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Biomedical subjects

S Caccia

Publications and source records attributed to S Caccia.

At least 127 records · Page 7Linked to original sources
PubMed1982

Effect of dimethylamino-2-ethoxyimino-2-adamantane (CM 54903), a non-polar dimethylaminoethanol analog, on brain regional cholinergic neurochemical parameters.

CM 54903, a new psychotropic drug with a particular pharmacological profile, produced a widespread but short-lasting decrease in acetylcholine content in rat brain hemispheric regions but not in the midbrain-hindbrain or cerebellum at the dose of 40 mg/kg, i.p. The decrease was most conspicuous in the striatum. Brian regional choline contents were unaltered as were the acetylcholine turnover rates in the striatum and hippocampus. Neither choline acetyltransferase nor acetylcholinesterase activities were altered after the in vitro incubation or the in vivo administration of high amounts of the drug. CM 54903 was found to be a competitive, reversible inhibitor of the sodium-dependent high affinity uptake of choline by crude hippocampal and striatal synaptosomal preparations showing an IC50 of 10 microM in vitro. Despite the fact that the drug readily crosses the blood-brain barrier and achieves brain concentrations several-fold greater than its in vitro IC50, CM 54903 did not inhibit choline uptake in vivo although it was capable of preventing the pentylenetetrazol-stimulated choline uptake by hippocampal synaptosomes. The changes in striatal acetylcholine content induced by the blockade or the stimulation of muscarinic cholinergic receptors or dopaminergic receptors did not interfere with the effect of CM 54903 on striatal acetylcholine content while pentylenetetrazol completely prevented the decrease. The results taken together indicate that the major effect of CM 54903 on the cholinergic neurons is at the presynaptic level to compete with choline at its uptake sites.

Acetylcholine↗
PubMed1982

Brain levels of tofizopam in the rat and relationship with benzodiazepine receptors.

The effect of tofizopam on 3H-flunitrazepam binding was studied in rat hippocampus and cerebellum. Tofizopam (at a concentration of 10(-7) M) increased 3H-Flu binding through a 30% rise in the Bmax with no modification of Kd in either brain area. Similar results were obtained when the binding was measured in tofizopam (50 mg/kg p.o.) pretreated rats. Even though tofizopam has no anticonvulsive action against pentetrazol-induced convulsions, it significantly potentiated the action of diazepam but with no modification of brain diazepam levels and metabolism. The brain levels of tofizopam are reported and compared to plasma levels after oral administration of 5 and 50 mg/kg to rats.

Animals↗
PubMed1982

Antileptazol activity and kinetic of CP 1414 S (7-nitro-2-amino-5-phenyl-3-H-,1,5-benzodiazepine-4-one) in the rat and mouse.

The antileptazol effect of CP 1414 S (7-nitro-2-amino-3-phenyl-3H-1,5-benzodiazepine-4-one) a newly developed 1,5 benzodiazepine, lasts longer in mice than in rats. After intraperitoneal injection (10 mg/kg) brain levels of the drug were higher and persisted for longer in the mouse than in the rat. Although it cannot be excluded tht possible metabolites of CP 1414 S may contribute to the anticonvulsant effect of CP 1414 S, in both species the protective effect correlates well with the brain concentrations of the drug.

Animals↗
PubMed1982

Species differences in phenazepam kinetics and metabolism.

The kinetic profiles of phenazepam and its hydroxylated derivative were compared in rat, dog, cat and man after administration of single oral doses of the parent compound. The absorption of phenazepam was reasonably rapid in all the species studied. Blood peak concentrations (Cmax) were reached at 1 h in rats (0.32 +/- 0.03 microgram/ml), at 0.5 h in dogs 0.54 +/- 0.10 microgram/ml), at about 2 h in cats (1.65 +/- 0.23 microgram/ml), about only at 4 h in man (0.038 microgram/ml) at the highest dose tested. The largest normalized (value/dose) Cmax and area under the curve (AUC) were observed in man, while the rat gave the lowest values. The half-life of phenazepam was about 60 h in man, 13.72 +/- 2.09 h in the cat, 6.35 +/- 2.32 h in the dog and 7.49 +/- 1.88 h in the rat (beta-half-life). 3-OH-phenazepam was rapidly detected in cat, rat, and dog blood but no measurable amounts (less than 3 ng/ml) were found in human blood. At the oral doses tested, the ratio of the AUC for 3-OH-phenazepam to phenazepam was 0.01, 0.48, and 0.53 in the dog, rat, and cat, respectively. The half-life of the metabolite was shorter than that of the parent compound in the dog, but it was comparable in the rat and longer in the cat. The results suggest that 3-OH-phenazepam might contribute to the overall pharmacological effects of the parent compound in those species in which it accumulates in significant amounts.

Animals↗
PubMed1982

Plasma and brain levels of glutamate and pyroglutamate after oral monosodium glutamate to rats.

Plasma and brain levels of pyroglutamate (Py), a compound connected with the pathway of glutamate (GA) metabolism, were measured in rats after oral administration of monosodium glutamate (MSG) or Py. Oral MSG (1 g/kg) was followed by only a small rise in plasma Py levels. No increase of Py or GA brain levels was observed in these experimental conditions. Oral administration of Py (0.05, 0.5 and 1 g/kg) resulted in a marked dose-dependent increase of plasma Py, but no increase of plasma or brain GA levels. However, Py accumulated in brain in a dose-related manner. After 0.05 mg/kg the basal brain levels remained unchanged at all the times considered. Rat brain Py levels significantly increased when the oral dose of Py was raised to 0.5 g/kg. Peak brain levels were reached at 240 min, and were about 3 and 4 times the basal levels after 0.5 and 1 g/kg, respectively.

Administration, Oral↗
PubMed1982

Notes on buspirone's mechanisms of action.

Buspirone is a novel psychotropic drug with clear anxiolytic activity in man. There are a number of neurochemical differences between buspirone and both neuroleptics and benzodiazepines. Moreover, buspirone is extensively metabolized, and several metabolites are present in the brain together with the parent compound. One of these, 1-PP, is present in the brain at higher concentrations than the parent drug, particularly when the drug is given orally. On the basis of the reported experimental data, it can be postulated that buspirone's anticonflict activity in rats may be mediated, at least partially, through 1-PP, without involving any effect on the dopaminergic system. The possibility that buspirone and 1-PP may mimic the action of benzodiazepine on some sites in the complex benzodiazepine-GABA receptors is discussed.

Acetylcholine↗
PubMed1982

Species differences in the kinetics and metabolism of fenfluramine isomers.

After single oral doses of racemic fenfluramine to man and animals (male CD-COBS Sprague-Dawley rat, male CD1-COBS mice and male beagle dogs) plasma and/or brain concentrations of the d- and l-isomers and their deethylated metabolite were measured by gas-liquid chromatography. In rat and mouse d-fenfluramine had a longer half-life (T 1/2) and gave a larger area under the curve (AUC) than the l-isomer. These differences were consistent with stereoselective N-deethylation of l-fenfluramine. Thus, in both species the plasma and brain AUC of the l-metabolite were double that of the d-form. In man and dog slight or no differences were seen between te kinetic and metabolic profiles of the isomers. Comparison of the plasma concentrations time curve of fenfluramine showed slower elimination in man than in the other species. The T 1/2 of the d-isomer was 2.6 hr in rat, 2.5 +/- 0.2 hr in the dog. 4.3 hr in the mouse and 17.8 +/- 0.9 hr in man. The deethylated metabolite norfenfluramine was present in plasma or brain, or both, of all the species examined as a major metabolite of the drug. At the oral doses of racemic fenfluramine tested the ration of the AUC for d-norfenfluramine to d-fenfluramine was 4.4, 2.0, 0.8, 0.3, and the dog, rat man and mouse respectively. The T 1/2 of the metabolite was longer than that of the parent drug in all these species. Similar studies with d-fenfluramine indicated that its kinetic profile was identical to that of d-fenfluramine administered in the racemic form. The l-isomer therefore does not change the absorption, distribution and metabolism of the d-isomer which should be considered as the active form.

Adult↗
PubMed1981

Determination of plasma and brain concentrations of trazodone and its metabolite, 1-m-chlorophenylpiperazine, by gas-liquid chromatography.

A sensitive and specific gas chromatographic procedure is described for the quantitation of trazodone and its active metabolite, 1-m-chlorophenylpiperazine (mCPP), in plasma and brain. After addition of internal standards, the samples were extracted with benzene and the extracts divided into two portions. One portion was evaporated to dryness, and residue dissolved in methanol and the solution injected into a gas chromatograph equipped with a nitrogen-selective detector, for trazodone quantitation. To the remaining half of the extracts, 100 microliter of heptafluorobutyric anhydride solution were added and the metabolite was measured as the heptafluorobutyryl derivative by electron-capture detection. Gas chromatography-mass spectrometry was used to confirm the specificity of the analyses. The kinetic profile of trazodone and its metabolite was investigated after oral administration of trazodone (25 mg/kg). The parent drug and its metabolite both accumulated in brain, reaching concentrations several times those in plasma. More mCPP than the parent compound entered the brain; the ratio of the area under the curve for trazodone to mCPP in plasma was about 4, whereas in brain it was only about 0.8.

Animals↗
PubMed1981

Kinetics of fenfluramine isomers in the rat.

The kinetics of fenfluramine isomers were studied in the rat following oral doses of racemic fenfluramine. The data, analyzed using an analogue computer, indicate that the d-fenfluramine is metabolised and excreted at a slower rate than the 1-isomer, resulting in higher plasma and brain concentrations. The kinetic parameters of both isomers were dose-dependent. The rates of disappearance decreased as the dose was raised. The increase in brain area under the curves (AUC) was much greater than the increase of the dose. These findings suggested the rat has a limited capacity for disposition of fenfluramine.

Animals↗
PubMed1981

Studies on some pharmacological activities of 7-nitro-2-amino-5-phenyl-3H-1,5-benzodiazepine (CP 1414 S) in the rat. A comparison with diazepam.

Brain distribution and various pharmacological effects of 7-nitro-2-amino-5-phenyl-1,5-benzodiazepine (CP 1414 S) and diazepam were studied in rats. Injected at 10 mg/kg i.p., the compounds reached brain peak concentrations 15 min after administration and showed an apparent half-life of about 50 min. CP 1414 S was about ten times less potent than diazepam in protecting rats from pentetrazole convulsions, increasing punished responses in a "conflict" test and disrupting rotarod performance. At the lowest doses effective in these tests diazepam, but not CP 1414 S, caused significant reduction of spontaneous locomotor activity in rats. On the basis of the test selected, it is concluded that CP 1414 S causes effects similar to those shown by diazepam in the same conditions, although with less potency. It causes less depression of motor behaviour than diazepam, at least at the lowest doses and in rats.

Animals↗
PubMed1981

Antileptazol activity and kinetics of clobazam and N-desmethyl-clobazam in the guinea-pig.

The kinetic profiles and antileptazol activity of clobazam and its main metabolite were compared to assess the metabolite's contribution to the anticonvulsant activity of clobazam in the guinea-pig. The metabolite was less effective than the parent compound in terms of doses and active brain levels. However, the metabolite formed after clobazam administration accounted for the persistence of antileptazol activity in this animal species.

Animals↗