Showing papers by "Leif Bertilsson published in 1985"

Homicide, suicide and CSF 5‐HIAA

Abstract: Concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 4-hydroxy-3-methoxyphenyl glycol (HMPG) in lumbar spinal fluid were measured by mass fragmentography in 16 men convicted for criminal homicide, 22 men who had attempted suicide, and 39 healthy male control subjects. Those men who had killed a sexual partner, and those who had attempted suicide, had lower levels of the serotonin metabolite, 5-HIAA in spinal fluid than the controls. It is suggested that low levels of 5-HIAA in spinal fluid reflect a disorder of serotonin turnover, which makes the individual more prone to acts of violence in states of emotional turmoil.

Carbamazepine metabolism in man. Induction and pharmacogenetic aspects.

Abstract: The metabolism of carbamazepine (CBZ) was studied in 3 groups of subjects: (1) 6 healthy volunteers given a single dose of 200mg carbamazepine; (2) 4 epileptic patients on carbamazepine monotherapy; and (3) 5 patients receiving carbamazepine in combination with other anticonvulsants. Carbamazepine kinetics in the patients were investigated by use of 15N-CBZ. The mean plasma clearances of carbamazepine were 19.8, 54.6 and 113.3 ml/h/kg in groups 1, 2 and 3, respectively. The increased clearance in the patients was mainly due to an induction of the epoxide-diol pathway, as reflected by an increased urinary excretion of the trans-CBZ-diol metabolite. The urinary excretion (as a percentage of the administered dose) of 9-hydroxymethyl-10-carbamoyl-acridan (9-OH-CBZ) was also increased, whereas the excretion of 2-OH-CBZ and 3-OH-CBZ in groups 2 and 3 were decreased in comparison with group 1. As it has been suggested that 9-OH-CBZ is formed from carbamazepine-10,11-epoxide (CBZ-E) or trans-CBZ-diol, the formation of 9-OH-CBZ was investigated in 3 patients with trigeminal neuralgia treated with carbamazepine or CBZ-E as monotherapy on separate occasions. The urinary excretion of 9-OH-CBZ was 1.9, 3.3 and 4.0% of the trans-CBZ-diol excretion during CBZ-E therapy and 23, 32 and 24%, respectively, during carbamazepine administration. Thus only a minor part of the 9-OH-CBZ excreted in urine during carbamazepine therapy is formed via the epoxide-diol pathway. Data on plasma concentrations of carbamazepine and CBZ-E, and on urinary excretion of trans-CBZ-diol from 4 patients on carbamazepine therapy were used to calculate the plasma clearance of CBZ-E. The hydration of CBZ-E during carbamazepine therapy was found to be induced, but to a lesser extent than the epoxidation of carbamazepine. The interrelationship between carbamazepine-epoxidation and oxidative metabolic reactions of some other drugs was also studied in 8 healthy volunteers. Carbamazepine-epoxidation was not correlated to 4-hydroxylation of debrisoquine, oxidation of sparteine, 3- and 4-hydroxylation and demethylation of antipyrine, demethylation of amitriptyline, or total metabolism of theophylline.

Plasma concentrations of nortriptyline and its 10-hydroxy metabolite in depressed patients--relationship to the debrisoquine hydroxylation metabolic ratio.

Abstract: In 20 depressed patients treated with nortriptyline (NT) there was a significant relationship between the plasma concentration of NT and the debrisoquine metabolic ratio (rs = 0.77; P less than 0.01). (The debrisoquine test was performed after stopping NT treatment). This is in agreement with the hypothesis that the hydroxylations of NT and debrisoquine are mediated by similar enzymatic mechanisms. In contrast there was no significant relationship between the debrisoquine metabolic ratio and the plasma concentrations of the active metabolite 10-hydroxy-nortriptyline. In 11 of the patients the debrisoquine metabolic ratio was significantly higher during than after NT treatment. This may be due to an inhibition of the debrisoquine hydroxylation by NT.

Alaproclate a novel antidepressant? A biochemical and clinical comparison with zimeldine.

Abstract: – Clinical and biochemical effects of two selective 5-HT uptake inhibitors, zimeldine and alaproclate, were studied in 24 hospitalized patients with endogenous depression. According to a randomized parallel group design 14 patients were treated with zimeldine and 10 with alaproclate. The dosage of both zimeldine and alaproclale was 200 mg daily. For the evaluation of the clinical effect, Montgomery & Asberg Depression Rating Scale (MADRS) was used. Seven of 14 patients treated with zimeldine and seven of 10 treated with alaproclate improved. 5-HT uptake inhibition in patients’ platelets and concentration of amine metabolities (5-HIAA, HVA, HMPG) in CSF were studied before and during treatment. After 3 weeks of treatment with zimeldine 5-HIAA and HMPG in CSF decreased significantly while HVA in CSF increased significantly. Zimeldine produced a significant 5-HT uptake inhibition in platelets. During treatment with alaproclate no significant change in amine metabolites concentration in CSF was found and there were no mean changes on 5-HT uptake inhibition in platelets.

CSF and plasma levels of nortriptyline and its 10-hydroxy metabolite.

Abstract: After 3 weeks' nortriptyline (NT) treatment the mean plasma concentration of its 10-hydroxy metabolite (10-OH-NT) (599 +/- 207 nmol l-1) was higher than that of the parent drug (433 +/- 199 nmol l-1) in 25 depressed patients. Also in the cerebrospinal fluid (CSF) the mean level of 10-OH-NT (67 +/- 20 nmol l-1) was higher than that of NT (39 +/- 23 nmol l-1). There was a strong correlation (P less than 0.001) between the CSF and plasma concentration of both NT (r = 0.92) and 10-OH-NT (r = 0.77). The interindividual variation in the CSF/plasma ratio of both compounds was small, compared to the variation in plasma levels. These results show that 10-OH-NT passes the blood-brain barrier as it is present in concentrations higher than those of NT in the CSF. 10-OH-NT has previously been shown to be a potent blocker of noradrenaline uptake and to have much less affinity for muscarinic receptors than NT itself. This active metabolite might therefore be a potential antidepressant with less disturbing anticholinergic side-effects.