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Review

Istradefylline – a first generation adenosine A2A antagonist for the treatment of Parkinson’s disease

, , &
Pages 317-333 | Received 20 Nov 2020, Accepted 08 Jan 2021, Published online: 22 Feb 2021

References

  • Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and movement disorder society evidence-based medicine review: update on treatments for the motor symptoms of parkinson’s disease. Mov Disord. 2018;33:1248–1266.
  • Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease. Neurology. 2009;72:S1–136.
  • Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of parkinson’s disease. N Engl J Med. 2004;351:2498–2508.
  • Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30:80–89.
  • Gonzalez-Latapi P, Bhowmick SS, Saranza G, et al. Non-dopaminergic treatments for motor control in parkinson’s disease: an update. CNS Drugs. 2020;34:1025-1044.
  • Hung AY, Schwarzschild MA. Treatment of parkinson’s disease: what’s in the non-dopaminergic pipeline? Neurotherapeutics. 2014;11:34–46.
  • Lang AE, Obeso JA. Time to move beyond nigrostriatal dopamine deficiency in parkinson’s disease. Ann Neurol. 2004;55:761–765.
  • 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:S71–S85.
  • Obeso JA, Marin C, Rodriguez-Oroz C, et al. The basal ganglia in parkinson’s disease: current concepts and unexplained observations. Ann Neurol. 2008;64(Suppl 2):S30–46.
  • Kalia LV, Brotchie JM, Fox SH. Novel nondopaminergic targets for motor features of parkinson’s disease: review of recent trials. Mov Disord. 2013;28:131–144.
  • Duty S, Jenner P. Animal models of parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol. 2011;164:1357–1391.
  • Compta Y, Tolosa E. Anticholinergic medications. In: Koller WC, Melamed E, editors. Handbook of Clinical Neurology. Vol. 84. Amsterdam, Netherlands. Elsevier; 2007. p. 121–125.
  • Crispo JAG, Willis AW, Thibault DP, et al. Associations between anticholinergic burden and adverse health outcomes in Parkinson disease. PLoS One. 2016;11:e0150621.
  • Kong M, Ba M, Ren C, et al. An updated meta-analysis of amantadine for treating dyskinesia in parkinson’s disease. Oncotarget. 2017;8:57316–57326.
  • Amantadine and other antiglutamate agents: management of Parkinson’s disease. Mov Disord. 2002;17(Suppl 4):S13–22.
  • Pahwa R, Tanner CM, Hauser RA, 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;74:941–949.
  • Takahashi T, Yamashita H, Zhang YX, et al. Inhibitory effect of MK-801 on amantadine-induced dopamine release in the rat striatum. Brain Res Bull. 1996;41:363–367.
  • Mizoguchi K, Yokoo H, Yoshida M, et al. Amantadine increases the extracellular dopamine levels in the striatum by re-uptake inhibition and by N-methyl-D-aspartate antagonism. Brain Res. 1994;662:255–258.
  • Peeters M, Page G, Maloteaux JM, et al. Hypersensitivity of dopamine transmission in the rat striatum after treatment with the NMDA receptor antagonist amantadine. Brain Res. 2002;949:32–41.
  • Gianutsos G, Chute S, Dunn JP. Pharmacological changes in dopaminergic systems induced by long-term administration of amantadine. Eur J Pharmacol. 1985;110:357–361.
  • Elkurd MT, Bahroo LB, Pahwa R. The role of extended-release amantadine for the treatment of dyskinesia in parkinson’s disease patients. Neurodegener Dis Manage. 2018;8:73–80.
  • Bermejo PE, Anciones B. A review of the use of zonisamide in parkinson’s disease. Ther Adv Neurol Disord. 2009;2:313–317.
  • Iwaki H, Tagawa M, Iwasaki K, et al. Comparison of zonisamide with non-levodopa, anti-parkinson’s disease drugs in the incidence of parkinson’s disease-relevant symptoms. J Neurol Sci. 2019;402:145–152.
  • Sonsalla PK, Wong LY, Winnik B, et al. The antiepileptic drug zonisamide inhibits MAO-B and attenuates MPTP toxicity in mice: clinical relevance. Exp Neurol. 2010;221:329–334.
  • Yamamura S, Ohoyama K, Nagase H, et al. Zonisamide enhances delta receptor-associated neurotransmitter release in striato-pallidal pathway. Neuropharmacology. 2009;57:322–331.
  • Tohgi H, Abe T, Takahashi S. The effects of L-threo-3,4-dihydroxyphenylserine on the total norepinephrine and dopamine concentrations in the cerebrospinal fluid and freezing gait in parkinsonian patients. J Neural Transm. 1993;5:27–34.
  • Sahli ZT, Tarazi FI. Pimavanserin: novel pharmacotherapy for parkinson’s disease psychosis. Expert Opin Drug Discov. 2018;13:103–110.
  • Kianirad Y, Simuni T. Pimavanserin, a novel antipsychotic for management of parkinson’s disease psychosis. Expert Rev Clin Pharmacol. 2017;10:1161–1168.
  • Li Z, Yu Z, Zhang J, et al. Impact of rivastigmine on cognitive dysfunction and falling in parkinson’s disease patients. Eur Neurol. 2015;74:86–91.
  • Henderson EJ, Lord SR, Close JC, et al. The respond trial–rivastigmine to stabilise gait in parkinson’s disease a phase II, randomised, double blind, placebo controlled trial to evaluate the effect of rivastigmine on gait in patients with parkinson’s disease who have fallen. BMC Neurol. 2013;13:188.
  • Milardi D, Quartarone A, Bramanti A, et al. The cortico-basal ganglia-cerebellar network: past, present and future perspectives. Front Syst Neurosci. 2019;13:61.
  • Nutt JG, Bohnen NI. Non-dopaminergic therapies. J Parkinsons Dis. 2018;8:S73–S78.
  • Haskó G, Pacher P, Vizi ES, et al. Adenosine receptor signaling in the brain immune system. Trends Pharmacol Sci. 2005;26:511–516.
  • Parkinson FE, Xiong W, Zamzow CR. Astrocytes and neurons: different roles in regulating adenosine levels. Neurological Res. 2005;27:153–160.
  • Klotz KN, Hessling J, Hegler J, et al. Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells. Naunyn-Schmiedeberg’s Arch Pharmacol. 1998;357:1–9.
  • Fredholm BB, Abbracchio MP, Burnstock G, et al. Nomenclature and classification of purinoceptors. Pharmacol Rev. 1994;46:143–156.
  • Jarvis MF, Williams M. Direct autoradiographic localization of adenosine A2 receptors in the rat brain using the A2-selective agonist, [3H]CGS 21680. Eur J Pharmacol. 1989;168:243–246.
  • Rosin DL, Robeva A, Woodard RL, et al. Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J Comp Neurol. 1998;401:163–186.
  • Svenningsson P, Hall H, Sedvall G, et al. Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study. Synapse. 1997;27:322–335.
  • Ishiwata K, Mishina M, Kimura Y, et al. First visualization of adenosine A2A receptors in the human brain by positron emission tomography with [11C]TMSX. Synapse. 2005;55:133–136.
  • Ferré S, Fredholm BB, Morelli M, et al. Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci. 1997;20:482–487.
  • Mori A, Shindou T. Modulation of Gabaergic transmission in the striatopallidal system by adenosine A2A receptors: a potential mechanism for the antiparkinsonian effects of A2A antagonists. Neurology. 2003;61:S44–8.
  • Jenner P, Mori A, Hauser R, et al. Adenosine, adenosine A2A antagonists, and parkinson’s disease. Parkinsonism Relat Disord. 2009;15:406–413.
  • Cui G, Jun SB, Jin X, et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature. 2013;494:238–242.
  • Schiffmann SN, Jacobs O, Vanderhaeghen JJ. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J Neurochem. 1991;57:1062–1067.
  • Ena SL, De Backer JF, Schiffmann SN, et al. FACS array profiling identifies ecto-5ʹ nucleotidase as a striatopallidal neuron-specific gene involved in striatal-dependent learning. J Neurosci. 2013;33:8794–8809.
  • Augusto E, Matos M, Sévigny J, et al. Ecto-5ʹ-nucleotidase (CD73)-mediated formation of adenosine is critical for the striatal adenosine A2A receptor functions. J Neurosci. 2013;33:11390–11399.
  • Kuwana Y, Shiozaki S, Kanda T, et al. Antiparkinsonian activity of adenosine A2A antagonists in experimental models. Adv Neurol. 1999;80:121–123.
  • Kanda T, Jackson MJ, Smith LA, et al. Combined use of the adenosine A2A antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp Neurol. 2000;162:321–327.
  • Hodgson RA, Bertorelli R, Varty GB, et al. Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression. J Pharmacol Exp Ther. 2009;330:294–303.
  • Hauser RA, Cantillon M, Pourcher E, et al. Preladenant in patients with parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol. 2011;10:221–229.
  • Factor SA, Wolski K, Togasaki DM, et al. Long-term safety and efficacy of preladenant in subjects with fluctuating Parkinson’s disease. Mov Disord. 2013;28:817–820.
  • Michel A, Downey P, Van Damme X, et al. Behavioural assessment of the A2A/NR2B combination in the unilateral 6-OHDA-lesioned rat model: a new method to examine the therapeutic potential of non-dopaminergic drugs. PLoS One. 2015;10:e0135949.
  • Michel A, Nicolas JM, Rose S, et al. Antiparkinsonian effects of the “Radiprodil and Tozadenant” combination in MPTP-treated marmosets. PLoS One. 2017;12:e0182887.
  • Hauser RA, Olanow CW, Kieburtz KD, et al. Tozadenant (SYN115) in patients with parkinson’s disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol. 2014;13:767–776.
  • Papapetropoulos S, Borgohain R, Kellett M, et al. The adenosine A2A receptor antagonist BIIB014 is effective in improving ON-time in parkinson’s disease (PD) patients with motor fluctuations. Mov Disord. 2010;25(Suppl 2):S305.
  • Pinna A, Pontis S, Borsini F, et al. Adenosine A2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6-hydroxydopamine rat model of parkinson’s disease. Synapse. 2007;61:606–614.
  • Pinna A. Adenosine A2A receptor antagonists in parkinson’s disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs. 2014;28:455–474.
  • Aoyama S, Kase H, Borrelli E. Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. J Neurosci. 2000;20:5848–5852.
  • Ochi M, Shiozaki S, Kase H. Adenosine A2A receptor-mediated modulation of GABA and glutamate release in the output regions of the basal ganglia in a rodent model of parkinson’s disease. Neuroscience. 2004;127:223–231.
  • Mori A. Chapter four - mode of action of adenosine A2a receptor antagonists as symptomatic treatment for parkinson’s disease. In: Mori A, editor. International Review of Neurobiology. Vol. 119. London, UK. Academic Press; 2014. p. 87–116.
  • Mori A. How do adenosine A(2A) receptors regulate motor function? Parkinsonism Relat Disord. 2020;80(Suppl 1):S13–s20.
  • Canals M, Marcellino D, Fanelli F, et al. Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem. 2003;278:46741–46749.
  • Fuxe K, Ferre S, Canals M, et al. Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function. J Mol Neurosci. 2005;26:209–220.
  • Chen JF, Moratalla R, Impagnatiello F, et al. The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice. Proc Natl Acad Sci USA. 2001;98:1970–1975.
  • Ramlackhansingh AF, Bose SK, Ahmed I, et al. Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology. 2011;76:1811–1816.
  • Mishina M, Ishiwata K, Naganawa M, et al. Adenosine A2A receptors measured with [C]TMSX PET in the striata of parkinson’s disease patients. PLoS One. 2011;6:e17338–e17338.
  • Hettinger BD, Lee A, Linden J, et al. Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of gabaergic neurons in rat striatum. J Comp Neurol. 2001;431:331–346.
  • Corsi C, Melani A, Bianchi L, et al. Striatal A2A adenosine receptor antagonism differentially modifies striatal glutamate outflow in vivo in young and aged rats. Neuroreport. 2000;11:2591–2595.
  • Corsi C, Melani A, Bianchi L, et al. Striatal A2A adenosine receptors differentially regulate spontaneous and K+-evoked glutamate release in vivo in young and aged rats. Neuroreport. 1999;10:687–691.
  • Preston Z, Lee K, Widdowson L, et al. Adenosine receptor expression and function in rat striatal cholinergic interneurons. Br J Pharmacol. 2000;130:886–890.
  • Richardson PJ, Dixon AK, Lee K, et al. Correlating physiology with gene expression in striatal cholinergic neurones. J Neurochem. 2000;74:839–846.
  • Tozzi A, de Iure A, Di Filippo M, et al. The distinct role of medium spiny neurons and cholinergic interneurons in the D₂/A₂A receptor interaction in the striatum: implications for parkinson’s disease. J Neurosci. 2011;31:1850–1862.
  • Schiffmann SN, Libert F, Vassart G, et al. Distribution of adenosine A2 receptor mRNA in the human brain. Neurosci Lett. 1991;130:177–181.
  • Fink JS, Weaver DR, Rivkees SA, et al. Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Brain Res Mol Brain Res. 1992;14:186–195.
  • Augood SJ, Emson PC. Adenosine A2A receptor mRNA is expressed by enkephalin cells but not by somatostatin cells in rat striatum: a co-expression study. Brain Res Mol Brain Res. 1994;22:204–210.
  • Svenningsson P, Le Moine C, Aubert I, et al. Cellular distribution of adenosine A2A receptor mRNA in the primate striatum. J Comp Neurol. 1998;399:229–240.
  • Obeso JA, Rodriguez-Oroz MC, Rodriguez M, et al. Pathophysiology of the basal ganglia in parkinson’s disease. Trends Neurosci. 2000;23:S8–19.
  • Schiffmann SN, Fisone G, Moresco R, et al. Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol. 2007;83:277–292.
  • Calon F, Dridi M, Hornykiewicz O, et al. Increased adenosine A2A receptors in the brain of parkinson’s disease patients with dyskinesias. Brain. 2004;127:1075–1084.
  • Mishina M, Ishiwata K. Adenosine receptor PET imaging in human brain. Int Rev Neurobiol. 2014;119:51–69.
  • Correa M, Wisniecki A, Betz A, et al. The adenosine A2A antagonist KF17837 reverses the locomotor suppression and tremulous jaw movements induced by haloperidol in rats: possible relevance to parkinsonism. Behav Brain Res. 2004;148:47–54.
  • Shiozaki S, Ichikawa S, Nakamura J, et al. Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP. Psychopharmacol (Berl). 1999;147:90–95.
  • Hauber W, Neuscheler P, Nagel J, et al. Catalepsy induced by a blockade of dopamine D1 or D2 receptors was reversed by a concomitant blockade of adenosine A2A receptors in the caudate-putamen of rats. Eur J Neurosci. 2001;14:1287–1293.
  • Salamone JD. Preladenant, a novel adenosine A2A receptor antagonist for the potential treatment of parkinsonism and other disorders. Drugs. 2010;13:723–731.
  • Collins LE, Sager TN, Sams AG, et al. The novel adenosine A2A antagonist Lu AA47070 reverses the motor and motivational effects produced by dopamine D2 receptor blockade. Pharmacol Biochem Behavior. 2012;100:498–505.
  • Kanda T, Shiozaki S, Shimada J, et al. KF17837: a novel selective adenosine A2A receptor antagonist with anticataleptic activity. Eur J Pharmacol. 1994;256:263–268.
  • Rose S, Ramsay Croft N, Jenner P. The novel adenosine A2A antagonist ST1535 potentiates the effects of a threshold dose of l-dopa in unilaterally 6-OHDA-lesioned rats. Brain Res. 2007;1133:110–114.
  • Koga K, Kurokawa M, Ochi M, et al. Adenosine A2A receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats. Eur J Pharmacol. 2000;408:249–255.
  • Fenu S, Pinna A, Ongini E, et al. Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats. Eur J Pharmacol. 1997;321:143–147.
  • Ferré S, Rubio A, Fuxe K. Stimulation of adenosine A2 receptors induces catalepsy. Neurosci Lett. 1991;130:162–164.
  • Rose S, Jackson MJ, Smith LA, et al. The novel adenosine A2A receptor antagonist ST1535 potentiates the effects of a threshold dose of L-DOPA in MPTP treated common marmosets. Eur J Pharmacol. 2006;546:82–87.
  • Grondin R, Bedard PJ, Hadj Tahar A, et al. Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys. Neurology. 1999;52:1673–1677.
  • Hodgson RA, Bedard PJ, Varty GB, et al. Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders. Exp Neurol. 2010;225:384–390.
  • Kanda T, Tashiro T, Kuwana Y, et al. Adenosine A2A receptors modify motor function in MPTP-treated common marmosets. Neuroreport. 1998;9:2857–2860.
  • Kanda T, Jackson MJ, Smith LA, et al. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol. 1998;43:507–513.
  • Uchida S, Tashiro T, Kawai-Uchida M, et al. Adenosine A2A-receptor antagonist istradefylline enhances the motor response of L-DOPA without worsening dyskinesia in MPTP-treated common marmosets. J Pharmacol Sci. 2014;124:480–485.
  • Uchida S, Soshiroda K, Okita E, et al. The adenosine A2A receptor antagonist, istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets. Eur J Pharmacol. 2015;766:25–30.
  • Jones N, Bleickardt C, Mullins D, et al. A2A receptor antagonists do not induce dyskinesias in drug-naive or L-dopa sensitized rats. Brain Res Bull. 2013;98:163–169.
  • Tronci E, Simola N, Borsini F, et al. Characterization of the antiparkinsonian effects of the new adenosine A2A receptor antagonist ST1535: acute and subchronic studies in rats. Eur J Pharmacol. 2007;566:94–102.
  • Lundblad M, Vaudano E, Cenci MA. Cellular and behavioural effects of the adenosine A2A receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia. J Neurochem. 2003;84:1398–1410.
  • Bibbiani F, Oh JD, Petzer JP, et al. A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson’s disease. Exp Neurol. 2003;184:285–294.
  • Jenner P. Istradefylline, a novel adenosine A2A receptor antagonist, for the treatment of Parkinson’s disease. Expert Opin Invest Drugs. 2005;14:729–738.
  • Dungo R, Deeks ED. Istradefylline: first global approval. Drugs. 2013;73:875–882.
  • Saki M, Yamada K, Koshimura E, et al. In vitro pharmacological profile of the A2A receptor antagonist istradefylline. Naunyn Schmiedebergs Arch Pharmacol. 2013;386:963–972.
  • Bekar L, Libionka W, Tian GF, et al. Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor. Nat Med. 2008;14:75–80.
  • Boswell-Smith V, Spina D, Page CP. Phosphodiesterase inhibitors. Brit J Pharmacol. 2006;147(Suppl 1):S252–S257.
  • Knebel W, Rao N, Uchimura T, et al. Population pharmacokinetic analysis of istradefylline in healthy subjects and in patients with parkinson’s disease. J Clin Pharmacol. 2011;51:40–52.
  • Müller T. Suitability of the adenosine antagonist istradefylline for the treatment of parkinson’s disease: pharmacokinetic and clinical considerations. Expert Opin Drug Metab Toxicol. 2013;9:1015–1024.
  • NOURIANZ™ (istradefylline) tablets, for oral use. US Prescribing information. Available at https://www.nourianz.com/assets/pdf/nourianz-full-prescribing-information.pdf. Last accessed February 1, 2021.
  • Hauser RA, Hubble JP, Truong DD. Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD. Neurology. 2003;61:297–303. .
  • Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A2A receptor antagonist treatment of parkinson’s disease. Neurology. 2003;61:293–296.
  • Poewe W. The role of COMT inhibition in the treatment of parkinson’s disease. Neurology. 2004;62:S31–8.
  • Hauser RA, Friedlander J, Zesiewicz TA, et al. A home diary to assess functional status in patients with parkinson’s disease with motor fluctuations and dyskinesia. Clin Neuropharmacol. 2000;23:75–81.
  • Fernandez HH, Greeley DR, Zweig RM, et al. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord. 2010;16:16–20.
  • LeWitt PA, Guttman M, Tetrud JW, et al. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces “off” time in parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol. 2008;63:295–302.
  • Stacy M, Silver D, Mendis T, et al. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology. 2008;70(23):2233–2240. .
  • Hauser RA, Shulman LM, Trugman JM, et al. Study of istradefylline in patients with parkinson’s disease on levodopa with motor fluctuations. Mov Disord. 2008;23:2177–2185.
  • Pourcher E, Fernandez HH, Stacy M, et al. Istradefylline for Parkinson’s disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Parkinsonism Related Disord. 2012;18(2):178–184. .
  • Kyowa Hakko Kirin UK L. A 16-week, Double-Blind, Placebo-Controlled, Randomised, Parallel-Group, Multicentre, International Study to Evaluate the Efficacy and Safety of 40 mg/Day KW-6002 (Istradefylline) and That of Entacapone Versus Placebo as Treatment for Parkinson’s Disease in Patients With Motor Response Complications on Levodopa Therapy. 2005. Available from: https://clinicaltrials.gov/ct2/show/study/NCT00199394. Last accessed February 1, 2021.
  • Mizuno Y, Hasegawa K, Kondo T, et al. Clinical efficacy of istradefylline (KW-6002) in parkinson’s disease: a randomized, controlled study. Mov Disord. 2010;25:1437–1443.
  • Mizuno Y, Kondo T. Japanese istradefylline study g. adenosine A2A receptor antagonist istradefylline reduces daily OFF time in parkinson’s disease. Mov Disord. 2013;28:1138–1141.
  • Kyowa Hakko Kirin Pharma I. A Phase 3, 12-week, Double-Blind, Placebo-Controlled, Randomized, Multicenter Study to Evaluate the Efficacy of Oral Istradefylline 20 and 40 mg/Day as Treatment for Subjects With Moderate to Severe Parkinson’s Disease 2016. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01968031. Last accessed February 1, 2021.
  • Kondo T, Mizuno Y. A long-term study of istradefylline safety and efficacy in patients with Parkinson disease. Clin Neuropharmacol. 2015;38:41–46.
  • Factor S, Mark MH, Watts R, et al. A long-term study of istradefylline in subjects with fluctuating parkinson’s disease. Parkinsonism Related Disord. 2010;16:423–426.
  • Center for drug evaluation and research. Clinical Review: NDA 022075. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022075Orig1s000MedR.pdf. Last accessed November 2020. Last accessed February 1, 2021.
  • Takahashi M, Fujita M, Asai N, et al. Safety and effectiveness of istradefylline in patients with parkinson’s disease: interim analysis of a post-marketing surveillance study in japan. Expert Opin Pharmacother. 2018;19:1635–1642.
  • Kyowa Hakko Kirin Co. L. Kyowa Hakko Kirin Initiates a Global Phase 3 Trial of Istradefylline (KW-6002) for Parkinson’s Disease 2013. Available from: https://www.kyowakirin.com/media_center/news_releases/2013/e20131121_01.html. Last accessed February 1, 2021.
  • Kyowa Hakko Kirin Announces Top-Line Results of Global Phase 3 Trial of KW-6002 (Istradefylline) for Parkinson’s Disease [Internet]. 2016; December 13. Available from: https://www.kyowakirin.com/media_center/news_releases/2016/pdf/e20161213_01.pdf. Last accessed Jan 2021.
  • Lewitt P, Aradi S, Hauser RA, et al. The challenge of developing adenosine A2 A antagonists for Parkinson disease: istradefylline, preladenant, and tozadenant. Parkinsonism Relat Disord. 2020;80(Supp 1):S54–S63.
  • Hauser RA, Stocchi F, Rascol O, et al. Preladenant as an adjunctive therapy with levodopa in Parkinson disease: two randomized clinical trials and lessons learned. JAMA Neurol. 2015;72:1491–1500.
  • Center for drug evaluation and research. Summary Review: 022075Orig1s000. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022075Orig1s000SumR.pdf. Last accessed February 1, 2021.
  • Kyowa Kirin Announces FDA Approval of NOURIANZ™ (istradefylline) for Use in Parkinson’s Disease [Internet]. 2019; August 28. Available from: https://www.kyowakirin.com/media_center/news_releases/2019/e20190828_01.html. Last accessed Jan 2021.
  • Kyowa Kirin Announces Marketing Authorisation Application for Istradefylline Validated by European Medicines Agency. Available at https://www.kyowakirin.com/media_center/news_releases/2020/e20200106_01.html. Last accessed February 1, 2021.
  • Jenner P, Mori A, Kanda T. Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson’s disease? Parkinsonism Relat Disord. 2020;80(Supp 1):S28–S36.
  • Abe K, Fujita M, Yoshikawa H. Effectiveness of istradefylline for fatigue and quality of life in parkinson’s disease patients’ and of their caregivers’. Adv Parkinsons Dis. 2016;5:24–28.
  • Nagayama H, Kano O, Murakami H, et al. Effect of istradefylline on mood disorders in Parkinson’s disease. J Neurol Sci. 2019;396:78–83.
  • Ito H, Fukutake S, Kamei T, et al. Clinical efficacy of istradefylline for depression in parkinson’s disease. J Neurol Neurosci. 2018;9:261.
  • Kitta T, Yabe I, Kanno Y, et al. Long-term outcome of adenosine A2a receptor antagonist on lower urinary tract symptoms in male Parkinson disease patients. Clin Neuropharmacol. 2018;41:98–102.
  • Kitta T, Yabe I, Takahashi I, et al. Clinical efficacy of istradefylline on lower urinary tract symptoms in parkinson’s disease. Int J Urol. 2016;23:893–894.
  • Matsuura K, Kajikawa H, Tabei KI, et al. The effectiveness of istradefylline for the treatment of gait deficits and sleepiness in patients with parkinson’s disease. Neurosci Lett. 2018;662:158–161.
  • Suzuki K, Miyamoto M, Miyamoto T, et al. Istradefylline improves daytime sleepiness in patients with parkinson’s disease: an open-label, 3-month study. J Neurol Sci. 2017;380:230–233.
  • Suzuki K, Miyamoto T, Miyamoto M, et al. Could istradefylline be a treatment option for postural abnormalities in mid-stage parkinson’s disease? J Neurol Sci. 2018;385:131–133.
  • Iijima M, Orimo S, Terashi H, et al. Efficacy of istradefylline for gait disorders with freezing of gait in parkinson’s disease: a single-arm, open-label, prospective, multicenter study. Exp Opin Pharmacother. 2019;20:1405–1411.
  • Fujioka S, Yoshida R, Nose K, et al. A new therapeutic strategy with istradefylline for postural deformities in parkinson’s disease. Neurol Neurochir Pol. 2019;53:291–295.
  • Kataoka H, Sugie K. Does istradefylline really have a dystonic mechanism? J Neurol Sci. 2018;388:233–234.
  • Huang ZL, Zhang Z, Qu WM. Roles of adenosine and its receptors in sleep-wake regulation. Int Rev Neurobiol. 2014;119:349–371.
  • French IT, Muthusamy KA. A review of the pedunculopontine nucleus in parkinson’s disease. Front Aging Neurosci. 2018;10:99.
  • Chaudhuri KR, Yates L, Martinez-Martin P. The non-motor symptom complex of parkinson’s disease: a comprehensive assessment is essential. Curr Neurol Neurosci Rep. 2005;5:275–283.
  • Mitchell SL, Harper DW, Lau A, et al. Patterns of outcome measurement in parkinson’s disease clinical trials. Neuroepidemiology. 2000;19:100–108.
  • Kyowa Kirin Announces Positive Phase 2b Results for KW-6356 in Patients with Parkinson’s Disease [Internet]. 2020. Available from: https://www.kyowakirin.com/media_center/news_releases/2020/pdf/e20201021_01.pdf. Last accessed February 1, 2021.
  • Hong CT, Chan L, Bai C-H. The effect of caffeine on the risk and progression of parkinson’s disease: a meta-analysis. Nutrients. 2020;12:1860.
  • Ikeda K, Kurokawa M, Aoyama S, et al. Neuroprotection by adenosine A2A receptor blockade in experimental models of parkinson’s disease. J Neurochem. 2002;80:262–270.
  • Cunha RA. Neuroprotection by adenosine in the brain: from A1 receptor activation to A2A receptor blockade. Purinergic Sig. 2005;1:111–134.
  • Kachroo A, Schwarzschild MA. Adenosine A2A receptor gene disruption protects in an alpha-synuclein model of parkinson’s disease. Ann Neurol. 2012;71:278–282.
  • Hu QD, Ren XP, Liu Y, et al. Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy. Exp Neurol. 2016;283:213–223.
  • Chen JF, Schwarzschild MA. Do caffeine and more selective adenosine A2A receptor antagonists protect against dopaminergic neurodegeneration in parkinson’s disease? Parkinsonism Relat Disord. 2020;80(Supp 1):S45–S53.
  • Dai SS, Zhou YG, Li W, et al. Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J Neurosci. 2010;30:5802–5810.
  • Brambilla R, Cottini L, Fumagalli M, et al. Blockade of A2A adenosine receptors prevents basic fibroblast growth factor-induced reactive astrogliosis in rat striatal primary astrocytes. Glia. 2003;43:190–194.
  • Boison D, Chen JF, Fredholm BB. Adenosine signaling and function in glial cells. Cell Death Diff. 2010;17:1071–1082.
  • Hui CW, Zhang Y, Herrup K. Non-neuronal cells are required to mediate the effects of neuroinflammation: results from a neuron-enriched culture system. PLoS One. 2016;11:e0147134.
  • Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003;278:25009–25013.
  • Cuervo AM, Stefanis L, Fredenburg R, et al. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004;305:1292–1295.
  • Sinha RA, Farah BL, Singh BK, et al. Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology. 2014;59:1366–1380.
  • Liu YW, Yang T, Zhao L, et al. Activation of Adenosine 2A receptor inhibits neutrophil apoptosis in an autophagy-dependent manner in mice with systemic inflammatory response syndrome. Sci Rep. 2016;6:33614.
  • Ferreira DG, Batalha VL, Vicente Miranda H, et al. Adenosine A2A receptors modulate alpha-synuclein aggregation and toxicity. Cereb Cortex. 2017;27:718–730.
  • Orr AG, Hsiao EC, Wang MM, et al. Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat Neurosci. 2015;18:423–434.
  • Orr AG, Lo I, Schumacher H, et al. Istradefylline reduces memory deficits in aging mice with amyloid pathology. Neurobiol Dis. 2018;110:29–36.
  • Pierri M, Vaudano E, Sager T, et al. KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse. Neuropharmacology. 2005;48:517–524.
  • Chen JF, Xu K, Petzer JP, et al. Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of parkinson’s disease. J Neurosci. 2001;21:Rc143.