Pharmacological treatment of Parkinson's disease: life beyond dopamine D2/D3 receptors?

Parkinson's disease (PD) is a multisystemic disorder in which several neurotransmitters other than dopamine are affected. Drugs acting on non-dopaminergic systems are envisaged as promising agents to treat PD and levodopa-induced dyskinesias (LID). However, compounds targeting glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed in human studies showing negative, inconsistent or unsatisfactory results. Most of these drugs had been tested previously in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, as well as in the classic 6-hydroxydopamine-lesioned rat model. These failures raise several questions and concerns about the true reliability of animal studies, the adequacy of the working hypotheses and design of clinical trials, the validity of tools in current use to evaluate a particular effect, and the selectivity of the drugs used. More importantly, observed discrepancies between the results in models and patients, could challenge the validity of current ideas about the pathophysiology of parkinsonism and LID.

Severe stuttering and motor tics responsive to cocaine.

Developmental stuttering and tics share many clinical and therapeutical aspects. Dopaminergic neurotransmission seems to be involved in the pathophysiology of both, tics and stuttering. We report on a patient with severe stuttering and mild facial tics which were dramatically improved by cocaine, challenging previous reports.

[Treatment of Parkinson disease: therapeutic reserve of the dopaminergic agonist]. / Tratamiento de la enfermedad de Parkinson: reserva terapéutica de los agonistas dopaminérgicos.

Parkinson's disease (PD) is a neurodegenerative, chronic and progressive disease whose evolutive course changed significantly after the introduction of levodopa. However, no antiparkinsonian drug has been able to stop the progression of PD. Thus, as the years have passed, greater drug doses have been necessary, either alone or in different combinations. Therefore, it is useful to have drugs with a wide threshold between effective dose and maximum tolerated dose. The concept of therapeutic reserve (TR) can be considered equivalent to therapeutic index or therapeutic window and could be defined as the difference between the dose needed to achieve an optimum therapeutic response at a given time and the dose that causes adverse events (maximum recommended dose or "ceiling dose"). This difference indicates the threshold that makes it possible to use higher doses as the disease advances to maintain an optimum clinical effect without the appearance of adverse events. This concept is important in the case of dopaminergic agonists whose efficacy seems to be similar in the daily clinical practice. Although there are no direct comparative studies, the analysis of the results of different studies suggests that the TR of ropinirole is superior to that of other dopaminergic agonists. The first effective dose, defined as an improvement superior to 30 % is observed with 9 mg/day in 75 % of the patients while the maximum recommended dose is 24 mg/day. This threshold is less with other dopamine agonists.

Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up.

Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

Effects of gabapentin on the motor response to levodopa: a double-blind, placebo-controlled, crossover study in patients with complicated Parkinson disease.

BACKGROUND: Motor fluctuations and dyskinesias affect many parkinsonian patients chronically treated with levodopa. Imbalance between gabaergic direct and indirect striatopallidal pathways may originate them. Manipulating GABA neurotransmission may be effective in the treatment of these patients. Gabapentin is an antiepileptic drug that increases the synthesis and release of GABA. Previous studies suggest that gabapentin may be useful in Parkinson disease (PD). OBJECTIVE: To know the effects of gabapentin on the motor response to levodopa in PD patients with motor complications. DESIGN: A randomized double-blind, placebo-controlled, cross-over trial with four weeks of treatment. SETTING: A tertiary referral center. PARTICIPANTS: Twenty subjects with PD and motor fluctuations and dyskinesias on stable antiparkinsonian treatment, took gabapentin up to a maximum dose of 2.400 mg/d in three doses and placebo. METHODS: Three levodopa challenges were performed: at the beginning of the study and at the end of each period of treatment (4 weeks). Basal (off) and best (on) motor status were assessed by the UPDRS III. Latency to peak effect, magnitude of motor response (difference between "on" and "off" scores in the UPDRS III), duration of motor response and severity and duration of dyskinesias after each levodopa challenge were assessed. Patients' diaries were administered. RESULTS: : Fifteen patients completed the study. A significant improvement in the basal UPDRS III resulting in a significant reduction in the magnitude of the motor response after gabapentin was obtained (P < 0.001). No other changes were observed, either on pharmacological parameters or in levodopa-induced dyskinesias. Number of daily hours spent in "on," "on with dyskinesias" and "off" also remained unchanged. Tolerance was good, dizziness being the most common side effect. CONCLUSION: Gabapentin improved parkinsonian symptoms (basal UPDRS III and magnitude of the motor response) following levodopa. This improvement was not reflected in the daily motor situation of patients. Dyskinesias remained unchanged. Gabapentin was well tolerated. Further studies are needed to know the impact of these results in the long-term.

[Hypothesis: Parkinson's disease, reward deficiency syndrome and addictive effects of levodopa]. / Hipótesis: Enfermedad de Parkinson, síndrome de deficiencia de recompensa y efectos adictivos de la levodopa.

Since Parkinson's disease (PD) patients could suffer from a reward deficiency syndrome, they are particularly prone to develop addictive behaviours. Dopamine is involved in reward processing and in addiction. Pulsatile administration of antiparkinsonian drugs may lead to the development of dyskinesias and addictive behaviours. However, this phenomenon occurs in very few cases. Indeed, both processes share molecular mechanisms although with some differences such as the topography of the changes (it predominates in motor regions in PD with dyskinesias and in limbic regions in addictions). Nevertheless, investigations conducted to know the physiopathology of levodopa-induced dyskinesias may lead to important cues for understanding the underlying mechanisms responsible for addiction. Thus, this may have important implications for the discovery of new therapeutic strategies.

Bilateral subthalamic nucleus stimulation improves health-related quality of life in PD.

In order to assess the impact of bilateral subthalamic nucleus (STN) stimulation in PD on quality of life, the PD Quality of Life questionnaire was assessed in 60 consecutive patients with PD before surgery and 12 months after surgery. All aspects of quality of life, including motor (+48%), systemic (+34%), emotional (+29%), and social (+63%) dimensions, significantly improved with long-term STN stimulation.

Predictors of effective bilateral subthalamic nucleus stimulation for PD.

To identify factors predictive of effective bilateral subthalamic nucleus (STN) stimulation for PD with severe motor complications, pre- and postoperative Unified PD Rating Scale (UPDRS) scores were analyzed in a series of 54 patients who received bilateral STN stimulation. Younger age and levodopa responsiveness predict a favorable response to bilateral STN stimulation. For individual PD symptoms, those that improve with a suprathreshold dose levodopa challenge are likely to improve with stimulation.

Effect of subthalamic nucleus stimulation on levodopa-induced dyskinesia in Parkinson's disease.

Article abstract-The authors studied the effect of bilateral subthalamic nucleus stimulation on levodopa-induced dyskinesias in 24 consecutive parkinsonian patients with disabling dyskinesias. The improvement in the three subtypes of levodopa-induced dyskinesias was significant from the third postoperative month and was mainly due to the decrease in the daily dose of levodopa allowed by the stimulation-induced improvement in the motor score.

Thalamic, subthalamic nucleus and internal pallidum stimulation in Parkinson's disease.

The limits of drug therapy in severe forms of Parkinson's disease have lead to a renewal of functional neurosurgery of the basal ganglia and the thalamus. Deep brain stimulation (DBS) of these structures was developed with the aims of reducing the morbidity of surgery and of offering an adaptative treatment. DBS was first applied to the thalamus in patients with severe tremor. Tremor of the hemibody is greatly reduced by stimulation of the contralateral electrode in 85% of the cases. There is little change in other symptoms. However, motor fluctuations and dyskinesias are a more frequent problem than severe tremor; in attempt to treat these symptoms, DBS has recently been applied to the subthalamic nucleus (STN) and the internal pallidum (GPi). STN stimulation greatly decreases off motor symptoms and motor fluctuations, which allows a reduction of drug dosage and consequently of dyskinesias. GPi stimulation decreases dyskinesias in most patients, but the effect on off motor symptoms is more variable from one series to another, from very good to nil. The severe morbidity of DBS applied to these 3 targets is low. Comparative studies of the cost and the efficacy of DBS and lesions applied to these different targets are now required.

Asymmetry of basal ganglia glucose metabolism and dopa responsiveness in parkinsonism.

We investigated, by positron emission tomography (PET) with [18F]fluoro-2-deoxy-d-glucose (FDG) (FDG-PET), brain glucose metabolism in 19 patients with parkinsonian features. We compared local pattern of FDG uptake and asymmetry indexes in patients with therapeutic response to levodopa (L-dopa) (group 1, presumed Parkinson's disease, n = 9) and patients without L-dopa therapeutic response (group 2, presumed striatonigral degeneration, n = 10). Limb dystonia was present in 11% of patients in group 1 and in 40% of patients in group 2. Asymmetry in basal ganglia metabolism was distributed differently in the two groups (analysis of variance, p < 0.04). In superior and inferior putamen, superior and middle caudate, ventral striatum, and inferior thalamus, relative reduction in metabolism on the side contralateral to predominant parkinsonian signs was associated with L-dopa unresponsiveness. On the contrary, in middle caudate, ventral striatum, and inferior thalamus, a relative increase in metabolism on the side contralateral to the predominant side, parkinsonian signs were found in L-dopa-responsive patients. Our FDG-PET study using simple statistical procedures demonstrates inverse asymmetry of basal ganglia glucose metabolism in parkinsonian patients grouped on the sole basis of L-dopa responsiveness.

Dissociation in the neural control of single-joint and multi-joint movements in the thalamic ataxia syndrome.

We report a patient presenting with a right thalamic ataxia syndrome following a hemorrhage located in the left lateral and posterior thalamus. We investigated the fast goal-directed movements of the wrists (single-joint movements) and the fast pointing movements in the upper limbs (multi-joint movements). On the right side, single-joint movements were markedly hypermetric and characterized by an asymmetry in kinematics, an abnormality of ballistic movements which is considered to be a fundamental cerebellar disorder. By contrast, rapid multi-joint movements were only very slightly impaired. These results suggest that ballistic movements of the wrist are under the strong influence of the cerebello-thalamo-cortical pathway, while rapid pointing multi-joint movements in upper limb are mostly influenced by another pathway emerging from the lateral cerebellum, possibly the dentato-rubral or the dentato-reticular projections in the brainstem. The roles of these neuroanatomical pathways in the control of fast single-joint and multi-joint movements are discussed.

Microdialysis-HPLC for plasma levodopa and metabolites monitoring in parkinsonian patients.

We used in vitro microdialysis-HPLC to determine L-3,4-dihydroxyphenylalanine (L-DOPA) and its metabolites in plasma of patients with advanced Parkinson disease. Blood samples and clinical evaluations were obtained 0, 30, 60, 90, 120, and 150 min after oral administration of carbidopa/L-DOPA (25/100 mg, 12.5/125 mg, and 50/200 mg). In vitro recoveries for L-DOPA and metabolites ranged from 22% to 36%. Linear correlation was found between metabolite concentrations in the dialysate and in the surrounding medium. There was a significant positive correlation between L-DOPA dose and plasma concentration of L-DOPA and homovanillic acid (P < 0.04). Clinical response was maximum 60 min after L-DOPA administration. Threshold L-DOPA plasma concentration averaged 7.74 +/- 3.3 mumol/L. Motor effect is longer with the highest L-DOPA peak concentration (P < 0.01). Microdialysis-HPLC is readily applicable, reproducible, and allows monitoring of plasma L-DOPA and metabolites in parkinsonian patients.