<?xml version="1.1" encoding="utf-8"?>
<article xsi:noNamespaceSchemaLocation="http://jats.nlm.nih.gov/publishing/1.1/xsd/JATS-journalpublishing1-mathml3.xsd" dtd-version="1.1" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"><front><journal-meta><journal-id journal-id-type="publisher-id">HPR</journal-id><journal-title-group><journal-title>Health Psychology Research</journal-title></journal-title-group><issn>TBA</issn><eissn>2420-8124</eissn><publisher><publisher-name>Health Psychology Research</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.52965/001c.36074</article-id><article-categories><subj-group subj-group-type="heading"><subject>General</subject></subj-group></article-categories><title>Opicapone, a Novel Catechol-O-methyl Transferase Inhibitor, for   Treatment of Parkinson’s Disease “Off” Episodes</title><url>https://healthpr.org/journal/HPR/10/5/10.52965/001c.36074</url><author>A. BergerAmnon,WinnickAriel,IzygonJonathan,M. JacobBinil,S. KayeJessica,J. KayeRachel,E. NeuchatElisa,M. KayeAdam,S. AlpaughEdward,M. CornettElyse,H. HanAndrew,D. KayeAlan</author><pub-date pub-type="publication-year"><year>2022</year></pub-date><volume>10</volume><issue>5</issue><history><date date-type="pub"><published-time>2022-06-28</published-time></date></history><abstract>Parkinson&amp;rsquo;s Disease (PD) is a common neurodegenerative disorder and the leading cause of disability. It causes significant morbidity and disability through a plethora of symptoms, including movement disorders, sleep disturbances, and cognitive and psychiatric symptoms. The traditional pathogenesis theory of PD involves the loss of dopaminergic neurons in the substantia nigra (SN). Classically, treatment is pursued with an assortment of medications that are directed at overcoming this deficiency with levodopa being central to most treatment plans. Patients taking levodopa tend to experience &amp;ldquo;off episodes&amp;rdquo; with decreasing medication levels, causing large fluctuations in their symptoms. These off episodes are disturbing and a source of morbidity for these patients. Opicapone is a novel, peripherally acting Catechol-O-methyl transferase (COMT) inhibitor that is used as adjunctive therapy to carbidopa/levodopa for treatment and prevention of &amp;ldquo;off episodes.&amp;rdquo; It has been approved for use as an adjunct to levodopa since 2016 in Europe and has recently (April 2020) gained FDA approval for use in the USA. By inhibiting COMT, opicapone slows levodopa metabolism and increases its availability. Several clinical studies demonstrated significant improvement in treatment efficacy and reduction in duration of &amp;ldquo;off episodes.&amp;rdquo; The main side effect demonstrated was dyskinesia, mostly with the 100mg dose, which is higher than the approved, effective dose of 50mg. Post-marketing surveillance and analysis are required to further elucidate its safety profile and contribute to patient selection. This paper reviews the seminal and latest evidence in the treatment of PD &amp;ldquo;off episodes&amp;rdquo; with the novel drug Opicapone, including efficacy, safety, and clinical indications.</abstract><keywords>Opicapone, neurodegenerative, rigidity, parkinsonism, COMT, levodopa</keywords></article-meta></front><body/><back><ref-list><ref id="B1" content-type="article"><label>1</label><element-citation publication-type="journal"><p>1. Kouli A, Torsney KM, Kuan WL. Parkinson&amp;rsquo;s Disease: Etiology, Neuropathology, and Pathogenesis. In: Parkinson&amp;rsquo;s Disease: Pathogenesis and Clinical Aspects. Codon Publications; 2018:3-26. https://doi.org/10.15586/codonpublications.parkinsonsdisease.2018.ch1&amp;nbsp;2. Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548-560. doi:10.1001/jama.2019.22360&amp;nbsp;3. Marras C, Beck JC, Bower JH, et al. Prevalence of Parkinson&amp;rsquo;s disease across North America. npj Parkinson&amp;rsquo;s Disease. 2018;4(1):21. doi:10.1038/s41531-018-0058-0&amp;nbsp;4. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson&amp;rsquo;s disease: variation by age, gender, and race/ethnicity. American Journal of Epidemiology. 2003;157(11):1015-1022. doi:10.1093/aje/kwg068&amp;nbsp;5. Elbaz A, Bower JH, Maraganore DM, et al. Risk tables for parkinsonism and Parkinson&amp;rsquo;s disease. Journal of Clinical Epidemiology. 2002;55(1):25-31. doi:10.1016/s0895-4356(01)00425-5&amp;nbsp;6. Stocchi F. The levodopa wearing-off phenomenon in Parkinson&amp;rsquo;s disease: Pharmacokinetic considerations. Expert Opinion on Pharmacotherapy. 2006;7(10):1399-1407. doi:10.1517/14656566.7.10.1399&amp;nbsp;7. Marsden CD, Parkes JD. &amp;ldquo;ON-OFF&amp;rdquo; EFFECTS IN PATIENTS WITH PARKINSON&amp;rsquo;S DISEASE ON CHRONIC LEVODOPA THERAPY. The Lancet. 1976;307(7954):292-296. doi:10.1016/s0140-6736(76)91416-1&amp;nbsp;8. Chou KL, Stacy M, Simuni T, et al. The spectrum of &amp;ldquo;off&amp;rdquo; in Parkinson&amp;rsquo;s disease: What have we learned over 40 years? Parkinsonism &amp;amp; Related Disorders. 2018;51:9-16. doi:10.1016/j.parkreldis.2018.02.001&amp;nbsp;9. Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in Parkinson&amp;rsquo;s disease: Frequent and disabling. Neurology. 2002;59(3):408-413. doi:10.1212/wnl.59.3.408&amp;nbsp;10. Richard IH, Frank S, McDermott MP, et al. The ups and downs of Parkinson disease: A prospective study of mood and anxiety fluctuations. Cognitive and Behavioral Neurology. 2004;17(4):201-207.&amp;nbsp;11. Kerr C, Lloyd EJ, Kosmas CE, et al. Health-related quality of life in Parkinson&amp;rsquo;s: impact of &amp;lsquo;off&amp;rsquo; time and stated treatment preferences. Qual Life Res. 2016;25(6):1505-1515. doi:10.1007/s11136-015-1187-0&amp;nbsp;12. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson&amp;rsquo;s Disease. N Engl J Med. 2004;351(24):2498-2508. doi:10.1056/nejmoa033447&amp;nbsp;13. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16(3):448-458. doi:10.1002/mds.1090&amp;nbsp;14. Wan Y, Yuan C, Hou X, et al. Wearing-off Identification in Parkinson&amp;rsquo;s Disease: The shapd-woq Study. Front Neurol. 2020;11. doi:10.3389/fneur.2020.00116&amp;nbsp;15. Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson&amp;rsquo;s disease. Neurology. 1991;41(2):202-205. doi:10.1212/wnl.41.2_part_1.202&amp;nbsp;16. Schrag A, Ben-Shlomo Y, Brown R, Marsden CD, Quinn N. Young-onset Parkinson&amp;rsquo;s disease revisited&amp;mdash;clinical features, natural history, and mortality. Mov Disord. 1998;13(6):885-894. doi:10.1002/mds.870130605&amp;nbsp;17. Bhidayasiri R, Hattori N, Jeon B, et al. Asian perspectives on the recognition and management of levodopa &amp;lsquo;wearing-off&amp;rsquo; in Parkinson&amp;rsquo;s disease. Expert Review of Neurotherapeutics. 2015;15(11):1285-1297. doi:10.1586/14737175.2015.1088783&amp;nbsp;18. Lutz SG, Holmes JD, Ready EA, Jenkins ME, Johnson AM. Clinical presentation of anxiety in Parkinson&amp;rsquo;s disease: A scoping review. OTJR: Occupation, Participation and Health. 2016;36(3):134-147. doi:10.1177/1539449216661714&amp;nbsp;19. Breen DP, Halliday GM, Lang AE. Gut&amp;ndash;brain axis and the spread of &amp;alpha;-synuclein pathology: Vagal highway or dead end? Mov Disord. 2019;34(3):307-316. doi:10.1002/mds.27556&amp;nbsp;20. Ray Dorsey E, Elbaz A, Nichols E, et al. Global, regional, and national burden of Parkinson&amp;rsquo;s disease, 1990&amp;ndash;2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology. 2018;17(11):939-953. doi:10.1016/s1474-4422(18)30295-3&amp;nbsp;21. Pringsheim T, Jette N, Frolkis A, Steeves TDL. The prevalence of Parkinson&amp;rsquo;s disease: A systematic review and meta-analysis. Mov Disord. 2014;29(13):1583-1590. doi:10.1002/mds.25945&amp;nbsp;22. Meoni S, Macerollo A, Moro E. Sex differences in movement disorders. Nat Rev Neurol. 2020;16(2):84-96. doi:10.1038/s41582-019-0294-x&amp;nbsp;23. Factor SA, McDonald WM, Goldstein FC. The role of neurotransmitters in the development of Parkinson&amp;rsquo;s disease-related psychosis. Eur J Neurol. 2017;24(10):1244-1254. doi:10.1111/ene.13376&amp;nbsp;24. Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson&amp;rsquo;s disease. Mov Disord. 2015;30(12):1600-1611. doi:10.1002/mds.26431&amp;nbsp;25. Braak H, Del Tredici K, R&amp;uuml;b U, De Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson&amp;rsquo;s disease. Neurobiology of Aging. 2003;24(2):197-211. doi:10.1016/s0197-4580(02)00065-9&amp;nbsp;26. Borghammer P, Van Den Berge N. Brain-First versus Gut-First Parkinson&amp;rsquo;s Disease: A Hypothesis. JPD. 2019;9(s2):S281-S295. doi:10.3233/jpd-191721&amp;nbsp;27. Li D, Mastaglia FL, Fletcher S, Wilton SD. Progress in the molecular pathogenesis and nucleic acid therapeutics for Parkinson&amp;rsquo;s disease in the precision medicine era. Med Res Rev. 2020;40(6):2650-2681. doi:10.1002/med.21718&amp;nbsp;28. Chen ML, Wu RM. LRRK 2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson&amp;rsquo;s disease: A review. J Biomed Sci. 2018;25(1). doi:10.1186/s12929-018-0454-0&amp;nbsp;29. Walden H, Muqit MMK. Ubiquitin and Parkinson&amp;rsquo;s disease through the looking glass of genetics. Biochemical Journal. 2017;474(9):1439-1451. doi:10.1042/bcj20160498&amp;nbsp;30. Manecka DL, Vanderperre B, Fon EA, Durcan TM. The neuroprotective role of protein quality control in halting the development of alpha-synuclein pathology. Front Mol Neurosci. 2017;10. doi:10.3389/fnmol.2017.00311&amp;nbsp;31. Park JS, Davis RL, Sue CM. Mitochondrial Dysfunction in Parkinson&amp;rsquo;s Disease: New Mechanistic Insights and Therapeutic Perspectives. Curr Neurol Neurosci Rep. 2018;18(5). doi:10.1007/s11910-018-0829-3&amp;nbsp;32. Xilouri M, Brekk OR, Stefanis L. Autophagy and Alpha-Synuclein: Relevance to Parkinson&amp;rsquo;s Disease and Related Synucleopathies. Mov Disord. 2016;31(2):178-192. doi:10.1002/mds.26477&amp;nbsp;33. Gao F, Yang J, Wang D, et al. Mitophagy in Parkinson&amp;rsquo;s disease: Pathogenic and therapeutic implications. Front Neurol. 2017;8(OCT). doi:10.3389/fneur.2017.00527&amp;nbsp;34. Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson&amp;rsquo;s: From familial to sporadic disease. Trends in Biochemical Sciences. 2015;40(4):200-210. doi:10.1016/j.tibs.2015.02.003&amp;nbsp;35. Manzoni C. The LRRK2&amp;ndash;macroautophagy axis and its relevance to Parkinson&amp;rsquo;s disease. Biochemical Society Transactions. 2017;45(1):155-162. doi:10.1042/bst20160265&amp;nbsp;36. Nguyen TN, Padman BS, Lazarou M. Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. Trends in Cell Biology. 2016;26(10):733-744. doi:10.1016/j.tcb.2016.05.008&amp;nbsp;37. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. Journal of Cell Biology. 2008;183(5):795-803. doi:10.1083/jcb.200809125&amp;nbsp;38. Cacabelos R. Parkinson&amp;rsquo;s disease: From pathogenesis to pharmacogenomics. IJMS. 2017;18(3):551. doi:10.3390/ijms18030551&amp;nbsp;39. Caputi V, Giron M. Microbiome-gut-brain axis and toll-like receptors in parkinson&amp;rsquo;s disease. IJMS. 2018;19(6):1689. doi:10.3390/ijms19061689&amp;nbsp;40. Chiang HL, Lin CH. Altered Gut Microbiome and Intestinal Pathology in Parkinson&amp;rsquo;s Disease. JMD. 2019;12(2):67-83. doi:10.14802/jmd.18067&amp;nbsp;41. Bullich C, Keshavarzian A, Garssen J, Kraneveld A, Perez-Pardo P. Gut Vibes in Parkinson&amp;rsquo;s Disease: The Microbiota-Gut-Brain Axis. Mov Disord Clin Pract. 2019;6(8):639-651. doi:10.1002/mdc3.12840&amp;nbsp;42. Devos D, Lebouvier T, Lardeux B, et al. Colonic inflammation in Parkinson&amp;rsquo;s disease. Neurobiology of Disease. 2013;50(1):42-48. doi:10.1016/j.nbd.2012.09.007&amp;nbsp;43. Clairembault T, Kamphuis W, Leclair-Visonneau L, et al. Enteric GFAP expression and phosphorylation in Parkinson&amp;rsquo;s disease. J Neurochem. 2014;130(6):805-815. doi:10.1111/jnc.12742&amp;nbsp;44. Iwaki H, Blauwendraat C, Leonard HL, et al. Genomewide association study of Parkinson&amp;rsquo;s disease clinical biomarkers in 12 longitudinal patients&amp;rsquo; cohorts. Mov Disord. 2019;34(12):1839-1850. doi:10.1002/mds.27845&amp;nbsp;45. Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol. 2012;72(6):893-901. doi:10.1002/ana.23687&amp;nbsp;46. Bellou V, Belbasis L, Tzoulaki I, Evangelou E, Ioannidis JPA. Environmental risk factors and Parkinson&amp;rsquo;s disease: An umbrella review of meta-analyses. Parkinsonism &amp;amp; Related Disorders. 2016;23:1-9. doi:10.1016/j.parkreldis.2015.12.008&amp;nbsp;47. Dirkx MF, Zach H, Bloem BR, Hallett M, Helmich RC. The nature of postural tremor in Parkinson disease. Neurology. 2018;90(13):e1095-e1102. doi:10.1212/wnl.0000000000005215&amp;nbsp;48. Marinus J, Zhu K, Marras C, Aarsland D, van Hilten JJ. Risk factors for non-motor symptoms in Parkinson&amp;rsquo;s disease. The Lancet Neurology. 2018;17(6):559-568. doi:10.1016/s1474-4422(18)30127-3&amp;nbsp;49. Kalia LV, Lang AE. Parkinson&amp;rsquo;s disease. The Lancet. 2015;386(9996):896-912. doi:10.1016/s0140-6736(14)61393-3&amp;nbsp;50. Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci. 2017;18(7):435-450. doi:10.1038/nrn.2017.62&amp;nbsp;51. Hess CW, Hallett M. The Phenomenology of Parkinson&amp;rsquo;s Disease. Semin Neurol. 2017;37(2):109-117. doi:10.1055/s-0037-1601869&amp;nbsp;52. Marras C, Lang A. Parkinson&amp;rsquo;s disease subtypes: Lost in translation? Journal of Neurology, Neurosurgery &amp;amp; Psychiatry. 2013;84(4):409-415. doi:10.1136/jnnp-2012-303455&amp;nbsp;53. Fereshtehnejad SM, Zeighami Y, Dagher A, Postuma RB. Clinical criteria for subtyping Parkinson&amp;rsquo;s disease: Biomarkers and longitudinal progression. Brain. 2017;140(7):1959-1976. doi:10.1093/brain/awx118&amp;nbsp;54. Bjornestad A, Pedersen KF, Tysnes OB, Alves G. Clinical milestones in Parkinson&amp;rsquo;s disease: A 7-year population-based incident cohort study. Parkinsonism &amp;amp; Related Disorders. 2017;42:28-33. doi:10.1016/j.parkreldis.2017.05.025&amp;nbsp;55. Shulman LM, Katzel LI, Ivey FM, et al. Randomized clinical trial of 3 types of physical exercise for patients with parkinson disease. JAMA Neurol. 2013;70(2):183-190. doi:10.1001/jamaneurol.2013.646&amp;nbsp;56. Amara AW, Memon AA. Effects of Exercise on Non-motor Symptoms in Parkinson&amp;rsquo;s Disease. Clinical Therapeutics. 2018;40(1):8-15. doi:10.1016/j.clinthera.2017.11.004&amp;nbsp;57. Schenkman M, Moore CG, Kohrt WM, et al. Effect of high-intensity treadmill exercise on motor symptoms in patients with De Novo Parkinson disease a phase 2 randomized clinical trial. JAMA Neurol. 2018;75(2):219-226. doi:10.1001/jamaneurol.2017.3517&amp;nbsp;58. Ives NJ, Stowe RL, Marro J, et al. Monoamine oxidase type B inhibitors in early Parkinson&amp;rsquo;s disease: Meta-analysis of 17 randomised trials involving 3525 patients. BMJ. 2004;329(7466):593-596. doi:10.1136/bmj.38184.606169.ae&amp;nbsp;59. Goetz CG, Koller WC, Poewe W, et al. Amantadine and other antiglutamate agents. Mov Disord. 2002;17(S4):S13-S22. doi:10.1002/mds.5557&amp;nbsp;60. Schwab RS. Amantadine in Parkinson&amp;rsquo;s disease. Review of more than two years&amp;rsquo; experience. JAMA: The Journal of the American Medical Association. 1972;222(7):792-795. doi:10.1001/jama.222.7.792&amp;nbsp;61. Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. N Engl J Med. 1967;276(7):374-379. doi:10.1056/nejm196702162760703&amp;nbsp;62. Miyasaki JM, Martin W, Suchowersky O,Weiner WJ, Lang AE. Practice parameter: initiation of treatment for Parkinson&amp;rsquo;s disease: an evidence-based review: Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2002;58(1):11-17. doi:10.1212/wnl.58.1.11&amp;nbsp;63. Stowe RL, Ives NJ, Clarke C, et al. Dopamine agonist therapy in early Parkinson&amp;rsquo;s disease. Cochrane Database of Systematic Reviews. 2008;(2). doi:10.1002/14651858.cd006564.pub2&amp;nbsp;64. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: A review. JAMA. 2014;311(16):1670-1683. doi:10.1001/jama.2014.3654&amp;nbsp;65. Dhall R, Kreitzman DL. Advances in levodopa therapy for Parkinson disease: Review of RYTARY (carbidopa and levodopa) clinical efficacy and safety. Neurology. 2016;86(14):S13-S24. doi:10.1212/wnl.0000000000002510&amp;nbsp;66. Schrag A. Entacapone in the treatment of Parkinson&amp;rsquo;s disease. Lancet Neurology. 2005;4(6):366-370. doi:10.1016/s1474-4422(05)70098-3&amp;nbsp;67. Limousin P, Foltynie T. Long-term outcomes of deep brain stimulation in Parkinson disease. Nat Rev Neurol. 2019;15(4):234-242. doi:10.1038/s41582-019-0145-9&amp;nbsp;68. Jankovic J, Aguilar LG. Current approaches to the treatment of Parkinson&amp;rsquo;s disease. NDT. 2008;4(4):743-757. doi:10.2147/ndt.s2006&amp;nbsp;69. Horn S, Stern MB. The comparative effects of medical therapies for Parkinson&amp;rsquo;s disease. Neurology. 2004;63(7 Suppl 2):S7-S12. doi:10.1212/wnl.63.7_suppl_2.s7&amp;nbsp;70. Vollum DI, Parkes JD, Doyle D. Livedo Reticularis during Amantadine Treatment. BMJ. 1971;2(5762):627-628. doi:10.1136/bmj.2.5762.627&amp;nbsp;71. Dong J, Cui Y, Li S, Le W. Current Pharmaceutical Treatments and Alternative Therapies of Parkinson&amp;rsquo;s Disease. CN. 2016;14(4):339-355. doi:10.2174/1570159x14666151120123025&amp;nbsp;72. Moore TJ, Glenmullen J, Mattison DR. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs. JAMA Intern Med. 2014;174(12):1930. doi:10.1001/jamainternmed.2014.5262&amp;nbsp;73. Nomoto M, Takeda A, Iwai K, Nishimura A, Hattori N. Effect of Opicapone Tablets on Levodopa and 3-O-Methyldopa Pharmacokinetics in Healthy Japanese Subjects: Phase 1 Study. Clinical Pharmacology in Drug Development. 2020;10(2):180-189. doi:10.1002/cpdd.799&amp;nbsp;74. Kiss LE, Ferreira HS, Torr&amp;atilde;o L, et al. Discovery of a long-acting, peripherally selective inhibitor of catechol- O -methyltransferase. J Med Chem. 2010;53(8):3396-3411. doi:10.1021/jm1001524&amp;nbsp;75. Rascol O, Payoux P, Ory F, Ferreira JJ, Brefel-Courbon C, Montastruc JL. Limitations of current Parkinson&amp;rsquo;s disease therapy. Ann Neurol. 2003;53(S3):S3-S15. doi:10.1002/ana.10513&amp;nbsp;76. Lang AE, Lees A. Management of Parkinson&amp;rsquo;s disease: An evidence-based review. Mov Disord. 2002;17(S4):i-i. doi:10.1002/mds.5554&amp;nbsp;77. Brooks DJ. Safety and tolerability of COMT inhibitors. Neurology. 2004;62(1 Suppl 1):S39-S46. doi:10.1212/wnl.62.1_suppl_1.s39&amp;nbsp;78. Dingemanse J, Jorga KM, Schmitt M, et al. Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans. Clin Pharmacol Ther. 1995;57(5):508-517. doi:10.1016/0009-9236(95)90035-7&amp;nbsp;79. Nissinen H, Kuoppam&amp;auml;ki M, Leinonen M, Schapira AH. Early versus delayed initiation of entacapone in levodopa-treated patients with Parkinson&amp;rsquo;s disease: A long-term, retrospective analysis. European Journal of Neurology. 2009;16(12):1305-1311. doi:10.1111/j.1468-1331.2009.02726.x&amp;nbsp;80. Kiss LE, Ferreira HS, Torr&amp;atilde;o L, et al. Discovery of a long-acting, peripherally selective inhibitor of catechol- O -methyltransferase. J Med Chem. 2010;53(8):3396-3411. doi:10.1021/jm1001524&amp;nbsp;81. Almeida L, Rocha JF, Falc&amp;atilde;o A, et al. Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-o-methyltransferase inhibitor, in healthy subjects: Prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor. Clin Pharmacokinet. 2013;52(2):139-151. doi:10.1007/s40262-012-0024-7&amp;nbsp;82. Salamon A, Z&amp;aacute;dori D, Szpisjak L, Kliv&amp;eacute;nyi P, V&amp;eacute;csei L. Opicapone for the treatment of Parkinson&amp;rsquo;s disease: an update. Expert Opinion on Pharmacotherapy. 2019;20(18):2201-2207. doi:10.1080/14656566.2019.1681971&amp;nbsp;83. FDA, CDER. HIGHLIGHTS OF PRESCRIBING INFORMATION&amp;nbsp;84. Opicapone | C15H10Cl2N4O6 - PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/Opicapone&amp;nbsp;85. Ker&amp;auml;nen T, Gordin A, Karlsson M, et al. Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone. Eur J Clin Pharmacol. 1994;46(2):151-157. doi:10.1007/bf00199880&amp;nbsp;86. Ongentys | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/ongentys&amp;nbsp;87. Rocha JF, Almeida L, Falc&amp;atilde;o A, et al. Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects. Br J Clin Pharmacol. 2013;76(5):763-775. doi:10.1111/bcp.12081&amp;nbsp;88. Ferreira JJ, Rocha JF, Falc&amp;atilde;o A, et al. Effect of opicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity and motor fluctuations in patients with Parkinson&amp;rsquo;s disease. Eur J Neurol. 2015;22(5):815-e56. doi:10.1111/ene.12666&amp;nbsp;89. Lopes N, Ferreira J, Lees A, Costa R, Disorders ASM. Exploratory efficacy of opicapone in combination with dopamine agonists or MAO-B inhibitors on the treatment of motor fluctuations in Parkinson&amp;rsquo;s disease. Published online 2015.&amp;nbsp;90. Almeida L, Rocha JF, Falc&amp;atilde;o A, et al. Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-o-methyltransferase inhibitor, in healthy subjects: Prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor. Clin Pharmacokinet. 2013;52(2):139-151. doi:10.1007/s40262-012-0024-7&amp;nbsp;91. Almeida L, Rocha JF, Falc&amp;atilde;o A, et al. Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-O-methyltransferase inhibitor, in healthy subjects: prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor. Clin Pharmacokinet. 2013;52(2):139--151.&amp;nbsp;i:10.1007/s40262-012-0024-7&amp;nbsp;92. Rocha JF, Santos A, Falc&amp;atilde;o A, et al. Effect of moderate liver impairment on the pharmacokinetics of opicapone. Eur J Clin Pharmacol. 2014;70(3):279-286. doi:10.1007/s00228-013-1602-993. Rocha JF, Santos A, Falc&amp;atilde;o A, et al. Effect of moderate liver impairment on the pharmacokinetics of opicapone. Eur J Clin Pharmacol. 2014;70(3):279-286. doi:10.1007/s00228-013-1602-994. Svetel M, Tomić A, Kresojević N, Kostić V. Pharmacokinetic drug evaluation of opicapone for the treatment of Parkinson&amp;rsquo;s disease. Expert Opinion on Drug Metabolism &amp;amp; Toxicology. 2018;14(3):353-360. doi:10.1080/17425255.2018.143013895. Falc&amp;atilde;o A, Rocha JF, Santos A, Nunes T, Soares-da-Silva P. Opicapone pharmacokinetics and pharmacodynamics comparison between healthy Japanese and matched white subjects. Clinical Pharmacology in Drug Development. 2016;5(2):150-161. doi:10.1002/cpdd.21396. Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P. Opicapone as an adjunct to levodopa in patients with Parkinson&amp;rsquo;s disease and end-of-dose motor fluctuations: A randomised, double-blind, controlled trial. The Lancet Neurology. 2016;15(2):154-165. doi:10.1016/s1474-4422(15)00336-197. Lees AJ, Ferreira J, Rascol O, et al. Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol. 2017;74(2):197-206. doi:10.1001/jamaneurol.2016.470398. Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P. Long-term efficacy of opicapone in fluctuating Parkinson&amp;rsquo;s disease patients: a pooled analysis of data from two phase 3 clinical trials and their open-label extensions. Eur J Neurol. 2019;26(7):953-960. doi:10.1111/ene.1391499. Reichmann H, Lees A, Rocha JF, et al. Effectiveness and safety of opicapone in Parkinson&amp;rsquo;s disease patients with motor fluctuations: The OPTIPARK open-label study. Transl Neurodegener. 2020;9(1):9. doi:10.1186/s40035-020-00187-1100. Lees AJ, Ferreira J, Rascol O, et al. Opicapone as adjunct to levodopa therapy in patients with Parkinson disease and motor fluctuations a randomized clinical trial. JAMA Neurol. 2017;74(2):197-206. doi:10.1001/jamaneurol.2016.4703101. Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P. Long-term efficacy of opicapone in fluctuating Parkinson&amp;rsquo;s disease patients: a pooled analysis of data from two phase 3 clinical trials and their open-label extensions. Eur J Neurol. 2019;26(7):953-960. doi:10.1111/ene.13914102. Rocha JF, Ferreira JJ, Falc&amp;atilde;o A, et al. Effect of 3 single-dose regimens of opicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity and motor response in patients with Parkinson disease. Clinical Pharmacology in Drug Development. 2016;5(3):232-240. doi:10.1002/cpdd.217103. Goetz CG, Poewe W, Rascol O, et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: Status and recommendations. Mov Disord. 2004;19(9):1020-1028. doi:10.1002/mds.20213104. Zhang Y, Huang X. Concerns Regarding Opicapone as Adjunct to Levodopa Therapy. JAMA Neurol. 2017;74(7):872-873. doi:10.1001/jamaneurol.2017.0723105. Committee for Medicinal Products for Human Use (CHMP). EMA Assessment Report - Ongentys. 2016;44(April).106. Lees AJ, Ferreira J, Rascol O, et al. Opicapone as adjunct to levodopa therapy in patients with Parkinson disease and motor fluctuations a randomized clinical trial. JAMA Neurol. 2017;74(2):197-206. doi:10.1001/jamaneurol.2016.4703107. Annus &amp;Aacute;, V&amp;eacute;csei L. Spotlight on opicapone as an adjunct to levodopa in parkinson&amp;rsquo;s disease: design, development and potential place in therapy. DDDT. 2017;11:143-151. doi:10.2147/dddt.s104227108. Pinto R, l&amp;rsquo;Hostis P, Patat A, et al. Evaluation of opicapone on cardiac repolarization in a thorough QT/QTc study. Clinical Pharmacology in Drug Development. 2015;4(6):454-462. doi:10.1002/cpdd.188109. Fabbri M, Ferreira JJ, Lees A, et al. Opicapone for the treatment of Parkinson&amp;rsquo;s disease: A review of a new licensed medicine. Mov Disord. 2018;33(10):1528-1539. doi:10.1002/mds.27475110. Opicapone: Drug information - UpToDate. https://www.uptodate.com/contents/opicapone-drug-information?search=opicapone&amp;amp;source=panel_search_result&amp;amp;selectedTitle=1~2&amp;amp;usage_type=panel&amp;amp;kp_tab=drug_general&amp;amp;display_rank=1#F54346825</p><pub-id pub-id-type="doi"/></element-citation></ref></ref-list></back></article>
