[Arguments in favor of early treatment of Parkinson's disease with dopaminergic agonists].
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Antiparkinson Agents↗
Biomedical subjects
O Rascol
Publications and source records attributed to O Rascol.
Clinical pharmacology of levodopa-induced dyskinesia in parkinsonian patients.
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Antiparkinson Agents↗
L-dopa-induced peak-dose dyskinesias in patients with Parkinson's disease: a clinical pharmacologic approach.
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Antiparkinson Agents↗
Pressor and bradycardic effects of tacrine and other acetylcholinesterase inhibitors in the rat.
The cardiovascular effects of three different acetylcholinesterase inhibitors: physostigmine, tacrine and rivastigmine injected by intravenous (i.v.) route were compared in freely moving Wistar rats. The three drugs significantly increased both systolic and diastolic blood pressure and decreased heart rate. Compared to physostigmine, a 20-fold higher dose of tacrine and a 40-fold higher dose of rivastigmine was necessary to induce a comparable pressor effect. Tacrine was chosen as a model to study the mechanisms underlying the cardiovascular effects of i.v. cholinesterase inhibitors. Atropine totally abolished while methylatropine did not affect tacrine pressor effects. Conversely, both drugs abolished tacrine-induced bradycardia. The alpha1-adrenoceptor antagonist prazosin or the vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2, Arg8] vasopressin partially but significantly reduced tacrine pressor effect and mostly abolished it when administered concomitantly. The tacrine pressor response was inhibited in a dose-dependent manner by the i.c.v. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 1.45 microg), the muscarinic M1 receptor antagonist pirenzepine (ID50 = 4.33 microg), the muscarinic M2 receptor antagonist methoctramine (ID50 = 1.39 microg) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50 = 31.19 microg). Central injection of such muscarinic receptor antagonists did not affect tacrine-induced bradycardia. Our results show that acetylcholinesterase inhibitors induce significant cardiovascular effects with a pressor response mediated mainly by the stimulation of central muscarinic M2 receptors inducing a secondary increase in sympathetic outflow and vasopressin release. Conversely, acetylcholinesterase inhibitor-induced bradycardia appears to be mediated by peripheral muscarinic mechanisms.
Adrenergic Antagonists↗
Central cardiovascular effects of tacrine in the conscious dog: a role for catecholamines and vasopressin release.
Centrally acting cholinergic agents are currently reported to increase blood pressure in various species through the stimulation of muscarinic cholinoceptors. Moreover, several cardiovascular adverse effects have been reported from clinical studies. The aim of this study was to investigate the effects of tacrine, an acetylcholinesterase inhibitor which has been reported to have therapeutic potential in Alzheimer's disease, on blood pressure and two vasopressor systems (sympathetic and vasopressinergic) in Beagle dogs. Intravenous (i.v.) tacrine (2 mg kg(-1)) induced, in conscious and anesthetized dogs, an increase in systolic and diastolic blood pressure, accompanied by bradycardia. This increase was dose-dependent with a peak effect at 1.5 min following administration. Tacrine also induced an increase in noradrenaline, adrenaline and vasopressin plasma levels. Pretreatment with the muscarinic receptor antagonist, atropine (2 mg kg(-1), i.v.), abolished the pressor response to i.v. injection of tacrine while pretreatment with the peripheral muscarinic receptor antagonist, methylscopolamine (0.2 mg kg(-1), i.v.), did not alter the increase in blood pressure. Similarly, noradrenaline and adrenaline changes in plasma levels were not modified by methylscopolamine but were abolished by atropine pretreatment. A similar tendency although not significant was observed for vasopressin plasma levels. The present results demonstrate that in dogs, tacrine (2 mg kg(-1), i.v.) stimulates central muscarinic cholinoceptors to increase blood pressure through activation of the two components of the sympathetic nervous system (i.e., neuroneuronal noradrenergic and the neurohormonal adrenergic pathways) as well as through increasing noradrenaline, adrenaline and vasopressin plasma levels.
Animals↗
Ropinirole in the treatment of early Parkinson's disease: a 6-month interim report of a 5-year levodopa-controlled study. 056 Study Group.
The efficacies of ropinirole and levodopa were compared after 6 months of treatment in a planned interim analysis of a 5-year, double-blind, randomized, multicenter study of patients with early Parkinson's disease requiring dopaminergic therapy. The percentage of improvement in the Unified Parkinson's Disease Rating Scale total motor examination score was significantly higher for levodopa (44%) than for ropinirole (32%). The proportion of "responders" (Unified Parkinson's Disease Rating Scale improvement of at least 30%) did not differ between groups (levodopa, 58%; ropinirole, 48%). There was no difference between the groups for improvement on the Clinical Global Impression scale in patients with Hoehn and Yahr stages I, I.5, or II, but a significantly higher proportion of patients with Hoehn and Yahr stages II.5 or III showed Clinical Global Impression score improvement with levodopa. Emergent adverse events occurred in 84% of patients in both treatment groups, the principal symptom in each group being nausea. The incidence of serious adverse events was low (8% for ropinirole, 9% for levodopa). The results suggest that ropinirole and levodopa are equally effective in less severe Parkinson's disease; in more advanced Parkinson's disease, levodopa is superior.
Adult↗
Ropinirole versus bromocriptine in the treatment of early Parkinson's disease: a 6-month interim report of a 3-year study. 053 Study Group.
We compared the efficacy and safety of ropinirole with that of bromocriptine after 6 months of treatment in a planned interim analysis of a 3-year, double-blind, randomized, multicenter study of 335 patients with early Parkinson's disease requiring dopaminergic therapy. Patients, treated with or without selegiline, received either ropinirole or bromocriptine. The mean Unified Parkinson's Disease Rating Scale (UPDRS) total motor examination scores (Part III) at baseline were similar in the four strata. Overall, and in the non-selegiline subgroup, the percentage improvement in the UPDRS total motor examination score was significantly higher for ropinirole than for bromocriptine, as was the proportion of "responders." In the selegiline subgroup, however, there was no significant difference between treatments. Similarly, in the non-selegiline subgroup, there was a significantly higher proportion of "improvers" on the Clinical Global Impression scale with ropinirole than with bromocriptine, whereas in the selegiline subgroup, there was no significant difference. Emergent adverse events occurred in 80% of patients in both treatment groups, the principal symptom in each group being nausea. The incidence of serious adverse events was low (3% for ropinirole, 6.6% for bromocriptine). The data indicate that (a) in the absence of selegiline, ropinirole is effective and superior to bromocriptine; and (b) selegiline does not affect the response in patients treated with ropinirole, but enhances the effects of bromocriptine.
Adult↗
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↗
Normal frontal perfusion in patients with frozen gait.
We have studied the frontal perfusion in the resting condition of two groups of patients with frozen gait: 10 patients with the syndrome of "isolated gait ignition failure" (IGIF) and 8 patients with idiopathic Parkinson's disease (PD) and severe "off" freezing. These patients were compared with two other groups: one including 20 age-matched volunteers as normal control subjects and the other one including 12 patients with progressive supranuclear palsy (PSP) as a positive control with expected frontal hypoperfusion. Frontal perfusion was assessed using single photon emission computed tomography (SPECT) regional cerebral blood flow measurement with intravenous 133Xenon. A significant frontal hypoperfusion was only present in the PSP group but not in the three others. These results do not support the hypothesis that start hesitations and freezing when walking are related to a frontal lobe dysfunction. However, it is possible that frontal neuronal dysfunction occurs without measurable cerebral blood flow changes in the resting condition.
Aged↗
Effect of food on the pharmacokinetics of ropinirole in parkinsonian patients.
AIMS: Ropinirole is a specific non-ergoline dopamine D2-receptor agonist with antiparkinsonian properties. The pharmacokinetic parameters of ropinirole taken in the fasted condition were compared with those when it was co-administered with food. METHODS: This was an open, randomized, two sessions cross over study in 12 patients with Parkinson's disease, comparing the steady-state pharmacokinetic profiles of ropinirole on two different study days: 'fasted' and 'fed'. RESULTS: The mean Cmax was lower in the 'fed' regimen than in the 'fasted' one (-25%, P=0.002). The median tmax was observed 2.6 h later in the 'fed' regimen than in the 'fasted' regimen (P<0.05). There was a slight but significant decrease in AUC(0,8 h) in the 'fed' regimen (P=0.03). CONCLUSIONS: Food decreases the rate of absorption of ropinirole, but has little effect on the extent of absorption.
Aged↗
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↗
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↗
Endogenous central cholinergic systems and baroreflex modulation in the conscious dog.
Intracisternal atropine and mecamylamine failed to modify baroreflex sensitivity in dogs, suggesting a lack of cholinergic neurons integrated in baroreflex pathways. Conversely, neostigmine lowered baroreflex sensitivity suggesting a putative cholinergic modulation.
Acetylcholine↗
[Parkinson "plus"].
"Parkinson plus" is a group of sporadic degenerative disorders associating Parkinsonism, poorly sensitive to L-dopa, to other neurological syndromes. Thus, progressive supranuclear palsy includes Parkinson's disease, vertical gaze paralysis, nuchal dystonia and dementia; multisystem atrophies associate to different degrees Parkinson's disease (striatonigral degeneration), a cerebellar syndrome (olivopontocerebellar atrophy), dysautonomia (Shy-Drager syndrome), pyramidal syndrome, etc. Other diseases (corticobasal degeneration, diffuse Lewy body disease) also belong to the Parkinson "plus" group. Clinical differentiation between Parkinson "plus" and idiopathic Parkinson's disease is difficult. Their prognosis and treatment are substantially different. Certain diagnosis is based solely upon anatomical observations.
Antiparkinson Agents↗
[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↗
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↗
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↗
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↗