Showing papers by "Leif Bertilsson published in 1986"
TL;DR: The results show that during carbamazepine therapy, the contribution of the epoxide to the effect is considerable and a similar optimal plasma concentration range was found in a controlled study in trigeminal neuralgia.
Abstract: Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression.
253 citations
TL;DR: Treatment with imipramine inhibited metabolism of both sparteine and debrisoquine (MR values about doubled), but did not affect the interpatient correlations.
Abstract: Thirty-five imipramine treated patients were phenotyped with regard to polymorphic drug oxidation using sparteine and/or debrisoquine.
95 citations
TL;DR: The data suggest that there may be a common regulation of the hydroxylation of D and the oxidative metabolism of amitriptyline in nonsmokers, and it is hypothesized that an additional demethylase/hydroxylase is induced in smokers that is not involved in D hydroxyation.
Abstract: Eleven healthy nonsmokers with wide variation in the ability to hydroxylate debrisoquin (D) were given single oral doses of amitriptyline and nortriptyline on different occasions. The urinary D/4-hydroxy-D ratio correlated significantly (P < 0.01) with all three parameters of amitryptyline disposition measured (total plasma clearance, clearance by demethylation, and clearance by pathways other than demethylation), with rs= − 0.89, − 0.78, and − 0.83, respectively. In contrast, we failed to demonstrate such correlations in a previous sample of smokers. Our data suggest that there may be a common regulation of the hydroxylation of D and the oxidative metabolism of amitriptyline in nonsmokers. It is hypothesized that an additional demethylase/hydroxylase is induced in smokers that is not involved in D hydroxylation.
Clinical Pharmacology and Therapeutics (1986) 39, 369–371; doi:10.1038/clpt.1986.56
83 citations
TL;DR: It is shown that it is mainly the epoxide‐diol pathway that is induced, both during autoinduction and after induction with other antiepileptic agents.
Abstract: Drugs labeled with stable isotopes have been useful to study time-dependent changes in kinetics. Early studies suggested that carbamazepine (CBZ) may induce its own metabolism, but this could not be proved until tetradeuterium-labeled CBZ (CBZ-D4) was synthesized and then given to patients. CBZ-D4 was administered to three children during long-term treatment of epilepsy with CBZ. After 17 to 32 days of treatment, the plasma clearance of CBZ-D4 was doubled, but during the next four months, there was no further increase, indicating that autoinduction was complete within one month. Two patients with chronic alcoholism were treated with CBZ for five days. Half of the first dose of 600 mg was comprised of CBZ-D4. The half-life of this CBZ-D4 dose in the two patients (20 and 26 hr, respectively) was similar to the post-steady-state half-life of CBZ (23 hr in both patients) measured later. A single dose of CBZ given one week after the last maintenance dose had a longer half-life (46 and 45 hr, respectively), which probably is close to the disposition of the drug before starting the treatment with CBZ. This shows that autoinduction of CBZ metabolism was completed during the very first doses of CBZ. Autoinduction also disappeared rapidly after stopping the treatment. We have shown that it is mainly the epoxide-diol pathway that is induced, both during autoinduction and after induction with other antiepileptic agents.
48 citations
TL;DR: Single oral doses of 50 mg E‐10‐OH‐NT significantly increased the plasma levels of norepinephrine in both the supine and standing positions (P < 0.01), and Pulse rate increased in the standing but not the standing position.
Abstract: The active and major metabolite of nortriptyline (NT), E-10-hydroxynortriptyline (E-10-OH-NT), was taken orally as the hydrogen maleate in single doses by nine healthy subjects. The doses (10 to 100 mg) were completely absorbed, as shown by the high urinary recovery of 86.1% ± 9.9%. Of the given dose, 51.2% ± 8.7% was recovered as conjugated E-10-OH-NT and 23.9% ± 4.3% was recovered as unchanged compound. The plasma t1/2 of E-10-OH-NT was 8.0 ± 1.2 hours and total plasma clearance was 47.5 ± 10.3 L/hr. The rate of elimination varied little between individuals. There was no indication of dose-dependent elimination. The mean apparent volume of distribution was 7.7 ± 2.1 L/kg. Single oral doses of 50 mg E-10-OH-NT significantly increased the plasma levels of norepinephrine in both the supine and standing positions (P < 0.01). Pulse rate increased in the standing but not the supine position. These effects might result from inhibition of neuronal uptake of norepinephrine by E-10-OH-NT. Coupled with its low affinity for muscarinic receptors, these kinetic and pharmacodynamic features of E-10-OH-NT call for further phase I studies.
Clinical Pharmacology and Therapeutics (1986) 40, 261–267; doi:10.1038/clpt.1986.173
40 citations
Journal Article•
TL;DR: There were no significant changes in the monoamine metabolites 3 weeks after initiation of ECT in 12 patients with melancholia; however, there was a tendency for HVA to increase, indicating a decreased affinity for serotonin in the carrier.
Abstract: The effects of ECT on 5-hydroxyindoleacetic acid, homovanillic acid (HVA), and 4-hydroxy-3-methoxyphenylglycol in cerebrospinal fluid and on kinetic parameters of platelet serotonin uptake were studied in 12 patients with melancholia. There were no significant changes in the monoamine metabolites 3 weeks after initiation of ECT in 12 patients; however, there was a tendency for HVA to increase. The V(max) of serotonin uptake (measured in seven patients) remained unchanged after ECT, but there was a significant increase in K(m), indicating a decreased affinity for serotonin in the carrier.
8 citations