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S Garattini

Publications and source records attributed to S Garattini.

At least 181 records · Page 10Linked to original sources
PubMed1985

In vivo stereospecific [3H]spiperone binding in rat brain: characteristics, regional distribution, kinetics and pharmacological properties.

The time course of [3H]spiperone distribution in the three major pools (specifically and non-specifically membrane-bound and soluble) of different brain areas, was studied in rats given a tracer amount of the drug. In addition, the stereospecificity, dissociation kinetics and pharmacological nature of the in vivo bound [3H]spiperone were investigated. The data show that [3H]spiperone binding sites in the striatum, olfactory tubercles and hypophysis differ clearly from those of the cortical regions. In the prevalently dopaminergic areas the amount of ligand bound to membranes is, up to 24 h post-treatment, proportional to the total 3H present. However a more correct analysis of the data was obtained in all the experiments when membrane-bound was measured instead of total radioactivity. Thus assay of the in vivo specifically bound [3H]spiperone appears essential for a correct evaluation of the density, affinity, regional distribution, pharmacological nature and kinetics of the drug-receptor interaction.

Animals↗
PubMed1985

Blockade of the diazepam-induced increase in rat striatal acetylcholine content by the specific benzodiazepine antagonists ethyl-beta-carboline-3-carboxylate and Ro 15-1788.

Diazepam increased the acetylcholine content in the striatum and the hippocampus of the rat. This effect was antagonized in both brain areas by treatment with the specific central benzodiazepine blockers ethyl-beta-carboline-3-carboxylate and Ro 15-1788, whereas the peripheral antagonist Ro 5-4864 was ineffective. Pretreatment with picrotoxin, a known GABA antagonist did not interfere with the diazepam-induced acetylcholine increase. These results indicate a specific involvement of benzodiazepine receptors in the cholinergic action of diazepam and this effect appears to be independent of GABA receptor activation.

Acetylcholine↗
PubMed1985

Anorectic effect of fenfluramine isomers and metabolites: relationship between brain levels and in vitro potencies on serotonergic mechanisms.

A study of the possible molecular mechanisms of action by which the isomers and metabolites of fenfluramine increase serotonin transmission, leading to anorectic activity, is presented. The actual brain levels of fenfluramine and norfenfluramine isomers after administration of equi-anorectic doses to rats are compared with their potencies in affecting serotonergic mechanisms in vitro. Isomers and metabolites of fenfluramine can have the same pharmacological action by influencing serotonin uptake, release and binding in a quantitatively different manner.

Animals↗
PubMed1985

Pharmacokinetics of fenfluramine and norfenfluramine in volunteers given D- and DL-fenfluramine for 15 days.

The kinetics of accumulation and elimination of d- and l-fenfluramine (F) and norfenfluramine (NF) have been studied in 8 young healthy volunteers given daily doses of 60 mg of sugar-coated tablets of 20 mg dl-F hydrochloride (dl-F) t.i.d. and capsules of 15 mg d-F hydrochloride (d-F) b.i.d. for 15 days. Repeated doses of d-F plus l-F gave the same values for the parameters measured as did d-F administered alone. Steady-state concentrations of all compounds were achieved within 4-8 days. The predicted mean steady-state concentrations of d-F and elimination half-lives calculated from the results of a previous single dose study were similar to those measured at steady state in this study, confirming the lack of effect of the drug on hepatic microsomal enzymes and on kinetics after repeated dosing. d-NF concentrations were approximately half those of the parent drug and the half-life was almost twice as long. Steady state concentrations both of L-f and l-NF were consistently about 40-50% higher than of the d-isomers and there was a comparable in the half-life.

Adult↗
PubMed1985

Effects of serotonin antagonists on the performance of a simple food acquisition task in rats treated with fenfluramine isomers.

The effect of fenfluramine on food-rewarded runway behaviour was studied in rats that had reached stable performance levels in a three-trials test procedure. d-Fenfluramine was about twice as potent as 1-fenfluramine in its influence on all aspects of runway behaviour: starting speed, running speed and the number of pellets eaten in each trial. Blockade of peripheral serotonin receptor sites by pretreatment with xylamidine, at a dose (2 mg/kg) blocking serotonin-induced inhibition of food intake, was unable to counteract the decrease in runway performance that resulted from treatment with either 2.5 mg/kg d-fenfluramine or 5.0 mg/kg 1-fenfluramine. However pretreatment with metergoline (2 mg/kg), an antagonist that affects both central and peripheral receptor sites, improved the performance of rats given these doses of d- and 1-fenfluramine. It is concluded that both isomers of fenfluramine affect food-rewarded runway behaviour through a mechanism that involves the stimulation of central but not peripheral serotoninergic pathways.

Amidines↗
PubMed1985

Kinetics of monosodium glutamate in human volunteers under different experimental conditions.

The kinetics of glutamic acid (GA) in plasma was studied in human volunteers after administration of monosodium glutamate (MSG) at different doses--43 mg/kg (3 g/70 kg) and 64 mg/kg (4.5 g/70 kg)--and in bouillon solutions of different concentrations (1.5-3.5%). MSG was administered to the subjects either during fasting or immediately after a standard meal. In the fasted subjects MSG administration caused a dose-dependent increase in plasma GA levels. In contrast, ingestion of MSG with a meal did not result in any significant increases in plasma GA levels in comparison with the wide variations observed in plasma GA after ingestion of a meal without added MSG.

Adult↗
PubMed1985

Caffeine distribution in acute toxic response among inbred mice.

The median lethal dose (LD50) and the median lethal concentration (LC50) of caffeine administered intravenously (i.v.) and orally (p.o.) were calculated in adult male CD2F1/Crl BR mice. Acute toxic behavioral responses to the drug were observed after administration via the two routes. Deaths followed severe tetanic convulsions: some animals had transient convulsions and survived, and others presented no acute toxicity. In a further study, the LD50 of caffeine was given i.v. and by gavage to animals randomly paired. At the death of one of the two mice the other was killed and caffeine assayed in blood and tissues of both. Different patterns of distribution were observed inter- and intra-route of administration, animals which died always having higher drug levels, although they had received the same dose. These findings suggest that besides the well-known factors affecting acute toxic response to exogenous compounds, drug distribution also has to be taken into account in a multifactorial toxicological investigation.

Animals↗
PubMed1985

Kinetic and pharmacological studies on estazolam in mice and man.

After i.v. and oral doses of estazolam (5 mg/kg) to mice, the drug was rapidly cleared with a beta half-life (t1/2 beta) of 0.7 h. The active metabolite, 1-oxo-estazolam, was present in traces in mouse plasma and brain. Its elimination t1/2 (beta), determined after i.v. injection of 1-oxo-estazolam (5 mg/kg) to mice, was similar to that of the parent drug in both plasma and brain. After a single oral dose of estazolam (4 mg) to four human volunteers the drug was rapidly absorbed and reached maximum plasma concentrations in one to three hours. Elimination t1/2 of estazolam in humans was 19 h. The metabolite was undetectable in human plasma after either single or multiple doses of estazolam. These results, together with the finding that 1-oxo-estazolam was less effective than estazolam, in terms of ED50 and brain concentrations necessary to antagonize leptazol convulsions and disrupt rota-rod performance in mice, indicate that the metabolite does not contribute significantly to the pharmacological effects of its parent drug.

Administration, Oral↗
PubMed1985

Toxic effects of chemicals: difficulties in extrapolating data from animals to man.

This review attempts an analysis of the major components which make it extremely difficult to extrapolate toxicological data obtained with chemicals from animals to man. A first problem concerns the use of doses to express the unit of comparison across animal species; the dose is a parameter exogenous to the body and when a chemical enters the body concentrations should be utilized. There is in fact evidence that for several chemicals equal doses in different animal species do not mean equal concentrations in blood or tissues. Concentrations of chemicals should be measured for extrapolation purposes as close as possible to the site of the toxic effect. A second problem regards the fact that several chemical are transformed in the body into other chemical species--sometimes few and sometimes many--and some of these species (active metabolites) display biological activity in some cases higher than different from or antagonistic to those of the parent compounds. Some of these metabolites are highly reactive and therefore bind to body components, particularly macromolecules such as proteins and nucleic acids. There is evidence that metabolism is quantitatively and/or qualitatively different in various animal species. A third problem concerns the difference in various animal species in the biological substrates on which chemicals exert their toxic effects. Equal concentrations of chemicals and their metabolites do not mean equal toxic effects across animal species because endogenous metabolic processes, cell permeability, enzymes, and receptors are not necessarily the same in animals and man. To overcome these difficulties there is a need for closer integration of different disciplines in the toxicological evaluation of chemicals. A scientific rather than a routine approach in toxicology is emphasized.

Animals↗
PubMed1985

Minaprine, a new drug with antidepressant properties.

Minaprine is a new psychotropic drug which has recently proved to be effective in the treatment of various depressive states. In rodents, minaprine exhibits an atypical spectrum of antidepressant and dopaminomimetic activities. Thus in mice minaprine antagonizes the effects of reserpine, decreases immobility time in the behavioural despair test and potentiates the effects of 5-HTP; in rats it antagonizes muricidal behaviour (blocked by PCPA or raphectomy). However, minaprine does not affect yohimbine lethality and does not induce anticholinergic effects in mice. Minaprine also activates central dopaminergic transmission. Thus at low doses the drug antagonizes neuroleptic-induced catalepsy and induces stereotypies in rats. These stereotypies are blocked by neuroleptics. In addition, minaprine (like apomorphine) induces contralateral turning in mice with a unilateral lesion of the striatum, whereas d-amphetamine induces ipsilateral rotations. Unlike classical dopaminomimetic drugs, minaprine does not stimulate locomotor activity in rats. The mechanisms by which minaprine exerts its effects are still unclear, since in vitro minaprine does not affect monoamine uptake or release and does not interact with monoamine receptors. In vivo, minaprine (acute doses) increases 5-HT, decreases 5-HIAA levels in various brain areas and weakly and reversibly inhibits type A MAO; subacute treatments lead to a decrease in the number of 5-HT1 and 5-HT2 receptors. In addition, in the striatum the drug decreases HVA and DOPAC, and increases 3-MT levels, without affecting DA levels. Minaprine also weakly displaces (3H)-spiperone from striatal D2 receptors and increases striatal ACh levels. Finally, minaprine fails to affect brain NA or MHPG levels in acute doses and does not modify beta receptor density in subacute treatment. Thus minaprine appears to be a chemically and pharmacologically original antidepressant drug which activates both 5-HT- and DA-mediated transmission but which is devoid of NAergic and anticholinergic effects. This latter statement is confirmed by the good cardiovascular tolerance of minaprine in dog, monkey and humans, and by the lack of "tricyclic-like" anticholinergic side-effects in man.

Acetylcholine↗
PubMed1985

An experimental rat model of local bone cancer invasion and its responsiveness to ethane-1-hydroxy-1,1-bis(phosphonate).

Line A Walker carcinoma differs from line B in that it does not elicit hypercalcemia and hypercalciuria when implanted in rats at various sites (s.c, i.m., intraaortically). However, Walker 256/A, unlike line B, may invade the tibia when implanted i.m. in the adjacent gastrocnemius muscle. This invasion was evaluated by measuring the increased weight of the bone and decreased calcium concentration per unit weight of the tibia, by reduced opacity to X-ray, and by the presence of tumor cells in the compact bone cortex. Ethane-1-hydroxy-1,1-bis(phosphonate), a diphosphonate derivative, at a dose of 10 to 30 mg/kg/day s.c., prevented cancer cell invasion of the tibia as judged by the above criteria. This inhibition was obtained with no apparent effect on the growth of Walker 256/A carcinoma.

Animals↗
PubMed1985

Prostaglandin and thromboxane synthesis by Lewis lung carcinoma during growth.

The five stable metabolites [prostaglandin F2 alpha, prostaglandin D2, prostaglandin E2 (PGE2), thromboxane B2, and 6-keto-prostaglandin F1 alpha] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in Lewis lung carcinoma homogenates at various times after tumor implantation (11 to 25 days). Vegetating and necrotic sections of the primary tumor and lung metastases were examined. Vegetating tumor showed a very active AA metabolism. Synthesis of PGE2, the most abundant product, markedly increased during tumor growth (up to 30 micrograms/g). A high and increasing synthetic capacity was also noted for prostaglandin D2 (up to 9 micrograms/g). Minor time differences and lower levels (up to 1.4 micrograms/g) were found for the other AA metabolites. PGE2 and prostaglandin D2 were the major products in necrotic tumor, too, but synthesis was markedly less than in vegetating tumor, and no increase was noted over time. Metastatic tissue showed a different AA metabolic profile, as compared to primary tumor and surrounding lung tissue, with PGE2 and 6-keto-prostaglandin F1 alpha being the main metabolites.

Animals↗
PubMed1984

Central side effects of pentamethylmelamine: biochemical and behavioural studies.

The central side effects of pentamethylmelamine (PMM), an antitumoral agent, were studied on brain neurotransmitters from the biochemical and behavioural points of view. PMM causes a dose-related reduction in the body temperature and motility of mice. 100 mg/kg of PMM lowers the levels of noradrenaline (NA) and raises 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in the telencephalon. A similar dose increased striatal levels of dopamine (DA) metabolites, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), at earlier times (30 min), reducing their levels at 2 hr. These effects disappear at longer times (4 hr). No changes were observed in the levels of 3-methoxytyramine (3-MT), the extraneuronal metabolite of DA. The serotonin metabolite 5-hydroxyindolacetic acid (5HIAA) was almost not affected. PMM and its metabolites do not displace [3H]-spiroperidol from mouse striatal binding sites. These data show that some of the neurological effects induced by PMM are associated with changes in the metabolism and/or release of brain catecholamines but are not mediated by direct action on DA receptors.

Altretamine↗
PubMed1984

Stimulation of serotonin synthesis in rat brain after antiepilepsirine, an antiepileptic piperine derivative.

Piperine and two of its derivatives, antiepilepsirine (AE or 3,4-methylendioxycynnamoylpiperine) and compound 7448 (N-isopropyl 3 (4 chloro-phenyl) propenoylamide) are very effective in stimulating serotonin (5HT) synthesis. AE raises the ratio of free-to-bound tryptophan (TP) in plasma and induces a long-lasting increase of this aminoacid in brain. At the same time in striatum and limbic area it causes a lasting increase in 5 hydroxyindolacetic acid (5HIAA) a 5HT metabolite and to a lesser extent, an increase in the levels of the monoamine itself. Together with this action on 5HT metabolism we found that AE caused release of 3H-5HT from an in vitro synaptosomal preparation. It thus appears that piperine and its derivatives AE and compound 7148 affect the central serotonergic system.

Animals↗
PubMed1984

Anxiolytic activity on locus coeruleus-mediated suppression of muricidal aggression.

The evidence suggests that stimulation of brain noradrenergic neurons plays an inhibitory role in rat mouse-killing (muricidal) aggression. Anxiolytic benzodiazepines inhibit locus coeruleus activity and previous data showed that chlordiazepoxide was capable of antagonizing the locus coeruleus-mediated suppression of muricidal aggression. The present experiments showed that this effect is common to new anxiolytic triazolobenzodiazepines and to other non-benzodiazepine derivatives with anxiolytic activity. In this framework, 10 mg/kg of buspirone, of 1-pyrimidine-piperazine and of MJ-13805 proved to be as active as 2.5 mg/kg of alprazolam and as 5 mg/kg of chlordiazepoxide in inhibiting the locus coeruleus-mediated suppression of muricidal aggression.

Aggression↗
PubMed1984

Diazepam increases membrane fluidity of rat hippocampus synaptosomes.

Diazepam in vitro produced a concentration-dependent increase of membrane fluidity in crude synaptic membranes from rat hippocampus, but not cerebellum. Similar effects were obtained with higher concentrations of Ro 15-1788 and PK 11195, while zopiclone was completely inactive. In vivo acute treatment with diazepam and Ro 15-1788 gave results similar to those in vitro. The specific benzodiazepine antagonist also significantly increased membrane fluidity and was not able to reverse diazepam's effect. The data are discussed in terms of a possible role of protein kinase inhibition by the drugs not mediated by the 'central' or 'peripheral' type of benzodiazepine receptors.

Animals↗