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Biomedical subjects

L Bertilsson

Publications and source records attributed to L Bertilsson.

At least 199 records · Page 11Linked to original sources
PubMed1982

Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities.

Thirty-eight healthy subjects were given single oral doses of debrisoquine and sparteine in a crossover study. The close correlation between urinary metabolic ratios of the two drugs (rs = 0.91; P less than 0.001) demonstrates that the polymorphic N-oxidation of sparteine and 4-hydroxylation of debrisoquine are related pharmacogenetic entities; the metabolism of the two drugs is regulated by identical or closely related genetic factors.

Adult↗
PubMed1982

Urinary excretion of 5-hydroxyindoleacetic acid--no relationship to the level in cerebrospinal fluid.

Concentrations of 5-hydroxyindoleacetic acid (5-HIAA) were determined in urine and cerebrospinal fluid (CSF) by mass fragmentography. A pronounced day-to-day variation in the urinary excretion of 5-HIAA was found both in psychiatric patients and a healthy control. Lumbar punctures performed twice 3-12 weeks apart in 11 healthy controls resulted in reproducible levels of 5-HIAA in CSF (r = 0.89; P less than 0.001). The mean of three periods of daily 5-HIAA excretion was not correlated to the CSF level measured in 18 psychiatric patients (r = 0.09). Three weeks of chlorimipramine treatment significantly decreased CSF 5-HIAA levels (P less than 0.05), but not the urinary excretion of 5-HIAA. It might be concluded that measurement of urinary 5-HIAA excretion is of little value compared to CSF levels in studies of serotonin in the central nervous system.

Clomipramine↗
PubMed1981

Monoamine metabolites in CSF and suicidal behavior.

Cerebrospinal fluid concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) were measured in 30 psychiatric patients who had attempted suicide and 45 healthy volunteers. The suicide attempters had a significantly lower CSF 5-HIAA level than the controls, especially those who had made more violent attempts. After adjustment for differences in body height and age between controls and patients, the difference in 5-HIAA level became even more marked. Concentrations of 5-HIAA also were lower than normal in suicidal patients who were not diagnosed as depressed at the time of lumbar puncture, while HVA levels were lowered only in the depressives. A follow-up study of these and 89 more patients (depressed and/or suicidal) revealed a 20% mortality by suicide within a year after lumbar puncture in patients with a CSF-HIAA level below the median.

Adult↗
PubMed1981

Platelet MAO activity and monoamine metabolites in cerebrospinal fluid in depressed and suicidal patients and in healthy controls.

Platelet monoamine oxidase (MAO) activity and cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were simultaneously measured in 20 currently depressed patients, 11 recovered depressed patients, 15 nondepressed suicide attempters, and 42 healthy control subjects. Both 5HIAA and HVA were positively and significantly correlated to platelet MAO activity in the healthy subjects, but not in any of the patient groups. Suicide attempters had significantly lower CSF 5HIAA than nonsuicidal patients.

Blood Platelets↗
PubMed1981

E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation.

Eight healthy subjects [who were phenotyped with a debrisoquine (D) hydroxylation test] were selected to cover a wide range in the ratio between D and 4-hydroxydebrisoquine (4-OH-D) in the urine. After a single oral dose of nortriptyline (NT) the metabolic clearance by 10-hydroxylation in the E-position, but not in the Z-position, correlated closely to the metabolic ratio D/4-OH-D (rs = -0.88, p less than 0.01). This indicates that common enzymatic mechanisms are involved in the hydroxylation of D and the E- but not the Z-10-hydroxylation of NT. Slow hydroxylators of NT and D excreted less 10-hydroxynortriptyline in urine and had lower plasma clearance of NT than the rapid hydroxylators. The strong correlation (r = 0.96) between the total plasma clearance of NT and the metabolic clearance by E-10-hydroxylation shows that this metabolic reaction is important in the disposition of the drug.

Debrisoquin↗
PubMed1981

Bromocriptine treatment of depressive disorders. Clinical and biochemical effects.

Fifteen depressed patients were treated with increasing doses of bromocriptine in an open study. Twelve were treated for 5 weeks (final dose 20-60 mg daily) and nine of these recovered almost completely. As expected from a dopamine agonist, bromocriptine decreased the level of homovanillic acid (HVA) in cerebrospinal fluid (CSF) by 15% (P less than 0.05) and 23% (P less than 0.01) after 2 and 5 weeks of treatment, respectively. After 2 but not after 5 weeks of treatment there was also a small but significant decrease (13%; P less than 0.001) of the noradrenaline metabolite HMPG in CSF. Although there was no mean effect on 5-HIAA in CSF, there was a significant relationship between the HVA and 5-HIAA levels (as % of pretreatment level) both after 2 and 5 weeks of treatment (r = 0.96 and r = 0.62, respectively). This may indicate that the drug has an effect on the serotonin system secondary to the dopamine receptor stimulation. The amelioration of depression was not related to HVA, but did correlate to HMPG in CSF (r = 0.65; P less than 0.05) both metabolites measured before treatment. These results indicate that bromocriptine may have antidepressant effects possibly mediated through the noradrenergic system rather than the dopaminergic system.

Adult↗
PubMed1980

Carbamazepine therapy in trigeminal neuralgia: clinical effects in relation to plasma concentration.

Seven patients with trigeminal neuralgia were treated with carbamazepine at three dose levels, each period lasting for six days. A single-blind technique was used, the patients being unaware of the dose changes. During the last three days of each dose treatment, the pain score was determined by the patients and the plasma concentrations of carbamazepine and its epoxide metabolite were measured. There was a correlation between the dose and plasma level of carbamazepine (r = .56; P < .01). At the carbamazepine doses studied (200 to 1,400 mg/day), no indication of saturation kinetics was seen. As the ratio between the plasma levels of the epoxide and carbamazepine was relatively low and constant, it was not possible to evaluate the potency of the epoxide. In six of the patients studied a plasma level-effect relationship was found. The best effect was seen at carbamazepine levels between 24 and 43 mu mole/L (5.7 and 10.1 microgram/mL). In one patient who was studied twice, the plasma level-response curve was different on the two occasions. Side effects were recorded in two patients, both with carbamazepine plasma levels above 33 mu mole/L (7.9 microgram/mL).

Carbamazepine↗
PubMed1980

Cortisol in the CSF of depressed and suicidal patients.

Cortisol concentrations in CSF were measured by radioimmunoassay in healthy controls, depressed patients, patients who had attempted suicide but were not depressed, and obsessive-compulsive patients. The factors that contributed most to the variance in CSF cortisol levels were a diagnosis of depression, height, and important life changes during the six months preceding the investigation. Depression was by far the most important factor. The depressed patients had significantly higher CSF cortisol levels than the controls. In obsessive-compulsive and depressed patients treated with clomipramine hydrochloride, the levels were significantly correlated with mean urinary cortisol excretion. Of the three monoamine metabolites measured, only 5-hydroxy-indoleacetic acid level was weakly correlated with CSF cortisol level. This correlation was confined to the depressed patients and could be accounted for by the common correlation with height.

Adjustment Disorders↗
PubMed1980

Clomipramine treatment of obsessive-compulsive disorder. II. Biochemical aspects.

Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid, and the noradrenaline metabolite 4-hydroxy-3-methoxyphenyl glycol were measured in CSF before and after three weeks' treatment of severe obsessive-compulsive disorder with clomipramine hydrochloride. Patients who responded to clomipramine treatment had significantly higher CSF levels of 5-HIAA before treatment. The amelioration of obsessive-compulsive symptoms was positively correlated to the reduction of CSF concentrations of 5-HIAA during clomipramine treatment but negatively correlated to plasma concentrations of clomipramine. Reduction of CSF concentrations of 5-HIAA, which probably reflects drug action on central serotonin neurons, was maximal at a plasma clomipramine concentration of about 300 nmole/L. At higher levels, the reduction of CSF levels of 5-HIAA was smaller. The antiobsessive effect of clomipramine may be connected to its capacity to inhibit serotonin uptake.

Adult↗
PubMed1980

Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine.

Two subjects from each of the three groups of homozygous rapid, heterozygous, and homozygous non-metabolizers (N-oxidation) of sparteine received a single oral dose of debrisoquine. The urinary ratio of debrisoquine/4-hydroxy-debrisoquine, reflecting the individual's capacity to C-hydroxylate debrisoquine, was closely related to his phenotype for sparteine metabolism. This indicates that the two metabolic reactions are controlled by similar if not identical genetic factors.

Adult↗
PubMed1980

Monoamine metabolites in cerebrospinal fluid during treatment of hypertension with prazosin.

Six hypertensive patients were treated with prazosin up to a final dose of 3-4.5 mg/day. There was a significant reduction of blood pressure. The cerebrospinal fluid (CSF) concentrations of the major metabolites of noradrenaline, dopamine and serotonin were unchanged. This indicates that the antihypertensive effect is not mediated via central monoaminergic neurons as suggested by animal studies.

Biogenic Amines↗
PubMed1980

Biochemical effects of zimelidine in man.

The novel drug zimelidine 50--300 mg/day was administered to 12 depressed patients. After about 3 weeks plasma levels of the demethyl metabolite, norzimelidine, were almost thrice those of the parent drug. During incubation of slices of rat brain cortex in plasma from the treated patients, the neuronal uptake of serotonin and noradrenaline was 51.7 +/- 10.2 and 82.8 +/- 9.6%, respectively, of the control values. The uptake inhibition both of serotonin and noradrenaline was correlated with the plasma level of norzimelidine (r = 0.62 and 0.63, respectively). The major central metabolites of serotonin (5-HIAA) and noradrenaline (HMPG) in cerebrospinal fluid (CSF) decreased significantly (29 and 11%, respectively) during treatment with zimelidine. Although there was no mean change in the major dopamine metabolite (HVA) in CSF, the level during treatment (as percentage of the pretreatment level) was correlated with the effect of 5-HIAA in CSF. Thus, administration of zimelidine caused a relatively selective inhibition of serotonin uptake, mainly due to norzimelidine. A small but significant inhibition of noradrenaline uptake was also seen, but this effect was less pronounced than during chlorimipramine treatment. There was an effect on the dopaminergic system, probably secondary to the action of serotonergic neurons.

Animals↗
PubMed1980

Autoinduction of carbamazepine metabolism in children examined by a stable isotope technique.

Autoinduction of carbamazepine (CBZ) metabolism was investigated in 3 children (10 to 13 yr old) using tetradeuterium-labeled CBZ (CBZ-D4). Prior to treatment, CBZ and CBZ-D4 given as a mixture had almost identical kinetics in each patient. During maintenance therapy with CBZ, part of the CBZ was exchanged for CBZ-D4 on 3 occasions. The clearance of CBZ-D4 given on the second day of therapy was 0.036 +/- 0.003 1 . kg-1 . hr-1, whereas it had been 0.028 +/- 0.003 before treatment. After 17 to 32 days of treatment, clearance doubled (0.056 +/- 0.010) but during the next 4 mo there was no further increase, indicating that the autoinduction was complete within 1 mo. As a corollary there was a decrease in steady-state plasma levels.

Adolescent↗
PubMed1980

Interindividual differences in amitriptyline demethylation.

Amitriptyline (AT) and its demethyl metabolite nortriptyline (NT) were given orally and intramuscularly to 6 normal subjects, and the areas under the blood concentration--time curves (AUC) were calculated. The mean unbound fraction of AT and NT in plasma was 5.4% and 8.3%, respectively. The blood-plasma ratio of NT was nearly double that of AT, which was close to unity. The mean systemic availability of oral relative to intramuscular AT and NT was 43% and 61%. The calculated mean oral blood clearance of AT as measured by dose (oral)/AUC was 1.6 1/min. The demethylation of orally administered AT varied considerably between the 6 individuals (from 25% to 89%) and correlated with oral drug clearance. Demethylation was estimated from the AUC applied to the NT metabolite. The estimated oral clearance of AT from demethylation ranged from 0.21 to 1.80 1/min.

Administration, Oral↗