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Biomedical subjects

S Bleich

Publications and source records attributed to S Bleich.

At least 55 records · Page 3Linked to original sources
PubMed2000

[New antidepressant drugs. What side effects and interactions are to be expected?].

The new antidepressants, selective serotonin reuptake inhibitors (SSRI), selective serotonin noradrenalin reuptake inhibitors (SSNRI) and selective noradrenalin reuptake inhibitors (SNRI) have few clinically relevant side effects. Overall, the new antidepressants are better tolerated and cause fewer side effects than the classical tricyclic antidepressants (TCA). They have virtually no anticholinergic effects, a low level of toxicity, and produce no psychomotoric or cognitive impairment. Both the frequency and severity of gastrointestinal and CNS side effects, as well as tremor, are low. The results of the drug safety program (AMSP) confirm the good tolerability and low clinical side effects of these new substances.

Antidepressive Agents↗
PubMed2000

Oxidative stress and an altered methionine metabolism in alcoholism.

The exact mechanism of brain atrophy in patients with chronic alcoholism remains unknown. There is growing evidence that chronic alcoholism is associated with oxidative stress and with a derangement in sulphur amino acid metabolism (e.g. ethanol-induced hyperhomocysteinemia). Furthermore, it has been reported that homocysteine induces neuronal cell death by stimulating N-methyl-D-aspartate receptors as well as by producing free radicals. To further evaluate this latter hypothesis we analysed serum levels of both homocysteine and markers of oxidative stress (malondialdehyde) in alcoholic patients who underwent withdrawal from alcohol. Homocysteine and malondialdehyde were quantified by high performance liquid chromatography (HPLC) in serum samples of 35 patients (active drinkers). There was a significant correlation (P<0. 01) between blood alcohol concentration and elevated homocysteine (Spearman's r=0.71) and malondialdehyde (r=0.90) levels on admission. In addition, homocysteine and malondialdehyde levels were found to be significant decreased after 3 days of withdrawal treatment (Wilcoxon test: homocysteine, Z=-5.127; malondialdehyde, Z=-3.120; P<0.01). We postulate that excitatory neurotransmitters and mechanisms of oxidative stress in patients with chronic alcoholism may partly mediate excitotoxic neuronal damage and hereby cause brain shrinkage.

Adult↗
PubMed2000

Plasma homocysteine is a predictor of alcohol withdrawal seizures.

An adaptive consequence of prolonged ethanol consumption is a compensatory up-regulation of NMDA receptors in certain brain areas. Taking into account that homocysteine and its breakdown products (i.e. homocysteic acid) are putative neurotransmitters and agonists at the NMDA receptor, the aim of this study was to assess the influence of levels of homocysteine on alcohol withdrawal seizures. Six patients with chronic alcoholism who suffered from withdrawal seizures had significantly higher levels of homocysteine on admission (84.7 +/- 29.8 micromol/l) than patients (n = 26) who did not develop seizures (30.2 +/- 23.2 micromol/l; U = 8.0, p = 0.0007). Furthermore, seizure patients had significantly lower levels of folate and significantly higher blood alcohol concentrations. Using a logistic regression analysis, withdrawal seizures were best predicted by a high homocysteine level on admission (p < 0.01; odds ratio = 1.05). Homocysteine levels on admission may be a useful screening method to identify patients at risk for withdrawal seizures.

Adult↗
PubMed2000

Homocysteine and alcoholism.

Chronic alcohol consumption can induce alterations in the function and morphology of most if not all brain systems and structures. However, the exact mechanism of brain damage in alcoholics remains unknown. Partial recovery of brain function with abstinence suggests that a proportion of the deficits must be functional in origin (i.e. plastic changes of nerve cells) while neuronal loss from selected brain regions indicates permanent and irreversible damage. There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Recently, it has been shown that excitatory amino acid (EAA) neurotransmitters and homocysteine levels are elevated in patients who underwent withdrawal from alcohol. Furthermore, it has been found that homocysteine induces neuronal cell damage by stimulating NMDA receptors as well as by producing free radicals. Homocysteine neurotoxicity via overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both brain shrinkage and withdrawal seizures linked to alcoholism.

Adult↗
PubMed2000

[Follow-up study after enteral manganese poisoning: clinical, laboratory and neuroradiological findings].

Manganese intoxication is an unusual, severe form of intoxication. This report deals with a patient now 80 years old who accidentally ingested a solution of potassium permanganate for a period of at least 4 weeks 14 years ago. Since then, the patient suffers from a mild parkinsonian syndrome and distally accentuated polyneuropathies. Psychiatric disorders, especially demential or depressive symptoms, were not observed. Manganese analysis of his hair still shows a clear increase in manganese concentration. The MRI of his brain showed no pathological changes, in particular none of those often described with symmetric signal elevation in T1 in the area of the basal ganglia. In this study, we present clinical, laboratory, and neuroradiological findings. Unusual in this case with a short exposition is the long duration and clinical improvement without L-dopa treatment.

Aged↗
PubMed2000

Creutzfeldt-Jakob disease and oxidative stress.

OBJECTIVES: Substantial evidence supports the hypothesis that oxygen free radicals are involved in various neurodegenerative disorders. To assess the presence of oxidative stress in Creutzfeldt-Jakob disease (CJD) we examined the concentrations of malondialdehyde (MDA) as an established marker of lipid peroxidation. MATERIAL AND METHODS: MDA was quantified by high performance liquid chromatography (HPLC) in cerebrospinal fluid (CSF; n=12) and in serum (n=11) samples of CJD patients and healthy controls (n = 15). RESULTS: Mean values in healthy controls: 2.56 nmol/ml +/- 0.46 (CSF) and 1.94 nmol/ ml +/- 0.67 (serum); mean values in CJD patients: 2.64 nmol/ml +/- 0.67 (CSF) and 1.68 nmol/ml +/- 0.79 (serum). No significant (P>0.05) difference between CJD patients and controls was observed. CONCLUSIONS: The results indicated that the CSF and serum of CJD patients showed no higher endogenous levels of MDA as compared to normal healthy controls. These findings provide no evidence for an additional role of oxidative stress in the pathogenetic mechanism underlying CJD neurodegeneration.

Biomarkers↗
PubMed2000

[Diagnostic steps in Alzheimer dementia before treatment with new antidimentives].

The dementia of the Alzheimer type (DAT) is a chronic neurodegenerative illness. It will continue to increase because of rising life expectancy in the industrialized countries. Apart from the physicians interest to treat, there is also an economically justified interest to reduce the disease progression in this group of patients. The main intention of the treating physicians is to keep their patients independent as long as possible. Up to now Alzheimer's disease can only be treated symptomatically. The verified diagnosis of DAT still depends on the neuropathological investigation of brain tissue. Therefore the clinical diagnosis of DAT during lifetime should be supported by chemical analysis of typical changes in the cerebrospinal fluid (CSF) at an early stage. Meanwhile, several therapeutics with proven effectiveness in clinical studies are certified for the symptomatic treatment of DAT. However, these therapeutics are still relatively expansive. Due to this fact the clinical diagnosis of DAT should be supported by clinical-chemical markers before the beginning of such a treatment. In this paper we present the diagnostic steps in dementia patients, who are examined in our departments. Patients suspicious of DAT always are asked for a spinal tap in addition to other diagnostic tools. In case of a typical clinical constellation, the exclusion of a primarily vascular dementia as well as the proof of decreased A beta 1-42 peptides and an increased tau protein in CSF we recommend the new drugs for DAT as meaningful and justified therapeutics to yield optimal treatment.

Aged↗
PubMed2000

A prospective PMS study to validate the sensitivity for change of the D-scale in advanced stages of dementia using the NMDA-antagonist memantine.

The present postmarketing surveillance (PMS) study is the first large scale systematic and prospective clinical trial of pharmacotherapeutic intervention in advanced stages of dementia. Within a validation program this study aimed at demonstrating the sensitivity of the D-Scale of change (DS-C) for measuring ADL-function. Efficacy of treatment with the NMDA-antagonist memantine was investigated in 531 patients with advanced dementia employing a parallel group design that stratified patient cohorts by severity according to GDS stages (Reisberg, 1992). Efficacy was determined on two independent levels: by the assessment of the physicians' Clinical Global Impression of Change (CGI-C) at the end of a 6-week observation period, and by the assessment of change in elementary ADL-functions by the caregivers using the D-Scale-of-Change. With the D-Scale-of-Change the caregivers can assess a change in broad functional items, i.e. cognitive and motor functions and also elementary functions of daily life. The effect size of this improvement increased constantly during the observation period. Even in patients of GDS stage 7 an improvement could be measured. These results were also seen by the physicians, who recorded an overall clinical improvement in 75.5% of the patients after 6 weeks. Tolerability evaluations resulted in the ratings "very well" by 59.5% or "well" by 35.0% of the patients. No serious adverse drug reactions occurred. A correlation analysis demonstrated a high congruency of both assessments. Furthermore, the observed time course of these improvements paralleled with the time course of symptomatic benefit by effects of memantine that had been repeatedly demonstrated in randomised, double-blind, placebo-controlled studies in mild to moderate dementia. Together with the evaluation of the scale-properties of the D-Scale for assessment of severity the D-Scale and the D-Scale-of-Change can be regarded as validated.

Activities of Daily Living↗
PubMed1999

Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via activation of voltage independent potassium channels. Rapid communication.

The spectrum of action of flupirtine includes analgesia, muscle relaxation and neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonism has been discussed as a possible mechanism of action of this compound with little direct evidence. The objective of the present study was to develop a plausible model to explain flupirtine's spectrum of action. A four-stage strategy was selected for this purpose: Firstly, the serum concentration of flupirtine under therapeutic conditions was determined on the basis of the current literature. The second stage involved assessing the known in-vitro effects in light of the therapeutic active concentration. Using whole cell patch clamp recordings from cultured rat superior colliculus neurones interactions between flupirtine and NMDA receptors were assessed. Only very high concentrations of flupirtine antagonized inward currents to NMDA (200 microM) at -70 mV with an lC50 against steady-state responses of 182.1+/-12.1 microM. The effects of flupirtine were voltage-independent and not associated with receptor desensitization making actions within the NMDA receptor channel or at the glycine modulatory site unlikely. NMDA receptor antagonism probably has little relevance for the clinical efficacy of flupirtine as the concentrations needed were far higher than those achieved in clinical practice. However, the activation of a G-protein-regulated inwardly rectifying K+ channel was identified as an interesting molecular target site of flupirtine. In the next stage, the central nervous spectrum of action of experimental K+ channel openers (PCO) was considered. As far as they have been studied, experimental K+ channel openers display a spectrum of action comparable to that of flupirtine. In the final stage, a global model was developed in which flupirtine stabilizes the resting membrane potential by activating inwardly rectifying K+ channels, thus indirectly inhibiting the activation of NMDA receptors. The model presented here reconciles the known functional NMDA receptor antagonism of flupirtine with the activation of K+ channels that occurs at therapeutic concentrations, thus providing an understanding of flupirtine's spectrum of action. This makes flupirtine the prototype of a clinically applicable substance group with analgesic, muscle-relaxant and neuroprotective properties.

Aminopyridines↗
PubMed1999

[Neuronal potassium channel opening with flupirtine].

The spectrum of action of flupirtine includes analgesic, muscle-relaxant and neuroprotective properties. The substance's mechanism of action has yet to be fully explained. Over the past few years, however, evidence has accumulated that flupirtine interacts with the glutamatergic N-Methyl-D-Aspartate (NMDA) receptor. Although it was not possible to demonstrate a direct effect on the NMDA receptor, all of the findings pointed to an indirect influence on the NMDA receptor in the sense of a functional NMDA antagonism. It was thus postulated that a site of action "up- or downstream" of the NMDA receptor is influenced. Such a site of action proved to be the G-protein-activated inwardly rectifying K+ channels (GIRK), the opening of which leads to a stabilization of the resting membrane potential of neuronal cells and thus causes an indirect inhibition of the NMDA receptor. At therapeutically relevant concentrations, flupirtine is a neuronal potassium channel opener. This mechanism may explain the spectrum of action of flupirtine. Selective neuronal potassium channel opening (SNEPCO) thus proves to be a new principle of action, making flupirtine the prototype of a new substance class with analgesic, muscle-relaxant and neuroprotective properties. The experimental basis for this working hypothesis and the resulting model concepts are presented from the perspective of a four-stage approach.

Aminopyridines↗