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G Sedvall

Publications and source records attributed to G Sedvall.

At least 145 records · Page 8Linked to original sources
PubMed1985

Preparation of 11C-labelled Raclopride, a new potent dopamine receptor antagonist: preliminary PET studies of cerebral dopamine receptors in the monkey.

A new dopamine receptor antagonist, Raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy- 6-methoxybenzamide, FLA 870) (1), has been labelled using [11C]ethyl iodide for alkylation of the nitrogen of the pyrrolidine ring in the corresponding secondary amine (5). The synthesis of 5 and an efficient method for the preparation of [11C]ethyl iodide are described. The 11C-labelled FLA 870 (1) was purified by HPLC and then used in positron emission tomography to visualize the dopamine receptor-rich areas of the monkey brain. The images obtained show selective accumulation of FLA 870 in striatum and a 10-fold separation between the binding to caudate vs cerebellum.

Animals↗
PubMed1985

Imaging of [11C]-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography.

The benzodiazepine antagonist Ro 15-1788 was labelled with [11C] and examined for possible use as ligand for PET scan studies on benzodiazepine receptors in the brain of cynomolgus monkeys and human subjects. [11C] Ro 15-1788 allowed the in vivo visualization of benzodiazepine receptor binding in cerebral and cerebellar cortical areas as well as in basal brain nuclei in PET scan images. [11C] Ro 15-1788 exhibited a high ratio of specific benzodiazepine receptor binding (cerebral cortex) to non-specific binding (pons) and the kinetics of binding should be satisfactory for quantitative clinical PET scan studies using [11C]. The in vivo binding of [11C] Ro 15-1788 in the cerebral cortex of cynomolgus monkeys and healthy human subjects was reduced by approximately 90% within 10 min after the intravenous injection of a high dose of unlabelled Ro 15-1788 (0.5 mg/kg i.v.). Different areas of the healthy human brain showed an approximately 10-fold variation in maximal [11C] Ro 15-1788 binding that corresponded to the previously known distribution of benzodiazepine receptors in these regions. The highest degree of binding was obtained in the medial occipital cerebral cortex followed by frontal cortex, cerebellum, thalamus, striatum and pons. Two psychiatric patients with anxiety syndromes who had been treated for a long time with high doses of benzodiazepines had roughly the same degree of maximal [11C] Ro 15-1788 binding in brain regions as the healthy subjects but the rate of decline of [11C] Ro 15-1788 in the brain was higher. This indicates that there is measurable competition between [11C] Ro 15-1788 binding and clinical benzodiazepine concentrations in the body fluids of psychiatric patients. The results demonstrate that [11C] Ro 15-1788 should be a valuable tool for quantitative analyses of benzodiazepine receptor characteristics and receptor occupancy in the brain of patients with neuropsychiatric disorders.

Adult↗
PubMed1985

Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography.

Two substituted benzamides, FLB 524 and raclopride, were labeled with 11C and examined for their possible use as ligands for positron emission tomography (PET)-scan studies on dopamine-2 (D-2) receptors in the brains of monkeys and healthy human subjects. Both ligands allowed the in vivo visualization of D-2 receptor binding in the corpus striatum caudate nucleus/putamen complex in PET-scan images. [11C]Raclopride showed a high ratio of specific striatal to nonspecific cerebellar binding, and the kinetics of binding of this ligand made it optimal for PET studies. The in vivo binding of [11C]raclopride in the striatum of cynomolgus monkeys was markedly reduced by displacement with haloperidol. This and previous in vitro data indicate that [11C]raclopride binds selectively to striatal D-2 dopamine receptors. In healthy human subjects, [11C]raclopride binding in the caudate nucleus/putamen was 4- to 5-fold greater than nonspecific binding in the cerebellum. In comparison with previously available ligands for PET-scan studies on central dopamine receptors in man, [11C]raclopride appears to be advantageous with regard to (i) specificity of binding to D-2 receptors, (ii) the high ratio between binding in dopamine-rich (caudate, putamen) and dopamine-poor (cerebellum) human brain regions, and (iii) rapid association and reversibility of specific binding. [11C]Raclopride should be a valuable tool for characterizing D-2 receptors in the brains of patients with neuropsychiatric disorders.

Animals↗
PubMed1985

Plasma amino acids in relation to cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy controls.

Compared to healthy controls, unmedicated schizophrenic patients had significantly higher plasma concentrations of taurine, methionine, valine, isoleucine, leucine, phenylalanine, and lysine. Except for taurine, these amino acids share the L-transport system for neutral amino acids. In the patients, homovanillic (HVA) acid levels in CSF were decreased and the plasma levels of the amino acids competing with tyrosine and tryptophan for transport into the brain, were all negatively correlated to the CSF concentrations of HVA and 5-HIAA. These findings could be explained by a change in the affinity of the L-system or by a decrease in its overall capacity in schizophrenia. Raised plasma levels of the competing amino acids may limit the brain uptake of tyrosine, leading to a diminished dopamine turnover, and resulting in a compensatory development of supersensitive dopamine receptors.

Adult↗
PubMed1984

Bilateral skin conductance activity, clinical symptoms and CSF monoamine metabolite levels in unmedicated schizophrenics, differing in rate of habituation.

Bilateral skin conductance (SC) and heart rate (HR) were recorded for 18 RDC-diagnosed unmedicated recently admitted psychotic patients (13 schizophrenic and 5 paranoid) and for age- and sex-matched controls, during rest and tone stimulation (85 dBA, 1000 Hz, 1 sec duration and 0.25 msec rise time). Schizophrenics had more SC spontaneous fluctuations and faster HR, indicating higher arousal. SC spontaneous fluctuations were more frequent in left hand and showed an increasing trend over the session. Several SC measures indicated higher responsivity and a more irregular responding pattern in schizophrenics. These patients had higher levels of the noradrenaline metabolite (MHPG). Paranoid psychotic patients had a more stable SC habituation course than controls, and higher levels of the dopamine (HVA) and serotonin metabolites (5-HIAA). Schizophrenic nonhabituators had fewer positive psychotic symptoms than habituators, suggesting that poor habituation is not due to interference by symptoms. It may be related to higher arousal, or to deficient information processing.

Adult↗
PubMed1984

Amino acids in plasma and CSF and monoamine metabolites in CSF: interrelationship in healthy subjects.

Plasma and cerebrospinal fluid (CSF) concentrations of amino acids were measured in 65 healthy volunteers (50 men and 15 women). The CSF levels of the monoamine metabolites homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) were also determined. Sex differences were observed in both plasma and CSF amino acid levels as well as in the relationship between these concentrations. No significant correlations were observed between the CSF levels of HVA and 5-HIAA, and the concentrations of their precursor amino acids in either plasma or CSF. The MOPEG level in CSF correlated positively with the plasma concentrations of several amino acids.

Adult↗
PubMed1984

5-hydroxytryptophol in human cerebrospinal fluid: conjugation, concentration gradient, relationship to 5-hydroxyindoleacetic acid, and influence of hereditary factors.

The serotonin metabolite 5-hydroxytryptophol was studied in human cerebrospinal fluid. A minor fraction (approximately 13%) was found in conjugated form from which it was liberated by treatment with sulphatase containing beta-glucuronidase activity. A concentration gradient of 5-hydroxytryptophol concentration was shown on lumbar tapping and the concentration in ventricular CSF was about 2.5 times higher than that in lumbar CSF. 5-Hydroxytryptophol and 5-hydroxyindoleacetic acid concentrations were significantly correlated in healthy, psychotic, and depressed subjects, but not in alcoholics. 5-Hydroxytryptophol concentrations in CSF of psychotic and depressed subjects were not different from those of healthy controls (4.22 pmol/ml +/- 0.15, SEM). In healthy subjects, hereditary factors seemed to have little influence on the CSF level of 5-hydroxytryptophol.

Adolescent↗
PubMed1984

Clinical evaluation of sulpiride in schizophrenic patients--a double-blind comparison with chlorpromazine.

To evaluate the clinical potential of sulpiride for the treatment of schizophrenic patients, a double-blind study was performed comparing fixed doses of sulpiride (800 mg daily) and chlorpromazine (400 mg daily). Twenty-five schizophrenic (RDC) patients participated in each treatment group. Antipsychotic effects were evaluated by CPRS and NOSIE ratings before and after 1, 2, 4 and 8 weeks of treatment. Interrater reliabilities for CPRS items and subscales were satisfactory. Treatment with sulpiride or chlorpromazine resulted in a significant reduction of psychotic morbidity as estimated by CPRS and global ratings. CPRS scores reflecting autism were significantly reduced in all ratings of sulpiride-treated patients, but only after four weeks in the chlorpromazine group. Total NOSIE scores indicated improvement in both treatment groups. A significant difference in favour of sulpiride was obtained for the NOSIE subscale "retardation". Extrapyramidal side effects occurred at a similar frequency in both treatment groups. Autonomic side effects occurred to a greater extent in chlorpromazine-treated patients. Lactation was reported only in four sulpiride-treated patients. Liver transaminase enzymes in serum were markedly elevated only in chlorpromazine-treated patients. The results indicate that sulpiride has a marked antipsychotic effect which is at least not inferior to that of chlorpromazine. A better effect on autistic components of behaviour was demonstrated for sulpiride. The results indicate a higher risk of lactation but a lower risk of anticholinergic side effects and liver toxicity for treatment with sulpiride than with chlorpromazine.

Adolescent↗
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↗
PubMed1984

Evidence of disturbed CSF circulation and brain atrophy in cases of schizophrenic psychosis.

The cerebrospinal fluid (CSF) circulation was studied with isotope cisternography in 30 patients with a schizophrenic type of psychosis. All had previously received neuroleptic treatment. Disturbed CSF circulation was found in 10 cases. In four of these, persistent intraventricular radioactivity was observed as well as partly obstructed CSF spaces. In the other six cases a slow CSF circulation was noted as well as evidence of partly obstructed CSF spaces especially of the upper posterior frontal region. Signs of atrophy of the cortex and vermis were found on CT scan in 10 cases. In four of these subjects a local atrophy was noticed in the upper posterior frontal cortex and around the frontal part of the interhemispheric fissure. Seventeen of the patients (57 per cent) had pathological findings at isotope cisternography and/or at CT. Disturbed circulation did not correlate with CT-findings, age, duration of psychosis, alcohol abuse, drug consumption or family history for psychosis. CT evidence of brain atrophy was significantly related to nonfamilial type of psychosis.

Adult↗
PubMed1983

Central nervous system noradrenaline metabolism and alcohol consumption in man.

The levels of 3-methoxy-4-hydroxy ethyleneglycol, MOPEG, the main metabolite of noradrenaline in the CNS, were determined in lumbar cerebrospinal fluid of healthy male volunteers. The subjects had been alcohol-free for at least one week and were investigated after intake of 60, 80 or 120 g of ethanol. One week before or after the experiment control samples were obtained. All subjects showed increased MOPEG levels during intoxication, and the MOPEG elevation was significantly correlated to blood ethanol concentration. During control conditions MOPEG levels were fairly constant over time but there were higher levels at night than in the morning. The baseline levels of MOPEG were negatively correlated to the reported habitual alcohol intake of the subjects, and also to the occurrence of dependency traits in their drinking pattern. Subjects with first-degree relatives with alcohol problems had lower MOPEG levels than the rest. Assuming that changes of MOPEG levels in cerebrospinal fluid are dependent on changes of central nervous system noradrenaline turnover, the results indicate that alcohol intoxication is related to a central noradrenergic stimulation, and that the activity of central noradrenaline systems is of importance for longterm alcohol habits in man.

Adult↗
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↗