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The effects of chronic administration of sodium valproate (200 mg/Kg/d i.p.) and diazepam (5 mg/Kg/d i.m.) alone or in association on the plasma levels of the pituitary hormones (prolactin, FSH and LH) were studied in the m ale rat. Sodium valproate increases prolactin plasma levels. This effect is antagonized by diazepam. Both molecules do not affect FSH levels, whereas they increase LH levels when given alone or in association. This pharmacological data state precisely the hypothalamohypophysiotropic effects of valproate and diazepam during its association.

Circadian rhythms of blood total proteins, albumin, alpha 1-, alpha 2-, beta- and gamma-globulins were documented in 80 Wistar SPF adult male rats, synchronized by natural light (06.00-18.00 h) and darkness (18.00-06.00 h) during the month of October 78. Blood was sampled at four fixed time points in the 24 h scale (i.e. 04.00, 10.00, 16.00 or 24.00 h). Total proteins, albumin, alpha 2- and gamma-globulins showed a statistically significant rhythm with a maximum at 04.00 h. The data obtained in anaesthetized rats under artificial synchronization and in man are compared, taking into account that the rat is a nocturnally active rodent. The present work partially confirms the hypotheses of previous chronopharmacological studies, thus e.g. curarizing substances have a mimimum activity when the protein plasma level, especially albumin, is the highest.

The kinetic profile of diazepam (DZP) was studied in plasma, erythrocytes, and eleven discrete brain areas of the rat, after intramuscular subchronic administration (15 days-5 mg/kg). DZP was rapidly distributed in brain areas. Its concentrations and its kinetic parameters were not uniform in the different brain areas we studied. The results showed the highest content of DZP in the hypothalamus, followed by the nucleus caudatus and the colliculi. Our data presented the erythrocyte as a "deep compartment". Comparatively to the results obtained after single administration, this study showed an increase of the apparent elimination half-life. Indeed, one observes a 2 fold increase for the plasma, and a 3.5 fold increase for the cerebral compartment. In the three brain areas studied (nucleus caudatus, hippocampus, and cerebellum) we observed a linear relationship with plasmatic or erythrocytic levels (0.978 less than or equal to r less than or equal to 0.992). It seems important to be considered in clinical pharmacology.

Relationships between epilepsy, antiepileptic drugs and neuroendocrinological events justify the study of an eventual influence of antiepileptic drugs of the regulation mechanisms of ovulation. Thus carbamazepine effects on the oestrus cycle of female rats and on FSH, LH and PRL serum levels has been studied. Carbamazepine was given orally once daily for 21 consecutive days to Wistar AF SPF female (exhibiting regular 4 days cycles) and male rats: three doses were used: 100, 10 and 5 mg per kg bodyweight. Oestrous cycle was studied by daily vaginal smears. Our data show that carbamazepine do not significantly modify the evolution of oestrous cycle nor FSH, LH or PRL serum levels. These results agree with those of literature even if literature data have been obtained with a single administration in man. Finally our data confirm also a previous work on oestrous cycle effects of perinatal exposure to carbamazepine in the female rat.

1. The aim of the present study was to investigate an eventual influence of the hour of administration on lidocaine kinetics in the rat. 280 Wistar AF SPF adult male rats were used for this study and maintained under controlled environmental conditions (LD: 06.00-18.00) during the month of October. A single 50 mg . kg-1 dose of lidocaine was given by intramuscular route, at four different fixed time points of a 24-hour period (i.e.: 10.00, 16.00, 22.00 and 04.00) to 70 rats. At each specified time point blood samples were taken 5, 15, 30 min., 1, 2, 4 and 6 hours after the drug administration. Lidocaine plasma levels (free and bound) were determinated according to a specific gas chromatographic method. 2. Our data showed circadian variations of pharmacokinetic parameters (Formula: see text) 3. Lidocaine free fraction varied with time and the protein binding of lidocaine showed a circadian variation. 4. The observed variations may be related to 1) daily fluctuations of absorption or binding of the drug 2) to diurnal variation of the hepatic drug metabolising enzymes responsible for the inactivation of the drug and/or 3) to diurnal variations in excretion rate of lidocaine. Finally our results agree with those of Lutsch and Morris who found a circadian periodicity in susceptibility to lidocaine in the mouse with maximal convulsant activity at 21.00.

The effects of the acute or chronic administration of clobazam (20 mg/kg per os) on the plasma levels of the main anterior pituitary hormones (prolactin, FSH and LH) were studied in the male rat. This 1,5 benzodiazepine did not induce any modification of the hormones levels either after acute or chronic administration. These negative data are discussed as compared to the effects of other benzodiazepines or GABA and GABAmimetic drugs on the pituitary hormones levels according to particular experimental conditions.

1. We previously reported circadian variations of pharmacokinetic parameters of lidocaine in the rat after a single 50 mg.kg-1. I.M. dose of this drug administered at four different fixed time points of a 24-hours period (i.e.: 10.00, 16.00, 22.00 or 04.00 h). As diurnal variations of membrane permeability was one of the suggested hypothesis, we investigated this possibility through the search of an eventual influence of the hour of administration of lidocaine on its intraerythrocytic passage. 2. Plasmatic and intraerythrocytic levels of lidocaine were determinated during 6 hours after each administration (10.00, 16.00, 22.00 or 04.00 h). 3. Our data show a circadian variation of the intraerythrocytic passage of lidocaine higher intraerythrocytic levels of this drug are observed when lidocaine is administered at 22.00 h; at this time the red blood cell level of the drug represent 73,6% of the plasmatic level. 4. The circadian variation of the intraerythrocytic passage of lidocaine in the rat may reflect circadian variations of membrane permeability, explaining in part the circadian fluctuations of lidocaine pharmacokinetics.

The comparative study of 4 Benzamides effects on the oestrus cycle of female rats has been done. These compounds were administered once daily for 21 consecutive days (1; 0,1; and 0,001 mg.kg-1.SC) on Wistar AF SPF rats smears. Our data show that sulpiride and sultopride suppress oestrus cycle substituted by a permanent dioestrus, while metoclopramide only extend the duration of the cycle and tiapride does not influence oestrus cycle.