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M S Benedetti

Publications and source records attributed to M S Benedetti.

At least 37 records · Page 2Linked to original sources
PubMed1991

Effects of ageing on the content in sulfur-containing amino acids in rat brain.

Concentrations of the sulfur-containing amino acids methionine, homocysteic acid, cysteic acid and taurine were measured in brain structures of young and old Wistar rats in an attempt to establish a possible link between the increase in oxidative stress with ageing and changes in tissue levels of these amino acids. Contrary to data reported by others, in all brain structures of young and old rats homocysteic acid levels could not be quantified. Compared with young rats, in old animals taurine and methionine concentrations significantly decreased in striatum and cortex; decreased taurine levels were also found in nucleus accumbens and cerebellum and lower concentrations of methionine were found in midbrain, hippocampus and pons-medulla. Cysteic acid levels either did not change or significantly increased in cortex and hippocampus. These results are discussed taking into account the biosynthesis of sulfur-containing amino acids in rat brain and the decrease in glutathione in relation to oxidative stress with ageing. Changes in aspartic acid, glutamic acid, serine, glutamine, glycine and GABA concentrations with ageing were also determined in the same brain structures and were in good agreement with those previously reported (Strolin Benedetti et al., 1990 a, b).

Aging↗
PubMed1990

In vivo interaction of cabergoline with rat brain dopamine receptors labelled with [3H]N-n-propylnorapomorphine.

Cabergoline is a potent dopaminergic agent that interacts with agonists and antagonists of dopamine receptors in vitro. We studied the binding of [3H]N-n-propylnorapomorphine ([3H]NPA) to dopamine receptors after i.v. and oral administration of cabergoline to determine whether cabergoline crosses the blood-brain barrier; bromocriptine was used as a reference drug. Cabergoline and/or its active metabolite(s) did cross the blood-brain barrier and reach dopamine receptors. Comparative time-course analysis of the regional inhibition of [3H]NPA binding showed that cabergoline was more potent than bromocriptine in inhibiting [3H]NPA binding and that it occupied the receptor for longer. These effects were observed in all areas of the rat brain studied (striatum, olfactory tubercles, adeno- and neurohypophysis, thalamus and hypothalamus). Further studies in the striatum and adenohypophysis showed that cabergoline receptor occupancy was dose-dependent and still detectable 72 h after i.v. administration of the drug. While cabergoline was more potent in the striatum than in the adenohypophysis when administered i.v., the reverse was observed after its oral administration. Cabergoline was equally potent in the adenohypophysis after oral and i.v. administration, as determined 1 and 8 h later.

Administration, Oral↗
PubMed1990

Biosynthesis of salsolinol, a tetrahydroisoquinoline alkaloid, in healthy subjects.

The R enantiomer of salsolinol was detected in the urine of two out of six healthy subjects, whereas 1,2-dehydrosalsolinol was present in the urine of all the subjects. (S)-salsolinol was never detected. Administration of Madopar for 7 days resulted in the presence of large amounts of (R)- and (S)-salsolinol in the urine of five out of the six subjects, the urinary excretion of 1,2-dehydrosalsolinol being generally not markedly increased. The presence of 1,2-dehydrosalsolinol in urine suggests that the biosynthesis of salsolinol in healthy volunteers should occur by condensation of dopamine with pyruvic acid, in keeping with Hahn's hypothesis. The absence of salsolinol in the urine of one subject after Madopar administration seems to indicate that the biological system(s) involved in the reduction of the C = N bond in 1,2-dehydrosalsolinol can be missing or not, or poorly, functional in some individuals, and suggests that there is no alternative pathway for the formation of salsolinol in healthy volunteers.

Adult↗
PubMed1990

The disposition and urinary metabolism of 14C-labelled FCE 22891, a pro-drug of FCE 22101, in animals.

[2-14C]FCE 22891 was given orally and intravenously to the rat, orally to the dog and monkey. Radioactivity was eliminated by both the renal and faecal route after oral administration, but mainly in the urine after the iv route in the rat. Radioactivity as expired 14CO2 was detected in the rat and accounted for less than 1% of the dose after iv and 3.2% after oral dosage within 72 h. After oral FCE 22891 labelled by 14C in the acetoxymethyl moiety, radioactivity recovered as expired 14CO2 accounted for over 55% of the dose at 72 h in the rat. No FCE 22891 was detected in plasma, whereas consistent amounts of FCE 22101 were detected. The metabolism was studied by radio-HPLC in the urine of the animals treated with [2-14C]FCE 22891. No unchanged drug was detected at any time interval. FCE 22101 was the main urinary metabolite with the exception of the dog and accounted for about one-half of the radioactivity excreted in 0-24 h urine. Significant amounts of metabolite P1, an open beta-lactam ring derivative obtained by action of dehydropeptidase, were found in the urine of rat and monkey but not in the dog. The remaining urinary radioactivity was due to other metabolites, named P, X and LP, which might originate from P1, as stability of P1 is pH-dependent.

Administration, Oral↗
PubMed1989

Pharmacokinetics and tolerance of a new penem antibiotic, FCE 22101, in healthy volunteers after a single intravenous dose.

The clinical tolerance and pharmacokinetics of FCE 22101 (sodium (5R, 6S)-6-[(1R)-hydroxyethyl]-2-carbamoyloxymethyl-2-penem-3-carboxylate), a new penem antibiotic, have been studied after giving a single i.v. dose of 4 mg.kg-1 to ten healthy male volunteers. The pharmacokinetics was estimated according to a two-compartment open model. The peak plasma concentration (Cmax) was 15.5 (1.08) micrograms.ml-1, mean (SEM). FCE 22101 was rapidly cleared from the systemic circulation [t 1/2 lambda z = 44.2 (4.2) min; CL = 7.21 (0.47) ml.kg-1.min-1]. The mean apparent volume of distribution at steady-state was 246 (16.9) ml.kg-1. The mean residence time relative to the 10 min infusion was 39.4 (1.5) min. Urinary recovery of FCE 22101 showed wide inter-subject variation, ranging from 10.2 to 53.6% of the dose. No subject complained of adverse effects.

Adult↗
PubMed1985

Age-related changes in sorbitol dehydrogenase activity of rat brain, liver, kidney and eye.

Sorbitol dehydrogenase (SDH) activity was measured in whole brain, different brain areas, liver, kidney and eye of old rats (23-26 months) and compared with matched animals (3 months). A significant increase in SDH activity was found in whole brain (34%) of old rats, as well as in all brain areas studied: brainstem (59%), hypothalamus (38%), cerebral cortex (35%), striatum (30%), midbrain (27%), hippocampus (27%) and cerebellum (19%). The increase in SDH activity in brain of old rats is due to Vmax. These results do not favour an accumulation of sorbitol in brain of old rats. A significant decrease (36%) in SDH activity was found in kidney and no significant change in liver and eye of old rats when compared with young rats. Our previous and present results suggest that an accumulation of sorbitol might occur in some tissues of old rats, particularly in the eye, and cause cataract formation.

Aging↗
PubMed1984

[Biochemical mechanisms of the hepatotoxicity of psychotropic drugs].

The first part of this article presents the mechanisms for the hepatotoxicity of xenobiotics known to date, in particular the interference with the metabolism of bilirubin, hepatotoxicity arising from the metabolism of drugs as well as hepatotoxicity due to immunological factors. In the second part, the classification of the diverse hepatic diseases due to drugs is presented: acute injury (cytotoxic, cholestatic, mixed) and chronic damage. The extrahepatic manifestations of drug-induced hepatic injury are also mentioned. Finally, in the third part, we present the principal cases of hepatotoxicity caused by psychotropic drugs: antidepressants (MAOIs and tricyclics), neuroleptics (phenothiazines, thioxanthenes, butyrophenones and benzamides) and anxiolytics, to which we add the anticonvulsants (phenytoin, phenacemide, oxazolidinediones, carbamazepine and valproic acid). We describe the mechanism of hepatotoxicity when known and we attempt to present the type(s) of hepatic injury it causes.

Acute Disease↗
PubMed1983

Intestinal metabolism of tyramine by both forms of monoamine oxidase in the rat.

The two forms of monoamine oxidase (MAO) in rat intestine and brain homogenates were found to have different Km and Vmax values towards tyramine. The Km values for the A-form of the enzyme towards this substrate were around 120 microM in both cases, whereas the values for the B-form were about 240 microM. As a consequence, the ratio of activities (MAO-A: MAO-B) towards tyramine are dependent upon the substrate concentration. The MAO-A-selective inhibitors, toloxatone and cimoxatone, were found to be competitive inhibitors of the oxidation of tyramine by the A-form of this enzyme in the rat intestine, with Ki values of 3.4 microM and 3.7 nM respectively. The significance of these results in relation to the "cheese effect", a pressor response to tyramine after monoamine oxidase inhibition, are discussed.

Animals↗
PubMed1983

Differential changes in superoxide dismutase activity in brain and liver of old rats and mice.

Superoxide dismutase (SOD) activity was measured in the brain and liver of 24-26- and 3-month-old rats. No significant age-related differences in Cu/Zn-SOD activity were found in any of the tissues studied. A small but significant increase in total SOD activity was observed in the whole brain (10-20%), cerebral cortex (11%), and hypothalamus (18%) of old rats, whereas a much more important increase in Mn-SOD activity was found in the whole brain (48%), cerebral cortex (70%), striatum (60%), and hypothalamus (30%). The increase of Mn-SOD activity in the brain of old rats suggests the enzyme may play an important role in the process of aging. Mn-SOD is found only in the mitochondrion, which could be an important site of oxygen free radical production, and a significant increase in the enzyme activity was also found in the lung of hypoxic rats. A significant decrease in total SOD and Mn-SOD activity was observed in the liver of old rats. Preliminary experiments in 23-24-month-old mice similarly showed an increase and a decrease in total SOD and Mn-SOD activity, respectively, in the whole brain and liver. These results suggest that the regulatory mechanisms of Mn-SOD in the brain and liver vary differentially with age.

Aging↗
PubMed1983

The metabolism of dopamine by both forms of monoamine oxidase in the rat brain and its inhibition by cimoxatone.

In the rat brain, dopamine is metabolised by both A and B forms of monoamine oxidase (MAO), although the A form of the enzyme is the major component. The Km of MAO-A toward dopamine (120 microM) is lower than the Km of MAO-B toward this substrate (340 microM). The activity of MAO-A was lower in old rats than in young rats, and the same degree of decrease was found for 5-hydroxytryptamine as for dopamine as substrates for this enzyme form. The activity of MAO-B was higher in the old rats, the degree of increase being the same for dopamine as for beta-phenethylamine as substrates for this enzyme form. The Ki values of the inhibition of MAO-A by cimoxatone and MD770222 (the principal plasma metabolite of cimoxatone) were independent of the substrate used to assay for activity, but were lower than the Ki values for the inhibition of MAO-B by these compounds.

Aging↗
PubMed1982

Pharmacokinetics and pharmacodynamics of the antiarrhythmic compound MD750819 in dogs with experimentally induced arrhythmias.

Pharmacokinetics and pharmacodynamics were studied in three dogs with interventricular coronary artery ligatures (ligature of Harris) and in three control animals. Weighted nonlinear analysis was used to fit equations describing two and three compartment open models to the experimental data, obtained after intravenous injection (5 mg/kg) of the drug. The three compartment model gave a reduction in the weighted sum of squared residuals and an improvement in the randomness of scatter of the experimental points about the theoretical curve. The postdistribution elimination half-life was longer, the area under the plasma elimination curve larger, and the total body plasma clearance and apparent volume of distribution was reduced in the animals with arrhythmias. The pharmacological response was assessed by recording the ECG and calculating the percentage of normal sinus rhythm/min. A combined pharmacokinetic-pharmacodynamic model was used to analyze data from individual animals. keO, a measure of the lag time of pharmacological response behind changes in plasma concentration, and Ce (50), a measure of the sensitivity of the cardiac site of action of the drug, were determined.

Animals↗
PubMed1982

Disposition of 2,3-dihydro-8-[2-hydroxy-3-[4-[1-oxo-3-(3,4, 5-trimethoxyphenyl)-2-propenyl]-1-piperazinyl]-propoxy]-1, 4-benzodioxin-5-carboxylic acid, isopentyl ester (TPBE) in rat and dog, and its hydrolysis in vitro in rat, dog and man.

1. 14C-Labelled 2,3-dihydro-8-[2-hydroxy-3-[4-[1-oxo-3-(3,4, 5-trimethoxyphenyl)-2-propenyl]-1-piperazinyl]propoxy]-1, 4-benzodioxin-5-carboxylic acid, isopentyl ester (TPBE) was administered orally and intravenously to rats and dogs and excretion in urine and faeces studied. Large amounts of radioactivity were present in faeces after i.v. drug administration, indicating that biliary excretion was important. 2. Biliary excretion in bile-duct cannulated rats and dogs showed that within one hour after i.v. dosage, greater than 50% dose was excreted in the bile of both species. Much lower amounts of radioactivity were excreted in bile after oral administration, indicating that absorption was incomplete. 3. T.l.c. of urine, bile and faeces showed that the hydrolysis product of TPBE was the major metabolite in urine and bile of the rat, but was less predominant in dog. 4. Incubation of TPBE in rat whole blood, and with homogenates of liver and small intestine, demonstrated hydrolysis of the drug. Hydrolysis by small intestine and colon contents was low. In the dog, only liver homogenates were capable of extensive hydrolysis of the drug. Hydrolysis also occurred in human blood in vitro; hydrolysis was most rapid in blood of rat then man and finally dog. 5. Experiments in vitro indicate that hydrolysis of TPBE in dog in vivo is likely to be mainly hepatic, whereas in rat hydrolysis in vivo is likely to be both hepatic and extrahepatic (blood and intestines). Results from rat, dog and man indicate that man is likely to be similar to the rat in hydrolysis of TPBE.

Animals↗
PubMed1982

Pharmacokinetics of toloxatone in man following intravenous and oral administrations.

Pharmacokinetics of the antidepressant drug toloxatone were investigated in man following intravenous and oral administration. Five healthy adult volunteers received a single 1 mg/kg dose given as a gelatin capsule (p.o.) and an i.v. infusion. After p.o. administration toloxatone was rapidly absorbed, peak plasma concentrations (Cmax) ranging from 0.384 to 0.640 mg/l occurred between 0.53 and 1.00 h. Plasma curves were fitted according to a one-compartment open model. After absorption, toloxatone was cleared from plasma with a half-life (t 1/2 beta) of 0.96-1.81 h. Following i.v. administration Cmax values from 0.623 to 0.840 mg/l were reached at the end of the 0.5-h infusion. As observed for the capsule form, the elimination of the drug from the plasma was monophasic with t 1/2 beta of 0.88-2.46 h. Plasma clearance of toloxatone was high (0.462 to 0.860 l/h . kg) and the apparent volume of distribution ranged between 1.09 and 1.64 l/kg. Protein binding to plasma proteins is near 50% and appears almost exclusively due to albumin. Free fatty acids do not modify substantially the degree of binding which is constant over the range of concentrations from 0.05 to 100 mg/l. The availability of the gelatin capsule was 50-62% of the i.v. infusion. Since toloxatone is extensively eliminated in urine as metabolites, the reduced availability of the drug appears to be related mainly to first pass metabolism.

Administration, Oral↗
PubMed1981

Absorption, distribution, elimination and metabolism of 14C-heptaminol hydrochloride in rat.

Absorption, distribution, excretion and metabolism studies with 14C-labelled 6-amino-2-methyl-2-heptanol hydrochloride (14C-heptaminol hydrochloride, Hept-amyl) were carried out in rat. After a 10 mg/kg p.o. dose heptaminol was rapidly and entirely absorbed. Following the administration of 8 mg/kg i.v. or 12 mg/kg p.o., all tissues studied, except brain, contained higher levels of radioactivity than did plasma. No evidence of accumulation of the drug was seen in any tissue. Whole-body autoradiography revealed a preferential localisation in salivary glands, hypophysis and adrenal medulla 1 h after a 10 mg/kg i.v. or p.o. dose. Brain autoradiography showed radioactivity localised only in highly vascularised areas (choroid plexus and pia mater). Excretion occurred mainly by kidney, 68% of the radioactivity being excreted in urine 4 h after a dose of 10 mg/kg i.v. Biliary and faecal elimination accounted for less than 1% of the radioactivity administered. Heptaminol was metabolized to a hydroxylated metabolite, 6-amino-2-methyl-1,2-heptanediol, which was excreted unconjugated in urine. As doses increased from 10 to 200 mg/kg p.o., the amount of metabolite excreted in the 24-h urines decreased from 7.05% to 4.24% of the urinary radioactivity, indicating a saturation of the metabolism at high doses. Pretreatment of rats with phenobarbital increased the percentage of metabolite excreted in urine, but was unable to prevent the saturation of the metabolism at high doses of heptaminol.

Amino Alcohols↗