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Popławska-Domaszewicz K, Metta V, Odin P, Chaudhuri KR. The device-aided intrajejunal delivery of levodopa-entacapone-carbidopa intestinal gel the treatment of Parkinson's disease: overview of efficacy and safety. Expert Rev Med Devices 2025:1-12. [PMID: 40331578 DOI: 10.1080/17434440.2025.2499153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 04/24/2025] [Indexed: 05/08/2025]
Abstract
INTRODUCTION Device-aided therapies (DATs) have been developed to provide continuous drug delivery (CDD) to people with advanced Parkinson's disease (PD) whose symptoms can no longer be effectively managed with oral or transdermal therapy. Intrajejunal infusion of levodopa-carbidopa intestinal gel (LCIG), delivered via the CADD Legacy 1400 pump, is an established CDD option, while levodopa-entacapone-carbidopa intestinal gel (LECIG), delivered via the Crono LECIG pump, is a more recent addition to the range of DAT options in Europe. AREAS COVERED This article explores the rationale for the development of LECIG infusion, the role of entacapone in the formulation, and the attributes and specifications of the LECIG infusion pump device. Clinical and real-world data reporting its efficacy, safety and tolerability of LECIG in advanced PD patients from a range of European centers are reviewed, with a focus on the practical benefits that a smaller, lighter and quieter device can provide for patients who wish to start treatment with intrajejunal levodopa infusion. EXPERT OPINION LECIG infusion delivered via the LECIG infusion pump offers another valuable DAT option to consider for suitable people with advanced PD providing both good long-term clinical benefits and a favorable treatment experience for patients.
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Affiliation(s)
- Karolina Popławska-Domaszewicz
- Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
- Parkinson's Foundation Centre of Excellence, King's College Hospital, London, UK
| | - Vinod Metta
- Parkinson's Foundation Centre of Excellence, King's College Hospital, London, UK
- Parkinson's Centre, King's College Hospital London, Dubai, UAE
| | - Per Odin
- Division of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden
- Department of Neurology, Rehabilitation Medicine, Memory and Geriatrics, SkåneUniversity Hospital, Lund, Sweden
| | - K Ray Chaudhuri
- Parkinson's Foundation Centre of Excellence, King's College Hospital, London, UK
- Parkinson's Centre, King's College Hospital London, Dubai, UAE
- Dementech Neuroscience Clinical Academic Centre, London, UK
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Mirab F, Pirhaghi M, Otzen DE, Saboury AA. Parkinson's disease and gut microbiota metabolites: The dual impact of vitamins and functional amyloids. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167862. [PMID: 40254265 DOI: 10.1016/j.bbadis.2025.167862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 04/08/2025] [Accepted: 04/17/2025] [Indexed: 04/22/2025]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the abnormal accumulation of alpha-synuclein (α-Syn). Recent research emphasizes the significant role of the gut microbiota, the diverse community of microbes living in the intestines, in modulating α-Syn pathology. This review explores the bi-directional communication along the microbiota-gut-brain axis, highlighting the paradoxical impact of two gut microbiota metabolites-functional bacterial amyloids (FuBA) and vitamins-on neurodegenerative diseases, particularly PD. FuBA contributes to PD pathogenesis by promoting α-Syn aggregation, while vitamins offer neuroprotection through their anti-amyloidogenic, antioxidant, and anti-inflammatory properties. Understanding these processes could lead to precision clinical approaches and novel strategies for managing and preventing PD.
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Affiliation(s)
- Fatemeh Mirab
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417614335, Iran
| | - Mitra Pirhaghi
- Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan 6673145137, Iran
| | - Daniel E Otzen
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus, C 1592-224, Denmark
| | - Ali Akbar Saboury
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417614335, Iran.
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Liu S, Liu T, Li J, Hong J, Moosavi-Movahedi AA, Wei J. Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors. Neurosci Bull 2025; 41:676-690. [PMID: 39754628 PMCID: PMC11978575 DOI: 10.1007/s12264-024-01342-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 10/15/2024] [Indexed: 01/06/2025] Open
Abstract
Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
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Affiliation(s)
- Shufen Liu
- Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | - Tingting Liu
- Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | - Jingwen Li
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | - Jun Hong
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | | | - Jianshe Wei
- Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China.
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China.
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Reese R, Koeglsperger T, Schrader C, Tönges L, Deuschl G, Kühn AA, Krack P, Schnitzler A, Storch A, Trenkwalder C, Höglinger GU. Invasive therapies for Parkinson's disease: an adapted excerpt from the guidelines of the German Society of Neurology. J Neurol 2025; 272:219. [PMID: 39985674 PMCID: PMC11846738 DOI: 10.1007/s00415-025-12915-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/07/2025] [Accepted: 01/12/2025] [Indexed: 02/24/2025]
Abstract
BACKGROUND Parkinson's disease (PD) is characterized by hypokinetic motor symptoms, tremor, and various non-motor symptoms with frequent fluctuations of symptoms in advanced disease stages. Invasive therapies, such as deep brain stimulation (DBS), ablative therapies, and continuous subcutaneous or intrajejunal delivery of dopaminergic drugs via pump therapies are available for the management of this complex motor symptomatology and may also impact non-motor symptoms. The recent update of the clinical guideline on PD by the German Neurological Society (Deutsche Gesellschaft für Neurologie e.V.; DGN) offers clear guidance on the indications and applications of these treatment options. METHODS The guideline committee formulated diagnostic questions for invasive therapies and structured them according to the PICOS framework (Population-Intervention-Comparisons-Outcome-Studies). A systematic literature review was conducted. Questions were addressed using the findings from the literature review and consented by the guideline committee. RESULTS Specific recommendations are given regarding (i) the optimal timing for starting invasive therapies, (ii) the application of DBS, (iii) the use of pump therapies in advanced PD, (iv) the indications for ablative procedures, and (iv) selecting the most appropriate therapy according to individual patient characteristics. CONCLUSION This review is an adapted excerpt of the chapters on the use of invasive therapies in PD of the novel German guideline on PD. Clear recommendations on the use of treatment options for advanced PD are provided.
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Affiliation(s)
- René Reese
- Department of Neurology, Rostock University Medical Center, Rostock, Germany.
- Klinik und Poliklinik für Neurologie, Universitätsmedizin Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany.
| | - Thomas Koeglsperger
- Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany
| | | | - Lars Tönges
- Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
- Neurodegeneration Research, Protein Research Unit Ruhr (PURE), Ruhr University Bochum, Bochum, Germany
| | - Günther Deuschl
- Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Andrea A Kühn
- Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité, University Medicine Berlin, Berlin, Germany
| | - Paul Krack
- Movement Disorders Center, Department of Neurology, University Hospital (Inselspital) and University of Bern, Bern, Switzerland
| | - Alfons Schnitzler
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
- Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
| | - Alexander Storch
- Department of Neurology, Rostock University Medical Center, Rostock, Germany
- Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, Rostock, Germany
- German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany
| | - Claudia Trenkwalder
- Paracelsus-Elena-Klinik, Kassel, Germany
- Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
| | - Günter U Höglinger
- Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Szablewski L. Associations Between Diabetes Mellitus and Neurodegenerative Diseases. Int J Mol Sci 2025; 26:542. [PMID: 39859258 PMCID: PMC11765393 DOI: 10.3390/ijms26020542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years and older are type 2 diabetes mellitus (T2DM) and cognitive impairment. It was found that diabetes mellitus is a major risk for cognitive decline, dementia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Different mechanisms of associations between these diseases and diabetes mellitus have been suggested. For example, it is postulated that an impaired intracellular insulin signaling pathway, together with hyperglycemia and hyperinsulinemia, may cause pathological changes, such as dysfunction of the mitochondria, oxidative stress inflammatory responses, etc. The association between diabetes mellitus and neurodegenerative diseases, as well as the mechanisms of these associations, needs further investigation. The aim of this review is to describe the associations between diabetes mellitus, especially type 1 (T1DM) and type 2 diabetes mellitus, and selected neurodegenerative diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Suggested mechanisms of these associations are also described.
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Affiliation(s)
- Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland
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Öthman M, Bergquist F, Odin P, Scharfenort M, Johansson A, Markaki I, Svenningsson P, Dizdar N, Nyholm D. Levodopa-entacapone-carbidopa intestinal gel: Data from the Swedish national registry for Parkinson's disease. Eur J Neurol 2025; 32:e16582. [PMID: 39625298 PMCID: PMC11613213 DOI: 10.1111/ene.16582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 11/18/2024] [Accepted: 11/21/2024] [Indexed: 12/06/2024]
Abstract
BACKGROUND Levodopa-entacapone-carbidopa intestinal gel (LECIG) was introduced on the Swedish market in 2019. The therapy is aimed at patients with Parkinson's disease (PD) with fluctuations and dyskinesias. Long-term efficacy and safety data are lacking. OBJECTIVE To investigate the efficacy, tolerability, and safety of LECIG in regular clinical practice for Parkinson's disease in Sweden. METHODS Real-world data were collected from the Swedish registry for Parkinson's disease (ParkReg) for all patients reported to receive LECIG during the period from 2019 until 31 August 2022. RESULTS A total of 150 patients were identified. Sixty-one (41%) of 150 patients were females. At the start of treatment, the median age was 73 years (range: 43-86). The median duration since motor symptoms onset was 17 years (IQR: 9). Fifty (33%) of 150 patients switched from another device-assisted therapy, mostly LCIG (39 patients). Reported complications were mainly related to PEG-J tube and stoma (30%). Twenty (13.3%) of 150 patients discontinued LECIG and 11 (7.3%) patients died while on LECIG. The Parkinson KinetiGraph scores for bradykinesia, dyskinesia, fluctuations, tremor, and immobility for 53 patients during LECIG showed good therapy control. The median (IQR) p-Hcy during LECIG was 12 (4.6) μmol/L (n = 44). The median (IQR) PDQ-8 summary index during LECIG was 31 (17) (n = 52). The median (IQR) EQ5D during LECIG was 0.62 (0.32) (n = 41). CONCLUSIONS Data from ParkReg covering 150 patients over 3 years show LECIG to be an effective and safe device-aided therapy for advanced PD. However, the long-term efficacy and tolerability of LECIG need to be further investigated.
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Affiliation(s)
- Mezin Öthman
- Department of Medical Sciences, NeurologyUppsala UniversityUppsalaSweden
- Department of NeurologyUppsala University HospitalUppsalaSweden
| | - Filip Bergquist
- Department of PharmacologyUniversity of GothenburgGothenburgSweden
- Sahlgrenska University HospitalGothenburgSweden
| | - Per Odin
- Division of Neurology, Department of Clinical Sciences Lund, Faculty of MedicineLund UniversityLundSweden
- Department of Neurology, Rehabilitation Medicine, Memory and GeriatricsSkane University HospitalLundSweden
| | - Monica Scharfenort
- Division of Neurology, Department of Clinical Sciences Lund, Faculty of MedicineLund UniversityLundSweden
- Department of Neurology, Rehabilitation Medicine, Memory and GeriatricsSkane University HospitalLundSweden
| | - Anders Johansson
- Section of Neurology, Department of Clinical NeuroscienceKarolinska InstitutetStockholmSweden
| | - Ioanna Markaki
- Section of Neurology, Department of Clinical NeuroscienceKarolinska InstitutetStockholmSweden
| | - Per Svenningsson
- Section of Neurology, Department of Clinical NeuroscienceKarolinska InstitutetStockholmSweden
| | - Nil Dizdar
- Department of Neurology and Department of Biomedical and Clinical SciencesLinköping UniversityLinköpingSweden
| | - Dag Nyholm
- Department of Medical Sciences, NeurologyUppsala UniversityUppsalaSweden
- Department of NeurologyUppsala University HospitalUppsalaSweden
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Devi YM, Kumar M, Tiwari A, Dhar M, Kumari S, Kumar N. Comparison of Clinical and Electrophysiologic Characteristics of Peripheral Neuropathy in Progressive Supranuclear Palsy and Parkinson's Disease: An Observational Study. Ann Indian Acad Neurol 2025; 28:72-78. [PMID: 39639527 DOI: 10.4103/aian.aian_512_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 11/08/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Although widely described in Parkinson's disease (PD), peripheral neuropathy (PNP) is scarcely reported in progressive supranuclear palsy (PSP). We aimed to compare the frequency, clinical and electrophysiologic characteristics of PNP in PSP and PD patients. METHODS This cross-sectional study included 23 PSP and 93 PD patients. Demographic data, Movement Disorders Society-Unified Parkinson's Disease Rating Scale-III (MDS-UPDRS-III), Hoehn-Yahr staging, Toronto Clinical Neuropathy Score, nerve conduction study (NCS), and sympathetic skin response (SSR) were recorded. Diagnosing isolated large fiber neuropathy required abnormal NCS. Isolated small fiber neuropathy required clinical findings of pinprick and thermal sensory loss and/or allodynia and/or hyperalgesia with/without impaired SSR, along with normal NCS. RESULTS PNP was commoner in PSP than PD (65.2% vs. 50.5%, P = 0.21). While a comparable proportion in both groups had clinical neuropathy, NCS abnormalities predominated in PSP (65.2% vs. 39.8%, P = 0.03). All patients had distal symmetrical axonal polyneuropathy. A significantly higher proportion of PSP patients had large fiber involvement (65.21% vs. 39.78%, χ 2 = 4.82; P = 0.03) and mixed fiber PNP (60.9% vs. 33.3%, P = 0.01). PSP patients with neuropathy had a significantly shorter disease duration [median (interquartile range {IQR} = 2 (2-3) years vs. 6 (3-9) years, P < 0.001], higher MDS-UPDRS-III score [median (IQR) = 47 (36-54) vs. 34 (28-49), P = 0.049], higher Hoehn-Yahr stage [median (IQR) = 4 (2-5) vs. 3 (1-5), P < 0.001], and shorter duration of levodopa use [median (IQR) = 2 (1-2) years vs. 3.5 (2-5) years, P = 0.006]. NCS parameters were comparable between PSP and PD patients with neuropathy. While PNP in PSP was not associated with any of the clinical variables, a longer disease duration was independently associated with PNP in PD. CONCLUSIONS PNP affected two-thirds of PSP patients and was more prevalent than PD. Both groups had distal symmetrical axonal polyneuropathy, with mixed fiber PNP predominating in PSP. A longer disease duration in PD was associated with PNP.
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Affiliation(s)
- Yumkham M Devi
- Department of General Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Mritunjai Kumar
- Department of Neurology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Ashutosh Tiwari
- Department of Neurology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Minakshi Dhar
- Department of General Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
- Department of Geriatric Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Sweety Kumari
- Department of Ophthalmology, MediCiti Institute of Medical Sciences, Hyderabad, Telangana, India
| | - Niraj Kumar
- Department of Neurology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
- Department of Neurology, All India Institute of Medical Sciences, Bibinagar, Telangana, India
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Rekik A, Santoro C, Poplawska-Domaszewicz K, Qamar MA, Batzu L, Landolfo S, Rota S, Falup-Pecurariu C, Murasan I, Chaudhuri KR. Parkinson's disease and vitamins: a focus on vitamin B12. J Neural Transm (Vienna) 2024; 131:1495-1509. [PMID: 38602571 PMCID: PMC11608379 DOI: 10.1007/s00702-024-02769-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 03/19/2024] [Indexed: 04/12/2024]
Abstract
Parkinson's disease (PD) has been linked to a vast array of vitamins among which vitamin B12 (Vit B12) is the most relevant and often investigated specially in the context of intrajejunal levodopa infusion therapy. Vit B12 deficiency, itself, has been reported to cause acute parkinsonism. Nevertheless, concrete mechanisms through which B12 deficiency interacts with PD in terms of pathophysiology, clinical manifestation and progression remains unclear. Recent studies have suggested that Vit B12 deficiency along with the induced hyperhomocysteinemia are correlated with specific PD phenotypes characterized with early postural instability and falls and more rapid motor progression, cognitive impairment, visual hallucinations and autonomic dysfunction. Specific clinical features such as polyneuropathy have also been linked to Vit B12 deficiency specifically in context of intrajejunal levodopa therapy. In this review, we explore the link between Vit B12 and PD in terms of physiopathology regarding dysfunctional neural pathways, neuropathological processes as well as reviewing the major clinical traits of Vit B12 deficiency in PD and Levodopa-mediated neuropathy. Finally, we provide an overview of the therapeutic effect of Vit B12 supplementation in PD and posit a practical guideline for Vit B12 testing and supplementation.
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Affiliation(s)
- Arwa Rekik
- Department of Neurology of Sahloul Hospital, Sousse, Tunisia.
- Faculty of Medicine of Sousse, Sousse, Tunisia.
| | - Carlo Santoro
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70100, Bari, Italy
| | - Karolina Poplawska-Domaszewicz
- Department of Neurology, Poznan University of Medical Sciences, 60-355, Poznan, Poland
- Parkinson's Foundation Center of Excellence, King's College Hospital, Denmark Hill, London, UK
| | - Mubasher Ahmad Qamar
- Parkinson's Foundation Center of Excellence, King's College Hospital, Denmark Hill, London, UK
- Division of Neuroscience, Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 9RT, UK
| | - Lucia Batzu
- Parkinson's Foundation Center of Excellence, King's College Hospital, Denmark Hill, London, UK
- Division of Neuroscience, Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 9RT, UK
| | - Salvatore Landolfo
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70100, Bari, Italy
| | - Silvia Rota
- Parkinson's Foundation Center of Excellence, King's College Hospital, Denmark Hill, London, UK
- Division of Neuroscience, Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 9RT, UK
| | - Cristian Falup-Pecurariu
- Faculty of Medicine, Transilvania University of Brasov, 500036, Brasov, Romania
- Department of Neurology, County Clinic Hospital, Brasov, Romania
| | - Iulia Murasan
- Faculty of Medicine, Transilvania University of Brasov, 500036, Brasov, Romania
| | - Kallol Ray Chaudhuri
- Parkinson's Foundation Center of Excellence, King's College Hospital, Denmark Hill, London, UK
- Division of Neuroscience, Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 9RT, UK
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Öthman M, Nyholm D. A 4-Year Follow-Up of Levodopa-Entacapone-Carbidopa Intestinal Gel Treatment in Parkinson's Disease. Mov Disord Clin Pract 2024; 11:1609-1612. [PMID: 39445919 DOI: 10.1002/mdc3.14240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 08/10/2024] [Accepted: 10/08/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion was introduced to the Swedish market in 2019 for Parkinson's disease (PD) with motor fluctuations. Long-term data are lacking. OBJECTIVES To study long-term data on LECIG treatment. METHODS A retrospective analysis of the first 24 patients receiving LECIG in Sweden from 2019 to 2023. RESULTS Five of 24 (21%) patients discontinued LECIG because of side effects, mostly diarrhea. Eight of the 24 (33%) patients died while receiving LECIG. Eleven of 24 (46%) patients were still on LECIG. Median (range) for disease and treatment duration was 19 (9-30) and 3.6 (3.1-4.0) years, respectively, whereas health-related quality of life scales showed median (interquartile range; n) Parkinson's Disease Questionnaire 8-item summary index scores of 38 (4; n = 7), EuroQol 5D scores of 0.59 (0.17; n = 7), and EQ-5D visual analogue scale scores of 65 (10; n = 7). CONCLUSIONS LECIG infusion is a viable treatment option for PD patients with motor fluctuations, for up to 4 years in our cohort.
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Affiliation(s)
- Mezin Öthman
- Department of Medical Sciences, Neurology, Uppsala University, Uppsala, Sweden
| | - Dag Nyholm
- Department of Medical Sciences, Neurology, Uppsala University, Uppsala, Sweden
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Müller T. Clinical pharmacokinetics of levodopa and relevant add-on therapies for Parkinson's disease. Expert Opin Drug Metab Toxicol 2024:1-10. [PMID: 39523848 DOI: 10.1080/17425255.2024.2428831] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Parkinson's disease is a chronic neurodegenerative disease entity characterized by heterogeneity of symptoms and progression. Levodopa is an efficacious and well tolerated dopamine substituting drug for its therapy. Its O-methylation and generation of 3-O-methyldopa is enhanced by levodopa/dopa decarboxylase inhibitor formulations. Additional inhibition of catechol-O-methyltransferase is the relevant add on therapy for levodopa application. This pharmacologic approach increases the plasma appearance of levodopa and reduces 3-O-methyldopa synthesis. Available marketed compounds are entacapone, tolcapone and opicapone. Data on their effects on levodopa pharmacokinetics in patients are rare. AREAS COVERED This review describes the impact of this add-on therapy on the pharmacokinetic profile of levodopa and 3-O-methyldopa in plasma. The rationale was to perform a comparison with data from previously published pharmacokinetic trials with a standardized one time intake of levodopa/carbidopa without and with the available catechol-O-methyltransferase inhibitors. EXPERT OPINION Results of this analysis identified opicapone as the most efficacious inhibitor of catechol-O-methyltransferase in terms of changes of levodopa plasma concentrations. Opicapone induced higher levodopa plasma levels compared with the ones following application of levodopa/carbidopa alone or combined with entacapone or tolcapone. Co-administration of opicapone with its once daily intake regimen may support the efficacy of subcutaneous and intrajejunal levodopa infusions.
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Affiliation(s)
- Thomas Müller
- Department of Neurology, St. Joseph Hospital Berlin-Weißensee, Berlin, Germany
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Müller T, Riederer P. The vicious circle between homocysteine, methyl group-donating vitamins and chronic levodopa intake in Parkinson's disease. J Neural Transm (Vienna) 2024; 131:631-638. [PMID: 37329350 DOI: 10.1007/s00702-023-02666-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 06/13/2023] [Indexed: 06/19/2023]
Abstract
A biomarker for declined methylation capacity is elevation of homocysteine levels. They increase the risk for onset of vascular disease and contribute to progression of chronic neurodegeneration and aging. This narrative review discusses associations between homocysteine, consumption of methyl group-donating vitamins and impact on disease-generating mechanisms in levodopa-treated patients with Parkinson's disease. We conclude to recommend levodopa-treated patients to substitute themselves with methyl group-donating vitamins. This is harmless in terms of application of folic acid, methylcobalamin or hydroxocobalamin. Moreover, we suggest a crucial discussion on the value of the various popular hypotheses on Parkinson's disease-generating mechanisms. Findings from studies with acute levodopa exposure describe oxidative stress generation and impaired methylation capacity, which causes gene dysfunction. Their repeated occurrences contribute to onset of mitochondrial dysfunction, iron enrichment and pathologic protein accumulation in the long term. Current research underestimates these epigenetic, metabolic consequences of chronic levodopa application. Supplementary treatment strategies are recommended to avoid levodopa-related side effects.
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Affiliation(s)
- Thomas Müller
- Department of Neurology, St. Joseph Hospital Berlin-Weissensee, Gartenstr. 1, 13088, Berlin, Germany.
| | - Peter Riederer
- Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Margarete-Höppel Platz 1, 97080, Würzburg, Germany
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Szász JA, Dulamea AO, Constantin VA, Mureşanu DF, Dumbravă LP, Tiu C, Jianu DC, Simu M, Ene A, Axelerad A, Falup-Pecurariu C, Lungu M, Danci AG, Sabau M, Strilciuc Ş, Popescu BO. Levodopa-Carbidopa-Entacapone Intestinal Gel in Advanced Parkinson Disease: A Multicenter Real-Life Experience. Am J Ther 2024; 31:e209-e218. [PMID: 38460175 DOI: 10.1097/mjt.0000000000001707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2024]
Abstract
BACKGROUND For Parkinson disease (PD) patients who have been diagnosed with advanced disease that can no longer be effectively controlled with optimized oral or transdermal medications, a range of device-aided therapies (DAT) are available, comprising either deep brain stimulation or infusion therapies providing continuous dopaminergic stimulation. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is the latest DAT for advanced PD (APD) that was approved in Romania in 2021. STUDY QUESTION What is the experience to date in real-world clinical practice in Romania regarding the efficacy and tolerability of LECIG in APD? STUDY DESIGN A retrospective evaluation of 74 APD patients treated with LECIG at 12 specialized APD centers in Romania. MEASURES AND OUTCOMES Demographic data and various clinical parameters were recorded, including Mini Mental State Evaluation score or Montreal Cognitive Assessment Test score. Levodopa-equivalent daily dose and the administered doses of levodopa and other PD medications were evaluated at baseline and after starting LECIG treatment. The efficacy of LECIG in reducing daily hours of off time, motor fluctuations, and dyskinesias were assessed. Any percutaneous endoscopic gastrojejunostomy system or device complications after starting LECIG treatment were noted. RESULTS At baseline, patients were taking oral levodopa for a mean of 5.3 times per day, with a high proportion also taking concomitant add-on therapies (dopamine agonists, 86%, monoamine oxidase type-B inhibitors, 53%; catechol-O-methyltransferase inhibitors, 64%). LECIG treatment significantly reduced daily off time versus baseline from 5.7 h/d to 1.7 hours per day ( P < 0.01). Duration and severity of dyskinesias was also significantly reduced versus baseline, and improvements were observed in Hoehn and Yahr Scale scores. LECIG treatment also allowed a significant reduction in the use of concomitant oral medications. CONCLUSIONS These findings suggest that LECIG treatment is an effective DAT option in APD that can simplify the treatment regimen.
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Affiliation(s)
- József Attila Szász
- Department of Neurology, "George Emil Palade" University of Medicine, Pharmacy, Science and Technology, Târgu Mureş, Romania
- Neurology Department, Emergency Clinical County Hospital, Targu Mures, Romania
| | - Adriana Octaviana Dulamea
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
- Department of Neurology, Fundeni Clinical Institute, Bucharest, Romania
| | | | - Dafin Fior Mureşanu
- Department of Neuroscience, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Neurology Department, Emergency Clinical County Hospital, Cluj-Napoca, Romania
| | - Lăcrămioara Perju Dumbravă
- Department of Neuroscience, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Neurology Department, Emergency Clinical County Hospital, Cluj-Napoca, Romania
| | - Cristina Tiu
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
- Neurology Department, Bucharest University Emergency Hospital, Bucharest, Romania
| | - Dragoş Cătălin Jianu
- Department of Neurology, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
- Neurology Department, "Pius Brânzeu" Emergency Clinical County Hospital, Timişoara, Romania
| | - Mihaela Simu
- Department of Neurology, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
- Neurology Department, "Pius Brânzeu" Emergency Clinical County Hospital, Timişoara, Romania
| | - Amalia Ene
- Neurology Department, Bucharest University Emergency Hospital, Bucharest, Romania
| | - Any Axelerad
- Department of Neurology, "Ovidius" University, Faculty of Medicine, Constanţa, Romania
- Neurology Department, Sfântul Andrei Emergency Clinical County Hospital, Constanţa, Romania
| | - Cristian Falup-Pecurariu
- Faculty of Medicine, Transilvania University, Braşov, Romania
- Neurology Department, Emergency Clinical County Hospital, Braşov, Romania
| | - Mihaela Lungu
- Neurology Department, Emergency Clinical Hospital Galati, Faculty of Medicine and Pharmacy, Dunărea de Jos University, Galati, Romania
| | - Adina Gabriela Danci
- Neurology Department, Cluj-Napoca Military Emergency Hospital, Cluj-Napoca, Romania
| | - Monica Sabau
- Department of Psycho-Neuroscience and Medical Recovery, University of Medicine and Pharmacy Oradea, Emergency Clinical Hospital Bihor, Romania; and
| | - Ştefan Strilciuc
- Department of Neuroscience, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Bogdan Ovidiu Popescu
- Department of Clinical Neurosciences, Colentina Clinical Hospital, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
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Szatmári S, Szász JA, Orbán-Kis K, Baróti B, Bataga S, Ciorba M, Nagy EE, Neagoe RM, Mihály I, Szász PZ, Kelemen K, Frigy A, Szilveszter M, Constantin VA. Levodopa-Entacapone-Carbidopa Intestinal Gel in the Treatment of Advanced Parkinson's Disease: A Single Center Real-World Experience. Pharmaceutics 2024; 16:453. [PMID: 38675114 PMCID: PMC11053778 DOI: 10.3390/pharmaceutics16040453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/17/2024] [Accepted: 03/21/2024] [Indexed: 04/28/2024] Open
Abstract
Levodopa-entacapone-carbidopa intestinal gel infusion is a relatively new treatment option for advanced Parkinson's disease. We aimed to describe and analyze the characteristics of de novo levodopa-entacapone-carbidopa intestinal gel therapy in 20 consecutive patients with advanced Parkinson's disease. We assessed the profile of motor complications by evaluating the following: motor fluctuations, dyskinesias, and the freezing phenomenon at baseline (before the testing period) and before discharge. The treatment significantly reduced the duration of daily hours spent in off time compared with baseline pre-treatment values from a mean of 4.8 ± 0.9 h/day to a mean of 1.4 ± 0.5 h per day (p < 0.001). The duration and severity of peak-dose dyskinesia were also significantly reduced compared with baseline values. Out of the 10 patients who reported freezing, 8 did not present this complication at the pre-discharge assessment. Significant improvements were observed in Hoehn and Yahr scale scores in both the on and off states. The levodopa-entacapone-carbidopa intestinal gel therapy was well tolerated during the follow-up period immediately after initiation. Despite a relatively severe stage of the disease, all patients experienced a significant improvement in motor fluctuations, dyskinesias, and the freezing phenomenon.
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Affiliation(s)
- Szabolcs Szatmári
- 2nd Clinic of Neurology, Târgu Mures County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (S.S.); (V.A.C.)
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
| | - József Attila Szász
- 2nd Clinic of Neurology, Târgu Mures County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (S.S.); (V.A.C.)
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
| | - Károly Orbán-Kis
- 2nd Clinic of Neurology, Târgu Mures County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (S.S.); (V.A.C.)
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
| | - Beáta Baróti
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
- Clinic of Radiology, Târgu Mures County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania
| | - Simona Bataga
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
- Department of Gastroenterology, Târgu Mures County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania
| | - Marius Ciorba
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
- Department of Gastroenterology, Târgu Mures County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania
| | - Előd Ernő Nagy
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
- Laboratory of Medical Analysis, Clinical County Hospital Mures, 540072 Târgu Mureș, Romania
| | - Radu Mircea Neagoe
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
- 2nd Clinic of Surgery, Târgu Mures County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania
| | - István Mihály
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
- Department of Neurology, Emergency County Hospital, 530173 Miercurea-Ciuc, Romania
| | - Péter Zsombor Szász
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
| | - Krisztina Kelemen
- 2nd Clinic of Neurology, Târgu Mures County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (S.S.); (V.A.C.)
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
| | - Attila Frigy
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
- Department of Internal Medicine IV, Clinical County Hospital Mures, 540072 Târgu Mureș, Romania
| | - Mónika Szilveszter
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mures, 540142 Târgu Mureș, Romania; (B.B.); (S.B.); (I.M.); (P.Z.S.); (A.F.)
| | - Viorelia Adelina Constantin
- 2nd Clinic of Neurology, Târgu Mures County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (S.S.); (V.A.C.)
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14
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Phokaewvarangkul O, Bhidayasiri R, Garcia-Ruiz P, Odin P, Riederer P, Müller T. Homocysteine, vitamin B metabolites, dopamine-substituting compounds, and symptomatology in Parkinson's disease: clinical and therapeutic considerations. J Neural Transm (Vienna) 2023; 130:1451-1462. [PMID: 37603058 DOI: 10.1007/s00702-023-02684-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 08/09/2023] [Indexed: 08/22/2023]
Abstract
Emerging studies suggest a correlation between elevated plasma homocysteine (hcy) levels and the risk of atherosclerosis, vascular disorders, and neurodegenerative diseases, including Parkinson's disease (PD). This narrative review delves into the intricate relationships between Hcy, vitamin B metabolites, dopamine-substituting compounds, and various symptoms of PD. Patients undergoing a long-term L-dopa/dopa-decarboxylase inhibitor (DDI) regimen, especially without a concurrent catechol-O-methyl transferase (COMT) inhibitor or methyl group-donating vitamin supplementation, such as vitamins B6 and B12, exhibit an elevation in Hcy and a decline in vitamin B metabolites. These altered concentrations appear to be associated with heightened risks of developing non-motor symptoms, including peripheral neuropathy and cognitive disturbances. The review underscores the impact of levodopa metabolism via COMT on homocysteine levels. In light of these findings, we advocate for the supplementation of methyl group-donating vitamins, notably B6 and B12, in patients undergoing a high-dose L-dopa/DDI regimen, particularly those treated with L-dopa/carbidopa intestinal gel (LCIG) infusion.
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Affiliation(s)
- Onanong Phokaewvarangkul
- Chulalongkorn Centre of Excellence for Parkinson's Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand
| | - Roongroj Bhidayasiri
- Chulalongkorn Centre of Excellence for Parkinson's Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand.
- The Academy of Science, The Royal Society of Thailand, Bangkok, 10330, Thailand.
| | - Pedro Garcia-Ruiz
- Movement Disorders Unit, Department of Neurology, Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain
| | - Per Odin
- Division of Neurology, Department of Clinical Sciences Lund, Restorative Parkinson Unit, Lund University, 221 84, Lund, Sweden
| | - Peter Riederer
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Margarete-Höppel Platz 1, 97080, Würzburg, Germany
| | - Thomas Müller
- Department of Neurology, St. Joseph Hospital Berlin-Weissensee, Gartenstr. 1, 13088, Berlin, Germany
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15
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Antonini A, D'Onofrio V, Guerra A. Current and novel infusion therapies for patients with Parkinson's disease. J Neural Transm (Vienna) 2023; 130:1349-1358. [PMID: 37672049 PMCID: PMC10645652 DOI: 10.1007/s00702-023-02693-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 08/24/2023] [Indexed: 09/07/2023]
Abstract
Advanced Parkinson's disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite the manipulation of levodopa doses and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase-B inhibitors and dopamine agonists. The implementation of drug delivery systems allows to bypass problems related to irregular and often unpredictable intestinal absorption of oral levodopa, which significantly affects its bioavailability and contributes to the development and persistence of motor complications. Subcutaneous apomorphine and levodopa/carbidopa jejunal infusion systems have been available for many years and their efficacy is confirmed by randomized studies and long-term experience in many centers worldwide. Recently, a new formulation of levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone has been introduced to the market. The use of entacapone allows to reduce total daily dose of administered levodopa. Two different soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) have completed clinical development, and both can ensure subcutaneous delivery by a portable pump infusion system. ABBV-951 uses a foslevodopa/foscarbidopa formulation, both prodrugs to improve absorption and tolerability. Both systems provide effective improvement of motor complications and are likely to expand the therapeutic options in advanced patients. Future efforts should focus on the earlier detection of patients who are candidates for device-aided therapies, increasing appropriate referral and broadening the availability of these treatments globally.
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Affiliation(s)
- Angelo Antonini
- Parkinson and Movement Disorders Unit, Centre for Rare Neurological Diseases (ERN-RND), Department of Neuroscience, University of Padua, Via Giustiniani 3, 35121, Padua, Italy.
- Padova Neuroscience Center (PNC), University of Padua, Padua, Italy.
| | | | - Andrea Guerra
- Parkinson and Movement Disorders Unit, Centre for Rare Neurological Diseases (ERN-RND), Department of Neuroscience, University of Padua, Via Giustiniani 3, 35121, Padua, Italy
- Padova Neuroscience Center (PNC), University of Padua, Padua, Italy
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16
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Zalyalova ZA, Ekusheva EV. Vitamin B<sub>12</sub> deficiency and Parkinson’s disease. NEUROLOGY, NEUROPSYCHIATRY, PSYCHOSOMATICS 2023; 15:121-127. [DOI: 10.14412/2074-2711-2023-3-121-127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disease with various clinical manifestations, its origin not always can be explained only by dopamine deficiency. Long-term treatment with levodopa (especially its intraduodenal administration), as well as clinical manifestations of polyneuropathy, cognitive deficits, postural disorders with freezing of gate, REM sleep behavioral disorders, are more often associated with vitamin B12 deficiency. Several reasons for this association and mechanisms of their development are discussed. Early detection of cobalamin deficiency in PD, especially in patients from high-risk groups, makes it possible to stop this pathological condition timely and prevent irreversible changes. Modern data on the use of high-dose (1000 μ g) oral vitamin B12 are presented, it has comparable clinical efficacy and significant advantages, compared with the parenteral form, in terms of the ease of use and the ability to avoid undesirable postinjection reactions.
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Affiliation(s)
- Z. A. Zalyalova
- Kazan State Medical University, Ministry of Health of Russia; Consultative and Diagnostic Center for Extrapyramidal Pathology and Botulinum Toxin Therapy of the Republic of Tatarstan
| | - E. V. Ekusheva
- Academy of Postgraduate Education, Federal Scientific and Clinical Center for Specialized Types of Medical Aid and Medical Technologies, FMBA of Russia; Belgorod State National Research University
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17
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Modica JS, Déry C, Canissario R, Logigian E, Bonno D, Stanton M, Dupré N, McDermott MP, Bouchard M, Lang AE, Lizarraga KJ. A systematic review of the potential consequences of abnormal serum levels of vitamin B6 in people living with Parkinson's disease. J Neurol Sci 2023; 450:120690. [PMID: 37210937 DOI: 10.1016/j.jns.2023.120690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/21/2023] [Accepted: 05/15/2023] [Indexed: 05/23/2023]
Abstract
The prevalences of polyneuropathy and epilepsy are higher in people living with Parkinson's disease (PwPD) when compared to older adults. Vitamin B6 is widely available and affordable. PwPD are at higher risk of having abnormal serum levels of vitamin B6, which are associated with polyneuropathy and epilepsy that are potentially preventable and treatable. Potential contributors to abnormal B6 levels in PwPD include age, dietary habits, vitamin supplement misuse, gastrointestinal dysfunction and complex interactions with levodopa. The literature on the potential consequences of abnormal B6 levels in PwPD is limited by a small number of observational studies focused on polyneuropathy and epilepsy. Abnormal B6 levels have been reported in 60 of 145 PwPD (41.4% relative frequency). Low B6 levels were reported in 52 PwPD and high B6 levels were reported in 8 PwPD. There were 14 PwPD, polyneuropathy and low B6. There were 4 PwPD, polyneuropathy and high B6. There were 4 PwPD, epilepsy and low B6. Vitamin B6 level was low in 44.6% of PwPD receiving levodopa-carbidopa intestinal gel and in 30.1% of PwPD receiving oral levodopa-carbidopa. In almost all studies reporting low B6 in PwPD receiving oral levodopa-carbidopa, the dose of levodopa was ≥1000 mg/day. Rigorous epidemiological studies will clarify the prevalence, natural history and clinical relevance of abnormal serum levels of vitamin B6 in PwPD. These studies should account for diet, vitamin supplement use, gastrointestinal dysfunction, concurrent levels of vitamin B12, folate, homocysteine and methylmalonic acid, formulations and dosages of levodopa and other medications commonly used in PwPD.
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Affiliation(s)
| | - Catherine Déry
- Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada
| | | | - Eric Logigian
- Department of Neurology, University of Rochester, NY, USA
| | - Deana Bonno
- Department of Neurology, University of Rochester, NY, USA
| | | | - Nicolas Dupré
- Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada
| | - Michael P McDermott
- Department of Biostatistics and Computational Biology, University of Rochester, NY, USA
| | - Manon Bouchard
- Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada
| | - Anthony E Lang
- The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, University of Toronto, Toronto, Ontario, Canada
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18
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Sabari SS, Balasubramani K, Iyer M, Sureshbabu HW, Venkatesan D, Gopalakrishnan AV, Narayanaswamy A, Senthil Kumar N, Vellingiri B. Type 2 Diabetes (T2DM) and Parkinson's Disease (PD): a Mechanistic Approach. Mol Neurobiol 2023:10.1007/s12035-023-03359-y. [PMID: 37118323 PMCID: PMC10144908 DOI: 10.1007/s12035-023-03359-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/19/2023] [Indexed: 04/30/2023]
Abstract
Growing evidence suggest that there is a connection between Parkinson's disease (PD) and insulin dysregulation in the brain, whilst the connection between PD and type 2 diabetes mellitus (T2DM) is still up for debate. Insulin is widely recognised to play a crucial role in neuronal survival and brain function; any changes in insulin metabolism and signalling in the central nervous system (CNS) can lead to the development of various brain disorders. There is accumulating evidence linking T2DM to PD and other neurodegenerative diseases. In fact, they have a lot in common patho-physiologically, including insulin dysregulation, oxidative stress resulting in mitochondrial dysfunction, microglial activation, and inflammation. As a result, initial research should focus on the role of insulin and its molecular mechanism in order to develop therapeutic outcomes. In this current review, we will look into the link between T2DM and PD, the function of insulin in the brain, and studies related to impact of insulin in causing T2DM and PD. Further, we have also highlighted the role of various insulin signalling pathway in both T2DM and PD. We have also suggested that T2DM-targeting pharmacological strategies as potential therapeutic approach for individuals with cognitive impairment, and we have demonstrated the effectiveness of T2DM-prescribed drugs through current PD treatment trials. In conclusion, this investigation would fill a research gap in T2DM-associated Parkinson's disease (PD) with a potential therapy option.
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Affiliation(s)
- S Sri Sabari
- Department of Zoology, School of Basic Sciences, Stem Cell and Regenerative Medicine/Translational Research, Central University of Punjab (CUPB), Bathinda, 151401, Punjab, India
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Kiruthika Balasubramani
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Mahalaxmi Iyer
- Department of Biotechnology, Karpagam Academy of Higher Education (Deemed to Be University), Coimbatore, 641021, Tamil Nadu, India
| | - Harysh Winster Sureshbabu
- Department of Zoology, School of Basic Sciences, Stem Cell and Regenerative Medicine/Translational Research, Central University of Punjab (CUPB), Bathinda, 151401, Punjab, India
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Dhivya Venkatesan
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, 632 014, India
| | - Arul Narayanaswamy
- Department of Zoology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Nachimuthu Senthil Kumar
- Department of Biotechnology, Mizoram University (A Central University), Aizawl, 796004, Mizoram, India
| | - Balachandar Vellingiri
- Department of Zoology, School of Basic Sciences, Stem Cell and Regenerative Medicine/Translational Research, Central University of Punjab (CUPB), Bathinda, 151401, Punjab, India.
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India.
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19
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Valkovič P, Minár M, Matejička P, Gmitterová K, Boleková V, Košutzká Z. Tolcapone improves outcomes in patients with Parkinson disease treated by levodopa/carbidopa intestinal gel: A pilot study. Medicine (Baltimore) 2022; 101:e29526. [PMID: 35960120 PMCID: PMC9371526 DOI: 10.1097/md.0000000000029526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Patients with Parkinson disease (PD) treated with levodopa/carbidopa intestinal gel (LCIG) have higher prevalence of hyperhomocysteinemia and peripheral nerves damage. OBJECTIVE The aim of our study was to test the effect of catechol-O-methyl transferase inhibitor tolcapone-as an add-on therapy to LCIG in patients with PD-on homocysteine (HCY) metabolism and nerve conduction study (NCS) parameters. METHODS We evaluated NCS and serum B12, folic acid, and homocysteine in 16 patients with advanced PD on LCIG. Quality of life (QoL) was also assessed. Six subjects were treated with tolcapone add-on therapy (and LCIG dose reduction), 5 with B vitamin supplementation, and 5 without additional treatment. RESULTS The level of HCY increased among patients without treatment (4.95 ± 12.54), and decreased in the vitamin (-17.73 ± 11.82) and tolcapone groups (-8.81 ± 8.36). Patients with tolcapone demonstrated improvement in polyneuropathic symptoms and signs compared with patients treated with vitamins or those without additional treatment (-0.83, d = 0.961). Although the most robust improvement in NCS parameters were observed with tolcapone, the findings were inconsistent to prove the effect of any intervention. Only tolcapone treatment was associated with improvement in QoL (d = 1.089). CONCLUSION Our study indicates potential of tolcapone add-on therapy in LCIG treated patients in control of homocysteine levels, and improvement of polyneuropathic symptoms, as well as QoL.
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Affiliation(s)
- Peter Valkovič
- Second Department of Neurology, Comenius University Bratislava, Bratislava, Slovakia
- Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia
- * Correspondence: Peter Valkovič, MD, PhD, Second Department of Neurology, Faculty of Medicine of Comenius University, Limbová 5, 83305 Bratislava, Slovakia (e-mail: )
| | - Michal Minár
- Second Department of Neurology, Comenius University Bratislava, Bratislava, Slovakia
| | - Peter Matejička
- Second Department of Neurology, Comenius University Bratislava, Bratislava, Slovakia
| | - Karin Gmitterová
- Second Department of Neurology, Comenius University Bratislava, Bratislava, Slovakia
| | - Veronika Boleková
- Second Department of Neurology, Comenius University Bratislava, Bratislava, Slovakia
| | - Zuzana Košutzká
- Second Department of Neurology, Comenius University Bratislava, Bratislava, Slovakia
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20
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Nyholm D, Jost WH. Levodopa–entacapone–carbidopa intestinal gel infusion in advanced Parkinson’s disease: real-world experience and practical guidance. Ther Adv Neurol Disord 2022; 15:17562864221108018. [PMID: 35785401 PMCID: PMC9244918 DOI: 10.1177/17562864221108018] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/31/2022] [Indexed: 11/24/2022] Open
Abstract
As Parkinson’s disease (PD) progresses, treatment needs to be adapted to maintain symptom control. Once patients develop advanced PD, an optimised regimen of oral and transdermal medications may no longer provide adequate relief of OFF periods and motor complications can emerge. At this point, patients may wish to consider a device-aided therapy (DAT) that provides continuous dopaminergic stimulation to help overcome these issues. Levodopa–entacapone–carbidopa intestinal gel (LECIG) infusion is a recently developed DAT option. The aim of this article is twofold: (1) to give an overview of the pharmacokinetics of LECIG infusion and clinical experience to date of its use in patients with advanced PD, including real-world data and patient-reported outcomes from a cohort of patients treated in Sweden, the first country where it was introduced, and (2) based on that information to provide practical guidance for healthcare teams starting patients on LECIG infusion, whether they are transitioning from oral medications or from other DATs, including recommendations for stepwise dosing calculation and titration. In terms of clinical efficacy, LECIG infusion has been shown to have a similar effect on motor function to standard levodopa–carbidopa intestinal gel (LCIG) infusion but, due to the presence of entacapone in LECIG, the bioavailability of levodopa is increased such that lower overall levodopa doses can be given to achieve therapeutically effective plasma concentrations. From a practical standpoint, LECIG infusion is delivered using a smaller cartridge and pump system than LCIG infusion. In addition, for patients previously treated with LCIG infusion who have an existing percutaneous endoscopic transgastric jejunostomy (PEG-J) system, this is compatible with the LECIG infusion system. As it is a relatively new product, the long-term efficacy and safety of LECIG infusion remain to be established; however, real-world data will continue to be collected and analysed to provide this information and help inform future clinical decisions.
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21
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Müller T. Perspective: cell death mechanisms and early diagnosis as precondition for disease modification in Parkinson's disease: are we on the right track? Expert Rev Mol Diagn 2022; 22:403-409. [PMID: 35400295 DOI: 10.1080/14737159.2022.2065198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Current research paradigms on biomarkers for chronic neurodegenerative diseases, such as Parkinson's disease, focus on identification of reliable, easy-to-apply tools for diagnostic screening and progression assessment. AREAS COVERED This perspective discusses possible misconceptions of biomarker research in chronic neurodegeneration from a clinician's view based on a not systematic literature search. Multifactorial disease triggers, heterogeneity of symptom and their progression are main reasons for the still missing availability of biomarkers. EXPERT OPINION Onset of chronic neurodegenerative disease entities may probably result from a decompensated endogenous repair machinery in the central nervous system, for example the neogenin receptor associated repulsive guidance molecule pathway. Future clinical research is warranted on these repair structures and aim to identify markers for the imbalance between damage and repair, which hypothetically contributes to generation of disease. An assignment to a specific chronic neurodegenerative disease entity probably appears to be secondary. Decryption of probable molecular signals of an impaired repair potential will enable an earlier diagnosis, better monitoring of disease progress and of treatment response. This concept will hopefully provide better preconditions for prevention, cure or therapeutic beneficial disease modification. These unmet therapeutic needs may be achieved for example via antagonism of repulsive guidance molecule A.
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Affiliation(s)
- Thomas Müller
- Department of NeurologySt. Joseph Hospital Berlin-Weißensee, Gartenstr.1 Berlin, Germany
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22
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Yasuda H, Furukawa Y, Nishioka K, Sasaki M, Tsukune Y, Shirane S, Hattori N, Ando M, Komatsu N. Vitamin B6 deficiency as a cause of polyneuropathy in POEMS syndrome: rapid recovery with supplementation in two cases. Hematology 2022; 27:463-468. [PMID: 35413228 DOI: 10.1080/16078454.2022.2060456] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The etiology of POEMS syndrome and its associated polyneuropathy have not been fully elucidated. The clinical picture of POEMS-associated polyneuropathy and nutritional polyneuropathy due to vitamin B6 (VB6) deficiency are strikingly similar, both being typically sensorimotor, symmetrical, stocking and glove distribution, and more severe in the lower extremities. CASE PRESENTATION We report two consecutive POEMS patients with VB6 deficiency who showed unusual rapid and drastic recovery of polyneuropathies within 6-8 weeks after oral VB6 supplementation. Case 1 was supplemented with VB6 from time of autologous stem cell transplantation. Polyneuropathy began to improve within one week, and he became walker-free and could walk unaided with a cane within 6 weeks. Case 2 was supplemented with VB6 from time of stem cell harvest, and he became cane-free and his gait almost normalized within two months. Nerve conduction studies were also confirmatory of neurologic recovery in both cases. CONCLUSIONS Objective physical improvement of POEMS-associated polyneuropathy has been reported to typically require approximately a year after autologous stem cell transplantation, and together with our observations of VB6 deficiency and supplementations leading to accelerated recoveries of polyneuropathy, VB6 deficiency most probably contributes to POEMS-associated polyneuropathy. VB6 acts as a coenzyme in approximately 150 biochemical reactions. VB6 has been reported to inhibit the hypoxia-inducible factor/vascular endothelial growth factor (VEGF) pathway, and VEGF levels are known to corollate with disease activity of POEMS syndrome. Therefore, VB6 deficiency may contribute not only to POEMS-associated polyneuropathy, but also to the etiology of POEMS syndrome itself.
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Affiliation(s)
- Hajime Yasuda
- Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yoshiki Furukawa
- Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kenya Nishioka
- Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
| | - Makoto Sasaki
- Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yutaka Tsukune
- Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan
| | - Shuichi Shirane
- Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan
| | - Nobutaka Hattori
- Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
| | - Miki Ando
- Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan
| | - Norio Komatsu
- Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan.,Laboratory for the Development of Therapies Against MPN, Juntendo University School of Medicine, Tokyo, Japan.,Department of Advanced Hematology, Juntendo University School of Medicine, Tokyo, Japan
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23
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Che NN, Jiang QH, Ding GX, Chen SY, Zhao ZX, Li X, Malik RA, Ma JJ, Yang HQ. Corneal nerve fiber loss relates to cognitive impairment in patients with Parkinson’s disease. NPJ Parkinsons Dis 2021; 7:80. [PMID: 34504084 PMCID: PMC8429586 DOI: 10.1038/s41531-021-00225-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 08/10/2021] [Indexed: 11/27/2022] Open
Abstract
Cognitive impairment in Parkinson’s disease (PD) adversely influences quality of life. There is currently no available biomarker to predict cognitive decline in PD. Corneal confocal microscopy (CCM) has been used as a non-invasive tool for quantifying small nerve damage in PD. The present study investigated whether corneal nerve measures were associated with cognitive function in PD. Patients with PD were classified into those with normal cognitive function (PD-CN), mild cognitive impairment (PD-MCI), and dementia (PDD). Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were quantified with CCM and compared with a control group. Sixty-five PD patients and thirty controls were studied. CNFD was decreased and CNBD was increased in PD patients compared to controls (P < 0.05). CNBD and CNBD/CNFD ratio was higher in PD-CN compared to controls. CNFD was positively correlated with the Montreal cognitive assessment (MoCA) score (r = 0.683, P < 0.001), but negatively associated with unified Parkinson disease rating scale (UPDRS)-part III (r = −0.481, P < 0.001) and total UPDRS scores (r = −0.401, P = 0.001) in PD patients. There was no correlation between CNFD and Levodopa equivalent daily dose (LEDD) (r = 0.176, P = 0.161). CNFD, CNBD, CNFL, and CNBD/CNFD ratio was lower with increasing Hoehn and Yahr stage. PD patients show evidence of corneal nerve loss compared with controls and corneal nerve parameters are associated with the severity of cognitive and motor dysfunction in PD. CCM could serve as an objective in vivo ophthalmic imaging technique to assess neurodegeneration in PD.
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Pauls KAM, Toppila J, Koivu M, Eerola-Rautio J, Udd M, Pekkonen E. Polyneuropathy monitoring in Parkinson's disease patients treated with levodopa/carbidopa intestinal gel. Brain Behav 2021; 11:e2408. [PMID: 34758207 PMCID: PMC8671764 DOI: 10.1002/brb3.2408] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 09/06/2021] [Accepted: 10/12/2021] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVES Levodopa-carbidopa-intestinal-gel (LCIG) infusion is an effective treatment for advanced PD with motor fluctuations. Polyneuropathy occurs as a complication in 10-15% of patients. We wanted to assess the frequency of polyneuropathy in Finnish advanced Parkinson's disease (PD) patients with continuous LCIG infusion, and the value of different clinical monitoring parameters during follow-up. MATERIALS AND METHODS Patient records of PD patients started on LCIG infusion at Helsinki University Hospital who received nerve conduction studies at baseline and 6 months after treatment initiation were reviewed for epidemiological information, mini mental state examination, baseline and 6 months' UPRDS-III, weight, body mass index, levodopa dose (LD), plasma homocysteine levels, folate, vitamin B6 and B12. RESULTS Out of 19 patients (n = 6 on B-vitamin substitution), two (10.5%) developed new-onset polyneuropathy after initiation of LCIG therapy (n = 0 with vitamin substitution). Neuropathy was associated with significant weight loss (BMI reduction > 1.5), but not with other monitoring parameters. Homocysteine rose significantly in patients not substituted with B-vitamin complex, but not in patients with B-vitamin substitution. Homocysteine changes correlated with LD changes in the absence of vitamin B substitution. After oral B-vitamin substitution, both patients' polyneuropathy remained electrophysiologically and clinically stable. CONCLUSIONS Rates of polyneuropathy in Finnish PD patients with LCIG treatment are comparable to previous studies. Patients' weight should be included in regular follow up monitoring and can be used for patient self-monitoring. Vitamin B substitution appears to reduce coupling between levodopa dose and homocysteine and may be useful to prevent polyneuropathy related to LCIG.
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Affiliation(s)
- K Amande M Pauls
- Department of Neurology, Helsinki University Hospital and Department of Clinical Neurosciences (Neurology), University of Helsinki, Helsinki, Finland.,BioMag Laboratory, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jussi Toppila
- Department of Clinical Neurophysiology, HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland
| | - Maija Koivu
- Department of Neurology, Helsinki University Hospital and Department of Clinical Neurosciences (Neurology), University of Helsinki, Helsinki, Finland
| | - Johanna Eerola-Rautio
- Department of Neurology, Helsinki University Hospital and Department of Clinical Neurosciences (Neurology), University of Helsinki, Helsinki, Finland
| | - Marianne Udd
- Department of Gastrointestinal Surgery, Helsinki University Hospital, Helsinki, Finland
| | - Eero Pekkonen
- Department of Neurology, Helsinki University Hospital and Department of Clinical Neurosciences (Neurology), University of Helsinki, Helsinki, Finland
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25
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Jenner P, Rocha JF, Ferreira JJ, Rascol O, Soares-da-Silva P. Redefining the strategy for the use of COMT inhibitors in Parkinson's disease: the role of opicapone. Expert Rev Neurother 2021; 21:1019-1033. [PMID: 34525893 DOI: 10.1080/14737175.2021.1968298] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Levodopa remains the gold-standard Parkinson's disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery. AREAS COVERED Peripheral inhibition of dopa-decarboxylase has long been considered an essential component of levodopa treatment at every stage of illness. In contrast, only relatively recently have catechol-O-methyltransferase (COMT) inhibitors been utilized to block the other major pathway of degradation and optimize levodopa delivery to the brain. First and second-generation COMT inhibitors were deficient because of toxicity, sub-optimal pharmacokinetics or a short duration of effect. As such, they have only been employed once 'wearing-off' has developed. However, the third-generation COMT inhibitor, opicapone has overcome these difficulties and exhibits long-lasting enzyme inhibition without the toxicity observed with previous generations of COMT inhibitors. In clinical trials and real-world PD studies opicapone improves the levodopa plasma profile and results in a significant improvement in ON time in 'fluctuating' disease, but it has not yet been included in the algorithm for early treatment. EXPERT OPINION This review argues for a shift in the positioning of COMT inhibition with opicapone in the PD algorithm and lays out a pathway for proving its effectiveness in early disease.
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Affiliation(s)
- Peter Jenner
- Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | | | - Joaquim J Ferreira
- Laboratory of Clinical Pharmacology and Therapeutics, Faculdade De Medicina, Universidade De Lisboa, Lisboa, Portugal.,CNS - Campus Neurológico, Torres Vedras, Portugal
| | - Olivier Rascol
- Clinical Investigation Center CIC1436, Departments of Clinical Pharmacology and Neurosciences, NS-Park/FCRIN Network and Toulouse NeuroToul Coen Center; Inserm, University Hospital of Toulouse, and University of Toulouse 3, Toulouse, France
| | - Patrício Soares-da-Silva
- Department of Research & Development, BIAL - Portela & Ca SA, Portugal.,Department of Pharmacology and Therapeutics, Faculty of Medicine, University Porto, Porto, Portugal
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Szász JA, Constantin VA, Orbán-Kis K, Bancu LA, Ciorba M, Mihály I, Nagy EE, Szász RM, Kelemen K, Simu MA, Szatmári S. Management Challenges of Severe, Complex Dyskinesia. Data from a Large Cohort of Patients Treated with Levodopa-Carbidopa Intestinal Gel for Advanced Parkinson's Disease. Brain Sci 2021; 11:826. [PMID: 34206596 PMCID: PMC8301838 DOI: 10.3390/brainsci11070826] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/12/2021] [Accepted: 06/18/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND In the advanced stages of Parkinson's disease (APD), complex forms of dyskinesia may severely impair the patient's quality of life. OBJECTIVE In the present study, we aimed to analyze the evolution under LCIG therapy of the most important motor fluctuations and complex disabling dyskinesias, including diphasic dyskinesia. METHODS In this retrospective study, we analyzed the characteristics of patients with APD who had at least 30 min of diphasic dyskinesia (DID) in 3 consecutive days, were considered responders and were treated with LCIG in our clinic. Patients were evaluated before and after PEG and at 6, 12 and 18 months, when the changes in the therapy were recorded, and they completed a 7-point Global Patient Impression of Improvement (PGI-I) scale. RESULTS Forty patients fulfilled the inclusion criteria-out of which, 34 performed all visits. There was a substantial difference between the calculated and real LCIG (1232 ± 337 mg vs. 1823 ± 728 mg). The motor fluctuations and most dyskinesias improved significantly after starting LCIG, but an increasing number of patients needed longer daily administrations of LCIG (24 instead of 16 h). CONCLUSIONS Patients with APD with complex dyskinesias must be tested in dedicated hospitals, and they need a special therapeutic approach. The properly adapted LCIG treatment regarding the dose and time of administration completed with well-selected add-on medication should offer improvement for patients who want to or can only choose this DAT vs. others.
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Affiliation(s)
- József Attila Szász
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (J.A.S.); (V.A.C.); (I.M.); (K.K.); (S.S.)
- “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania; (L.A.B.); (M.C.); (E.E.N.); (R.M.S.)
| | - Viorelia Adelina Constantin
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (J.A.S.); (V.A.C.); (I.M.); (K.K.); (S.S.)
- Doctoral School, ”Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timișoara, Romania
| | - Károly Orbán-Kis
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (J.A.S.); (V.A.C.); (I.M.); (K.K.); (S.S.)
- “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania; (L.A.B.); (M.C.); (E.E.N.); (R.M.S.)
| | - Ligia Ariana Bancu
- “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania; (L.A.B.); (M.C.); (E.E.N.); (R.M.S.)
- 1st Clinic of Internal Medicine, Târgu Mures County Emergency Clinical Hospital, 540142 Târgu Mureș, Romania
| | - Marius Ciorba
- “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania; (L.A.B.); (M.C.); (E.E.N.); (R.M.S.)
- Department of Gastroenterology, Târgu Mures County Emergency Clinical Hospital, 540142 Târgu Mureș, Romania
| | - István Mihály
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (J.A.S.); (V.A.C.); (I.M.); (K.K.); (S.S.)
- “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania; (L.A.B.); (M.C.); (E.E.N.); (R.M.S.)
| | - Előd Ernő Nagy
- “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania; (L.A.B.); (M.C.); (E.E.N.); (R.M.S.)
- Laboratory of Medical Analysis, Clinical County Hospital Mures, 540142 Târgu Mureș, Romania
| | - Róbert Máté Szász
- “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania; (L.A.B.); (M.C.); (E.E.N.); (R.M.S.)
| | - Krisztina Kelemen
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (J.A.S.); (V.A.C.); (I.M.); (K.K.); (S.S.)
- “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania; (L.A.B.); (M.C.); (E.E.N.); (R.M.S.)
| | - Mihaela Adriana Simu
- Department of Neurology II, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timișoara, Romania;
- ”Pius Branzeu” Emergency Clinical County Hospital, 300723 Timișoara, Romania
| | - Szabolcs Szatmári
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, 540136 Târgu Mureș, Romania; (J.A.S.); (V.A.C.); (I.M.); (K.K.); (S.S.)
- “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania; (L.A.B.); (M.C.); (E.E.N.); (R.M.S.)
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Boelens Keun JT, Arnoldussen IA, Vriend C, van de Rest O. Dietary Approaches to Improve Efficacy and Control Side Effects of Levodopa Therapy in Parkinson's Disease: A Systematic Review. Adv Nutr 2021; 12:2265-2287. [PMID: 34113965 PMCID: PMC8634393 DOI: 10.1093/advances/nmab060] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/19/2021] [Accepted: 04/20/2021] [Indexed: 12/26/2022] Open
Abstract
Although levodopa remains the most effective drug for symptomatic management of Parkinson's Disease (PD), treatment during advanced disease stages may raise unpredictable motor fluctuations and other complications. Counteracting these complications with other pharmacological therapies may prompt a vicious circle of side effects, and here, nutritional therapy may have great potential. Knowledge about the role of diet in PD is emerging and multiple studies have investigated nutritional support specifically with respect to levodopa therapy. With this systematic review, we aim to give a comprehensive overview of dietary approaches to optimize levodopa treatment in PD. A systematic search was performed using the databases of PubMed and Scopus between January 1985 and September 2020. Nutritional interventions with the rationale to optimize levodopa therapy in human PD patients were eligible for this study and their quality was assessed with the Cochrane risk-of-bias tool. In total, we included 22 papers that addressed the effects of dietary proteins (n = 10), vitamins (n = 7), fiber (n = 2), soybeans (n = 1), caffeine (n = 1), and ketogenic diets (n = 1) on levodopa therapy. Interventions with protein redistribution diets (PRDs), dietary fiber, vitamin C, and caffeine improved levodopa absorption, thereby enhancing clinical response and reducing motor fluctuations. Furthermore, supplementation of vitamin B-12, vitamin B-6, and folic acid successfully reduced high homocysteine concentrations that emerged from levodopa metabolism and promoted many metabolic and clinical complications, such as neuropathology and osteoporosis. In conclusion, dietary interventions have the potential to optimize levodopa efficacy and control side effects. Nutrition that improves levodopa absorption, including PRDs, fiber, vitamin C, and caffeine, is specifically recommended when fluctuating clinical responses appear. Supplements of vitamin B-12, vitamin B-6, and folic acid are advised along with levodopa initiation to attenuate hyperhomocysteinemia, and importantly, their potential to treat consequent metabolic and clinical complications warrants future research.
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Affiliation(s)
- Jikke T Boelens Keun
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Ilse Ac Arnoldussen
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands,Department of Medical Imaging, Anatomy, Radboud University Medical Center, Nijmegen, The Netherlands,Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands
| | - Chris Vriend
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam, The Netherlands,Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, Amsterdam, The Netherlands
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28
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Antonini A, Odin P, Pahwa R, Aldred J, Alobaidi A, Jalundhwala YJ, Kukreja P, Bergmann L, Inguva S, Bao Y, Chaudhuri KR. The Long-Term Impact of Levodopa/Carbidopa Intestinal Gel on 'Off'-time in Patients with Advanced Parkinson's Disease: A Systematic Review. Adv Ther 2021; 38:2854-2890. [PMID: 34018146 PMCID: PMC8189983 DOI: 10.1007/s12325-021-01747-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 10/08/2020] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Levodopa/carbidopa intestinal gel (LCIG; carbidopa/levodopa enteral suspension) has been widely used and studied for the treatment of motor fluctuations in levodopa-responsive patients with advanced Parkinson's disease (PD) when other treatments have not given satisfactory results. Reduction in 'off'-time is a common primary endpoint in studies of LCIG, and it is important to assess the durability of this response. This systematic literature review was conducted to qualitatively summarise the data on the long-term effects of LCIG therapy on 'off'-time. METHODS Studies were identified by searching PubMed, EMBASE and Ovid on 30 September 2019. Studies were included if they reported on patients with PD, had a sample size of ≥ 10, LCIG was an active intervention and 'off'-time was reported for ≥ 12 months after initiation of LCIG treatment. Randomised clinical trials, retrospective and prospective observational studies, and other interventional studies were included for selection. Data were collected on: 'off'-time (at pre-specified time periods and the end of follow-up), study characteristics, Unified Parkinson's Disease Rating Scale (UPDRS) II, III and IV total scores, dyskinesia duration, quality of life scores, non-motor symptoms and safety outcomes. RESULTS Twenty-seven studies were included in this review. The improvement in 'off'-time observed shortly after initiating LCIG was maintained and was statistically significant at the end of follow-up in 24 of 27 studies. 'Off'-time was reduced from baseline to end of follow-up by 38-84% and was accompanied by a clinically meaningful improvement in quality of life. Stratified analysis of 'off'-time demonstrated mean relative reductions of 47-82% at 3-6 months and up to 83% reduction at 3-5 years of follow-up. Most studies reported significant improvements in activities of daily living and motor complications. Most frequent adverse events were related to the procedure or the device. CONCLUSION In one of the largest qualitative syntheses of published LCIG studies, LCIG treatment was observed to provide a durable effect in reducing 'off'-time. INFOGRAPHIC Video Abstract.
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Affiliation(s)
- Angelo Antonini
- Parkinson and Movement Disorders Unit, Center for Rare Neurological Diseases (ERN-RND), Department of Neurosciences, University of Padova, Padua, Italy.
| | - Per Odin
- Division of Neurology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden
| | - Rajesh Pahwa
- Department of Neurology, University of Kansas Medical Center, Kansas City, USA
| | - Jason Aldred
- Selkirk Neurology and Inland Northwest Neurological, Spokane, WA, USA
| | - Ali Alobaidi
- AbbVie Inc., North Chicago, USA
- University of Illinois at Chicago, Chicago, USA
| | | | | | | | - Sushmitha Inguva
- Center for Pharmaceutical Marketing and Management, University of Mississippi, University, Oxford, USA
| | | | - K Ray Chaudhuri
- King's College London, and Parkinson's Foundation International Centre of Excellence, King's College Hospital, London, UK
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Role of Vitamins in Advanced Therapy for Parkinson's Disease: Decoding the Paradox. Can J Neurol Sci 2021; 49:3-4. [PMID: 33988104 DOI: 10.1017/cjn.2021.106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Abstract
Levodopa-carbidopa intestinal gel infusion (LCIG) is an established therapy for advanced Parkinson disease (PD), resulting in a significant improvement of quality of life. With increased LCIG adoption worldwide, potential complications due to abnormal vitamin absorption or metabolism have been reported in these patients. Neurologists are unfamiliar with vitamins physiology and pathophysiological mechanisms in case of their deficiency. Unfortunately, clinical and laboratory guidelines related to vitamin monitoring and supplementation in the context of treatment with LCIG are not available. We herein summarize the current knowledge on three vitamins that are reduced with LCIG therapy reporting on their physiology, laboratory testing, and clinical impact of their deficiency/excess. In addition, we proposed an opinion-based recommendation for clinicians treating LCIG patients. Patients and caregivers should be informed about the risk of vitamin deficiency. Vitamin B12, homocysteine, and methylmalonic acid (MMA) should be tested before starting LCIG, six months after and once/year thereafter. Vitamin B6 and folate testing is not universally available but it should be considered if homocysteine is elevated but MMA and/or total vitamin B12 are normal. Prophylaxis of vitamin deficiency should be started as soon as LCIG is implemented, possibly even before. Dietary recommendations are enough in most patients although a subgroup of patients is at higher risk and should receive Vitamin B12 regularly and cycles of B6. Finally, once diagnosed a vitamin deficiency should be readily treated and accompanied by clinical and laboratory monitoring. Resistant cases should receive non-oral routes of administration and possibly discontinue LCIG, even temporarily.
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Müller T. Experimental Dopamine Reuptake Inhibitors in Parkinson's Disease: A Review of the Evidence. J Exp Pharmacol 2021; 13:397-408. [PMID: 33824605 PMCID: PMC8018398 DOI: 10.2147/jep.s267032] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/03/2021] [Indexed: 12/21/2022] Open
Abstract
Parkinson’s disease (PD) is the second most chronic neurodegenerative disorder worldwide. Deficit of monoamines, particularly dopamine, causes an individually varying compilation of motor and non-motor features. Constraint of presynaptic uptake extends monoamine stay in the synaptic cleft. This review discusses possible benefits of dopamine reuptake inhibition for the treatment of PD. Translation of this pharmacologic principle into positive clinical study results failed to date. Past clinical trial designs did not consider a mandatory, concomitant stable inhibition of glial monoamine turnover, i.e. with monoamine oxidase B inhibitors. These studies focused on improvement of motor behavior and levodopa associated motor complications, which are fluctuations of motor and non-motor behavior. Future clinical investigations in early, levodopa- and dopamine agonist naïve patients shall also aim on alleviation of non-motor symptoms, like fatigue, apathy or cognitive slowing. Oral levodopa/dopa decarboxylase inhibitor application is inevitably necessary with advance of PD. Monoamine reuptake (MRT) inhibition improves the efficacy of levodopa, the blood brain barrier crossing metabolic precursor of dopamine. The pulsatile brain delivery pattern of orally administered levodopa containing formulations results in synaptic dopamine variability. Ups and downs of dopamine counteract the physiologic principle of continuous neurotransmission, particularly in nigrostriatal, respectively mesocorticolimbic pathways, both of which regulate motor respectively non-motor behavior. Thus synaptic dopamine pulsatility overwhelms the existing buffering capacity. Onset of motor and non-motor complications occurs. Future MRT inhibitor studies shall focus on a stabilizing and preventive effect on levodopa related fluctuations of motor and non-motor behavior. Their long-term study designs in advanced levodopa treated patients shall allow a cautious adaptation of oral l-dopa therapy combined with a mandatory inhibition of glial monoamine turnover. Then the evidence for a preventive and beneficial, symptomatic effect of MRT inhibition on motor and non-motor complications will become more likely.
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Affiliation(s)
- Thomas Müller
- Department of Neurology, St. Joseph Hospital Berlin-Weissensee, Berlin, 13088, Germany
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Lee JJ, Baik JS. Peripheral Neuropathy in de novo Patients with Parkinson's Disease. Yonsei Med J 2020; 61:1050-1053. [PMID: 33251779 PMCID: PMC7700880 DOI: 10.3349/ymj.2020.61.12.1050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/05/2020] [Accepted: 11/10/2020] [Indexed: 11/27/2022] Open
Abstract
PURPOSE This study aimed to investigate the prevalence of peripheral neuropathy (PNP) and its related serum metabolites in de novo patients with Parkinson's disease (PD). PNP is a type of frequent comorbidity in PD. Although the administration of levodopa has been described as a presumptive risk factor in its development, few studies have explored its effect on unmedicated PD patients. MATERIALS AND METHODS This study included 105 drug-naïve de novo PD patients. A standardized nerve conduction study (NCS) technique was used to evaluate motor or sensory neuropathy. We analyzed serologic tests including metabolic markers of vitamin B12, homocysteine (Hcy), and uric acid (UA). RESULTS We found abnormal nerve conduction velocity findings in 24 out of 105 total patients. Among them, 20 patients showed a type of combined motor-sensory, while three were a type of pure sensory and one was a pure motor. Nine patients had carpal tunnel syndrome. PD with PNP group demonstrated higher serum levels of Hcy and UA compared to PD without PNP group. CONCLUSION Our data demonstrated a potential role of Hcy and UA on PNP in de novo patients with PD. These results suggest the contribution of the inherent metabolic pathway in deterioration of the peripheral nervous system in PD.
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Affiliation(s)
- Jae Jung Lee
- Department of Neurology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Jong Sam Baik
- Department of Neurology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea.
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Urso D, Chaudhuri KR, Qamar MA, Jenner P. Improving the Delivery of Levodopa in Parkinson's Disease: A Review of Approved and Emerging Therapies. CNS Drugs 2020; 34:1149-1163. [PMID: 33146817 DOI: 10.1007/s40263-020-00769-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/26/2020] [Indexed: 01/28/2023]
Abstract
Levodopa is the most effective drug for the treatment of Parkinson's disease, but its use as an oral medication is complicated by its erratic absorption, extensive metabolism and short plasma half-life. On long-term use and with disease progression, there is a high incidence of motor and non-motor complications, which remain a major clinical and research challenge. It is widely accepted that levodopa needs to be administered using formulations that result in good and consistent bioavailability and the physiologically relevant and continuous formation of dopamine in the brain to maximise its efficacy while avoiding and reversing 'wearing off' and dyskinesia. However, the physicochemical properties of levodopa along with its pharmacokinetic and pharmacodynamic profile make it difficult to deliver the drug in a manner that fulfils these criteria. In this review, we examine the problems associated with the administration of levodopa in Parkinson's disease and how the use of novel technologies and delivery devices is leading to a more consistent and sustained levodopa delivery with the aim of controlling motor function as well as non-motor symptoms.
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Affiliation(s)
- Daniele Urso
- Department of Neurosciences, King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, London, SE5 8AF, UK. .,Parkinson's Foundation Centre of Excellence, King's College Hospital, Denmark Hill, London, UK.
| | - K Ray Chaudhuri
- Department of Neurosciences, King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, London, SE5 8AF, UK.,Parkinson's Foundation Centre of Excellence, King's College Hospital, Denmark Hill, London, UK
| | - Mubasher A Qamar
- Department of Neurosciences, King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, London, SE5 8AF, UK.,Parkinson's Foundation Centre of Excellence, King's College Hospital, Denmark Hill, London, UK
| | - Peter Jenner
- Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College, London, UK
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Vitamin B6 Deficiency in Patients With Parkinson Disease Treated With Levodopa/Carbidopa. Clin Neuropharmacol 2020; 43:151-157. [DOI: 10.1097/wnf.0000000000000408] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Constantin VA, Szász JA, Orbán-Kis K, Rosca EC, Popovici M, Cornea A, Bancu LA, Ciorba M, Mihály I, Nagy E, Szatmári S, Simu M. Levodopa-Carbidopa Intestinal Gel Infusion Therapy Discontinuation: A Ten-Year Retrospective Analysis of 204 Treated Patients. Neuropsychiatr Dis Treat 2020; 16:1835-1844. [PMID: 32801718 PMCID: PMC7395851 DOI: 10.2147/ndt.s256988] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 06/25/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Parkinson's disease (PD) is the second most common progressive neurodegenerative disease. In the advanced stages, the continuous delivery of levodopa (LD) as levodopa-carbidopa intestinal gel (LCIG) has demonstrated significant improvement of motor and nonmotor complications and improvement of the patients' quality of life (QoL). Despite the growing global experience with this treatment, anumber of unsolved practical issues remain, and currently, the data on the reasons that can lead to the discontinuation of LCIG are scarce. OBJECTIVE In the present study, we aimed to analyze the causes that led to the discontinuation of LCIG therapy. METHODS In this retrospective study, after 10 years of experience with LCIG as a therapeutic option in advanced PD, we analyzed the data of all dropout cases among the 204 patients that initiated LCIG therapy in two Romanian centers. RESULTS Of the 204 patients enrolled, 43 patients dropped out. Disease duration until LCIG infusion was significantly longer (11.67±4.98 vs 9.44±3.44) and the overall clinical picture more sever (both regarding motor symptoms and cognitive decline) in dropout patients (compared to patients who continued treatment). The dropout patients also presented significant differences regarding the incidence of polyneuropathy (32.5% vs 11.18%). The main cause of discontinuation was death. CONCLUSION The causes of discontinuation from LCIG therapy in Romanian patients are similar to those from other centers; however, the rate of dropouts is somewhat lower. The clinician's experience in selecting and treating the patients in advanced stages of PD can increase therapeutic adherence. Also, the presence of a well-trained caregiver along with the availability of a proper aftercare system is mandatory for maintaining the long-term benefits of the therapy and the overall best outcome possible. Targeted prospective studies are needed to confirm whether a more severe stage of the disease and cognitive impairment at the time of initiation, respectively, the association of polyneuropathy can be considered as predictive factors for dropout.
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Affiliation(s)
- Viorelia Adelina Constantin
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, Târgu Mureș, Romania
- Doctoral School, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - József Attila Szász
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, Târgu Mureș, Romania
- Department of Neurology, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureș, Romania
| | - Károly Orbán-Kis
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, Târgu Mureș, Romania
- Department of Physiology, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureș, Romania
| | - Elena Cecilia Rosca
- Department of Neurology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
- Department of Neurology, “Pius Branzeu” Emergency Clinical County Hospital, Timisoara, Romania
| | | | - Amalia Cornea
- Department of Neurology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
- Department of Neurology, “Pius Branzeu” Emergency Clinical County Hospital, Timisoara, Romania
| | - Ligia Ariana Bancu
- Department of Internal Medicine, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureș, Romania
- 1 Clinic of Internal Medicine, Târgu Mureș County Emergency Clinical Hospital, Târgu Mureș, Romania
| | - Marius Ciorba
- Department of Internal Medicine, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureș, Romania
- Department of Gastroenterology, Târgu Mureș County Emergency Clinical Hospital, Târgu Mureș, Romania
| | - István Mihály
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, Târgu Mureș, Romania
- Department of Physiology, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureș, Romania
| | - Előd Nagy
- Department of Biochemistry and Environmental Chemistry, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureș, Romania
- Laboratory of Medical Analysis, Clinical County Hospital Mureș, Târgu Mureș, Romania
| | - Szabolcs Szatmári
- 2nd Clinic of Neurology, Târgu Mureș County Emergency Clinical Hospital, Târgu Mureș, Romania
- Department of Neurology, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureș, Romania
| | - Mihaela Simu
- Department of Neurology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
- Department of Neurology, “Pius Branzeu” Emergency Clinical County Hospital, Timisoara, Romania
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Abstract
Peripheral neuropathy (PN) is a common neurological problem defined as a dysfunction of sensory, motor, and autonomic nerves. The presence of peripheral neuropathy has recently been noticed in Parkinson's disease (PD) This comorbidity is concerning as it increases the burden on patients whose motor functions are previously compromised. A comprehensive computer-based literature review utilizing multiple peer-reviewed databases (e.g., Embase, PsycINFO, CINAHL, etc.) was conducted. There is evidence for the utility of robust diagnostic criteria to distinguish between large fiber neuropathy (LFN) and small fiber neuropathy (SFN). Some studies have established links between prolonged L-DOPA exposure and prevalence with increased levels of homocysteine (HCY) and methylmalonic acid (MMA) as pathological underlying mechanisms. PN in PD patients with relatively truncated exposure to L-DOPA therapy may have underlying mutations in the Parkin and MHTFR gene or separate mitochondrial disorders. Vitamin B12 and cobalamin deficiencies have also been implicated as drivers of PN. Accumulation of phosphorylated α-synuclein is another central feature in PN and deems urgent exploration via large cohort studies. Importantly, these underlying mechanisms have been linked to peripheral denervation. This review delves into the potential treatments for PN targeting B12 deficiencies and the use of COMT inhibitors along with other novel approaches. Avenues of research with powerful randomized controlled and long-term cohort studies exploring genetic mechanisms and novel treatment pathways is urgently required to alleviate the burden of disease exerted by PN on PD.
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Blaise AS, Baille G, Carrière N, Devos D, Dujardin K, Grolez G, Kreisler A, Kyheng M, Moreau C, Mutez E, Seguy D, Defebvre L. Safety and effectiveness of levodopa-carbidopa intestinal gel for advanced Parkinson's disease: A large single-center study. Rev Neurol (Paris) 2020; 176:268-276. [DOI: 10.1016/j.neurol.2019.07.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/21/2019] [Accepted: 07/23/2019] [Indexed: 01/15/2023]
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Müller T. Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson’s disease. Expert Opin Drug Metab Toxicol 2020; 16:403-414. [DOI: 10.1080/17425255.2020.1750596] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Thomas Müller
- Department of Neurology, St. Joseph Hospital Berlin-Weißensee, Berlin, Germany
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Nevmerzhytska NM, Orzheshkovskyi VV, Dzevulska IV, Savosko SI. Mechanisms of Toxic Effects of Homocysteine on the Nervous System. NEUROPHYSIOLOGY+ 2020. [DOI: 10.1007/s11062-020-09832-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Gwathmey KG, Grogan J. Nutritional neuropathies. Muscle Nerve 2019; 62:13-29. [PMID: 31837157 DOI: 10.1002/mus.26783] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 12/07/2019] [Accepted: 12/07/2019] [Indexed: 12/17/2022]
Abstract
Neuropathies associated with nutritional deficiencies are routinely encountered by the practicing neurologist. Although these neuropathies assume different patterns, most are length-dependent, sensory axonopathies. Cobalamin deficiency neuropathy is the exception, often presenting with a non-length-dependent sensory neuropathy. Patients with cobalamin and copper deficiency neuropathy characteristically have concomitant myelopathy, whereas vitamin E deficiency is uniquely associated with a spinocerebellar syndrome. In contrast to those nutrients for which deficiencies produce neuropathies, pyridoxine toxicity results in a non-length-dependent sensory neuronopathy. Deficiencies occur in the context of malnutrition, malabsorption, increased nutrient loss (such as with dialysis), autoimmune conditions such as pernicious anemia, and with certain drugs that inhibit nutrient absorption. When promptly identified, therapeutic nutrient supplementation may result in stabilization or improvement of these neuropathies.
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Affiliation(s)
| | - James Grogan
- University of Virginia, Charlottesville, Virginia
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van Wamelen DJ, Grigoriou S, Chaudhuri KR, Odin P. Continuous Drug Delivery Aiming Continuous Dopaminergic Stimulation in Parkinson's Disease. JOURNAL OF PARKINSONS DISEASE 2019; 8:S65-S72. [PMID: 30584160 PMCID: PMC6311379 DOI: 10.3233/jpd-181476] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Continuous dopaminergic stimulation in Parkinson's disease (PD) has several advantages over pulsatile, non-continuous, stimulation. These therapies currently consist of pump-based and transcutaneous therapies and are based on a more constant delivery of the dopaminergic drug resulting in continuous dopaminergic stimulation and a more stable treatment effect. Several clinical and experimental observations have shown that continuous stimulation of dopaminergic receptors induces fewer complications, such as dyskinesia, compared to pulsatile stimulation. Currently available non-oral pharmacological continuous therapies in PD include the transdermal Rotigotine (RTG) patch, infusion therapies with Apomorphine and Intrajejunal Levodopa (IJLI) and the Rivastigmine patch. Here we aim to provide a concise review of these current therapies and discuss ongoing and future developments of continuous non-oral pharmacological dopaminergic therapies in PD.
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Affiliation(s)
- Daniel J van Wamelen
- Institute of Psychiatry, Psychology & Neuroscience at King's College London, Department of Basic & Clinical Neuroscience, De Crespigny Park, London, United Kingdom.,Parkinson Foundation International Centre of Excellence, King's College Hospital, Denmark Hill, London, United Kingdom.,Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands
| | | | - K Ray Chaudhuri
- Institute of Psychiatry, Psychology & Neuroscience at King's College London, Department of Basic & Clinical Neuroscience, De Crespigny Park, London, United Kingdom.,Parkinson Foundation International Centre of Excellence, King's College Hospital, Denmark Hill, London, United Kingdom
| | - Per Odin
- University of Lund, Faculty of Medicine, Lund, Sweden.,University Hospital Reinkenheide, Bremerhaven, Germany
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Large-Fiber Neuropathy in Parkinson's Disease: Clinical, Biological, and Electroneurographic Assessment of a Romanian Cohort. J Clin Med 2019; 8:jcm8101533. [PMID: 31554346 PMCID: PMC6832533 DOI: 10.3390/jcm8101533] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 09/15/2019] [Accepted: 09/23/2019] [Indexed: 12/15/2022] Open
Abstract
(1) Background: Increased attention has lately been given to polyneuropathy in Parkinson’s Disease (PD). Several papers postulated that large-fiber neuropathy (PNP) in PD is related to vitamin B12 deficiency and L-Dopa exposure. (2) Methods: Using a cross-sectional, observational study, we evaluated 73 PD patients without a previously known cause of PNP using clinical scores (UPDRS II and III and Toronto Clinical Scoring System), biological evaluation of vitamin B12 and folic acid, and nerve conduction studies to assess the prevalence and features of PNP. (3) Results: The prevalence of PNP was 49.3% in the study group. In the L-Dopa group, the frequency of PNP was 67.3% as compared to PNP in the non-L-Dopa group, where one subject had PNP (χ2 = 23.41, p < 0.01). PNP was predominantly sensory with mild to moderate axonal loss. Cyanocobalamin correlated with L-Dopa daily dose (r = −0.287, p < 0.05) and L-Dopa duration of administration (r = −0.316, p < 0.05). L-Dopa daily dose correlated with the amplitudes of sensory nerve action potentials of the superficial peroneal and radial nerves (r = −0.312, p < 0.05) (r = −0.336, p < 0.05), respectively. (4) Conclusions: PNP is more frequent in L-Dopa-treated patients than in L-Dopa-naïve patients. The results imply that longer exposure to high doses of L-Dopa may cause vitamin B12 and folate imbalance and PNP, secondarily.
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A potential role for T-type calcium channels in homocysteinemia-induced peripheral neuropathy. Pain 2019; 160:2798-2810. [DOI: 10.1097/j.pain.0000000000001669] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Romagnolo A, Merola A, Artusi CA, Rizzone MG, Zibetti M, Lopiano L. Levodopa-Induced Neuropathy: A Systematic Review. Mov Disord Clin Pract 2018; 6:96-103. [PMID: 30838307 DOI: 10.1002/mdc3.12688] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 12/30/2022] Open
Abstract
Background Clinical, neurophysiological, and pathological evidence suggest an association between Parkinson's disease (PD) and peripheral neuropathy (PNP), with a possible causative role of levodopa metabolic products, such as homocysteine and methylmalonic acid. Methods We conducted a systematic review of studies reporting cases of PNP in l-dopa-treated PD patients indexed in PubMed between January 1990 and March 2018. Results We identified 38 articles reporting cases of PNP in PD patients treated with oral l-dopa or with l-dopa/carbidopa intestinal gel infusion (LCIG). Prevalence of PNP was 30.2% in the former group and 42.1% in the latter. Oral l-dopa was mostly associated with slowly progressive PNP, whereas LCIG showed an acute or subacute onset in 35.7% of cases. In both groups, there was an association between PNP and higher l-dopa doses, as well as with the following biochemical alterations: increased homocysteine; reduced vitamin B12; increased methylmalonic acid; and reduced vitamin B6. A skin biopsy was performed in 181 patients, showing signs of small fibers neuropathy in 169 (93.4%). Positive, yet preliminary, results were observed in patients receiving periodic vitamin supplementation. Conclusions Over one third of PD patients in treatment with l-dopa may develop PNP, with a significantly higher prevalence of acute and subacute forms in those receiving LCIG. Pathogenic mechanisms remain unclear, but possibly related to a complex interplay between peripheral neurodegenerative processes and l-dopa neurotoxic metabolites. Prospective, randomized, clinical trials are required to identify factors associated with the onset and progression of PD-associated PNP and clarify the protective role of B-group vitamin supplementation.
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Affiliation(s)
- Alberto Romagnolo
- Department of Neuroscience "Rita Levi Montalcini" University of Turin Torino Italy
| | - Aristide Merola
- Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology University of Cincinnati Cincinnati Ohio USA
| | - Carlo Alberto Artusi
- Department of Neuroscience "Rita Levi Montalcini" University of Turin Torino Italy
| | | | - Maurizio Zibetti
- Department of Neuroscience "Rita Levi Montalcini" University of Turin Torino Italy
| | - Leonardo Lopiano
- Department of Neuroscience "Rita Levi Montalcini" University of Turin Torino Italy
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Kaur H, Bhatia K, Yelam A, Shukla A, Asher I, Govindarajan R. Infusion-rate-dependent Acute Neuropathic Pain with Duopa in a Patient with Parkinson's Disease and Pre-existing Neuropathy. Cureus 2018; 10:e3055. [PMID: 30276034 PMCID: PMC6160297 DOI: 10.7759/cureus.3055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The association of peripheral neuropathy (PN) with the cumulative use of levodopa, presumably by vitamin B12 deficiency, has been well-documented in the literature. However, less is known about the L-dopa infusion-rate-dependent precipitation of pre-existing peripheral neuropathy. We report an unusual case of Parkinson’s disease in a patient who presented with acute exacerbations of pre-existing peripheral neuropathy on exceeding certain rates of continuous Carbidopa-Levodopa Infusions (CLI). We present a case of a 68-year-old gentleman with a 20-year history of idiopathic Parkinson's disease with bilateral subthalamic nucleus deep brain stimulation who was started on Duopa therapy for worsening dyskinesias. Workup before initiating Duopa was significant for idiopathic sensorimotor axonal polyneuropathy, although the symptoms were well controlled with medications. Subsequently, the patient developed severe neuropathic pain within 24 hours of initiating Duopa characterized by burning and stinging in his feet. Symptoms resolved within four hours of reducing the continuous infusion rates without modifying the bolus doses. The patient was doing well with extra bolus doses to manage off periods with no further recurrence of symptoms. With the support of this case report, we would like to conclude that the acute worsening of neuropathic pain with infusion rate or duration of treatment might limit the clinical benefits of Duopa and adds to the expanding spectrum of neurotoxic side effects associated with this therapy. Further prospective studies are needed to monitor the acute worsening of neuropathic pain in patients with pre-existing PN, after initiating CLI and its association with doses of levodopa/carbidopa.
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Affiliation(s)
- Harleen Kaur
- Neurology, Univeristy of Missouri, Columbia, USA
| | - Kunal Bhatia
- Neurology, University of Missouri, Columbia, USA
| | | | | | - Irving Asher
- Neurology, University of Missouri, Columbia, USA
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Fernandez HH, Boyd JT, Fung VSC, Lew MF, Rodriguez RL, Slevin JT, Standaert DG, Zadikoff C, Vanagunas AD, Chatamra K, Eaton S, Facheris MF, Hall C, Robieson WZ, Benesh J, Espay AJ. Long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced Parkinson's disease. Mov Disord 2018; 33:928-936. [DOI: 10.1002/mds.27338] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 01/09/2018] [Accepted: 01/11/2018] [Indexed: 11/09/2022] Open
Affiliation(s)
| | - James T. Boyd
- University of Vermont Larner College of Medicine, Burlington; Vermont USA
| | | | - Mark F. Lew
- Keck/University of Southern California School of Medicine; Los Angeles California USA
| | - Ramon L. Rodriguez
- University of Florida College of Medicine, Gainesville, Florida, USA, and Orlando Veterans Affairs Medical Center; Orlando Florida USA
| | - John T. Slevin
- University of Kentucky Medical Center; Lexington Kentucky USA
| | | | - Cindy Zadikoff
- Feinberg School of Medicine; Northwestern University; Chicago Illinois USA
| | | | | | | | | | | | | | | | - Alberto J. Espay
- University of Cincinnati Academic Health Center; Cincinnati Ohio USA
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Tambasco N, Romoli M, Calabresi P. Levodopa in Parkinson's Disease: Current Status and Future Developments. Curr Neuropharmacol 2018; 16:1239-1252. [PMID: 28494719 PMCID: PMC6187751 DOI: 10.2174/1570159x15666170510143821] [Citation(s) in RCA: 156] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 04/25/2017] [Accepted: 05/09/2017] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the treatment of Parkinson's Disease (PD). However, long-term levodopa (LD) treatment is frequently associated with fluctuations in motor response with serious impact on patient quality of life. The pharmacokinetic and pharmacodynamic properties of LD are pivotal to such motor fluctuations: discontinuous drug delivery, short half-life, poor bioavailability, and narrow therapeutic window are all crucial for such fluctuations. During the last 60 years, several attempts have been made to improve LD treatment and avoid long-term complications. METHODS Research and trials to improve the LD pharmacokinetic since 1960s are reviewed, summarizing the progressive improvements of LD treatment. RESULTS Inhibitors of peripheral amino acid decarboxylase (AADC) have been introduced to achieve proper LD concentration in the central nervous system reducing systemic adverse events. Inhibitors of catechol-O-methyltransferase (COMT) increased LD half-life and bioavailability. Efforts are still being made to achieve a continuous dopaminergic stimulation, with the combination of oral LD with an AADC inhibitor and a COMT inhibitor, or the intra-duodenal water-based LD/ carbidopa gel. Further approaches to enhance LD efficacy are focused on new non-oral administration routes, including nasal, intra-duodenal, intrapulmonary (CVT-301) and subcutaneous (ND0612), as well as on novel ER formulations, including IPX066, which recently concluded phase III trial. CONCLUSION New LD formulations, oral compounds as well as routes have been tested in the last years, with two main targets: achieve continuous dopaminergic stimulation and find an instant deliver route for LD.
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Affiliation(s)
- Nicola Tambasco
- Address correspondence to this author at the Clinica Neurologica, Azienda Ospedaliera e Universitaria di Perugia, Loc. S.Andrea delle Fratte 06156, Perugia, Italy; Tel: +39-075-5783830; Fax: +39-075-5784229;, E-mail:
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Rispoli V, Simioni V, Capone JG, Golfrè Andreasi N, Preda F, Sette E, Tugnoli V, Sensi M. Peripheral neuropathy in 30 duodopa patients with vitamins B supplementation. Acta Neurol Scand 2017; 136:660-667. [PMID: 28608472 DOI: 10.1111/ane.12783] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2017] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Peripheral neuropathy (PN) is a significant concern and potential cause of withdrawal in patients with Parkinson's disease (PD) treated with Levodopa/Carbidopa Intestinal Gel (LCIG) infusion. Vitamin B deficiency and/or hyperhomocysteinemia levodopa-related are considered possible causative factors. In this study, we evaluated PN incidence in LCIG-PD patients treated since the beginning of infusion with vitamins B supplementation. MATERIALS & METHODS In this prospective open-label pilot study, 30 consecutive patients with PD on LCIG infusion were evaluated with clinical, neurophysiological, and biochemical assessments for a mean follow-up of 42.4 months (range 24-72). All evaluations were repeated every 6 months. RESULTS At baseline, 21 of 30 presented no signs or symptoms of PN, and 9 of 30 had pre-existing chronic PN. In whole population, a progressive worsening in nerve conduction studies of sural sensory and peroneal motor nerves was observed during the long-term follow-up. 4 of 21 patients, with normal clinical, electrophysiological assessment at baseline, developed distal symmetrical axonal polyneuropathy that remained asymptomatic during the long-term follow-up. Patients with pre-existing PN (9 of 30) showed a mild worsening of electrophysiological features during the period of observation. In none PN was cause of discontinuation of LCIG therapy. No incident cases of acute-subacute PN were documented. No correlation was found with age, sex, Levodopa dosage, duration of levodopa exposure, and homocysteine plasma levels. CONCLUSION In this consecutive series of 30 patients with PD on LCIG infusion, with early and continuous vitamins B integration, we observed a low rate (19%) of new onset peripheral polyneuropathy that remained stable after long-term follow-up. Larger studies, controlled, with blinded evaluation, are needed to confirm these findings.
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Affiliation(s)
- V. Rispoli
- Neurology Department; Az. Ospedaliero-Universitaria Arcispedale Sant'Anna; Cona Ferrara Italy
| | - V. Simioni
- Neurology Department; Az. Ospedaliero-Universitaria Arcispedale Sant'Anna; Cona Ferrara Italy
| | - J. G. Capone
- Neurology Department; Az. Ospedaliero-Universitaria Arcispedale Sant'Anna; Cona Ferrara Italy
| | - N. Golfrè Andreasi
- Neurology Department; Az. Ospedaliero-Universitaria Arcispedale Sant'Anna; Cona Ferrara Italy
| | - F. Preda
- Neurology Department; Ospedale Bufalini; Cesena Italy
| | - E. Sette
- Neurology Department; Az. Ospedaliero-Universitaria Arcispedale Sant'Anna; Cona Ferrara Italy
| | - V. Tugnoli
- Neurology Department; Az. Ospedaliero-Universitaria Arcispedale Sant'Anna; Cona Ferrara Italy
| | - M. Sensi
- Neurology Department; Az. Ospedaliero-Universitaria Arcispedale Sant'Anna; Cona Ferrara Italy
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Andréasson M, Brodin L, Laffita-Mesa JM, Svenningsson P. Correlations Between Methionine Cycle Metabolism, COMT Genotype, and Polyneuropathy in L-Dopa Treated Parkinson’s Disease: A Preliminary Cross-Sectional Study. JOURNAL OF PARKINSONS DISEASE 2017; 7:619-628. [DOI: 10.3233/jpd-171127] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Mattias Andréasson
- Department of Neurology, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Lovisa Brodin
- Department of Neurology, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - José Miguel Laffita-Mesa
- Department of Clinical Neuroscience, Translational Neuropharmacology, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Per Svenningsson
- Department of Neurology, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Department of Clinical Neuroscience, Translational Neuropharmacology, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
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Loens S, Chorbadzhieva E, Kleimann A, Dressler D, Schrader C. Effects of levodopa/carbidopa intestinal gel versus oral levodopa/carbidopa on B vitamin levels and neuropathy. Brain Behav 2017; 7:e00698. [PMID: 28523235 PMCID: PMC5434198 DOI: 10.1002/brb3.698] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 02/15/2017] [Accepted: 03/03/2017] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES To determine the possible interactions between levodopa therapy and plasma levels of B vitamins in patients with advanced idiopathic Parkinson's disease (IPD) in the context of either oral levodopa therapy or levodopa/carbidopa intestinal gel (LCIG). Secondly, to determine the prevalence of neuropathy and its relation to plasma levels of B vitamins and homocysteine. METHODS Medication doses, neurographies, and serum levels of pyridoxine, cobalamin, folate, and homocysteine of eight LCIG and 13 orally treated advanced IPD patients matched for age, Hoehn & Yahr stage, and UPRDS III were collected. This data was analyzed for correlation with daily levodopa dose (LDD). RESULTS LICG patients had a longer disease duration and higher LDD. All LCIG patients and most orally treated patients had sensorimotor axonal polyneuropathy. Of all plasma vitamin levels, pyridoxine was decreased most and significantly lower in the LCIG group. Cobalamin and folate, however, were within the lower reference range, and homocysteine highly elevated, all without any significant difference between both groups. LDD correlated significantly with pyridoxine deficiency (p = .02) irrespective of the route of application and with hyperhomocysteinemia in the LCIG group (p = .03). At LDDs above 2,000 mg, pyridoxine deficiency was almost always detectable. CONCLUSIONS Pyridoxine deficiency and hyperhomocysteinemia are dependent on the daily levodopa/carbidopa dose, while levels of cobalamin and folate are not. The mode of application of levodopa/carbidopa has no impact on B-vitamin levels. Neuropathy is very frequent in advanced IPD; however, it remains to be investigated further whether neuropathy is more frequent in LCIG than in orally levodopa/carbidopa-treated advanced IPD patients.
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Affiliation(s)
- Sebastian Loens
- Department of Neurology and Clinical Neurophysiology Hannover Medical School Hannover Germany
| | - Elena Chorbadzhieva
- Department of Neurology and Clinical Neurophysiology Hannover Medical School Hannover Germany
| | - Alexandra Kleimann
- Department of Psychiatry Social Psychiatry and Psychotherapy Hannover Medical School Hannover Germany
| | - Dirk Dressler
- Department of Neurology and Clinical Neurophysiology Hannover Medical School Hannover Germany
| | - Christoph Schrader
- Department of Neurology and Clinical Neurophysiology Hannover Medical School Hannover Germany
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