[Pharmacokinetic, biochemical and histological study of the carbamazepine-josamycin interaction in the rat following chronic administration]. / Etude pharmacocinétique, biochimique et histologique de l'interaction carbamazépine-josamycine chez le rat aprés administration chronique.

The determination of possible modifications of pharmacokinetic parameters of carbamazepine by josamycin in an experimental study after chronic administration of the drugs in the rat was undertaken to assay, or not, the enzymatic inhibition hypothesis which is supported in human clinical studies. Our data do not show any alteration in the Cmax, Tmax and AUC parameters of carbamazepine (total and unbound fraction) in case of conjunction with josamycin, but an earlier increase of plasmatic concentrations. The biochemical parameters are not modified, but a significant decrease of total bilirubin compared with controls and carbamazepine alone. The histological study does not show any liver lesion.

[Pharmacokinetic study of the regional cerebral distribution of diazepam following chronic administration. Correlations with plasma and erythrocyte levels]. / Etude pharmacocinétique de la distribution régionale cérébrale du diazépam après administration chronique, corrélations avec les taux plasmatiques et érythrocytaires.

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.

[Effects of the acute and chronic administration of clobazam on plasma prolactin and gonadotrophins in the male rat]. / Effets de l'administration aiguë et chronique de clobazam sur la prolactine et les gonadotrophines plasmatiques chez le rat mâle.

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.

Effect of the hour of administration on the pharmacokinetics of lidocaine in the rat.

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 X 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. Blood samples were taken at the following time points: 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. The data showed circadian variations of pharmacokinetic parameters:--Elimination half-life: max. 2.12 +/- 0.05 h at 10.00, min. 1.50 +/- 0.03 h at 16. --Initial concentration: max. 5.05 +/- 0.65 micrograms X ml-1 at 16.00; min. 2.97 +/- 0.29 micrograms X ml-1 at 04.00.--Elimination constant rate: max. 0.4618 +/- 0.0094 h-1 at 16.00, min 0.3279 +/- 0.0079 h-1 at 10.00.--Area under curve (experimental): max. 11.11 +/- 1.07 micrograms X kg-1 X h-1 at 16.00, min. 7.45 +/- 0.84 micrograms X kg-1 X h-1 at 04.00.--Apparent volume of distribution: max. 16.67 +/- 1,67 L X kg-1 at 04.00, min. 9.75 +/- 1.04 L X kg-1 at 16.00. The lidocaine-free fraction varied with time and the protein binding of lidocaine showed a circadian variation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Circadian variations in the intraerythrocytic transport of lidocaine]. / Variations circadiennes du passage intraerythrocytaire de la lidocaine.

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.

[Neuroendocrine effects of the chronic administration of carbamazepine in male and female rats]. / Effets neuroendocriniens de l'administration chronique de carbamazépine chez le rat male et femelle.

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.

[Absence of effects of sodium valproate on the estrous cycle of the rat]. / Absence d'effets du valproate de sodium sur le cycle oestral de la ratte.

Regarding interrelationships between epilepsy, antiepileptic drugs and neuroendocrinological events, sodium valproate effects on estrous cycle of the rat have been performed by daily vaginal smears for twenty one days with 200, 100, 20 and 10 mg per kg bodyweight. Our data showed that sodium valproate did not significantly modify the evolution of estrous cycle even if intracerebral GABA content increase has been reported to influence hormonal secretions.

[Chronopharmacokinetic study of lidocaine in the rat (author's transl)]. / Etude chronocinétique de la lidocaine chez le 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.

[Neuro-endocrine effects of chronic clonidine administration in rats]. / Etude des effets neuro-endocriniens de l'administration chronique de clonidine chez la ratte.

Neuroendocrine effects of chronic clonidine administration - which has been proposed as antimanic drug - have been evaluated in the female rat for a twenty one days period at the following doses : 0,5 ; 5 ; 25 and 50 micrograms.kg-1.day-1. No modification of the evolution of the oestrus cycle was observed, whereas pituitary hormones (PRL, FSH and LH) plasma levels were not statistically modified. The results of this study are opposed to those frequently observed with classical neuroleptic drugs.

Sodium valproate: kinetic profile and effects on GABA levels in various brain areas of the rat.

1. The kinetic profile of sodium valproate (VPA) and the GABA levels were studied in discrete brain areas of the rat after an i.p. injection of 200 mg/kg. The results were discussed comparatively with GABA-T and GAD activities reported in the literature. 2. VPA was rapidly distributed in brain areas; its concentrations, its kinetic parameters and the GABA levels after the drug administration were not uniform in the different brain areas studied. 3. The results showed a particular relation of the VPA to the olfactory bulbs; in this specific area the VPA effect on GABA level was stronger; the VPA apparent half life of elimination was longest; the VPA apparent disappearance rate constant was smallest; the initial GABA level was higher; the activities of GABA-T and GAD were higher than in other brain areas studied except the hypothalamus. 4. These data were correlated with the role of the olfactory bulbs in the behaviour of the rodents.

[Use of intramuscular lidocaine in the acute stage of myocardial infarction]. / Utilisation de la lidocaïne intra-musculaire à la phase aiguë de l'infarctus du myocarde.

Methods of using intramuscular lignocaine and its relay with an intravenous infusion were studied in 34 patients with reference to serum levels. A first group of 9 patients with myocardial infarction received an intramuscular injection of 300 mg lignocaine into the deltoid or gluteral muscles at five day intervals. The deltoid appears to be the better site of injection in patients confined to bed because of its quick absorption, higher serum levels between the 15th and 90th minute (+47%), and longer duration of action (180 compared to 120 minutes). The difference is not observed in ambulatory patients and seems to be related to sluggish circulation in the gluteral muscles during bed rest. Its relay with intravenous infusion was studied in 14 patients. In the first 6 patients, intradeltoid injection was immediately followed by an infusion of 2.5 mg/mn, giving an average plasma lignocaine level between the 15th and 60th minute greater than 5 mu/ml. In the 8 other patients, a period of I hour was allowed to elapse before starting the infusion. The plasma levels were found to be within the therapeutic range in all patients and no side effects were observed. The administration of an intravenous infusion of 150 mg/hr of lignocaine for 48 hours led to excessively high plasma levels in 8 patients at the 24th hour, 3 of whom had side effects. Reducing the dosage to 100 mg/hr from the 12th hour onwards in II patients avoided this complication. A 300 mg intradeltoid injection of lignocaine is easy to give in the patient's home and therefore, is the best adapted method for the pre hospital treatment of myocardial infarction. When necessary, it may be relayed with an intravenous infusion one hour later, in the coronary care unit.

[Experimental study of sulpiride-bromocriptine association on the female rat estrous cycle (author's transl)]. / Etude expérimentale de l'association sulpiride-bromocriptine sur le cycle oestral de la ratte.

The effects of joint treatment by sulpiride (1 mg . kg-1 S.C. pro die) and bromocriptine (3 mg . kg-1 S.C. pro die) on female rat estrous cycles were carried out on a group of ninety animals for a twenty-one days period. The results thus obtained show that: (i) bromocriptine alone does not disturb the estrous cycle, (ii) when given both with sulpiride, it prevents from this psycholeptic's estrous cycle blockade, (iii) finally, it leads to the regression of a blockade induced by an eight days sulpiride pretreatment. Therefore, it is likely that these two drugs act antagonistically at tuberoinfundibular dopaminergic receptors involved in the prolactin and gonadotropins release.