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Biomedical subjects

Olivier Rascol

Publications and source records attributed to Olivier Rascol.

At least 19 recordsLinked to original sources
PubMed2007

Sarizotan as a treatment for dyskinesias in Parkinson's disease: a double-blind placebo-controlled trial.

The objective of this study is to conduct a dose-finding study of sarizotan in Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound with full 5-HT(1A) agonist properties and additional high affinity for D(3) and D(4) receptors. An open label study documented improvements in PD patients with levodopa-induced dyskinesia. There is no precedent for study designs or outcome measures in pivotal trials of antidyskinesia therapies. The approach used here was a multicenter, randomized, placebo-controlled, double-blind, parallel study. Included were PD patients optimized to levodopa and dopaminergic drugs with moderately disabling dyskinesias present greater than or equal to 25% of the waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching placebo, given in two doses. There were two outcome measures: the primary measure was change from baseline in diary-based on time without dyskinesia; the secondary measures were change from baseline in scores on the Abnormal Involuntary Movement Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale (UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total of 398 subjects were randomized, with 381 included in the intention-to-treat population. No significant changes occurred on sarizotan compared to placebo on any diary-based measure of dyskinesia or the AIMS score. The composite score of UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a trend at 10 mg/day. Adverse events were not significantly different in sarizotan- and placebo-treated patients, but off time significantly increased with sarizotan 10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To test its role in abating dyskinesia, future studies should focus on this dose and will use the composite score of UPDRS Items 32+33 as the primary outcome.

Adult↗
PubMed2007

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan.

This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.

Disability Evaluation↗
PubMed2006

Methylphenidate modulates cerebral post-stroke reorganization.

OBJECTIVE: We hypothesized that a single dose of methylphenidate (MP) would modulate cerebral motor activation and behavior in patients having suffered a subcortical stroke. METHODS: Eight men with a single stroke on the corticospinal tract resulting in a pure motor hemiparesia were included in a randomized, cross-over, double-blind, placebo-controlled study. Patients were first evaluated 17 days after stroke onset by validated neurological scales, motor tests and fMRI (flexion/extension of the digits) after 20 mg MP or placebo. Seven days later, the patients underwent the same protocol and received the drug they had not taken at the first evaluation. Each patient was his own control. RESULTS: Placebo intake did not change performance. MP compared to placebo elicited a significant improvement in motor performance of the affected hand at the finger tapping test. MP induced: (1) a hyperactivation of the ipsilesional primary sensorimotor cortex including the motor hand and face areas and of the contralesional premotor cortex; (2) a hypoactivation of the ipsilesional anterior cingulum. Hyperactivation in the face motor area correlated positively with the improvement in performance. CONCLUSION: We demonstrated that the reorganized network may efficiently be targeted by the drug and that the effect of MP might partly rely on an improvement in attention/effort through cingulum modulation.

Aged↗
PubMed2006

Development of dyskinesias in a 5-year trial of ropinirole and L-dopa.

A 5-year trial of ropinirole and levodopa in early Parkinson's disease showed that ropinirole is associated with reduced incidence of dyskinesias. This post hoc analysis investigated whether the dyskinesia-sparing benefit of ropinirole is lost when levodopa is added to the regimen and evaluated other risk factors for developing dyskinesias. Patients receiving levodopa had a significantly higher risk of dyskinesias than those taking ropinirole monotherapy (hazard ratio [HR], 6.67; 95% confidence interval [CI], 3.23-14.29; P < 0.001). When patients randomized to ropinirole were treated with supplementary levodopa, the development of dyskinesias was not significantly different from that in those receiving levodopa from the start (HR, 0.80; 95% CI, 0.48-1.33; P = 0.39). However, the onset of dyskinesias was delayed by around 3 years compared with levodopa monotherapy. Adjusted analyses taking into account baseline and on-treatment factors that influenced use of supplementary levodopa or the development of dyskinesias produced similar results. In conclusion, the risk of developing dyskinesias during maintained initial ropinirole monotherapy is very low. Only once levodopa is added does the risk substantially change. Early use of ropinirole postpones the onset of dyskinesias, but these benefits decline when levodopa therapy is started, with no evidence of a subsequent rapid "catch-up" or a persisting preventive effect.

Antiparkinson Agents↗
PubMed2006

Early piribedil monotherapy of Parkinson's disease: A planned seven-month report of the REGAIN study.

Piribedil is a D2 dopamine agonist, which has been shown to improve symptoms of Parkinson's disease (PD) when combined with L-dopa. The objective of this study was to compare the efficacy of piribedil monotherapy to placebo in patients with early PD over a 7-month period. Four hundred and five early PD patients were randomized (double-blind) to piribedil (150-300 mg/day) or placebo. L-dopa open-label supplementation was permitted. Unified Parkinson Disease Rating Scale part III (UPDRS III) score as the last observation on monotherapy over 7 months was the primary outcome measure. Secondary outcomes were proportion of responders (UPDRS III improvement > 30%), patients remaining on monotherapy after 7 months, UPDRS III subscores, and UPDRS II. UPDRS III improved on piribedil (-4.9 points) versus a worsening on placebo (2.6 points; estimated effect = 7.26 points; 95% CI = 5.38-9.14; P < 0.0001). The proportion of responders was significantly higher for piribedil (42%) than for placebo (14%) (OR = 4.69; 95% CI = 2.82-7.80; P < 0.001). Piribedil significantly improved several UPDRS III subscores. UPDRS II improved on piribedil by -1.2 points, while it deteriorated by 1.5 points on placebo (estimated effect = 2.71; 95% CI = 1.8-3.62; P < 0.0001). The proportion of patients remaining on monotherapy after 7 months was greater in the piribedil group (OR = 3.72; 95% CI = 2.26-6.11; P < 0.001). Safety was consistent with that reported for other dopamine agonists, gastrointestinal side effects being the most common (22% of patients in piribedil group vs. 14% on placebo). Piribedil is effective and safe as early PD therapy.

Adult↗
PubMed2006

Cerebral autoregulation is preserved in multiple system atrophy: A transcranial Doppler study.

Patients with multiple system atrophy (MSA) present large changes in blood pressure (BP) due to autonomic disturbances. We analyzed how this change may influence dynamic cerebral autoregulation (DCA). Simultaneous recordings of arterial BP (Finapres) and middle cerebral artery (MCA) blood flow velocity (BFV) (transcranial Doppler) were performed in 10 patients with MSA (61 +/- 12 yr of age) and 12 healthy volunteers (61 +/- 11 yr of age): cerebral BFV response to oscillations in mean BP was studied in the supine position by cross-spectral analysis of mean BP and mean MCA BFV. The DCA was also studied during the decrease in BP the first seconds when standing up from a sitting position by the assessment of the cerebrovascular resistance index (CR; mean BP/mean MCA BFV ratio). The MCA BFV/BP cross-spectral analysis showed a phase for the mid-frequency band (0.07-0.2 Hz) significantly larger in MSA, suggesting more active autoregulation in response to larger changes in BP. Changes in CR reflecting the rate of autoregulation, when standing did not differ between the two groups. These data suggest that dynamic cerebral autoregulation is preserved in MSA.

Aged↗
PubMed2006

Clinical studies with ropinirole in Parkinson's disease and RLS.

Ropinirole is a modern dopamine agonist with a half-life of medium extent that is highly selective for D(2)-receptors. Ropinirole is an indole derivative and thus does not belong to the group of ergoline dopamine receptor agonists. Its effect has been proved in a number of controlled studies in both monotherapy and combination treatments of Parkinson's disease. We can meanwhile refer to the long-term data of studies that have been run for more than 10 years. The substance has also been approved for the management of restless legs syndrome. A long-acting formula of the substance will be available soon.

Antiparkinson Agents↗
PubMed2006

Ergoline and non-ergoline derivatives in the treatment of Parkinson's disease.

There are a large variety of dopamine agonists available. Especially de novo patients are treated with dopamine agonists to avoid dyskinesia. Dopamine agonists can be subdivided into ergoline and non-ergoline derivatives. This distinction raises the question whether there are differences in the effects to treat symptoms, not only in the side effects between the individual dopamine agonists but also between these two groups. Pergolide is now considered a second line drug because of its particularly high tendency towards valvular heart disease. Some authors claim that all ergoline-derivatives may cause this problem, while own results do not necessarily support this view. We recommend performing echocardiography on those patients being treated with an ergot-derivative. New data support the view that all dopaminergic drugs may cause somnolence and that there is no preference for non-ergots. It may be that the number of gamblers is slightly higher among patients treated with pramipexole than in others. Dopamine agonists with a high affinity to D3 receptors have a good anti-anhedonic potency. In cell culture all dopamine agonists studied so far show neuroprotective properties in cell culture. The introduction of a slow-release formulation for ropinirole and the rotigotine and lisuride patches have opened new ways of continuous dopamine receptor stimulation. Taken together, dopamine agonists show individual properties and there are differences between ergot and non-ergot derivatives.

Dopamine Agonists↗
PubMed2005

Modulation of behavior and cortical motor activity in healthy subjects by a chronic administration of a serotonin enhancer.

UNLABELLED: SSRIs are postulated to modulate motor behavior. A single dose of selective serotoninergic reuptake inhibitors (SSRIs) like fluoxetine, paroxetine, or fluvoxamine, has been shown to improve motor performance and efficiency of information processing for simple sensorimotor tasks in healthy subjects. At a cortical level, a single dose of SSRI was shown to induce a hyperactivation of the primary sensorimotor cortex (S1M1) involved in the movement (Loubinoux, I., Boulanouar, K., Ranjeva, J. P., Carel, C., Berry, I., Rascol, O., Celsis, P., and Chollet, F., 1999. Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks. J. Cereb. Blood Flow Metab. 19 1365--1375, Loubinoux, I., Pariente, J., Boulanouar, K., Carel, C., Manelfe, C., Rascol, O., Celsis, P., and Chollet, F., 2002. A Single Dose of Serotonin Neurotransmission Agonist Paroxetine Enhances Motor Output. A double-blind, placebo-controlled, fMRI study in healthy subjects. NeuroImage 15 26--36). Since SSRIs are usually given for several weeks, we assessed the behavioral and cerebral effects of a one-month chronic administration of paroxetine on a larger group. In a double-blind, placebo controlled and crossover study, 19 subjects received daily 20 mg paroxetine or placebo, respectively, over a period of 30 days separated by a wash-out period of 3 months. After each period, the subjects underwent an fMRI (active or passive movement, dexterity task, sensory discrimination task) and a behavioral evaluation. Concurrently, a TMS (transcranial magnetic stimulation) study was conducted (Gerdelat-Mas, A., Loubinoux, I., Tombari, D., Rascol, O., Chollet, F., Simonetta-Moreau, M., 2005. Chronic administration of selective serotonin re-uptake inhibitor (SSRI) paroxetine modulates human motor cortex excitability in healthy subjects. NeuroImage 27,314--322). RESULTS: On the one hand, paroxetine improved motor performances at the finger tapping test (P=0.02) without affecting choice reaction time, strength and dexterity significantly. Subjects were also faster in processing the spatial incongruency between a stimulus and the motor response (P=0.04). In order to differentiate behavioral components, a principal component analysis was performed on all motor tests, and several characteristics were differentiated: strength, speed, skill, attention, and motor response coding. Paroxetine would improve the efficiency of motor response coding (MANOVA on the factors; factor 3, P=0.01). On the other hand, the chronic administration induced a significant hypoactivation of S1M1 whatever the task: motor or sensory, simple or complex (random effect analysis, P<0.05). The hypoactivation correlated with the improvement of performances at the finger tapping test (P<0.05) suggesting more efficiency in cerebral motor processing. CONCLUSIONS: Our results showed a clear modulation of sensory and motor cerebral activation after a chronic paroxetine administration. An improvement in both behavior and cerebral efficiency was suggested. It could be hypothesized that monoamines, by an unspecific effect, may tune the response of pyramidal neurons to optimize performances.

Adult↗
PubMed2005

Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004.

The objective of this study is to update a previous evidence-based medicine (EBM) review on Parkinson's disease (PD) treatments, adding January 2001 to January 2004 information. The Movement Disorder Society (MDS) Task Force prepared an EBM review of PD treatments covering data up to January 2001. The authors reviewed Level I (randomized clinical trials) reports of pharmacological and surgical interventions for PD, published as full articles in English (January 2001-January 2004). Inclusion criteria and ranking followed the original program and adhered to EBM methodology. For Efficacy Conclusions, treatments were designated Efficacious, Likely Efficacious, Non-Efficacious, or Insufficient Data. Four clinical indications were considered for each intervention: prevention of disease progression; treatment of Parkinsonism, as monotherapy and as adjuncts to levodopa where indicated; prevention of motor complications; treatment of motor complications. Twenty-seven new studies qualified for efficacy review, and others covered new safety issues. Apomorphine, piribedil, unilateral pallidotomy, and subthalamic nucleus stimulation moved upward in efficacy ratings. Rasagiline, was newly rated as Efficacious monotherapy for control of Parkinsonism. New Level I data moved human fetal nigral transplants, as performed to date, from Insufficient Data to Non- efficacious for the treatment of Parkinsonism, motor fluctuations, and dyskinesias. Selegiline was reassigned as Non-efficacious for the prevention of dyskinesias. Other designations did not change. In a field as active in clinical trials as PD, frequent updating of therapy-based reviews is essential. We consider a 3-year period a reasonable time frame for published updates and are working to establish a Web-based mechanism to update the report in an ongoing manner.

Amantadine↗
PubMed2005

Effect of levodopa on pain threshold in Parkinson's disease: a clinical and positron emission tomography study.

Patients suffering from Parkinson's disease (PD) frequently experienced painful sensations that could be in part due to central modification of nociception. We compared pain threshold before and after administration of levodopa in PD patients and in controls, and investigated cerebral activity with positron emission tomography (PET) during experimental nociceptive stimulation. Pain threshold was determined using thermal stimulation during two randomized conditions: off and on. We performed H(2) (15)O PET analysis of regional cerebral blood flow on subjects while they received alternate randomized noxious and innocuous stimuli during off and on conditions. In off condition, pain threshold in nine PD patients was significantly lower than in nine controls. Administration of levodopa significantly raised pain threshold in PD patients but not in controls. During off condition, there was a significant increase in pain-induced activation in right insula and prefrontal and left anterior cingulate cortices in PD compared to control group. Levodopa significantly reduced pain-induced activation in these areas in PD. This study shows that pain threshold is lower in PD patients but returns to normal ranges after levodopa administration. Moreover, PD patients have higher pain-induced activation in nociceptive pathways, which can be reduced by levodopa.

Aged↗
PubMed2005

Rasagiline in the pharmacotherapy of Parkinson's disease--a review.

Despite the current efficacious symptomatic approaches, the search is on for new therapies for Parkinson's disease that can control the cardinal symptoms of the disease (tremor, rigidity and bradykinesia), control/prevent motor complications induced by long-term levodopa, act on non-motor disease symptoms (dementia, dysautonomia, pain, insomnia, falls) and halt disease progression. Rasagiline is a monoamine oxidase-B inhibitor that has demonstrated efficacy against the cardinal symptoms of Parkinson's disease when used as monotherapy in early Parkinson's disease, and as an adjunct to levodopa in advanced disease stages. It reduces the duration and severity of poor symptom response episodes in fluctuating patients. Preliminary results allow discussion of putative effects of rasagiline on some non-motor signs and disease progression. This article outlines the evidence surrounding the efficacy and safety of rasagiline, and discusses its potential to address some of the currently unmet needs of Parkinson's disease therapy.

Antiparkinson Agents↗
PubMed2004

Subthalamic nucleus stimulation reduces abnormal motor cortical overactivity in Parkinson disease.

BACKGROUND: Based on the basal ganglia model, it has been hypothesized that the efficacy of high-frequency stimulation of the subthalamic nucleus (STN) against parkinsonian symptoms relies on the activation of cortical premotor regions. In previous positron emission tomography activation studies, STN high-frequency stimulation was associated with selective activation of midline premotor areas during hand movements but mainly reduced the regional cerebral blood flow in movement-related areas, peculiarly at rest. OBJECTIVE: To investigate with positron emission tomography the role of regional cerebral blood flow reduction in the clinical improvement provided by STN high-frequency stimulation. METHODS: Seven patients with advanced Parkinson disease, who were markedly improved by bilateral STN high-frequency stimulation, underwent positron emission tomography with H2(15)O while the right STN electrode was turned off. The patients were studied at rest and during right-hand movements in 3 electrode conditions: no stimulation, inefficient low-frequency stimulation, and efficient high-frequency stimulation. RESULTS: The main effect of high-frequency stimulation was to reduce regional cerebral blood flow in the left primary sensorimotor cortex, the lateral premotor cortex, the right cerebellum, and the midline premotor areas. The selective activation of the anterior cingulate cortex and the left primary sensorimotor cortex during hand movement under STN high-frequency stimulation was attributed to decreased regional cerebral blood flow at rest, rather than increased activation induced by STN high-frequency stimulation. Akinesia was correlated with the abnormal overactivity in the contralateral primary sensorimotor cortex and the ipsilateral cerebellum. CONCLUSION: High-frequency stimulation of the STN acts through the reduction of abnormal resting overactivity in the motor system, allowing selective cortical activation during movement.

Aged↗