D2 dopamine receptor gene in myoclonic dystonia and essential myoclonus.
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Adolescent↗
Biomedical subjects
F Durif
Publications and source records attributed to F Durif.
Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations?
Autosomal dominant DOPA-responsive dystonia (DRD) is usually caused by mutation in the gene encoding guanosine triphosphate-cyclohydrolase I (GTPCH I). We studied 22 families with a phenotype of levodopa-responsive dystonia by sequencing the six coding exons, the 5'-untranslated region and the exon-intron boundaries of the GTPCH I gene. Eleven heterozygous mutations were identified, including five missense mutations, one splice site mutation, two small deletions and two nonsense mutations, in 12 families that included 27 patients and 13 asymptomatic carriers. Six mutations were new and five had already been reported. Four of the mutations caused truncation of the GTPCH I protein. One family carried a base-pair change in the 5'-untranslated region, not detected in controls, that could be responsible for the phenotype. Three of the remaining 10 families had deletions in the parkin gene on chromosome 6, underlining how difficult it is to distinguish, in some cases, between DRD and parkin mutations. No mutations were identified in seven families. The clinical spectrum extended from the classical DRD phenotype to parkinsonism with levodopa-induced dyskinesias, and included spastic paraplegia as well as the absence of dystonia.
Adolescent↗
Worsening of levodopa-induced dyskinesias by motor and mental tasks.
Ten patients who had Parkinson's disease with disabling dyskinesia were included in this study to evaluate the role of mental (mental calculation) and motor (flexion/extension of right fingers, flexion/extension of left fingers, flexion/extension of the neck, speaking aloud) tasks on the worsening of peak-dose dyskinesia following administration of an effective single dose of apomorphine. Compared with the score at rest (1.3+/-0.3), a significant aggravation of the dyskinesia score was observed during speaking aloud (5.2+/-1.1, p<0.05), movements of right (4.5+/-1.0, p<0.05) and left (3.7+/-0.8, p<0.05) fingers, movements of the neck (5.1+/-1.0, p<0.05), and mental calculation (3.1+/-1.0, p<0.05). These results suggest that activation tasks such as "speaking aloud" could be used for objective assessment of dyskinesia severity.
Analysis of Variance↗
Direct stereotactic MRI location in the globus pallidus for chronic stimulation in Parkinson's disease.
We evaluated the direct location in the globus pallidus (GP) under stereotactic MRI (sMRI) guidance in five parkinsonians treated with chronic deep brain stimulation (four bilaterally). The sMRI consisted of three orthogonal (horizontal, frontal, sagittal) sets of images obtained with a stereotactic frame and its localiser. The sMRI was coupled with ventriculography to compare the location with the classic indirect method based on commissural landmarks. The target was defined on T2-weighted slices in the anterior part of the medial GP, at the vertex of the nucleus. It was reached via one track with a semi-micro-electrode and step by step high frequency stimulation, then replaced by a quadripolar electrode once we located the site enabling the optimal clinical improvement. Stereotactic x-rays localised the final position of the electrode. A company software matched sMRI, ventriculography, and peroperative (perop) x-rays, with reference to the stereotactic location boxes. We analysed the effects of acute (perop) and chronic (six-month follow-up) stimulation of active plots (acplots), i.e. leading to optimal clinical improvement. Three distances with reference to the acplots were measured both on sMRI and ventriculography: the laterality from the median sagittal plane of the third ventricle; the anterior position from the midpoint of the intercommissural line (Icl), and the vertical position with regard to the Icl. We then compared the differences in measurements (n = 64) with the Bland and Altman method. The mean difference was 0.09 mm with 95% of the values between +/- 1 mm, but only the laterality had a statistically significant agreement (all the differences included between +/- two times the standard deviation of the mean). The acplots distances from the dorsal, ventral, and medial boundaries of GP (defined by manual surrounding on frontal and horizontal planes) were measured on sMRI. With one exception, the acplots were all included in the nucleus. The six-month acplots were located dorsally with reference to the perop ones. Clinical benefit at six-months follow-up showed results comparable to the literature. Direct location of GP target based on sMRI seems a simple and reliable method.
Cerebral Ventriculography↗
Acute and chronic effects of anteromedial globus pallidus stimulation in Parkinson's disease.
OBJECTIVE: To evaluate the effects of acute and chronic stimulation in the anteromedial part of the globus pallidus internus (GPi) on the symptoms of patients with Parkinson's disease. METHODS: Six patients with severe Parkinson's disease (Hoehn and Yahr stage 4-5 in "off" drug condition) with motor fluctuations and levodopa induced dyskinesia (LID) were operated on. Chronic electrodes were implanted in the anteromedial GPi bilaterally in five patients and unilaterally in one patient. The effect of stimulation via the four contacts for each electrode (n=11) was assessed postoperatively on the contralateral parkinsonian signs in the off condition and on the contralateral and ipsilateral LID in the "on" condition. The core assessement program for intracerebral transplantation protocol was performed before surgery and then 1, 3, and 6 months after surgery in on and off conditions and in on and off stimulation conditions. RESULTS: Stimulation performed postoperatively showed a significant improvement (p<0.05) by 47% (contralateral rigidity) and 32% (contralateral bradykinesia) when stimulation was applied through the distal contact. Levodopa induced dyskinesias were improved by 95% (contralateral LID) and by 66% (ipsilateral LID) when stimulation was applied through the distal contact. Six months after the surgery, GPi stimulation in the off condition led to a mean improvement in the motor score of UPDRS by 36%. The mean daily duration in the off state decreased by 52% (p<0.05). The mean duration of LIDs decreased by 68% (p<0.05) and their severity by 53% (p<0.05). CONCLUSION: Chronic stimulation in the anteromedial GPi shows that this is a safe and effective treatment for advanced Parkinson's disease with benefit sustained for at least 6 months.
Aged↗
Treating and preventing levodopa-induced dyskinesias: current and future strategies.
Prevention of levodopa-induced dyskinesias is a therapeutic challenge for physicians. At present, it seems only possible to delay dyskinesias and motor fluctuations. In younger patients (aged <50 years), the strategy is to use a dopamine D2 agonist as monotherapy and then to add levodopa treatment when the parkinsonian symptoms progress. In older patients, (aged >50 years to <70 years), the therapeutic approach is to use early combination therapy of levodopa and a D2 agonist. The treatment of levodopa-induced dyskinesias must be considered in regard to the subtype and the severity of dyskinesias, and the patient. The general approach to the treatment of peak dose dyskinesias is to maintain dopamine brain stimulation at as stable a level as possible by keeping plasma and brain levodopa concentrations in the therapeutic range (above the therapeutic threshold but below the dyskinesia threshold). An appropriate strategy is to reduce the individual dose of levodopa, to spread out the daily levodopa dose and/or to try treatment with the sustained-release form of the drug. Combination treatment with the standard and sustained-release levodopa formulations is also possible. Stopping selegiline (deprenyl) therapy may reduce dyskinesias; reducing the dose of, or stopping treatment with, a dopamine agonist may also be beneficial. Anti-dyskinetic drugs such as amantadine, buspirone, fluoxetine, propanolol and principally clozapine may be used. In severe dyskinesias, apomorphine infusion may be tried. In refractory dyskinesia, surgical procedures such as pallidotomy and chronic deep brain stimulation (globus pallidus/subthalamic nucleus) may be proposed. Theoretically, treatment of diphasic dyskinesias requires the maintenance of plasma levodopa concentrations above the dyskinesia threshold. However, this approach leads to constant and severe dyskinesia after only a few weeks of treatment. Thus, the strategy used to treat diphasic dyskinesia is close to the treatment of peak-dose dyskinesias. Apomorphine (or the liquid form of levodopa) may be helpful to prevent diphasic dyskinesias. In selected patients, a midday rest in the 'off' phase may decrease the duration of dyskinesia. Treatment of early morning dystonia is based on the addition to the regimen of the sustained release formulation of levodopa before bedtime. Liquid levodopa and apomorphine injection may be used just before the appearance of the dystonic posture. Botulinum toxin may be helpful in severe dystonia.
Clinical Trials as Topic↗
The phenomenology of L-dopa-induced dyskinesias in Parkinson's disease.
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Animals↗
Tolcapone, bromocriptine, and Parkinson's disease. French Tolcapone Study Group.
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Antiparkinson Agents↗
Effect of tolcapone on plasma and striatal apomorphine disposition in rats.
The influence of tolcapone, an inhibitor of catechol-O-methyl transferase, was evaluated on the disposition of apomorphine, a dopamine agonist used to treat Parkinson's disease, to explain a previously observed increase of duration of the effect of apomorphine associated with tolcapone. Sampling was performed in rats before and at different times after administration of apomorphine and following that of tolcapone or saline. Both in plasma and striatum, times to reach maximal-concentration and maximal concentrations did not significantly differ between the two groups but the elimination half-life times and areas under the curve were significantly greater following tolcapone treatment than in the saline group. These results show that tolcapone can increase plasma apomorphine bioavailability by modifying its liver catabolism.
Animals↗
Psychiatric and sexual disorders induced by apomorphine in Parkinson's disease.
A similar pattern of psychosexual disorders has been observed after long-term treatment with levodopa therapy in four male parkinsonian patients treated with apomorphine for severe on-off motor fluctuations. An acute episode in each case had led them to the hospital in the context of a psychiatric emergency (after punishable sexual acts in two cases). In each case, this episode had been preceded by an increase of self-administered apomorphine, whereas other antiparkinsonian drugs remained unchanged. Questioning had revealed psychosexual disturbances as early as the onset of apomorphine treatment, which tended to progressively worsen with the number of apomorphine daily doses. A decrease in the dosage of apomorphine had been followed by the improvement of the psychiatric condition without worsening of the motor status. Recurrence of psychiatric disorders with similar features had been observed when two patients again increased the number of apomorphine daily injections. The absence of somatic manifestations when apomorphine treatment was withdrawn or reduced, with persistence of psychosexual disturbances, could suggest a psychological dependence from the drug.
Aged↗
Low-dose clozapine improves dyskinesias in Parkinson's disease.
The severity of parkinsonian motor disability and dyskinesias was evaluated in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist apomorphine, before and after low-dose clozapine (50 mg) for 18 +/- 2 days. There was a significant 59% improvement (p < 0.05) of apomorphine-induced dyskinesias without aggravation of parkinsonian motor disability following clozapine treatment. The results suggest that low-dose clozapine, already shown to improve psychotic symptoms, may help to reduce severe levodopa-induced dyskinesias in parkinsonian patients.
Aged↗
Study of the antinociceptive effect of tetrahydro-papaveroline derivatives. Interaction with opioids.
The antinociceptive effect of racemic tetrahydropapaveroline (THP), of its two R(+)- and S(-) enantiomers, of 1-2-dehydro-THP and of 1-carboxy-THP was assessed using different pain tests in mice. None of these drugs possessed a significant activity in the hot-plate and tail-flick tests. However, after i.p. injection, they reduced the number of abdominal writhes induced by phenylbenzoquinone, with ED50 values of 51 +/- 7, 73 +/- 9 and 79 +/- 7 mg/kg for the most potent compounds: 1,2-dehydro-THP, +/- THP and -THP, respectively. This activity was not antagonized by naloxone (1 mg/kg, s.c.). However combination of inactive doses of these three compounds (32 mg/kg, i.p.) and of morphine (0.5 mg/kg, s.c.) led to a significant antinociceptive effect (83 to 85% of reduction of the number of writhes). This synergistic potentiation confirmed with the combination of +/- THP (16 mg/kg, i.p.) and morphine (0.5 mg/kg, s.c.) was totally inhibited by naloxone (1 mg/kg, s.c.). These results, although excluding a direct agonistic effect of THP derivatives on opiate receptors, suggest an indirect interaction of these drugs with the endogenous opioid system.
Analgesia↗
Levodopa-induced dyskinesias are improved by fluoxetine.
We evaluated the severity of motor disability and dyskinesias in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist, apomorphine, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced dyskinesias without modification of parkinsonian motor disability. The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias (onset- and end-of-dose dyskinesias) and in the upper limbs during choreic mid-dose dyskinesias. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce levodopa- or dopamine agonist-induced dyskinesias without aggravating parkinsonian motor disability.
Antiparkinson Agents↗
Comparison between percutaneous and subcutaneous routes of administration of apomorphine in rabbit.
Apomorphine (0.5 mg/kg) was administered subcutaneously and percutaneously to rabbit in order to compare the pharmacokinetic data obtained according these two different routes. For the percutaneous administration, an apomorphine gel was prepared by dissolution of apomorphine in an hydroxypropylmethylcellulose gel of medium viscosity. The evaluation of plasma levels after percutaneous route showed an absorption in all the animals. The time to peak plasma concentration (29.4 +/- 7.8 min) was close than after the subcutaneous route (25.8 +/- 4.9 min). The absorption of apomorphine was of 90% at minute 68 and minute 321 min after the subcutaneous and the percutaneous route, respectively. The peak plasma concentration and the area under the curve were significantly greater with the subcutaneous route. The bioequivalence of the percutaneous route was 35% of the subcutaneous administration. Those data suggested that the percutaneous route of apomorphine could be evaluated in humans to test its efficacy in the treatment of motor fluctuations in parkinsonian patients.
Absorption↗
Apomorphine and diphasic dyskinesia.
We report on three observations of parkinsonian patients with levo-dopa-induced diphasic dyskinesias, who received subcutaneous apomorphine to reduce the duration of abnormal movements. Apomorphine was effective in reducing the duration of diphasic dyskinesias at doses higher than the threshold doses necessary to induce an "on" phase (mean increase: 43%). However, after a few months of treatment, apomorphine was ineffective in stopping abnormal movements, even when doses were increased. In two patients, apomorphine remained effective in the morning, but increased the intensity of the dyskinesias in the afternoon. Acute diurnal variations of the pharmacodynamic striatal response are suggested explanation for these clinical observations.
Aged↗
Relation between clinical efficacy and pharmacokinetic parameters after sublingual apomorphine in Parkinson's disease.
Apomorphine was administered sublingually in two single doses (0.3 and 0.6 mg/kg) to seven patients with idiopathic Parkinson's disease (PD) to assess the relation between clinical efficacy, dosage, and pharmacokinetic parameters of apomorphine. On day 1 and day 3, patients were given 0.3 mg/kg and 0.6 mg/kg of apomorphine, respectively (3 mg tablets). Before apomorphine administration and during the following 4 h, motor score was assessed by measuring tremor, akinesia scores, rising from a chair, and walking speed. The delay to turn on was not different between the two doses but after the 0.3 mg/kg dose, only three patients turned on, whereas all the patients treated with 0.6 mg/kg turned on. Apomorphine (0.3 mg/kg) induced a shorter duration of the "on" period than 0.6 mg/kg (0.3 mg/kg: 24.2 +/- 14.6 min; 0.6 mg/kg: 86.7 +/- 14.9 min). The time to obtain the peak plasma concentration (tmax) obtained with the two doses were not different (0.3 mg/kg: 31.5 +/- 3.4 min; 0.6 mg/kg: 38.3 +/- 2.8 min). Peak plasma concentrations (Cmax) and areas under the curve (AUC) were significantly higher after 0.6 mg/kg than 0.3 mg/kg (Cmax: 0.3 mg/kg: 7.5 +/- 3.2 ng/ml; 0.6 mg/kg: 22.7 +/- 3.6 ng/ml; p < 0.01; AUC: 0.3 mg/kg: 929 +/- 109 ng/ml/min; 0.6 mg/kg; 2,277 +/- 209 ng/ml/min; p < 0.01). There was a significant linear correlation between the duration of therapeutic effect, AUC, and Cmax (r = 0.86, p < 0.01 for AUC; r = 0.63, p < 0.05 for Cmax). These results show that sublingual apomorphine could be of interest in the treatment of "off" phases in parkinsonian patients with motor fluctuations.
Administration, Sublingual↗
Apomorphine in treatment of Parkinson's disease: comparison between subcutaneous and sublingual routes.
The efficacy of two routes of apomorphine, subcutaneous (SC) and sublingual (SL), successively administered in 7 Parkinsonian patients with motor fluctuations, was compared in reducing the daily duration of "off" phases. The mean duration of SC and SL treatment was 7.7 and 6.8 months respectively. The mean time spent in "off" phase was 55% after SC and 68% after SL treatment. The mean time before turning "on" after an "off" period was 14 minutes after SC and 28 minutes after SL treatment. Two patients developed stomatitis after SL route. SL apomorphine may be helpful in the treatment of motor fluctuations in PD.
Administration, Sublingual↗
Dopamine-derived tetrahydroisoquinolines and Parkinson's disease.
The daily urinary excretion of salsolinol, 1,2-dehydrosalsolinol, and norsalsolinol, as free, glucuronide, and sulfate, has been measured in parkinsonian patients and age-matched controls in an attempt to examine whether the determination of dopamine-derived alkaloids in urine may be used as a marker of the decrease in brain dopamine levels associated with the disease. In contrast with a preliminary study where the daily urinary excretion of total salsolinol was significantly higher in young controls than in parkinsonians, in the present study no difference was found between parkinsonian patients and controls concerning salsolinol and norsalsolinol excretion. However, the urinary excretion of total 1,2-dehydrosalsolinol was significantly higher in the control group, owing to a statistically significant increase in its excretion as sulfate in this group. Further studies appear to be necessary to establish whether 1,2-dehydrosalsolinol, salsolinol, and/or any other dopamine-derived alkaloid may serve for the detection of subjects with dysfunctions of the dopaminergic system.
Aged↗