Parkinson Disease: Rascol O

Schrag A, Barone P, Brown RG, Leentjens AF, McDonald WM, Starkstein S, Weintraub D, Poewe W, Rascol O, Sampaio C, Stebbins GT, Goetz CG. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK. · Mov Disord. · Pubmed #17394234 links to  free full text

Abstract: Depression is a common comorbid condition in Parkinson's disease (PD) and a major contributor to poor quality of life and disability. However, depression can be difficult to assess in patients with PD due to overlapping symptoms and difficulties in the assessment of depression in cognitively impaired patients. As several rating scales have been used to assess depression in PD (dPD), the Movement Disorder Society commissioned a task force to assess their clinimetric properties and make clinical recommendations regarding their use. A systematic literature review was conducted to explore the use of depression scales in PD and determine which scales should be selected for this review. The scales reviewed were the Beck Depression Inventory (BDI), Hamilton Depression Scale (Ham-D), Hospital Anxiety and Depression Scale (HADS), Zung Self-Rating Depression Scale (SDS), Geriatric Depression Scale (GDS), Montgomery-Asberg Depression Rating Scale (MADRS), Unified Parkinson's Disease Rating Scale (UPDRS) Part I, Cornell Scale for the Assessment of Depression in Dementia (CSDD), and the Center for Epidemiologic Studies Depression Scale (CES-D). Seven clinical researchers with clinical and research experience in the assessment of dPD were assigned to review the scales using a structured format. The most appropriate scale is dependent on the clinical or research goal. However, observer-rated scales are preferred if the study or clinical situation permits. For screening purposes, the HAM-D, BDI, HADS, MADRS, and GDS are valid in dPD. The CES-D and CSDD are alternative instruments that need validation in dPD. For measurement of severity of depressive symptoms, the Ham-D, MADRS, BDI, and SDS scales are recommended. Further studies are needed to validate the CSDD, which could be particularly useful for the assessment of severity of dPD in patients with comorbid dementia. To account for overlapping motor and nonmotor symptoms of depression, adjusted instrument cutoff scores may be needed for dPD, and scales to assess severity of motor symptoms (e.g., UPDRS) should also be included to help adjust for confounding factors. The HADS and the GDS include limited motor symptom assessment and may, therefore, be most useful in rating depression severity across a range of PD severity; however, these scales appear insensitive in severe depression. The complex and time-consuming task of developing a new scale to measure depression specifically for patients with PD is currently not warranted.

Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, Larsen JP, Lees A, Oertel W, Poewe W, Rascol O, Sampaio C, Anonymous00036, Anonymous00037. · Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Eur J Neurol. · Pubmed #17038032 No free full text.

Abstract: To provide evidence-based recommendations for the management of late (complicated) Parkinson's disease (PD), based on a review of the literature. Complicated PD refers to patients suffering from the classical motor syndrome of PD along with other motor or non-motor complications, either disease-related (e.g. freezing) or treatment-related (e.g. dyskinesias or hallucinations). MEDLINE, Cochrane Library and INAHTA database literature searches were conducted. National guidelines were requested from all EFNS societies. Non-European guidelines were searched for using MEDLINE. Part II of the guidelines deals with treatment of motor and neuropsychiatric complications and autonomic disturbances. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement ('good practice point') is made.

Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, Larsen JP, Lees A, Oertel W, Poewe W, Rascol O, Sampaio C, Anonymous00034, Anonymous00035. · Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Eur J Neurol. · Pubmed #17038031 No free full text.

Abstract: The aim of the study was to provide evidence-based recommendations for the management of early (uncomplicated) Parkinson's disease (PD), based on a review of the literature. Uncomplicated PD refers to patients suffering from the classical motor syndrome of PD only, without treatment-induced motor complications and without neuropsychiatric or autonomic problems. MEDLINE, Cochrane Library and International Network of Agencies for Health Technology Assessment (INAHTA) database literature searches were conducted. National guidelines were requested from all European Federation of Neurological Societies (EFNS) societies. Non-European guidelines were searched for using MEDLINE. Part I of the guidelines deals with prevention of disease progression, symptomatic treatment of motor features (parkinsonism), and prevention of motor and neuropsychiatric complications of therapy. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement (good practice point) is made.

Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, Giladi N, Holloway RG, Moore CG, Wenning GK, Yahr MD, Seidl L, Anonymous00253. · Rush University Medical Center, 1725 W. Harrison Street, Chicago, IL 60612, USA. · Mov Disord. · Pubmed #15372591 links to  free full text

Abstract: The Movement Disorder Society Task Force for Rating Scales for Parkinson's disease (PD) prepared a critique of the Hoehn and Yahr scale (HY). Strengths of the HY scale include its wide utilization and acceptance. Progressively higher stages correlate with neuroimaging studies of dopaminergic loss, and high correlations exist between the HY scale and some standardized scales of motor impairment, disability, and quality of life. Weaknesses include the scale's mixing of impairment and disability and its non-linearity. Because the HY scale is weighted heavily toward postural instability as the primary index of disease severity, it does not capture completely impairments or disability from other motor features of PD and gives no information on nonmotor problems. Direct clinimetric testing of the HY scale has been very limited, but the scale fulfills at least some criteria for reliability and validity, especially for the midranges of the scale (Stages 2-4). Although a "modified HY scale" that includes 0.5 increments has been adopted widely, no clinimetric data are available on this adaptation. The Task Force recommends that: (1) the HY scale be used in its original form for demographic presentation of patient groups; (2) when the HY scale is used for group description, medians and ranges should be reported and analysis of changes should use nonparametric methods; (3) in research settings, the HY scale is useful primarily for defining inclusion/exclusion criteria; (4) to retain simplicity, clinicians should "rate what you see" and therefore incorporate comorbidities when assigning a HY stage; and (5) because of the wide usage of the modified HY scale with 0.5 increments, this adaptation warrants clinimetric testing. Without such testing, however, the original five-point scales should be maintained.

Seppi K, Rascol O. · No affiliation provided · Neurology. · Pubmed #17709701 No free full text.

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Rascol O. · No affiliation provided · Mov Disord. · Pubmed #16673409 No free full text.

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Rascol O. · No affiliation provided · Neurology. · Pubmed #16217047 No free full text.

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Rascol O, Perez-Lloret S. · Clinical Investigation Center and Neurosciences Institute, Department of Clinical Pharmacology, Faculty of Medicine, INSERM U 825, Toulouse, France. · Expert Opin Pharmacother. · Pubmed #19239399 No free full text.

Abstract: BACKGROUND: Rotigotine is a non-ergot dopamine agonist that has been developed as a new transdermal formulation, and is indicated for use in early (USA and Europe) and advanced (Europe only) Parkinson's disease (PD). The potential advantages of the rotigotine patch include immediacy of effect onset as intestinal absorption in unneeded, constant drug delivery, and ease of use via application of a once-daily adhesive patch. An interesting element of this profile is constant drug delivery, which may avoid pulsatile dopaminergic stimulation, which has been postulated to be related to the development of motor complications. OBJECTIVE: To consider the evidence surrounding the profile of rotigotine and, in particular, whether its constant delivery system offers significant benefits to the treatment of early and advanced PD. METHODS: Source material was identified using a PubMed search for the term 'rotigotine' (up to March 2008). The review focuses only on publications related to the rotigotine indication for PD. RESULTS/CONCLUSION: The rotigotine transdermal patch demonstrates clinical efficacy, alongside a tolerability profile that appears to be well within the range of that observed with other non-ergot dopamine agonists. The once-daily patch formulation may favour compliance but, in similarity with the other theoretical advantages of constant drug delivery (for example reduced emergence of motor complications, improved tolerance to peripheral AEs), requires further detailed study.

Rascol O. · Clinical Investigation Center, Department of Neurosciences, University Hospital of Toulouse, INSERM UMR 825, Toulouse, France. · Neurology. · Pubmed #19221315 No free full text.

Abstract: "Neuroprotective" compounds that block dopamine cell death are expected to slow the progression of the neurologic symptoms of Parkinson disease (PD) and therefore "modify" the disease course. However, presently, no fully satisfying efficacy "disease-modification" study design exists, and no drug has yet been approved for that indication. This is inherent to the slow progression of PD with respect to the limited time for patient follow-up and exposure to placebo, the modest effects of investigated drugs, and the confounding effects of symptomatic medications used to treat patients with PD. Disease-modification trials assessing drug efficacy on PD progression are currently prospective, randomized, parallel-group, placebo-controlled, long-term (1-3 year) studies. Untreated patients with early PD represent the main target population because more neurons remain for protection, PD may progress faster, and symptomatic medications are not needed at this stage. "Long lasting" prevention/postponement of disability is a relevant objective for such trials and two main types of outcome and analysis are proposed: slopes analysis of cardinal clinical feature progression (Unified PD Rating Scale, UPDRS) or survival curve analysis of "time to emergence" of clinically relevant milestones (time to dopaminergic therapy, Hoehn and Yahr stage III, etc.). The use of biomarkers remains investigational. Wash-out and delayed-start designs have been proposed to disentangle symptomatic and neuroprotective mechanisms, although this clarification might not be so important practically, as long as the effect on disability is large and long-lasting. To observe clinically relevant changes, several years of follow-up is required, and controlled, randomized, pragmatic trials should be considered when establishing clinical development plans.

Rascol O. · Laboratoire de pharmacologie clinique, Centre d'Investigation clinique, INSERM U825, pôle neurosciences, Centre hospitalier universitaire, Toulouse. · Rev Neurol (Paris). · Pubmed #18680822 No free full text.

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Rascol O. · Department of Clinical Pharmacology, Clinical Investigation Center and Neurosciences Institute, Faculty of Medicine, 37 Allees Jules Guesde, Toulouse 31073, France. · Expert Opin Pharmacother. · Pubmed #16197359 No free full text.

Abstract: 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.

Goetz CG, Poewe W, Rascol O, Sampaio C. · Department of Neurological Sciences, Department of Pharmacology, Rush University Medical Center, Chicago, Illinois 60612, USA. · Mov Disord. · Pubmed #15818599 links to  free full text

Abstract: 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.

Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Bonucelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P, Katzenschlager R, Langston WJ, LeWitt P, Melamed E, Mena MA, Michel PP, Mytilineou C, Obeso JA, Poewe W, Quinn N, Raisman-Vozari R, Rajput AH, Rascol O, Sampaio C, Stocchi F. · Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Mov Disord. · Pubmed #15372588 No free full text.

Abstract: Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

Rascol O, Ferreira JJ, Payoux P, Brefel-Courbon Ch, Montastruc JL. · Service de Pharmacologie, Faculté de Médecine, Centre d'Investigations Cliniques, INSERM U455, 37, Allées Jules-Guesde, 31073 Toulouse, France. · Rev Neurol (Paris). · Pubmed #12690671 No free full text.

Abstract: There are three main therapeutic strategies to manage levodopa-induced dyskinesias in parkinsonian patients: (1) prevent the occurrence of the priming phenomenon which generates the abnormal movements, (2) avoid the expression of dyskinesias in already primed brain with antidyskinetic symptomatic interventions and (3) reverse, once primed, the changes that occurred in the basal ganglia to induce dyskinesias. To prevent, at least partly, priming for dyskinesias is attempted by the early use of dopamine D2 agonists, which delays the need for levodopa. To avoid the expression of dyskinesias in already primed patients, amantadine is presently the most efficacious symptomatic medication, while functional stereotactic surgery is required in the most severe cases. There are several ways to try to reverse, at least partly, dyskinesia priming. The strategy is to reduce as much as possible (ideally completely) the daily dose of levodopa, by the mean of adjunct interventions like high doses of oral agonists, or more efficiently, with apormorphine subcutaneous infusion or subthalamic deep brain stimulation.

Rascol O, Payoux P, Ory F, Ferreira JJ, Brefel-Courbon C, Montastruc JL. · Clinical Investigation Centre and Department of Clinical Pharmacology, Toulouse, University Hospital France. · Ann Neurol. · Pubmed #12666094 No free full text.

Abstract: Levodopa and other dopaminergic medications drastically improve the motor symptoms and quality of life of patients with Parkinson's disease in the early stages of the disease. However, once the "honeymoon" period has waned, usually after a few years of dopaminergic therapy, patients become progressively more disabled despite an ever more complex combination of available antiparkinsonian treatments. Sooner or later, they suffer from "dopa-resistant" motor symptoms (speech impairment, abnormal posture, gait and balance problems), "dopa-resistant" nonmotor signs (autonomic dysfunction, mood and cognitive impairment, sleep problems, pain) and/or drug-related side effects (especially psychosis, motor fluctuations, and dyskinesias). Therefore, the current antiparkinsonian therapy cannot be considered as ideal with regard to both efficacy and safety.

Rascol O, Brefel-Courbon C, Payoux P, Ferreira J. · Department of Clinical Pharmacology and Pharmacovigilance, Clinical Investigations Centre, INSERM, Toulouse, France. · Adv Neurol. · Pubmed #12442679 No free full text.

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Rascol O, Payoux P, Ferreira J, Brefel-Courbon C. · Department of Clinical Pharmacology, Clinical Investigation Center, INSERM U455, Toulouse University Hospital, Toulouse, France. · Parkinsonism Relat Disord. · Pubmed #12217623 No free full text.

Abstract: A major problem in the management of early Parkinson's disease is to choose the first medication to prescribe. This decision should rely on the level of available clinical evidence, largely based, at least for efficacy, on the results of randomised clinical trials. Safety and costs are also crucial to consider. Other factors like for example pathophysiological concepts, individual experience, marketing pressure, socio-economical environment, patients needs and expectations have, however, also their own influence. Levodopa is efficacious and cheap, but induces long-term motor complications. The early use of dopamine agonists is more and more frequently promoted, because large prospective L-dopa-controlled trials demonstrated that this strategy reduces the risk of such long-term complications. Integrating individual clinical expertise to the best available external clinical evidence (evidence-based medicine) is the best strategy in making decisions about the care of individual patients.

Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. · Clinical Investigation Centre and the Department of Clinical Pharmacology, INSERM U 455, Toulouse University Hospital, 31073 Toulouse Cedex, France. · Lancet. · Pubmed #12047983 No free full text.

Abstract: We did a systematic review, with a uniform method of assessment of efficacy and safety, to assess the different interventions available for the management of Parkinson's disease (drugs, surgical interventions, and physical treatments) with respect to the following indications: prevention of disease progression, symptomatic treatment of motor features (parkinsonism), symptomatic control of motor complications, prevention of motor complications, and symptomatic treatment of non-motor features. Our aim was not to define practice guidelines, but rather to improve clinicians' knowledge of the presently available published clinical evidence, based mainly on randomised controlled trials. We hope that our review will help doctors to incorporate this background into their own decision-making strategy to make appropriate choices with respect to the treatment of individual patients with Parkinson's disease.

Rascol O, Ferreira J, Montastruc JL. · Laboratoire de Pharmacologie Médicale et Clinique, Centre d'Investigation Clinique, Unité de Neuropharmacologie, INSERM U455, Centre Hospitalier Universitaire de Toulouse, France. · Rev Neurol (Paris). · Pubmed #11885528 No free full text.

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Chollet F, Loubinoux I, Pariente J, Carel C, Albucher JF, Rascol O, Guiraud-Chaumeil B. · INSERM U455 et Fédération de Neurologie, Hôpital Purpan, Place Baylac, 31059 Toulouse, France. · Rev Neurol (Paris). · Pubmed #11677404 No free full text.

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Rascol O, Ferreira JJ, Thalamas C, Galitsky M, Montastruc JL. · Department of Clinical Pharmacology, Faculty of Medicine, 31073 Toulouse, France. · Adv Neurol. · Pubmed #11553990 No free full text.

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Senard JM, Brefel-Courbon C, Rascol O, Montastruc JL. · Laboratory of Medical and Clinical Pharmacology, INSERM U317, Faculty of Medicine, Paul Sabatier University, Toulouse, France. · Drugs Aging. · Pubmed #11482743 No free full text.

Abstract: Orthostatic hypotension is common in elderly patients, and is now considered to be an important prognostic factor for cognitive decline and mortality. In patients with Parkinson's disease, the prevalence of symptomatic orthostatic hypotension may be as high as 20%. Two factors could explain this high prevalence. First, dopaminergic drugs may induce or worsen orthostatic hypotension. Secondly, Parkinson's disease is a cause of primary autonomic failure with an involvement of the peripheral autonomic system as shown by the ubiquitous distribution of Lewy bodies and reduced iobenguane [metaiodobenzylguanidine (MIBG)] cardiac uptake. These pathological and pharmacological characteristics clearly differentiate autonomic failure of Parkinson's disease from multiple system atrophy. If autonomic abnormalities appear to be present from the first stage of the disease, early onset (within the first year) of symptomatic orthostatic hypotension in the course of parkinsonism can be considered as an exclusion criteria for idiopathic Parkinson's disease. No specific clinical trials have evaluated the effects of antihypotensive drugs in patients with Parkinson's disease and thus no specific therapeutic strategy can be recommended. The management of orthostatic hypotension in patients with Parkinson's disease should always start with patient education and nonpharmacological treatment. Drug therapy should be reserved for symptomatic patients who do not get benefit from nonpharmacological management. Among the available drugs, alpha1-adrenergic agonists (mainly midodrine) or plasma volume expanders (mainly fludrocortisone) are the most frequently used. There are also some drugs that are currently investigational such as yohimbine and droxidopa. Other drugs such as desmopressin or octreotide may be of interest in some situations. Domperidone is widely used in patients with parkinsonism with no proven effect on orthostatic hypotension.

Rascol O, Fabre N, Brefel-Courbon C, Montastruc JL. · Department of Clinical Pharmacology, Toulouse University, 31073 Toulouse, France. · Adv Neurol. · Pubmed #11347230 No free full text.

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Olanow W, Schapira AH, Rascol O. · Dept of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Trends Neurosci. · Pubmed #11052229 No free full text.

Abstract: Chronic L-dopa therapy is associated with the development of motor complications in the majority of Parkinson's disease (PD) patients. Although the precise mechanism responsible for these events is not known, increasing laboratory and clinical evidence points to a sequence of events that is initiated by abnormal pulsatile stimulation of dopamine receptors by the intermittent administration of agents with short half-lives such as L-dopa. Initiating therapy with a long-acting dopamine agonist has been shown to delay the onset and reduce the severity of motor complications in MPTP monkeys and PD patients. Administering L-dopa with a catechol-O-methyltransferase (COMT) inhibitor to block its peripheral metabolism increases its plasma half-life and might have a similar effect. Thus, a rational strategy for treating PD would be to initiate therapy with a long-acting dopamine-receptor agonist and supplement at the appropriate time with L-dopa combined with a COMT inhibitor.

Rascol O. · Laboratoire de Pharmacologie Mèdicale et Clinique, Faculté de Médicine, Toulouse, France. · J Neurol. · Pubmed #10991666 No free full text.

Abstract: The clinical management of levodopa-induced dyskinesia is difficult. Once present, dyskinesias are only partially improved by lowering the daily dose of levodopa and co-administering a D2 dopamine agonist. Therefore it appears to be necessary to use an NMDA-antagonist, such as amantadine, as an antidyskinetic agent. Clozapine may also improve dyskinesia without worsening akinesia, but it requires strict haematological monitoring. A long-term continuous subcutaneous infusion of apomorphine significantly reduces the dose of levodopa required, thereby markedly reducing dyskinesia, but this is difficult from a practical point of view. If none of these pharmacological strategies is successful, surgery should then be considered. Since the management of established levodopa-induced dyskinesia is difficult and often disappointing, efforts should be encouraged to try to prevent the occurrence of dyskinesia, before levodopa priming. This seems to be best achieved by the use of D2 dopamine agonists in the early stages of the disease, before, or in combination with, levodopa.