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

QUALITE ET CONTROLE DANS LE SECTEUR DES SERVICES : LE CAS DE L'ACCOMPAGNEMENT A LA CREATION D'ENTREPRISES

Cette communication s'intéresse à la performance des organisations oeuvrant dans le secteur des services. Elle consiste en un propos d'étape d'une recherche qui a pour objectif de répondre à la question suivante : est-il possible de déterminer des indicateurs de qualité de la relation de service susceptibles d'être utilisés comme indicateurs de performance pour le contrôle de telles organisations ? Elle s'appuie sur le cas des organisations accompagnant la création d'entreprise. L'analyse des entretiens conduits auprès de 20 créateurs d'entreprise a fait émerger trois familles de critères de qualité de la relation de service susceptibles de conduire à des indicateurs de performance. Certains critères relèvent du résultat de l'acte de service, c'est-à-dire de ce que le client reçoit durant la rencontre de service, d'autres sont liés aux perceptions des interactions qui ont lieu durant le service, d'autres enfin sont relatifs au sentiment de justice sociale.CONTROLE ; QUALITE ; INDICATEURS DE PERFORMANCE ; SERVICES

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

UNE APPROCHE COGNITIVE DE LA PERFORMANCE D'UN RESEAU : LE CAS D'UN PLAN LOCAL D'INSERTION PAR L'ECONOMIQUE

Dans un réseau inter-institutions, la question de la performance est multidimensionnelle et problématique. L'étude des représentations des acteurs d'un réseau, le Plan Local d'Insertion par l'Economique, montre que les acteurs n'ont pas besoin de s'accorder sur les buts pour agir, la convergence sur les moyens suffit. Les divergences sur les objectifs lues comme facteur de performance remettent en cause l'idée d'une vision commune des buts comme condition nécessaire à l'action organisée.Performance ; réseau ; cartographie cognitive ; cohésion

Les normes entre simplifications et complexification : le cas des entrées dans les musées et des sorties du dispositif RMI

Cette communication illustre les rapports entre simplification et complexification dans le choix de normes pour le contrôle, en se fondant sur les cas des musées et du RMI. Elle conclut, paradoxalement, que plus des organisations sont complexes, plus leur système de contrôle est simple.Contrôle; norme; complexité; musées; RMI

Cyclic properties of sand:dynamic behaviour for seismic applications

Seismic wave propagation in granular soils can induce large strain amplitudes in case of strong earthquakes. Seismic motions are irregular in frequency content and in amplitude, and have three different components in orthogonal directions. In this context, the main objective of this PhD research deals with nonlinear effects observed in granular soils under such complex loadings. The assumptions and simplifications usually considered for representing seismic loadings are evaluated, focusing on two main aspects: (i) cyclic stress frequency applied to the sample (ii) superposition of two independent stresses. For that purpose, the nonlinear behaviour of two different sands, Leman Sand and Fonderie Sand, is explored with cyclic and seismic triaxial tests. These tests are performed with unidirectional or bidirectional loadings, at medium to high strain amplitude, and in the earthquake frequency range. A dynamic triaxial press was developed to perform such tests, with dry and undrained saturated sand samples. Axial and lateral stresses can be applied independently with large amplitudes for various loading shapes. An innovative non-contact measurement technique was developed to continuously monitor the sample radius; this testing equipment is based on three laser sensors, set up around the triaxial cell, which detect the position of the sample surface thanks to optical triangulation. The obtained data are processed through a complex calibration system to provide the radial strain evolution at mid-height of the sample. The mounting structure supporting the sensors allows precise positioning and is equipped for manual vertical scanning of the sample profile. The first triaxial tests are performed with classical cyclic loadings, to characterize the behaviour of the two sands in pseudo-dynamic conditions. These dry and undrained saturated tests allow to describe the decrease of stiffness which leads to failure of the sand sample. Failure of undrained saturated sand occurs by liquefaction. Dry and undrained cyclic tests performed on Leman Sand at various frequencies from 0.1 to 6.5 Hz show that the behaviour of this granular material is frequency-dependent at medium to large strains. Sand stiffness, which depends on stress conditions, seems to influence the extent of frequency effects on soil behaviour: for tests with lower stiffness, the soil response to low frequency is significantly amplified (i.e. higher strain amplitude, more pore pressure increase, etc.) compared to the high frequency range. The overall rate-sensitivity may be enhanced by the angularity of the grains. Other cyclic undrained saturated tests on Leman Sand demonstrate that the superposition of two different loadings, one axial and one lateral (bidirectional tests), induce coupling effects in the nonlinear soil response. Bidirectional effects result in an amplification of the sand response until the occurrence of cyclic liquefaction. The phase angle between axial and lateral stresses is the key parameter influencing the coupling. Moreover, the comparison between unidirectional and bidirectional irregular seismic loadings show that bidirectional conditions slightly influence undrained sand response, with conditions of amplification very similar to cyclic tests. Experimental results are finally modelled with the linear equivalent method and with a multi-mechanism elastoplastic model (ECP Hujeux). Nonlinear effects observed in laboratory experiments, and particularly the increase of strain amplitude leading to cyclic liquefaction of dense sand, are well captured by the elastoplastic model. The linear equivalent method gives a very crude approximation, even at medium strain level, and is not suitable for accurate evaluation of stiffness degradation observed during our cyclic tests. To conclude, assessing the behaviour of granular soils under earthquake loadings requires to take into account the nonlinear features of sand behaviour in terms of pore pressure generation and strain amplitude. In particular, frequency content and bidirectional loadings influence the sand response for medium to large strains. These experimental results could be considered for improving the analysis of strong ground motions. They constitute an important contribution for promoting more accurate nonlinear modelling of site effects in natural sands

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