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G Avanzini

Publications and source records attributed to G Avanzini.

At least 91 records · Page 5Linked to original sources
PubMed1995

Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part II. Phenytoin, carbamazepine, sulthiame, lamotrigine, vigabatrin, oxcarbazepine and felbamate.

This article is the second part of a review of the pharmacokinetics of antiepileptic drugs (AEDs) in paediatric patients. It reviews 139 papers published since 1969 on the pharmacokinetics of phenytoin, carbamazepine, sulthiame, lamotrigine (phenyltriazine), vigabatrin, oxcarbazepine and felbamate in this population. The pharmacokinetics of phenytoin are significantly affected by age. The terminal elimination half-life (t1/2z) is relatively long in neonates; it then decreases during the first postnatal month to lower values than in adults, and then progressively increases with age due to an age-dependent decrease in the metabolic rate. Rate of elimination is strongly dose-dependent at all ages. The combination of these factors makes it difficult to predict what plasma concentrations would result from dose per kilogram (dose/kg) adjustments in neonates and children, especially when phenytoin is coadministered with other liver enzyme-inducing drugs, such as phenobarbital and carbamazepine. The concentration of phenytoin in brain and other tissues depends on the unbound/total concentration ratio. For neonates this ratio is higher than that found in adults; it then decreases over the first 3 postnatal months to approach adult values. The fraction of unbound phenytoin is significantly higher in patients also receiving valproic acid. Carbamazepine is almost completely epoxidised to the active metabolite carbamazepine epoxide, which is in turn converted to carbamazepine diol. Metabolic conversion of carbamazepine and renal clearance of carbamazepine diol are much higher in children than in adults; t1/2z of carbamazepine is thus very short in young children, increasing with age. No data are available on the neonatal period. The carbamazepine epoxide/carbamazepine ratio may be significantly increased by metabolic inducers (e.g. phenytoin, phenobarbital and primidone) or by inhibitors of the carbamazepine epoxide to carbamazepine diol conversion (e.g. valproic acid). Macrolides inhibit carbamazepine metabolism, thus increasing carbamazepine plasma concentrations. Drug-induced changes in carbamazepine kinetics are particularly pronounced in children. In children, a higher dose/kg of sulthiame, lamotrigine, oxcarbazepine and felbamate than in adults is required to obtain an effective plasma concentration. The published data do not support the use of a different dose/kg of vigabatrin in children age between 1 month and 15 years. The pharmacokinetic information in the paediatric literature may help in assessing AED prescriptions in childhood to prevent seizures and AED-related adverse effects on the ongoing maturational processes of the brain.

Adult↗
PubMed1995

Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy.

The properties of voltage-dependent calcium currents were compared in thalamic neurons acutely dissociated from a rat model of absence epilepsy, designated as Genetic Absence Epilepsy Rat from Strasbourg (GAERS), and from a Nonepileptic Control strain (NEC). Two populations of neurons were isolated: thalamocortical relay neurons of the nucleus ventrobasalis (VB) and neurons of the nucleus reticularis (RT) of the thalamus. Whole-cell patch-clamp analysis demonstrated an increase in the amplitude of the calcium (Ca2+) current with a low threshold of activation (IT) in RT neurons of GAERS in comparison to that of the seizure-free rat strain (-198 +/- 19 pA and -128 +/- 14 pA, respectively), whereas the sustained component (IL) was not significantly different. The kinetic properties, voltage dependence, and basic pharmacological sensitivity of the Ca2+ conductances were similar in the two populations of neurons. The amplitude of both IT and IL in RT neurons increased after birth, and differences in IT between GAERS and NEC attained significance after postnatal day 11. At corresponding ages, the Ca2+ currents in VB thalamocortical relay neurons were not altered in GAERS in comparison to those in NEC. We conclude that the selective increase in IT of RT neurons enhances the probability of recurrent intrathalamic burst activity, thereby strengthening the synchronizing mechanisms in thalamocortical systems, and, as such, represents a possible primary neuronal dysfunction that relates to the pathological increase in synchronization underlying the generation of bilateral and synchronous spike and wave discharges (SWDs) in an established genetic model of generalized epilepsy.

Aging↗
PubMed1994

Neurons dissociated from neocortex fire with 'burst' and 'regular' trains of spikes.

Neurons acutely dissociated from neocortex slices of 14-16-day-old rats were patch-clamped in physiological conditions. Different pyramidal cells, spontaneously or in response to current steps, generate regular spiking and intrinsically bursting behaviour during long periods of time. We show that typical firing properties recorded in somatosensory neocortex slices are preserved in dissociated pyramidal neurons originating from the slices themselves, thus, providing a way for the related characterization of biophysical properties of currents in identified subtypes of pyramidal neurons.

Action Potentials↗
PubMed1994

Fluoride reversibly blocks HVA calcium current in mammalian thalamic neurones.

The effect of intracellular fluoride ions on voltage-dependent calcium currents was tested during whole-cell voltage-clamp recordings in thalamic neurones acutely dissociated from young adult rats. It is demonstrated that 5-30 mM intracellular fluoride selectively and reversibly suppresses the high voltage-activated, dihydropyridine-sensitive calcium current, without affecting the transient, low voltage-activated calcium current. Intracellular diffusion of a fluoride-free solution restores the blocking effect on the slow inactivating current induced by a transitory fluoride perfusion obtained by filling the patch microelectrode tip with caesium fluoride.

Animals↗
PubMed1994

PME of Unverricht-Lundborg type in the Mediterranean region: linkage and linkage disequilibrium confirm the assignment to the EPM1 locus.

Seven phenotypically homogeneous Mediterranean myoclonus families were studied using DNA markers from the genetically defined EPM1 region on chromosome 21. No recombinations between the disease phenotype and the markers studied were detected. Within the EPM1 region, the highest lod score value of 5.07 (at theta = 0.00) was reached at locus PFKL. Significant allelic association (P = 0.02) between the disease mutation and PFKL was detected suggesting a founder effect in Mediterranean myoclonus. However, haplotype data using four marker loci residing within 300 kb of each other and of EPM1 suggest the occurrence of more than one mutation. The data are compatible with Mediterranean myoclonus being caused by mutations in the EPM1 gene and strengthen the concept that a large subset of progressive myoclonus epilepsies conforms with Unverricht-Lundborg disease and that this subset is an etiologically homogeneous entity.

Adolescent↗
PubMed1994

Serial evoked potentials in multiple sclerosis bouts. Relation to steroid treatment.

Serial recordings of multimodal sensory (visual, acoustic and somatosensory) evoked potentials were made in 19 relapsing-remitting Multiple Sclerosis patients enrolled in a clinical trial designed to evaluate the efficacy of dexamethasone versus high- and low-dose methylprednisolone in acute multiple sclerosis bouts. Electrophysiological and clinical evaluations were performed at the onset of therapy and until 6 months after the end of treatment. Using an arbitrary Evoked Potentials score that takes into account both latency and waveform alterations, we found a positive correlation between evoked potentials and clinical disability scores. Furthermore, different electrophysiological profiles were detected in the three therapeutic subgroups. Evoked potentials may be useful for monitoring acute Multiple Sclerosis bouts and evaluating the effect of therapy.

Adult↗
PubMed1994

Double cortex syndrome: electroclinical study of three cases.

We describe three female patients (aged 10, 11 and 21 years) with a Magnetic Resonance appearance of band heterotopia, a diffuse neuronal migration disorder, also known as double cortex syndrome. The clinical picture was characterized by the association of epilepsy and mental retardation in all three cases, as has been previously described in patients with double cortex syndrome. The epileptic syndrome (Lennox-Gastaut syndrome in one case, and symptomatic partial epilepsy in the other two), the response to medical treatment, and the severity of mental retardation were markedly different in the three patients. No clear-cut relationship was found between the clinical picture and the severity of the neuronal migration disorder, as revealed by magnetic resonance imaging. In the three cases, EEG shares some common features: multifocal epileptic activity with frequent bilateral diffusion, and high-amplitude anterior fast activity, intermingled in two patients with bursts of repetitive spikes.

Adult↗
PubMed1994

Ultrastructural features of the isolated guinea-pig brain maintained in vitro by arterial perfusion.

The morphological features of cerebral tissue in the isolated guinea-pig brain maintained in vitro by arterial perfusion are described. Light and electron microscopic analysis of the thalamus, the somatosensory cortex and the limbic cortices (hippocampus, piriform and entorhinal cortices) was performed after different periods of incubation in vitro (1, 7 and 12 h), in parallel with an electrophysiological study. The morphological analysis showed that neuronal elements retained their normal appearance at both cellular and subcellular level in the examined brain regions up to an incubation period of 12 h. Immunoreactivity for GABA was also preserved for up to 12 h of in vitro perfusion. Vasogenic edema and perivascular extracellular swelling appeared after 7 h, together with signs of progressive astrocytic deterioration. These findings show that normal electrophysiological recordings correlate with good anatomical preservation of the isolated guinea-pig brain preparation after prolonged times of arterial in vitro perfusion.

Animals↗
PubMed1994

Ocular movements.

The internal representation of saccade commands has been shown to combine with visual information for saccade programming. In normative studies saccade parameters have been found consistent across tests. Their variability is highly correlated in both eyes suggesting a common saccade generator. Experimental and clinical studies specify the role of frontal eye fields in the volitional, inhibitory control of visually triggered saccades. The parietal lobe instead seems mainly concerned with privileged target selection. A parallel processing of saccade related signals occurs in corticostriatal circuits. Pursuit movements elicited by intermittently illuminated moving targets result from a predictive estimate of eye velocity based on previous eye velocity and visual feedback. Evidence for peristriate and parietal cortical areas to encode the information relevant to smooth pursuit generation is provided by clinical studies.

Brain Stem↗
PubMed1994

Discussion of stereoelectroencephalography.

Stereoelectroencephalography (SEEG) provides the neurosurgeon with crucial information for directing surgical strategies aimed at removing the epileptogenic foci. In lesional epilepsies the epileptogenic area does not necessarily correspond with the lesional area as defined by imaging techniques. In the case of good correspondence, lesion-directed surgery may be beneficial for the associated epilepsy even without the guide of presurgical SEEG. According to personal observation, this seems to be the case for epileptogenic cavernous angiomas, while for low grade gliomas the criteria for SEEG indication are still to be defined. The SEEG definition of the primary epileptogenic area is based on the detection of leading epileptic potentials by optimally placed depth electrodes. Experimental results demonstrate that epileptic discharges recorded from the hippocampus as the apparent leading phenomena may in fact result from subtle changes in excitability taking place upstream in the piriform cortex. This may lead to misjudgment of the location of primary epileptogenic areas unless suitable techniques of SEEG analysis are applied.

Brain↗
PubMed1993

Expression of intrinsic bursting properties in neurons of maturing sensorimotor cortex.

Intrinsically bursting (IB) neurons, responding with a burst of action potentials to just threshold intracellular depolarizing current pulses, are encountered in layer V of mature rodent sensorimotor cortex. We report the results of intracellular recordings performed on neocortical slices obtained from immature rats between postnatal day (P) 7 and P21, as compared to adult animals (above P60). The bursting properties are here reported to mature abruptly around P14. After this time a subpopulation of IB neurons was recognizable on the basis of both physiological and morphological characteristics (i.e. extensive apical and basal dendrites arborization, axon collaterals limited to layers V-VI). Maturational changes in number and distribution of Ca2+/K+ channels may account for this developmental step. The immaturity of IB neurons may be correlated with the poorly synchronized character of cortical activities in the very young animals.

Action Potentials↗
PubMed1993

GABAA receptor impairment in the genetic absence epilepsy rats from Strasbourg (GAERS): an immunocytochemical and receptor binding autoradiographic study.

Some aspects of the GABA and cholinergic systems have been investigated in the cortex and thalamus of GAERS Wistar rats, a model of petit-mal epilepsy, and in a non-epileptic control strain. GABA and its synthetic enzyme, glutamic acid decarboxylase (GAD), were located by immunocytochemistry; the GABAA receptors were evaluated by autoradiography of GABA-enhanced 3H-flunitrazepam binding and by immunocytochemistry using specific antibodies against the beta 2-beta 3 subunits of GABAA receptor protein. GABA and GAD immunocytochemistry did not show up any difference in density or distribution of immunoreactive elements (fibers, terminals and neurons) between epileptic and control animals, but autoradiographic and immunocytochemical studies showed a decreased enhancement of 3H-flunitrazepam binding and of beta 2-beta 3 subunits of GABAA receptor in the sensorimotor cortex and anterior thalamic areas of the epileptic strain. No differences were found in benzodiazepine receptors in the two strains. GABAB receptors were measured as 3H-baclofen binding in a crude synaptic membrane preparation and there was no difference between epileptic and control animals. Choline acetyltransferase, the synthetic enzyme for acetylcholine, and muscarinic receptor subtypes (M1 and M2), visualized respectively by an immunocytochemical procedure and binding autoradiography, did not differ in epileptic and normal rats. The data suggest an impairment of the 'GABAA system' in restricted brain regions of epileptic rats, due to a reduction of receptor beta 2-beta 3 subunits and coupling to benzodiazepine receptors despite the normal synthesis and location of the neurotransmitter.

Acetylcholine↗
PubMed1993

Lamotrigine in resistant childhood epilepsy.

Fourteen children (6 M, 8 F) suffering from refractory epilepsy received LTG as add-on therapy. LTG was administered twice daily at dosages increasing up to 2 mg/kg/day (for patients taking VPA) or to 10 mg/kg/day for patients taking AEDs that induce hepatic metabolism. The drug was withdrawn for side effects in 3 cases (rash: two cases, hirsutism: one), because of increased seizure frequency in 2 cases and because of unchanged seizure frequency in one. One patient died from acute respiratory failure, after repeated respiratory tract infections. A decrease in seizure frequency after one year of treatment with LTG was observed in 6 of the 7 patients who completed the study. The median total seizure frequency decreased from 10.7 +/- 7.3 to 3.8 +/- 4.6 seizures per day. At the end of the study, seizure frequency had decreased by more than 50% in 2 patients, by more than 75% in 2 patients, and 2 patients were seizure-free; in the remaining patient seizure frequency was unchanged. The best results were obtained with plasma LTG concentrations ranging from 0.5 to 5.4 micrograms/ml; no further improvement was observed at higher LTG concentrations.

Adolescent↗
PubMed1993

Progressive myoclonus epilepsies: an electroclinical, biochemical, morphological and molecular genetic study of 17 cases.

Electroclinical, morphological, biochemical and molecular genetic data from 17 patients affected by progressive myoclonus epilepsies (PME) are reported. Twelve patients were characterized by prominent action myoclonus, sporadic seizures, mild ataxia, lack of dementia and persistence of normal EEG background activity; three patients showed a more rapid worsening of symptomatology, characterized by early mental impairment, massive and action myoclonus, cerebellar signs and tonic clonic seizures; in these patients EEG background activity was slow, even in early stages of the disease. In two patients, previously classified as cryptogenetic PME, a mitochondrial aetiology was recognized by the presence of ragged red fibers in muscle biopsy and by a reduction of the respiratory chains enzymes. Molecular genetical investigation of mtDNA demonstrated the reported heteroplasmic point mutation at nt 8344 of mtDNA in the two MERRF patients, while it was negative in all of the others.

Adolescent↗
PubMed1992

Role of the thalamic reticular nucleus in the generation of rhythmic thalamo-cortical activities subserving spike and waves.

The role of the reticular thalamic nucleus (RTN) in pacing rhythmic cortical activities subserving spike-waves (SW) discharges has been investigated in rats. Intracellular recordings from thalamic slices in vitro demonstrated that RTN neurons from control animals possess a set of Ca2+/K+ membrane conductances which enable them to produce rhythmic oscillatory activities. In vivo, studies of Ca(2+)-conductance blockade by intrathalamic injections of Cd2+ were performed on 24 callosotomized Wistar rats displaying spontaneous SW discharges, bred at the Centre de Neurochimie, Strasbourg. A significant decrement in ipsilateral SW activity was consistently observed in all RTN-injected animals 40 min after Cd2+ injection. By contrast, animals which received Cd2+ injection into the ventroposterior complex (VP) showed only small changes in ipsilateral SW. It is concluded that Ca(2+)-dependent oscillatory properties of the RTN are critical for the expression of genetically determined SW discharges in the Wistar model.

Action Potentials↗