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Biomedical subjects

J M Senard

Publications and source records attributed to J M Senard.

At least 37 records · Page 2Linked to original sources
PubMed1999

Treatment of Parkinson's disease should begin with a dopamine agonist.

The occurrence of side effects with long-term levodopa therapy, such as fluctuations in motor performance or abnormal movements, led to a search for new antiparkinsonian drugs. Dopamine agonists include ergot derivatives such as bromocriptine, lisuride, pergolide, and cabergoline and other agents which do not possess the ergot structure such as pramipexole and ropinirole. They all are powerful stimulators of the D2 dopamine receptor which probably underlies their therapeutic effects. The clinical consequences of their binding to other dopamine receptor subtypes (D1 or D3) remains unknown. They are usually prescribed in combination with levodopa when late side effects begin to occur. This review summarizes the available pharmacologic and clinical data to support the early use of dopamine agonists in Parkinson's disease. Several strategies can be used, such as monotherapy or "early" or "late" combination with levodopa. Results of recent well-performed, modern clinical trials show that early use of the new dopamine agonists is able to effectively control the clinical symptoms for more than 3 years thereby offering the possibility of delaying the occurrence of levodopa-induced late motor side effects.

Benzothiazoles↗
PubMed1999

Increase in epinephrine-induced responsiveness during microgravity simulated by head-down bed rest in humans.

The epinephrine (Epi)-induced effects on the sympathetic nervous system (SNS) and metabolic functions were studied in men before and during a decrease in SNS activity achieved through simulated microgravity. Epi was infused at 3 graded rates (0.01, 0.02, and 0. 03 microg. kg(-1). min(-1) for 40 min each) before and on the fifth day of head-down bed rest (HDBR). The effects of Epi on the SNS (assessed by plasma norepinephrine levels and spectral analysis of systolic blood pressure and heart rate variability), on plasma levels of glycerol, nonesterified fatty acids (NEFA), glucose and insulin, and on energy expenditure were evaluated. HDBR decreased urinary norepinephrine excretion (28.1 +/- 4.2 vs. 51.5 +/- 9.1 microg/24 h) and spectral variability of systolic blood pressure in the midfrequency range (16.3 +/- 1.9 vs. 24.5 +/- 0.9 normalized units). Epi increased norepinephrine plasma levels (P < 0.01) and spectral variability of systolic blood pressure (P < 0.009) during, but not before, HDBR. No modification of Epi-induced changes in heart rate and systolic and diastolic blood pressures were observed during HDBR. Epi increased plasma glucose, insulin, and NEFA levels before and during HDBR. During HDBR, the Epi-induced increase in plasma glycerol and lactate levels was more pronounced than before HDBR (P < 0.005 and P < 0.001, respectively). Epi-induced energy expenditure was higher during HDBR (P < 0.02). Our data suggest that the increased effects of Epi during simulated microgravity could be related to both the increased SNS response to Epi infusion and/or to the beta-adrenergic receptor sensitization of end organs, particularly in adipose tissue and skeletal muscle.

Adrenergic alpha-Agonists↗
PubMed1999

Impaired atrial M(2)-cholinoceptor function in obesity-related hypertension.

The aim of this study was to investigate the activity of the parasympathetic limb of the baroreflex arch in a canine model of obesity-related hypertension. Twelve male beagle dogs were randomized into 2 groups. Six dogs were fed with normal canine food and 6 were submitted to a 10-week high-fat diet (HFD). We have evaluated the consequences of HFD on heart rate (HR) and blood pressure (BP) circadian cycles and methylscopolamine dose-response curves. Binding of [(3)H]-AF-DX 384 and adenylyl cyclase activity were investigated to determine the density and functionality of M(2)-cholinoceptors on right atrial membranes from control and HFD dogs. HFD induced a significant increase in body weight (15+/-1 vs 12+/-1 kg), systolic BP (161+/-5 vs 145+/-4 mm Hg), diastolic BP (92+/-3 vs 79+/-2 mm Hg), and HR (96+/-4 vs 81+/-3 bpm). Circadian rhythms of HR and BP observed in the baseline period were abolished after 9 weeks of HFD. After propranolol (1 mg/kg) pretreatment, the dose of methylscopolamine able to induce 50% maximum tachycardia was significantly increased after 9 weeks of HFD (7.4+/-0.3 vs 4.7+/-0.1 microg/kg). In the control group, the experimental period failed to modify these parameters. The numbers of M(2)-cholinoceptors measured in right atrial membranes were significantly lower in HFD than in control groups (54+/-6 vs 27+/-6 fmol/mg protein). The ability of carbachol to inhibit isoproterenol-stimulated adenylyl cyclase activity was significantly lower in HFD than in control groups (IC(50)=47+/-12 vs 6.4+/-1.4 micromol/L). However, the basal activity of adenylyl cyclase was unchanged by HFD. HFD decreases M(2)-cholinoceptor number and function in cardiomyocytes. This could explain the abolition of circadian rhythm of HR and the changes in chronotropic effect brought about by methylscopolamine.

Adenylyl Cyclases↗
PubMed1999

[Pharmacological vigilance and pharmacological epidemiology: principles, definition, methods and current trends in neurology].

It is now well established that only clinical trials performed before drug approval are not sufficient for a full modern pharmacological evaluation of drugs and treatments. The need of both pharmacovigilance and pharmacoepidemiology is underlined in order to evaluate drugs under real conditions. After a summary of methods used in pharmacoepidemiological trials (spontaneous reports, imputability assessment, cohorts, case control studies etc.), recent pharmacoepidemiological data useful for the neurologist are summarized: side effects of tacrine and vaccines, serotoninergic syndrome and side effects of new antiepileptic drugs.

Anticonvulsants↗
PubMed1999

[Reduction of the pressor effect of fluoxetine after V1A-vasopressin receptor blockade in the conscious rats].

Pharmacovigilance data have reported some cases of arterial hypertension in patients treated with serotonin reuptake inhibitors. This side effect is now called serotonin syndrome. Moreover, some authors have shown that these drugs could reduce, at least in part, the fall in blood pressure (BP) observed in experimental models or in human forms of orthostatic hypotension, suggesting a modulation of the autonomic nervous system by these drugs. These data led us to study in freely moving Wistar rats the mechanisms involved and the putative involvement of autonomic nervous system. Intracerebroventricular (i.c.v.) administration of fluoxetine (5-50 micrograms) induced an increase in BP similar to which was obtained following central administration of serotonin (5-HT) (0.5-5 micrograms). After 5-HT, the pressor effect was immediate (1 min following injection) and involved the baroreflex pathway (bradycardia). The fluoxetine-induced pressor response reached its maximal 1 hour after injection without any significant change in heart rate (HR). At the dose of 10 micrograms i.c.v., fluoxetine significantly increased mean BP by 16 +/- 4 mmHg. This pressor response was partially but significantly reduced by a pretreatment by the alpha 1-adrenoreceptor antagonist, prazosin (500 micrograms.kg-1 i.v.) (+7 +/- 4 mmHg, p < 0.05) or by a V1A-vasopressin receptor antagonist (20 micrograms.kg-1 i.v.) (+5 +/- 3 mmHg, p < 0.05). However, pretreatment by the beta-adrenoreceptor antagonist, propranolol (1 mg.kg-1 i.v.) and the antagonist 5-HT2, ketanserine (5 mg.kg-1 i.v.) did not modify the fluoxetine-induced pressor response. In freely moving rats receiving fluoxetine (10 micrograms i.c.v.), vasopressin plasma levels were significantly higher (+39 +/- 5 pg.mL-1) than in rats receiving saline (100 microL i.c.v.) (+14 +/- 4 pg.mL-1), thus confirming the involvement of vasopressinergic mechanisms in the fluoxetine-induced pressor response. These data suggest that in freely moving Wistar rats, central acute administration of fluoxetine induces a pressor response mediated by both an increase in sympathetic tone and a vasopressin release. This observation could suggest the putative use of alpha 1-adrenoreceptors antagonists and/or V1A-vasopressin receptor antagonists in the treatment of the serotonin syndrome.

Analysis of Variance↗
PubMed1998

Efaroxan, an alpha-2 antagonist, in the treatment of progressive supranuclear palsy.

We have tested, in a prospective randomized, double-blind, placebo-controlled, crossover, 12-week study, the effects of 2 mg efaroxan, a potent alpha-2 antagonist, given three times per day to 14 patients with progressive supranuclear palsy. Efaroxan did not induce any significant change on any motor assessment criteria. The present data do not confirm the assumption that the blockade of alpha-2 receptors might be a useful pharmacologic strategy to improve patients with progressive supranuclear palsy.

Adrenergic alpha-Antagonists↗
PubMed1998

Cortical motor overactivation in parkinsonian patients with L-dopa-induced peak-dose dyskinesia.

We have studied the regional cerebral blood flow (rCBF) changes induced by the execution of a finger-to-thumb opposition motor task in the supplementary and primary motor cortex of two groups of parkinsonian patients on L-dopa medication, the first one without L-dopa induced dyskinesia (n = 23) and the other with moderate peak-dose dyskinesia (n = 15), and of a group of 14 normal subjects. Single photon emission tomography with i.v. 133Xe was used to measure the rCBF changes. The dyskinetic parkinsonian patients exhibited a pattern of response which was markedly different from those of the normal subjects and non-dyskinetic parkinsonian patients, with a significant overactivation in the supplementary motor area and the ipsi- and contralateral primary motor areas. These results are compatible with the hypothesis that an hyperkinetic abnormal involuntary movement, like L-dopa-induced peak dose dyskinesia, is due to a disinhibition of the primary and associated motor cortex secondary to an excessive outflow of the pallidothalamocortical motor loop.

Aged↗
PubMed1998

Fluoxetine in orthostatic hypotension of Parkinson's disease: a clinical and experimental pilot study.

Recent clinical studies have reported a beneficial effect of fluoxetine, a serotonin reuptake inhibitor, in patients with severe refractory orthostatic hypotension. The present study was undertaken to investigate the effect of fluoxetine in orthostatic hypotension occurring during Parkinson's disease on both blood pressure values and number of clinical symptoms during orthostatic procedure evaluated using a validated clinical rating scale. In a pilot study performed in fourteen patients with idiopathic Parkinson's disease plus orthostatic hypotension, fluoxetine hydrochloride (20 mg orally daily during one month) significantly reduced the fall in systolic blood pressure [-33 +/- 21 (SD) mmHg before fluoxetine vs -22 +/- 19 mmHg after fluoxetine, P = 0.03] elicited by standing without modifying heart rate. The drug also significantly reduced the number of postural symptoms occurring during the orthostatic procedure [2.9 +/- 1.5 (SD) before fluoxetine vs 1.2 +/- 1.3 after fluoxetine, P = 0.006]. A similar pattern of response was obtained in an experimental model of neurogenic orthostatic hypotension obtained in chronically sino-aortic denervated dogs submitted to an 80 degrees head-up tilt test procedure under chloralose anaesthesia. Fluoxetine did not change plasma noradrenaline levels. This pilot study suggests a slight but clinically significant effect of fluoxetine on both hemodynamic parameters and clinical symptoms in parkinsonian patients suffering from orthostatic hypotension.

Aged↗
PubMed1998

Simulated microgravity increases beta-adrenergic lipolysis in human adipose tissue.

The effect of a sustained decrease in sympathetic nervous activity, achieved through 5-day head-down bed rest (HDBR), on the beta-adrenergic lipolytic activity of s.c. adipose tissue was studied in eight healthy men. The in situ beta-adrenoceptor (AR) sensitivity was studied using the microdialysis method. Local perfusion of increasing concentrations of isoprenaline showed an increased beta-AR sensitivity to lipolysis (assessed by extracellular glycerol concentration) and to vascular tone (assessed by the ethanol clearance). The adrenergic sensitivity of isolated adipocytes was studied in vitro. Basal lipolysis and the response to nonselective (isoprenaline) or selective (dobutamine, terbutaline, and CGP 12177) beta-AR agonists were increased after HDBR as was the lipolytic effect of dibutyryl cAMP. When data were expressed as a percentage of the dibutyryl cAMP effect to rule out the postreceptor events, basal and lipolytic responses to beta-AR agonists where similar before and during HDBR. The alpha 2-AR-mediated antilipolytic effects of adrenaline were not modified. Lymphocyte beta-AR number was unchanged during HDBR. Our results demonstrate that a sustained sympathoinhibition induces an increase in the lipolytic beta-adrenergic response in adipose tissue and suggest that this hypersensitization is linked to an increase in the postreceptor steps of the lipolytic cascade in the adipocyte rather than to changes in beta-adrenoceptors.

Adipocytes↗
PubMed1998

[Twenty-four hour time and frequency domain variability of systolic blood pressure and heart rate in an experimental model of arterial hypertension plus obesity].

Modifications of heart rate (HR) and systolic blood pressure (SBP) variabilities (V) have been reported in the human syndrome arterial hypertension plus insulin-resistance. The aim of this study was to characterize the 24 h SBPV and HRV in both time and frequency domains during weight increase in dogs fed ad libitum with a high fat diet. Implantable transmitter units for measurement of blood pressure and heart rate were surgically implanted in five beagle male dogs. BP and HR were continuously recorded using telemetric measurements during 24 hours, before and after 6 and 9 weeks of hypercaloric diet in quiet animals submitted to a 12h light-dark cycle. To study nychtemeral cycle of SBP and HR, two periods were chosen: day (from 6.00 h to 19.00 h) and night (from 23.00 h to 6.00 h). Spontaneous baroreflex efficiency was measured using the sequence method. Spectral variability of HR and SBP was analyzed using a fast Fourier transformation on 512 consecutive values and normalized units of low (LF: 50-150 mHz, reflecting sympathetic activity) and high (HF: respiratory rate +/- 50 mHz, reflecting parasympathetic activity) frequency bands were calculated. The energy of total spectrum (from 0.004 to 1 Hz) was also studied. Body weight (12.4 +/- 0.9 vs 14.9 +/- 0.9 kg, p < 0.05). SBP (132 +/- 1 vs 147 +/- 1 mmHg, p < 0.05) significantly increased after 9 weeks of hypercaloric diet. A nycthemeral HR rhythm was present at baseline (day: 79 +/- 1 vs night: 71 +/- 1 bpm) but not after 9 weeks (day: 91 +/- 4 bpm ; night: 86 +/- 2 bpm). Concomitantly, the efficiency of spontaneous baroreflex decreased at 6 weeks (36 +/- 1 vs 42 +/- 2 mmHg/ms, p < 0.05). A significant decrease in HF energy of HRV was found after 6 but not after 9 weeks. LF energy of SBPV was increased at 6 but not at 9 weeks (table). [table: see text] In conclusion, this study shows that an hyperlipidic and hypercaloric diet induces transient variations in autonomic nervous system activity which could be the physiopathological link between obesity, insulin-resistance and arterial hypertension.

Animals↗
PubMed1997

[Movement disorders of drug origin].

The involvement of a drug must be suspected in each patient suffering from a movement disorder. Besides classical neuroleptics used as antipsychotics (butyrophénones, phenothiazines or benzamides), many drugs, mainly "hidden" neuroleptics (prescribed as antinausea, antivomiting, antivertigo, antispasmodic or antihypertensive drugs) or agents prescribed in psychiatric (antidepressants, lithium) or neurological (levodopa in Parkinson's disease, antiepileptics) diseases are known to be able to reveal or produce a movement disorder. Other drug prescribed in internal medicine can also be involved. This review discusses the main characteristics of drug-induced movement disorders as well as their pharmacological approach.

Adverse Drug Reaction Reporting Systems↗
PubMed1997

A dose-ranging study of selegiline in patients with Parkinson's disease: effect of platelet monoamine oxidase activity.

A dose-ranging study of selegiline was performed in patients with Parkinson's disease to determine the minimal dosage of the drug able to inhibit > or = 95% of platelet monoamine oxidase (MAO) activity. Different doses of selegiline (5 or 10 mg daily, 10 or 20 mg weekly) were studied in four groups of six patients with Parkinson's disease. Platelet MAO activity was measured before and after 1 month's treatment with selegiline. The doses of 5 or 10 mg daily and 20 mg (i.e., 10 mg x 2) weekly induced a complete inhibition of platelet MAO-B activity from day 7 to day 28 (96.0-99.5%). In contrast, platelet MAO-B inhibition was only 75.9% of the basal value after a dosage of 10 mg weekly. These results demonstrate that 20 mg weekly is the minimal dosage of selegiline able to induce a maximal and long-lasting inhibition of platelet MAO-B activity in patients with parkinsonism. Further clinical trials are needed to investigate the clinical efficacy of this dose.

Adult↗
PubMed1997

Glutamate antagonists and Parkinson's disease: a review of clinical data.

Several lines of evidence demonstrate that glutamate antagonists can reverse experimental parkinsonism in animals. However, few clinical studies have been undertaken, principally because there is a shortage of glutamate antagonists which are considered safe for human use. This paper details the results of preliminary studies carried out on dextromethorphan, an anti-tussive agent and a weak open-channel blocker of the NMDA receptor; and the cerebral anti-ischaemic drug ifenprodil, a novel non-competitive inhibitor of the polyamine modulatory site on the NMDA receptor. Trials with these two compounds in small groups of parkinsonian volunteers have not demonstrated conclusive symptomatic improvement. These results do not exclude a possible role for NMDA receptor antagonists in the pharmacotherapy of Parkinson's disease, but rather point to the need for developing more potent and safe NMDA antagonists, with better pharmacodynamic and pharmacokinetic profiles.

Antiparkinson Agents↗
PubMed1997

Lack of haemodynamic effects of nitric oxide on post-capillary pulmonary hypertension induced by acute sino-aortic denervation.

1. The aims of the present experiments were to define a new experimental model of pulmonary hypertension induced by a post-capillary mechanism and to assess the haemodynamic effects of nitric oxide on post-capillary pulmonary hypertension. 2. Cardiopulmonary variables of 28 male beagle dogs, anaesthetized with chloralose, 16 spontaneous breathing and 12 with assisted ventilation, were studied before and after sino-aortic denervation (SAD). The haemodynamic effects of inhaled nitric oxide (25 p.p.m., 10 min). N(omega)-nitro-L-arginine methyl ester (20 mg kg-1, i.v.), urapidil (0.5 mg kg-1-, i.v.) and propranolol (300 micrograms kg-1, i.v.) were studied after SAD. 3. SAD induced an acute and transient pulmonary hypertension, more marked in spontaneous breathing dogs. This pulmonary hypertension involved a post-capillary mechanism, secondary to the left ventricular haemodynamic effects of the acute increase of left ventricular after-load induced by systemic hypertension. In fact, the increase of mean pulmonary arterial pressure after SAD and the decrease of this parameter after urapidil or propranolol were strongly correlated with the variations of pulmonary capillary wedge pressure. Furthermore, no significant change in pulmonary vascular resistance was found after SAD or administration of alpha or beta-adrenoceptor antagonists. 4. Inhaled nitric oxide did not reverse pulmonary hypertension induced by SAD. N(omega)-nitro-L-arginine methyl ester had no significant haemodynamic effect of pulmonary circulation. 5. In conclusion, the lack of effect of inhaled nitric oxide and nitric synthase inhibitor on pulmonary circulation parameters SAD suggest that endothelium-derived oxide is not involved in the mechanisms leading to post-capillary pulmonary hypertension.

Adrenergic beta-Antagonists↗
PubMed1997

The ipsilateral cerebellar hemisphere is overactive during hand movements in akinetic parkinsonian patients.

We compared the rCBF changes induced by the execution of a finger-to-thumb opposition motor task in the cerebellar hemispheres of 12 normal subjects, 12 parkinsonian patients whose medication had been withheld for at least 18 h and 16 parkinsonian patients on medication using single photon emission tomography and i.v. 133Xe. The normal subjects and parkinsonian patients on medication exhibited the same pattern of response, with a significant increase in rCBF in the contralateral primary motor cortex and in the supplementary motor areas. No significant rCBF change was detected in the cerebellum of these two groups; this finding was expected since our technique cannot detect cerebellar activation when the motor task is executed at a relatively low rate and small amplitude as it was in this study. The parkinsonian patients off medication exhibited a markedly different pattern of activation characterized by a significant overactivation in the ipsilateral cerebellar hemisphere and a significant underactivation in the supplementary motor areas. These results suggest that parkinsonian patients off medication may try to compensate for their basal ganglia-cortical loop's dysfunction using other motor pathways involving cerebellar relays.

Brain Mapping↗
PubMed1997

Effects of octreotide on experimental neurogenic orthostatic hypotension in anaesthetized dogs.

This paper investigates the effects of octreotide (0.1 mg/kg, subcutaneous) on cardiovascular adaptation during head-up tilt test in an experimental model of neurogenic orthostatic hypotension (OH) obtained by chronic sinoaortic denervation in anaesthetized dogs. Blood pressure (BP), heart rate (HR), spectral variability (Fast Fourier transformation on 512 consecutive points, delta t: 2 Hz) and plasma catecholamine levels were measured in a double blind cross-over randomized study versus placebo, in supine position and during a head-up tilt test (80 degrees, 10 min) in six sinoaortic denervated and six control (normal) dogs. In normal dogs, head-up tilt test significantly increased HR and diastolic blood pressure (DBP). Plasma noradrenaline levels and energy of the low frequency band (40-150 mHz) of systolic blood pressure (SBP) significantly increased whereas the energy of the low frequency band of HR significantly decreased. Placebo and octreotide failed to modify supine and head-up tilt values of the measured parameters (except the value of low frequency band of SBP, which increased after octreotide). In sinoaortic denervated dogs, supine values of BP, HR and plasma noradrenaline levels were significantly higher than in controls whereas the energy of the low frequency spectral band of HR and SBP was similar to controls. Head-up tilt test induced a dramatic decrease in BP. HR, plasma noradrenaline levels and energy of the low frequency band of SBP and HR remained unchanged during head-up tilt tests. Neither supine nor head-up tilt values of these parameters were modified 45 min after octreotide or placebo administration. These results show that sinoaortic denervation is a reproducible model of OH characterized by a lack of activation of sympathetic efferent pathways during head-up tilt tests. Octreotide at the dose used remains ineffective to prevent the fall in BP under these experimental conditions.

Anesthesia↗
PubMed1997

Effects of yohimbine, an alpha 2-adrenoceptor antagonist, on experimental neurogenic orthostatic hypotension.

Yohimbine has been proposed for the treatment of neurogenic orthostatic hypotension; however, no controlled trial has been performed in experimental models of orthostatic hypotension or in patients with autonomic failure. The aim of the present study was to compare the effects of yohimbine (0.05 mg/kg, intravenously [i.v.]) and placebo (saline) in a new model of neurogenic orthostatic hypotension obtained by sinoaortic denervation (SAD) in chloralose-anaesthetized dogs. Blood pressure, heart rate, noradrenaline plasma levels and systolic blood pressure and heart rate short-term variabilities (calculated on low frequency [40-50 MHz] and high frequency [390-490 MHz] bands) were measured in supine position and after a 10 min 80 degrees head-up tilting. The drugs were administered in a double-blind cross-over randomized fashion. The head-up tilting performed in normal animals increased diastolic blood pressure (+12 +/- 4 mmHg), heart rate (+39 +/- 12 beats per minute [bpm]), the low frequency band of systolic blood pressure and noradrenaline plasma level, without changing systolic blood pressure or heart rate variability. In SAD dogs, a marked fall in systolic (-80 +/- 11 mmHg) and diastolic (-43 +/- 4 mmHg) blood pressures was observed within 1 min after placebo, without modification in heart rate, systolic blood pressure and heart rate short-term variabilities and noradrenaline plasma levels. In SAD dogs, yohimbine (0.05 mg/kg, i.v.) delayed the blood pressure fall elicited by head-up tilting, but failed to modify its magnitude. These results show that, in the model of orthostatic hypotension obtained by SAD, yohimbine, at an alpha 2-adrenoceptor selective dose (0.05 mg/kg), delays the fall in blood pressure elicited by head-up tilting. The effect of yohimbine can be explained by an increase in sympathetic tone.

Adrenergic alpha-Antagonists↗