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Biomedical subjects

L Bertilsson

Publications and source records attributed to L Bertilsson.

At least 217 records · Page 12Linked to original sources
PubMed1980

Monitoring tricyclic antidepressants.

As a result of their slow onset of action, the difficulty of assessing dose-effect, and the marked interindividual variability of steady-state plasma concentration, tricyclic antidepressants present a special challenge, as well as opportunity, for therapeutic drug monitoring. As shown particularly by the twin studies of Alexanderson, the most important factor responsible for interindividual variation is metabolism; in comparison, differences in binding to plasma proteins are much less significant. Despite the problems posed by the complexity of action of tricyclic antidepressants and their active metabolites on noradrenaline and serotonin metabolism and on monoaminergic receptor sites--as well as the heuristic difficulty calling for a combination of analytical, clinical, pharmacological, and psychiatric expertise--some headway is being made in our understanding the responses of patient populations to this family of drugs. The following conclusions are drawn: (a) monitoring of the plasma concentration of some tricyclics in some types of depressives may improve the clinical use of these drugs; (b) such measurements are valuable mainly in non-responders to normal therapeutic doses; and (c) there seem to exist biochemical subgroups of depressive patients for whom drug choice must be tailored.

Antidepressive Agents, Tricyclic↗
PubMed1980

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

Seven patients (mean age 60 years) with idiopathic trigeminal neuralgia previously treated with Carbamazepine(CBZ) were studied as in patients. One patient was examined twice. CBZ (Tegretol) was given twice daily in three different dose-levels to each patient, six days on each level. A single-blind technique was used. The doses were individually chosen with previous dose requirements as a basis. Plasma samples were taken immediately before the morning dose the three last days on each dose-level. CBZ and CBZ-10, 11-epoxide were analysed using liquid chromatography. All pain paroxysms were graded and registered by the patient and pain scores were calculated. The CBZ-doses given ranged from 200 to 1 400 mg/day, the mean being 733 mg/day. In six courses of treatment, patients experienced complete or almost complete pain relief, achieved at CBZ-plasma-concentrations of 24-43 mumol/l. Patients with high pain-scores at plasma-concentrations of 30 mumol/l did not benefit from further dose increase. Small adjustments of plasma-concentration otherwise resulted in pronounced changes in pain-score. Side-effects were not reported below 34 mumol/l. No conclusions could be drawn as to the possible clinical effect of CBZ-10,11-epoxide.

Carbamazepine↗
PubMed1979

Techniques for plasma protein binding of demethylchlorimipramine.

The cerebrospinal fluid (CSF) and plasma levels of demethylchlorimipramine (DMCI) were determined during treatment of depression or obsessive-compulsive disorders with chlorimipramine. In 18 patients the mean CSF/plasma ratio of DMCI was 2.6% +/- 0.7 SD with fourfold variation (1.1% to 4.0%). In spite of this variation, the levels in CSF and plasma at steady state correlated closely (r = 0.91; p less than 0.001). With equilibrium dialysis for the determination of the protein binding of DMCI, a much higher free fraction was found in patients (8.0 +/- 1.6%) and in control subjects (8.2 +/- 1.4%). It was shown that part of the plasma binding capacity was lost during the incubation. Results obtained by ultrafiltration (3.9 +/- 1.0% unbound drug) were closer to the in vivo results, but this method also had disadvantages; much of the drug was absorbed on the ultrafiltration dialysis membrane. Our results suggest that there is a need for care in the selection of a technique for studies of drug protein binding.

Blood Proteins↗
PubMed1979

Intraindividual similarity in the metabolism of amitriptyline and chlorimipramine in depressed patients.

The two structurally similar tricyclic antidepressant drugs amitriptyline (AT) and chlorimipramine (CI) were administered to 15 patients in a cross-over study. Approximately equimolar daily doses of the two drugs (5 mumol/kg body weight) were given as commercial tablets. Steady state plasma levels of the parent drugs and the demethyl metabolites were determined by high performance liquid chromatography. An about 5-fold interindividual variation was found in plasma levels of all four compounds. As the reciprocal plasma level during multiple dosing is proportional to the clearance of a compound, this parameter was used for linear regression analysis. In the 15 patients there was a significant correlation between the reciprocal plasma levels of CI and its metabolite demethylchlorimipramine (r = 0.76; p less than 0.001) and also between AT and its metabolite nortriptyline (r = 0.52; p less than 0.05). The reciprocal plasma levels of the parent compounds AT and CI were closely correlated (r = 0.87; p less than 0.001). A similar correlation was found for the demethyl metabolites (r = 0.77; p less than 0.001). The results indicate that similar factors control the plasma levels of AT and CI during treatment and that similar enzymes may be involved in the metabolism of the two drugs.

Amitriptyline↗
PubMed1978

Mechanism of action of benzodiazepines - the GABA hypothesis.

Benzodiazepines influence on a number of neurotransmitters such as acetylcholine, catecholamines, serotonin, glycine and gamma-aminobutyric acid (GABA), but during recent years the major interest has been focused on the inhibitory transmitter GABA. This paper reviews the hypothesis that benzodiazepines act via GABA-ergic mechanisms in the central nervous system. At NIMH in Washington D.C. a novel method to measure the turnover rate of GABA in rat brain nuclei has been developed (Bertilsson et al., J. Pharmacol. Exp. Therap. 200: 277, 1977). The incorporation of 13C from glucose into glutamic acid and GABA was quantitated in stereomicroscopically isolated nuclei. Using this technique it was shown that the GABA agonist muscimol and diazepam have a similar action. Both drugs decreased the turnover rate of GABA in N. caudatus and accumbens, but not in globus pallidus (Mao et al., Biol. Psychiatry 12: 395, 1977). This gives further support to the theory that diazepam acts as a GABA-mimetic drug.

Acetylcholine↗
PubMed1977

Monoamine metabolites in cerebrospinal fluid during treatment with clonidine or alprenolol.

Lumbar cerebrospinal fluid (CSF) concentrations of the major metabolites of noradrenaline (4-hydroxy-3-methoxyphenyl glycol, HMPG), serotonin (5-hydroxyindoleacetic acid) and dopamine (homovanillic acid) were measured before and during the administration of clonidine or alprenolol to hypertensive patients. The noradrenaline receptor stimulant clonidine significantly decreased the CSF level of HMPG, but there was no consistent change in the concentration of serotonin or dopamine metabolites. Patients on alprenolol showed no change in the levels of these metabolites in CSF.

Adult↗
PubMed1977

The turnover rate of gamma-aminobutyric acid in the nuclei of telencephalon: implications in the pharmacology of antipsychotics and of a minor tranquilizer.

The turnover rate of GABA is measured in substantia nigra, globus pallidus, N. accumbens, and striatum of rats injected with muscimol, a potent GABA agonist, and diazepam. The similarity of action of the two drugs on GABA turnover further supports the theory that diazepam acts as a GABA-mimetic drug. Haloperidol and clozapine affect GABA turnover differently in different nuclei. Haloperidol decreases GABA turnover in caudate but does not affect that in substantia nigra, whereas clozapine increases GABA turnover in both areas. However, both drugs accelerate GABA turnover in globus pallidus and N. accumbens. It is suggested that an increase of GABA turnover and perhaps of GABA release in striatum and substantia nigra may account for the lack of tardive dyskinesia and extrapyramidal side effects of clozapine.

Aminobutyrates↗
PubMed1977

Application of principles of steady-state kinetics to the estimation of gamma-aminobutyric acid turnover rate in nuclei of rat brain.

13C-labeled glucose (50 mumol/kg/min) was infused into the rat tail vein for 10 minutes. The animals were killed by a microwave beam focused to the skull at various times after the infusion. In brain nuclei the concentrations of glutamate and gamma-aminobutyric acid (GABA) and their enrichment in 13C were measured by mass fragmentography. The results showed that in the five brain areas studied, substantia nigra contained the highest GABA concentration, followed by globus pallidus, N. accumbens, deep cerebellar nuclei, N. caudatus and cerebellar cortex. The concentrations of glutamate and GABA were comparable in some nuclei (substantia nigra and globus pallidus), but not in others. The glutamate content was 3 to 6 times greater than GABA content in cerebellum (cortex and nuclei) N. accumbens and N. caudatus. The turnover rates of GABA in substantia nigra, globus pallidus, N. caudatus and N. accumbens were calculated by applying principles of steady-state kinetics to the changes with time in the 13C enrichment of glutamic acid and GABA. In substantia nigra, N. accumbens and N. caudatus, the percentage of 13C incorporation into glutamic acid and GABA reached its maximum 10 to 15 minutes after the infusion. In N. caudatus and N. accumbens, the percentage of 13C incorporation into GABA was higher than that in substantia nigra and globus pallidus. The turnover rates of GABA were very similar in N. caudatus, N. accumbens, substantia nigra and globus pallidus (385-562 nmol/mg of protein per hr), but the turnover times were much faster in N. caudatus and N. accumbens. It must be kept in mind that in N. caudatus and N. accumbens the glutamate pool was several-fold greater than that of GABA. Since the data obtained indicate that the compartmentation is more complicated than in the model assumed for turnover estimations, this method should be used only for comparative purposes in drug studies. The validity of this method to obtain absolute measurements of GABA turnover remains to be documented.

Aminobutyrates↗
PubMed1976

Mass fragmentographic quantitation of glutamic acid and gamma-aminobutyric acid in cerebellar nuclei and sympathetic ganglia of rats.

A method for the simultaneous quantitation of glutamic acid and gamma-aminobutyric acid (GABA) in tissue by mass fragmentography has been developed. The amino and carboxylic groups of the two amino acids were in a convenient one-step reaction derivatized with pentafluoropropionic anhydride and hexafluoroisopropanol. Deuterium-labeled glutamic acid and GABA and a homologue of GABA have been used as internal standards. The usefulness of the technique has been demonstrated by measurements in parts of rat cerebellum and in the superior cervical ganglion.

Aminobutyrates↗
PubMed1976

Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during treatment of epilepsy.

Carbamazepine and its epoxide in plasma were measured by liquid chromatography in 25 patients treated with a mean dose of carbamazepine of 12.5 +/- 3.3 mg/kg body weight. The mean concentrations of parent drug and metabolite were 5.4 +/- 2.5 mug/ml and 1.10 +/- 0.42 mug/ml, respectively. A singificant correlation was found between the plasma concentrations of the two compounds (r = 0.64; p less than 0.001), but marked interindividual variation existed in the ratio of carbamazepine to carbamazepine to epoxide. Based on simultaneous measurements in plasma and cerebrospinal fluid, the unbound fraction of carbamazepine in plasma was of the order of 20% as compared to 45% for the epoxide. Thirteen ambulant patients suffering from partial epilepsy with complex symptomatology, who were already being treated with phenytoin in optimal doses (plasma level 14-20 mug/ml) were also given carbamazepine. At plasma levels of the latter of about 5 mug/ml there was no further reduction in the frequency of partial or generalized epileptic seizures. In five patients the dose was increased to produce plasma concentrations of 7 - 8 mug/ml. There was still no improvement and side-effects were seen in three patients.

Carbamazepine↗
PubMed1976

"Serotonin depression"--a biochemical subgroup within the affective disorders?

The distribution of 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid of 68 depressed patients was bimodal. Twenty-nine percent of the patients were in the lower mode, with a concentration of 5-HIAA below 15 nanograms per milliliter. Although there were no differences in overall severity of depression between the two modes, there was a significant correlation between the concnetration of 5-HIAA and severity of depression in the lower, but not in the upper, mode. The finding suggests the existence of a biochemical subgroup of depressive disorder, characterized by a disturbance of serotonin turnover.

Antidepressive Agents↗
PubMed1976

Reduction of tryptophan hydroxylase activity and 5-hydroxytryptamine concentration in certain rat brain nuclei after p-chloroamphetamine.

High-pressure liquid chromatography and mass fragmentography have been used to determine tryptophan hydroxylase activity and 5-hydroxytryptamine (5-HT) concentration, respectively, in certain rat brain nuclei. (+/-)-p-Chloroamphetamine (100 mumol/kg i.p.) decreased enzyme activity in 5-HT terminals of the caudate, hippocampus and septum to a minimum level within 3 days. In hippocampus, but not in septum, the enzyme activity and 5-HT content remained maximally depleted (about 80%) for as long as 2 months after the p-chloroamphetamine injection. Of the 5-HT cell body areas investigated, only in the B9 nucleus was the tryptophan hydroxylase activity and 5-HT content still significantly reduced (about 25-50%) at 21 and 60 days after the drug injection. The enzyme activity and 5-HT content of the B7 and B8 nuclei were not significantly different from control values at these times. These results suggest that the primary site of action of p-chloroamphetamine is on nerve terminals followed by secondary effects on serotonergic cell bodies.

Amphetamines↗