Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson’s disease

References

• Przuntek H, Müller T, Riederer P. Diagnostic staging of Parkinson’s disease: conceptual aspects. J Neural Transm. 2004;111(2):201–216.
   Google Scholar
• Birkmayer W, Hornykiewicz O. The effect of l-3,4-dihydroxyphenylalanine (= DOPA) on akinesia in parkinsonism. 1961. Wien Klin Wochenschr. 2001;113(22):851–854.
   Google Scholar
• Foley P, Mizuno Y, Nagatsu T, et al. The L-DOPA story - an early Japanese contribution. Parkinsonism Relat Disord. 2000;6(1):1.
   Google Scholar
• Müller T. Detoxification and antioxidative therapy for levodopa-induced neurodegeneration in Parkinson’s disease. Expert Rev Neurother. 2013;13(6):707–718.
   Google Scholar
• Aquilonius SM, Nyholm D. Development of new levodopa treatment strategies in Parkinson’s disease-from bedside to bench to bedside. Ups J Med Sci. 2017;122(2):71–77.
   Google Scholar
• Chase TN. The significance of continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Drugs. 1998;55(Suppl 1):1–9.
   Google Scholar
• Obeso JA, Luquin MR, Martinez Lage JM. Intravenous lisuride corrects oscillations of motor performance in Parkinson’s disease. Ann Neurol. 1986;19(1):31–35.
   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.
   Google Scholar
• Stocchi F, Vacca L, De Pandis MF, et al. Subcutaneous continuous apomorphine infusion in fluctuating patients with Parkinson’s disease: long-term results. Neurol Sci. 2001;22(1):93–94.
   Google Scholar
• Jenner P. Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation. Neurology. 2004;62(Issue 1, Supplement 1):S47–S55.
   Google Scholar
• Destee A, Rerat K, Bourdeix I. Is there a difference between levodopa/dopa-decarboxylase inhibitor and entacapone and levodopa/dopa-decarboxylase inhibitor dose fractionation strategies in Parkinson’s disease patients experiencing symptom re-emergence due to wearing-off? The Honeymoon Study. Eur Neurol. 2009;61(2):69–75.
   Google Scholar
• Mundt-Petersen U, Odin P. Infusional therapies, continuous dopaminergic stimulation, and nonmotor symptoms. Int Rev Neurobiol. 2017;134:1019–1044.
   Google Scholar
• Ramot Y, Nyska A, Maronpot RR, et al. Ninety-day local tolerability and toxicity study of ND0612, a novel formulation of levodopa/ carbidopa,administered by subcutaneous continuous infusion in minipigs. Toxicol Pathol. 2017;45(6):764–773.
   Google Scholar
• Jankovic J, Stacy M. Medical management of levodopa-associated motor complications in patients with Parkinson’s disease. CNS Drugs. 2007;21(8):677–692.
   Google Scholar
• Riederer P, Gerlach M, Müller T, et al. Relating mode of action to clinical practice: dopaminergic agents in Parkinson’s disease. Parkinsonism Relat Disord. 2007;13(8):466–479.
   Google Scholar
• Cotzias GC, Papavasiliou PS, Gellene R. Experimental treatment of parkinsonism with L-dopa. Neurology. 1968;18(3):276–277.
   Google Scholar
• Trenkwalder C, Kuoppamaki 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–e1496.
   Google Scholar
• Cassani E, Cilia R, Laguna J, et al. Mucuna pruriens for Parkinson’s disease: low-cost preparation method, laboratory measures and pharmacokinetics profile. J Neurol Sci. 2016;365:175–180.
   Google Scholar
• Johnson SL, Park HY, DaSilva NA, et al. Levodopa-reduced mucuna pruriens seed extract shows neuroprotective effects against Parkinson’s disease in murine microglia and human neuroblastoma cells, Caenorhabditis elegans, and Drosophila melanogaster. Nutrients. 2018;10(9):1139.
   Google Scholar
• Rijntjes M. Knowing your beans in Parkinson’s disease: a critical assessment of current knowledge about different beans and their compounds in the treatment of Parkinson’s disease and in animal models. Parkinsons Dis. 2019;2019:1349509.
   Google Scholar
• Soumyanath A, Denne T, Hiller A, et al. Analysis of levodopa content in commercial Mucuna pruriens products using high-performance liquid chromatography with fluorescence detection. J Altern Complement Med. 2018;24(2):182–186.
   Google Scholar
• Ciesielska A, Samaranch L, San SW, et al. Depletion of AADC activity in caudate nucleus and putamen of Parkinson’s disease patients; implications for ongoing AAV2-AADC gene therapy trial. PLoS One. 2017;12(2):e0169965.
   Google Scholar
• Müller T. Catechol-O-methyltransferase inhibitors in Parkinson’s disease. Drugs. 2015;75(2):157–174.
   Google Scholar
• Lee ES, Chen H, King J, et al. The role of 3-O-methyldopa in the side effects of L-dopa. Neurochem Res. 2008;33(3):401–411.
   Google Scholar
• Lees AJ. Catechol-0-methyl transferase inhibitors in the treatment of Parkinson’s disease. Neurologia. 1998;13(Suppl 1):72–75.
   Google Scholar
• Müller T, Woitalla D, Fowler B, et al. 3-OMD and homocysteine plasma levels in parkinsonian patients. J Neural Transm. 2002;109(2):175–179.
   Google Scholar
• Müller T, Kolf K, Ander L, et al. Catechol-O-methyltransferase inhibition improves levodopa-associated strength increase in patients with Parkinson disease. Clin Neuropharmacol. 2008;31(3):134–140.
   Google Scholar
• Müller T. The impact of COMT-inhibition on gastrointestinal levodopa absorption in patients with Parkinson’s disease. Clin Med Insights: Ther. 2010;2:155–168.
   Google Scholar
• Delea TE, Thomas SK, Hagiwara M, et al. Adherence with levodopa/carbidopa/entacapone versus levodopa/carbidopa and entacapone as separate tablets in patients with Parkinson’s disease. Curr Med Res Opin. 2010;26(7):1543–1552.
   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.
   Google Scholar
• Brooks DJ, Leinonen M, Kuoppamaki M, et al. Five-year efficacy and safety of levodopa/DDCI and entacapone in patients with Parkinson’s disease. J Neural Transm. 2008;115(6):843–849.
   Google Scholar
• Hauser RA, Panisset M, Abbruzzese G, et al. Double-blind trial of levodopa/carbidopa/entacapone versus levodopa/carbidopa in early Parkinson’s disease. Mov Disord. 2009;24(4):541–550.
   Google Scholar
• Piccini P, Brooks DJ, Korpela K, et al. The catechol-O-methyltransferase (COMT) inhibitor entacapone enhances the pharmacokinetic and clinical response to Sinemet CR in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2000;68(5):589–594.
   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.
   Google Scholar
• Gershanik O, Emre M, Bernhard G, et al. Efficacy and safety of levodopa with entacapone in Parkinson’s disease patients suboptimally controlled with levodopa alone, in daily clinical practice: an international, multicentre, open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:963–971.
   Google Scholar
• Müller T. Entacapone. Expert Opin Drug Metab Toxicol. 2010;6(8):983–993.
   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.
   Google Scholar
• Müller T, Erdmann C, Muhlack S, et al. Inhibition of catechol-O-methyltransferase contributes to more stable levodopa plasma levels. Mov Disord. 2006;21(3):332–336.
   Google Scholar
• Müller T, Erdmann C, Muhlack S, et al. Pharmacokinetic behaviour of levodopa and 3-O-methyldopa after repeat administration of levodopa/carbidopa with and without entacapone in patients with Parkinson’s disease. J Neural Transm. 2006;113(10):1441–1448.
   Google Scholar
• Almeida L, Rocha JF, Falcao 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.
   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.
   Google Scholar
• Bonifacio MJ, Torrao L, Loureiro AI, et al. Pharmacological profile of opicapone, a third-generation nitrocatechol catechol-O-methyl transferase inhibitor, in the rat. Br J Pharmacol. 2015;172(7):1739–1752.
   Google Scholar
• Ferreira JJ, Rocha J-F, Falcao A, et al. Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics, motor response, and erythrocyte-COMT activity in Parkinson’s patients co-administered with levodopa/dopa-decarboxylase inhibitor. J Neurol Sci. 2013;333:e109–e151.
   Google Scholar
• Ferreira JJ, Lees A, Rocha J-F, et al. Long-term efficacy of opicapone in fluctuating Parkinson’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.
   Google Scholar
• Lees AJ, Ferreira JJ, Costa R, et al. Efficacy and safety of opicapone, a new COMT-inhibitor, for the treatment of motor fluctuations in Parkinson’s disease patients: BIPARK-II study. J Neurol Sci. 2013;333:e109–e151.
   Google Scholar
• 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.
   Google Scholar
• Rocha JF, Almeida L, Falcao 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.
   Google Scholar
• Grosset D. Therapy adherence issues in Parkinson’s disease. J Neurol Sci. 2010;289(1–2):115–118.
   Google Scholar
• Adler CH, Singer C, O’Brien C, et al. Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Tolcapone Fluctuator Study Group III. Arch Neurol. 1998;55(8):1089–1095.
   Google Scholar
• Baas H, Zehrden F, Selzer R, et al. Pharmacokinetic-pharmacodynamic relationship of levodopa with and without tolcapone in patients with Parkinson’s disease. Clin Pharmacokinet. 2001;40(5):383–393.
   Google Scholar
• Benabou R, Waters C. Hepatotoxic profile of catechol-O-methyltransferase inhibitors in Parkinson’s disease. Expert Opin Drug Saf. 2003;2(3):263–267.
   Google Scholar
• Ceravolo R, Piccini P, Bailey DL, et al. 18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson’s disease. Synapse. 2002;43(3):201–207.
   Google Scholar
• Factor SA, Molho ES, Feustel PJ, et al. Long-term comparative experience with tolcapone and entacapone in advanced Parkinson’s disease. Clin Neuropharmacol. 2001;24(5):295–299.
   Google Scholar
• Fava M, Rosenbaum JF, Kolsky AR, et al. Open study of the catechol-O-methyltransferase inhibitor tolcapone in major depressive disorder. J Clin Psychopharmacol. 1999;19(4):329–335.
   Google Scholar
• Jorga K, Fotteler B, Banken L, et al. Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies. Br J Clin Pharmacol. 2000;49(1):39–48.
   Google Scholar
• Müller T. Tolcapone addition improves Parkinson’s disease associated nonmotor symptoms. Ther Adv Neurol Disord. 2014;7(2):77–82.
   Google Scholar
• Napolitano A, Dotto PD, Petrozzi L, et al. Pharmacokinetics and pharmacodynamics of L-dopa after acute and 6-week tolcapone administration in patients with Parkinson’s disease. Clin Neuropharmacol. 1999;22(1):24–29.
   Google Scholar
• Inzelberg R, Carasso RL, Schechtman E, et al. A comparison of dopamine agonists and catechol-O-methyltransferase inhibitors in Parkinson’s disease. Clin Neuropharmacol. 2000;23(5):262–266.
   Google Scholar
• Martignoni E, Cosentino M, Ferrari M, et al. Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism. Neurology. 2005;65(11):1820–1822.
   Google Scholar
• Russ H, Müller T, Woitalla D, et al. Detection of tolcapone in the cerebrospinal fluid of parkinsonian subjects. Naunyn Schmiedebergs Arch Pharmacol. 1999;360(6):719–720.
   Google Scholar
• Hauser RA, Molho E, Shale H, et al. A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson’s disease patients. Tolcapone De Novo Study Group. Mov Disord. 1998;13(4):643–647.
   Google Scholar
• Bartl J, Muller T, Grunblatt E, et al. Chronic monoamine oxidase-B inhibitor treatment blocks monoamine oxidase-A enzyme activity. J Neural Transm. 2014;121(4):379–383.
   Google Scholar
• Riederer P, Laux G. MAO-inhibitors in Parkinson’s disease. Exp Neurobiol. 2011;20(1):1–17.
   Google Scholar
• Burke WJ, Li SW, Chung HD, et al. Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases. Neurotoxicology. 2004;25(1–2):101–115.
   Google Scholar
• Burke WJ, Kumar VB, Pandey N, et al. Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathol. 2008;115(2):193–203. .
   Google Scholar
• Panneton WM, Kumar VB, Gan Q, et al. The neurotoxicity of DOPAL: behavioral and stereological evidence for its role in Parkinson disease pathogenesis. PLoS One. 2010;5(12):e15251.
   Google Scholar
• Bar-Am O, Weinreb O, Amit T, et al. Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. Faseb J. 2005;19(13):1899–1901.
   Google Scholar
• Weinreb O, Amit T, Bar-Am O, et al. Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy. Ann N Y Acad Sci. 2007;1122(1):155–168.
   Google Scholar
• Akao Y, Maruyama W, Shimizu S, et al. Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan. J Neurochem. 2002;82(4):913–923.
   Google Scholar
• Akao Y, Maruyama W, Yi H, et al. An anti-Parkinson’s disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic bcl-2 in human dopaminergic SH-SY5Y cells. Neurosci Lett. 2002;326(2):105–108.
   Google Scholar
• Naoi M, Riederer P, Maruyama W. Modulation of monoamine oxidase (MAO) expression in neuropsychiatric disorders: genetic and environmental factors involved in type A MAO expression. J Neural Transm (Vienna). 2016;123(2):91–106.
   Google Scholar
• Shin HS. Metabolism of selegiline in humans. Identification, excretion, and stereochemistry of urine metabolites. Drug Metab Dispos. 1997;25(6):657–662.
   Google Scholar
• Bhatia M, Jain S, Maheshwari MC. Role of selegiline as initial monotherapy in early Parkinson’s disease. J Assoc Physicians India. 1994;42(1):30–32.
   Google Scholar
• Calzetti S, Negrotti A, Cassio A. L-deprenyl as an adjunct to low-dose bromocriptine in early Parkinson’s disease: a short-term, double-blind, and prospective follow-up study. Clin Neuropharmacol. 1995;18(3):250–257.
   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.
   Google Scholar
• Birkmayer W, Riederer P. Deprenyl prolongs the therapeutic efficacy of combined L-DOPA in Parkinson’s disease. Adv Neurol. 1984;40:475–481.
   Google Scholar
• Przuntek H, Conrad B, Dichgans J, et al. SELEDO: a 5-year long-term trial on the effect of selegiline in early Parkinsonian patients treated with levodopa. Eur J Neurol. 1999;6(2):141–150.
   Google Scholar
• Müller T, Hoffmann JA, Dimpfel W, et al. Switch from selegiline to rasagiline is beneficial in patients with Parkinson’s disease. J Neural Transm. 2013;120(5):761–765.
   Google Scholar
• Hoy SM, Keating GM. Rasagiline: a review of its use in the treatment of idiopathic Parkinson’s disease. Drugs. 2012;72(5):643–669.
   Google Scholar
• Rascol O. Rasagiline in the pharmacotherapy of Parkinson’s disease–a review. Expert Opin Pharmacother. 2005;6(12):2061–2075.
   Google Scholar
• Elmer LW. Rasagiline adjunct therapy in patients with Parkinson’s disease: post hoc analyses of the PRESTO and LARGO trials. Parkinsonism Relat Disord. 2013;19(11):930–936.
   Google Scholar
• Hauser RA, Silver D, Choudhry A, et al. Randomized, controlled trial of rasagiline as an add-on to dopamine agonists in Parkinson’s disease. Mov Disord. 2014;29(8):1028–1034.
   Google Scholar
• Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361(13):1268–1278.
   Google Scholar
• Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol. 2002;59(12):1937–1943.
   Google Scholar
• Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol. 2005;62(2):241–248.
   Google Scholar
• Rascol O, Fitzer-Attas CJ, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol. 2011;10(5):415–423.
   Google Scholar
• Müller T. Safinamide: an add-on treatment for managing Parkinson’s disease. Clin Pharmacol. 2018;10:31–41.
   Google Scholar
• Schapira AH, Stocchi F, Borgohain R, et al. Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson’s disease. Eur J Neurol. 2013;20(2):271–280.
   Google Scholar
• Schapira AH, Fox SH, Hauser RA. et al. Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with parkinson's disease and motor fluctuations. A Randomized Clinical Trial. Jama Neurol. 2017;74(2):216-224.
   Google Scholar
• Stocchi F, Borgohain R, Onofrj M, et al. A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson’s disease patients. Mov Disord. 2012;27(1):106–112.
   Google Scholar
• Stocchi F, Arnold G, Onofrj M, et al. Improvement of motor function in early Parkinson disease by safinamide. Neurology. 2004;63(4):746–748.
   Google Scholar
• Doudet DJ, Chan GLY, Holden JE, et al. Effects of monoamine oxidase and catechol-O-methyltransferase inhibition on dopamine turnover: a PET study with 6-[18F]L-DOPA. Eur J Pharmacol. 1997;334(1):31–38.
   Google Scholar
• Olanow CW, Kieburtz K, Stocchi F. Initiating levodopa therapy for Parkinson’s disease. Mov Disord. 2014;29(3):430.
   Google Scholar
• Müller T, Möhr J-D. Long-term management of Parkinson’s disease using levodopa combinations. Expert Opin Pharmacother. 2018;19(9):1003–1011.
   Google Scholar
• Muhlack S, Herrmann L, Salmen S, et al. Fewer fluctuations, higher maximum concentration and better motor response of levodopa with catechol-O-methyltransferase inhibition. J Neural Transm. 2014;121(11):1357–1366.
   Google Scholar
• Loewen G, LeWitt P, Olanow C, et al. Pharmacokinetics of opicapone and effect on COMT and levodopa pharmacokinetics in patients with Parkinson’s disease. J Mov Disord. 2019;34:S7 (Abstract).
   Google Scholar
• Olanow WC, 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.
   Google Scholar
• Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749–759.
   Google Scholar
• Garcia-Gavin J, Parente J, Goossens A. Allergic contact dermatitis caused by sodium metabisulfite: a challenging allergen: a case series and literature review. Contact Dermatitis. 2012;67(5):260–269.
   Google Scholar
• Ng Ying Kin NM, Lal S, Thavundayil JX. Stability of apomorphine hydrochloride in aqueous sodium bisulphite solutions. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25(7):1461–1468.
   Google Scholar
• Müller T, Benz S, Börnke C, et al. Repeated rating improves value of diagnostic dopaminergic challenge tests in Parkinson’s disease. J Neural Transm (Vienna). 2003;110(6):603–609.
   Google Scholar
• Klostermann F, Jugel C, Bomelburg M, et al. Severe gastrointestinal complications in patients with levodopa/carbidopa intestinal gel infusion. Mov Disord. 2012;27(13):1704–1705.
   Google Scholar
• Klostermann F, Jugel C, Müller T, et al. Malnutritional neuropathy under intestinal levodopa infusion. J Neural Transm (Vienna). 2012;119(3):369–372.
   Google Scholar
• Müller T, Jugel C, Ehret R, et al. Elevation of total homocysteine levels in patients with Parkinson’s disease treated with duodenal levodopa/carbidopa gel. J Neural Transm (Vienna). 2011;118(9):1329–1333.
   Google Scholar
• Harati A, Müller T. Neuropsychological effects of deep brain stimulation for Parkinson’s disease. Surg Neurol Int. 2013;4(7):S443–S447.
   Google Scholar
• Figee M, de KP, Klaassen S, et al. Deep brain stimulation induces striatal dopamine release in obsessive-compulsive disorder. Biol Psychiatry. 2014;75(8):647–652.
   Google Scholar
• Meer W, Reum T, Paul G, et al. Striatal dopaminergic metabolism is increased by deep brain stimulation of the subthalamic nucleus in 6-hydroxydopamine lesioned rats. Neurosci Lett. 2001;303(3):165–168.
   Google Scholar
• Meer W, Harnack D, Paul G, et al. Deep brain stimulation of subthalamic neurons increases striatal dopamine metabolism and induces contralateral circling in freely moving 6-hydroxydopamine-lesioned rats. Neurosci Lett. 2002;328(2):105–108.
   Google Scholar
• Shoulson I, Oakes D, Fahn S, et al. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol. 2002;51(5):604–612.
   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.
   Google Scholar
• Liedhegner EA, Steller KM, Mieyal JJ. Levodopa activates apoptosis signaling kinase 1 (ASK1) and promotes apoptosis in a neuronal model: implications for the treatment of Parkinson’s disease. Chem Res Toxicol. 2011;24(10):1644–1652. .
   Google Scholar
• Müller T. Motor complications, levodopa metabolism and progression of Parkinson’s disease. Expert Opin Drug Metab Toxicol. 2011;7(7):847–855.
   Google Scholar
• White AR, Barnham KJ, Huang X, et al. Iron inhibits neurotoxicity induced by trace copper and biological reductants. J Biol Inorg Chem. 2004;9(3):269–280.
   Google Scholar
• Hinz M, Stein A, Cole T. The Parkinson’s disease death rate: carbidopa and vitamin B6. Clin Pharmacol. 2014;6:161–169.
   Google Scholar
• De Bonis ML, Tessitore A, Pellecchia MT, et al. Impaired transmethylation potential in Parkinson’s disease patients treated with L-dopa. Neurosci Lett. 2010;468(3):287–291.
   Google Scholar
• Feng LR, Maguire-Zeiss KA. Dopamine and paraquat enhance alpha-synuclein-induced alterations in membrane conductance. Neurotox Res. 2011;20(4):387–401.
   Google Scholar
• Hashim HZ, Wan Musa WR, Ngiu CS, et al. Parkinsonism complicating acute organophosphate insecticide poisoning. Ann Acad Med Singapore. 2011;40(3):150–151.
   Google Scholar
• Schwartz RS, Halliday GM, Cordato DJ, et al. Small-vessel disease in patients with Parkinson’s disease: a clinicopathological study. Mov Disord. 2012;27(12):1506–1512.
   Google Scholar
• Müller T, Woitalla D, Muhlack S. Inhibition of catechol-O-methyltransferase modifies acute homocysteine rise during repeated levodopa application in patients with Parkinson’s disease. Naunyn Schmiedebergs Arch Pharmacol. 2011;383(6):627–633.
   Google Scholar
• Müller T, Kuhn W. Homocysteine levels after acute levodopa intake in patients with Parkinson’s disease. Mov Disord. 2009;24(9):1339–1343.
   Google Scholar
• Lamberti P, Zoccolella S, Iliceto G, et al. Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson’s disease patients. Mov Disord. 2005;20(1):69–72.
   Google Scholar
• Müller T, Muhlack S. Peripheral COMT inhibition prevents levodopa associated homocysteine increase. J Neural Transm. 2009;116(10):1253–1256.
   Google Scholar
• Nevrly M, Kanovsky P, Vranova H, et al. Effect of entacapone on plasma homocysteine levels in Parkinson’s disease patients. Neurol Sci. 2010;31(5):565–569.
   Google Scholar
• O’Suilleabhain PE, Bottiglieri T, Dewey RB Jr., et al. Modest increase in plasma homocysteine follows levodopa initiation in Parkinson’s disease. Mov Disord. 2004;19(12):1403–1408.
   Google Scholar
• Ostrem JL, Kang GA, Subramanian I, et al. The effect of entacapone on homocysteine levels in Parkinson disease. Neurology. 2005;64(8):1482.
   Google Scholar
• Postuma RB, Espay AJ, Zadikoff C, et al. Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: a randomized controlled study. Neurology. 2006;66(12):1941–1943.
   Google Scholar
• Valkovic P, Benetin J, Blazicek P, et al. Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients. Parkinsonism Relat Disord. 2005;11(4):253–256.
   Google Scholar
• Zesiewicz TA, Wecker L, Sullivan KL, et al. The controversy concerning plasma homocysteine in Parkinson disease patients treated with levodopa alone or with entacapone: effects of vitamin status. Clin Neuropharmacol. 2006;29(3):106–111.
   Google Scholar
• Graham DJ, Williams JR, Hsueh Y-H, et al. Cardiovascular and mortality risks in Parkinson’s disease patients treated with entacapone. Mov Disord. 2013;28(4):490–497.
   Google Scholar
• Isobe C, Murata T, Sato C, et al. Increase of total homocysteine concentration in cerebrospinal fluid in patients with Alzheimer’s disease and Parkinson’s disease. Life Sci. 2005;77(15):1836–1843.
   Google Scholar
• Selley ML, Close DR, Stern SE. The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer’s disease. Neurobiol Aging. 2002;23(3):383–388.
   Google Scholar
• de Souza FG, Rodrigues MD, Tufik S, et al. Acute stressor-selective effects on homocysteine metabolism and oxidative stress parameters in female rats. Pharmacol Biochem Behav. 2006;85(2):400–407.
   Google Scholar
• Duan W, Ladenheim B, Cutler RG, et al. Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease. J Neurochem. 2002;80(1):101–110.
   Google Scholar
• Streck EL, Vieira PS, Wannmacher CM, et al. In vitro effect of homocysteine on some parameters of oxidative stress in rat hippocampus. Metab Brain Dis. 2003;18(2):147–154.
   Google Scholar
• Müller T, Kuhn W. Cysteine elevation in levodopa-treated patients with Parkinson’s disease. Mov Disord. 2009;24(6):929–932.
   Google Scholar
• Müller T, Muhlack S. Cysteinyl-glycine reduction as marker for levodopa induced oxidative stress in Parkinson’s disease patients. Mov Disord. Forthcoming 2010.
   Google Scholar
• Müller T, Muhlack S. Levodopa-related cysteinyl-glycine and cysteine reduction with and without catechol-O-methyltransferase inhibition in Parkinson’s disease patients. J Neural Transm. 2014;121(6):643–648.
   Google Scholar
• Nissinen E, Linden IB, Pohto P. Antioxidant properties of nitecapone are potentiated by glutathione. Biochem Mol Biol Int. 1995;35(2):387–395.
   Google Scholar
• Sabens EA, Distler AM, Mieyal JJ. Levodopa deactivates enzymes that regulate thiol-disulfide homeostasis and promotes neuronal cell death - implications for therapy of Parkinson’s disease. Biochemistry. 2010;49(12):2715–2724.
   Google Scholar
• Sagara Y, Dargusch R, Chambers D, et al. Cellular mechanisms of resistance to chronic oxidative stress. Free Radic Biol Med. 1998;24(9):1375–1389.
   Google Scholar
• Müller T, Kohlhepp W. Nigral depigmentation reflects monoamine exhaustion as initial step to Parkinson’s disease. Med Hypotheses. 2018;110:46–49.
   Google Scholar
• Youdim MBH, Fridkin M, Zheng H. Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. Mech Ageing Dev. 2005;126(2):317–326.
   Google Scholar
• Müller T, Laar TV, Cornblath DR, et al. Peripheral neuropathy in Parkinson’s disease: levodopa exposure and implications for duodenal delivery. Parkinsonism Relat Disord. 2013;19(5):501–507.
   Google Scholar
• Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351:2498–2508.
   Google Scholar
• Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med. 2019;380(4):315–324.
   Google Scholar
• Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol. 2003;54(1):93–101.
   Google Scholar
• Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. JAMA. 2000;284(15):1931–1938.
   Google Scholar
• Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA. 2002;287(13):1653–1661.
   Google Scholar
• Schapira AH, McDermott MP, Barone P, et al. Pramipexole in patients with early Parkinson’s disease (PROUD): a randomised delayed-start trial. Lancet Neurol. 2013;12(8):747–755.
   Google Scholar
• Müller T, Lang UE, Muhlack S, et al. Impact of levodopa on reduced nerve growth factor levels in patients with Parkinson disease. Clin Neuropharmacol. 2005;28:238–240.
   Google Scholar
• Müller T, Hellwig R, Muhlack S. Levodopa induces synthesis of nerve growth factor and growth hormone in patients with Parkinson disease. Clin Neuropharmacol. 2011;34(3):101–103.
   Google Scholar
• Murer MG, Dziewczapolski G, Menalled LB, et al. Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann Neurol. 1998;43(5):561–575.
   Google Scholar
• Müller T, Trommer I, Muhlack S, et al. Levodopa increases oxidative stress and repulsive guidance molecule A levels: a pilot study in patients with Parkinson’s disease. J Neural Transm (Vienna). 2016;123(4):401–406.
   Google Scholar
• Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann Neurol. 1996;39(1):37–45.
   Google Scholar
• Beal MF, Oakes D, Shoulson I, et al. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol. 2014;71(5):543–552.
   Google Scholar
• Ambrozi L, Danielczyk W. Treatment of impaired cerebral function in psychogeriatric patients with memantine–results of a phase II double-blind study. Pharmacopsychiatry. 1988;21(3):144–146.
   Google Scholar
• Storozhuk VM, Zinyuk LE. Specific features of sensorimotor cerebral cortex activity modulation by dopamine releaser amantadine. Exp Brain Res. 2007;182(2):157–167.
   Google Scholar
• Müller T. Pharmacokinetic drug evaluation of safinamide mesylate for the treatment of mid-to-late stage Parkinson’s disease. Expert Opin Drug Metab Toxicol. 2017;13(6):693–699.
   Google Scholar
• Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet. 2005;365(9463):947–954.
   Google Scholar
• Titova N, Chaudhuri KR. Non-motor Parkinson disease: new concepts and personalised management. Med J Aust. 2018;208(9):404–409.
   Google Scholar