Những Thuốc Cũ, Hệ Thống Giao Phối Mới Trong Bệnh Parkinson

Adler CH. Relevance of motor complications in Parkinson’s disease. Neurology. 2002;58(4 Suppl 1):S51–6. Chou KL, Stacy M, Simuni T, Miyasaki J, Oertel WH, Sethi K, et al. The spectrum of “off” in Parkinson’s disease: what have we learned over 40 years? Parkinsonism Relat Disord. 2018;51:9–16. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30(1):80–9. Widnell K. Pathophysiology of motor fluctuations in Parkinson’s disease. Mov Disord. 2005;20(Suppl 11):S17–22. Fasano A, Visanji NP, Liu LW, Lang AE, Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol. 2015;14(6):625–39. Contin M, Martinelli P. Pharmacokinetics of levodopa. J Neurol. 2010;257(Suppl 2):S253–61. Calabresi P, Di Filippo M, Ghiglieri V, Tambasco N, Picconi B. Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to-bedside gap. Lancet Neurol. 2010;9(11):1106–17. Fabbrini G, Juncos J, Mouradian MM, Serrati C, Chase TN. Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson’s disease. Ann Neurol. 1987;21(4):370–6. Virmani T, Tazan S, Mazzoni P, Ford B, Greene PE. Motor fluctuations due to interaction between dietary protein and levodopa in Parkinson’s disease. J Clin Mov Disord. 2016;3:8. Anderson DP. Apomorphia Hydrochloride. Can Med Assoc J. 1935;33(1):74–5. Duby SE, Cotzias GC, Papavasiliou PS, Lawrence WH. Injected apomorphine and orally administered levodopa in Parkinsonism. Arch Neurol. 1972;27(6):474–80. Sharma JC, Macnamara L, Hasoon M, Vassallo M. Diagnostic and therapeutic value of apomorphine in Parkinsonian patients. Int J Clin Pract. 2004;58(11):1028–32. Rossi P, Colosimo C, Moro E, Tonali P, Albanese A. Acute challenge with apomorphine and levodopa in Parkinsonism. Eur Neurol. 2000;43(2):95–101. Clarke CE, Davies P. Systematic review of acute levodopa and apomorphine challenge tests in the diagnosis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2000;69(5):590–4. de la Fuente-Fernandez R. Role of DaTSCAN and clinical diagnosis in Parkinson disease. Neurology. 2012;78(10):696–701. Jenner P, Katzenschlager R. Apomorphine - pharmacological properties and clinical trials in Parkinson’s disease. Parkinsonism Relat Disord. 2016;33(Suppl 1):S13–21. Dewey RB Jr, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol. 2001;58(9):1385–92. Pfeiffer RF, Gutmann L, Hull KL Jr, Bottini PB, Sherry JH, Investigators APOS. Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson’s disease. Parkinsonism Relat Disord. 2007;13(2):93–100. Pahwa R, Koller WC, Trosch RM, Sherry JH, Investigators APOS. Subcutaneous apomorphine in patients with advanced Parkinson’s disease: a dose-escalation study with randomized, double-blind, placebo-controlled crossover evaluation of a single dose. J Neurol Sci. 2007;258(1–2):137–43. https://www.apokyn.com/sites/all/themes/apokyn/content/resources/Apokyn_PI.pdf. Accessed 23 Apr 2019. Kolls BJ, Stacy M. Apomorphine: a rapid rescue agent for the management of motor fluctuations in advanced Parkinson disease. Clin Neuropharmacol. 2006;29(5):292–301. LeWitt PA, Ondo WG, Van Lunen B, Bottini PB. Open-label study assessment of safety and adverse effects of subcutaneous apomorphine injections in treating “off” episodes in advanced Parkinson disease. Clin Neuropharmacol. 2009;32(2):89–93. Ondo WG, Hunter C, Ferrara JM, Mostile G. Apomorphine injections: predictors of initial common adverse events and long term tolerability. Parkinsonism Relat Disord. 2012;18(5):619–22. Lees AJ, Montastruc JL, Turjanski N, Rascol O, Kleedorfer B, Peyro Saint-Paul H, et al. Sublingual apomorphine and Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1989;52(12):1440. Deffond D, Durif F, Tournilhac M. Apomorphine in treatment of Parkinson’s disease: comparison between subcutaneous and sublingual routes. J Neurol Neurosurg Psychiatry. 1993;56(1):101–3. Hauser RA, Olanow CW, Dzyngel B, Bilbault T, Shill H, Isaacson S, et al. Sublingual apomorphine (APL-130277) for the acute conversion of OFF to ON in Parkinson’s disease. Mov Disord. 2016;31(9):1366–72. Espay AJ, et al. Efficacy of sublingual apomorphine film (APL-130277) for the treatment of OFF episodes in subjects with Parkinson’s disease: preliminary results from the Phase-3 study dose-titration phase. Parkinsonism Relat Disord. 2018;46:e19. Navia BSF, Pahwa R, Hauser R, Worden M, Bhargava P, Vakili G, Blum D, 2nd Pan American Parkinson’s Disease and Movement Disorders Congress. Late-breaking abstracts, efficacy and safety of sublingual apomorphine film (APL-130277) for the treatment of off episodes in patients with Parkinson’s disease: results from a double-blind, placebo-controlled trial. 2018; p. 3. Shill H, Pappert E, Dzyngel B, Bilbault T, Argo A. The effects of sublingual apomorphine (APL-130277) by disease severity on the acute management of OFF episodes in Parkinson’s Disease (P2.336). Neurology. 2016;86(16 Supplement):P2.336. Pahwa R, Hauser R, Worden M, Bhargava P, Vakili G, Agro A, Blum D, Olanow W, Navia B. Safety of sublingual apomorphine film (APL-130277) for the treatment of OFF episodes in patients with Parkinson’s disease: Results from a Phase 3 double-blind, placebo-controlled trial [abstract]. Mov Disord. 2018;33 (suppl 2). Colzi A, Turner K, Lees AJ. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1998;64(5):573–6. Pietz K, Hagell P, Odin P. Subcutaneous apomorphine in late stage Parkinson’s disease: a long term follow up. J Neurol Neurosurg Psychiatry. 1998;65(5):709–16. Stocchi F, Vacca L, De Pandis MF, Barbato L, Valente M, Ruggieri S. Subcutaneous continuous apomorphine infusion in fluctuating patients with Parkinson’s disease: long-term results. Neurol Sci. 2001;22(1):93–4. Katzenschlager R, Poewe W, Rascol O, Trenkwalder C, Deuschl G, Chaudhuri KR, 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):749–59. Garcia Ruiz PJ, Sesar Ignacio A, Ares Pensado B, Castro Garcia A, Alonso Frech F, Alvarez Lopez M, et al. Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinson’s disease with motor fluctuations: a multicenter study. Mov Disord. 2008;23(8):1130–6. van Laar T, Postma AG, Drent M. Continuous subcutaneous infusion of apomorphine can be used safely in patients with Parkinson’s disease and pre-existing visual hallucinations. Parkinsonism Relat Disord. 2010;16(1):71–2. Borgemeester RWK, van Laar T. Continuous subcutaneous apomorphine infusion in Parkinson’s disease patients with cognitive dysfunction: a retrospective long-term follow-up study. Parkinsonism Relat Disord. 2017;45:33–8. Deleu D, Hanssens Y, Northway MG. Subcutaneous apomorphine: an evidence-based review of its use in Parkinson’s disease. Drugs Aging. 2004;21(11):687–709. Borgemeester RW, Drent M, van Laar T. Motor and non-motor outcomes of continuous apomorphine infusion in 125 Parkinson’s disease patients. Parkinsonism Relat Disord. 2016;23:17–22. Kimber TE, Fang J, Huddy LJ, Thompson PD. Long-term adherence to apomorphine infusion in patients with Parkinson disease: a 10-year observational study. Intern Med J. 2017;47(5):570–3. Poltawski L, Edwards H, Todd A, Watson T, Lees A, James CA. Ultrasound treatment of cutaneous side-effects of infused apomorphine: a randomized controlled pilot study. Mov Disord. 2009;24(1):115–8. Todorova A, Samuel M, Brown RG, Chaudhuri KR. Infusion therapies and development of impulse control disorders in advanced Parkinson disease: clinical experience after 3 years’ follow-up. Clin Neuropharmacol. 2015;38(4):132–4. Barbosa P, Lees AJ, Magee C, Djamshidian A, Warner TT. A retrospective evaluation of the frequency of impulsive compulsive behaviors in Parkinson’s disease patients treated with continuous waking day apomorphine pumps. Mov Disord Clin Pract. 2017;4(3):323–8. Ramot Y, Nyska A, Adar L, Durlach C, Fishelovitch D, Sacco G, et al. ND0701, A novel formulation of apomorphine for subcutaneous infusion, in comparison to a commercial apomorphine formulation: 28-Day pharmacokinetic study in Minipigs and a phase I Study in healthy volunteers to assess the safety, tolerability, pharmacokinetics and relative bioavailability. CNS Drugs. 2018;32(5):443–54. Giladi N, Boroojerdi B, Korczyn AD, Burn DJ, Clarke CE, Schapira AH, et al. Rotigotine transdermal patch in early Parkinson’s disease: a randomized, double-blind, controlled study versus placebo and ropinirole. Mov Disord. 2007;22(16):2398–404. Parkinson Study G. A controlled trial of rotigotine monotherapy in early Parkinson’s disease. Arch Neurol. 2003;60(12):1721–8. Watts RL, Jankovic J, Waters C, Rajput A, Boroojerdi B, Rao J. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology. 2007;68(4):272–6. LeWitt PA, Lyons KE, Pahwa R, Group SPS. Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study. Neurology. 2007;68(16):1262–7. Mizuno Y, Nomoto M, Hasegawa K, Hattori N, Kondo T, Murata M, et al. Rotigotine vs ropinirole in advanced stage Parkinson’s disease: a double-blind study. Parkinsonism Relat Disord. 2014;20(12):1388–93. Trenkwalder C, Kies B, Rudzinska M, Fine J, Nikl J, Honczarenko K, et al. Rotigotine effects on early morning motor function and sleep in Parkinson’s disease: a double-blind, randomized, placebo-controlled study (RECOVER). Mov Disord. 2011;26(1):90–9. Giladi N, Ghys L, Surmann E, Boroojerdi B, Jankovic J. Effects of long-term treatment with rotigotine transdermal system on dyskinesia in patients with early-stage Parkinson’s disease. Parkinsonism Relat Disord. 2014;20(12):1345–51. Antonini A, Chaudhuri KR, Boroojerdi B, Asgharnejad M, Bauer L, Grieger F, et al. Impulse control disorder related behaviours during long-term rotigotine treatment: a post hoc analysis. Eur J Neurol. 2016;23(10):1556–65. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021829s001lbl.pdf. Accessed 15 Jan 2019. http://serinatherapeutics.com/wp-content/uploads/2015/10/Fact-Sheet-on-SER-214.pdf. Accessed 15 Jan 2019. Eskow Jaunarajs KL, Standaert DG, Viegas TX, Bentley MD, Fang Z, Dizman B, et al. Rotigotine polyoxazoline conjugate SER-214 provides robust and sustained antiparkinsonian benefit. Mov Disord. 2013;28(12):1675–82. https://clinicaltrials.gov/ct2/show/NCT00296192. Accessed 4 Jan 2019. Perez-Lloret S, Rascol O. Piribedil for the treatment of motor and non-motor symptoms of Parkinson disease. CNS Drugs. 2016;30(8):703–17. Rascol O, Azulay JP, Blin O, Bonnet AM, Brefel-Courbon C, Cesaro P, et al. Orodispersible sublingual piribedil to abort OFF episodes: a single dose placebo-controlled, randomized, double-blind, cross-over study. Mov Disord. 2010;25(3):368–76. Montastruc JL, Ziegler M, Rascol O, Malbezin M. A randomized, double-blind study of a skin patch of a dopaminergic agonist, piribedil, in Parkinson’s disease. Mov Disord. 1999;14(2):336–41. Hofmann C, Penner U, Dorow R, Pertz HH, Jahnichen S, Horowski R, et al. Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis. Clin Neuropharmacol. 2006;29(2):80–6. Vaamonde J, Luquin MR, Obeso JA. Subcutaneous lisuride infusion in Parkinson’s disease. Response to chronic administration in 34 patients. Brain. 1991;114(Pt 1):601–17. https://www.ema.europa.eu/documents/medicine-qa/questions-answers-withdrawal-marketing-authorisation-application-nenad-lisuride_en.pdf. Accessed 20 Dec 2018. Virhammar J, Nyholm D. Levodopa-carbidopa enteral suspension in advanced Parkinson’s disease: clinical evidence and experience. Ther Adv Neurol Disord. 2017;10(3):171–87. Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, 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):141–9. Pahwa R, Lyons KE. Outpatient titration of carbidopa/levodopa enteral suspension (Duopa). Int J Neurosci. 2017;127(5):459–65. Busk K, Nyholm D. Long-term 24-h levodopa/carbidopa gel infusion in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(8):1000–1. Fernandez HH, Boyd JT, Fung VSC, Lew MF, Rodriguez RL, Slevin JT, et al. Long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced Parkinson’s disease. Mov Disord. 2018;33(6):928–36. Rispoli V, Simioni V, Capone JG, Golfre Andreasi N, Preda F, Sette E, et al. Peripheral neuropathy in 30 duodopa patients with vitamins B supplementation. Acta Neurol Scand. 2017;136(6):660–7. Senek M, Nielsen EI, Nyholm D. Levodopa-entacapone-carbidopa intestinal gel in Parkinson’s disease: a randomized crossover study. Mov Disord. 2017;32(2):283–6. Koller WC, Pahwa R. Treating motor fluctuations with controlled-release levodopa preparations. Neurology. 1994;44(7 Suppl 6):S23–8. Erni W, Held K. The hydrodynamically balanced system: a novel principle of controlled drug release. Eur Neurol. 1987;27(Suppl 1):21–7. Goetz CG, Tanner CM, Shannon KM, Carroll VS, Klawans HL, Carvey PM, et al. Controlled-release carbidopa/levodopa (CR72-Sinemet) in Parkinson’s disease patients with and without motor fluctuations. Neurology. 1988;38(7):1143–6. Dempski RE, Scholtz EC, Oberholtzer ER, Yeh KC. Pharmaceutical design and development of a Sinemet controlled-release formulation. Neurology. 1989;39(11 Suppl 2):20–4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203312s000lbl.pdf. Accessed 8 Jan 2019. Espay AJ, Pagan FL, Walter BL, Morgan JC, Elmer LW, Waters CH, et al. Optimizing extended-release carbidopa/levodopa in Parkinson disease: consensus on conversion from standard therapy. Neurol Clin Pract. 2017;7(1):86–93. Pahwa R, Lyons KE, Hauser RA, Fahn S, Jankovic J, Pourcher E, et al. Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson’s disease. Parkinsonism Relat Disord. 2014;20(2):142–8. Hauser RA, Hsu A, Kell S, Espay AJ, Sethi K, Stacy M, 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):346–56. Stocchi F, Hsu A, Khanna S, Ellenbogen A, Mahler A, Liang G, et al. Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients. Parkinsonism Relat Disord. 2014;20(12):1335–40. Nausieda PA, Pfeiffer RF, Tagliati M, Kastenholz KV, DeRoche C, Slevin JT. A multicenter, open-label, sequential study comparing preferences for carbidopa-levodopa orally disintegrating tablets and conventional tablets in subjects with Parkinson’s disease. Clin Ther. 2005;27(1):58–63. Ondo WG, Shinawi L, Moore S. Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: a single-dose, double-blind, double-dummy, placebo-controlled, crossover trial. Mov Disord. 2010;25(16):2724–7. LeWitt PA, Hauser RA, Grosset DG, Stocchi F, Saint-Hilaire MH, Ellenbogen A, et al. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord. 2016;31(9):1356–65. LeWitt PA, Pahwa R, Sedkov A, Corbin A, Batycky R, Murck H. Pulmonary safety and tolerability of inhaled levodopa (CVT-301) administered to patients with Parkinson’s disease. J Aerosol Med Pulm Drug Deliv. 2018;31(3):155–61. Grosset D, Dhall R, Gurevich T, Kassubek J, Poewe WH, Rascol O, et al. Long-term efficacy of inhaled levodopa in Parkinson’s disease subjects with motor fluctuations: a phase 3 open-label randomized study (S26.008). Neurology. 2018;90(15 Supplement):S26.008. Grosset D, Dhall R, Gurevich T, Kassubek J, Poewe WH, Rascol O, et al. Long-term pulmonary safety of inhaled levodopa in Parkinson’s disease subjects with motor fluctuations: a phase 3 open-label randomized study (S26.006). Neurology. 2018;90(15 Supplement):S26.006. LeWitt PA, Hauser RA, Pahwa R, Isaacson SH, Fernandez HH, Lew M, 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):145–54. 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):71–7. Nyholm D, Ehrnebo M, Lewander T, Trolin CG, Backstrom T, Panagiotidis G, et al. Frequent administration of levodopa/carbidopa microtablets vs levodopa/carbidopa/entacapone in healthy volunteers. Acta Neurol Scand. 2013;127(2):124–32. Stocchi F, Vacca L, Grassini P, Pawsey S, Whale H, Marconi S, et al. L-dopa pharmacokinetic profile with effervescent melevodopa/carbidopa versus standard-release levodopa/carbidopa tablets in Parkinson’s disease: a randomised study. Parkinsons Dis. 2015;2015:369465. Fasano A, Bove F, Gabrielli M, Ragazzoni E, Fortuna S, Tortora A, et al. Liquid melevodopa versus standard levodopa in patients with Parkinson disease and small intestinal bacterial overgrowth. Clin Neuropharmacol. 2014;37(4):91–5. https://www.intecpharma.com/wp-content/uploads/2018/06/AP-CD_LD_Comp-PK-and-Safety_AAN-2018_Pos_FINAL.pdf. Accessed 21 Dec 2018. Navon N, Weiss Z, Gendreau RM, Meckler J. Optimizing delivery of carbidopa/levodopa via the accordion pill™: comparative PK and safety from 2 randomized crossover studies in healthy volunteers (P2.040). Neurology. 2018;90(15 Supplement):P2.040. LeWitt PA, Giladi N, Gurevich T, Shabtai H, Djaldetti R, Roizen N, Hassin-Baer S, Cohen O, Yahalom G, Schlessinger I, Nassar M, Milo R, Anca M, Farkas P, Lamp Y, Navon N, Flaishon L. Accordion pill carbidopa/levodopa (AP-CD/LD) for treatment of advanced PD [abstract]. Mov Disord. 2014;29(Suppl 1):668 (Internet). Quinn N, Parkes JD, Marsden CD. Control of on/off phenomenon by continuous intravenous infusion of levodopa. Neurology. 1984;34(9):1131–6. Eisler T, Eng N, Plotkin C, Calne DB. Absorption of levodopa after rectal administration. Neurology. 1981;31(2):215–7. Fix JA, Alexander J, Cortese M, Engle K, Leppert P, Repta AJ. Short-chain alkyl esters of L-dopa as prodrugs for rectal absorption. Pharm Res. 1989;6(6):501–5. Chun IK, Lee YH, Lee KE, Gwak HS. Design and evaluation of levodopa methyl ester intranasal delivery systems. J Parkinsons Dis. 2011;1(1):101–7. Giladi NYC, Gurevich T, Djaldetti R, Adar L, Rachmilewitz Minei T, Oren S. ND0612 (levodopa/carbidopa for subcutaneous infusion) achieves stable levodopa plasma levels when administered in low and high doses in patients with PD. Mov Disord. 2017;32(Suppl 2). Caraco Y, Giladi N, Oren S, LeWitt PA. Continuous subcutaneous carbidopa improves levodopa pharmacokinetics in Parkinson’s disease patients. Mov Disord. 2012;27(Suppl 1):349. Sintov AC, Levy HV, Greenberg I. Continuous transdermal delivery of L-DOPA based on a self-assembling nanomicellar system. Pharm Res. 2017;34(7):1459–68. Lewitt PA, Ellenbogen A, Chen D, Lal R, McGuire K, Zomorodi K, et al. Actively transported levodopa prodrug XP21279: a study in patients with Parkinson disease who experience motor fluctuations. Clin Neuropharmacol. 2012;35(3):103–10. LeWitt PA, Huff FJ, Hauser RA, Chen D, Lissin D, Zomorodi K, et al. Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson’s disease. Mov Disord. 2014;29(1):75–82. Nomoto M, Nagai M, Nishikawa N, Ando R, Kagamiishi Y, Yano K, et al. Pharmacokinetics and safety/efficacy of levodopa pro-drug ONO-2160/carbidopa for Parkinson’s disease. eNeurologicalSci. 2018;13:8–13. Blindauer K, Shoulson I, Oakes D, Kieburtz K, Schwid S, Fahn S, et al. A randomized controlled trial of etilevodopa in patients with Parkinson disease who have motor fluctuations. Arch Neurol. 2006;63(2):210–6. Müller T, Kuoppamäki M, Vahteristo M, Aho V, Ellmén J, Trenkwalder C. Novel levodopa product ODM-101 vs levodopa/carbidopa/entacapone in Parkinson’s disease with response fluctuations. Mov Disord. 2013;28(Suppl 1):409. Verhagen Metman L, Stover N, Chen C, Cowles VE, Sweeney M. Gastroretentive carbidopa/levodopa, DM-1992, for the treatment of advanced Parkinson’s disease. Mov Disord. 2015;30(9):1222–8. Robakis D, Fahn S. Defining the role of the monoamine oxidase-B inhibitors for Parkinson’s disease. CNS Drugs. 2015;29(6):433–41. Blair HA, Dhillon S. Safinamide: a review in Parkinson’s disease. CNS Drugs. 2017;31(2):169–76. Schapira AH, Fox SH, Hauser RA, Jankovic J, Jost WH, Kenney C, et al. Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson disease and motor fluctuations: a randomized clinical trial. JAMA Neurol. 2017;74(2):216–24. Clarke A, Brewer F, Johnson ES, Mallard N, Hartig F, Taylor S, et al. A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition. J Neural Transm (Vienna). 2003;110(11):1241–55. Waters CH, Sethi KD, Hauser RA, Molho E, Bertoni JM, Zydis Selegiline Study G. Zydis selegiline reduces off time in Parkinson’s disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study. Mov Disord. 2004;19(4):426–32. Ondo WG, Hunter C, Isaacson SH, Silver DE, Stewart RM, Tetrud JW, et al. Tolerability and efficacy of switching from oral selegiline to Zydis selegiline in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2011;17(2):117–8. Lew MF, Pahwa R, Leehey M, Bertoni J, Kricorian G, Zydis Selegiline Study G. Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of ‘off’ episodes in patients with Parkinson’s disease. Curr Med Res Opin. 2007;23(4):741–50. Pahwa R, Tanner CM, Hauser RA, Isaacson SH, Nausieda PA, Truong DD, et al. ADS-5102 (Amantadine) extended-release capsules for levodopa-induced dyskinesia in parkinson disease (EASE LID Study): a randomized clinical trial. JAMA Neurol. 2017;74(8):941–9. Oertel W, Eggert K, Pahwa R, Tanner CM, Hauser RA, Trenkwalder C, et al. Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson’s disease (EASE LID 3). Mov Disord. 2017;32(12):1701–9. Sharma VD, Lyons KE, Pahwa R. Amantadine extended-release capsules for levodopa-induced dyskinesia in patients with Parkinson’s disease. Ther Clin Risk Manag. 2018;14:665–73. OSMOLEX ER [prescribing information]. Bridgewater NVP, LLC. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209410s000lbl.pdf. Accessed 23 Apr 2019. Kapoor R, Turjanski N, Frankel J, Kleedorfer B, Lees A, Stern G, et al. Intranasal apomorphine: a new treatment in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1990;53(11):1015. van Laar T, Jansen EN, Essink AW, Neef C. Intranasal apomorphine in parkinsonian on-off fluctuations. Arch Neurol. 1992;49(5):482–4. Dewey RB Jr, Maraganore DM, Ahlskog JE, Matsumoto JY. A double-blind, placebo-controlled study of intranasal apomorphine spray as a rescue agent for off-states in Parkinson’s disease. Mov Disord. 1998;13(5):782–7. Priano L, Albani G, Calderoni S, Baudo S, Lopiano L, Rizzone M, et al. Controlled-release transdermal apomorphine treatment for motor fluctuations in Parkinson’s disease. Neurol Sci. 2002;23(Suppl 2):S99–100. Li GL, de Vries JJ, van Steeg TJ, van den Bussche H, Maas HJ, Reeuwijk HJ, et al. Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment. J Control Release. 2005;101(1–3):199–208. Van Laar T, Jansen EN, Essink AW, Rutten WJ, Neef C. Rectal apomorphine: a new treatment modality in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1992;55(8):737–8. van Laar T, Jansen EN, Neef C, Danhof M, Roos RA. Pharmacokinetics and clinical efficacy of rectal apomorphine in patients with Parkinson’s disease: a study of five different suppositories. Mov Disord. 1995;10(4):433–9. Borkar N, Mu H, Holm R. Challenges and trends in apomorphine drug delivery systems for the treatment of parkinson’s disease. Asian J Pharm Sci. 2017;13:507–17. Grosset KA, Malek N, Morgan F, Grosset DG. Inhaled dry powder apomorphine (VR040) for ‘off’ periods in Parkinson’s disease: an in-clinic double-blind dose ranging study. Acta Neurol Scand. 2013;128(3):166–71. Manson AJ, Hanagasi H, Turner K, Patsalos PN, Carey P, Ratnaraj N, et al. Intravenous apomorphine therapy in Parkinson’s disease: clinical and pharmacokinetic observations. Brain. 2001;124(Pt 2):331–40. Katzenschlager R. A reappraisal of apomorphine. ACNR. 2015;15(5):14–6.