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Biomedical subjects

D Bentué-Ferrer

Publications and source records attributed to D Bentué-Ferrer.

At least 19 recordsLinked to original sources
PubMed2002

[Effect of almitrine/raubasine on cerebral metabolism in the elderly].

Recent neurobiological data has led to renewed interest in oxygen (O2). The discovery of neuroglobin, protein varyingly present in the brain, has been enhanced by the elucidation of the mechanisms through which oxygen intervenes in neuronal metabolism. Almitrine/raubasine activates the metabolism of hypoxic/ischemic neurones by increasing O2 bioavailability. This mechanism supports the effects on behaviour obtained in various animal models and the benefits observed during clinical trials in elderly patients presenting with cognitive defects.

Aged↗
PubMed2001

Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam.

Several recent studies have demonstrated that alprazolam and lorazepam, administered at low doses to healthy volunteers, improve cognitive functions and psychomotor performances. Paradoxical effects of low-dose benzodiazepines have been also observed in mice, in experimental pharmacology. The aim of this work was to determine, in rat, the effect of similar low-doses of benzodiazepines on spontaneous locomotor activity and performance in the elevated zero-maze, and to investigate the underlying neurobiological mechanisms. The dose-effect and the time-course of the action were studied for both compounds. Spontaneous locomotor activity was measured using a photoelectric actimeter. The level of anxiety of the animals was assessed in the elevated zero-maze. Dopamine, serotonin, and their metabolites were assayed in the extracellular striatal fluid of the awake rat, obtained by microdialysis, by HPLC--EC. Spontaneous locomotor activity observed in rats given low-dose alprazolam and lorazepam evidenced a stimulatory effect only with alprazolam. The effect was maximum 90 min after administration of 0.0050 mg/kg alprazolam. An anxiogenic-like action was evidenced with the elevated zero-maze for the two compounds. We observed a statistically significant increase in striatal dopamine concentrations only with alprazolam, during the period corresponding to the behavioral stimulatory effects. We also showed a marked trend towards increased levels of serotonin with alprazolam but this modification was not significant, in spite of statistically significant variations of 5-HIAA. In the rat, behavioral stimulatory effects of low-dose benzodiazepines is evidenced with alprazolam but not lorazepam. This effect could be explained, at least in part, by increased extracellular dopamine concentrations in the striatum. Their different structures could explain the different pattern observed for the two benzodiazepines.

Alprazolam↗
PubMed2001

Effect of training status on the sympathoadrenal activity during a supramaximal exercise in human.

BACKGROUND: The study investigated the concentrations of plasma catecholamine, adrenaline (A) and noradrenaline (NA), and the adrenal medulla responsiveness to the sympathetic nervous activity in sprinters (S), endurance runners (E) and untrained subjects (U) during a supramaximal exercise (the Wingate-test). METHODS: A group of 19 men took part in the tests: 6 S (20.5+/-0.7 years), 6 E (21.0+/-1.0 years) and 7 U (20.9+/-0.4 years). The maximal power (Wmax) and the mean power (W) were determined from the Wingate-test on a cycle ergometer. The plasma lactate, A and NA were analysed at rest (La0, A0 and NA0), immediately at the end of the exercise (Amax and NA(max)) and after 5 min recovery (La(max), A5 and NA5). The disappearance of A and NA was judged by the difference between the maximal values and those determined after 5 min recovery (Amax-A5 and NA(max)-NA5) and the ratio A/NA was considered as an index of the adrenal medulla responsiveness to the sympathetic nervous activity. RESULTS: During the Wingate-test S exhibited higher performances and higher La(max) than the two other groups. At the end of the Wingate-test the NA(max) values were similar in the three groups whereas the Amax values were significantly higher in S than in E and U (8.00+/-0.5 nmol x l(-1) in S vs 3.47+/-0.30 nmol x l(-1) and 3.29+/-1.14 nmol x l(-1) respectively in E and U). This leads to a higher Amax/NA(max) ratio for S compared to the other two groups (0.77+/-0.10 in S vs 0.23+/-0.03 and 0.28+/-0.05, respectively in E and U). As the disappearance of A (Amax-A5) was significantly higher in S (6.80+/-0.47 nmol x l(-1) in S vs 2.64+/-0.19 nmol x l(-1) and 1.64+/-1.37 nmol x l(-1), respectively in E and U), the higher values of Amax in S could be explained by an increase of the adrenal medullary secretory capacity in this group. CONCLUSIONS: It was concluded that essentially short term and intense exercises as sprint ones or interval-training may alter the adrenal medulla responsiveness to supramaximal exercise but not long duration exercises.

Adrenal Medulla↗
PubMed2000

Five-year follow-up of early lisuride and levodopa combination therapy versus levodopa monotherapy in de novo Parkinson's disease. The French Lisuride Study Group.

The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson's disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson's disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson's Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.

Adult↗
PubMed2000

[The physiopathology of migraine].

Although the neurobiological causative factors are now beginning to be understood, to a large extent the complex mechanisms involved in migraine remain an enigma, with the appearance of a transient unilateral cephalic pain, possibly preceded by a protean aura and associated with several other symptoms. The factors involved include three clinical signs or symptoms, i.e., pain, the aura (focalized neurological and neurosensory signs), and accompanying symptoms (e.g., sensory, psychological, or digestive); and three anatomical sites, i.e., the brain, the meningeal or intracranial vessel and a peripheral cranial nerve, the trigeminus (V). Familial hemiplegic migraine (FHM) has led to a consideration of the genetic origin of ionic channel-dependent pathologies (channelopathies), while certain other arguments which are for the most part indirect favor the hypothesis of abnormalities, again possibly of genetic origin, in the central neurotransmitters (including serotonin), which are involved in the transmission of pain messages and in vasomotor control. However, the main point is that each of the sites involved has its specific pharmacopoeia, which can contribute towards the treatment of migraine.

Humans↗
PubMed1999

[Beta interferon in multiple sclerosis: pharmacological differences].

Interferons beta (INF) would be a good recombinant therapeutic choice for the management of relapsing remitting multiple sclerosis (RRMS). Three forms are approved in various countries including one IFN beta-1b (Betaféron) and two IFN beta-1a (Avonex and Ribif). These agents are apparently similar although they are not identical. Differences may be of clinical relevance. Important differences are described here in terms of pharmacokinetics, the spectrum of side effects and molecular chemistry. The clinical consequences on the benefit/risk ratio are discussed. This review recalls the difficulty in developing such compounds and in reaching marketing approval. An improvement in the acceptability and efficiency of IFN beta could by obtained when analyzing basic research data.

Adjuvants, Immunologic↗
PubMed1998

5-HT-moduline, a 5-HT(1B/1D) receptor endogenous modulator, interacts with dopamine release measured in vivo by microdialysis.

5-Hydroxytryptamine-moduline (5-HT-moduline) is an endogenous tetrapeptide (Leu-Ser-Ala-Leu) recently isolated and characterized from mammalian brain. This compound interacts with 5-HT1B receptors as a non-competitive, high-affinity antagonist and has the properties of an allosteric modulator. 5-HT-moduline could play an important role in the regulation of serotonergic transmission and also, through heteroreceptors, dopaminergic transmission. The aim of this work was to examine the potential ability of 5-HT-moduline to modify the basal extracellular concentration of dopamine and its metabolites (3-methoxytyramine, dihydroxyphenylacetic acid and homovanillic acid), in the rat striatum and to determine its potential interaction with the stimulating activity of a specific 5-HT1B receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl) pyrrolo [3,2-b] pyrid-5-one (CP-93,129), on the release of dopamine. The technique is based on in vivo microdialysis using probes implanted in the striatum of the conscious rat. Results showed that the perfusion of 5-HT-moduline directly into this structure (1.25 mM) increased the striatal level of dopamine by two-fold (104% of the absolute basal release values, P = 0.0015) and that of 3-methoxytyramine by 3-fold (293%, P = 0.0001) without any change in the terminal metabolite concentrations. The intrastriatal administration of CP-93,129 induced a statistically significant, dose-dependent increase of dopamine levels (P < 0.0001). Coperfusion of 5-HT-moduline did not significantly alter the effect of CP-93,129 at 0.1 and 0.5 mM, but appeared to have an additive effect on the lowest dose (P = 0.0406). The results obtained show that 5-HT-moduline directly administered into the striatum increases the release of dopamine in this area. Presumably, this effect results from the desensitization of 5-HT1B receptors located on dopamine terminals. However, the fact that a 5-HT1B receptor agonist (CP-93,129) also increased the release of dopamine in the striatum and that 5-HT-moduline exhibited a slight additive effect with that of a low concentration of CP-93,129 suggests that the two substances interact with different mechanisms.

Animals↗
PubMed1998

Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia.

To characterise the role played by dopamine receptors in ischaemic brain damage, we have evaluated the effects of pergolide, bromocriptine and lisuride (dopamine D2 receptor agonists), haloperidol (a dopamine D2 receptor antagonist), 2,3,4,5-tetrahydro-7,8,dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393; a dopamine D1 receptor agonist) and (R)-(+)-8-chloro 2,3,4,5-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SCH 23390; a dopamine D1 receptor antagonist) in the gerbil model of global cerebral ischaemia. Ischaemia was induced by 5 min of bilateral carotid artery occlusion under halothane anaesthesia. Sham operated animals were used as controls. Pergolide (0.5 or 1.0 mg/kg i.p), bromocriptine (0.5 or 1.0 mg/kg i.p.), lisuride (0.5 or 1.0 mg/kg i.p.), SCH 23390 (0.1 or 1.0 mg/kg i.p.), haloperidol (0.5, 1.0 or 2 mg/kg i.p.) and SKF 38393 (1.0 or 2 mg/kg i.p.) were administered 1 h before occlusion. Five-minute-occluded animals had extensive damage in the CA1 region of the hippocampus 5 days after surgery. Pergolide 0.5 and 1.0 mg/kg i.p. provided significant (P < 0.05 and P < 0.01, respectively) neuroprotection against the ischaemia-induced hippocampal damage. Bromocriptine and lisuride also provided significant (P < 0.05) neuroprotection, but only at the higher 1.0 mg/kg dose. In contrast, the dopamine D2 receptor antagonist (haloperidol), the dopamine D1 receptor agonist (SKF 38393) and the dopamine D1 receptor antagonist (SCH 23390) failed to provide any neuroprotection in the model. These results support studies indicating that dopamine is important in ischaemic situations. The results also indicate that dopamine D2 receptor agonists are neuroprotective against ischaemia-induced brain injury and may play a role in neurodegenerative disorders.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

Adrenal medulla responsiveness to the sympathetic nervous activity in sprinters and untrained subjects during a supramaximal exercise.

The purpose of this study was to compare the adrenal medullar responsiveness to the sympathetic nervous activity between sprinters and untrained subjects after a supramaximal exercise (Wingate-test). Thirteen subjects took part in this study: 7 male athletes (20.3+/-1.8 years) competing in sprint running (S) and 6 untrained men (UT) (21+/-1.3 years). They performed an incremental treadmill test to determine the maximal oxygen uptake (VO2max), a force-velocity test and a Wingate-test on 3 different days, separated by a maximal interval of 15 days. The maximal power (Wmax) and the mean power (W) were determined from the Wingate-test on a cycle ergometer. Plasma lactate, adrenaline and noradrenaline concentrations were determined at rest (La0, A0, NA0), immediately after the Wingate-test (Amax, NAmax) and after 5 minutes recovery (Lamax, A5 and NA5). S exhibited higher performances than UT during the Wingate-test as shown by their significantly higher values of Wmax (1111+/-38 w in S vs 886+/-148 w in UT), W (822+/-37 w in S vs 646+/-69 w in UT) and Lamax (16.8+/1.8 mmol x l(-1) in S vs 12.2+/-2.5 mmol x l(-1) in UT). At the end of the test the NAmax values were similar in both groups whereas the Amax were significantly higher in S (7.6 +/- 1.4 nmol x l(-1) in S vs 3.6 +/- 3.2 nmol x l(-1) in UT). This leads to a higher Amax/NAmax ratio for sprinters compared to untrained subjects (0.7+/-0.2 in S vs 0.3+/-0.2 in UT, p < 0.05). As the disappearance of A (estimated by the Amax-A5 difference) was not lower in S (6.4+/1.5 nmol x l(-1) in S vs 1.8+/-4 nmol x l(-1) in UT), the higher Amax values in S might be explained by a greater secretion level of A. Conversely the identical NAmax values in both groups suggested that this kind of exercise induced the same sympathetic input in S and UT. Consequently the higher Amax/NAmax ratio in S argued in favor of a higher responsiveness of the adrenal medulla of sprinters to the same sympathetic input.

Adrenal Medulla↗
PubMed1998

Experimental and clinical methods in the development of anti-Alzheimer drugs.

Methodology used for the development of anti-Alzheimer's disease (AD) drugs raises specific problems which are rarely examined in the literature. While the general development scheme is similar to that required for most drugs, some specific aspects must be analyzed, highly dominated by the dual goal of pharmacology, i.e., to obtain both symptomatic and etiopathogenic drugs. During preclinical studies, aged or lesioned animals are mainly useful for symptomatic drugs, whereas transgenic models or neurodegeneration-induced techniques would probably lead to etiopathogenic drugs potentially slowing down the process of AD. The first administrations of a new compound to human beings raise the question of the activity measurement techniques. Psychometry remains the most informative procedure to detect and analyze the activity of the drugs on the different components of cognition. Electrophysiology and neuroimaging need some complementary studies before they can be proposed as surrogate criteria in phase III trials. At this stage of development, American and the recently published European guidelines are of great help while insisting on long-term (6 months) placebo controlled trials with the use of the triple efficacy criterion: an objective cognition scale, a global assessment, and the opinion of the caregiver. In the long term, pharmacoepidemiology and pharmacoeconomy will have to confirm the rationale of this recent progress in the methodology of anti-AD drug development.

Aging↗
PubMed1998

Clinical efficacy of almitrine-raubasine. An overview.

Different pharmacological properties of almitrine-raubasine show that this combination may be a good therapy for the treatment of age-related cerebral disorders and functional rehabilitation after stroke. Many clinical studies have been carried out in France and in the rest of Europe, confirming the value of this compound in such situations. Without discussing the complexity of clinical trials in both the areas of cognitive disorders and stroke, we shall present two studies demonstrating the beneficial effects of almitrine-raubasine against cognitive impairments. The first is a double-blind controlled study versus placebo with a 3-month follow-up period involving patients (aged between 60 and 85) with memory loss, lack of concentration, impaired mental altertness, and emotional instability. The second is a controlled multicenter study of 155 outpatients (age 70-85) presenting with cognitive decline (assessed by MMSE, SCAG). In both these studies, almitrine-raubasine significantly improved symptomatology and was superior to placebo, especially in the vascular cases. This confirms the validity of previous studies and justifies the indication of these compounds in the treatment of age-related cognitive disorders. Other studies also demonstrated the beneficial effect of this compound on neurosensory vascular disorders, with specific studies carried out on chorioretinal dysfunctions (visual symptomatology) and in vestibular disorders (vertigo associated with electronystagmographic modifications). The appropriate and usual dosage (2 tablets per day) and the good tolerance of the compound have been confirmed in a French multicentric study in 5,361 outpatients.

Aged↗
PubMed1997

Lisuride prevents learning and memory impairment and attenuates the increase in extracellular dopamine induced by transient global cerebral ischemia in rats.

In this experiment, we tested the efficacy of neuroprotection with lisuride, a dopamine agonist, using the 4-vessel occlusion rat model. Functional improvement was evaluated with two behavior tests exploring learning and memorization capacity in the rat, the Morris water maze and the 14-unit T-maze, 18 days after ischemia. Extracellular dopamine levels during ischemia were determined in search of a possible neuroprotection mechanism. Dopamine and its metabolites, DOPAC and HVA, as well as the serotonin metabolite, 5-HIAA, were assayed with HPLC-EC, in striatal extracellular fluid obtained by in vivo microdialysis in the awake rat. Lisuride was administered at a total dose of 10 ng by continuous intrastriatal infusion or at the dose of 0.5 mg/kg by i.p. infusion, 160 minutes before onset of ischemia for the neurochemical study and at the dose of 0.5 mg/kg via i.p. infusion, 1 hour before occlusion of the carotid arteries, for the behavior tests. Behavioral testing showed significantly better recovery in both sets of behavioral tests, with more pronounced positive results with the 14-unit T-maze, in comparison with the saline-treated animals. Microdialysis confirmed a significant attenuation of the ischemia-induced dopamine surge, whatever the mode of administration, compared with saline-treated animals. These results show that lisuride offers significant neuroprotection from the effect of experimental transient global forebrain cerebral ischemia in the rat; the mechanism would imply, at least in part, reduced levels of extracellular dopamine.

Animals↗
PubMed1997

[Parkinson disease: interrogations and solutions].

A NEURODEGENERATIVE DISEASE: Idiopathic Parkinson's disease is initially due to a selective and specific destruction of the pars compacta dopaminergic neurons in substantia nigra. Since the inaugural description in 1817 by J. Parkinson, therapeutic progress rapidly accelerated mainly due to a better knowledge of the neurobiology of the central nervous system dopaminergic pathways. THERAPEUTIC GOAL: The question today is not merely to give a short term pharmacological benefit but to maintain a long-term effect while avoiding motor complications such as fluctuations, dystonias and dyskinesias. This goal can be achieved while using low doses of levodopa, dopaminergic agonists and inhibitors of monoamine-oxydase-B. PERSPECTIVES: Some more improvements are expected through new avenues (inhibitors of catechol-O-methyl transferase, thalamic stimulation, fetal grafts). The main challenge is represented by compounds potentially antagonizing cell death. In any case, the therapeutic approaches have to be guided by good quality clinical trials.

Dopamine Agents↗
PubMed1997

Is chlormethiazole neuroprotective in experimental global cerebral ischemia? A microdialysis and behavioral study.

Chlormethiazole, an anticonvulsive agent, has been shown to have a possible neuroprotective effect against cerebral ischemia. In addition, chlormethiazole inhibits methamphetamine-induced release of dopamine, protecting against this neurotransmitter's neurotoxicity. The aim of this work was to ascertain whether, in experimental cerebral ischemia, chlormethiazole administration attenuated the ischemia-induced rise of the extracellular concentration of aminergic neurotransmitters and whether it reduces ischemia-induced deficits in memory and learning. Histology for assessment of ischemic damage was a so included. The four-vessel occlusion rat model was used to induce global cerebral ischemia. Aminergic neurotransmitters and their metabolites in the striatal extracellular fluid obtained by microdialysis were assayed by high-performance liquid chromatography-electrochemical detection. The drug was administered either IP (50 mg/kg-1) or directly through the dialysis probe (30 microM) 80 min before ischemia. For the behavioral test and histology, the drug was given IP (100 mg/kg-1) 1 h postischemia. The results obtained did not demonstrate any statistically significant evidence that chlormethiazole has an effect on the ischemia-induced rise in extracellular dopamine and serotonin levels. There was also no variation in metabolite levels. Behavioral measures (learning, recall) were not changed appreciably by the treatment. We observed no significant cell protection in the hippocampus (CA1, CA1), striatum, and entorhinal cortex in animals treated with chlormethiazole. We conclude that, under our experimental conditions, chlormethiazole has little or no effect on the neurochemical, neurobehavioral, and histological consequences of global cerebral ischemia.

Animals↗
PubMed1996

Effect of brain microdialysis on aminergic transmitter levels in repeated cerebral global transient ischemia in rat.

The effect of repeated transient global ischemia and microdialysis on changes in aminergic neurotransmitter release was investigated using the rat four-vessel occlusion model of global ischemia. To examine the possible transient or permanent changes in neurotransmitter release, ischemia was induced at varying time points in 5 groups of rats. The first ischemia occurred either 24 h (groups I, II, IV, V) or 96 h (group III) following vertebral artery electro-coagulation and guide probe implantation(s), and the second ischemia was induced either 48 h (groups I, IV, V) or 72 h (group II) following the first ischemia. To assess the consequence of repeated microdialysis on the results, one group of rats (group IV) was not dialysed during the first ischemia and another group (group V) was bilaterally dialysed during the second ischemia. Finally, amphetamine-induced neurotransmitter release was also studied in rats submitted to ischemia and compared with that in normal rats. In each case, dopamine, serotonin and their main metabolites were measured by HPLC with electrochemical detection. Monoamine release was inhibited during the second episode of transient ischemia; this non-release was linked to the repeated microdialysis and not to the repeated ischemia. Although the results of chronic studies using brain microdialysis have been widely recognized as valid, the findings presented here indicate that combined with ischemia, probe reinsertion modifies the level of neurotransmitter release.

Amphetamines↗
PubMed1994

Monoamine oxidase inhibitors, cognitive functions and neurodegenerative diseases.

Recent data obtained in animals and in humans suggest that both MAO-A and MAO-B inhibitors present cognitive enhancing properties of possible interest in the treatment of cognitive disorders. In addition, the rational for using selegiline as a neuroprotector in Parkinson's disease may also be applicable in Alzheimer's disease in which a dramatic increase in the MAO-B activity has been reported. It seems then worthwhile to investigate the neuroprotective effect of MAOIs in humans and to assess, furthermore, the real therapeutical benefit of their cognitive enhancing properties.

Alzheimer Disease↗
PubMed1994

Temporal profile of aminergic neurotransmitter release in striatal dialysates in rats with post-ischemic seizures.

The temporal profiles of aminergic neurotransmitter levels and of their acid metabolites after transient global cerebral ischemia in awake rats with and without subsequent seizures were compared using a microdialysis approach. In seizure animals, the post-ischemic levels of dopamine and serotonin were higher than the levels observed in the non-seizure controls. Inversely, the levels of the three neurotransmitter metabolites increased rapidly in the controls but not in seizure animals, where they remained at the low levels observed during and immediately after ischemia. This particular pattern is similar to that observed in rats submitted to prolonged ischemia or pretreated with monoamine oxidase inhibitors. In the seizure animals, neurotransmitter metabolites remained at low levels, as if the hypoxia had continued after the period of ischemia, inhibiting monoamine oxidase activity and, perhaps, neurotransmitter recapture.

3,4-Dihydroxyphenylacetic Acid↗