Consensus statement on the role of acute dopaminergic challenge in Parkinson's disease.

Available evidence on the practice of acute pharmacological challenge tests in parkinsonian patients was reviewed by a committee of experts, which achieved a general consensus. The published data deal mainly with the acute administration of levodopa and apomorphine in Parkinson's disease. Such challenge may serve different purposes, e.g., research, diagnosis, or tailoring of treatment. Unique protocols describing the clinical setting and practice parameters are not available. The present paper describes the scientific background and supplies practical guidelines, whenever possible, to perform and evaluate acute challenge tests in parkinsonian syndromes. With the appropriate indication and setting, acute challenge tests are useful in diagnosis and therapy of Parkinson's disease and related disorders.

Lorazepam-induced modifications of saccadic and smooth-pursuit eye movements in humans: attentional and motor factors.

In a placebo-controlled, double-blind study, we measured the effects of low dose lorazepam on attentional and motor factors involved in saccadic and smooth pursuit eye movements. We manipulated the temporal interval between the extinction of the central fixation target and the appearance of a second eccentric target (gap/overlap step paradigm). The second target was either stationary (saccade trial) or moving in a direction opposite to the step (pursuit trial). Gap/overlap effects on the latency of saccadic and smooth pursuit eye movements were measured before and after oral intake of either lorazepam or placebo. Pharmacological effects on the dynamics and the accuracy of both types of eye movements were also investigated. In 14 healthy volunteers, we found that the temporal interval between fixation target offset and eccentric target onset modulates the latency of saccadic and smooth pursuit eye movements in a similar way. As compared to placebo, lorazepam significantly increased the latency of both types of eye movements, but did not modify the gap/overlap effect. Moreover, lorazepam significantly decreased the peak velocity of the first saccade towards the eccentric stationary target, as well as the gain of tracking towards the eccentric moving target. However, the overall accuracy of both behaviors was not significantly affected, indicating that systematic errors in foveating or tracking were detected and corrected by appropriate corrective or catch-up saccades, respectively. Results are discussed in terms of shared/different mechanisms for saccadic and pursuit systems in primates.

[Midodrine (Gutron) prescription practice at a University Hospital Center]. / Etude des pratiques de prescriptions de midodrine (Gutron) dans un Centre Hospitalier Universitaire.

A historical study of the prescription of midodrine was carried out at the university hospital of Toulouse (France) between 1994 and 1998. The aim was to compare the observed prescriptions and the ideal prescriptions in accordance with the Summary of Product Characteristics (SPC). The analysis of 97 consecutive medical reports found discrepancies in prescription concerning the non-respect of contraindications and of potentially hazardous drug associations. Fifty-four (55.7 per cent) patients would have been excluded from prescription if the physicians had strictly respected the SPC. The inappropriate prescription of midodrine was associated with an increase in adverse drug reactions (ADRs). ADRs occurred in 34.0 per cent of cases overall and required drug discontinuation in 15.5 per cent.

Effect of the alpha 2 adrenoreceptor antagonist, idazoxan, on motor disabilities in MPTP-treated monkey.

1. The motor effect of the alpha 2 adrenoreceptor antagonist, idazoxan, was compared to that of L-dopa in MPTP-treated monkeys. 2. Idazoxan 2.0 mg/kg improved parkinsonian motor abnormalities which was comparable to the effects of a minimal effective dose of L-dopa. 3. At 2.0 and 5.0 mg/kg, the parkinsonian rigidity was the item most frequently alleviated by idazoxan (respectively 63.6% and 68.2%). 4. These findings provide support for the therapeutic utility of alpha 2 antagonists in the treatment of Parkinson's disease.

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.

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.

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.

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.

Prevalence of orthostatic hypotension in Parkinson's disease.

OBJECTIVES: To investigate the prevalence of orthostatic hypotension and the nature of the postural events related to a fall in blood pressure in patients with Parkinson's disease. METHODS: Blood pressure was measured first in a supine position after a rest of at least 15 minutes and every minute during 10 minutes of an active standing up procedure. Orthostatic hypotension was considered as present when a fall of at least 20 mm Hg of systolic blood pressure was recorded. Postural events which occurred during the standing test were identified from a questionnaire and self reporting. Statistical analysis was performed to determine the relation between orthostatic hypotension and disease characteristics (duration, severity) and the use of antiparkinsonian drugs. Ninety one consecutive patients with Parkinson's disease (48 women, 43 men, mean age 66 (SD 9) years) participated to the study. RESULTS: A fall of at least 20 mm Hg of systolic blood pressure was found in 58.2% of the patients. Orthostatic hypotension was asymptomatic in 38.5% and associated with postural events in 19.8% of the patients. Symptomatic (but not asymptomatic) orthostatic hypotension was related to duration and severity of the disease and with the use of higher daily levodopa and bromocriptine doses. The analysis of the relation between the postural symptoms (and the need for standing test abortion) with the fall in systolic blood pressure allowed the identification of six clinical criteria specific of orthostatic hypotension. A direct relation between the postural changes in systolic blood pressure and the number of clinical events in this clinical scale was found. CONCLUSION: The frequency of orthostatic hypotension in Parkinson's disease is high and it is possible to establish a clinical rating scale which could be used to assess the effects of drugs employed in the management of orthostatic hypotension.

Antivertigo medications and drug-induced vertigo. A pharmacological review.

The approach to drug treatment of vertigo is almost exclusively symptomatic. There are 3 major goals for drug treatment of vertigo. The first one is to eliminate the hallucination of motion. Drugs with vestibular 'suppressant' properties are used for this purpose. The major vestibular suppressants are anticholinergic and antihistamine drugs. The second goal is to reduce the accompanying neurovegetative and psychoaffective signs (nausea, vomiting, anxiety). Antidopaminergics are used for this purpose. The third goal is to enhance the process of 'vestibular compensation' to allow the brain to find a new sensory equilibrium in spite of the vestibular lesion. Until now, the pharmacological manipulation of vestibular compensation has been assessed in animals but not in humans with vestibular lesions. Vestibular suppressant drugs delay rather than enhance compensation. A variety of other drugs is also used in the treatment of vertigo, including benzodiazepines, histaminergic agents, sympathomimetics and calcium antagonists. Their mechanism of action is poorly understood. The data base derived from clinical trials evaluating antivertigo medications is often questionable because of methodological limitations. This explains why habits of prescription are mainly empirical, and why striking differences can be noticed from one country to another. We can hope that new treatments may emerge from the present interest in receptor subclasses and neuromodulators of the vestibular system, and we must be ready to evaluate these potential new pharmacological agents with reliable clinical methods in humans.

Central cardiovascular effects of acetylcholine in the conscious dog.

1. The effects of central cholinomimetic drugs on cardiovascular and vasoactive hormonal responses (blood pressure, heart rate, catecholamines, vasopressin, atrial natriuretic factor, neuropeptide Y plasma levels and plasma renin activity) were investigated in conscious Beagle dogs. For this purpose a catheter was chronically implanted into each dog's cisterna magna to allow repeated central injections in the awake animals. 2. Intracisternal acetylcholine (20 micrograms kg-1) significantly increased systolic and diastolic blood pressure. These changes were accompanied by an initial short term tachycardia followed by a long lasting bradycardia. Intracisternal acetylcholine also increased noradrenaline, adrenaline and vasopressin plasma levels, decreased plasma renin activity but did not modify plasma levels of neuropeptide Y and atrial natriuretic factor. 3. The effects of acetylcholine were completely abolished by pretreatment with intracisternal injection of the muscarinic antagonist, atropine (5 micrograms kg-1) but not by the intracisternal injection of the nicotinic antagonist, mecamylamine (25 micrograms kg-1). 4. The present results demonstrate that there are qualitative and quantitative differences between the central cardiovascular effects of acetylcholine in conscious dogs compared to what we previously reported, using a comparable protocol, in anaesthetized dogs. Under both conditions, we observed a central cholinergically mediated increase in blood pressure secondary to an increase in sympathetic tone and vasopressin release but these responses were shorter (less than 10 min) in the conscious dogs than in anaesthetized dogs (more than 10 min). Moreover, we detected in the response to the central cholinergic stimulation in the conscious dogs a significant increase in plasma adrenaline levels and biphasic changes in heart rate which were not described previously in the anaesthetized dog.