Buspirone and Zolmitriptan Combination for Dyskinesia: A Randomized, Controlled, Crossover Study.

BACKGROUND: Preclinical evidence suggests that co-administration of the 5-HT1A agonist buspirone and the 5-HT1B/1D agonist zolmitriptan act synergistically to reduce dyskinesia to a greater extent than that achieved by either drug alone. OBJECTIVES: Assess the therapeutic potential of a fixed-dose buspirone and zolmitriptan combination in Parkinson's disease (PD) patients with levodopa-induced dyskinesia. METHODS: Single-center, randomized, placebo-controlled, two-way crossover study (NCT02439203) of a fixed-dose buspirone/zolmitriptan regimen (10/1.25 mg three times a day) in 30 patients with PD experiencing at least moderately disabling peak-effect dyskinesia. RESULTS: Seven days of treatment with buspirone/zolmitriptan added to levodopa significantly reduced dyskinesia as assessed by Abnormal Involuntary Movement Scale scores versus placebo (mean treatment effect vs. placebo: -4.2 [-6.1, -2.3]) without significantly worsening Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON) scores (mean treatment effect vs. placebo: 0.6 [-0.1, 1.3]). No serious adverse events were reported. CONCLUSIONS: In this proof-of-concept study, addition of buspirone/zolmitriptan to the patients' PD medication regimen significantly reduced dyskinesia severity without worsening motor function. © 2024 International Parkinson and Movement Disorder Society.

Anticholinergic drugs for parkinsonism and other movement disorders.

Anticholinergic (AC) drugs, a medication class that acts by blocking nicotinic and muscarinic acetylcholine receptors, were first utilized for therapeutic purposes in the mid-19th century. Initial applications were as symptomatic therapy for Parkinson disease (PD), a practice continuing to the present. Initially, the AC drugs used were naturally-occurring plant compounds. Synthetic AC drugs were developed in the late 1940s and predominated in neurological therapeutics. Until the advent of pharmaceuticals acting upon striatal dopaminergic motor pathways, AC drugs provided the only effective means for lessening tremors and other clinical problems of the PD patient. However, because dopaminergic compounds are so effective at meeting the needs of the typical PD patient, AC medications are far less utilized by clinicians today. In recent years, there has been only a few investigations of AC drugs as neurological treatments. This review will revisit the clinical landscape of AC pharmacology and application for movement disorders along with recent research in search of improving therapeutics with AC drugs.

Diagnostic metabolomic profiling of Parkinson's disease biospecimens.

BACKGROUND: Reliable and sensitive biomarkers are needed for enhancing and predicting Parkinson's disease (PD) diagnosis. OBJECTIVE: To investigate comprehensive metabolomic profiling of biochemicals in CSF and serum for determining diagnostic biomarkers of PD. METHODS: Fifty subjects, symptomatic with PD for ≥5 years, were matched to 50 healthy controls (HCs). We used ultrahigh-performance liquid chromatography linked to tandem mass spectrometry (UHPLC-MS/MS) for measuring relative concentrations of ≤1.5 kDalton biochemicals. A reference library created from authentic standards facilitated chemical identifications. Analytes underwent univariate analysis for PD association, with false discovery rate-adjusted p-value (≤0.05) determinations. Multivariate analysis (for identifying a panel of biochemicals discriminating PD from HCs) used several biostatistical methods, including logistic LASSO regression. RESULTS: Comparing PD and HCs, strong differentiation was achieved from CSF but not serum specimens. With univariate analysis, 21 CSF compounds exhibited significant differential concentrations. Logistic LASSO regression led to selection of 23 biochemicals (11 shared with those determined by the univariate analysis). The selected compounds, as a group, distinguished PD from HCs, with Area-Under-the-Receiver-Operating-Characteristic (ROC) curve of 0.897. With optimal cutoff, logistic LASSO achieved 100% sensitivity and 96% specificity (and positive and negative predictive values of 96% and 100%). Ten-fold cross-validation gave 84% sensitivity and 82% specificity (and 82% positive and 84% negative predictive values). From the logistic LASSO-chosen regression model, 2 polyamine metabolites (N-acetylcadaverine and N-acetylputrescine) were chosen and had the highest fold-changes in comparing PD to HCs. Another chosen biochemical, acisoga (N-(3-acetamidopropyl)pyrrolidine-2-one), also is a polyamine metabolism derivative. CONCLUSIONS: UHPLC-MS/MS assays provided a metabolomic signature highly predictive of PD. These findings provide further evidence for involvement of polyamine pathways in the neurodegeneration of PD.

Application of Neuromelanin MR Imaging in Parkinson Disease.

MRI has been used to develop biomarkers for movement disorders such as Parkinson disease (PD) and other neurodegenerative disorders with parkinsonism such as progressive supranuclear palsy and multiple system atrophy. One of these imaging biomarkers is neuromelanin (NM), whose integrity can be assessed from its contrast and volume. NM is found mainly in certain brain stem structures, namely, the substantia nigra pars compacta (SNpc), the ventral tegmental area, and the locus coeruleus. Another major biomarker is brain iron, which often increases in concert with NM degeneration. These biomarkers have the potential to improve diagnostic certainty in differentiating between PD and other neurodegenerative disorders similar to PD, as well as provide a better understanding of pathophysiology. Mapping NM in vivo has clinical importance for gauging the premotor phase of PD when there is a greater than 50% loss of dopaminergic SNpc melanized neurons. As a metal ion chelator, NM can absorb iron. When NM is released from neurons, it deposits iron into the intracellular tissues of the SNpc; the result is iron that can be imaged and measured using quantitative susceptibility mapping. An increase of iron also leads to the disappearance of the nigrosome-1 sign, another neuroimage biomarker for PD. Therefore, mapping NM and iron changes in the SNpc are a practical means for improving early diagnosis of PD and in monitoring disease progression. In this review, we discuss the functions and location of NM, how NM-MRI is performed, the automatic mapping of NM and iron content, how NM-related imaging biomarkers can be used to enhance PD diagnosis and differentiate it from other neurodegenerative disorders, and potential advances in NM imaging methods. With major advances currently evolving for rapid imaging and artificial intelligence, NM-related biomarkers are likely to have increasingly important roles for enhancing diagnostic capabilities in PD. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Inhaled levodopa for threatening impending OFF episodes in managing Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that leads to the degeneration of dopaminergic neurons resulting in a widespread pathology of motor and non-motor symptoms. Oral levodopa remains the most effective symptomatic treatment of PD, but motor complications such as Off episodes occur over time. The spectrum of manifestation of OFF episodes varies, e.g., early morning akinesia, end-of-dose wearing OFF, delayed ON, suboptimal ON and dose failure. The functional disability substantially impacts the quality of life for PD patients. An innovative on-demand therapy to treat Off episodes was approved for patients receiving oral levodopa/dopa deacarboxylase inhibitor: inhaled levodopa powder (Inbrija®). The pulmonary delivery of inhaled levodopa powder provides a predictable and fast treatment effect, independent of gastrointestinal dysfunctions or food intake, which could affect levodopa absorption. Levodopa is administered with a breath-actuated inhaler device and the approved dose is 84 mg per Off episode. During the pivotal SPAN-PD phase III trial, significant improvement in Unified Parkinson Disease Rating Scale III score was measured 30 min post-dose at week 12. Improvement was already seen for the first measured time point 10 min post-dose. No differences in pulmonary function was observed when using inhaled levodopa powder regularly for up to 12 months. Inhaled levodopa powder was also approved for early morning Off episodes. The aim of this review article is to give an overview of the different clinical studies of the innovative inhaled levodopa powder, a new on-demand therapy to treat Off episodes in PD.

Are Parkinson's disease patients referred too late for device-aided therapies and how can better informed and earlier referrals be encouraged?

In the advanced Parkinson's disease, motor and non-motor symptoms become more severe and more difficult to treat. Oral therapy may become insufficient in controlling a patient´s motor complications, which results in a substantial deterioration of the patient's quality of life, ability to work and self-reliance. This is when device-aided treatments should be considered and offered, if suitable for a given patient. They include subcutaneous and intestinal infusion therapies, deep brain stimulation and, more recently, MRI-guided focussed ultrasound. Device-aided treatments should be offered in accordance with guidelines and treatment standardization. Also there is a need to ensure availability of treatment and education of patients and physicians.

Subcutaneous Levodopa Infusion for Parkinson's Disease: 1-Year Data from the Open-Label BeyoND Study.

BACKGROUND: Continuous, subcutaneous (SC) levodopa/carbidopa infusion with ND0612 is under development as a treatment for patients with Parkinson's disease (PD) and motor fluctuations. OBJECTIVE: Evaluate 1-year safety data. METHODS: BeyoND is an open-label study evaluating the long-term safety of two ND0612 dosing regimens. RESULTS: Of the 214 enrolled patients (24-hour SC infusion: n = 90; 16-hour SC infusion: n = 124), 120 (56%) completed 12 months of treatment. Leading causes for study discontinuation were consent withdrawal (19.6%) and adverse events (17.3%). Rates of discontinuation were reduced from 49% to 29% after a protocol revision and retraining. Systemic safety was typical for PD patients treated with levodopa/carbidopa. Most patients experienced infusion site reactions, particularly nodules (30.8%) and hematoma (25.2%), which were judged mostly mild to moderate and led to discontinuation in only 10.3% of the participants. CONCLUSIONS: Subcutaneous levodopa/carbidopa continuous infusion with ND0612 is generally safe, with typical infusion site reactions for SC delivery as the main adverse event. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Focused ultrasound opening of the blood-brain barrier for treatment of Parkinson's disease.

The expanding landscape of options for Parkinson's disease (PD) therapeutics calls for novel ways to improve delivery of treatments to counteract neurodegeneration or enhance symptomatic control. This unmet need is particularly relevant for opportunities in gene therapy, which, in recent PD clinical trials, has required invasive neurosurgical approaches into the CNS. One of the promising techniques to bring new therapies into the brain for PD therapeutics involves an evolving technology, focused ultrasound. Focused ultrasound has been used to alleviate tremor by thermal ablation with high-energy sonication. Using similar equipment but much lower sonication energy, focused ultrasound assisted with micro-bubbles can temporarily open the blood-brain barrier at specific brain targets to facilitate real-time magnetic resonance-guided delivery of therapeutic agents. To explore the current status and future of focused ultrasound in transvascular therapeutics for PD, a November 2018 workshop reviewed its accomplishments and challenges. This report summarizes key points of discussion and provides further background to the promising roles focused ultrasound offers. © 2019 International Parkinson and Movement Disorder Society.

Pimavanserin use in a movement disorders clinic: a single-center experience.

BACKGROUND: Parkinson's disease psychosis (PDP) is a disabling non-motor symptom of Parkinson's disease (PD) that is challenging to treat. Dopamine receptor blockers (DRB) are used to treat PDP, though these may be associated with adverse effects, including worsening of Parkinsonism. Pimavanserin, a selective 5-HT2A receptor inverse agonist, was recently FDA-approved for treatment of PDP; however, there is limited information on its long-term use in PDP patients. METHODS: A retrospective chart review of patients prescribed pimavanserin was performed in August, 2017. Data on demographics, psychotic features, sleep, and adverse effects was collected using a semi-structured telephone interview with patients or caregivers. Hallucination severity (HS) was quantified as mild (< 1 episode/week), moderate (1/week to < 1/day), or severe (daily/continuous). RESULTS: Seventeen patients consented to participate in the study; 16 were diagnosed with PDP, 1 with Lewy body dementia. Fourteen had co-morbid cognitive impairment/dementia. The mean duration of Parkinsonism was 11.8 ± 8.0 years, with 2.6 ± 1.9 years of psychosis. Eleven of the seventeen patients reported improvement of hallucinations of which 5/8 were initiated on pimavanserin monotherapy, and 6/9 reported improvement of HS with combination of DRB. Six of nine patients prescribed DRB were able to discontinue this medication after introduction of pimavanserin. Four patients discontinued medications (2, no benefit; 1, spontaneous resolution; 1, cost). No major side effects were reported, and two patients noted subjective improvement of sleep. CONCLUSION: In our series based on a small sample size, pimavanserin is well-tolerated and effective as both monotherapy and adjuvant treatment for moderate to severe. This medication can facilitate reduction or cessation of DRB medication.

Prospective evaluation of pulmonary function in Parkinson's disease patients with motor fluctuations.

BACKGROUND: Spirometry patterns suggesting restrictive and obstructive pulmonary dysfunction have been reported in Parkinson's disease (PD). However, the patterns' precise relation to PD pathophysiology remains unclear. Purpose/Aim. To assess ON- versus OFF-state pulmonary function, the quality of its spirometric evaluation, and the quality of longitudinal spirometric findings in a large sample of PD patients with motor fluctuations. METHODS: During a placebo-controlled trial of an inhaled levodopa formulation, CVT-301, in PD patients with ≥2 h/d of OFF time, spirometry was performed by American Thoracic Society (ATS) guidelines at screening and throughout the 4-week treatment period. RESULTS: Among 86 patients, mean motor impairment during an OFF state at screening was moderately severe. However, mean spirometry results at screening were within normal ranges, and in a mixed model for repeated measures (MMRM), the results at screening were not dependent on motor state (ON vs. OFF). In the placebo group (n = 43), 76% of ON-state and 81% of OFF-state examinations throughout the study met ATS quality metrics, and in an MMRM analysis, mean findings at these patients' arrivals for treatment-period visits showed no significant 4-week change. Across all 86 patients, flow-volume curves prior to any study-drug administration showed only a 3% incidence of "sawtooth" morphology. CONCLUSIONS: In PD patients with motor fluctuations, longitudinal spirometry of acceptable quality was generally obtained. Although mean findings were normal, about a quarter of spirograms did not meet ATS quality criteria. Spirogram morphology may be less indicative of various forms of respiratory dysfunction than has previously been reported in PD.

A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson's disease.

BACKGROUND: Although levodopa is the most effective oral PD therapy, many patients experience motor fluctuations, including sudden loss of dose effect and delayed benefit. CVT-301 is a levodopa inhalation powder with the potential for rapid onset of action. The objective of this study was to evaluate CVT-301 self-administered by PD patients to relieve OFF episodes. METHODS: PD patients with ≥2 hours per day of OFF time despite oral levodopa ≥4 times per day were randomized to CVT-301 or placebo for 4 weeks, to be used up to 3 times per day for OFF episodes. After 2 weeks, the study-drug dose was escalated from 35 to 50 mg. The primary end point was mean change in UPDRS Part III score from a predose OFF state to the average of postdose scores obtained at 10, 20, 30, and 60 minutes, as assessed in-clinic at the end of week 4. Home diaries were recorded. RESULTS: Eighty-six patients used the study drug at an average frequency of 2.1 times per day for CVT-301 and for placebo. At 4 weeks, least-squares mean change in UPDRS Part III score favored CVT-301 by 7.0 points (P < 0.001). A treatment effect was evident at 10 minutes. At 4 weeks, least-squares mean OFF-time change from baseline favored CVT-301 by 0.9 hours per day (P = 0.045). The most frequently reported adverse events in the CVT-301 group were dizziness, cough, and nausea, each in 7% (3 of 43 patients). CONCLUSIONS: CVT-301 self-administered during OFF episodes provided rapid improvement of motor function, and daily OFF time was significantly reduced at the higher dose. CVT-301 was generally safe and well-tolerated. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

CSF Nrf2 and HSPA8 in Parkinson's disease patients with and without LRRK2 gene mutations.

Leucine-rich repeat kinase 2 (LRRK2) gene mutations are the most common genetic cause of Parkinson's disease (PD). CSF specimens from LRRK2 + PD patients and healthy LRRK2 mutation carriers are, therefore, useful for biomarker studies. This study examined the hypothesis that differences are present between subjects with sporadic PD (sPD), PD carriers of LRRK2 mutations (LRRK2 + PD), healthy control subjects lacking LRRK2 mutations (CTL), and LRRK2 mutation-carrying healthy controls (LRRK2 + CTL) for CSF concentrations of six potential PD biomarkers. Two of these proteins, nuclear factor (erythroid-derived 2)-like 2 ("Nrf2") and heat shock 70 kDa protein 8 ("HSPA8"), were detected in preliminary ELISAs, then measured in a larger cohort (60 sPD, 10 LRRK2 + PD, 23 CTL, 31 LRRK2 + CTL). No statistically significant differences were found between the groups (Nrf2 p = 0.13, HSPA8 p = 0.21). Nrf2 concentrations in LRRK2 + PD subjects were strongly positively associated with Unified Parkinson's Disease Rating Scale (UPDRS) total and motor scores [Spearman rho = 0.77 (p = 0.012) and 0.83 (p = 0.005)] and negatively associated with Montreal Cognitive Assessment (MoCA) scores (rho = -0.57; p = 0.11). Partial correlation coefficient calculations indicated that disease duration contributed to the associations of Nrf2 levels with UPDRS scores and with MoCA scores in this group. While CSF Nrf2 and HSPA8 do not appear to offer diagnostic biomarkers for PD, the associations between Nrf2 levels and UPDRS scores in LRRK2 + PD patients merit further investigation.

Levodopa therapy for Parkinson's disease: Pharmacokinetics and pharmacodynamics.

For all its imperfections at treating Parkinson's disease (PD), orally-administered levodopa (l-dopa) can be regarded as the "platinum" standard of PD therapeutics for its impact on disability and discomfort and its cost-effectiveness. The past half-century has confirmed that the typical l-dopa-treated patient gains improvement for most Parkinsonian features, presumably by conversion of this amino acid into dopamine in the striatum. However, fundamental questions remain as to its full mechanism of action and how adverse reactions evolve. Various aspects of clinical phenomenology associated with chronic l-dopa use (such as dyskinesias and the long-duration anti-Parkinsonian response) present a continuing challenge for better understanding of its pharmacology. The pharmacokinetics of l-dopa tend to predict some of problems that can emerge during chronic therapy, which can be linked with its irregular uptake and marked dose-by-dose variability in plasma concentrations. Several new pharmaceutical approaches are targeted at the unique physiology of l-dopa uptake and are likely to improve the consistency of its anti-Parkinsonian effect.

Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement.

The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long-established identity of Parkinson's disease (PD) as primarily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked deficiency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have undergone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibition, presynaptic α2 -adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4-dihydroxyphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strate gies have the potential for augmenting the effects of dopaminergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE deficiency, which may precede development of motor symptoms, could provide a window of opportunity for neuroprotective interventions.

Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease.

The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279-carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate-release carbidopa-levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279-carbidopa sustained-release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa-levodopa four or five times daily were optimized for 2 weeks each on carbidopa-levodopa four or five times daily and XP21279-carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double-blind/double-dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double-blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty-eight of 35 enrolled patients completed both double-blind treatments. The mean total daily off time was reduced from baseline by a mean (± standard error) of 2.7 hours (± 0.48 hours) for immediate-release carbidopa-levodopa and 3.0 hours (± 0.57 hours) for XP21279-carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279-carbidopa than carbidopa-levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279-carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa-levodopa administered four or five times daily, and the difference was not statistically significant. XP21279-carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa-levodopa.

Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial.

BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.

3-hydroxykynurenine and other Parkinson's disease biomarkers discovered by metabolomic analysis.

Parkinson's disease (PD) biomarkers are needed to enhance therapeutics research and to understand PD pathogenesis. Methods that simultaneously measure hundreds of small molecular-weight compounds-metabolomic analysis-"fingerprint" disease-specific alterations in individual compounds or metabolic pathways. Beyond a nontargeted search for PD biomarkers, we hypothesized that PD cerebrospinal fluid would show increased formation of the excitotoxin 3-hydroxykynurenine and diminished concentration of the antioxidant glutathione. Cerebrospinal fluid was collected at <4 hours postmortem from 48 pathologically-verified PD subjects and 57 comparably-aged controls. Assays involved ultra-high-performance liquid and gas chromatography linked to mass spectrometry. We used univariate techniques to determine fold-changes in concentrations of biochemicals; false-discovery rates were calculated to exclude spurious findings. Data was modeled using a Support Vector Machine for analyzing compounds selected by Welch's t test. Classification accuracy was determined by cross-validation. Of 243 structurally-identified biochemicals,19 compounds differentiated PD from controls at a 20% false-discovery level. In PD, mean 3-hydroxykynurenine concentration was increased by one-third, and mean oxidized glutathione was decreased by 40% (for each, P < .01). Four of the 19 compounds differentiating PD from controls were N-acetylated amino acids, suggesting a generalized alteration in N-acetylation activity. The Support Vector Machine classification model distinguished between groups at 83% sensitivity and 91% specificity for the learning data, and at 65% and 79% from cross-validation. In this study, the first for metabolomic profiling of PD cerebrospinal fluid, we found several novel biomarkers and offer new directions for recognizing disease-specific biochemical indicators. The findings support involvement of excitotoxicity and oxidative stress in the pathogenesis of PD.

Rotigotine transdermal system for long-term treatment of patients with advanced Parkinson's disease: results of two open-label extension studies, CLEOPATRA-PD and PREFER.

Open-label extensions [studies SP516 (NCT00501969) and SP715 (NCT00594386)] of the CLEOPATRA-PD and PREFER studies were conducted to evaluate the safety, tolerability and efficacy of the dopaminergic agonist, rotigotine, over several years of follow-up in patients with advanced Parkinson's disease (PD). Eligible subjects completing the double-blind trials received open-label adjunctive rotigotine (≤16 mg/24 h) for up to 4 and 6 years in Studies SP516 and SP715, respectively. Safety and tolerability were assessed using adverse events, vital signs and laboratory parameters, and efficacy assessed using the unified Parkinson's disease rating scale (UPDRS). Of the 395 and 258 patients enrolled in the SP516 and SP715 studies, 48 and 45 % completed, respectively. Adverse events were typically dopaminergic effects [e.g., somnolence (18-25 %/patient-year), insomnia (5-7 %/patient-year), dyskinesias (4-8 %/patient-year) and hallucinations (4-8 %/patient-year)], or related to the transdermal application of a patch (application site reactions: 14-15 %/patient-year). There were no clinically relevant changes in vital signs or laboratory parameters in either study. Mean UPDRS part II (activities of daily living) and part III (motor function) total scores improved from double-blind baseline during dose titration, then gradually declined over the maintenance period. In study SP516, mean UPDRS part II and III total scores were 0.8 points above and 2.8 points below double-blind baseline, respectively, at end of treatment. In study SP715, mean UPDRS part II and III total scores were 4.1 points above and 0.2 points below baseline, respectively, at end of treatment. In these open-label studies, adjunctive rotigotine was efficacious with an acceptable safety and tolerability profile in patients with advanced PD for up to 6 years.