Off-time Treatment Options for Parkinson’s Disease

Funding Information: Margherita Fabbri declares the following conflicts of interest: honoraria to speak: BIAL and AbbVie; Consultancy/ LVL Médicale. Raquel Barbosa declares the following conflicts of interest: financial support by Fundação para a Ciência e Tecnologia (FCT) through a Ph.D. Scholarship (SFRH/BD/143797/2019) and Prémio João Lobo Antunes by Santa Casa da Misericórdia de Lisboa. Olivier Rascol declares the following conficts of interest: advisory board and consultancy: BIAL; advisory boards and consultancy: AbbVie, Adamas, Acorda, Addex, AlzProtect, Apopharma, Astrazeneca, Axovant, Biogen, Britannia, Buckwang, Cerespir, Clevexel, Denali, INC Reasearch, Lundbeck, Lupin, Merck, MundiPharma, Neuratris, Neuroderm, Novartis, ONO Pharma, Osmotica, Parexel, Pfzer, Prexton Therapeutics, Quintiles, Roche, Sanof, Servier, Sunovion, Théranexus, Takeda, Teva, UCB, Vectura, Watermark Research, XenoPort, XO, and Zambon; grant: Agence Nationale de la Recherche (ANR), CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, MJFox Foundation, Programme Hospitalier de Recherche Clinique, European Commission (FP7, H2020), and Cure Parkinson IK; other: grant to participate in a symposium and contribute to the review of an IPMDS article . Publisher Copyright: © 2023, The Author(s).Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in responsiveness to dopaminergic drug treatments. MF are characterized by the loss of a stable response to levodopa over the nychthemeron with the reappearance of motor (and non-motor) parkinsonian clinical signs at various moments during the day and night. They normally appear after a few years of levodopa treatment and with a variable, though overall increasing severity, over the disease course. The armamentarium of first-line treatment options has widened in the last decade with new once-a-daily compounds, including a catechol O-methyltransferase inhibitor – Opicapone-, two MAO-B inhibitors plus channel blocker – Zonisamide and Safinamide and one amantadine extended-release formulation – ADS5012. In addition to apomorphine injection or oral levodopa dispersible tablets, which have been available for a long time, new on-demand therapies such as apomorphine sublingual or levodopa inhaled formulations have recently shown efficacy as rescue therapies for Off-time treatment. When the management of MF becomes difficult in spite of oral/on-demand options, more complex therapies should be considered, including surgical, i.e. deep brain stimulation, or device-aided therapies with pump systems delivering continuous subcutaneous or intestinal levodopa or subcutaneous apomorphine formulation. Older and less commonly used ablative techniques (radiofrequency pallidotomy) may also be effective while there is still scarce data regarding Off-time reduction using a new lesional approach, i.e. magnetic resonance-guided focused ultrasound. The choice between the different advanced therapies options is a shared decision that should consider physician opinion on contraindication/main target symptom, patients’ preference, caregiver’s availability together with public health systems and socio-economic environment. The choice of the right/first add-on treatment is still a matter of debate as well as the proper time for an advanced therapy to be considered. In this narrative review, we discuss all the above cited aspects of MF in patients with PD, including their phenomenology, management, by means of pharmacological and advanced therapies, on-going clinical trials and future research and treatment perspectives.publishersversionepub_ahead_of_prin

New treatments for levodopa-induced motor complications

Levodopa (l-dopa)-induced motor complications, including motor fluctuations and dyskinesia, affect almost all patients with Parkinson's disease (PD) at some point during the disease course, with relevant implications in global health status. Various dopaminergic and nondopaminergic pharmacological approaches as well as more invasive strategies including devices and functional surgery are available to manage such complications. In spite of undisputable improvements during the last decades, many patients remain significantly disabled, and a fully satisfying management of l-dopa-induced motor complications is still an important unmet need of PD therapy. This article reviews the recent trial results published from 2013 to April 2015 about pharmacological and nonpharmacological interventions to treat motor complications. Randomized controlled trials conducted in patients suffering from already established complications showed that new levodopa (l-dopa) formulations such as intrajejunal l-dopa-carbidopa infusion and bilayered extended-release l-dopa-carbidopa (IPX066) can improve motor fluctuations. Positive results were also obtained with a new monoamine oxidase B (MAO-B) inhibitor (safinamide) and a catechol-O-methyltransferase COMT inhibitor (opicapone). Pilot data suggest that new formulations of dopamine agonists (inhaled apomorphine) are also of potential interest. The development of novel nondopaminergic adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) to treat motor fluctuations showed conflicting results in phase 2 and phase 3 trials. For dyskinesia, trials with new amantadine extended-release formulations confirmed the interest of the glutamatergic N-methyl-d-aspartate (NMDA) antagonist approach. Positive pilot antidyskinetic effects were also recently reported using serotonin agents such as eltoprazine and glutamate mGluR5 modulators such as mavoglurant. However, the translation to clinical practice of such innovative concepts remains challenging, because subsequent phase 2 trials conducted to confirm the antidyskynetic effects of mavoglurant failed, leading to the interruption of the development of this compound for this indication.Fil: Rascol, Olivier. Universite de Toulose - Le Mirail; Francia. Inserm; FranciaFil: Pérez Lloret, Santiago. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Ferreira, Joaquim. Instituto de Medicina Molecular; Portugal. Universidade de Lisboa; Portuga

Nonmotor Symptoms Groups in Parkinson's Disease Patients: Results of a Pilot, Exploratory Study

Nonmotor symptoms (NMS) like neuropsychiatric symptoms, sleep disturbances or autonomic symptoms are a common feature of Parkinson's disease (PD). To explore the existence of groups of NMS and to relate them to PD characteristics, 71 idiopathic non-demented PD out-patients were recruited. Sleep was evaluated by the PD Sleep Scale (PDSS). Several neuropsychiatric, gastrointestinal and urogenital symptoms were obtained from the NMSQuest. Sialorrhea or dysphagia severity was obtained from the Unified PD Rating Scale activities of daily living section. MADRS depression scale was also administered. Exploratory factor analysis revealed the presence of 5 factors, explaining 70% of variance. The first factor included PDSS measurement of sleep quality, nocturnal restlessness, off-related problems and daytime somnolence; the second factor included nocturia (PDSS) and nocturnal activity; the third one included gastrointestinal and genitourinary symptoms; the forth one included nocturnal psychosis (PDSS), sialorrhea and dysphagia (UPDRS); and the last one included the MADRS score as well as neuropsychiatric symptoms. Sleep disorders correlated with presence of wearing-off, nocturia with age >69 years, and nocturnal psychosis with levodopa equivalent dose or UPDRS II score. Neuropsychiatric symptoms correlated with UPDRS II+III score and non-tricyclic antidepressants. These results support the occurrence of significant NMS grouping in PD patients

Emerging analgesic drugs for Parkinson's disease

Introduction: Pain affects between 40 and 85% of Parkinson's disease (PD) patients. It is a frequently disabling and overlooked feature, which can significantly reduce health-related quality of life. Unfortunately, there are no universally recommended treatments for this condition. Areas covered: Evidence about the efficacy and safety of available analgesic treatments is summarized in this review. Potential targets for upcoming therapies are then discussed in light of what is currently known about the physiopathology of pain in PD. Protocols for efficacy and safety assessment of novel analgesic therapies are discussed. Finally, critical aspects of study protocol design such as patient selection or outcomes to be evaluated are discussed. Expert opinion: Preliminary results indicate that duloxetine, cranial electrotherapy stimulation, rotigotine, subthalamic or pallidum nuclei stimulation or lesion or levodopa could be effective for treating pain in PD. Similarly, some case reports indicate that repetitive transcranial magnetic stimulation (rTMS) or apomorphine could be effective for relieving painful off-period dystonia. Clinical trials with rTMS or oxycodone/naloxone prolonged-release tablets for neuropathic pain or botulinum toxin for off-period dystonia are underway. Success of clinical trials about analgesic strategies in PD will depend on the selection of the right PD population to be treated, according to the type of pain, and the proper selection of study outcomes and follow-up of international recommendations.Fil: Perez Lloret, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; Francia. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: Rey, María Verónica. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; Francia. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: Dellapina, Estelle. Université Toulouse III Paul Sabatier; FranciaFil: Pellaprat, Jean. Université Toulouse III Paul Sabatier; FranciaFil: Brefel Courbon, Christine. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; FranciaFil: Rascol, Olivier. Centre National de la Recherche Scientifique; Francia. Université Toulouse III Paul Sabatier; Franci

Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach

© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.Introduction: There is currently a resurgence of levodopa as the initial treatment of choice for most patients with Parkinson's disease, albeit at lower doses than previously used. The addition of adjuvant treatments (including MAO-B inhibitors, COMT inhibitors and dopamine agonists) is an established strategy to reduce motor complications that develop with sustained levodopa therapy. Areas covered: In this narrative review, the authors discuss the evidence underpinning current levodopa optimization strategies, during early disease and once motor complications occur. To support the discussion, the authors performed a broad PubMed search with the terms 'levodopa/L-dopa/L-Dopa, and Parkinson's disease,' restricted to clinical trials. There is now a wealth of evidence that improving levodopa delivery to the brain improves outcomes and we discuss how agents can be combined earlier in the course of disease to leverage the full potential of this strategy. Expert opinion: Levodopa remains the cornerstone of antiparkinsonian therapy. Several promising advances in formulation have been made and include novel extended-release oral drugs as well as non-oral delivery systems. However, evidence has long suggested that anti-parkinsonian medications may be better used in combination earlier in the disease, and consequently patients will benefit from low doses of several agents rather than ever larger levodopa doses.This paper was supported by BIAL, who procured medical writing support but had no other influence on the content of the paper. No author received any remuneration for the preparation of this article.info:eu-repo/semantics/publishedVersio

Drugs associated with restless legs syndrome: A case/noncase study in the French pharmacovigilance database

BACKGROUND: Several case reports have suggested that drugs could induce restless legs syndrome. However, no systematic review of this adverse drug reaction (ADR) in a pharmacovigilance database has been published. OBJECTIVE: To assess the frequency of restless legs syndrome in the French Pharmacovigilance Database. METHODS: We selected all ADR reports from January 1, 1984 to December 31, 2009 coded as restless legs syndrome. Restless legs syndrome diagnosis was validated from case descriptions. Using a case/noncase approach, reporting odds ratio and 95% confidence interval were calculated for ''suspected'' drugs with 2 or more observations. RESULTS: Twenty-six ADR reports were found. Four cases were excluded because of alternative diagnosis. Fourteen cases were women (64%). Median age was 57. Most frequently suspected drugs were antidepressants (reporting odds ratio, 15.9 [6.4-39.7]; amitriptyline, escitalopram, mianserine, mirtazapine, duloxetine), neuroleptics (17.8 [6.1-51.7]; thioridazine, loxapine, risperidone, aripiprazole) or tramadol (18.2 [6.3-52.8]). CONCLUSIONS: Restless legs syndrome is a very rare ADR that was more frequently reported in association with antidepressants, neuroleptics, or tramadol.Fil: Perez Lloret, Santiago. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rey, María Verónica. Centre National de la Recherche Scientifique; FranciaFil: Bondon Guitton, Emmanuelle. Inserm; FranciaFil: Rascol, Olivier. Centre National de la Recherche Scientifique; FranciaFil: Montastruc, And Jean-Louis. Inserm; Franci

CASSIOPE: An expert system for conserved regions searches

<p>Abstract</p> <p>Background</p> <p>Understanding genome evolution provides insight into biological mechanisms. For many years comparative genomics and analysis of conserved chromosomal regions have helped to unravel the mechanisms involved in genome evolution and their implications for the study of biological systems. Detection of conserved regions (descending from a common ancestor) not only helps clarify genome evolution but also makes it possible to identify quantitative trait loci (QTLs) and investigate gene function.</p> <p>The identification and comparison of conserved regions on a genome scale is computationally intensive, making process automation essential. Three key requirements are necessary: consideration of phylogeny to identify orthologs between multiple species, frequent updating of the annotation and panel of compared genomes and computation of statistical tests to assess the significance of identified conserved gene clusters.</p> <p>Results</p> <p>We developed a modular system superimposed on a multi-agent framework, called CASSIOPE (Clever Agent System for Synteny Inheritance and Other Phenomena in Evolution). CASSIOPE automatically identifies statistically significant conserved regions between multiple genomes based on automated phylogenies and statistical testing. Conserved regions were searched for in 19 species and 1,561 hits were found. To our knowledge, CASSIOPE is the first system to date that integrates evolutionary biology-based concepts and fulfills all three key requirements stated above. All results are available at <url>http://194.57.197.245/cassiopeWeb/displayCluster?clusterId=1</url></p> <p>Conclusion</p> <p>CASSIOPE makes it possible to study conserved regions from a chosen query genetic region and to infer conserved gene clusters based on phylogenies and statistical tests assessing the significance of these conserved regions.</p> <p><b>Source code </b>is freely available, please contact: <email>[email protected]</email></p

Subjective sleep dysfunction and insomnia symptoms in Parkinson's disease: Insights from a cross-sectional evaluation of the French CoPark cohort

Introduction: Twenty-seven to 80% of patients with Parkinson's Disease (PD) complain of subjective sleep dysfunction and insomnia symptoms. Our aim is to describe the prevalence and features of subjective sleep dysfunction and insomnia symptoms in patients with PD compared to other patients. Methods: Cross-sectional analysis of 636 adult PD patients compared to 143 age and sex-matched non-PD control patients consulting their general practitioners. Insomnia symptoms and other sleep features were assessed by the Pittsburgh Sleep Quality Index (PSQI), a global score > 5 defining impaired sleep. The Chi-square test or the Student's t-test were used to assess the potential clinical and demographic differences between groups and between PD patients with vs. without sleep dysfunction. Logistic regression analysis was employed to test multivariate effects. Results: Sleep dysfunction and insomnia symptoms were more frequent in PD patients compared to control patients (63 vs. 45%, p = 0.001). Female gender, PD duration, presence of depression and anxiety were associated with the presence of insomnia in PD. Subjective sleep efficiency, habitual sleep quality, sleep disturbance and daytime dysfunction, but not sleep latency, were reduced in PD patients compared to controls. Conclusions: The prevalence of sleep dysfunction is higher in PD than in other general medical conditions. Insomnia in PD seems to affect sleep maintenance and consolidation, but not sleep onset.Fil: Ratti, Pietro Luca. Université Paul Sabatier; Francia. Inserm; Francia. Sleep and Epilepsy Center; Suiza. Toulouse University Hospital; FranciaFil: Negre Pages, Laurence. Toulouse University Hospital; Francia. Université Paul Sabatier; FranciaFil: Pérez Lloret, Santiago. Toulouse University Hospital; Francia. Université Paul Sabatier; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Manni, Raffaele. Istituto di Ricovero e Cura a Carattere Scientifico. Istituto Neurologico Nazionale a Carattere Scientifico; ItaliaFil: Damier, Philippe. Universite de Nantes; FranciaFil: Tison, Francois. Universite de Bordeaux; FranciaFil: Destée, Alain. Centre Hospitalier Universitaire de Lille. Pôle de Neurologie. Service de Neurologie et pathologie du mouvement; FranciaFil: Rascol, Olivier. Toulouse University Hospital; Francia. Inserm; Francia. Toulouse University Hospital; Francia. Université Paul Sabatier; Franci

Prevalence and pharmacological factors associated with impulse-control disorder symptoms in patients with parkinson disease

BACKGROUND: Impulse-control disorders (ICDs) occur in patients with Parkinson disease (PD), especially in younger patients on dopamine therapies. OBJECTIVE: To assess the prevalence of ICD symptoms and its pharmacological correlations in a sample of French patients with PD and without PD (poststroke). METHODS: Outpatients with PD and without PD (poststroke) were screened for compulsive behaviors related to hypersexuality, compulsive shopping, pathological gambling, or compulsive eating by means of the Questionnaire for Impulse-Control Disorders-short version. Full medical history and Unified Parkinson's Disease Rating Scale scores were also recorded. Dose of dopamine agonists were converted to defined daily doses (DDDs), according to the World Health Organization Anatomical Therapeutic Chemical classification system classification system. RESULTS: Two hundred three patients with PD and 52 patients without PD were recruited (mean ± SD age, 67 ± 1 vs 69 ± 2, P= 0.4; males: 62% vs 55% P= 0.2). Symptoms of ICDs were reported by 0% of poststroke patients and 25% of the patients with PD (P < 0.001). Hypersexuality was reported by 10% of the patients with PD, compulsive shopping by 6%, pathological gambling by 3%, and compulsive eating by 14%. A logistic regression analysis found that age younger than 68 years (odds ratio [OR], 3.3; 95% confidence interval, 1.6-6.6) and exposure to dopamine agonists (OR, 20.3; 95% confidence interval, 2.7-65.0) or monoaminooxidase-B inhibitor (OR, 3.7; 95% confidence interval, 1.1-12.6) were significant factors associated with increased ICD frequency. Patients with ICD symptoms were exposed to higher dopamine doses than those without them (1.6 ± 0.1 vs 1.0 ± 0.1 daily-defined doses; P < 0.001). A dose-response pharmacodynamic model disclosed a significant nonlinear dose-response relationship between dopamine agonists and frequency of ICD symptoms (P < 0.01). CONCLUSIONS: Impulse-control disorder symptoms were more frequent in the patients with PD than in the poststroke patients with PD. Impulse-control disorder symptoms were related to younger age and exposure to monoaminooxidase-B inhibitors, and showed a nonlinear dose-response relationship with dopamine agonists.Fil: Perez Lloret, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Inserm; FranciaFil: Rey, María Verónica. Inserm; FranciaFil: Fabre, Nelly. No especifíca;Fil: Ory, Fabienne. No especifíca;Fil: Spampinato, Umberto. No especifíca;Fil: Brefel Courbon, Christine. No especifíca;Fil: Montastruc, Jean Louis. No especifíca;Fil: Rascol, Olivier. Inserm; Franci