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R Roncucci

Publications and source records attributed to R Roncucci.

At least 19 recordsLinked to original sources
PubMed1997

A transgenic mouse model for the detection of cellular stress induced by toxic inorganic compounds.

Transgenic mice for genotoxicity testing have been developed, although no such models have been produced for the evaluation of toxic, nongenotoxic chemical compounds. We have developed a transgenic mouse model for the analysis of toxic inorganic compounds. We engineered a mouse lineage with the human growth hormone (hGH) gene under the control of the human hsp70 promoter, in which a plasma-detectable hGH response can be elicited by exposure to heat shock. In primary cell cultures from these mice, hGH release was observed following treatment with several toxic inorganics. Transgenic mice injected intraperitoneally with sodium arsenite, cadmium chloride, copper sulphate, or methylmercurium chloride showed significant hGH levels in plasma.

Animals↗
PubMed1991

Preclinical and clinical studies with recombinant human basic fibroblast growth factor.

Basic fibroblast growth factor is a polypeptide belonging to a family of natural proteins also known as heparin-binding growth factors endowed with a pleiotropism of biological activities, the most striking of which are related to wound healing. Large quantities of recombinant human basic fibroblast growth factor (rh-bFGF) of a clinical grade were obtained and used to undertake preclinical and clinical studies. In vivo the wound healing effect of rh-bFGF was evaluated in experimental targets such as the cornea and the tympanic membrane, showing a significantly increased epithelial healing rate in drug-treated animals. The deposition of labeled rh-bFGF after topical applications in ocular wounding models did not result in a systemic absorption of the intact rh-bFGF molecule. The acute and the subchronic toxicity studies undertaken after iv and topical administration of a stable pharmaceutical formulation of rh-bFGF did not result in irritation, and no signs of general toxicity were observed. Altogether these data permitted us to start recently with human studies, which are still ongoing, aimed to evaluate the tolerability and the activity of rh-bFGF on tegumental targets such as the cornea and the skin.

Animals↗
PubMed1991

FCE 23884, substrate-dependent interaction with the dopaminergic system. II. Preclinical biochemical studies.

The effects of FCE 23884 [4-(9,10-didehydro-6-methylergolin-8 beta-yl) methyl-piperazine-2,6-dione] were examined using a variety of biochemical methods. In vitro assays showed that FCE 23884 bound to D-2, alpha-2 and 5-hydroxytryptamine1A sites with Ki values of 6.5, 4.0 and 4.0 nM, respectively. The affinity for D-1 and S-2 receptors was moderate (submicromolar range) and slight or negligible for alpha-1, cholinergic and sigma receptors. In normal rats, FCE 23884 accelerated markedly dopamine (DA) turnover in the neostriatum and nucleus accumbens as indicated by the increased ratios of dihydroxphenyl acetic acid/DA and homovanillic acid/DA. The compound enhanced DA synthesis and utilization rate. After gamma-butyrolactone treatment, a model to study DA autoreceptors function, FCE 23884 almost antagonized completely the gamma-butyrolactone reversal induced by apomorphine on l-dihydroxyphenylalanine accumulation in the two brain areas. In addition, FCE 23884 induced a rapid 20-fold increase of serum prolactin confirming its DA antagonistic profile in normal rats. In contrast with these antidopaminergic properties, FCE 23884 consistently stimulated basal adenylate cyclase activity in vitro (ED50 = 0.6 microM) and elicited a rapid increase of cyclic AMP formation in the neostriatum of normal (35%) and reserpinized (82%) rats in vivo. Furthermore in this last condition both the DA turnover and synthesis rate in the neostriatum and nucleus accumbens decreased after treatment with FCE 23884. These neurochemical data support the behavioral studies indicating that FCE 23884 possesses mixed DA antagonist and agonist properties depending on the experimental conditions, the distinguishing factor being presence or absence of DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
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

The dispositional enantioselectivity of indobufen in rat and mouse.

The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen, a novel platelet aggregation inhibitor, have been studied in rats and mice given either the racemic compound or the individual enantiomers (rat 8 mg/kg racemate, 4 mg/kg enantiomers; mouse 25 mg/kg racemate, 12.5 mg/kg enantiomers). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. In rat, the two enantiomers have very different plasma elimination half lives (S, 3.9 hr; R, 12.2 hr), irrespective of the optical form administered. The plasma concentration-time curves of S-indobufen were identical after racemic or S-indobufen, but the plasma levels of R-indobufen were lower after the R-enantiomer than after the racemate. Urinary recovery of free and conjugated indobufen was less than 3% of the dose, independent of the optical form administered. In the mouse, R-indobufen was cleared from plasma more rapidly than its S-antipode (elimination T1/2 R, 2.5 hr; S, 3.8 hr) but differences were smaller than those seen in the rat. The plasma concentration-time curves of the S-enantiomer were the same after racemic or S-indobufen, but levels of its R-antipode were much lower when it was given alone than after administration of the racemate. The urinary recovery of free and conjugated indobufen also exhibited enantioselectivity, with preferential elimination of the S-enantiomer.

Animals↗
PubMed1990

MAO activity, metabolism and anticonvulsant activity of milacemide in rats and mice.

Milacemide was found to protect Swiss albino CD1 mice but not Sprague Dawley rats against bicuculline-induced lethality. Since it had been previously suggested that the anticonvulsant activity of milacemide might be related to MAO-B- mediated glycine formation, brain and liver MAO-A and-B activities and the urinary metabolic pattern of milacemide were determined in the same mice and rat strains. Similar brain and liver MAO activities were found in the two species, except for liver MAO-A activity which was higher in rats. After the same oral dose of milacemide, the percent of the dose excreted as glycinamide was significantly higher in mice than in rats, whereas that excreted as metabolite UK1 was significantly higher in rats. These results support the hypothesis of a glycine-mediated anticonvulsant activity for milacemide and suggest that the increased formation of UK1 to the detriment of glycinamide might account for the lack of protection against bicuculline-induced lethality by milacemide in rats.

Acetamides↗
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

Urinary metabolites of 14C-labelled FCE 22101 in animals.

The metabolism of 14C-FCE 22101 has been studied by radio-HPLC in the urine of various animal species. Five main chromatographic peaks were detected and named, in order of decreasing polarity, P, P1, X, UD (unchanged drug) and LP. P1 is the open beta-lactam ring metabolite obtained by the action of dehydropeptidase. The stability of FCE 22101 and P1 is pH-dependent, and differences between species in urinary metabolic patterns might therefore be partially explained by different urinary pH values.

Animals↗
PubMed1987

SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. I. Psychopharmacological profile in rodents.

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenyl-pyridazine], a novel compound, has been shown in preliminary experiments to inhibit type A monoamine oxidase (MAO). This report describes the activities of SR 95191 in behavioral experiments in mice and rats and shows that SR 95191 has the profile of a selective type A MAO inhibitor (MAOI). Moreover, SR 95191 also possesses dopamine (DA) stimulant properties. The activities of SR 95191 were compared to those of the MAOIs moclobemide, clorgyline, pargyline and l-deprenyl, as well as to those of the antidepressant drugs imipramine, nomifensine and indalpine and to those of the DAergic drugs (+)-amphetamine and apomorphine. SR 95191 p.o. antagonized the effects of reserpine in mice and rats, decreased immobility in the mouse despair test, antagonized haloperidol-induced catalepsy in rats and potentiated 5-hydroxytryptophan in mice and rats with an overall potency which was half that of imipramine. SR 95191, like moclobemide, did not potentiate yohimbine-induced lethality and did not antagonize oxotremorine-induced tremor. Like selective type A MAOIs, SR 95191 potentiated 5-hydroxytryptophan-induced tremor without affecting beta-phenethylamine-induced stereotypies in mice. SR 95191 did not antagonize 3-hydroxy-4-methyl-alpha-phenylethylamine-induced hyperthermia. Like all DA stimulant drugs, SR 95191 induced stereotypies in rats, which were blocked by haloperidol and alpha-methylparatyrosine, and induced contralateral turning in mice with a unilateral striatal 6-hydroxydopamine lesion. Based on these results, it is postulated that SR 95191 has a unique profile of activity combining the properties of a selective type A MAO inhibitor and those of an atypical DAergic drug.

5-Hydroxytryptophan↗
PubMed1986

Studies on the chronic phase of adjuvant arthritis: effect of SR 41319, a new diphosphonate.

We studied the course of adjuvant arthritis in rats by measuring clinical, biochemical, and histological parameters on day 36 after induction (representing the secondary reaction) and on day 171, which is at the stage of permanent deformity. The effect of SR 41319, a new diphosphonate, was evaluated on days 36 and 171, after three weeks of treatment (days 14-35 inclusive). In the absence of treatment all the measured parameters were markedly abnormal on day 36, indicating the presence of lesions that were still evolving. On day 171 clinical parameters and the lesion histological index remained the same, whereas the biochemical parameters and disease activity histological index had returned to normal, indicating that the lesions at this stage although severe were not inflammatory and consequently not progressing. SR 41319 treatment reduced the severity and progression of the disease both on day 36 and on day 171. We conclude that SR 41319 may be a potentially useful drug for the treatment of rheumatoid arthritis.

Animals↗
PubMed1986

Polysulphated polysaccharides: an in vitro study of their effects on proteoglycan biosynthesis by articular chondrocytes.

An in vitro model is described that allows evaluation of the activity of polysulphated polysaccharides on proteoglycan biosynthesis by articular chondrocytes in culture. Proteoglycan biosynthesis is monitored after brief exposure of the cells to sodium iodoacetate, which induces a substantial decrease in overall proteoglycan biosynthesis, leading to a general reduction of proteoglycan content in the culture medium and in the cartilage-like extracellular matrix. Using this in vitro model, pentosan polysulphate (SP 54) and a high molecular weight analogous (SR 24751) were shown to improve proteoglycan incorporation into the extracellular matrix. In contrast, Arteparon and a low molecular weight fraction of SP 54 (SR 25491) were inactive.

Animals↗
PubMed1985

Growth hormone-releasing factor modifies dopaminergic but not serotonergic activity in the arcuate nucleus of hypothalamus in the rat, as recorded in vivo by differential pulse voltammetry.

Parenteral (i.v.) injection of growth hormone-releasing factor (GRF) increases the height of the 3,4-dihydroxyphenylacetic acid oxidation peak (peak 2) but does not change 5-hydroxyindole extracellular content (peak 3) in the arcuate nucleus of the hypothalamus, both peaks being recorded by the differential pulse voltammetry technique using a single specifically pretreated monopyrolytic carbon fibre electrode. Conversely, no significant changes are observed in the peak 2 and peak 3 heights recorded in the medial or in the lateral nucleus of the hypothalamus. These data suggest a specific interaction between GRF and the dopaminergic system.

Animals↗
PubMed1985

Effects of 1-hydroxyethylidene-1,1 bisphosphonate and (chloro-4 phenyl) thiomethylene bisphosphonic acid (SR 41319) on the mononuclear cell factor-mediated release of neutral proteinases by articular chondrocytes and synovial cells.

Articular chondrocytes and synovial cells were stimulated to produce collagenase, neutral casein and proteoglycan-degrading proteinases by conditioned medium from human peripheral blood mononuclear cells. Collagenase, neutral casein and proteoglycan-degrading proteinase secretion was inhibited by SR 41319, a new bisphosphonate, in a concentration-dependent manner. Complete inhibition was achieved at about 0.3 mM. EHDP exhibited the same general profile but was about 10-fold less active and never completely inhibited the enzyme secretion. When added before MCF, SR 41319 had a protective effect against subsequent activation of the cells by MCF. SR 41319 also inhibited the increase of enzyme secretion by cells previously stimulated with MCF. The results suggest that the ability of SR 41319 to inhibit the MCF-mediated secretion of neutral enzymes involved in cartilage destruction could be valuable in the management of connective tissue damage in rheumatoid arthritis.

Animals↗
PubMed1985

Antithrombotic effect of ticlopidine in a platelet-independent model of venous thrombosis.

The antithrombotic activity of ticlopidine demonstrated in a variety of experimental models of thrombosis has been explained by its antiaggregating properties. This study describes the antithrombotic effect of ticlopidine in a platelet independent model of venous thrombosis. In the rat, ligature of the inferior vena cava induces thrombosis. Antiaggregating drugs (acetylsalicylic acid, dipyridamole, sulfinpyrazone) are inactive while anticoagulants (heparin, acenocoumarol) are highly antithrombotic. Ticlopidine reduces thrombus weight significantly and dose-dependently (ED 50 = 150 mg/kg/day X 3 days). Thrombocytopenia induced by injection of anti-platelet anti-serum was found not to modify thrombus formation. Yet, even in these conditions, ticlopidine remains active. Acetylsalicylic acid treatment does not prevent the antithrombotic effect of ticlopidine, indicating that its action is independent of PGI2 synthesis. These results demonstrate that ticlopidine acts as an antithrombotic agent in a venous thrombosis model in which platelets play a minor role.

Animals↗
PubMed1985

Comparative study of etidronate and SR 41319, a new diphosphonate, on passive cutaneous anaphylaxis and phospholipase A2 activity.

Diphosphonates are known to affect calcium metabolism. It was therefore felt of interest to investigate the effects of SR 41319, a new Diphosphonate, comparatively to Etidronate disodium (EHDP) on Passive Cutaneous Anaphylaxis (PCA) and on Phospholipase A2 (PLA2) activity which are both mediated by calcium-dependent mechanisms. Results showed that: (1) intravenously, SR 41319 induced a dose-dependent inhibition of PCA more pronounced than the EHDP one; (2) in PLA2 assay, marked inhibition was obtained with SR 41319 whereas EHDP was slightly active. Decrease in Ca entry into mast cells and anti-PLA2 activity of SR 41319 might partly explain the SR 41319 inhibition of PCA.

Animals↗