[Clozapine--an atypical neuroleptic with a unique clinical profile].
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Biomedical subjects
Publications and source records attributed to L Lindström.
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When performing forward trunk flexion, cervical cord injured (CCI) patients exhibit continuous and high EMG activity in the diaphragm and elevated abdominal pressures. This study addressed the question whether the trunk flexion manoeuvres cause such a high force development in the diaphragm that this muscle shows EMG signs of fatigue. Six patients with complete cervical cord lesions were tested sitting in their own wheelchairs. The tension-time indices obtained when patients were sitting in a relaxed position were moderately to markedly higher than in normal subjects. The force developed during trunk flexion averaged 30% of the maximal transdiaphragmatic pressure and was accompanied by clear EMG findings of diaphragmatic fatigue in all patients except one. The acute diaphragmatic load in certain CCI patients may well produce ischaemia and increase the risk of tissue impairment. Therefore, there appears to be a need for differing strategies in the short and in the long term treatment of CCI patients; longitudinal evaluation of main diaphragmatic function may be useful for an adequate amount of respiratory muscle training.
Interest has been focused on the diaphragm as the all important respiratory muscle in tetraplegia for decades but its unique role as a trunk extension muscle has not been considered. This study set out to establish the relationship, if any, between the roles of the diaphragm during arm exercise and trunk flexion. Eight male complete cervical cord injuries (CCI) patients, sitting in their wheelchairs, were studied during rest, trunk flexion and start of arm cranking. The average flow, volume, oesophageal and gastric pressures (Poes and Pga) and the myoelectric activity of the diaphragm (EMGdi) were recorded. The EMGdi pattern changed from phasic activity at rest to continuous or almost continuous activity during trunk flexion. Patients were then either spontaneously holding their breath or breathing irregularly with rapid or shallow breaths. Also, the normalised EMGdi signal strength increased by an average of 150% and the mean Pga by about 3 kPa, while mean Poes decreased by about 0.5 kPa. At the start of exercise, patients with poor triceps function, less than MRC grade 3, exhibited similar ventilatory and EMGdi changes as had been seen in trunk flexion. In patients with better triceps function, only minor changes in these variables were observed. The findings suggest that the diaphragm acts both as a trunk extensor muscle and a respiratory muscle. During posture imbalance, the postural needs temporarily override the respiratory needs.
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Controversy exists regarding the validity of various techniques for estimating rates of protein synthesis in vivo. In the present report, we have compared estimates of hepatic protein synthesis in normal mice with a pulse labelling of [1-14C]leucine and calculated hepatic protein synthetic rates in a conventional two-pool model and in a five-pool compartment analysis. Results obtained with pulse labelling were also compared to those obtained in animals receiving a flooding dose of 1.5 mumol L-phenylalanine and 0.4 microCi [U-14C]phenylalanine per gram of body weight or 1.0 mumol L-leucine and 0.4 microCi [l-14C]leucine per gram of body weight. Estimates of protein synthesis were calculated with plasma free amino acid, liver acid-soluble fraction and acylated tRNA specific radioactivities as being representative of the precursor pool for protein synthesis. Rates of hepatic protein synthesis obtained with pulse labelling and either leu-tRNA or acid-soluble fractions of liver leucine as the precursor for protein synthesis gave similar results (37 +/- 5 vs 42 +/- 5% per day) in a two-pool model, but disagreed in a five-pool model (37 +/- 5 vs 6 +/- 2% per day). Estimates based on plasma enrichment in leucine were only one fifth of values obtained with tRNA in labelling experiments. When the plasma pool with tracer amino acids was used to indicate the precursor labelling of protein synthesis, values obtained with the flooding dose of either phenylalanine or leucine agreed with those obtained with pulse labelling and enrichment in tRNA (30 +/- 3 nmol min-1 vs 28 +/- 4 nmol min-1); with however no agreement when the enrichment in the liver mixed tissue pool was used (76 +/- 5 nmol min-1). Complete equilibration of the amino acid pools did not occur despite flooding. Therefore, the flooding technique may only represent an approximate method to measure protein synthesis in vivo, although it gives absolute values that agree well with results from labelling techniques based on tRNA enrichment provided the plasma pool is used as the precursor enrichment.
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The clinical pharmacokinetics of clozapine, an atypical neuroleptic, was evaluated in 10 chronic schizophrenic male patients after intravenous and oral administration. The mean equilibrium-state concentration ratio between blood and plasma was experimentally determined to be 0.87. The average values for blood clearance, hepatic extraction ratio and oral bioavailability were 250 ml/min, 0.2 and 0.27, respectively. Plasma concentration peaked on average at 3 h. The mean volume of distribution at steady-state and the terminal half-life was 1.6 l/kg and 10.3 h, respectively. A large fraction of the dose is most probably metabolized by some extrahepatic presystemic routes. The large inter-individual variability in the bioavailability and clearance is probably the main reason for large variation in the steady-state plasma level in patients receiving the same oral dosage regimen.
The etiologic importance of postural dysfunction, as shown by many authors in adolescent idiopathic scoliosis (AIS), has been under great debate. The authors' hypothesis was that a factor that is involved in the development of the scoliotic curvature, would be present also in nonscoliotic siblings to scoliosis patients, as AIS is a hereditary transmitted disease. Postural function in 100 siblings to scoliotic children was investigated by means of stabilometry, and compared with a matched control group of healthy children, as well as a group of scoliotic children. The siblings showed a postural control function that was significantly different from both of the other groups. The siblings had a postural sway that was less than the sway measured in both controls and scoliosis patients. The sway was also more asymmetrical than in the two other groups. In the authors' opinion, the presence of this postural aberration in siblings indicates that it is a factor in the etiology of AIS.
The regional distribution of 3 11C-labelled dopamine receptor antagonists, N-methyl spiperone, raclopride and clozapine, in the brain of Rhesus monkeys was studied by positron emission tomography (PET). The measured radioactivities in the striatal area were similar for the 3 antagonists, although the highest selectivity as compared to cerebellum was found for 11C-raclopride 60 min after administration. The selectivity of the radiotracers for the serotonin and D2-dopamine receptors was evaluated after pretreatment of the monkeys with serotonin and dopamine receptor antagonists. 11C-N-methylspiperone and 11C-clozapine both bound to serotonin receptors in the frontal cortex and to D2-dopamine receptors in the striatal area. Raclopride was selectively bound to the D2-dopamine receptors. The radioactivities measured in the striatal area with cerebellum as reference were fitted to a 3-compartment model which made possible evaluation of receptor binding characteristics. The rate proportional to the association rate constant for the receptor, kon and number of receptors, Bmax, varied from 0.02-0.07 min-1 between the studied radiolabelled drugs, whereas the apparent dissociation rate was highest for clozapine. This means that clozapine had the lowest affinity for the receptors in the striatum, assuming that the Bmax values are identical. The observed difference in selective receptor binding and binding characteristics of the 3 tracers may have an influence both on the clinical efficacy and side effects of the studied dopamine receptor antagonists.
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Nine psychotic patients under continuous oral treatment with haloperidol were randomly given a test dose of 1.5-5 mg haloperidol orally and/or intravenously. Serum levels of haloperidol were determined by high performance liquid chromatography and serum concentration data obtained were submitted to pharmacokinetic analysis. The steady state concentration ratio between blood and plasma was determined and found to be 0.79 +/- 0.03. The blood clearance was then calculated to be 550 +/- 133 ml/min. The mean hepatic extraction ratio was intermediate (0.37). Consequently, for a drug mainly eliminated by hepatic metabolism like haloperidol, the total blood clearance and the extent of oral bioavailability can be affected by changes in hepatic blood flow, hepatic enzyme activities and drug binding. During continuous oral treatment with haloperidol, however, it can be shown that changes in the total metabolic capacity of the liver due to hepatic enzyme induction or inhibition should be important for the therapeutic effects of haloperidol. The volume of distribution at steady state (Vdss) was large (7.9 +/- 2.5 l/kg). The terminal half-life was 18.8 h after intravenous and 18.1 h after oral administration. The oral bioavailability (0.60 +/- 0.18) were in accordance with previous results in healthy subjects. A mean lag time after oral dose was 1.3 +/- 1.1 h and a longer absorption half-life (1.9 +/- 1.4 h) was found in the patients compared with healthy volunteers.
Opioid activity in cerebrospinal fluid (CSF) was estimated by radioreceptor-assay (RRA) in samples obtained from ten women at term pregnancy and in the early puerperal period. The samples were fractioned on Sephadex G-10 columns and two opioid receptor active fractions, FI and FII, were recovered. Two pools of FII materials from pregnant and puerperal women, respectively, were further analyzed by electrophoresis and the concentrations of opioid activity were measured by radioreceptor assay. There was a significant rise in receptor-assayed FII opioid activity in late pregnancy as well as in the early puerperal period compared to that of healthy, nonpregnant, nonpuerperal females. Pooled FII material obtained before delivery could be separated into two major components tentatively assigned the hexapeptide [Met]enkephalin-Lys6 and the heptapeptide [Met]enkephalin-Arg6-Phe7. These two opioid peptides both have their origin in the [Met]enkephalin precursor, proenkephalin A. In the puerperal period there was predominance of only one of these components.
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By means of positron emission tomography the uptake and kinetics of N-(methyl-11C)clozapine in different brain regions have been studied in Rhesus monkeys. 11C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5-12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of 11C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for 11C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.
Remoxipride is a novel substituted benzamide derivative with specific dopamine-(D2)-receptor blocking properties and selective action on brain mesolimbic functions. Ten inpatients with a DSM-III diagnosis of schizophrenia were treated with the drug in a 6-week open-label study. After 1 week placebo washout, the patients were given stepwise increased doses from 20 to 100 mg t.i.d. Most patients showed a clinically significant improvement; the mean scores in the Brief Psychiatric Rating Scale decreased from 25.8 at baseline to 11.3 at endpoint. Few adverse events were recorded and the rated extrapyramidal symptoms were lower at endpoint than at baseline. No abnormalities in clinical chemistry, haematology, cardiovascular assessments or EEG recordings were seen.
Haptoglobin and transferrin types were studied in schizophrenic patients and controls. In the haptoglobin system a significant departure from the Hardy-Weinberg equilibrium with an excess of heterozygotes was found among the patients (p less than 0.01). The distribution of haptoglobin types in the schizophrenic patients was significantly different from that in the controls. The distribution of transferrin types showed a good agreement with the Hardy-Weinberg equilibrium. There was no significant difference between patients and controls with respect to transferrin types.
The gene and phenotype frequencies of alpha 1-antitrypsin were studied in patients with (49) and without (92) a family history of schizophrenia. A significant difference with respect to phenotype (p less than 0.05) and gene (p less than 0.025) frequencies was found between the two groups of patients. Among patients with a family history of schizophrenia there was a significant increase of the M1 gene and a decrease of the M2 gene. There were no significant differences between schizophrenic patients and controls.