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Biomedical subjects

H Wetzel

Publications and source records attributed to H Wetzel.

At least 19 recordsLinked to original sources
PubMed1995

Seroquel (ICI 204 636), a putative "atypical" antipsychotic, in schizophrenia with positive symptomatology: results of an open clinical trial and changes of neuroendocrinological and EEG parameters.

Preclinical data indicated that seroquel (ICI 204 636), a dibenzothiazepine with 5-HT2 and D2-like receptor antagonistic properties, might be an effective antipsychotic agent, causing fewer extrapyramidal side effects than typical neuroleptics. In the present study, 12 patients suffering from schizophrenia or schizophreniform disorder with predominantly positive symptomatology were treated in an open clinical trial for 4 weeks with seroquel at a maximum dosage of 750 mg/day. The drug was generally well tolerated, and virtually no adverse extrapyramidal side effects such as acute dystonia, parkinsonism or akathisia were observed. Total scores for BPRS (item score 0-6; baseline: 42.0 +/- 2.3; mean +/- SEM), SAPS (64.5 +/- 4.8) and SANS (55.0 +/- 4.3) showed a moderate decrease at the end of treatment (BPRS: 30.0 +/- 3.5; SAPS: 36.1 +/- 6.7; SANS: 42.5 +/- 5.9), when intention-to-treat analysis was applied. There were considerable interindividual differences in treatment response, with some subjects showing almost full remission of positive symptoms, in contrast to about half of the patients who showed no satisfactory clinical improvement. Interestingly, patients showing good antipsychotic response reported slight initial side effects like mild sedation. Prolactin and TSH levels were not altered during seroquel administration. As to pharmaco-EEG investigations, seroquel caused a moderate increase of the absolute power in the alpha, theta, and beta frequency bands, paralleled by a decrease of delta activity. There were no signs of paroxysmal EEG activity under seroquel.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

The neuroendocrinological profile of roxindole, a dopamine autoreceptor agonist, in schizophrenic patients.

Roxindole is a potent autoreceptor-selective dopamine agonist with additional properties as a serotonin reuptake inhibitor and 5-HT1A agonist. In order to get more insight into its mode of action in various psychiatric populations, we evaluated the effects of subchronic roxindole treatment on pituitary and adrenal hormone secretion, i.e. release of prolactin, thyroid stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH), and cortisol. Fifteen schizophrenic patients with positive and negative symptomatology, respectively, were treated with roxindole for 28 days. Both basal and thyrotropin releasing hormone (TRH) -induced prolactin secretion diminished significantly to 26.4% and 22.8% of baseline levels, respectively, under roxindole. Basal GH secretion was insignificantly elevated by 89%, whereas GH levels increased nearly 3-fold after stimulation by TRH. TSH levels decreased insignificantly to 57.5% of baseline levels, while TRH-induced TSH release was not affected by subchronic roxindole. Roxindole treatment influenced neither LH secretion nor cortisol release. Our results indicate that roxindole's dopaminergic actions might prevail over its serotonergic effects, at least as far as the regulation of anterior pituitary hormone secretion is concerned.

Adult↗
PubMed1994

Pharmacokinetics and bioavailability of benperidol in schizophrenic patients after intravenous and two different kinds of oral application.

Pharmacokinetics and bioavailability of benperidol were determined in 13 schizophrenic patients after acute administration of 6 mg benperidol as an intravenous (i.v.) bolus injection, orally as liquid, and orally as tablets using a partially randomized cross-over design. Drug plasma levels were determined by high performance liquid chromatography with electrochemical detection and subjected to model independent pharmacokinetic analyses. After i.v. dosing the geometric means (mean-g) were 3.2 min for the distribution half-life, 5.80 h for the elimination half-life (t1/2 beta), 4.21 l/kg for the distribution volume, 7.50 h for the mean residence time (MRT), and 0.50 l/(h*kg) for the clearance. After oral administration as liquid and as tablet mean-g data for the time lag until the first appearance of measurable plasma concentrations were 0.33 and 1.1 h, mean-g t1/2 beta values were 5.5 and 4.7 h, respectively, mean-g tmax data were 1.0 h and 2.7 h, mean-g MRT values were 8.44 and 8.84 h, and mean-g Cmax maxvalues were 10.2 and 7.3 ng/ml. Differences between liquid and tablet administration were statistically significant for time lag, tmax, and Cmax. Mean-g absolute bioavailabilities were computed as 48.6% after liquid and 40.2% after tablet administration respectively. All parameters studied exhibited large intersubject variation. The plasma concentrations of the presumed metabolite "reduced benperidol" were found to be very low.

Administration, Oral↗
PubMed1994

Plasma levels of benperidol, prolactin, and homovanillic acid after intravenous versus two different kinds of oral application of the neuroleptic in schizophrenic patients.

Plasma levels of prolactin (PRL) and the butyrophenone neuroleptic benperidol (BPD) were closely followed 0 to 48 h after acute application of 6 mg BPD as intravenous injection, orally as liquid, and orally as tablets in 12 schizophrenic patients using a partially randomized cross over design. Drug concentrations showed application specific pharmacokinetic behavior with complete elimination within 48 h. All three applications led to a biphasic PRL response with pronounced initial plasma PRL peaks returning to baseline levels within 48 h. The results suggest that after acute neuroleptic challenge BPD plasma levels as low as 2-3 ng/ml can be sufficient for complete depletion of pituitary PRL stores. This initial peak was followed by a PRL plateau about twice above pretreatment values indicating doubling of the PRL synthesis and secretion independent of supraeffective actual BPD concentrations. The PRL plateau persisted as long as BPD concentrations were above those levels which triggered the initial PRL response. As compared with the time of maximum concentrations (tmax) for BPD, the PRL tmax was later after i.v. injection, equal after liquid application, and earlier after tablet administration leading to pronounced application specific differences in shape, direction, and position of resulting hysteresis curves. Plasma levels of homovanillic acid (HVA) were not affected by BPD treatment. The PRL and HVA levels registered after acute doses of BPD indicated that the hormone responses were most likely the result of acute depletion of PRL stores and subsequent stimulation of hormone synthesis whereas it seemed unlikely that dopaminergic activities were relevant.

Administration, Oral↗
PubMed1994

Roxindole, a dopamine autoreceptor agonist, in the treatment of positive and negative schizophrenic symptoms.

Twenty schizophrenic inpatients with either predominantly positive or predominantly negative symptoms were treated with the dopamine autoreceptor agonist roxindole in prospective open clinical trials. There was no antipsychotic effect in the subgroup with positive symptoms, whereas the subgroup with negative symptoms, especially those with the residual type of schizophrenia, showed a moderate but significant 20% reduction in total scores on the Scale for the Assessment of Negative Symptoms.

Dopamine Agents↗
PubMed1993

Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients.

Bidirectional drug interactions between fluvoxamine and classical antidepressants were studied in depressed patients. A column switching technique combined with high performance liquid chromatography (HPLC) enabled automated analyses of plasma for simultaneous determination of fluvoxamine, tricyclic and tetracyclic antidepressants and demethylated and major hydroxylated metabolites in a single HPLC run. The measurements revealed that fluvoxamine inhibited N-demethylation of imipramine, clomipramine, amitriptyline and maprotiline whereas interferences with hydroxylation reactions were restricted to aromatic 8-hydroxylation of clomipramine. In patients under fluvoxamine monotherapy before comedication, plasma concentrations of fluvoxamine increased after administration of a tricyclic antidepressant, thus indicating bidirectional drug interactions. The inhibitory effects of fluvoxamine on the metabolism of classical antidepressants disappeared after discontinuation of concomitant fluvoxamine treatment within at least 1-2 weeks. The reported alterations in drug metabolism observed in depressed patients who were under fluvoxamine/tricyclic antidepressant comedication suggested that careful supervision and regular drug monitoring are necessary in such patients.

Adult↗
PubMed1993

Roxindole, a dopamine autoreceptor agonist, in the treatment of major depression.

Roxindole is a potent autoreceptor-"selective" dopamine agonist originally developed for the treatment of schizophrenic syndromes. The drug also inhibits 5-HT uptake and has 5-HT1A agonistic actions. In this open clinical trial 12 in-patients suffering from a major depressive episode (DSM-III-R) were treated with roxindole for 28 days in a fixed dosage of 15 mg per day. A reduction of at least 50% in HAMD-17 total scores was observed in 8 out of 12 patients after 4 weeks (mean HAMD-17 reduction of 56% in all patients), while 4 patients did not respond to roxindole treatment. Half of the patients showed a complete psychopathological remission (HAMD-17 < 8). Roxindole's onset of antidepressant action was remarkably rapid. Seven out of eight responders improved within the first 2 weeks of treatment (at least 50% decrease in HAMD-17 total score), and four patients were nearly asymptomatic within 1 week. Our results indicate that roxindole may possess potent antidepressant properties and that its efficacy should be further evaluated by double-blind controlled studies against reference drugs.

Adult↗
PubMed1992

Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome--a functional approach.

In vitro receptor-binding profiles and in vivo pharmacological studies have shown risperidone to be a potent mixed serotonin-S2 dopamine-D2-like receptor antagonist. While anti-D2 activity may relate to the antipsychotic potency of neuroleptic drugs, an antidepressive efficacy of substances with anti-S2 activity has been suggested. In an open pilot-study, ten patients with schizodepressive disorders or a DSM-III-R diagnosis of psychotic major depressive episodes were treated with risperidone (2-10 mg/d) for six weeks. Weekly psychopathological evaluation was performed, including BPRS, SANS, SAPS, VAS scales, and AIMS and UKU for the assessment of side-effects. Generally, the psychotic syndrome (BPRS, SANS and SAPS) decreased markedly in all patients; seven patients also showed a clinically significant improvement of depressive symptoms (BPRS). Except for two patients who needed biperiden because of extrapyramidal side-effects, the tolerance of risperidone was good. The antipsychotic and antidepressive properties of risperidone shown in our pilot study are promising enough to merit full double-blind controlled trials for further evaluation of its therapeutic value in this broad spectrum of psychiatric disorders.

Adult↗
PubMed1992

Dopamine autoreceptor agonists in the treatment of schizophrenia and major depression.

Dopamine autoreceptor agonists reduce the firing rate, synthesis, and release of dopamine in dopaminergic neurons by means of a negative feedback mechanism via stimulation of autoreceptors. Moreover, dopamine autoreceptor agonists are able to stimulate supersensitive but not normosensitive postsynaptic receptors. For dopamine autoreceptor agonists, therapeutic effects by readjustment of excessive or deficient dopaminergic function have been postulated for positive and negative schizophrenic symptomatology as well as for subtypes of depressive disorders. Investigations on the therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia or depression have yielded inconsistent results. In order to reduce the excess of central dopaminergic activity postulated by the dopamine hypothesis of schizophrenia, dopamine autoreceptor agonists have been tested in open clinical trials in positive schizophrenic symptomatology. However, administration of selective dopamine autoreceptor agonists like talipexole or roxindole did not result in a significant improvement of positive psychotic symptoms. In negative schizophrenic symptomatology, a dopamine deficit rather than an excess has been hypothesized. Current evidence from pilot studies suggests that dopamine autoreceptor agonists like roxindole may produce a minor to moderate improvement of symptoms like affective flattening, depressed mood, alogia, and avolition, possibly by stimulation of supersensitive postsynaptic dopamine receptors. For certain subgroups of depression, a reduction of functional dopamine activity has been postulated. In an open pilot study in patients with a major depression, roxindole demonstrated antidepressive properties comparable to those of standard antidepressants, justifying further double-blind controlled trials against reference drugs.

Animals↗
PubMed1992

Automated determination of fluvoxamine in plasma by column-switching high-performance liquid chromatography.

A column-switching system with high-performance liquid-chromatographic separation and ultraviolet detection is described for automated determination of fluvoxamine in human plasma or serum. Samples were injected and the drug was retained in a clean-up column [20 x 4.6 mm (i.d.)] filled with C8 reversed-phase material (10-micron particles). After unwanted material was washed out, the drug was eluted and separated with an analytical chromatography column, 4.6 x 250 mm (i.d.), filled with Nucleosil 100 CN (5-micron particles) with an acetonitrile:methanol:0.01 mol/L phosphate buffer eluent (188:578:235 by vol) at a flow rate of 1.5 mL/min for < 20 min and detected by spectrometry at 214 nm. With oxaprotiline as internal standard, fluvoxamine could be easily quantified, and it was well separated from endogenous plasma constituents and various psychoactive drugs. The detection limit was 10 micrograms/L (31.6 nmol/L), the analytical recoveries were 97-100%, and the relationship between drug concentration and detector response was linear from 0 to 1000 micrograms/L (3160 nmol/L). The automated method is suitable for therapeutic monitoring of fluvoxamine in the treatment of psychiatric patients.

Adult↗
PubMed1991

Determination of benperidol and its reduced metabolite in human plasma by high-performance liquid chromatography and electrochemical detection.

An isocratic high-performance liquid chromatographic method with electrochemical detection for the quantification of benperidol and its suggested reduced metabolite TVX Q 5402 in human plasma is described. The method included a two-step solid-phase extraction on reversed-phase and cation-exchange material, followed by separation on a cyanopropyl silica gel column (5 microns; 250 mm x 4.6 mm I.D.). The eluent was 0.15 M acetate buffer (pH 4.7) containing 25% acetonitrile (w/w). Spiperone served as internal standard. The inclusion of the cation-exchange step provided sample purity higher than those achieved with other methods. After extraction of 1 ml of plasma, concentrations as low as 0.5 ng/ml were detectable for both benperidol and the metabolite. In plasma samples collected from a schizophrenic patient treated with a single oral dose of 6 mg of benperidol, plasma levels of benperidol and of the metabolite could be measured from 20 min to at least 12 h after administration.

Benperidol↗
PubMed1991

Savoxepine: invalidation of an "atypical" neuroleptic response pattern predicted by animal models in an open clinical trial with schizophrenic patients.

The new tetracyclic compound savoxepine exhibits potent antidopaminergic effects with preferential activity in the hippocampus as compared to striatum in rat brain. As a result of behavioural animal models and regional differences in dopamine receptor binding characteristics, it has been suggested to possess an "atypical" neuroleptic response pattern. In an open clinical trial, savoxepine was administered to 12 in-patients suffering from paranoid schizophrenia and schizophreniform disorder (DSM-III). Eight patients were treated with a stable dose of 0.5 mg per day throughout the study, while in the remaining patients higher doses up to 20 mg/day were administered. Mean total BPRS scores and subscores demonstrated a moderate improvement of mainly positive schizophrenic symptoms. In contrast to animal test results, savoxepine in a broad dose range produced typical untoward extrapyramidal symptoms in the majority of patients. Our results indicate that savoxepine may not possess the expected "atypical" neuroleptic response pattern, and that the predictive validity of the animal models in question used to separate antipsychotic effects from extrapyramidal reactions may be ill-founded.

Adult↗
PubMed1991

[Zotepine versus perazine in patients with paranoid schizophrenia: a double-blind controlled trial of its effectiveness].

The dibenzothiepine zotepine is a new potential "atypical" neuroleptic exhibiting powerful antiserotonergic and antidopaminergic properties. The efficacy of zotepine was evaluated in a double-blind controlled trial versus the tricyclic neuroleptic perazine in 41 patients suffering mainly from the paranoid-hallucinatory type of schizophrenia. The key outcome variable was the extent of mental disturbance as defined by the total score of the BPRS. Additional outcome variables were GAS and CGI. In addition, adverse reactions and extrapyramidal side effects were assessed according to the FSUCL scale and the Gerlach and AIMS rating scale, respectively. Additional variables recorded were blood pressure, heart rate and routine laboratory parameters as well as electrocardiogram and electroencephalogram. In the first two days, standard equivalent doses of both drugs were administered. Thereafter, doses were administered as required. The efficacy of both substances was compared after 7, 14 and 28 days of treatment. Both drugs showed a similar antipsychotic efficacy. Under zotepine treatment a 55% improvement of the BPRS total score was observed while perazine led to a 41% BPRS score reduction. After 7 days the zotepine group was significantly more improved than the perazine group, possibly due to a dosing effect in the perazine group. In the zotepine group, fewer adverse reactions and a better benefit/risk index were observed although the differences between the two treatment groups did not reach levels of statistical significance. There were no drug-specific abnormal laboratory findings. Thus, in the present study there was no significant difference between zotepine and perazine with respect to antipsychotic efficacy and side-effect rates. However, zotepine showed a trend to a better benefit/risk index at the end of treatment.

Adult↗
PubMed1991

Extrapyramidal symptoms and their relationship to clinical efficacy under perphenazine treatment. A controlled prospective handwriting-test study in 22 acutely ill schizophrenic patients.

In order to verify the hypothesis of a strict relationship between clinical improvement and extrapyramidal side-effects, especially micrographia, twenty-two acutely ill schizophrenics were treated with perphenazine in a controlled prospective 28-day trial. During the study period, psychopathometric data, prolactin plasma levels, and handwriting samples were collected. According to the remission criteria fixed before the study began (both BPRS less than or equal to 25 and GAS greater than or equal to 80 points), 45.5% (10/22) of the total patient sample were classified as treatment responders. Handwriting tests were quantified in 21 patients. "Positive" handwriting results, i.e., a reduction of at least 13% in the overall area of 50% or more of the handwriting samples collected during the trial, were demonstrable in three of nine responders (33%) and nine of twelve nonresponders (75%). These results show that there is no positive correlation between clinical response and reduction in handwriting area. Consequently, the handwriting test is unable to predict clinical response. It is only one of a number of parameters with which to monitor the neurological side-effects of neuroleptic treatment. Outcome parameters show that psychopathological remission can be achieved with low neuroleptic dosages and few or virtually no extrapyramidal side-effects.

Acute Disease↗
PubMed1988

Improving depression severity assessment--I. Reliability, internal validity and sensitivity to change of three observer depression scales.

The Hamilton Depression Scale (HAMD) is the most commonly used scale for depression severity assessment and for antidepressant treatment evaluation. Alternative scales have been proposed by Bech and Rafaelsen (BRMS) and by Montgomery and Asberg (MADRS) to try to overcome the shortcomings of HAMD: they are based on different concepts of severity and different scaling procedures. Comparisons with respect to reliability, validity and ability to detect change have been performed using these scales in different samples. The BRMS proved superior. This result makes it necessary to question the usual procedure of testing the efficacy of antidepressants by means of HAMD alone. Problems in defining the severity of depression and in testing the validity of severity scales are discussed.

Adult↗