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Parkinson Disease: HELP
Articles by Peter A. Lewitt
Based on 47 articles published since 2008

Between 2008 and 2019, Peter LeWitt wrote the following 47 articles about Parkinson Disease.
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial The pharmacodynamics of placebo: expectation effects of price as a proxy for efficacy. 2015

LeWitt, Peter A / Kim, Scott. ·From the Department of Neurology (P.A.L.), Parkinson's Disease and Movement Disorders Center, Henry Ford West Bloomfield Hospital · Department of Neurology (P.A.L.), Wayne State University School of Medicine, Detroit, MI · and Department of Bioethics (S.K.), National Institutes of Health, Bethesda, MD. ·Neurology · Pubmed #25632090.

ABSTRACT: -- No abstract --

2 Editorial Predicting the development of levodopa-induced dyskinesias: a presynaptic mechanism? 2014

Lewitt, Peter A / Mouradian, M Maral. ·From the Department of Neurology (P.A.L.), Henry Ford Hospital, Bloomfield · the Department of Neurology (P.A.L.), Wayne State University School of Medicine, Detroit, MI · and Center for Neurodegenerative and Neuroimmunologic Diseases (M.M.M.), Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ. ·Neurology · Pubmed #24719487.

ABSTRACT: After chronic levodopa use, many patients with Parkinson disease (PD) develop involuntary movements. Whether disabling or minor, levodopa-induced dyskinesia (LID) constitutes an undesirable outcome calling for better treatment strategies. Options for managing LID include delaying its onset by combining a dopaminergic agonist with levodopa from the start(1) or symptomatic control using amantadine. However, fundamental questions about LID remain: by what mechanisms does it develop, and why don't all patients go on to experience LID after sustained levodopa exposure?

3 Editorial Is levodopa toxic? Insights from a brain bank. 2011

LeWitt, Peter A / Dubow, Jordan / Singer, Carlos. · ·Neurology · Pubmed #21917780.

ABSTRACT: -- No abstract --

4 Editorial Relief of parkinsonism and dyskinesia: one and the same dopaminergic mechanism? 2010

Lewitt, Peter A. · ·Neurology · Pubmed #20237309.

ABSTRACT: -- No abstract --

5 Review Nighttime Sleep and Daytime Sleepiness Improved With Pimavanserin During Treatment of Parkinson's Disease Psychosis. 2018

Patel, Neepa / LeWitt, Peter / Neikrug, Ariel B / Kesslak, Patrick / Coate, Bruce / Ancoli-Israel, Sonia. ·Parkinson's Disease and Movement Disorders Program, Henry Ford Hospital, West Bloomfield, MI. · Department of Psychiatry and Human Behavior, University of California Irvine, Irvine. · ACADIA Pharmaceuticals Inc, San Diego. · Departments of Psychiatry and Medicine, University of California, San Diego, La Jolla, CA. ·Clin Neuropharmacol · Pubmed #30303817.

ABSTRACT: INTRODUCTION: Impaired nocturnal sleep and excessive daytime sleepiness are common problems for patients with Parkinson's disease, and patients with Parkinson's disease with sleep dysfunction are 5 times more likely to experience psychotic symptoms. Pimavanserin, a 5-HT2A inverse agonist approved to treat Parkinson's disease psychosis, may improve sleep quality in patients with Parkinson's disease experiencing sleep disturbances. METHODS: Scales for Outcomes in Parkinson's Disease nighttime sleep (SCOPA-NS) and SCOPA-daytime sleepiness (DS) data obtained during 2 double-blind placebo-controlled studies of pimavanserin in persons with Parkinson's disease psychosis were evaluated. Data from the placebo and pimavanserin 34 mg groups in the 2 studies were pooled to provide further information on the effect of pimavanserin 34 mg on sleep. Additional analyses on the pooled study data were performed on participants with significantly impaired nighttime sleep and daytime sleepiness, defined as SCOPA-NS ≥7 and SCOPA-DS ≥5, respectively. RESULTS: In the pooled analysis, treatment effects, expressed as least squares mean reductions in SCOPA-NS at week 6, were -1.4 for pimavanserin 34 mg and -0.5 for placebo. At week 6, the decrease from baseline in SCOPA-DS for the pimavanserin 34 mg group was -1.7 and -1.2 for the placebo group (P = 0.108). When evaluating participants with impaired nighttime sleep and daytime sleepiness at baseline, the SCOPA-NS score change was -4.4 for the pimavanserin 34 mg group and -2.3 for the placebo group (P = 0.002), whereas the SCOPA-DS change was -2.9 and -1.9 for the pimavanserin 34 mg and placebo groups (P = 0.120), respectively. CONCLUSION: The data from the trials suggest that nighttime sleep improved with administration of pimavanserin, a novel 5-HT2A receptor inverse agonist/antagonist.

6 Review Neurogenic orthostatic hypotension and supine hypertension in Parkinson's disease and related synucleinopathies: prioritisation of treatment targets. 2016

Espay, Alberto J / LeWitt, Peter A / Hauser, Robert A / Merola, Aristide / Masellis, Mario / Lang, Anthony E. ·Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA. Electronic address: alberto.espay@uc.edu. · Parkinson's Disease and Movement Disorders Program, Henry Ford Hospital, West Bloomfield, MI, USA; Department of Neurology, Wayne State University School of Medicine, West Bloomfield, MI, USA. · USF Health Byrd NPF Parkinson's Disease and Movement Disorders Center of Excellence, Tampa, FL, USA. · Department of Neuroscience, University of Torino, Torino, Italy. · Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. · Movement Disorders Clinic and the Edmond J Safra Program in Parkinson's Disease, University Health Network, University of Toronto, Toronto, ON, Canada. ·Lancet Neurol · Pubmed #27478953.

ABSTRACT: Neurogenic orthostatic hypotension and supine hypertension are common manifestations of cardiovascular dysautonomia in Parkinson's disease and related synucleinopathies. Because these disorders are haemodynamic opposites, improvement in one might be achieved at the expense of worsening of the other. Thus, management decisions necessitate assessment of the individual risks for patients with coexistent neurogenic orthostatic hypotension and supine hypertension. Whereas neurogenic orthostatic hypotension poses risks for falls and can be associated with cognitive impairment in the short term, chronic supine hypertension can be associated with stroke and myocardial infarction in the long term. Because few clinical trial data exist for outcomes in patients with coexistent neurogenic orthostatic hypotension and supine hypertension, clinicians need to balance, on the basis of comorbidities and disease staging, the potential immediate benefits of treatment for neurogenic orthostatic hypotension and the long-term risks of supine hypertension treatment in each patient. Future research needs to focus on ascertaining a safe degree of supine hypertension when treating neurogenic orthostatic hypotension; the effectiveness of nocturnal antihypertensive therapy in patients with coexistent neurogenic orthostatic hypotension and supine hypertension; and the prevalence, scope, and therapeutic requirements for managing neurogenic orthostatic hypotension that manifests with falls or cognitive impairment, but without postural lightheadedness or near syncope.

7 Review Nocardia asteroides-Induced movement abnormalities in mice: Relevance for Parkinson's disease? 2016

Loeffler, David A / LeWitt, Peter A / Camp, Dianne M. ·Department of Neurology, Beaumont Hospital-Royal Oak, Beaumont Health, Royal Oak, Michigan, USA. · Department of Neurology, Henry Ford West Bloomfield Hospital, West Bloomfield, Michigan, USA. · Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA. · National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland, USA. ·Mov Disord · Pubmed #27411508.

ABSTRACT: -- No abstract --

8 Review Levodopa therapy for Parkinson disease: A look backward and forward. 2016

LeWitt, Peter A / Fahn, Stanley. ·From the Department of Neurology (P.A.L.), Henry Ford Hospital · Department of Neurology (P.A.L.), Wayne State University School of Medicine, Detroit, MI · and Department of Neurology (S.F.), Columbia University Medical Center, New York, NY. ·Neurology · Pubmed #27044648.

ABSTRACT: Although levodopa is widely recognized as the most effective therapy for Parkinson disease (PD), its introduction 5 decades ago was preceded by several years of uncertainty and equivocal clinical results. The translation of basic neuroscience research by Arvid Carlsson and Oleh Hornykiewicz provided a logical pathway for treating PD with levodopa. Yet the pioneering clinicians who transformed PD therapeutics with this drug--among them Walther Birkmayer, Isamu Sano, Patrick McGeer, George Cotzias, Melvin Yahr, and others--faced many challenges in determining whether the concept and the method for replenishing deficient striatal dopamine was correct. This article reviews highlights in the early development of levodopa therapy. In addition, it provides an overview of emerging drug delivery strategies that show promise for improving levodopa's pharmacologic limitations.

9 Review New levodopa therapeutic strategies. 2016

LeWitt, Peter A. ·Department of Neurology, Henry Ford Hospital and Wayne State University School of Medicine, 6777 West Maple Road, West Bloomfield, MI 48322, USA. Electronic address: plewitt1@hfhs.org. ·Parkinsonism Relat Disord · Pubmed #26459662.

ABSTRACT: During its almost half-century of use for treating Parkinson's disease, levodopa therapy has permitted most patients to reverse much of this disorder's symptomatology. However, the full range of its therapeutic properties is not completely understood, as levodopa is showing itself to be more than just a metabolic intermediate for dopamine synthesis. Improving the constancy of drug delivery is the next frontier for enhancing therapeutic options with levodopa. Because conventional immediate-release carbidopa-levodopa tablets yield such variable pharmacokinetic profiles (as do other marketed products attempting to extend levodopa effect), improved formulations are greatly needed by patients experiencing motor fluctuations. Products under development or recently released in the U.S. include intestinal infusion, sustained-release microtablets, gastric-retentive formulations, a levodopa pro-drug, and methods for delivery of the drug by inhalation or subcutaneous infusion.

10 Review Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease--Clinical practice recommendations. 2015

Trenkwalder, Claudia / Chaudhuri, K Ray / García Ruiz, Pedro J / LeWitt, Peter / Katzenschlager, Regina / Sixel-Döring, Friederike / Henriksen, Tove / Sesar, Ángel / Poewe, Werner / Anonymous6190836 / Baker, Mary / Ceballos-Baumann, Andres / Deuschl, Günther / Drapier, Sophie / Ebersbach, Georg / Evans, Andrew / Fernandez, Hubert / Isaacson, Stuart / van Laar, Teus / Lees, Andrew / Lewis, Simon / Martínez Castrillo, Juan Carlos / Martinez-Martin, Pablo / Odin, Per / O'Sullivan, John / Tagaris, Georgios / Wenzel, Karoline. ·Centre of Parkinsonism and Movement Disorders, Paracelsus-Elena Hospital, Kassel, Germany; Department of Neurosurgery, University Medical Centre, Goettingen, Germany. Electronic address: trenkwalder@pk-mx.de. · National Parkinson Foundation Centre of Excellence, Kings College Hospital, Denmark Hill Campus, London, UK. · Movement Disorders Unit, Department of Neurology, Fundacion Jimenez Diaz, Madrid, Spain. · Wayne State University School of Medicine, Parkinson's Disease and Movement Disorders Program, Henry Ford West Bloomfield Hospital, West Bloomfield, MI, USA. · Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Danube Hospital, Vienna, Austria. · Centre of Parkinsonism and Movement Disorders, Paracelsus-Elena Hospital, Kassel, Germany; Department of Neurology, Philipps-University, Marburg, Germany. · Movement Disorder Clinic, Bispebjerg Hospital, Copenhagen, Denmark. · Department of Neurology, Hospital Clínico Universitario, Santiago de Compostela, Spain. · Department of Neurology, Medical University of Innsbruck, Austria. ·Parkinsonism Relat Disord · Pubmed #26189414.

ABSTRACT: Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical practice. This document outlines best-practice recommendations for selecting appropriate candidates for apomorphine intermittent injection (the pen-injection formulation) or apomorphine continuous infusion (the pump formulation), for initiating patients onto therapy and for managing their ongoing treatment. Apomorphine is a suitable therapeutic option for PD patients who experience troublesome 'off' periods despite optimized treatment with oral PD medications. Due to its speed of onset, apomorphine injection is particularly suited to those patients requiring rapid, reliable relief of both unpredictable and predictable 'off' periods, those who require reliable and fast relief when anticipating an 'off', those with levodopa absorption or gastric emptying problems resulting in delayed or failed 'on', or for rapid relief of early morning dystonia or akinesia. Apomorphine infusion(1) is suited for patients whose 'off' periods can no longer be adequately controlled by standard oral PD treatment or for those in whom rescue doses of apomorphine injection are effective but either needed too frequently (more than 4-6 times per day), or are associated with increasing dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine infusion may be effective for the management of specific non-motor symptoms of PD associated with 'off' periods. Apomorphine infusion is less invasive than other non-oral treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain stimulation.

11 Review Effective delivery of apomorphine in the management of Parkinson disease: practical considerations for clinicians and Parkinson nurses. 2015

Bhidayasiri, Roongroj / Chaudhuri, K Ray / LeWitt, Peter / Martin, Anne / Boonpang, Kamolwan / van Laar, Teus. ·*Chulalongkorn Center of Excellence on Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; †Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA; ‡National Parkinson Foundation Centre of Excellence, King's College Hospital, Denmark Hill Campus, London, United Kingdom; §Wayne State University School of Medicine, Parkinson's Disease and Movement Disorders Program, Henry Ford West Bloomfield Hospital, West Bloomfield, MI; ║King's College Hospital, Denmark Hill Campus, London, United Kingdom; ¶Chulalongkorn Center of Excellence on Parkinson's Disease and Related Disorders, Bangkok, Thailand; and #Department of Neurology, Movement Disorder Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. ·Clin Neuropharmacol · Pubmed #25970277.

ABSTRACT: The clinical utility of long-term oral levodopa therapy in Parkinson disease (PD) is often limited by the emergence of motor complications. Over time, many patients with PD experience regular and/or unpredictable "off" periods, despite taking optimized oral medication regimens, with a major negative impact on their ability to undertake routine activities of daily living and consequently on their overall quality of life. One established approach for treating patients experiencing off periods and controlling motor fluctuations refractory to conventional oral drug therapy is the subcutaneous administration of the dopaminergic agonist apomorphine. This article outlines how the pharmacokinetic properties of apomorphine underpin its efficacy for the treatment of PD and provides practical guidance for the 3 main approaches in which it is used: subcutaneous intermittent apomorphine injection as a "rescue" therapy for off states, subcutaneous continuous apomorphine infusion for PD patients with intractable motor fluctuations as an alternative to other dopaminergic treatment, and in the apomorphine response (or challenge) test for assessment of dopamine-induced motor response in patients thought to have PD, or in establishing the optimal tolerated dose of apomorphine in patients already known to have PD. Also discussed is the management of potential adverse events with subcutaneous administration of apomorphine, the majority of which are mild and easily managed in practice. The importance of a multidisciplinary PD team in the optimal management of PD patients is now recognized, in particular the role of the specialist PD nurse.

12 Review Levodopa therapy for Parkinson's disease: Pharmacokinetics and pharmacodynamics. 2015

LeWitt, Peter A. ·Parkinson's Disease and Movement Disorders Center, Henry Ford Hospital, West Bloomfield, Michigan, and the Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA. ·Mov Disord · Pubmed #25449210.

ABSTRACT: 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.

13 Review Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement. 2014

Espay, Alberto J / LeWitt, Peter A / Kaufmann, Horacio. ·Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA. ·Mov Disord · Pubmed #25297066.

ABSTRACT: 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.

14 Review Recent advances in CSF biomarkers for Parkinson's disease. 2012

LeWitt, Peter. ·Department of Neurology, Henry Ford Hospital, Michigan 48322, USA. plewitt1@hfhs.org ·Parkinsonism Relat Disord · Pubmed #22166453.

ABSTRACT: Though the search for cerebrospinal fluid (CSF) biomarkers of Parkinson's disease (PD) began more than 40 years ago, the most promising results are relatively recent. Disease-specific indicators have been sought among the hundreds of proteins and other biochemicals found in CSF (which is contiguous with the extracellular fluid compartment of the brain). Initially, research focused on the selective neurotransmitter disturbance in PD. While investigations of dopamine metabolism (as reflected by its major metabolite, homovanillic acid [HVA]) have been relatively uninformative, we found that indexing HVA concentration to that of the purine metabolite xanthine permits differentiation of PD specimens from healthy controls (p < 0.0016) [Brain Research 2011;1408:88-97]. In another recent biomarker study, we utilized ultrahigh-performance liquid chromatography linked to gas chromatography-mass spectrometry for metabolomic analysis [Movement Disorders 2011;26(Suppl 2):S193]. Using t-tests to differentiate PD and control groups at p < 0.02, we found changes in compounds not known to be related to the neurodegenerative process (4 increased in CSF concentration and 8 decreased). Other recent investigations have reported distinctive biomarker findings in proteins and other biochemicals. The ultimate goal is for CSF biomarkers also found in peripheral biospecimens, aiding in diagnostic screening applications and providing further clues as to the etiology of PD.

15 Review MAO-B inhibitor know-how: back to the pharm. 2009

Lewitt, Peter A. ·Department of Neurology, Henry Ford Hospital, Detroit, MI, USA. palewitt@ameritech.net ·Neurology · Pubmed #19365057.

ABSTRACT: -- No abstract --

16 Review Levodopa therapeutics for Parkinson's disease: new developments. 2009

LeWitt, Peter A. ·Department of Neurology, Henry Ford Hospital, and the Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48034, USA. palewitt@ameritech.net ·Parkinsonism Relat Disord · Pubmed #19131040.

ABSTRACT: Levodopa serves as the gold standard of anti-parkinsonian therapy and nearly every patient with Parkinson's disease eventually receives this drug. To improve upon levodopa therapy, several forms of treatment have been devised to augment its actions, and new delivery systems are under development. This new research offers promise for improving outcomes with this highly effective therapy.

17 Review Levodopa for the treatment of Parkinson's disease. 2008

Lewitt, Peter A. ·Department of Neurology, Henry Ford Hospital, and the Department of Neurology, Wayne State University School of Medicine, Detroit, USA. palewitt@ameritech.net ·N Engl J Med · Pubmed #19052127.

ABSTRACT: -- No abstract --

18 Review Protection against Parkinson's disease progression: clinical experience. 2008

LeWitt, Peter A / Taylor, Danette C. ·Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA. palewitt@ameritech.net ·Neurotherapeutics · Pubmed #18394564.

ABSTRACT: Treatments with potential neuroprotective capability for Parkinson's disease (PD) have been investigated in randomized, controlled, clinical trials and other studies since the mid-1980s. Although promising leads have arisen, no therapy has been proven to halt or slow disease progression. Several large-scale studies have highlighted progress in methodology, as well as the frustrations of translating laboratory science to practical applications. This review summarizes findings from clinical trials with several classes of compounds, including monoamine oxidase-B inhibitors (selegiline, lazabemide, rasagiline), dopaminergic drugs (ropinirole, pramipexole, levodopa), antioxidant strategies (alpha-tocopherol), mitochondrial energy enhancers (coenzyme Q(10), creatine), antiapoptotic agents (TCH346, minocycline, CEP-1347), and antiglutamatergic compounds (riluzole). Beyond small-molecule pharmacology, gene therapy approaches, such as delivering neurotrophic substances (e.g., neurturin) by viral vector, are the next generation of treatment options.

19 Clinical Trial Effect of Concomitant Medications on the Safety and Efficacy of Extended-Release Carbidopa-Levodopa (IPX066) in Patients With Advanced Parkinson Disease: A Post Hoc Analysis. 2018

LeWitt, Peter A / Verhagen Metman, Leo / Rubens, Robert / Khanna, Sarita / Kell, Sherron / Gupta, Suneel. · ·Clin Neuropharmacol · Pubmed #29432286.

ABSTRACT: OBJECTIVES: Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in "off" time, "on" time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). METHODS: ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR- and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures ("off" time and "on" time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. RESULTS AND CONCLUSIONS: Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in "off" time and "on" time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD-LD formulation provides approximately an additional hour of "good" on time.

20 Clinical Trial Metabolomic biomarkers as strong correlates of Parkinson disease progression. 2017

LeWitt, Peter A / Li, Jia / Lu, Mei / Guo, Lining / Auinger, Peggy / Anonymous1740896. ·From the Departments of Neurology (P.A.L.) and Public Health Science (J.L., M.L.), Henry Ford Health System · Wayne State University School of Medicine (P.A.L.), Detroit MI · Metabolon, Inc (L.G.), Durham, NC · and Center for Human Experimental Therapeutics (P.A.), University of Rochester, NY. ·Neurology · Pubmed #28179471.

ABSTRACT: OBJECTIVE: To determine whether a Parkinson disease (PD)-specific biochemical signature might be found in the total body metabolic milieu or in the CSF compartment, especially since this disorder has systemic manifestations beyond the progressive loss of dopaminergic nigrostriatal neurons. METHODS: Our goal was to discover biomarkers of PD progression. Using ultra-high-performance liquid chromatography linked to gas chromatography and tandem mass spectrometry, we measured concentrations of small-molecule (≤1.5 kDa) constituents of plasma and CSF from 49 unmedicated, mildly affected patients with PD (mean age 61.4 years; mean duration of PD 11.4 months). Specimens were collected twice (baseline and final) at intervals up to 24 months. During this time, mean Unified Parkinson's Disease Rating Scale (UPDRS) parts 2 + 3 scores increased 47% (from 28.8 to 42.2). Measured compounds underwent unbiased univariate and multivariate analyses, including fitting data into multiple linear regression with variable selection using least absolute shrinkage and selection operator (LASSO). RESULTS: Of 575 identified plasma and 383 CSF biochemicals, LASSO led to selection of 15 baseline plasma constituents with high positive correlation (0.87, CONCLUSIONS: Metabolomic profiling of plasma yielded strong prediction of PD progression and offered biomarkers that may provide new insights into PD pathogenesis.

21 Clinical Trial The Efficacy Profile of Rotigotine During the Waking Hours in Patients With Advanced Parkinson's Disease: A Post Hoc Analysis. 2016

LeWitt, Peter A / Poewe, Werner / Elmer, Lawrence W / Asgharnejad, Mahnaz / Boroojerdi, Babak / Grieger, Frank / Bauer, Lars. ·*Department of Neurology, Henry Ford Hospital; and †Department of Neurology, Wayne State University School of Medicine, Detroit, MI; ‡Medical University of Innsbruck, Innsbruck, Austria; §Gardner-McMaster Parkinson Center, University of Toledo, Toledo, OH; ∥UCB Pharma, Raleigh, NC; and ¶UCB Pharma, Monheim am Rhein, Germany. ·Clin Neuropharmacol · Pubmed #26882318.

ABSTRACT: OBJECTIVES: Transdermal delivery of rotigotine maintains stable plasma concentrations for 24 hours. Three phase 3 studies of rotigotine as add-on to levodopa in advanced Parkinson's disease showed a significant reduction in "off" time from baseline to end of maintenance (EoM). However, detailed analyses over the range of a day have not yet been performed. The objective was to examine the time course of the efficacy profile of rotigotine throughout the day. METHODS: Post hoc analysis of diary data from 3 double-blind, placebo-controlled studies of rotigotine in patients with advanced Parkinson's disease inadequately controlled with levodopa, with average "off" time of ≥2.5 h/d (CLEOPATRA-PD [NCT00244387], 16-week maintenance; PREFER, 24-week maintenance; SP921 [NCT00522379], 12-week maintenance). Patients marked 30-minute intervals as "off," "on without troublesome dyskinesia," "on with troublesome dyskinesia," or "sleep." Diaries completed on the 3 days before EoM were analyzed. A 2-sample t test was performed for comparison of rotigotine + levodopa versus placebo + levodopa for mean percentage of time per status during four 6-hour periods: 12:00AM (midnight) to 6:00AM, 6:00AM to 12:00PM (noon), noon to 6:00PM, and 6:00PM to midnight. RESULTS: Data were available for 967 patients (placebo + levodopa, 260; rotigotine + levodopa, 707). During the 24-hour period at EoM, an advantage in mean percentage time spent "off" and "on without troublesome dyskinesia" was observed with rotigotine + levodopa versus placebo + levodopa during the three 6-hour periods from 6:00AM to midnight (P < 0.05; exploratory analysis). CONCLUSIONS: These exploratory analyses of patients with motor fluctuations suggest that the efficacy of rotigotine transdermal patch, as captured by diary data, in reducing "off" time and increasing "on time without troublesome dyskinesia" may cover the full waking day.

22 Clinical Trial Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease. 2014

LeWitt, Peter A / Huff, F Jacob / Hauser, Robert A / Chen, Dan / Lissin, Dmitri / Zomorodi, Katie / Cundy, Kenneth C. ·Department of Neurology, Henry Ford Hospital, West Bloomfield, Michigan, USA; Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA. ·Mov Disord · Pubmed #24339234.

ABSTRACT: 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.

23 Clinical Trial Actively transported levodopa prodrug XP21279: a study in patients with Parkinson disease who experience motor fluctuations. 2012

Lewitt, Peter A / Ellenbogen, Aaron / Chen, Dan / Lal, Ritu / McGuire, Kristin / Zomorodi, Katie / Luo, Wendy / Huff, F Jacob. ·Department of Neurology, Henry Ford Hospital, West Bloomfield, MI 48322, USA. plewitt1@hfhs.org ·Clin Neuropharmacol · Pubmed #22406623.

ABSTRACT: OBJECTIVE: The objectives of this study were to assess the pharmacokinetic profile, efficacy, and safety of XP21279 administered with carbidopa (CD) in subjects with Parkinson disease (PD) experiencing motor fluctuations and explore dose correspondence between CD-levodopa (LD) and XP21279 administered with CD. METHODS: Subjects received CD-LD 3 or 4 times daily for 2 weeks, followed by XP21279 plus CD 3 times daily for 2 weeks at fixed dosing times, allowing dose adjustment to optimize clinical response, in this multiple-dose, multicenter, open-label, 2-period, sequential-treatment study. Pharmacokinetic parameters, including LD exposure, were assessed over 16 hours on the last day of each treatment period. Levodopa exposure variability was assessed for each treatment using the absolute % deviation from average concentration (Cavg) in each subject. Efficacy assessments included daily self-ratings of OFF time, ON time, and dyskinesias. RESULTS: XP21279 provided significantly less variability in LD concentration compared with CD-LD (P < 0.05) in 10 PD subjects with motor fluctuations, consistent with lower peak-to-trough fluctuation for XP21279. Patterns of percentage of subjects OFF were consistent with the LD concentration-time profiles for each respective treatment. Compared with CD-LD treatment, 6 of 10 study completers experienced reduction of 30% or greater in average daily OFF time during the last 4 days in the XP21279 treatment period. XP21279 resulted in an increase in the time spent ON without troublesome dyskinesias, and the mean time to ON after the first morning XP21279 dose was not delayed, as compared with CD-LD. CONCLUSIONS: XP21279 provided improved pharmacokinetic performance (highlighted by reduction in variability of LD concentration) compared with CD-LD and therefore may provide better control of PD motor fluctuations.

24 Clinical Trial Pharmacokinetic-pharmacodynamic crossover comparison of two levodopa extension strategies. 2009

LeWitt, Peter A / Jennings, Danna / Lyons, Kelly E / Pahwa, Rajesh / Rabinowicz, Adrian L / Wang, James / Guarnieri, Maria / Hubble, Jean P / Murck, Harold. ·Department of Neurology, Henry Ford Hospital and Wayne State University School of Medicine, Detroit, Michigan, USA. palewitt@ameritech.net ·Mov Disord · Pubmed #19412946.

ABSTRACT: Controlled-release carbidopa and levodopa (CL-CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L-dopa) effects. In a randomized, open-label crossover study of 17 PD subjects with wearing-off responses, we compared 8-hour L-dopa pharmacokinetics (PK) and clinical effects after two doses of CL-CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near-equivalent mean L-dopa area-under-the-concentration-curve values (639,490 ng min/mL for two doses of CLE, and 662,577 for CL-CR, P = 0.86). The mean hourly fluctuation index for L-dopa concentration was 235% for CLE and 196% for CL-CR (P = 0.004). The mean maximal concentration for the first CLE dose was 1,926 +/- 760 ng/mL and for CL-CR, 1,840 +/- 889 (P = 0.33). During the PK studies, the mean time that L-dopa concentration was > or =1,000 ng/mL for CLE was 291 +/- 88 minutes and for CL-CR, 306 +/- 86 (P = 0.33). The mean percent-time in "off" state was 18% for CLE and 28% for CL-CR (P = 0.017), "on state without dyskinesia" was 64% for CLE and 65% for CL-CR (P = 0.803), and "on state with nontroublesome dyskinesia" was 18% for CLE and 7% for CL-CR (P = 0.03). Despite less "off" time with CLE, both formulations demonstrated similar mean PK values and marked intersubject PK variability.

25 Clinical Trial Open-label study assessment of safety and adverse effects of subcutaneous apomorphine injections in treating "off" episodes in advanced Parkinson disease. 2009

LeWitt, Peter A / Ondo, William G / Van Lunen, Brenda / Bottini, Peter B. ·Department of Neurology, Wayne State University School of Medicine and Henry Ford Hospital, Detroit, MI 48034, USA. palewitt@ameritech.net ·Clin Neuropharmacol · Pubmed #18978491.

ABSTRACT: OBJECTIVE: To assess the safety and adverse effect profile of continued use of intermittent subcutaneous apomorphine to treat "off" episodes in subjects with advanced Parkinson disease. METHODS: The study enrolled subjects with Hoehn and Yahr stage II-V Parkinson disease who were experiencing "off" events despite an optimized oral medication regimen. After baseline assessment and subcutaneous apomorphine dose titration (2-10mg/dose), subjects received > or =12 months of open-label treatment, as needed, for "off" episodes. RESULTS: Of the 546 subjects in the study population, the majority used apomorphine on a daily basis; the average dose was 4.0 mg. A total of 187 subjects discontinued treatment because of adverse events (AEs). Most AEs were mild to moderate and expected with apomorphine. The AEs most commonly classified as definitely, probably, or possibly treatment related were nausea and vomiting, dyskinesia, dizziness, somnolence, hallucination, yawning, and injection site bruising. Serious AEs occurred in 199 subjects, but only 27 were considered to be probably or possibly treatment related. None of the 45 deaths recorded in the study were attributed to apomorphine. CONCLUSIONS: Long-term use of intermittent apomorphine dosing for treatment of "off" episodes was generally associated with mild-to-moderate AEs.