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Background: Patient and public involvement and engagement (PPIE) in the design of trials is important, as participant experience critically impacts delivery. The Edmond J Safra Accelerating Clinical Trials in PD (EJS ACT-PD) initiative is a UK consortium designing a platform trial for disease modifying therapies in PD. Objective: The integration of PPIE in all aspects of trial design and its evaluation throughout the project. Methods: PwP and care partners were recruited to a PPIE working group (WG) via UK Parkinson's charities, investigator patient groups and participants of a Delphi study on trial design. They are supported by charity representatives, trial delivery experts, researchers and core project team members. PPIE is fully embedded within the consortium's five other WGs and steering group. The group's terms of reference, processes for effective working and PPIE evaluation were co-developed with PPIE contributors. Results: 11 PwP and 4 care partners have supported the PPIE WG and contributed to the development of processes for effective working. A mixed methods research-in-action study is ongoing to evaluate PPIE within the consortium. This includes the Patient Engagement in Research Scale -a quantitative PPIE quality measure; semi-structured interviews -identifying areas for improvement and overall impressions of involvement; process fidelity- recording adherence; project documentation review - identifying impact of PPIE on project outputs. Conclusions: We provide a practical example of PPIE in complex projects. Evaluating feasibility, experiences and impact of PPIE involvement in EJS ACT-PD will inform similar programs on effective strategies. This will help enable future patient-centered research.
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Ensayos Clínicos como Asunto , Enfermedad de Parkinson , Participación del Paciente , Humanos , Enfermedad de Parkinson/terapia , Ensayos Clínicos como Asunto/normas , Proyectos de Investigación , Participación de la Comunidad , Reino Unido , Técnica DelphiRESUMEN
BACKGROUND: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. OBJECTIVES: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. METHODS: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. RESULTS: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. CONCLUSIONS: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/diagnóstico , Índice de Severidad de la Enfermedad , Pruebas de Estado Mental y Demencia , Sociedades MédicasRESUMEN
INTRODUCTION: Parkinson's disease (PD) is a debilitating neurological disorder for which the identification of disease-modifying interventions represents a major unmet need. Diverse trial designs have attempted to mitigate challenges of population heterogeneity, efficacious symptomatic therapy and lack of outcome measures that are objective and sensitive to change in a disease modification setting. It is not clear whether consensus is emerging regarding trial design choices. Here, we report the protocol of a scoping review that will provide a contemporary update on trial design variability for disease-modifying interventions in PD. METHODS AND ANALYSIS: The Population, Intervention, Comparator, Outcome and Study design (PICOS) framework will be used to structure the review, inform study selection and analysis. The databases MEDLINE, Web of Science, Cochrane and the trial registry ClinicalTrials.gov will be systematically searched to identify published studies and registry entries in English. Two independent reviewers will screen study titles, abstracts and full text for eligibility, with disagreements being resolved through discussion or by a third reviewer where necessary. Data on general study information, eligibility criteria, outcome measures, trial design, retention and statistically significant findings will be extracted into a standardised form. Extracted data will be presented in a descriptive analysis. We will report our findings using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review extension. ETHICS AND DISSEMINATION: This work will provide an overview of variation and emerging trends in trial design choices for disease-modifying trials of PD. Due to the nature of this study, there are no ethical or safety considerations. We plan to publish our findings in a peer-reviewed journal.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Proyectos de Investigación , Literatura de Revisión como AsuntoRESUMEN
INTRODUCTION: Many people with Parkinson's (PwP) are not given the opportunity or do not have adequate access to participate in clinical research. To address this, we have codeveloped with users an online platform that connects PwP to clinical studies in their local area. It enables site staff to communicate with potential participants and aims to increase the participation of the Parkinson's community in research. This protocol outlines the mixed methods study protocol for the usability testing of the platform. METHODS AND ANALYSIS: We will seek user input to finalise the platform's design, which will then be deployed in a limited launch for beta testing. The beta version will be used as a recruitment tool for up to three studies with multiple UK sites. Usability data will be collected from the three intended user groups: PwP, care partners acting on their behalf and site study coordinators. Usability questionnaires and website analytics will be used to capture user experience quantitatively, and a purposive sample of users will be invited to provide further feedback via semistructured interviews. Quantitative data will be analysed using descriptive statistics, and a thematic analysis undertaken for interview data. Data from this study will inform future platform iterations. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of Plymouth (3291; 3 May 2022). We will share our findings via a 'Latest News' section within the platform, presentations, conference meetings and national PwP networks.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/terapia , Proyectos de Investigación , Encuestas y CuestionariosRESUMEN
People living with mobility-limiting conditions such as Parkinson's disease can struggle to physically complete intended tasks. Intent-sensing technology can measure and even predict these intended tasks, such that assistive technology could help a user to safely complete them. In prior research, algorithmic systems have been proposed, developed and tested for measuring user intent through a Probabilistic Sensor Network, allowing multiple sensors to be dynamically combined in a modular fashion. A time-segmented deep-learning system has also been presented to predict intent continuously. This study combines these principles, and so proposes, develops and tests a novel algorithm for multi-modal intent sensing, combining measurements from IMU sensors with those from a microphone and interpreting the outputs using time-segmented deep learning. It is tested on a new data set consisting of a mix of non-disabled control volunteers and participants with Parkinson's disease, and used to classify three activities of daily living as quickly and accurately as possible. Results showed intent could be determined with an accuracy of 97.4% within 0.5 s of inception of the idea to act, which subsequently improved monotonically to a maximum of 99.9918% over the course of the activity. This evidence supports the conclusion that intent sensing is viable as a potential input for assistive medical devices.
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BACKGROUND: Design of disease modification (DM) trials for Parkinson's disease (PD) is challenging. Successful delivery requires a shared understanding of priorities and practicalities. OBJECTIVE: To seek stakeholder consensus on phase 3 trials' overall goals and structure, inclusion criteria, outcome measures, and trial delivery and understand where perspectives differ. METHODS: An international expert panel comprising people with Parkinson's (PwP), care partners (CP), clinical scientists, representatives from industry, funders and regulators participated in a survey-based Delphi study. Survey items were informed by a scoping review of DM trials and PwP input. Respondents scored item agreement over 3 rounds. Scores and reasoning were summarized by participant group each round until consensus, defined as≥70% of at least 3 participant groups falling within the same 3-point region of a 9-point Likert scale. RESULTS: 92/121 individuals from 13 countries (46/69 PwP, 13/18 CP, 20/20 clinical scientists, representatives from 8/8 companies, 4/5 funders, and 1/1 regulator) completed the study. Consensus was reached on 14/31 survey items: 5/8 overall goals and structure, 1/8 Eligibility criteria, 7/13 outcome measures, and 1/2 trial delivery items. Extent of stakeholder endorsement for 428 reasons for scores was collated across items. CONCLUSIONS: This is the first systematic multi-stakeholder consultation generating a unique repository of perspectives on pivotal aspects of DM trial design including those of PwP and CP. The panel endorsed outcomes that holistically measure PD and the importance of inclusive trials with hybrid delivery models. Areas of disagreement will inform mitigating strategies of researchers to ensure successful delivery of future trials.
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Enfermedad de Parkinson , Humanos , Consenso , Técnica Delphi , Enfermedad de Parkinson/terapia , Proyectos de Investigación , Encuestas y Cuestionarios , Ensayos Clínicos Fase III como AsuntoRESUMEN
BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.
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Enfermedad de Parkinson , Humanos , Consenso , Progresión de la Enfermedad , Evaluación de Resultado en la Atención de Salud , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/psicología , Calidad de VidaRESUMEN
INTRODUCTION: Parkinson's disease (PD) is the second most common neurological disease globally, for which currently no one definitive cause or cure exists. Estimates suggest that 145 000 people with Parkinson's (PwP) live in the UK. PD presents with motor and non-motor symptoms fluctuating significantly in and between individuals continually throughout the day. PD adversely affects activities of daily living, quality of life and well-being. Self-efficacy is an important belief to improve for PwP as it enables the individual to develop confidence in their ability to exert control over their own motivation, behaviour and social environment. This scoping review aims to identify digital technologies which have been shown to positively impact on promoting self-efficacy in PwP. METHODS AND ANALYSES: Six bibliographic databases MEDLINE, PsycINFO, Web of Science, CINAHL, EMBASE and IEEE Xplore will be searched from the date of their inception to the May 2023. The primary outcome will be to identify interventions which are associated with a change in self-efficacy in PwP to enable positive and negative outcomes, as well as safety to be evaluated. The secondary outcomes of this review will focus on the intervention's proposed mechanisms for success, particularly looking at the impact they had on positive behaviour change(s) or modification(s) on study participants. ETHICS AND DISSEMINATION: This scoping review will not require ethical approval as it will use data collected from previously published primary studies. The findings of this review will be published in peer-reviewed journals and widely disseminated.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Autoeficacia , Actividades Cotidianas , Calidad de Vida , Tecnología Digital , Literatura de Revisión como AsuntoRESUMEN
INTRODUCTION: There is an ongoing digital revolution in the field of Parkinson's disease (PD) for the objective measurement of motor aspects, to be used in clinical trials and possibly support therapeutic choices. The focus of remote technologies is now also slowly shifting towards the broad but more "hidden" spectrum of non-motor symptoms (NMS). METHODS: A narrative review of digital health technologies for measuring NMS in people with PD was conducted. These digital technologies were defined as assessment tools for NMS offered remotely in the form of a wearable, downloadable as a mobile app, or any other objective measurement of NMS in PD that did not require a hospital visit and could be performed remotely. Searches were performed using peer-reviewed literature indexed databases (MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, Cochrane CENTRAL Register of Controlled Trials), as well as Google and Google Scholar. RESULTS: Eighteen studies deploying digital health technology in PD were identified, for example for the measurement of sleep disorders, cognitive dysfunction and orthostatic hypotension. In addition, we describe promising developments in other conditions that could be translated for use in PD. CONCLUSION: Unlike motor symptoms, non-motor features of PD are difficult to measure directly using remote digital technologies. Nonetheless, it is currently possible to reliably measure several NMS and further digital technology developments are underway to offer further capture of often under-reported and under-recognised NMS.
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Tecnología Biomédica/métodos , Tecnología Digital/métodos , Monitoreo Fisiológico/métodos , Enfermedad de Parkinson/diagnóstico , Evaluación de Síntomas/métodos , Femenino , Humanos , MasculinoRESUMEN
INTRODUCTION: Parkinson's disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure. METHODS AND ANALYSIS: This is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks.The primary outcome is the comparison of Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences. ETHICS AND DISSEMINATION: This trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format. TRIAL REGISTRATION NUMBERS: NCT04232969, ISRCTN14552789.
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Enfermedad de Parkinson , Ensayos Clínicos Fase III como Asunto , Método Doble Ciego , Exenatida , Humanos , Estudios Multicéntricos como Asunto , Enfermedad de Parkinson/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
OBJECTIVE: To provide guidance to researchers, funders, regulators and study delivery teams to ensure that research on COVID-19 is inclusive, particularly of groups disproportionately affected by COVID-19 and who may have been historically under-served by research. SUMMARY OF KEY POINTS: Groups who are disproportionately affected by COVID-19 include (but are not limited to) older people, people with multiple long-term conditions, people with disabilities, people from Black, Asian and Ethnic minority groups, people living with obesity, people who are socioeconomically deprived and people living in care homes. All these groups are under-served by clinical research, and there is an urgent need to rectify this if COVID-19 research is to deliver relevant evidence for these groups who are most in need. We provide a framework and checklists for addressing key issues when designing and delivering inclusive COVID-19 research, based on the National Institute for Health Research INnovations in CLinical trial design and delivery for the UnDEr-served project roadmap. Strong community engagement, codevelopment and prioritisation of research questions and interventions are essential. Under-served groups should be represented on funding panels and ethics committees, who should insist on the removal of barriers to participation. Exclusion criteria should be kept to a minimum; intervention delivery and outcome measurement should be simple, flexible and tailored to the needs of different groups, and local advice on the best way to reach and engage with under-served communities should be taken by study delivery teams. Data on characteristics that allow identification of under-served groups must be collected, analyses should include these data to enable subgroup comparisons and results should be shared with under-served groups at an early stage. CONCLUSION: Inclusive COVID-19 research is a necessity, not a luxury, if research is to benefit all the communities it seeks to serve. It requires close engagement with under-served groups and attention to aspects of study topic, design, delivery, analysis and dissemination across the research life cycle.
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Investigación Biomédica/organización & administración , COVID-19/epidemiología , Grupos Minoritarios , SARS-CoV-2 , HumanosRESUMEN
Older people are disproportionately affected by the COVID-19 pandemic, which has had a profound impact on research as well as clinical service delivery. This commentary identifies key challenges and opportunities in continuing to conduct research with and for older people, both during and after the current pandemic. It shares opinions from responders to an international survey, a range of academic authors and opinions from specialist societies. Priorities in COVID-19 research include its specific presentation in older people, consequences for physical, cognitive and psychological health, treatments and vaccines, rehabilitation, supporting care homes more effectively, the impact of social distancing, lockdown policies and system reconfiguration to provide best health and social care for older people. COVID-19 research needs to be inclusive, particularly involving older people living with frailty, cognitive impairment or multimorbidity, and those living in care homes. Non-COVID-19 related research for older people remains of critical importance and must not be neglected in the rush to study the pandemic. Profound changes are required in the way that we design and deliver research for older people in a world where movement and face-to-face contact are restricted, but we also highlight new opportunities such as the ability to collaborate more widely and to design and deliver research efficiently at scale and speed.
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Betacoronavirus , Investigación Biomédica/métodos , Infecciones por Coronavirus/epidemiología , Atención a la Salud/métodos , Pandemias/prevención & control , Neumonía Viral/epidemiología , Anciano , COVID-19 , Humanos , SARS-CoV-2 , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative condition affecting approximately 185,000 people in the UK. No drug has been proven to slow disease progression. Epidemiological and pre-clinical data support simvastatin, a widely used cholesterol-lowering drug with a well-established safety profile, having neuroprotective properties. The aim of this study (Simvastatin as a neuroprotective treatment for PD (PD STAT)) is to determine whether simvastatin has the potential to slow PD progression. The study is part of the International Linked Clinical Trials initiative coordinated by The Cure Parkinson's Trust. This paper describes the protocol for the PD STAT study. METHODS AND ANALYSIS: PD STAT is a double-blind, randomised, placebo-controlled, multi-centre, parallel group, futility trial in patients with PD of mild-moderate severity. 235 participants have been recruited and randomly allocated in a 1:1 ratio to receive either oral simvastatin or matched placebo. Treatment involves a 1-month low-dose phase (40 mg daily), followed by a 23-month high-dose phase (80 mg daily) and ends with a 2-month washout period. Participants are reviewed at clinic visits at 1 month, 6, 12, 18, 24 and 26 months post-baseline, with interim telephone follow-up to monitor for adverse events.The primary outcome is the change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III motor subscale score in the practically defined OFF medication state (OFF state) between baseline and 24 months. Primary analysis will be on a modified intention to treat basis and will include only those participants who progress to the high-dose phase of the study. ETHICS AND DISSEMINATION: The protocol has been approved by the North East-Newcastle and North Tyneside 2 Research Ethics Committee. The results will be disseminated via research articles in peer-reviewed journals and presentations at local, national and international scientific meetings, as well as disseminated via patient groups, websites and networks. A summary of the study findings will be posted to participants at the end of the study. TRIAL REGISTRATION: ISRCTN16108482 (prospectively registered); EudraCT 2015-000148-40; ClinicalTrials.gov NCT02787590; Pre-results.
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Enfermedad de Parkinson , Simvastatina , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Monitoreo de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Femenino , Humanos , Entrevistas como Asunto/métodos , Masculino , Persona de Mediana Edad , Examen Neurológico/métodos , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/efectos adversos , Evaluación de Resultado en la Atención de Salud , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Simvastatina/administración & dosificación , Simvastatina/efectos adversosAsunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Trastornos Parkinsonianos/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismoRESUMEN
BACKGROUND: Up to half of patients with dementia may not receive a formal diagnosis, limiting access to appropriate services. It is hypothesised that it may be possible to identify undiagnosed dementia from a profile of symptoms recorded in routine clinical practice. AIM: The aim of this study is to develop a machine learning-based model that could be used in general practice to detect dementia from routinely collected NHS data. The model would be a useful tool for identifying people who may be living with dementia but have not been formally diagnosed. DESIGN & SETTING: The study involved a case-control design and analysis of primary care data routinely collected over a 2-year period. Dementia diagnosed during the study period was compared to no diagnosis of dementia during the same period using pseudonymised routinely collected primary care clinical data. METHOD: Routinely collected Read-encoded data were obtained from 18 consenting GP surgeries across Devon, for 26 483 patients aged >65 years. The authors determined Read codes assigned to patients that may contribute to dementia risk. These codes were used as features to train a machine-learning classification model to identify patients that may have underlying dementia. RESULTS: The model obtained sensitivity and specificity values of 84.47% and 86.67%, respectively. CONCLUSION: The results show that routinely collected primary care data may be used to identify undiagnosed dementia. The methodology is promising and, if successfully developed and deployed, may help to increase dementia diagnosis in primary care.
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In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK in patients with Parkinson's disease (PD) and motor fluctuations: opicapone, a third-generation catechol-O-methyl transferase inhibitor, and safinamide, a monoamine oxidase B inhibitor. This clinical consensus outlines the practical considerations relating to motor fluctuations and managing wearing-off in patients with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and safinamide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from England, Scotland and Wales.
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Antiparkinsonianos/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/farmacocinética , HumanosRESUMEN
Many now believe the holy grail for the next stage of therapeutic advance surrounds the development of disease-modifying approaches aimed at intercepting the year-on-year neurodegenerative decline experienced by most patients with Parkinson's disease (PD). Based on recommendations of an international committee of experts who are currently bringing multiple, potentially disease-modifying, PD therapeutics into long-term neuroprotective PD trials, a clinical trial involving 198 patients is underway to determine whether Simvastatin provides protection against chronic neurodegeneration. Statins are widely used to reduce cardiovascular risk, and act as competitive inhibitors of HMG-CoA reductase. It is also known that statins serve as ligands for PPARα, a known arbiter for mitochondrial size and number. Statins possess multiple cholesterol-independent biochemical mechanisms of action, many of which offer neuroprotective potential (suppression of proinflammatory molecules & microglial activation, stimulation of endothelial nitric oxide synthase, inhibition of oxidative stress, attenuation of α-synuclein aggregation, modulation of adaptive immunity, and increased expression of neurotrophic factors). We describe the biochemical, physiological and pharmaceutical credentials that continue to underpin the rationale for taking Simvastatin into a disease-modifying trial in PD patients. While unrelated to the Simvastatin trial (because this conducted in patients who already have PD), we discuss conflicting epidemiological studies which variously suggest that statin use for cardiovascular prophylaxis may increase or decrease risk of developing PD. Finally, since so few disease-modifying PD trials have ever been launched (compared to those of symptomatic therapies), we discuss the rationale of the trial structure we have adopted, decisions made, and lessons learnt so far.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Simvastatina/uso terapéutico , Administración Oral , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Escala del Estado Mental , Enfermedades Neurodegenerativas/epidemiología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/prevención & control , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiologíaRESUMEN
Proliferator-activated receptor γ (PPARγ) activation can result in transcription of proteins involved in oxidative stress defence and mitochondrial biogenesis which could rescue mitochondrial dysfunction in Parkinson's disease (PD).The PPARγ agonist pioglitazone is protective in models of PD; however side effects have limited its clinical use. The cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) may have PPARγ dependent anti-oxidant properties. Here we investigate the effects of Δ9-THC and pioglitazone on mitochondrial biogenesis and oxidative stress. Differentiated SH-SY5Y neuroblastoma cells were exposed to the PD relevant mitochondrial complex 1 inhibitor 1-methyl-4-phenylpyridinium iodide (MPP+). We found that only Δ9-THC was able to restore mitochondrial content in MPP+ treated SH-SY5Y cells in a PPARγ dependent manner by increasing expression of the PPARγ co-activator 1α (PGC-1α), the mitochondrial transcription factor (TFAM) as well as mitochondrial DNA content. Co-application of Δ9-THC with pioglitazone further increased the neuroprotection against MPP+ toxicity as compared to pioglitazone treatment alone. Furthermore, using lentiviral knock down of the PPARγ receptor we showed that, unlike pioglitazone, Δ9-THC resulted in a PPARγ dependent reduction of MPP+ induced oxidative stress. We therefore suggest that, in contrast to pioglitazone, Δ9-THC mediates neuroprotection via PPARγ-dependent restoration of mitochondrial content which may be beneficial for PD treatment.
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1-Metil-4-fenilpiridinio/toxicidad , Dronabinol/farmacología , Mitocondrias/fisiología , Línea Celular Tumoral , Humanos , Enfermedades Mitocondriales/tratamiento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo , PPAR gamma/fisiología , Enfermedad de Parkinson/tratamiento farmacológico , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/análisis , Pioglitazona , Tiazolidinedionas/farmacologíaRESUMEN
In this study, we quantify the severity of drug-induced dyskinesias in the arms of Parkinson's disease (PD) patients using digitised spiral-drawing tasks. Two spiral drawings, namely a circular and a square spiral, are designed to, respectively, represent the continuous and discrete arm motions, and the size of the spiral is decided so that both the distal and proximal arm joints are involved. Fifteen PD patients, average disease duration 14.4+/-7.4 years, were assessed 30 min after a levodopa challenge whilst performing circular and square spiral-drawing tasks. The velocity of drawing movements was computed and the amplitude of the involuntary dyskinetic movements was measured as the standard deviation of the drawing velocity (SD-DV). The mean amplitude of dyskinetic movements was compared between arms and tasks and was correlated with clinical measures including the Bain dyskinesia scale and the total unified Parkinson's disease rating scale (UPDRS) score. The results showed that there was no statistically significant difference in the amplitude of dyskinesias either between the arms or between the continuous (circular) and discrete (square) spiral drawings in this group of PD patients, but interestingly the interaction between arm and drawing pattern was significant. Significant correlations were found between the magnitude of dyskinesia measured from the spiral-drawing tasks and both the 'on' or 'off' UPDRS and also the Bain dyskinesia scale. We conclude that the drawing tasks may be used to provide an objective method of quantifying the severity of drug-induced dyskinesias in the arm in PD patients.