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Biomedical subjects

P Giusti

Publications and source records attributed to P Giusti.

At least 55 records · Page 3Linked to original sources
PubMed1995

GYKI 52466 and related 2,3-benzodiazepines as anticonvulsant agents in DBA/2 mice.

The behavioural and anticonvulsant effects of several 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones (2,3-BZs) and of 11b-aryl-7,11-dihydro-3-phenyl[1,2,4]oxadiazolo[5,4-a][2,3]benz odiazepin-6-ones (2,3-OBZs) were studied after intraperitoneal (i.p.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The seizures were evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a hemispheric Perspex dome. The 2,3-benzodiazepines studied after 30 min pretreatment were generally less potent than the related derivative 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) except 3,5-dihydro-7,8-dimethoxy-1-phenyl-4H-2,3-benzodiazepin-4-one (2,3-BZ-2) and 2,3-BZ-2M (3-methyl derivative of 2,3-BZ-2) which showed comparable activity. Thirty minutes after i.p. administration of 2,3-benzodiazepines, the rank order of potency for anticonvulsant activity against clonus was 2,3-BZ-2 > GYKI 52466 > 2,3-BZ-2M > 2,3-BZ-1 > 2,3-BZ-3, > 2,3-OBZ-1, > 2,3-OBZ-2 2,3-OBZ-3. The intracerebroventricular (i.c.v.) injection of aniracetam on it own (12.5 - 100 nmol/mouse) had no convulsant activity, but it reversed the anticonvulsant effects of some 2,3-benzodiazepines. In particular, the pharmacological actions of GYKI 52466, 2,3-BZ-2 and 2,3-BZ-2M, which proved to be the most potent 2,3-benzodiazepine derivatives as anticonvulsants, were significantly reduced by an i.c.v. pretreatment with aniracetam (50 nmol/mouse). Concomitant treatment with aniracetam (50 nmol/mouse) shifted to the right the dose-response curves and significantly increased the ED50 values for GYKI 52466, 2,3-BZ-2 and 2,3-BZ-2M. After 30 min pretreatment 2,3-BZ-2 showed a similar potency to GYKI 52466 in antagonizing seizures induced by i.c.v. administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), thus suggesting a clear involvement of AMPA receptors in the anticonvulsant activity of these compounds. In addition, 2,3-BZ-2 and 2,3-BZ-2M showed anticonvulsant properties longer lasting than GYKI 52466.

Animals↗
PubMed1995

Melatonin protects primary cultures of cerebellar granule neurons from kainate but not from N-methyl-D-aspartate excitotoxicity.

the antiexcitotoxic efficacy of melatonin, a putative endogenous hydroxyl radical scavenger, was studied in primary cultures of rat cerebellar granule neurons. Excitotoxicity was induced in 7- to 9-day-old cultures by an exposure to glutamate (15 min in the absence of magnesium) or to glutamate receptor agonists, kainate (30 min), and N-methyl-D-aspartate (60 min in the absence of magnesium). Thereafter, cultures were returned to the culture-conditioned medium for 18 h at the end of which time viability was assessed by quantitative staining with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Cotreatment with melatonin (500 microM) protected the neurons completely from the toxicity of kainate (up to 1 mM) and shifted the ED50 for glutamate from 55 +/- 2.6 to 97 +/- 3.6 microM. Melatonin cotreatment was ineffective in protecting the neurons from N-methyl-D-aspartate toxicity. When melatonin was added to the cultures only before or after kainate treatment, there was no resultant protection from kainate toxicity. The neuroprotective effect of melatonin does not appear to be related to the direct action of melatonin on ionotropic glutamate receptors. That is, the kainate-stimulated inward currents measured by a patch-clamp technique in voltage clamped neurons and the kainate-stimulated increase in free cytosolic calcium measured at the single-cell level using digital imaging fluorescent microscopy with fura-2 were not affected by melatonin. Moreover, the binding of [3H]glutamate to rat cerebellar membranes was not competed off by melatonin. Further studies are needed to evaluate the pharmacologic relevance of the neuroprotective action of melatonin.

Animals↗
PubMed1995

Characterization of [3H]-imidazenil binding to rat brain membranes.

1. The binding of [3H]-imidazenil, an imidazobenzodiazepine carboxamide, to rat cerebellar membranes was characterized at different temperatures. 2. Specific binding was linear with tissue concentrations and reached maximum after 90, 30 and 5 min incubation at 0, 21 and 37 degrees C, respectively. The binding was of high affinity, specific and saturable; non linear regression and Scatchard analysis of the data was compatible with the presence of a single population of receptor sites with Bmax of 0.74 +/- 0.020, 0.90 +/- 0.011 and 1.0 +/- 0.036 pmol mg-1 protein at 0, 21 and 27 degrees C, respectively. Binding affinity decreased with increasing temperature: Kd were 0.29 +/- 0.051 nM (0 degrees C), 1.0 +/- 0.080 nM (21 degrees C) and 2.4 +/- 0.38 nM (37 degrees C). 3. At all tested temperatures, [3H]-imidazenil binding was reversible and the Kd calculated from the dissociation and association rate constants approximated the equilibrium Kd. 4. In the presence of gamma-aminobutyric acid (GABA), Kd increased 4 fold at 0 degrees C, whereas Bmax increased, albeit slightly, at all temperatures. 5. Benzodiazepines (BZDs), imidazopyridines and methyl-beta-carboline-3-carboxylate (beta CCM) were effective inhibitors of [3H]-imidazenil binding. Conversely, GABAA antagonists, barbiturates, picrotoxin and peripheral BZD receptor ligands were devoid of any activity. 6. Comparing [3H]-imidazenil to [3H]-flumazenil binding in various brain areas, similar densities of recognition sites as well as like regional differences in the distribution of binding sites for both radioligands were observed (cortex = striatum > cerebellum > spinal cord). 7. The present results indicate that [3H]-imidazenil specifically binds to the BZD sites of GABAA receptors. Furthermore, the effects of GABA and temperature differentiate imidazenil from classicalBZDs. It is suggested that the characteristics of imidazenil binding may be relevant to the in vivo pharmacology of the drug.

Animals↗
PubMed1995

Bioartificial materials based on collagen: 1. Collagen cross-linking with gaseous glutaraldehyde.

The effect of exposure time of thin films of soluble collagen to glutaraldehyde (GTA) vapour was studied at 37 degrees C, and was evaluated by examining the thermal and biological stability and the swelling ratio. It was found that the collagen films treated with GTA vapour for 18 h showed the highest denaturation temperature, the lowest swelling ratio, and an enhanced proteolytic stability. This study shows that soluble collagen can be effectively cross-linked with GTA vapour and that the degree of cross-linking can be controlled by varying the exposure time.

Animals↗
PubMed1995

Bioartificial materials based on collagen: 2. Mixtures of soluble collagen and poly(vinylalcohol) cross-linked with gaseous glutaraldehyde.

Thin films of both pure soluble collagen (CLG) and poly(vinylalcohol) (PVA) and mixtures of the two, ranging from 20-80% PVA composition were studied to test the effects of PVA content and of glutaraldehyde vapour cross-linking. Both the thermal and mechanical behavior and, in addition, proteolytic stability were clearly influenced by the ratio of CLG/PVA. The experimental results indicate that no thermodynamic compatibility occurs between the two homopolymers. However, there is evidence that strong interactions, probably due to hydrogen bond formation, occur between the biological and synthetic polymers. The interactions appear stronger in those films with a lower PVA content and which were not cross-linked. Both the thermal and biological stability are increased and there is an improvement of the mechanical properties. The mutual intermolecular influence appears to allow the attainment of a good mechanical compatibility between CLG and PVA.

Animals↗
PubMed1995

Characterization of the resistance of pyrolytic carbon to abrasive wear.

Si-alloyed pyrolitic carbon (PyC) is currently employed in many biomedical devices, due to its fairly good biological compatibility and non biodegradeability. For prosthetic heart valve applications, required to operate safely for many years, the resistance to abrasive wear is one of the limiting factors which must be accurately evaluated. The present study reports on abrasive wear testing of Ti/PyC and PyC/PyC sliding couples. For both couples it was found that the wear behaviour can be shifted from a low wear regime, characterised by very small wear rates and reduced scatter, to a high wear regime, characterised by high wear rates and high scatter, due to the presence of particle contamination coming from the environment and/or from the specimen polishing process. Actual biomedical devices, particularly heart valves, should not experience the high wear regime, due to the absence of any hard particle contamination source. The wear observed in these items is in fact minimal and may depend on mechanisms other than abrasive wear. In these conditions the experimental evaluation of the wear behaviour should definetely be performed by tests on actual devices.

Aluminum Oxide↗
PubMed1994

Chronic administration of an anticonvulsant dose of imidazenil fails to induce tolerance of GABAA receptor function in mice.

The ability of an anticonvulsant dose (0.1 mg/kg i.p.) of imidazenil, a new partial agonist of benzodiazepine receptors, to antagonize the convulsions and the increase in t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to the gamma-aminobutyric acid type A (GABAA) receptor elicited by isoniazid, an inhibitor of central GABAergic function, was evaluated in mice chronically treated (3 times daily for 30 days) with the same dose of imidazenil. The challenge dose of imidazenil, administered 36 h after the last injection of the chronic treatment protocol, reduced both isoniazid-induced convulsions and the isoniazid-induced increase in [35S]TBPS binding to the same marked extent as in control mice. These results indicate that long-term treatment with a pharmacologically effective dose of imidazenil failed to induce tolerance to both the anticonvulsant effect and the positive modulatory action on GABAA receptor function of this drug in mouse brain.

Animals↗
PubMed1994

Diazepam impairs place learning in native but not in maze-experienced rats in the Morris water maze.

Anxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature.

Animals↗
PubMed1994

Collagen-based new bioartificial polymeric materials.

Bioartificial polymeric materials, based on blends of biological and synthetic polymers, have been proposed as new materials for applications in the biomedical field. They should usefully combine the biocompatibility of the biological component with the physical and mechanical properties of the synthetic component. Blends of collagen with either poly(vinyl alcohol) or poly(acrylic acid) have been prepared by mixing aqueous solutions of the two polymers. Differential scanning calorimetry and dynamic mechanical thermal analysis has been carried out to investigate the miscibility properties of the polymers and the mechanical behaviour of the blends.

Acrylic Resins↗
PubMed1994

Imidazenil, a partial positive allosteric modulator of GABAA receptors, exhibits low tolerance and dependence liabilities in the rat.

Long-term treatment of rats with full (triazolam) or selective (diazepam) allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors rapidly induced tolerance to the protective effect of these drugs against bicuculline-induced convulsion. In contrast, long-term administration of partial allosteric modulators (imidazenil and bretazenil) of GABAA receptors, in doses equipotent to those of diazepam and triazolam that induce anticonvulsant tolerance, failed to elicit such a tolerance. Furthermore, no cross-tolerance was observed between diazepam and imidazenil. Discontinuation of long-term treatment with diazepam or triazolam, but not of long-term treatment with imidazenil or bretazenil, sensitized rats to behavioral inhibition by punishment (electric shock) in a manner that was potentiated by flumazenil. Administration of a single oral dose of [14C]diazepam or [3H] imidazenil to rats treated repeatedly with the corresponding unlabeled drug or vehicle revealed that the brain concentrations of drugs and their metabolites were similar in both groups of animals. This suggests that tolerance to the full or selective allosteric modulators of GABAA receptors may be associated with changes in the efficacy of the allosteric modulation rather than with changes in drug metabolism. Imidazenil has a longer half-life than an equipotent dose of diazepam and protects rats against bicuculline-induced convulsions for a significantly longer time than diazepam or bretazenil.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1994

Imidazenil, a new partial agonist of benzodiazepine receptors, reverses the inhibitory action of isoniazid and stress on gamma-aminobutyric acidA receptor function.

The imidazobenzodiazepine 6-(2-bromophenyl)-8-fluoro-4H-imidazo-[1,5-a] [1,4]benzodiazepine-3-carboxamide (imidazenil) is a new anxiolytic and anticonvulsant ligand of the benzodiazepine recognition site that possesses the characteristics of a partial allosteric modulator of the gamma-aminobutyric acid (GABA) type A receptor. The effects of imidazenil on GABAA receptor function were examined both in vitro and in vivo. Imidazenil inhibited [3H] flumazenil binding to mouse cerebral cortical membranes in vitro with an IC50 of 0.9 nM, showing that this compound binds with high affinity to benzodiazepine receptors. However, imidazenil failed to modify t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to washed or unwashed mouse cortical membrane preparations. Furthermore, imidazenil injected i.p. into mice failed to affect [35S]TBPS binding subsequently measured in unwashed cortical membranes. In contrast, imidazenil reduced in a dose-dependent manner the increase in [35S]TBPS binding elicited by isoniazid (200 mg/kg s.c.), an effect mimicked by lorazepam and abecarnil++ but not by bretazenil. As expected, i.p. administration of lorazepam or abecarnil induced within 30 min a marked reduction in [35S]TBPS binding subsequently measured in unwashed cortical membranes of control mice. Moreover, imidazenil at a dose as low as 0.05 mg/kg (i.p.) delayed the onset of convulsions and death elicited by isoniazid and reduced significantly the number of mice exhibiting seizures. Accordingly, imidazenil also showed great potency in antagonizing the convulsions induced by pentylenetetrazole in rats. Imidazenil also completely abolished the increase in [35S]TBPS binding induced by foot-shock or exposure to carbon dioxide. Finally, imidazenil antagonized both in vitro and in vivo the effects of bretazenil or lorazepam on GABAA receptor function.

Animals↗
PubMed1993

Physiological and pharmacological bases for the diverse properties of benzodiazepines and their congeners.

Benzodiazepines (BZs), which have been marketed by pharmaceutical companies since the sixties, are the most commonly prescribed psychotropic drugs. Diazepam, the prototype of this class of drugs, has a vast spectrum of therapeutic indications. It possesses, over a narrow dose-range, the well-known neuropsychopharmacological profile consisting of anxiolytic, anticonvulsant, sedative, and muscle relaxant effects, and CNS depression. Recently, BZ ligands that retain anxiolytic and antiepileptic properties at doses that are unable to produce a CNS depression have been developed. The pharmacological profiles of these drugs are discussed in light of: the heterogeneity of the structure of the GABAA receptor complex; intrinsic efficacy of the ligand; action of the BZ ligand on the mitochondrial BZ receptor.

Animals↗
PubMed1993

Imidazenil: a new partial positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors.

Positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors, including benzodiazepines and congeners, can be classified into three categories: 1) full allosteric modulators (i.e., triazolam and alprazolam) that act with high potency and efficacy at many GABAA receptors; 2) selective allosteric modulators (i.e., diazepam) that act with high potency and high efficacy at selected GABAA receptors; and 3) partial allosteric modulators (i.e., bretazenil) that act with high potency but low efficacy at many GABAA receptors. Imidazenil, an imidazobenzodiazepine carboxamide, has been characterized as a novel representative of the partial allosteric modulator class. When tested on a broad spectrum (native and recombinant) of GABAA receptors, imidazenil positively modulates the GABA-elicited Cl- currents with a 4- to 5-fold higher potency but an efficacy (30-50%) lower than that of diazepam, and it antagonizes the effects of the latter drug. Imidazenil in vitro (Ki = 5 x 10(-10) M) and in vivo (ID50 = 0.2 mumol/kg i.v.) displaces [3H]flumazenil from its brain binding sites and in vivo it possesses a marked anticonflict profile in the rat Vogel conflict-punishment test and is 10 times more potent than bretazenil and 100 times more potent than diazepam or alprazolam in antagonizing bicuculline- and pentylenetetrazol-induced seizures. Unlike diazepam and alprazolam, which induce sedation and ataxia and potentiate the effects of ethanol and thiopental at doses similar to those that produce anticonflict effects and occupy 50% of brain flumazenil binding sites, imidazenil does not produce ataxia or sedation in rats nor does it potentiate the effects of ethanol or thiopental in doses 30- to 50-fold higher than those required for the anticonflict effect and for 100% occupancy of brain flumazenil binding sites. Furthermore, when administered with diazepam, imidazenil blocks in a dose-related fashion the sedative, ataxic effects of this drug and thus acts on these unwanted responses as an antagonist (i.e., like flumazenil). In all tests, imidazenil has the pharmacological profile of a partial allosteric modulator, but is more potent than bretazenil, has a longer biological half-life and, in rodents, is virtually unable to cause sedation, ataxia or to potentiate ethanol toxicity.

Allosteric Regulation↗
PubMed1991

Development of small-diameter vascular prostheses which release bioactive agents.

A porous, distensible, tubular membrane which incorporates albumin and basic Fibroblast Growth Factor (bFGF), and is potentially utilizable as a bioactive small-diameter vascular prosthesis, was fabricated by a combined spraying, phase-inversion technique using a suspension of albumin and bFGF into a polyetherurethane-urea (Biomer) solution in dimethylacetamide (DMA). Scanning electron microscopy showed a material with an open-cell trabecular structure and small particles of albumin and/or bFGF entrapped in the bulk of the polyurethane trabeculae. The material released albumin and bFGF at an approximately constant rate for at least 2 weeks. The bFGF initially incorporated in the polymer remained biologically active as shown by in-vitro proliferation of human endothelial cells.

Albumins↗