-specific therapeutic window for children and adolescents. However, as the intraindividual variability of sertraline serum concentrations is known to be low, TDM may certainly help to predict serum concentrations after dose adjustment, to assess pharmacokinetic drug–drug interactions influencing serum concentrations and the patients compliance, finally allowing for personalizing dose through TDM.

Interaction of valproic acid and amitriptyline: analysis of therapeutic drug monitoring data under naturalistic conditions.

Abstract Amitriptyline (AMI) and valproic acid (VPA) are common psychotropic drugs which are frequently used in psychiatry and also administered in neurology or anesthesia in the absence of a psychiatric indication. On the basis of the case of a 73-year-old man with therapy-resistant major depressive episode who experienced anticholinergic delirium after adding VPA to AMI, we retrospectively analyzed therapeutic drug monitoring data of the years 2008 to 2010. We assessed cases receiving a combination of AMI and VPA, and obtained a control sample of AMI patients without VPA which were matched for sex, age, daily dose, and comedication. Both samples were compared regarding the serum levels of AMI and nortriptyline (NOR) as well as the ratio of NOR and AMI with the Mann-Whitney U test. The combination of AMI and VPA led to a remarkable increase of AMI and NOR serum levels. When comparing 33 patients who received comedication with VPA versus 33 matched controls, the total concentration by combining mean AMI and NOR serum levels (237.1 [119.9] vs 126.4 [52.8] ng/mL) and NOR/AMI ratio (1.300 [0.905] vs 0.865 [0.455]) was significantly higher. Both AMI and VPA are widely prescribed drugs. A combination of both is common for psychiatric or neurologic patients. A cautious dosing of AMI with VPA comedication is advisable, and therapeutic drug monitoring should be performed because this combination may lead to a remarkable increase of AMI and NOR serum levels.

The dopamine-related polymorphisms BDNF, COMT, DRD2, DRD3, and DRD4 are not linked with changes in CSF dopamine levels and frequency of HIV infection

We showed previously that higher levels in CSF dopamine in HIV patients are associated with the presence of the dopamine transporter (DAT) 10/10-repeat allele which was also detected more frequently in HIV-infected individuals compared to uninfected subjects. In the current study, we investigated further whether other genetic dopamine (DA)-related polymorphisms may be related with changes in CSF DA levels and frequency of HIV infection in HIV-infected subjects. Specifically, we studied genetic polymorphisms of brain-derived neurotrophic factor, catechol-O-methyltransferase, and dopamine receptors DRD2, DRD3, and DRD4 genetic polymorphisms in uninfected and HIV-infected people in two different ethnical groups, a German cohort (Caucasian, 72 individuals with HIV infection and 22 individuals without HIV infection) and a South African cohort (Xhosan, 54 individuals with HIV infection and 19 individuals without HIV infection). We correlated the polymorphisms with CSF DA levels, HIV dementia score, CD4+ T cell counts, and HIV viral load. None of the investigated DA-related polymorphisms was associated with altered CSF DA levels, CD4+ T cell count, viral load, and HIV dementia score. The respective allele frequencies were equally distributed between HIV-infected patients and controls. Our findings do not show any influence of the studied genetic polymorphisms on CSF DA levels and HIV infection. This is in contrast to what we found previously for the DAT 3′UTR VNTR and highlights the specific role of the DAT VNTR in HIV infection and disease.

Some reflections on iron dependent free radical damage in the central nervous system

We give a brief introduction into the chemical relationship between iron and oxidative stress serving two purposes: