[Main factors of variations in lidocaine pharmacokinetics].
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Biomedical subjects
Publications and source records attributed to M Valli.
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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.
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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.
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.
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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.
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The benzodiazepines (BZD) are widely used in clinical practice as anxiolytics, muscle relaxants, sedatives and anticonvulsants. Electrophysiological studies have shown a specific interaction of BZD with - aminobutyric acid (GABA), an inhibitory neurotransmitter, of which they enhance the physiological effects. The discovery of saturable and stereospecific binding sites with high affinity for BZD, and their brain distribution indicates a predominantly cortical action of BZD. Furthermore, BZD receptors seem to be linked to GABA receptors--modulating their inhibitory effects--and closely connected to the chloride conductance mechanism associated to the GABA receptor. The discovery of BZD receptors suggests the existence of endogenous ligands. Inosine, hypoxanthine or nicotinamide are reported to have BZD-like activities, in spite of a relative low affinity for their binding sites. Their putative role as endogenous anxiolytics needs to be supported by behavioral studies.
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.
Proteoglycans were extracted from bovine flexor digitorum profundus tendon (FDP) with 4 M-guanidine hydrochloride in the presence of proteinase inhibitors and purified by density-gradient centrifugation and ion-exchange chromatography. Tendon proteoglycans were fractionated into two major components, D1 and D2, and characterized by chemical analysis and enzymatic (chondroitinases and hyaluronidase) degradations. The two proteoglycans differ with respect to the structure of their glycan side chains; D1 chains were mainly chondroitinsulfate, whereas D2 contained 40% of dermatansulfate. In both proteoglycans keratansulfate chains are probably present. Tendon proteochondroitinsulfate was of larger size than proteodermatansulfate as judged by gel-chromatography on Sepharose 2B. Proteoglycan-collagen interactions were studied by affinity-chromatography on Sepharose 4B-collagen. Both proteochondroitinsulfate and proteodermatansulfate were resolved in two components, with different affinity for collagen. In proteodermatansulfate the component at higher affinity was predominant.
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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.
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.
Urinary GAGs from patients affected with Osteogenesis Imperfecta (O.I.) type I, type II and type III - according to Sillence et al. (1979) - have been investigated. Galactosamine to glucosamine ratio resulted significantly decreased in O.I. type II and III, whereas smaller differences in the mildest type of the disease were observed. Cellulose polyacetate electrophoresis of urinary GAGs purified from some patients showed the presence of a slowly moving polysaccharide substance, which did not appear in normal subjects. Moreover some pathological fractions, mainly constituted of ChS on the basis of chemical analysis and electrophoretic behaviour, were not digested by testicular hyaluronidase and presented anomalous structures as compared with the corresponding normal ones. These results seem to indicate that in some forms of O.I. the metabolic defect(s) not only affects the synthesis or the catabolism of a particular type of collagen, but also involves the proteoglycan component of the connective tissue.