Does fluoxetine aggravate Parkinson's disease? A pilot prospective study.
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Aged↗
Biomedical subjects
J M Senard
Publications and source records attributed to J M Senard.
Sublingual apomorphine: a new pharmacological approach in Parkinson's disease?
Apomorphine, a potent dopamine agonist with mixed D1 and D2 properties, has long been recognized to have antiparkinsonian effect. Its oral administration is limited by both its hepatic first pass metabolism and adverse side effects (nausea, vomiting, azotemia). It is now widely used by subcutaneous route for the treatment of severe "off" periods seen with levodopa treatment. However, the use of penjects can be difficult in some patients with severe tremor or akineto-rigid symptoms during "off" periods. Our group has recently investigated the effect of sublingual administration of apomorphine in patients suffering from Parkinson's disease. Sublingual apomorphine was shown to reduce extrapyramidal symptoms. The main characteristics of the pharmacodynamic effects of sublingual apomorphine in parkinsonians and the relationship between pharmacodynamic and pharmacokinetic effects are discussed. Sublingual apomorphine has the advantage of being easier to administer than subcutaneous injection. For the moment, the long-term use of sublingual apomorphine is limited by two major problems: first, time for dissolution and switch "on" (which is longer than after subcutaneous route) and secondly, the occurrence of local side effects (stomatitis). Further clinical studies using either more efficient (tablets with faster dissolution) and better tolerated sublingual formulations or other dopamine agonists should be carried on before recommending this approach in the treatment of Parkinson's disease.
Administration, Sublingual↗
N-methyl-D-aspartate (NMDA) antagonist and Parkinson's disease: a pilot study with dextromethorphan.
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Aged↗
Naltrexone, an opiate antagonist, fails to modify motor symptoms in patients with Parkinson's disease.
One month of adjunct treatment with naltrexone (100 mg/day) was compared with placebo in a double-blind, randomized, cross-over design in two groups of patients with Parkinson's disease. The first group was composed of 10 patients with a moderate motor impairment insufficiently controlled by monotherapy with bromocriptine. The second group was composed of eight patients with L-dopa-induced peak-dose dyskinesia. Naltrexone as compared with placebo did not demonstrate any significant change in motor function in either group. These negative clinical results do not support a significant role of endogenous opioid systems in the pathophysiology of motor impairment in Parkinson's disease.
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Naloxone does not prevent apomorphine-induced emesis or hypotension in dogs.
Previous data have shown that apomorphine-induced respiratory depression can be reversed by the opiate antagonist, naloxone. The present study investigates the influence of naloxone on cardiovascular changes and vomiting elicited by apomorphine in dogs. In chloralose-anaesthetized animals, naloxone (0.02 mg/kg i.v.) failed to modify either the decrease in blood pressure and the biphasic changes (bradycardia followed by a long-lasting tachycardia in heart rate or the characteristics (occurrence, latency, duration) of the emesis elicited by apomorphine (200 micrograms/kg i.v.). In contrast, in conscious animals, naloxone (0.02 mg/kg i.v.) increased both the number and the duration (but not latency) of vomiting induced by a lower dose of apomorphine (30 micrograms/kg i.v.). These data show that apomorphine-induced vomiting and arterial hypotension do not involve opiate receptors.
Anesthetics↗
Drug-induced parkinsonism: a review.
The main clinical features, pathophysiology and underlying mechanisms of drug-induced parkinsonism are reviewed. The clinical manifestations of drug-induced parkinsonism are often indistinguishable from idiopathic Parkinson's disease. However, some subtle differences may exist: for example drug-induced parkinsonism is often associated with tardive dyskinesias, bilateral symptoms and the absence of resting tremor, etc. Besides toxins (eg manganese, carbon monoxide or MPTP), many drugs are known to produce parkinsonism: dopamine blocking drugs (true neuroleptics used as antipsychotics: phenothiazines, butyrophenones, thioxanthenes but also sulpiride, "hidden" neuroleptics prescribed as anti-nausea or anti-vomiting drugs (such as metoclopramide and other benzamide derivatives), dopamine depleting drugs (reserpine, tetrabenazine), alpha-methyldopa, calcium channel blockers (flunarizine, cinnarizine, etc). The putative role of other drugs (eg fluoxetine, lithium, amiodarone) as well as the therapeutic management of this side effect are reviewed.
Humans↗
Normal activation of the supplementary motor area in patients with Parkinson's disease undergoing long-term treatment with levodopa.
Regional cerebral blood flow (rCBF) changes in cortical motor areas were measured during a movement of the dominant right hand in 15 patients with Parkinson's disease deprived of their usual levodopa treatment, in 11 patients with Parkinson's disease undergoing long-term treatment with levodopa, and in 15 normal volunteers. The supplementary motor areas were significantly activated in the normal subjects and in the patients receiving levodopa but not in the patients deprived of levodopa. The contralateral primary sensory motor area was significantly activated in all three groups. The ipsilateral primary sensory motor cortex was not activated in the normal subjects and the non-treated patients but was in the patients treated with levodopa. It is concluded that the supplementary motor area hypoactivation which is observed in akinetic non-treated patients with Parkinson's disease is not present in patients undergoing long-term treatment with levodopa. This result suggests that (a) levodopa improves the functional activity of supplementary motor areas in Parkinson's disease and (b) there is no pharmacological tolerance to this effect. The ipsilateral primary motor cortex activation observed in the patients treated with levodopa could be related to levodopa-induced abnormal involuntary movements.
Adult↗
A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson's disease: a five year follow up.
This pilot study was performed to compare the occurrence of long term motor complications in Parkinson's disease when the introduction of levodopa was delayed by an initial treatment with high doses of bromocriptine alone. The trial was a prospective randomised controlled study comparing 31 previously untreated patients with Parkinson's disease initially given bromocriptine alone to which levodopa was later added (group B/D) and 29 other previously untreated patients with Parkinson's disease immediately given levodopa alone (group D). The end point was the occurrence of the first motor complications (wearing off or dyskinesia). Group B/D patients received bromocriptine (52 (SEM 5) mg/day) for 2.7 years, to which levodopa was later added (471 (SEM 46) mg/day). Group D patients received a comparable dose of levodopa alone (569 (SEM 47) mg/day). Both had similar disability scores at the end of the study. Motor complications were fewer and appeared later in group B/D than in group D (56% after 4.9 (SEM 0.5) years of treatment v 90% after 2.7 (SEM 0.5) years, p < 0.01). Wearing off appeared later (p < 0.01) in group B/D (4.5 (SEM 0.6) years) than in group D (2.9 (SEM 0.6) years). Peak dose dyskinesia occurred less often in group B/D patients (three v 14 cases, p < 0.01). This study showed that a three year initial monotherapy with high doses of bromocriptine followed by addition of levodopa delayed the occurrence of long term motor complications usually found in patients with Parkinson's disease treated with levodopa alone from the beginning.
Bromocriptine↗
Relationship between arterial blood pressure disturbances and alpha adrenoceptor density.
To investigate the influence of blood pressure disturbances on human platelet alpha 2-adrenoceptor density, we studied 7 normotensive Parkinsonians with orthostatic hypotension and 23 mild essential hypertensive patients. Plasma catecholamine levels were measured by HPLC and alpha 2-adrenoceptor number and affinity determined by [3H]-yohimbine binding. Alpha-adrenergic reactivity was investigated by blood pressure response to noradrenaline infusion in Parkinsonians and by adrenaline-induced platelet aggregation in hypertensive patients. In Parkinsonians with orthostatic hypotension, in comparison with Parkinsonians without orthostatic hypotension and normotensive control subjects age and sex matched, noradrenaline plasma levels were significantly lower (62 +/- 11, 195 +/- 14 and 219 +/- 13 pg. ml-1 respectively, p < 0.05), platelet alpha 2-adrenoceptor number was significantly higher (313 +/- 52, 168 +/- 9 and 174 +/- 4 fmol.mg-1 protein respectively, p < 0.05) and the noradrenaline dose required for a 25 mm Hg increase of systolic blood pressure significantly lower (0.19 +/- 0.03, 0.86 +/- 0.11 and 0.68 +/- 0.10 microgram.Kg-1 respectively, p < 0.05). In hypertensive patients, in comparison with normotensive control subjects age and sex matched, plasma noradrenaline levels remained unchanged (306 +/- 68 vs 246 +/- 28 pg.ml-1) whereas both platelet alpha 2-adrenoceptor number (137 +/- 15 vs 177 +/- 15 fmol.mg-1 protein, p < 0.05) and velocity of adrenaline-induced platelet aggregation were significantly decreased. These results indicate that platelet alpha 2-adrenoceptor density is related to blood pressure values. In Parkinsonians with orthostatic hypotension, the up-regulation of alpha 2-adrenoceptors was induced by the decrease of endogenous catecholamines. In contrast, in essential hypertension a down-regulation of alpha 2-adrenoceptors was observed in spite of no significant increase of catecholamine levels. These results suggest that only sustained abnormal plasma noradrenaline levels could allow the development of alpha 2-adrenoceptor regulatory mechanisms.
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[Drug-induced parkinsonian syndromes: a 10-year experience at a regional center of pharmaco-vigilance].
Besides classical neuroleptics, several drugs can induce parkinsonian symptoms. The present retrospective study investigates the characteristics of drug-induced parkinsonism notified to the Midi-Pyrénées Pharmacovigilance Centre between 1983 and 1992. Among 3,923 side effects spontaneously reported between 1983 and 1992 to the center, 53 (1.4%) were drug-induced parkinsonism. Mean age was 65 +/- 2 (s.e.m.) years (range 21-88). Drug-induced parkinsonism appeared after a mean treatment duration of 473 +/- 142 days (range 1 day to 15 years) and occurred most frequently in women (63%). The occurrence onset of drug-induced Parkinsonism exhibited a bimodal pattern with a first peak (between 0 and 6 months) mainly due to peripheral or central antidopaminergic drugs and a second one later (between 9 and 12 months) due mostly to calcium channel blockers. Involved drugs were mostly antidopaminergic agents: neuroleptics (antipsychotic drugs: 39%) but also agents used for nausea or vomiting (domperidone, metoclopramide, metopimazine or triethylperazine: 12%) or symptoms associated with menopause (veralipride: 6%). Other cases were related mainly to drugs with "calcium channel blocker" properties (flunarizine and cinnarizine: 30%), H1 antihistamine (1 case), fluoxetine (1 case), alphamethyldopa (1 case) or reserpine (1 case) whereas 3 cases were due to drug interactions. Imputability scores (according to the method of assessment of unexpected drug reactions used in France) were "doubtful" (11%), "plausible" (34%) and "probable" (53%). The complete triad (tremor, akinesia plus rigidity) was seen in 13 (25%) cases. Symmetrical symptoms occurred in 41 (77%) patients. A total disappearance of the clinical feature occurred in 39 (74%) patients whereas in 8 cases (15%), drug-induced parkinsonism led to the diagnosis of underlying idiopathic Parkinson's disease. The present study shows that around 80% of drug-induced parkinsonism are due to two pharmacological classes: central and peripheral antidopaminergic agents and calcium channel blockers.
Adult↗
[Changes in myocardial beta adrenergic receptors in left ventricular hypertrophy caused by barometric and volumetric overloads].
While most prior studies examined late stages of heart failure, we determined initial changes of beta-adrenergic receptors (beta-AR) during left ventricular chronic volume and pressure overload. We investigated right auricular (RA) and left ventricular (LV) beta-AR density (Bmax, fmoles/mg protein) and beta 1-AR percentage in two groups of patients undergoing valve replacement without LV systolic dysfunction (LV ejection fraction > or = 60%), with normal plasma catecholamine levels and echocardiography LV hypertrophy. These results were compared with the values of a control group, composed by 8 patients with mitral stenosis and 5 cardiac transplant donors, and the values of 5 patients undergoing heart transplantation because of end-stage idiopathic dilated cardiomyopathy. These results show that, before alteration of LV systolic function occurs, left ventricular chronic overload induces a selective down-regulation of LV beta 1-AR compensated by an increase in beta 2-AR. These variations may be due to LV hypertrophy induced by volume or pressure overload.
Catecholamines↗
[Ambulatory measurement of blood pressure and plasma catecholamines in the study of orthostatic hypotension].
The purpose of the study was to investigate the interest of ambulatory blood pressure (BP) monitoring (ABPM) and plasma catecholamines in the management of orthostatic hypotension (OH). Fifteen patients, 4 men, 11 females, 53.3 +/- 21.1 years old, with OH were included in the study: 7 with dysautonomia (G1) = multiple systemic atrophy, pure autonomic failure, OH in elderly people; 8 with OH from other origin (G2) = hypovolemia, neurodystonia, vaso-vagal syncope. ABPM and plasma catecholamines assays (HPLC) in lying then in standing position were carried out in all patients. BP was 131.2 +/- 31.9/78.1 +/- 12.0 mmHg in lying and 112.1 +/- 25.3/75.4 +/- 15.8 in standing position (n = 15). The systolic (S) standing-induced (delta) decrease in BP after 1 min and 10 min (delta SBP) correlated with standard-deviation and variation coefficient of mean SBP (r = 0.78, p < 0.01; r = 0.82, p < 0.01 for delta sBP 1 min and r = 0.80, p < 0.01; r = 0.81, p < 0.01 for delta sBP 10 min), but not with norepinephrine (NorE) or epinephrine levels. There was a significant correlation between diastolic nycthemeral BP variability expressed by mean night-time DBP/mean day-time DBP ratio/diastolic N/D) and standing-induced decrease in DBP after 1 min (r = 0.59, p < 0.05). delta SBP 1 min and 10 min, delta DBP 1 min (p = 0.02, p = 0.05, p = 0.01) and systolic and diastolic N/D (p = 0.02; p < 0.01) were significantly different in G1 and G2.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Lacrimation in Parkinson's disease.
The present study compares lacrimal secretion in control subjects and patients with Parkinson's disease with use of Schirmer's test. Tear secretion was decreased in Parkinson's disease. The reduction was more marked in stages III-IV than in stages I-II. The results are discussed in relationship with autonomic dysfunction in Parkinson's disease.
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Pseudophaeochromocytoma in parkinsonian patient treated with fluoxetine plus selegiline.
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Adrenal Gland Neoplasms↗
The effect of yohimbine on sympathetic responsiveness in essential hypertension.
We have studied the sympathetic response to blockade of presynaptic alpha 2-adrenoceptors in essential hypertension by measuring plasma concentrations of noradrenaline after a single oral dose of yohimbine, an alpha 2-adrenoceptor antagonist. Mean baseline plasma noradrenaline and adrenaline concentrations were similar in the hypertensive and normotensive groups. Yohimbine (0.2 mg x kg-1 orally) caused a lesser increase in the plasma concentrations of noradrenaline in hypertensive patients (+67%) than in normotensive subjects (+178%) and a pressor response in hypertensive (but not in normotensive) patients. These results are consistent with an alteration in the balance of alpha-adrenoceptors (for example presynaptic alpha 2-adrenoceptor desensitization and post-synaptic alpha 1-adrenoceptor hyper-responsiveness) which would help to develop and/or maintain arterial hypertension.
Adult↗
Adrenoceptor regulation in orthostatic hypotension during autonomic failure.
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Aged↗
Effects of yohimbine on plasma catecholamine levels in orthostatic hypotension related to Parkinson disease or multiple system atrophy.
Different pathophysiological mechanisms may underly orthostatic hypotension (OH) observed in neurological degenerative disorders. The present study investigates the responses to the pharmacological activation of sympathetic pathways induced by yohimbine (0.2 mg/kg orally) through measurements of plasma catecholamine levels in parkinsonian patients with (n = 9) or without OH (n = 11), in patients with multiple system atrophy (MSA) plus OH (n = 9), and in controls (n = 6). Basal norepinephrine plasma levels in parkinsonian patients with OH (71 +/- 11 pg/ml) were significantly lower (p < 0.05) than in parkinsonian patients without OH (280 +/- 25 pg/ml) or in controls (259 +/- 48 pg/ml). In patients with MSA plus OH, basal catecholamine plasma levels were in the normal range (344 +/- 54 pg/ml). Yohimbine significantly increased norepinephrine (p < 0.05) but not epinephrine plasma levels in all groups. However, the increment obtained in parkinsonian patients with OH (+53 +/- 18 pg/ml) remained significantly lower (p < 0.05) than in parkinsonian patients without OH or in controls (+638 +/- 140 and +457 +/- 103 pg/ml, respectively) as well as in MSA plus OH (+633 +/- 142 pg/ml). Yohimbine failed to modify the blood pressure and heart rate at the dose used. The results suggest that the yohimbine test is useful to elucidate the site of the dysfunction of the efferent sympathetic pathways in these two conditions. In Parkinson disease with OH, the lesion is both central and postganglionnic, whereas in MSA it is only centrally located.
Aged↗
Effects of physiological and pharmacological variation of sympathetic nervous system activity on plasma non-esterified fatty acid concentrations in man.
1. The consequence of the sympatholytic effect of clonidine (alpha 2-adrenoceptor agonist) was compared with the effect of a physiological inhibition of sympathetic nervous system activity (change from upright to supine position) on plasma catecholamine and non-esterified fatty acid (NEFA) concentrations in overnight fasting healthy men. 2. Clonidine (150 micrograms orally) administered in upright position induced a significant reduction of plasma noradrenaline and NEFA concentrations. A change from upright to supine position which provoked a more marked decrease in plasma noradrenaline concentrations induced a weak increase in plasma NEFA concentrations. 3. The modification of plasma NEFA and catecholamine concentrations brought about by standing up was studied after placebo or yohimbine (alpha 2-adrenoceptor antagonist) administration. With placebo, standing up promotes a 100% increase in plasma noradrenaline concentrations (measured 5 and 15 min after rising) and a weak transient decrease in plasma NEFA concentrations (5 min after rising). In the supine position, yohimbine increased plasma noradrenaline and NEFA concentrations by about 100% and 55% respectively. Standing after yohimbine administration promoted large increases in plasma noradrenaline and NEFA concentrations. 4. These results indicate that a reduction of sympathetic nervous activity is not associated with a decrease of plasma NEFA concentrations and argue for a role of alpha 2-adrenoceptors in the NEFA mobilization from adipose tissue after sympathetic nervous system activation in man.
Adult↗