Biomedical subjects

S Nyberg

Publications and source records attributed to S Nyberg.

50 records · Page 3Linked to original sources

PubMed1995

D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate.

OBJECTIVE: The aim of this study was to examine the relationships among clinical effects, central D2 dopamine receptor occupancy, and plasma concentrations of haloperidol in eight clinically stabilized schizophrenic outpatients who were responding to treatment with low doses of haloperidol decanoate. METHOD: During a 4-week interval of haloperidol decanoate dosage (dose range = 30-50 mg), the patients' D2 receptor occupancy was determined with positron emission tomography on two occasions. Plasma concentrations of haloperidol were determined with a sensitive high-performance liquid chromatography method. RESULTS: One week after injection of haloperidol decanoate, the mean D2 receptor occupancy was 73% (range = 60%-82%), and the mean plasma concentration of haloperidol was 4.6 nmol/liter (range = 2.9-9.7). After 4 weeks, the mean D2 receptor occupancy had decreased to 52% (range = 20%-74%), and the mean haloperidol concentration to 2.3 nmol/liter (range = 1.0-4.4). CONCLUSIONS: The D2 receptor occupancy 1 week after injection was high and comparable to that previously found in patients responding to acute treatment with classic neuroleptics. Prevention of relapse was maintained despite low D2 receptor occupancy during the latter part of the treatment interval. These observations indicate that continuously high D2 receptor occupancy may not be necessary to prevent schizophrenic relapses. The results emphasize the need for systematic clinical evaluation of intermittent low-dose treatment strategies.

Adult↗

PubMed1995

Utilization of radioligands in schizophrenia research.

Interest in the role of monoaminergic mechanisms in schizophrenia has stimulated the development of specific radioligands that allow PET analysis of quantitative aspects of monoamine receptor subtypes in the living human brain. Clinical studies with such ligands have not consistently demonstrated specific alterations of the total populations of D1 and D2 dopamine receptors in the caudate putamen complex of drug-naive schizophrenic patients. However, recent studies using [11C]SCH 23390, a specific D1 dopamine receptor ligand, disclosed a highly significant reduction of ligand binding in pixel elements of the basal ganglia that normally contain high activity. This finding may be related to reduced D1 dopamine regulated transmission in subsets of neuronal pathways within the basal ganglia. D3, D4, and D5 receptor subtypes constitute minor fractions of the total number of dopamine receptors in the human brain. However, efforts to find selective ligands for D3 and D4 subtypes also show promise. Radioligands for monoamine receptors have also been used to follow drug effects on receptor subtypes in schizophrenic patients treated with different types of antipsychotic drugs. Such studies have allowed the analysis of relationships between occupancy of dopamine receptor subtypes and some clinical manifestations of drug treatment. Such studies with the selective D2 antagonist raclopride indicated quantitative relationships between the degree of D2 dopamine receptor occupancy in the basal ganglia and the extrapyramidal manifestations, as well as the antipsychotic action. Some of the currently available antipsychotic drugs also induced significant occupancy of D1 dopamine receptors. However, the selective D1 antagonist SCH 39166 in doses inducing a more than 70% occupancy of D1 dopamine receptors in the caudate putamen failed to induce an antipsychotic action. This indicates that, in contrast to D2 blockade, selective antagonism of D1-regulated pathways does not mediate antipsychotic action in schizophrenia. Some but not all antipsychotic drugs also induced high occupancy of neocortical 5HT2A receptors. Because selective 5HT2A antagonism does not appear to be an efficient treatment for schizophrenia, it seems most likely that 5HT2A receptors and, perhaps, D1 receptors act in concert to modify aspects of the mandatory D2 blockade to induce antipsychotic actions. Computer graphic methods for image analysis add new dimensions to brain imaging research, allowing three-dimensional visualization of receptor populations computed from molecular PET data. This will make possible further exploration of the detailed molecular compartmentalization of the human brain using radioligand binding.

Brain↗

PubMed1995

Recent developments in PET scan imaging of neuroreceptors in schizophrenia.

Among the brain imaging techniques developed during the past two decades, positron emission tomography (PET) has the highest sensitivity allowing the analysis of specific neurotransmitter mechanisms in the living human brain. By using a combination of selective ligands labeled with positron emitting isotopes D1- and D2 dopamine, serotonin 5HT2, and benzodiazepine receptors were examined in schizophrenic patients (DSM-III-R) and healthy control subjects. With this technique receptor populations could be excellently visualized and quantified with regard to number and binding characteristics in several brain regions. The characteristics of the total D1 and D2 dopamine receptor populations in the caudate and putamen did not differ in young drug-naive schizophrenic patients and age-matched control subjects. Also for 5HT2 and benzodiazepine receptors no major alteration of receptor characteristics was observed in several neocortical and limbic brain regions. However, in schizophrenic patients treated with chemically different types of antipsychotic drugs major reductions of ligand binding was observed indicating specific induction of neuroreceptor occupancy. Thus, all chemically different types of antipsychotic drugs examined induced a substantial occupancy of D2 dopamine receptors. Clozapine in high doses induced a significantly lower degree of D2 dopamine receptor occupancy than the conventional drugs. Some but not all antipsychotics also induced a significant D1 dopamine receptor occupancy. In spite of the fact that the selective D1 antagonist SCH 39166 induced a substantial D1 occupancy, this drug did not exhibit an antipsychotic effect in schizophrenic patients. A very high degree of 5HT2 occupancy in neocortical regions was observed after clinical treatment with antipsychotic drugs as clozapine, risperidone and thioridazine.(ABSTRACT TRUNCATED AT 250 WORDS)

Antipsychotic Agents↗

PubMed1995

Positron emission tomography studies on D2 dopamine receptor occupancy and plasma antipsychotic drug levels in man.

Positron emission tomography (PET) and the selective radioligand [11C]raclopride were used to measure D2 receptor occupancy in several studies in schizophrenic patients and healthy subjects. Clinical effects of the treatment were recorded, and drug plasma concentrations measured. The hypothesized curvilinear relationship between receptor occupancy and drug plasma concentrations was supported experimentally. We suggest that there may be a distinct threshold for antipsychotic effect at about 70% D2 receptor occupancy, and another threshold for extrapyramidal side effects above 80% D2 receptor occupancy. Receptor occupancy was high even at low plasma drug concentrations. Our data indicate a need to establish dose-response curves for the conventional neuroleptics. Such a dose-response relationship might be expected for a much lower dose interval than those previously examined.

Antipsychotic Agents↗

PubMed1994

D1-, D2-, and 5-HT2-receptor occupancy in clozapine-treated patients.

Positron emission tomography (PET) and selective radioligands were used to determine central D1- and D2-dopamine- and 5-HT2-receptor occupancy in clozapine-treated patients with schizophrenia. In 16 patients, the mean D2-receptor occupancy was 47% (range, 20%-67%), which is lower than that previously demonstrated in patients treated with classical neuroleptics (range, 70%-89%). In 11 patients, the mean D1-receptor occupancy was 44% (range, 33%-59%), which is high when compared with that for classical neuroleptics. In a group of 5 patients, including some treated with low doses of clozapine, the mean 5-HT2-receptor occupancy was a high 89% (range, 84%-94%). By comparison to classical neuroleptics, clozapine is atypical with regard to central binding characteristics in the brain of treated patients.

Adult↗

PubMed1993

5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone.

It has been suggested that a combined blockade of 5-HT2 and D2 dopamine receptors may be superior to D2 dopamine antagonists alone in the treatment of schizophrenia. Risperidone, which has a high affinity for 5-HT2 and D2 dopamine receptors in vitro, is a new antipsychotic drug that has been developed according to this hypothesis. The aim of this study was to examine if risperidone indeed induces 5-HT2 and D2 dopamine receptor occupancy in vivo in humans. Central receptor occupancy was examined by positron emission tomography (PET) in three healthy men after oral administration of 1 mg risperidone. [11C]N-methylspiperone ([11C]NMSP) was used as a radioligand for determination of 5-HT2 receptor occupancy in the neocortex. Both an equilibrium ratio analysis and a kinetic three-compartmental analysis indicated a 5-HT2 receptor occupancy about 60%. [11C]raclopride was used as a radioligand for determination of D2 dopamine receptor occupancy in the striatum and the calculated occupancy was about 50%. This is the first quantitative determination of 5-HT2 receptor occupancy induced by an antipsychotic drug in the living human brain. The results indicate that 5-HT2 receptor occupancy should be very high at the dose level of 4-10 mg risperidone daily, as suggested for clinical use. Risperidone is thus an appropriate compound for clinical evaluation of the benefit of combined 5-HT2 and D2 dopamine receptor blockade in the treatment of schizophrenia.

Adult↗

PubMed1993

Evidence for a functional beta 3-adrenoceptor in man.

1. The existence of a functional beta 3-adrenoceptor in man was investigated by studying the lipolytic action of selective beta-adrenoceptor agents in isolated white omental and subcutaneous fat cells. 2. The non-selective beta 1/beta 2-adrenoceptor antagonist, CGP 12177 was lipolytic in both omental and subcutaneous fat cells. The intrinsic activity relative to isoprenaline was greater in omental than in subcutaneous cells. 3. Addition of the beta 2-adrenoceptor antagonist, ICI 118,551 and the beta 1-adrenoceptor antagonist CGP 20712A in combination or the non-selective beta-adrenoceptor antagonist propranolol alone (all 10(-7) M), induced a rightward shift of the dose-response curves for isoprenaline- and BRL37344-stimulated lipolysis of about 4 and 2 log-units, respectively. However, the antagonists did not alter lipolysis induced by CGP12177. 4. Several concentrations of beta-adrenoceptor antagonists were used to determine the pA2 values by Schild analysis. The values for CGP 20712A and ICI 118,551 (6.63 +/- 0.20 and 6.25 +/- 0.12) as antagonists of the lipolytic effects of CGP 12177 were over 2 units lower than the pA2 value for CGP 20712A against the response to the selective beta 1-agonist dobutamine (8.58 +/- 0.23) and the pA2 value for ICI 118,551 against the response to the selective beta 2-agonist terbutaline (9.15 +/- 0.26). 5. beta 3-Adrenoceptor mRNA expression, investigated with a polymerase chain reaction assay, was demonstrated in both types of adipocytes in the same cell preparations that had a lipolytic response to CGP 12177. 6. In conclusion, human white fat cells express an atypical beta-adrenoceptor in addition to beta 1- and beta 2-adrenoceptors. This receptor is stimulated more selectively by the beta1/beta2-antagonist CGP 12177 than by BRL 37344 and is poorly sensitive to blockade by selective beta1- and beta2-antagonists. On the basis of the pharmacological properties and the mRNA analyses, we suggest that this atypical receptor corresponds to the beta 3-adrenoceptor subtype.

Adipocytes↗

PubMed1991

Multiple use of plants: studies on selenium incorporation in some agricultural species for the production of organic selenium compounds.

The technique of spraying plants with inorganic forms of selenium can be employed for phytochemical production of organic selenium compounds. Fractionation of the plant material makes it possible to produce a highly concentrated and well defined selenium supplement with potential use in animal and human nutrition. The fractionation also gives opportunities to combine production of organic selenium compounds with other products, for example plant fibres. Multiple use of plants can contribute to a more efficient utilization of land area (in comparison to monocultures solely adapted to food production). It also gives the opportunity to develop systems suitable for long term fixation of carbon, as long as the plant material is not reoxidised to carbon dioxide. Plant fibres could provide raw material for the production of paper or building materials in combination with the production of organic selenium compounds preferentially accumulated in another fraction of the processed plant.

Brassica↗

PubMed1991

DNA-bound proteins contribute much more than soluble intracellular compounds to the intrinsic protection against radiation-induced DNA strand breaks in human cells.

To assess the role of soluble intracellular compounds and DNA-bound proteins in the intrinsic protection against radiation-induced DNA strand breaks, the alkaline unwinding technique was applied to cellular, nuclear, and nucleoid monolayers. It was found that, when the soluble intracellular compounds were removed from human fibroblasts by permeabilization (nuclear monolayers) and irradiated in a phosphate buffer containing 150 mM monovalent cations (Na+ and K+) and 0.8 mM MgCl2, the frequency of radiation-induced DNA strand breaks increased twofold. Removal of both soluble intracellular compounds and DNA-bound proteins from the cells by a pretreatment with 2 M NaCl (nucleoid monolayers) resulted in a 100-fold increase in the frequency of strand-break induction by gamma radiation. Expressed as percentage of total intrinsic protection against radiation-induced DNA strand breaks, DNA-bound protein contributed 99% compared to 1% by soluble intracellular compounds. Using a different experimental approach it was found that the radioprotective capacity of soluble intracellular compounds was equivalent to about 5 mM dimethyl sulfoxide (DMSO) and DNA-bound proteins to about 70 mM DMSO. It is concluded that DNA-bound proteins play a much greater role than soluble intracellular compounds in the intrinsic protection against radiation-induced DNA strand breaks in cultured human cells.

Cells, Cultured↗

PubMed1990

Reversibility of canthaxanthin deposits within the retina.

As reported earlier, crystalline yellow-glistening deposits in the retinal inner layer were identified in 22 of 53 patients treated with PHENORO (containing 10 mg beta-carotene and 15 mg canthaxanthin per capsule) for various light sensitive dermatoses at cumulative doses of canthaxanthin of up to 178 g for up to 12 years. 14 of the 22 patients with deposits could now be investigated again, 5 years after discontinuation of treatment. There was an extensive reduction of the number of deposits, confirming other reports which have demonstrated that the formation of the crystalline deposits is reversible. Analysis of serum samples revealed significant concentrations of canthaxanthin, resulting from the intake of this carotenoid via food.

Adult↗

PubMed1989

Fluoxetine treatment of depression. Clinical effects, drug concentrations and monoamine metabolites and N-terminally extended substance P in cerebrospinal fluid.

In an open study of depressed inpatients, the effects of the selective serotonin uptake blocker fluoxetine on 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 4-hydroxy-3-methoxyphenyl glycol (HMPG) and N-terminally extended substance P (SP) in cerebrospinal fluid (CSF) were measured. Thirteen unmedicated patients who met the DSM-III criteria for major depressive episode were included, and 9 completed the study. During treatment the 5-HIAA concentration decreased by 46%. The HVA and HMPG concentrations also decreased significantly, but to a lesser degree. The mean level of N-terminally extended SP was unaffected by fluoxetine treatment, but the pretreatment level correlated significantly with the pretreatment level of HMPG. The pretreatment level of HVA was the only biochemically variable that appeared to predict therapeutic outcome. The plasma concentrations of both fluoxetine and its metabolite norfluoxetine increased significantly between 3 and 6 weeks. Plasma and CSF levels of both the parent drug and its active metabolite were correlated.

Adult↗

PubMed1984

Fluctuations in T-wave morphology and susceptibility to ventricular fibrillation.

Susceptibility of the ventricles to fibrillation has been related to the degree of spatial inhomogeneity in the repolarization process. We studied the pattern of beat-to-beat fluctuations in ventricular repolarization processes in order to determine whether a relationship also exists between the temporal variability of ventricular repolarization and susceptibility to ventricular fibrillation. We used the morphology of the T-wave recorded in surface and epicardial leads as a measure of the ventricular repolarization process. The Ventricular Fibrillation Threshold (VFT) was used as the standard measure of cardiac susceptibility to fibrillation. In dog experiments, T-wave morphologic indices were computed on 1,024 sequential beats. Histogram, autocorrelation and power spectrum analyses were performed on the sequence of T-wave morphologic indices. A series of 27 experiments were performed on 20 dogs in which VFT was reduced by several different interventions--hypothermia, tachycardia and coronary artery ligation. For all three interventions we observed the same characteristic change in the pattern of T-wave morphology fluctuations. In particular, we found that as the VFT was reduced, a pattern of T-wave alternans developed. This pattern was generally not detectable by visual inspection of the ECG. It was, on the other hand, easily quantified in terms of a T-wave alternans index (TWAI) which we computed from the power spectrum of the T-wave fluctuations. In 26 of the 27 experiments, measured VFT decreased (p less than .001); in 20 of these experiments the TWAI computed from the surface ECG increased (decreased) when VFT decreased (increased) (p less than .01). In 17 experiments epicardial electrograms were recorded. In 16 of these experiments VFT decreased (p less than .001). In 16 of these 17 experiments TWAI computed from the epicardial ECG increased (decreased) when the VFT decreased (increased) (p less than .001). We conclude that statistical analysis of fluctuations in ECG complex morphology may provide a sensitive probe of ventricular vulnerability to fibrillation.

Animals↗

PubMed1981

Picture simulation of contrast sensitivity in organic and functional amblyopia.

We have tried to illustrate some contrast sensitivity defects by picture simulation. We have used data obtained from 2 patients: a woman with optic nerve lesion (Snellen VA 0.5) and a 7.5-year-old boy with anisometropic amblyopia (VA 0.6). The optic nerve lesion was represented by profound contrast sensitivity loss for all spatial frequencies, while the anisometropic eye showed loss only at high spatial frequencies. A positive picture was decomposed into 1.25 X 10(6) pixels (picture elements), using a drum scanner. In a computer each spatial frequency component of the picture was multiplied by the ratio between the patient sensitivity value and that of an age-matched reference group and a modified image was processed. The pictures illustrate the poor image quality that is associated with general contrast sensitivity loss, even when Snellen visual acuity is only moderately impaired.

Amblyopia↗

PubMed1972

Electron microscopy of the toxin and hemagglutinin of type A Clostridium botulinum.

Electron micrographs of the toxin and the hemagglutinin of type A Clostridium botulinum showed the toxin to be either round or disclike particles of 4 to 4.5 nm. These particles could also be seen as arranged in long strands or tubules of 9 nm in width. The hemagglutinin appeared as a crystalloid monolayer of stacked particles of 9 nm forming regularly arranged structures of 20 nm. Seen in cross section, these structures appeared as tubules with a lumen of 9 nm. The regularity of the angle of 83 degrees to the long axis of the structure in which the individual particles were arranged suggested that the hemagglutinins formed a helix with sufficient space within its coil to admit the strands of the toxins. A model of the possible arrangement of the toxin and the hemagglutinin in the native state is proposed.

Antibodies, Bacterial↗