Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach

References

• Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384–386.
   PubMed Web of Science ®Google Scholar
• Kowal SL, Dall TM, Chakrabarti R, et al. The current and projected economic burden of Parkinson’s disease in the United States. Mov Disord. 2013;28(3):311–318.
   PubMed Web of Science ®Google Scholar
• Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3(17013). DOI:10.1038/nrdp.2017.13.
   PubMedGoogle Scholar
• Braak H, Del Tredici K. Neuropathological Staging of Brain Pathology in Sporadic Parkinson’s disease: separating the Wheat from the Chaff. J Parkinsons Dis. 2017;7(s1):S71–s85.
   PubMedGoogle Scholar
• Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson’s disease. Mov Disord. 2015;30(12):1600–1611.
   PubMed Web of Science ®Google Scholar
• Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591–1601.
   PubMed Web of Science ®Google Scholar
• Cotzias GC, Papavasiliou PS, Gellene R. L-dopa in Parkinson’s syndrome. N Engl J Med. 1969;281(5):272.
   PubMed Web of Science ®Google Scholar
• Papavasiliou PS, Cotzias GC, Düby SE, et al. Levodopa in Parkinsonism: potentiation of central effects with a peripheral inhibitor. N Engl J Med. 1972;286(1):8–14.
   PubMed Web of Science ®Google Scholar
• Tolosa E. Parkinson’s disease; modern treatment. Minn Med. 1973;56(6):497–502.
   PubMedGoogle Scholar
• Hunter KR, Boakes AJ, Laurence DR, et al. Monoamine oxidase inhibitors and L-dopa. Br Med J. 1970;3(5719):388.
   PubMedGoogle Scholar
• Lees AJ, Shaw KM, Kohout LJ, et al. Deprenyl in Parkinson’s disease. Lancet. 1977;2(8042):791–795.
   PubMed Web of Science ®Google Scholar
• Peretz C, Segev H, Rozani V, et al. Comparison of selegiline and rasagiline therapies in parkinson disease: a real-life study. Clin Neuropharmacol. 2016;39(5):227–231.
   PubMed Web of Science ®Google Scholar
• Cereda E, Cilia R, Canesi M, et al. Efficacy of rasagiline and selegiline in Parkinson’s disease: a head-to-head 3-year retrospective case-control study. J Neurol. 2017;264(6):1254–1263.
   PubMed Web of Science ®Google Scholar
• Marconi S, Zwingers T. Comparative efficacy of selegiline versus rasagiline in the treatment of early Parkinson’s disease. Eur Rev Med Pharmacol Sci. 2014;18(13):1879–1882.
   PubMed Web of Science ®Google Scholar
• Lees AJ, Stern GM. Sustained bromocriptine therapy in previously untreated patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1981;44(11):1020–1023.
   PubMed Web of Science ®Google Scholar
• Antonini A, Tolosa E, Mizuno Y, et al. A reassessment of risks and benefits of dopamine agonists in Parkinson’s disease. Lancet Neurol. 2009;8(10):929–937.
   PubMed Web of Science ®Google Scholar
• Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med. 2000;342(20):1484–1491.
   PubMed Web of Science ®Google Scholar
• Study Group P, Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Jama. 2000;284(15):1931–1938.
   PubMed Web of Science ®Google Scholar
• Olanow CW, Agid Y, Mizuno Y, et al. Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord. 2004;19(9):997–1005.
   PubMed Web of Science ®Google Scholar
• Katzenschlager R, Head J, Schrag A, et al. Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology. 2008;71(7):474–480.
   PubMed Web of Science ®Google Scholar
• Parkinson Study Group CALM Cohort Investigators. Long-term Effect of Initiating Pramipexole vs Levodopa in Early Parkinson Disease. Arch Neurol. 2009;66(5):563–70. DOI:10.1001/archneur.66.1.nct90001.
   PubMedGoogle Scholar
• Weintraub D, David AS, Evans AH, et al. Clinical spectrum of impulse control disorders in Parkinson’s disease. Mov Disord. 2015;30(2):121–127.
   PubMed Web of Science ®Google Scholar
• Antonini A, Barone P, Bonuccelli U, et al. ICARUS study: prevalence and clinical features of impulse control disorders in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2017;88(4):317–324.
   PubMed Web of Science ®Google Scholar
• Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351(24):2498–2508.
   PubMed Web of Science ®Google Scholar
• Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early parkinson disease practice guideline summary: a Report of the AAN Guideline Subcommittee. Neurology. 2021;97(20):942–957.
   PubMed Web of Science ®Google Scholar
• Aminoff MJ. Treatment should not be initiated too soon in Parkinson’s disease. Ann Neurol. 2006;59(3):562–564. discussion 564-5.
   PubMed Web of Science ®Google Scholar
• Clarke CE, Patel S, Ives N, et al. Should treatment for Parkinson’s disease start immediately on diagnosis or delayed until functional disability develops? Mov Disord. 2011;26(7):1187–1193.
   PubMed Web of Science ®Google Scholar
• Schapira AH, Obeso J. Timing of treatment initiation in Parkinson’s disease: a need for reappraisal? Ann Neurol. 2006;59(3):559–562.
   PubMed Web of Science ®Google Scholar
• Lang AE. The progression of Parkinson disease: a hypothesis. Neurology. 2007;68(12):948–952.
   PubMedGoogle Scholar
• Grosset D, Taurah L, Burn DJ, et al. A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson’s disease left untreated at diagnosis. J Neurol Neurosurg Psychiatry. 2007;78(5):465–469.
   PubMed Web of Science ®Google Scholar
• Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized Delayed-Start Trial of Levodopa in Parkinson’s Disease. New Engl J Med. 2019;380(4):315–324.
   PubMed Web of Science ®Google Scholar
• Ferreira JJ, Katzenschlager R, Bloem BR, et al. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson’s disease. Eur J Neurol. 2013;20(1):5–15.
   PubMed Web of Science ®Google Scholar
• NICE. Parkinson’s disease in adults. Available at: http://www.nice.org.uk/guidance/ng71. (2017). Last accessed 2023 Jan 11
   Google Scholar
• Lees AJ. Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson’s disease. Br Med J. 1995;311(7020):1602–1607.
   PubMedGoogle Scholar
• Lees AJ, Katzenschlager R, Head J, et al. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Neurology. 2001;57(9):1687–1694.
   PubMed Web of Science ®Google Scholar
• PD Med Collaborative Group, Gray R, Ives N, et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet. 2014;384(9949):1196–1205.
   PubMed Web of Science ®Google Scholar
• Przuntek H, Welzel D, Gerlach M, et al. Early institution of bromocriptine in Parkinson’s disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study. J Neural Transm. 1996;103(6):699–715.
   PubMed Web of Science ®Google Scholar
• Hauser RA. Initial choice of medication has little effect on short-term or long-term outcome for most patients with Parkinson’s disease. Evid Based Med. 2015;20(1):17.
   PubMedGoogle Scholar
• Riederer P, Gerlach M, Muller T, et al. Relating mode of action to clinical practice: dopaminergic agents in Parkinson’s disease. Parkinsonism Relat Disord. 2007;13(8):466–479.
   PubMed Web of Science ®Google Scholar
• Cilia R, Cereda E, Akpalu A, et al. Natural history of motor symptoms in Parkinson’s disease and the long-duration response to levodopa. Brain. 2020;143(8):2490–2501.
   PubMed Web of Science ®Google Scholar
• Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol. 2006;5(8):677–687.
   PubMed Web of Science ®Google Scholar
• LeWitt PA. Levodopa therapy for Parkinson’s disease: pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64–72.
   PubMed Web of Science ®Google Scholar
• Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17(8):587–592.
   PubMed Web of Science ®Google Scholar
• Leenders KL, Poewe WH, Palmer AJ, et al. Inhibition of L-[18F]fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography. Ann Neurol. 1986;20(2):258–262.
   PubMed Web of Science ®Google Scholar
• Nutt JG, Woodward WR, Hammerstad JP, et al. The “on-off” phenomenon in Parkinson’s disease. Relation to levodopa absorption and transport. N Engl J Med. 1984;310(8):483–488.
   PubMed Web of Science ®Google Scholar
• Shoulson I, Glaubiger GA, Chase TN. On-off response. Clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients. Neurology. 1975;25(12):1144–1148.
   PubMed Web of Science ®Google Scholar
• Stocchi F, Vacca L, Ruggieri S, et al. Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol. 2005;62(6):905–910.
   PubMedGoogle Scholar
• Muenter MD, Tyce GM. L-dopa therapy of Parkinson’s disease: plasma L-dopa concentration, therapeutic response, and side effects. Mayo Clin Proc. 1971;46(4):231–239.
   PubMed Web of Science ®Google Scholar
• Lees AJ, Shaw KM, Stern GM. “Off period” dystonia and “on period” choreoathetosis in levodopa-treated patients with Parkinson’s disease. Lancet. 1977;2(8046):1034.
   PubMed Web of Science ®Google Scholar
• Olanow CW, Obeso JA. Pulsatile stimulation of dopamine receptors and levodopa-induced motor complications in Parkinson’s disease: implications for the early use of COMT inhibitors. Neurology. 2000;55(11Suppl 4):S72–77. discussion S78–81.
   PubMedGoogle Scholar
• Stocchi F, Jenner P, Obeso JA. When Do Levodopa Motor Fluctuations First Appear in Parkinson’s Disease? Eur Neurol. 2010;63(5):257–266.
   PubMed Web of Science ®Google Scholar
• Kuoppamaki M, Korpela K, Marttila R, et al. Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily. Eur J Clin Pharmacol. 2009;65(5):443–455.
   PubMed Web of Science ®Google Scholar
• Grosset KA, Bone I, Grosset DG. Suboptimal medication adherence in Parkinson’s disease. Mov Disord. 2005;20(11):1502–1507.
   PubMed Web of Science ®Google Scholar
• Grosset D, Antonini A, Canesi M, et al. Adherence to antiparkinson medication in a multicenter European study. Mov Disord. 2009;24(6):826–832.
   PubMed Web of Science ®Google Scholar
• Nyholm D, Ehrnebo M, Lewander T, et al. Frequent administration of levodopa/carbidopa microtablets vs levodopa/carbidopa/entacapone in healthy volunteers. Acta Neurol Scand. 2013;127(2):124–132.
   PubMed Web of Science ®Google Scholar
• Gretarsdottir HM, Widman E, Johansson A, et al. Personalized Medicine Approach in Treating Parkinson’s Disease, Using Oral Administration of Levodopa/Carbidopa Microtablets in Clinical Practice. J Pers Med. 2021;11(8):8.
   Web of Science ®Google Scholar
• Hauser RA, McDermott MP, Messing S, et al. Factors Associated With the Development of Motor Fluctuations and Dyskinesias in Parkinson Disease. Arch Neurol. 2006;63(12):1756–1760.
   PubMed Web of Science ®Google Scholar
• Warren Olanow C, Kieburtz K, Rascol O, et al. Factors predictive of the development of Levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord. 2013;28(8):1064–1071.
   PubMed Web of Science ®Google Scholar
• Koller WC, Hutton JT, Tolosa E, et al. Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group. Neurology. 1999;53(5):1012–1019.
   PubMed Web of Science ®Google Scholar
• Goetz CG. Treatment of advanced Parkinson’s disease: an evidence-based analysis. Adv Neurol. 2003;91(213–28):213–228.
   PubMedGoogle Scholar
• Mao Z, Hsu A, Gupta S, et al. Population pharmacodynamics of IPX066: an oral extended-release capsule formulation of carbidopa-levodopa, and immediate-release carbidopa-levodopa in patients with advanced Parkinson’s disease. J Clin Pharmacol. 2013;53(5):523–531.
   PubMed Web of Science ®Google Scholar
• Hauser RA, Ellenbogen AL, Metman LV, et al. Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson’s disease. Mov Disord. 2011;26(12):2246–2252.
   PubMed Web of Science ®Google Scholar
• Stocchi F, Vacca L. A systematic review on the clinical experience with melevodopa/carbidopa fixed combination in patients with Parkinson disease. Minerva Med. 2019;110(575–85):575–585.
   PubMedGoogle Scholar
• Zangaglia R, Stocchi F, Sciarretta M, et al. Clinical experiences with levodopa methylester (melevodopa) in patients with Parkinson disease experiencing motor fluctuations: an open-label observational study. Clin Neuropharmacol. 2010;33(2):61–66.
   PubMed Web of Science ®Google Scholar
• Modi NB, Mittur A, Rubens R, et al. Single-Dose Pharmacokinetics and Pharmacodynamics of IPX203 in Patients With Advanced Parkinson Disease: a Comparison With Immediate-Release Carbidopa-Levodopa and With Extended-Release Carbidopa-Levodopa Capsules. Clin Neuropharmacol. 2019;42(1):4–8.
   PubMed Web of Science ®Google Scholar
• LeWitt PA, Giladi N, Navon N. Pharmacokinetics and efficacy of a novel formulation of carbidopa-levodopa (Accordion Pill(®)) in Parkinson’s disease. Parkinsonism Relat Disord. 2019;65(131–8):131–138.
   PubMedGoogle Scholar
• LeWitt PA, Huff FJ, Hauser RA, et al. Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson’s disease. Mov Disord. 2014;29(1):75–82.
   PubMed Web of Science ®Google Scholar
• Trenkwalder C, Kuoppamäki M, Vahteristo M, et al. Increased dose of carbidopa with levodopa and entacapone improves “off” time in a randomized trial. Neurology. 2019;92(13):e1487–96.
   PubMed Web of Science ®Google Scholar
• Verhagen Metman L, Stover N, Chen C, et al. Gastroretentive carbidopa/levodopa, DM-1992, for the treatment of advanced Parkinson’s disease. Mov Disord. 2015;30(9):1222–1228.
   PubMed Web of Science ®Google Scholar
• Hardie RJ, Lees AJ, Stern GM. On-off fluctuations in Parkinson’s disease. A clinical and neuropharmacological study. Brain. 1984;107(Pt 2):487–506.
   PubMedGoogle Scholar
• Quinn N, Marsden CD, Parkes JD. Complicated response fluctuations in Parkinson’s disease: response to intravenous infusion of levodopa. Lancet. 1982;2(8295):412–415.
   PubMed Web of Science ®Google Scholar
• Nyholm D, Nilsson Remahl AI, Dizdar N, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology. 2005;64(2):216–223.
   PubMed Web of Science ®Google Scholar
• Olanow CW, Kieburtz K, Odin P, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014;13(2):141–149.
   PubMed Web of Science ®Google Scholar
• Freire-Alvarez E, Kurča E, Lopez Manzanares L, et al. Levodopa-Carbidopa Intestinal Gel Reduces Dyskinesia in Parkinson’s Disease in a Randomized Trial. Mov Disord. 2021;36(11):2615–2623.
   PubMed Web of Science ®Google Scholar
• Öthman M, Widman E, Nygren I, et al. Initial experience of the levodopa-entacapone-carbidopa intestinal gel in clinical practice. J Pers Med. 2021;11(4):254.
   PubMed Web of Science ®Google Scholar
• Soileau MJ, Aldred J, Budur K, et al. Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson’s disease: a randomised, double-blind, active-controlled, phase 3 trial. Lancet Neurol. 2022;21(12):1099–1109.
   PubMed Web of Science ®Google Scholar
• Poewe W, Stocchi F, Arkadir D, et al. Subcutaneous Levodopa Infusion for Parkinson’s Disease: 1-Year Data from the Open-Label BeyoND Study. Mov Disord. 2021;36(11):2687–2692.
   PubMed Web of Science ®Google Scholar
• Bergquist F, Ehrnebo M, Nyholm D, et al. Pharmacokinetics of Intravenously (DIZ101), subcutaneously (DIZ102), and Intestinally (LCIG) infused levodopa in advanced parkinson disease. Neurology. 2022;99(10):e965–76.
   PubMed Web of Science ®Google Scholar
• LeWitt PA, Hauser RA, Pahwa R, et al. Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2019;18(2):145–154.
   PubMed Web of Science ®Google Scholar
• Brodsky MA, Park BS, Nutt JG. Effects of a dopamine agonist on the pharmacodynamics of levodopa in parkinson disease. Arch Neurol. 2010;67(1):27–32.
   PubMedGoogle Scholar
• Biundo R, Weis L, Abbruzzese G, et al. Impulse control disorders in advanced Parkinson’s disease with dyskinesia: the ALTHEA study. Mov Disord. 2017;32(11):1557–1565.
   PubMed Web of Science ®Google Scholar
• Voon V, Napier TC, Frank MJ, et al. Impulse control disorders and levodopa-induced dyskinesias in Parkinson’s disease: an update. Lancet Neurol. 2017;16(3):238–250.
   PubMed Web of Science ®Google Scholar
• Crispo JA, Fortin Y, Thibault DP, et al. Trends in inpatient antiparkinson drug use in the USA, 2001-2012. Eur J Clin Pharmacol. 2015;71(8):1011–1019.
   PubMed Web of Science ®Google Scholar
• Jost WH, Friede M, Schnitker J. Indirect meta-analysis of randomised placebo-controlled clinical trials on rasagiline and selegiline in the symptomatic treatment of Parkinson’s disease. Basal Ganglia. 2012;2(4, Supplement):S17–S26.
   Google Scholar
• Caslake R, Macleod A, Ives N, et al. Monoamine oxidase B inhibitors versus other dopaminergic agents in early Parkinson’s disease. Cochrane Database Syst Rev. 2009; (4):CD006661. DOI:10.1002/14651858.CD006661.pub2.
   PubMed Web of Science ®Google Scholar
• Onofrj M, Bonanni L, Thomas A. An expert opinion on safinamide in Parkinson’s disease. Expert Opin Investig Drugs. 2008;17(7):1115–1125.
   PubMed Web of Science ®Google Scholar
• Stocchi F. The levodopa wearing-off phenomenon in Parkinson’s disease: pharmacokinetic considerations. Expert Opin Pharmacother. 2006;7(10):1399–1407.
   PubMedGoogle Scholar
• Müller T. Catechol-O-methyltransferase inhibitors in Parkinson’s disease. Drugs. 2015;75(2):157–174.
   PubMed Web of Science ®Google Scholar
• Ingman K, Naukkarinen T, Vahteristo M, et al. The effect of different dosing regimens of levodopa/carbidopa/entacapone on plasma levodopa concentrations. Eur J Clin Pharmacol. 2012;68(3):281–289.
   PubMed Web of Science ®Google Scholar
• Müller T, Schlegel E, Zingler S, et al. Effects of One-Day Application of Levodopa/Carbidopa/Entacapone versus Levodopa/Carbidopa/Opicapone in Parkinson’s Disease Patients. Cells. 2022;11(9):1511.
   PubMed Web of Science ®Google Scholar
• Ferreira JJ, Poewe W, Rascol O, et al. Effect of opicapone on levodopa pharmacokinetics in patients with fluctuating parkinson’s disease. Mov Disord. 2022;37(11):2272–2283.
   PubMed Web of Science ®Google Scholar
• Gerlach M, van den Buuse M, Blaha C, et al. Entacapone increases and prolongs the central effects of l-DOPA in the 6-hydroxydopamine-lesioned rat. Naunyn Schmiedebergs Arch Pharmacol. 2004;370(5):388–394.
   PubMed Web of Science ®Google Scholar
• Bonifacio MJ, Sutcliffe JS, Torrao L, et al. Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor. Neuropharmacology. 2014;77:334–341.
   PubMed Web of Science ®Google Scholar
• Stocchi F, Rascol O, Kieburtz K, et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol. 2010;68(1):18–27.
   PubMed Web of Science ®Google Scholar
• Waters CH, Kurth M, Bailey P, et al. Tolcapone in stable Parkinson’s disease: efficacy and safety of long-term treatment. The Tolcapone Stable Study Group. Neurology. 1997;49(3):665–671.
   PubMed Web of Science ®Google Scholar
• Brooks DJ, Sagar H. Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson’s disease: a randomised, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry. 2003;74(8):1071–1079.
   PubMed Web of Science ®Google Scholar
• Watts RL, Lyons KE, Pahwa R, et al. Onset of dyskinesia with adjunct ropinirole prolonged-release or additional levodopa in early Parkinson’s disease. Mov Disord. 2010;25(7):858–866.
   PubMed Web of Science ®Google Scholar
• Olanow CW, Kieburtz K, Rascol O, et al. Factors predictive of the development of Levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord. 2013;28(8):1064–1071.
   PubMed Web of Science ®Google Scholar
• Jenner P, Rocha JF, Ferreira JJ, et al. Redefining the strategy for the use of COMT inhibitors in Parkinson’s disease: the role of opicapone. Expert Rev Neurother. 2021;21(9):1019–1033.
   PubMed Web of Science ®Google Scholar
• Tolosa E, Hernandez B, Linazasoro G, et al. Efficacy of levodopa/carbidopa/entacapone versus levodopa/carbidopa in patients with early Parkinson’s disease experiencing mild wearing-off: a randomised, double-blind trial. J Neural Transm. 2014;121(4):357–366.
   PubMed Web of Science ®Google Scholar
• Lyytinen J, Kaakkola S, Ahtila S, et al. Simultaneous MAO-B and COMT inhibition in L-Dopa-treated patients with Parkinson’s disease. Mov Disord. 1997;12(4):497–505.
   PubMed Web of Science ®Google Scholar
• Chaudhuri KR, Jenner P, Antonini A. Dyskinesia matters: but not as much as it used to. Mov Disord. 2020;35(5):900–901.
   PubMed Web of Science ®Google Scholar
• Deuschl G, Antonini A, Costa J, et al. European academy of neurology/movement disorder society-European Section Guideline on the Treatment of Parkinson’s Disease: i. Invasive Therapies. Mov Disord. 2022;37(7):1360–1374.
   PubMed Web of Science ®Google Scholar
• Titova N, Chaudhuri KR. Personalized medicine in Parkinson’s disease: time to be precise. Mov Disord. 2017;32(8):1147–1154.
   PubMed Web of Science ®Google Scholar
• Poewe W, Antonini A. Novel formulations and modes of delivery of levodopa. Mov Disord. 2015;30(1):114–120.
   PubMed Web of Science ®Google Scholar
• Hauser RA, Hsu A, Kell S, et al. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol. 2013;12(4):346–356.
   PubMed Web of Science ®Google Scholar
• Stocchi F, Hsu A, Khanna S, et al. Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients. Parkinsonism Relat Disord. 2014;20(12):1335–1340.
   PubMed Web of Science ®Google Scholar
• Modi NB, Mittur A, Dinh P, et al. Pharmacodynamics, Efficacy, and safety of IPX203 in parkinson disease patients with motor fluctuations. Clinical Neuropharmacol. 2019;42(5):149–156.
   PubMed Web of Science ®Google Scholar
• Nyholm D, Johansson A, Lennernäs H, et al. Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial. Eur J Neurol. 2012;19(6):820–826.
   PubMed Web of Science ®Google Scholar
• Senek M, Nielsen EI, Nyholm D. Levodopa-entacapone-carbidopa intestinal gel in Parkinson’s disease: a randomized crossover study. Mov Disord. 2017;32(2):283–286.
   PubMed Web of Science ®Google Scholar
• Giladi N, Gurevich T, Djaldetti R, et al. ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson’s disease and motor response fluctuations: a randomized, placebo-controlled phase 2 study. Parkinsonism Relat Disord. 2021;91:139–145.
   PubMed Web of Science ®Google Scholar
• Antonini A, Poewe W, Chaudhuri KR, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s: final results of the GLORIA registry. Parkinsonism Relat Disord. 2017;45(13–20):13–20.
   PubMedGoogle Scholar