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Biomedical subjects

S Caccia

Publications and source records attributed to S Caccia.

At least 109 records · Page 6Linked to original sources
PubMed1986

Effect of the anticonvulsant denzimol on the disposition of diazepam in the rat.

The influence of denzimol, a new imidazole derivative with anticonvulsant properties, on the disposition of diazepam (1 mg kg-1) was investigated in the rat. Denzimol pretreatment significantly increased plasma and brain concentrations of the benzodiazepine, consistent with reduced total clearance. The results suggest that the increase of diazepam brain concentrations by denzimol may produce enhancement of diazepam activity in the rat.

Animals↗
PubMed1986

1-(2-Pyrimidinyl)-piperazine as active metabolite of buspirone in man and rat.

Buspirone (BP), a newly developed antianxiety agent, forms 1-(2-pyrimidinyl)-piperazine (PmP) during its biotransformation in rats and man. After oral administration of pharmacologically effective doses of BP-hydrochloride to rats (1 and 10 mg/kg), the metabolite appears in significant amounts in body fluids and tissues; it is highly concentrated in the central nervous system, the brain-to-plasma concentration ratios being approximately 5 at the time of the maximum concentrations (Cmax). In man given the anxiolytic dose (20 mg) of BP the metabolite reaches higher plasma Cmax values than its parent drug. Its plasma elimination t1/2 is more than double that for BP. These results, together with the fact that PmP is biochemically and pharmacologically active, suggest that the metabolite may contribute significantly to the central effects of the parent drug.

Adult↗
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

Ionization constants and partition coefficients of 1-arylpiperazine derivatives.

The ionization constant (pKa) and liposolubilities (log P) of fourteen 1-arylpiperazines were determined by n-octanol/buffer partition. pKa varied little across the entire series. Log P values ranged from less than 1 to about 2 for the highly lipophilic derivatives of the preset series. The results are discussed in relation to the extent to which these derivatives, known to be centrally active, may enter the brain.

Buffers↗
PubMed1985

In-vivo metabolism in the rat and mouse of antrafenine to 1-m-trifluoromethylphenylpiperazine.

The analgesic antrafenine forms 1-m-trifluoromethylphenylpiperazine (mCF3PP) during its biotransformation in the rat and mouse. At least 14 and 3% of an antrafenine dose (25 mg kg-1 p.o.) reaches the systemic circulation as mCF3PP in the mouse and rat respectively. The metabolite easily enters the brain, reaching concentrations several times those in body fluids. This, together with the fact that mCF3PP is known to produce several pharmacological effects compatible with a stimulatory action on 5-hydroxytryptamine postsynaptic receptors, suggests that this metabolite may contribute to the parent drug's pharmacological effects.

Analgesics↗
PubMed1985

Disposition of the psychotropic drugs buspirone, MJ-13805 and piribedil, and of their common active metabolite 1-(2-pyrimidinyl)-piperazine in the rat.

1-(2-Pyrimidinyl)-piperazine (PmP) is a common metabolite of the structurally related drugs buspirone, MJ-13805 and piribedil. After i.v. injection (25 mumol/kg) to rats, all three parent drugs are rapidly cleared with a t 1/2 (beta) of about 30 min. The metabolite t 1/2 is about four times that of its parent drugs. About 25, 23 and 2% of buspirone, MJ-13805 and piribedil, respectively, reaches the systemic circulation as PmP. The metabolite concentrates in the brain where its A.U.C. is about twice those of buspirone and MJ-13805. Results indicate that PmP formation is a pharmacologically significant process for both buspirone and MJ-13805 but it is probably less important for piribedil.

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

Disposition and metabolism of minaprine in the rat.

After iv. injection (5 mg/kg) to rats, minaprine is cleared rapidly from plasma with an elimination t 1/2 of 34 min. After the same dose but given orally the drug is rapidly absorbed from the rat gastrointestinal tract. The ratio of the area under the curves (AUC) of the parent drug indicates low bioavailability (5%). Two metabolites of minaprine (M3 and M5) appeared rapidly in rat plasma and far exceed minaprine concentrations. Other known urinary metabolites of the drug were undetectable in rat plasma and brain within the limits of the sensitivity of the method. Minaprine rapidly enters the central nervous system and then distributes almost evenly in various regions beyond the blood/brain barrier. It concentrates in brain tissue reaching concentrations two-three times those in plasma. It metabolites enter the brain less rapidly and their brain AUC never reached 50% of the plasma AUC.

Administration, Oral↗
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↗
PubMed1984

Identification and quantitation of 1-arylpiperazines, metabolites resulting from side-chain cleavage of (4-substituted aryl-1-piperazinyl)alkyl heterocyclic derivatives in rat plasma and brain.

Many drugs contain the arylpiperazine moiety in the side-chain of their molecules. A common metabolic pathway of such drugs is cleavage of the side-chain with the formation of 1-arylpiperazines. This has been verified by combined gas chromatography-mass spectrometry of biological samples from rats given orally a series of heterocyclic derivatives bearing a 4-aryl(phenyl, pyrimidinyl, pyridyl or thiazolyl)-1-piperazinylalkyl moiety (oxypertine, zolertine, millipertine, empiprazole, dapiprazole, antrafenine, piribedil, azaperone). A sensitive and selective electron-capture gas-liquid chromatographic procedure for 1-arylpiperazines in rat plasma and brain is described. The overall recovery from plasma and brain was 70-90%. The limit of detection for substituted (halogenated) phenylpiperazines was 10-25 ng/ml or ng/g and 25-100 ng/ml or ng/g for other derivatives. Preliminary data are reported on the time course of the production and elimination of 1-arylpiperazines after oral administration of representative compounds with the arylpiperazine moiety (oxypertine, azaperone and S-3608).

Animals↗
PubMed1984

Kinetics and distribution of the beta-adrenergic agonist salbutamol in rat brain.

the kinetics of the beta-adrenergic agonist salbutamol and its distribution in the central nervous system were examined in rats by high-performance liquid chromatography with electrochemical detection. After 10 mg kg-1 i.v. salbutamol, the decline in drug plasma concentrations was biphasic and salbutamol was cleared very rapidly with a beta-half-life of about 37 min. Salbutamol rapidly penetrated the 'blood-brain barrier' and reached brain concentrations amounting to about 5% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands) the drug achieved concentrations more than 100 times those in whole brain. The results support the hypothesis that stimulation of central beta-adrenergic sites is responsible for salbutamol's pharmacological and biochemical effects.

Albuterol↗
PubMed1983

Quantitative analysis of minaprine and some of its metabolites with application to kinetic studies in rats.

A simple and rapid high-performance liquid chromatographic method is described for the quantitative analysis of the psychotropic drug minaprine and three of its metabolites (M1, M3 and M11), including one as yet undetected metabolite (M11) known as a monoamine oxidase type A inhibitor in vitro. After selective extraction all four compounds were separated on a reversed-phase muBondapak C18 column using sodium acetate (0.03 M)-acetonitrile-methanol (88:7:5) (pH 3.3) as the mobile phase. The eluted compounds were detected with a UV detector at 254 nm. The sensitivity of the method is 0.02 microgram per millilitre of body fluid or per gram of tissue for M1 and M11 and 0.05 microgram per minaprine and M3. The method has been applied successfully to the determination of minaprine and the metabolites in plasma and brain and is compared here with an gas-liquid chromatographic method with an electron-capture detector previously developed for the detection of minaprine and M11. M11 was identified in rat urine by gas chromatography-mass spectrometry.

Animals↗
PubMed1983

Pyroglutamate kinetics and neurotoxicity studies in mice.

Plasma and brain kinetics of L-glutamic (GA) and L-pyroglutamic (PY) acids were studied after oral administration of monosodium glutamate (MSG) or pyroglutamate to adult mice. Oral MSG (0.5 g/kg) increased plasma GA and PY levels 4.5 and 1.8 times, respectively. A small increase in brain PY (1.3 times the basal level) but not in brain GA, was observed. Oral administration of pyroglutamate (0.5 g/kg) increased plasma PY levels 56 times in adult mice and 69 times in infant mice. No lesions in the arcuate nucleus of the hypothalamus were observed when pyroglutamate was administered orally to infant mice at doses of 2 and 4 g/kg.

Animals↗
PubMed1983

Plasma pyroglutamic acid levels after oral administration of monosodium glutamate to human volunteers.

Plasma levels of pyroglutamic (PY) and glutamic (GA) acids have been measured after oral administration of monosodium glutamate (MSG) to 6 human volunteers. MSG (43 mg/kg) was administered either after an overnight fast or immediately after a normal meal. In fasting subjects plasma GA peak levels were about 2.3 times the basal levels whereas the increase in plasma PY levels were only 1.5-fold. When MSG was administered with a meal plasma GA levels were raised, to a lesser extent, while no increase could be observed in plasma PY.

Administration, Oral↗
PubMed1983

Disposition and metabolism of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in the rat.

After i.v. injection (10 mg/kg) to rats, buspirone is rapidly cleared from blood with a t1/2 (beta) or 30 min. After the same dose is given orally, the drug is not detectable in blood or brain within the limits of sensitivity of the method. The metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) has a longer t1/2 than buspirone. It is present to about the same extent in rat plasma and brain after either i.v. or p.o. buspirone. Unlike buspirone, 1-PP accumulates in the brain reaching concentrations between four-and five times those in plasma. Its brain AUC is higher than that of buspirone even when buspirone is given i.v. The results suggest that 1-PP may contribute to the pharmacological effect of the parent drug.

Animals↗
PubMed1983

Metabolic and pharmacological studies with N-methyl-N'-methyl-2'-allyl-2-benzoyl-4-chloro-glycinanilide (F 1797).

Three metabolites (F 1756, diazepam and N-desmethyl-diazepam) of N-methyl-N'-methyl-2'-allyl-2-benzoyl-4-chloro-glycinanilide (F 1797), a new potential anxiolytic agent, are formed by N-desmethylation or cyclisation in the rat. They were compared with F 1797 for their antileptazol activity in order to assess their contribution to the effect of the parent compound. F 1756 had little effect in this test. However, diazepam and N-desmethyl-diazepam formed after F 1797 certainly contributed to its antileptazol effect.

Anilides↗