Search

1. Litoxetine is a selective serotonin reuptake inhibitor with antidepressant activity in animal models and in depressed patients. 2. This double-blind, cross-over, placebo-controlled study was carried out in 12 healthy young male volunteers. The aim was to assess the EEG profile of litoxetine in parallel with its pharmacokinetics after a single dose or multiple administrations for 4 days (6 doses) of two dosages (10 mg and 25 mg). Spectral analysis of four EEG leads (F4-T4, F3-T3, T4-02 and T3-01) was done up to 12 h post-dose. 3. In single or multiple doses, litoxetine induced EEG changes characterised by a dose-related increase in fast beta energies, mainly beta 2, without any changes in slow waves (delta and theta). A slight reduction in alpha activity occurred only after repeated doses. 4. EEG changes occurred after a single oral administration and lasted at least 12 h with litoxetine blood concentrations ranging from 4 to 10 ng ml-1. With repeated administrations, the pharmacodynamic steady-state was achieved as the increase in beta 2 energies was the same before and 12 h post-dose. These effects occurred with litoxetine blood concentrations ranging from 3 to 7 ng ml-1 with the 10 mg dosage and from 8 to 18 ng ml-1 with the 25 mg dosage. The EEG profile did not change after 4 days of repeated administration, indicating that tolerance did not develop. 5. Cmax and AUC showed proportionality between the administered dosages of 10 and 25 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

The kinetics of distribution of di-propranolol (P) to various organs and tissues were studied in the rat after an i.v. dose of 2 mg/kg. The disposition of the drug can be adequately described by a two-compartment open model with a distribution half-life of 4.8 min, a terminal blood half-life of 63 min and an apparent volume of distribution beta of 8.5 liters/kg. Higher tissue concentrations were found to be present in heart, brain and kidney. Although the disappearance rate of P from abdominal aorta, muscles, adipose tissue and whole brain paralleled that of blood, the elimination rate constant for atria and kidney was significantly reduced suggesting a specific binding of P. After an i.v. dose of 5 mg/kg, P distributed rapidly to various brain areas following a vascularity pattern with higher concentrations in cortical areas of earlier times. An equilibrium between various brain areas was observed at 2 to 3 hr after dosing. There was a parallel decay of P concentrations in the blood and in cortical areas, whereas the elimination constants were significantly reduced for hypothealamic nuclei and the medulla (C1 and C2), suggesting again a specific binding. The data show that distribution, uptake and tissue binding of P in various peripheral organs and discrete brain areas is not a uniform process and they could give a partial explanation on the discrepancies observed clinically between the pharmacodynamics and pharmacokinetics. The data also suggest the possibility of specific P binding sites in heart, kidney and brain which could be of relevance for its mode of action.

The distribution and kinetics of D,L-propranolol in rat brain were examined after an intravenous injection of the drug. Measurements in brain areas and blood were performed by means of a sensitive and specific gas liquid chromatographic method. The disappearance rate in cortical areas paralleled that in blood. However D,L-propranolol decreased at a slower rate in hypothalamic and medullary nuclei. Since propranolol is believed to have central hypotensive effects, its retention by certain central nuclei involved in blood pressure regulation is of interest.

The behavioural effects of both apomorphine (stereotypies) and haloperidol (catalepsy and reversal of stereotypies) were significantly enhanced in hypophysectomized rats compared with sham-operated rats. Both the efficacy and duration of action were increased Hypophysectomized animals had significantly greater brain haloperidol concentrations than did sham-operated animals. The data suggest that changes in brain drug concentrations following hypophysectomy at least partially explain the behavioural alterations seen in this test situation.