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Biomedical subjects

F A Wiesel

Publications and source records attributed to F A Wiesel.

At least 91 records · Page 5Linked to original sources
PubMed1984

Relationships between drug concentrations in serum and CSF, clinical effects and monoaminergic variables in schizophrenic patients treated with sulpiride or chlorpromazine.

Schizophrenic patients were treated with fixed doses of sulpiride (800 mg) or chlorpromazine (400 mg) during eight weeks using a double-blind design. In order to examine relationships between pharmacokinetic, clinical and biochemical parameters in relation to treatment the following variables were recorded before and 1, 2, 4 and 8 weeks after treatment. Concentrations of sulpiride, CPZ, 7-OH-CPZ, nor1-CPZ were determined in serum and CSF using liquid chromatography and mass fragmentography. Clinical variables were psychotic morbidity and side effects as evaluated by CPRS, NOSIE and side effect ratings. Monoaminergic variables were concentrations of the major cerebral monoamine metabolites, HVA, 5-HIAA and MOPEG in the cerebrospinal fluid as measured by mass fragmentography. Prolactin levels in serum and CSF were measured by radioimmunoassay. During steady state, concentrations of sulpiride in serum varied fourfold between patients and CPZ twentyfold. Drug concentrations in serum and CSF were highly correlated in CPZ-but not in sulpiride-treated patients. Although sulpiride passed into the CSF, transport between serum and CSF was restricted. In the sulpiride group, improvement of psychotic morbidity and HVA elevation in CSF tended to be negatively related to the drug concentrations in serum. Sulpiride-treated patients with extrapyramidal side effects had significantly higher drug concentrations in serum. In CPZ-treated patients, improvement of psychotic morbidity, HVA elevation and prolactin elevation all tended to be positively correlated to drug concentrations in serum and CSF. CPZ-treated patients with extrapyramidal side effects also had significantly higher CPZ concentrations in serum. In both treatment groups, the MOPEG reduction in CSF tended to be correlated to improvement of psychotic morbidity. The study supplied clinical evidence for the view that antipsychotic drugs belonging to the phenothiazine and benzamide series induce antipsychotic effects in schizophrenic patients in a graded fashion which is proportional to the degree of interaction with the central dopaminergic mechanisms. The results also support the view that sulpiride has a more selective effect on central dopaminergic mechanisms than chlorpromazine. In the schizophrenic patients studied and with the doses used, sulpiride concentrations tended to be maximal with regard to clinical and biochemical effects. For CPZ on the other hand, drug concentrations in some patients seemed to be too low to induce optimal effects.

Adolescent↗
PubMed1984

Time course for effects of sulpiride and chlorpromazine on monoamine metabolite and prolactin levels in cerebrospinal fluid from schizophrenic patients.

Schizophrenic patients were treated with the dopamine (DA)-2 receptor blocking drug sulpiride (800 mg daily) or the non-selective DA receptor blocking compound chlorpromazine (400 mg daily). Samples of lumbar cerebrospinal fluid (CSF) and blood were drawn before and after 1, 2, 4 and 8 weeks of treatment. Concentrations of the monoamine metabolites HVA, MOPEG and 5-HIAA in CSF and of prolactin (PRL) in CSF and serum were determined. In both treatment groups there were significant and similar elevations of HVA concentrations. HVA levels reached peaks after 1 to 2 weeks treatment and subsequently declined almost to the pretreatment level after 8 weeks. CSF and serum levels of PRL reached maximal levels within 2 weeks and remained stable at that level in both treatment groups. There were significantly higher PRL levels in sulpiride- than in chlorpromazine-treated patients. Women had higher PRL elevations in CSF in both treatment groups. The HVA/PRL ratio in CSF was significantly reduced in the sulpiride but not in the chlorpromazine group. After 1 week there was a significantly elevated 5-HIAA level in the chlorpromazine but not in the sulpiride group. In both groups, the MOPEG concentrations were significantly reduced in relation to pretreatment levels. The reduction was significantly more pronounced in the chlorpromazine group. The results indicate that sulpiride affects central DA metabolism in a similar way as chlorpromazine when administered in doses that induce antipsychotic effects. After both drugs evidence was obtained for the development of tolerance to the effect on the receptors that regulate HVA levels in the CSF but not to receptors regulating PRL release. The different effects of the drugs on PRL, 5-HIAA and MOPEG levels indicate that sulpiride has a more specific effect than chlorpromazine on dopaminergic mechanisms.

Adolescent↗
PubMed1983

Cerebroventricular size and cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy volunteers.

Computed tomography (CT) measures and cerebrospinal fluid (CSF) levels of the monoamine metabolites homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were determined in 43 healthy volunteers and in 26 patients with an acute psychosis of the schizophrenic type. There were no differences in the mean CSF levels of monoamine metabolites between the two groups. However, the patients had significantly wider lateral and third ventricles as compared to the volunteers. In the volunteers there were no significant correlations between ventricular sizes and monoamine metabolite levels, whereas in the patients a significant negative correlation was obtained between the size of the lateral ventricles and the levels of HVA and 5-HIAA in the CSF. These results may indicate that the enlargements of the brain ventricles found in a subgroup of schizophrenic patients may be associated with deficiencies in central monoamine transmission mechanisms.

Adult↗
PubMed1982

Prolactin response following intravenous and oral sulpiride in healthy human subjects in relation to sulpiride concentrations.

Sulpiride (100 mg) was administered intravenously and orally to healthy human subjects. Serum concentrations of sulpiride and prolactin were followed for 36 h. Both routes of drug administration resulted in a pronounced and sustained increase in serum prolactin concentration. The prolactin response was positively correlated to the prolactin baseline value. The concentrations of prolactin remained at an elevated plateau for 9--36 h after drug treatment despite low drug concentrations. The level of this plateau was directly related to the normal circadian secretion of prolactin. The sustained prolactin elevation may be due to high affinity and strong binding of the compound to the regulating receptors or the formation of an active sulpiride metabolite. Prolactin and sulpiride concentrations were significantly correlated during the initial phase after intravenous sulpiride. Following intravenous and oral sulpiride the area under the concentration-time curve (AUC) for prolactin was similar despite a considerable difference in the sulpiride concentration.

Administration, Oral↗
PubMed1982

Computed tomography of the brain in patients with acute psychosis and in healthy volunteers.

Evidence has been obtained by computed tomography (CT) that some chronic schizophrenic patients have enlarged cerebral ventricles and other brain abnormalities when compared to other patient groups and to healthy controls (Johnstone et al. (1976), Weinberger et al. (1979)). In order to investigate whether structural brain abnormalities can be demonstrated also in younger patients with acute psychosis we have undertaken a CT study in 46 patients and 46 healthy volunteers. Twenty-eight of the patients fulfilled the Research Diagnostic Criteria for schizophrenia. Nineteen had not been hospitalized for psychiatric reasons before. The lateral and third ventricles were significantly wider in the patients than in the volunteers. In the volunteers there was a significant positive correlation between age and size of the lateral ventricles, whereas in the patients, particularly those fulfilling the criteria for schizophrenia, no such correlation was obtained. These results indicate that schizophrenia may be associated with patho-physiological processes which interfere with the normal age-related enlargement of the ventricles. Signs of cortical atrophy, CSF circulation disturbances and reversed asymmetry of the occipital lobes were more frequent in the patient group then among the controls. These results are in accordance with previously published findings and indicate that structural brain abnormalities can be found in relatively young patients with acute psychosis.

Adolescent↗
PubMed1982

Failure to detect immunologic stigmata in schizophrenia.

The sera of 17 patients with acute or chronic schizophrenia were tested for antibodies to a human brain extract or to Molt cells; a human T-cell line, with negative results. The level of in vivo lymphocyte stimulation was investigated by determination of the proportion of peripheral blood lymphocytes in the G1, S or G2 + M phases of the cell cycle and by their uptake of 3H-thymidine. There was no sign of increased lymphocyte mitotic activity by these two tests. Therefore, immunologic stigmata could not be detected by these methods in these schizophrenic patients.

Antibodies↗
PubMed1982

Relationships in healthy volunteers between secretion of monoamine metabolites in urine, and family history of psychiatric morbidity.

In 66 physically and mentally healthy human subjects the total concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), 5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and dihydroxyphenyl acetic acid (DOPAC) in urine collected between midnight and 8 AM were analyzed by mass fragmentography. In the volunteers reporting the occurrence of psychiatric morbidity among relatives an increased variance in their MOPEG levels was found as compared to the volunteers without such a family history. In the male subjects with no family history of psychiatric disease there was a positive correlation between urine and cerebrospinal fluid levels of MOPEG. The urine levels of 5-HIAA, HVA, and DOPAC did not demonstrate any changes that could be related to psychopathology within the family. Changes in urine secretion of MOPEG indicate an altered metabolism of norepinephrine/MOPEG in some subjects with the occurrence of severe psychiatric disease within the family. MOPEG levels in urine may be a predictor of a family vulnerability for psychiatric morbidity in healthy subjects.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Increased content of immunoreactive prostaglandin E in cerebrospinal fluid of patients with schizophrenia.

Immunoreactive prostaglandin E (I-PGE) and thromboxane B2 (I-TxB2) were measured in cerebrospinal fluid from patients with schizophrenia and from control subjects. Schizophrenics had higher I-PGE concentrations than healthy controls, patients classified as neurotics, and patients admitted for neurological investigation. I-TxB2 concentrations were similar in all four groups. These preliminary results are consistent with the hypothesis that at least in some forms of schizophrenia there may be an alteration of PG synthesis or metabolism.

Adult↗
PubMed1980

The pharmacokinetics of intravenous and oral sulpiride in healthy human subjects.

The pharmacokinetics of sulpiride was studied in 6 healthy volunteers after intravenous and oral (tablets) administration of 100 mg. An open two- and in two subjects a three-compartment model was applied following intravenous administration. The average total distribution volume during the terminal slope was 2.72 +/- 0.66 l/kg and total systemic clearance was 415 +/- 84 ml/min. The serum half-life of the terminal slope following intravenous administration averaged 5.3 h (range 3.7--7.1 h) according to the two-compartment model. In two subjects the half-lives were 11.0 and 13.9 h when the three-compartment model was applied. Determinations of urinary excretion rates of unchanged sulpiride indicated a half-life of 7.15 h. Following intravenous administration, 70 +/- 9% of the dose was recovered unchanged in urine within 36 h; the mean renal clearance was 310 +/- 91 ml/min. Sulpiride was absorbed slowly, with peak concentrations appearing between 3 and 6 h after oral administration. The recovery of unchanged drug in urine following oral administration was 15 +/- 5% of the dose, with a mean renal clearance of 223 +/- 47 ml/min. The bioavailability determined from combined plasma and urine data was only 27 +/- 9%. The low bioavailability was probably due to incomplete absorption.

Administration, Oral↗
PubMed1980

Relationships in healthy volunteers between concentrations of monoamine metabolites in cerebrospinal fluid and family history of psychiatric morbidity.

In 60 physically and mentally healthy human subjects, lumbar cerebrospinal fluid was analysed by mass fragmentography for 5-HIAA, HVA and MOPEG. Individuals with a family history of psychiatric morbidity had significantly greater variation in monoamine metabolite concentrations than subjects without such a family history. In subjects with a family history of schizophrenic psychosis 5-HIAA and HVA concentrations were significantly higher than in subjects with depressive disorders within the family. For subjects with deviant 5-HIAA levels the probability of having a psychiatric family history was 2.7 times higher than in subjects with normal values. For HVA and MOPEG similar relationships, but of a lower significance level, were found. The results suggest that the cerebral monoaminergic transmitter amines play critical roles in the pathophysiology of psychotic and depressive disorders with a family disposition. They also indicate a value of monoamine metabolite determination in CSF for the prediction of family vulnerability for psychiatric morbidity in healthy subjects.

Adolescent↗
PubMed1979

Quantitative analysis of sulpiride in body fluids by high-performance liquid chromatography with fluorescence detection.

A high-performance liquid chromatographic method for the analysis of sulpiride, N-ethyl-2-(2-methoxy-5-sulphonamido-benzamido-methyl)-pyrrolidine, in body fluids is described. A structurally related compound, N-ethyl-2-(2,4-dimethoxy-benzamido-methyl)-pyrrolidine, was used as internal standard. A fluorescence detector with excitation maximum at 299 nm and emission maximum at 342 nm was used for the quantitation. The detection limit was about 10 ng/ml in serum and cerebrospinal fluid and about 200 ng/ml in urine. The experimental error was 5--10% in the concentration range 25--100 ng/ml. Some preliminary data from a pharmacokinetic study in healthy volunteers are presented. The half-life for sulpiride in serum was about 8 h. Sulpiride was also measured in cerebrospinal fluid from five drug-treated psychotic patients.

Adult↗
PubMed1979

Effects of piracetam on brain monoamine metabolism and serum prolactin levels in the rat.

Levels of monoamine metabolites in three different regions of the rat brain were determined following treatment with piracetam (0.5 and 5 g/kg, i.p.). The concentration of prolactin in serum was also measured. Piracetam, at 5 g/kg, increased the levels of dihydroxyphenylacetic acid, homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, whereas 5-hydroxyindoleacetic acid was unaffected. The drug also increased prolactin concentrations in serum. The level of dopamine was unchanged in the olfactory tubercle and the striatum. These effects are different from those obtained with amphetamine-like drugs. The results would seem to indicate that piracetam accelerates brain catecholamine (CA) turnover via a blockade of CA receptors, as suggested for neuroleptic drugs. This effect could be responsible for the therapeutic action of piracetam on psychotic symptoms in psycho-organic disorders of old age. A blockade of brain CA receptors by piracetam is not compatible with facilitated learning, which seems to be mediated via other neuron systems than CA pathways.

Animals↗
PubMed1979

Developmental plasticity of central noradrenaline neurons after neonatal damage--changes in transmitter functions.

The effects of neonatal 6-hydroxydopamine (6-OH-DA) treatment (systemic administration) on noradrenaline (NA) metabolism, turn over, and receptor characteristics have been investigated in rat brain in the adult stage. This treatment is known to preferentially affect the locus coeruleus (LC) NA system leading to a marked NA denervation in the central cortex and hyperinnervation of NA nerve terminals in the pons and medulla oblongata without influencing the LC perikarya. The main NA metabolite, 3-methoxy-4-hydroxy-phenylglycol (MOPEG) was reduced by about 70% in the cerebral cortex after 6-OH-DA treatment at birth while the endogenous NA was almost completely depleted (-92%). The MOPEG levels were not significantly changed in the pons medulla after 6-OH-DA treatment in contrast to the 60% increase of the endogenous NA concentration. The relative reduction of NA in the cerebral cortex of 6-OH-DA treated rats increased in the cerebral cortex following administration of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (H44/68) compared to the control, while the H44/68 induced depletion of NA was reduced in the pons medulla after 6-OH-DA. The steady-state level of endogenous NA and the effect of H44/68 were unchanged in the LC perikarya after 6-OH-DA treatment. These results indicate that the NA turn over in remaining NA nerve terminals in the cerebral cortex is increased after 6-OH-DA, while decreased in the pons-medulla, possible related to changes in the activation of presynaptic alpha-adrenoreceptors in both regions. NA-induced formation of cAMP in vitro was found to be markedly increased in the cerebral cortex after 6-OH-DA, whereas no consistent change was observed in the pons medulla. Measurements of alpha- and beta-receptor binding in vitro using radioligand techniques showed an increase of binding sites (20%--50%) for both receptors in the neocortex aster 6-OH-DA, whereas no changes were observed in the pons medulla. The 6-OH-DA induced changes in NA turnover, cAMP generating systems, and receptor density may all represent compensatory processes following the altered development of the NA neurons induced by 6-OH-DA.

Aging↗
PubMed1978

Studies on dopamine turnover in ovariectomized or hypophysectomized female rats. Effects of 17 beta-estradiol benzoate, ethynodioldiacetate and ovine prolactin.

The effects of 17 beta-estradiol benzoate (EB), ethynodioldiacetate and ovine prolactin on dopamine (DA) turnover have been studied. As an index for a change in turnover, differences in DA depletion following tyrosine hydroxylase inhibition with alpha-methyl-tyrosine methylester were observed. DA was measured by means of mass fragmentographical analysis in the rat median eminence, the olfactory tubercle and the striatum. The actions of ethynodioldiacetate and ovine prolactin on DA turnover in various subregions of the rat median eminence were analysed by quantitative microfluorimetry. Repeated injections of EB to ovariectomized rats resulted in a significant increase of DA turnover in the median eminence. Administration of ethynodioldiacetate to ovariectomized rats almost significantly increased DA turnover in the olfactory tubercle. In the median eminence DA turnover was significantly increased only in the lateral palisade zone. In male hypophysectomized rats ovine prolactin increased DA turnover in both the lateral and the medial palisade zone of the median eminence. The results support the involvement of DA neurons in the control of prolactin and luteinizing hormone secretion. It is suggested that the tubero-infundibular DA neurons are involved in mediating the central inhibitory feedback actions of prolactin and gonadal steroids on prolactin and LH secretion, respectively.

Animals↗
PubMed1978

Effect of melperone, two of its metabolites and thiothixene on central monoamine metabolism and prolactin levels in rodents.

The effects of melperone and thiothixene on the concentrations of monoamine metabolites in brain and prolactin in the serum of rats and mice were determined. Both drugs increased brain concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in a dose-dependent manner. 5-Hydroxyindoleacetic acid (5-HIAA) was unaffected. The effect of thiothixene was longer lasting and about 5 times greater than that of melperone. Melperone, but not thiothixene, increased levels of 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG). Several hours after administration of melperone, levels of HVA and MOPEG were diminished. Both drugs increased prolactin concentrations in rat serum. Thiothixene was about 10 times more potent than melperone. Of two urinary metabolites of melperone investigated, one caused the same qualitative effects on monoamine metabolism as melperone itself but with reduced potency. The other metabolite was ineffective.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1977

Mass fragmentographic determination of 5-hydroxytryptamine and 5-hydroxyindole-3-acetic acid in brain tissue using deuterated internal standards.

A mass fragmentographic method for the determination of 5-hydroxytryptamine (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) in the same extract of rat brain tissue is decribed. Deuterium-labelled analogues were used as internal standards. 5-HT and 5-HIAA were separated by solvent extraction and pentafluoropropionyl derivatives were prepared for the mass fragmentographic analysis. Multiple ion analysis confirmed the identity of 5-HT and 5-HIAA in the rat brain. At the mass numbers used routinely for the determination of 5-HT and 5-HIAA in the rat brain. At the mass numbers used routinely for the determination of 5-HT and 5-HIAA, the experimental error was below 3% (calculated from mean values of 0.05 and 0.24 nmole, respectively). The recovery of the authentic compounds added to brain extracts was more than 95%. The levels of 5-HT and 5-HIAA in the rat brain were 2.95 +/- 0.16 and 0.64 +/- 0.18 nmole/g, respectively. More than 100 samples could be analyzed within 3 days. The presence of 5-hydroxytryptophol in rat brain was also investigated, but none could be detected either as a conjugate or as the free alcohol.

Animals↗