The Role of Monoamine Oxidase B Inhibitors in the Treatment of Parkinson’s
Disease - An Update

Zhi   Xin   Chew; Chooi   Ling   Lim; Khuen   Yen   Ng; Soi   Moi   Chye; Anna   Pick Kiong   Ling; Rhun   Yian   Koh
doi:10.2174/1871527321666211231100255
Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterised by reduced dopamine levels in the substantial nigra. This may lead to typical motor features such as bradykinesia, resting tremors and rigid muscles, as well as non-motor symptoms such as neuropsychiatric symptoms, sleep disorders, autonomic dysfunction, and sensory disturbances. Inhibitors of monoamine oxidase B (MAO-B) are used to alleviate symptoms by reducing monoamine oxidase-catalysed degradation of dopamine; hence, preserving functional levels of dopamine. The very first MAO-B inhibitor used therapeutically was selegiline, followed by rasagiline, its indane derivative which has superior efficacy and selectivity. Both inhibitors can be used as monotherapy or in combination with other anti- Parkinson drugs. Safinamide, a reversible MAO-B inhibitor that utilises both dopaminergic and non-dopaminergic mechanisms, was recently approved by the European Medicines Agency (EMA) (2015) and U.S. FDA (2017) as an add-on therapy for patients with mid- or late-stage Parkinson’s disease. Furthermore, MAO-B inhibitors were found to be associated with potential neuroprotective and disease modifying effects. However, evidence of their efficacy and role in PD models is scarce and warrants further investigation.
Keywords: Parkinson’s disease, monoamine oxidase B inhibitor, selegiline, rasagiline, safinamide, neuroprotective.
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[1]
Jost WH, Reichmann H. “An essay on the shaking palsy” 200 years old. Vol. 124. J Neural Transm (Vienna)  2017; 124: 899-900.
 [http://dx.doi.org/10.1007/s00702-017-1684-0]

[2]
Bereczki D. The description of all four cardinal signs of Parkinson’s disease in a Hungarian medical text published in 1690. Parkinsonism Relat Disord  2010; 16(4): 290-3.
 [http://dx.doi.org/10.1016/j.parkreldis.2009.11.006] [PMID: 19948422]

[3]
Teo KC, Ho SL. Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease. Transl Neurodegener  2013; 2(1): 19.
 [http://dx.doi.org/10.1186/2047-9158-2-19] [PMID: 24011391]

[4]
Moustafa AA, Chakravarthy S, Phillips JR, et al. Motor symptoms in Parkinson’s disease: A unified framework.  Neurosci Biobehav Rev.   2016; 68: pp. 727-40.

[5]
Elbaz A, Carcaillon L, Kab S, Moisan F. Epidemiology of Parkinson’s disease. Rev Neurol (Paris)  2016; 172(1): 14-26.
 [http://dx.doi.org/10.1016/j.neurol.2015.09.012] [PMID: 26718594]

[6]
Pringsheim T, Jette N, Frolkis A, Steeves TDL. The prevalence of Parkinson’s disease: A systematic review and meta-analysis. Mov Disord  2014; 29(13): 1583-90.
 [http://dx.doi.org/10.1002/mds.25945] [PMID: 24976103]

[7]
Simon DK, Tanner CM, Brundin P. Parkinson disease epidemiology, pathology, genetics, and pathophysiology. Clin Geriatr Med  2020; 36(1): 1-12.
 [http://dx.doi.org/10.1016/j.cger.2019.08.002] [PMID: 31733690]

[8]
Ray Dorsey E, Elbaz A, Nichols E, et al. GBD 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s disease, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol  2018; 17(11): 939-53.
 [http://dx.doi.org/10.1016/S1474-4422(18)30295-3] [PMID: 30287051]

[9]
Wanneveich M, Moisan F, Jacqmin-Gadda H, Elbaz A, Joly P. Projections of prevalence, lifetime risk, and life expectancy of Parkinson’s disease (2010-2030) in France. Mov Disord  2018; 33(9): 1449-55.
 [http://dx.doi.org/10.1002/mds.27447] [PMID: 30145805]

[10]
Rossi A, Berger K, Chen H, Leslie D, Mailman RB, Huang X. Projection of the prevalence of Parkinson’s disease in the coming decades: Revisited. Mov Disord  2018; 33(1): 156-9.
 [http://dx.doi.org/10.1002/mds.27063] [PMID: 28590580]

[11]
Dorsey ER, Sherer T, Okun MS, Bloem BR. The emerging evidence of the Parkinson pandemic. J Parkinsons Dis  2018; 8(s1): S3-8.
 [http://dx.doi.org/10.3233/JPD-181474] [PMID: 30584159]

[12]
Javadzadeh Y, Hamedeyaz S. Floating drug delivery systems for eradication of Helicobacter pylori in treatment of peptic ulcer disease. Trends Helicobacter pylori Infect  2014; i: 13.
 [http://dx.doi.org/10.5772/57353]

[13]
Marras C, Canning CG, Goldman SM. Environment, lifestyle, and Parkinson’s disease: Implications for prevention in the next decade. Mov Disord  2019; 34(6): 801-11.
 [http://dx.doi.org/10.1002/mds.27720] [PMID: 31091353]

[14]
Hindle JV. Ageing, neurodegeneration and Parkinson’s disease. Age Ageing  2010; 39(2): 156-61.
 [http://dx.doi.org/10.1093/ageing/afp223] [PMID: 20051606]

[15]
Schapira AHV. Present and future drug treatment for Parkinson’s disease. J Neurol Neurosurg Psychiatry  2005; 76(11): 1472-8.
 [http://dx.doi.org/10.1136/jnnp.2004.035980] [PMID: 16227533]

[16]
Vaubel RA, Raghunathan A, Erickson LA. Parkinson disease. Mayo Clin Proc  2016; 91(11): e155-6.
 [http://dx.doi.org/10.1016/j.mayocp.2016.06.017] [PMID: 27814845]

[17]
Oertel W, Schulz JB. Current and experimental treatments of Parkinson disease: A guide for neuroscientists  J Neurochem  2016; 139: 325-37.

[18]
Oertel WH. Recent advances in treating Parkinson’s disease. F1000 Res  2017; 6: 260.
 [http://dx.doi.org/10.12688/f1000research.10100.1] [PMID: 28357055]

[19]
Lee DJ, Dallapiazza RF, De Vloo P, Lozano AM. Current surgical treatments for Parkinson’s disease and potential therapeutic targets. Neural Regen Res  2018; 13(8): 1342-5.
 [http://dx.doi.org/10.4103/1673-5374.235220] [PMID: 30106037]

[20]
Dolhun R. Levodopa 2.0: New Strategies to Even Out the Peaks and Valleys. Pract Neurol  2015; 2015: 26-9.

[21]
Poewe W, Antonini A, Zijlmans JC, Burkhard PR, Vingerhoets F. Levodopa in the treatment of Parkinson’s disease: An old drug still going strong. Clin Interv Aging  2010; 5: 229-38.
 [PMID: 20852670]

[22]
Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P. Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: A randomised, double-blind, controlled trial. Lancet Neurol  2016; 15(2): 154-65.
 [http://dx.doi.org/10.1016/S1474-4422(15)00336-1] [PMID: 26725544]

[23]
Watts RL, Lyons KE, Pahwa R, et al. 228 Study Investigators. Onset of dyskinesia with adjunct ropinirole prolonged-release or additional levodopa in early Parkinson’s disease. Mov Disord  2010; 25(7): 858-66.
 [http://dx.doi.org/10.1002/mds.22890] [PMID: 20461803]

[24]
Warren Olanow C, Kieburtz K, Rascol O, et al. Stalevo Reduction in Dyskinesia Evaluation in Parkinson’s Disease (STRIDE-PD) Investigators. Factors predictive of the development of Levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord  2013; 28(8): 1064-71.
 [http://dx.doi.org/10.1002/mds.25364] [PMID: 23630119]

[25]
Zhu H, Lemos H, Bhatt B, et al. Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity. PLoS One  2017; 12(9): e0183484.
 [http://dx.doi.org/10.1371/journal.pone.0183484] [PMID: 28898256]

[26]
Saunders JAH, Estes KA, Kosloski LM, et al. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J Neuroimmune Pharmacol  2012; 7(4): 927-38.
 [http://dx.doi.org/10.1007/s11481-012-9402-z] [PMID: 23054369]

[27]
Kustrimovic N, Comi C, Magistrelli L, et al. Parkinson’s disease patients have a complex phenotypic and functional Th1 bias: Cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug- naïve and drug-treated patients. J Neuroinflammation  2018; 15(1): 205.
 [http://dx.doi.org/10.1186/s12974-018-1248-8] [PMID: 30001736]

[28]
Wang L, Li J, Chen J. Levodopa-carbidopa intestinal gel in parkinson’s disease: a systematic review and meta-analysis. Front Neurol  2018; 9: 620.
 [http://dx.doi.org/10.3389/fneur.2018.00620]

[29]
Othman AA, Rosebraugh M, Chatamra K, Locke C, Dutta S. Levodopa-carbidopa intestinal gel pharmacokinetics: Lower variability than oral levodopa-carbidopa. J Parkinsons Dis  2017; 7(2): 275-8.
 [http://dx.doi.org/10.3233/JPD-161042] [PMID: 28211816]

[30]
Koller WC, Stern MB, Watts R. The evolving role of monoamine oxidase inhibitors in the treatment of Parkinson’s disease. Neurology  2004; 63(7) (Suppl. 2): 1-3.
 [http://dx.doi.org/10.1212/WNL.63.7_suppl_2.S1]

[31]
Robakis D, Fahn S. Defining the role of the monoamine oxidase-B inhibitors for Parkinson’s disease. CNS Drugs  2015; 29(6): 433-41.
 [http://dx.doi.org/10.1007/s40263-015-0249-8] [PMID: 26164425]

[32]
Dezsi L, Vecsei L. Monoamine oxidase B inhibitors in Parkinson’s disease. CNS Neurol Disord Drug Targets  2017; 16(4): 425-39.
 [http://dx.doi.org/10.2174/1871527316666170124165222] [PMID: 28124620]

[33]
Riederer P, Müller T. Monoamine oxidase-B inhibitors in the treatment of Parkinson’s disease: Clinical-pharmacological aspects. J Neural Transm (Vienna)  2018; 125(11): 1751-7.
 [http://dx.doi.org/10.1007/s00702-018-1876-2] [PMID: 29569037]

[34]
National Center for Biotechnology Information (NCBI). MAOB: Monoamine oxidase B – Homo sapiens 2015.  Available from: https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=4129

[35]
Johnston JP. Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol  1968; 17(7): 1285-97.
 [http://dx.doi.org/10.1016/0006-2952(68)90066-X] [PMID: 5659776]

[36]
Tong J, Meyer JH, Furukawa Y, et al. Distribution of monoamine oxidase proteins in human brain: Implications for brain imaging studies. J Cereb Blood Flow Metab  2013; 33(6): 863-71.
 [http://dx.doi.org/10.1038/jcbfm.2013.19] [PMID: 23403377]

[37]
Chamoli M, Chinta SJ, Andersen JK. An inducible MAO-B mouse model of Parkinson’s disease: A tool towards better understanding basic disease mechanisms and developing novel therapeutics. J Neural Transm (Vienna)  2018; 125(11): 1651-8.
 [http://dx.doi.org/10.1007/s00702-018-1887-z] [PMID: 29713806]

[38]
Duncan J, Johnson S, Ou XM. Monoamine oxidases in major depressive disorder and alcoholism. Drug Discov Ther  2012; 6(3): 112-22.
 [http://dx.doi.org/10.5582/ddt.2012.v6.3.112] [PMID: 22890201]

[39]
Crispo JAG, Willis AW, Thibault DP, et al. Associations between anticholinergic burden and adverse health outcomes in Parkinson disease. PLoS One  2016; 11(3): e0150621.
 [http://dx.doi.org/10.1371/journal.pone.0150621] [PMID: 26939130]

[40]
Levitt P, Pintar JE, Breakefield XO. Immunocytochemical demonstration of monoamine oxidase B in brain astrocytes and serotonergic neurons. Proc Natl Acad Sci U S A  1982; 79(20 I): 6385-9.
 [http://dx.doi.org/10.1073/pnas.79.20.6385]

[41]
Chen Q, Xu Y, Zhang H, Tan X, Liu SH, Yan F. Immunocytochemical localization of monoamine oxidase type B in rat’s peripheral nervous system. J Biochem Mol Toxicol  2015; 29(11): 521-5.
 [http://dx.doi.org/10.1002/jbt.21722] [PMID: 26098618]

[42]
Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: Substantia nigra regional selectivity. Brain  1991; 114(Pt 5): 2283-301.
 [http://dx.doi.org/10.1093/brain/114.5.2283] [PMID: 1933245]

[43]
Fowler JS, Volkow ND, Wang GJ, et al. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging  1997; 18(4): 431-5.
 [http://dx.doi.org/10.1016/S0197-4580(97)00037-7] [PMID: 9330975]

[44]
Tong J, Rathitharan G, Meyer JH, et al. Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders. Brain  2017; 140(9): 2460-74.
 [http://dx.doi.org/10.1093/brain/awx172] [PMID: 29050386]

[45]
Riederer P, Laux G. MAO-inhibitors in Parkinson’s disease. Exp Neurobiol  2011; 20(1): 1-17.
 [http://dx.doi.org/10.5607/en.2011.20.1.1] [PMID: 22110357]

[46]
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): 1254-63.
 [http://dx.doi.org/10.1007/s00415-017-8523-y] [PMID: 28550482]

[47]
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.
 [http://dx.doi.org/10.1007/s00702-014-1362-4] [PMID: 25604428]

[48]
Mallajosyula JK, Kaur D, Chinta SJ, et al. MAO-B elevation in mouse brain astrocytes results in Parkinson’s pathology. PLoS One  2008; 3(2): e1616.
 [http://dx.doi.org/10.1371/journal.pone.0001616] [PMID: 18286173]

[49]
Savica R, Grossardt BR, Bower JH, Ahlskog JE, Rocca WA. Time trends in the incidence of parkinson disease. JAMA Neurol  2016; 73(8): 981-9.
 [http://dx.doi.org/10.1001/jamaneurol.2016.0947] [PMID: 27323276]

[50]
Nagatsu T, Sawada M. Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson’s disease: Possible implications of glial cells. J Neural Transm Suppl  2006; (71): 53-65.
 [http://dx.doi.org/10.1007/978-3-211-33328-0_7] [PMID: 17447416]

[51]
Radad K, Rausch WD, Gille G. Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respiration. Neurochem Int  2006; 49(4): 379-86.
 [http://dx.doi.org/10.1016/j.neuint.2006.02.003] [PMID: 16580092]

[52]
Kaludercic N, Carpi A, Nagayama T, et al. Monoamine oxidase B prompts mitochondrial and cardiac dysfunction in pressure overloaded hearts. Antioxid Redox Signal  2014; 20(2): 267-80.
 [http://dx.doi.org/10.1089/ars.2012.4616] [PMID: 23581564]

[53]
Noda S, Sato S, Fukuda T, Tada N, Hattori N. Aging-related motor function and dopaminergic neuronal loss in C57BL/6 mice. Mol Brain  2020; 13(1): 46.
 [http://dx.doi.org/10.1186/s13041-020-00585-6] [PMID: 32293495]

[54]
Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC. Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature  1984; 311(5985): 467-9.
 [http://dx.doi.org/10.1038/311467a0] [PMID: 6332989]

[55]
Hussain AM, Renno WM, Sadek HL, et al. Monoamine oxidase-B inhibitor protects degenerating spinal neurons, enhances nerve regeneration and functional recovery in sciatic nerve crush injury model. Neuropharmacology  2018; 128: 231-43.
 [http://dx.doi.org/10.1016/j.neuropharm.2017.10.020] [PMID: 29054367]

[56]
Szökő É, Tábi T, Riederer P, Vécsei L, Magyar K. Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson’s disease. J Neural Transm (Vienna)  2018; 125(11): 1735-49.
 [http://dx.doi.org/10.1007/s00702-018-1853-9] [PMID: 29417334]

[57]
Zindo FT, Joubert J, Malan SF. Propargylamine as functional moiety in the design of multifunctional drugs for neurodegenerative disorders: MAO inhibition and beyond. Future Med Chem  2015; 7(5): 609-29.
 [http://dx.doi.org/10.4155/fmc.15.12] [PMID: 25921401]

[58]
Ebadi M, Sharma S, Shavali S, El Refaey H. Neuroprotective actions of selegiline. J Neurosci Res  2002; 67(3): 285-9.
 [http://dx.doi.org/10.1002/jnr.10148] [PMID: 11813232]

[59]
Bar Am O, Amit T, Youdim MBH. Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline. Neurosci Lett  2004; 355(3): 169-72.
 [http://dx.doi.org/10.1016/j.neulet.2003.10.067] [PMID: 14732458]

[60]
Mytilineou C, Radcliffe P, Leonardi EK, Werner P, Olanow CW. L-deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro. J Neurochem  1997; 68(1): 33-9.
 [http://dx.doi.org/10.1046/j.1471-4159.1997.68010033.x] [PMID: 8978707]

[61]
Naoi M, Maruyama W. Monoamine oxidase inhibitors as neuroprotective agents in age-dependent neurodegenerative disorders. Curr Pharm Des  2010; 16(25): 2799-817.
 [http://dx.doi.org/10.2174/138161210793176527] [PMID: 20698822]

[62]
 Weinreb O, Amit T, Bar-Am O, Chillag-Talmor O, Youdim MBH. Multifunctional neuroprotective derivatives of rasagiline as anti-alzheimer’s disease drugs. Neurotherapeut 2009; 6(1): 163–174.

[63]
Mahmood I. Clinical pharmacokinetics and pharmacodynamics of selegiline. An update. Clin Pharmacokinet  1997; 33(2): 91-102.
 [http://dx.doi.org/10.2165/00003088-199733020-00002] [PMID: 9260033]

[64]
Binde CD, Tvete IF, Gåsemyr J, Natvig B, Klemp M. A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson’s disease. Br J Clin Pharmacol  2018; 84(9): 1917-27.
 [http://dx.doi.org/10.1111/bcp.13651] [PMID: 29847694]

[65]
Finberg JPM, Rabey JM. Inhibitors of MAO-A and MAO-B in psychiatry and neurology. Front Pharmacol  2016; 7: 340.
 [http://dx.doi.org/10.3389/fphar.2016.00340] [PMID: 27803666]

[66]
Müller T. Emerging approaches in Parkinson’s disease - adjunctive role of safinamide. Ther Clin Risk Manag  2016; 12: 1151-60.
 [http://dx.doi.org/10.2147/TCRM.S86393] [PMID: 27536120]

[67]
Weinreb O, Mandel S, Bar-Am O, et al. Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer’s disease drugs. Neurotherapeutics  2009; 6(1): 163-74.
 [http://dx.doi.org/10.1016/j.nurt.2008.10.030] [PMID: 19110207]

[68]
Knoll J. Experimental studies on the higher nervous activity of animals. V. The functional mechanism of the active conditioned reflex. Acta Physiol Acad Sci Hung  1956; 10(1): 89-100.
 [PMID: 13354409]

[69]
Knoll J, Kelemen K, Knoll B. Experimental studies on the higher nervous activity of animals. 3. Experimental studies on the active conditioned reflex. Acta Physiol Hung  1955; 8: 347-67.

[70]
Horwitz D, Lovenberg W, Engelman K, Sjoerdsma A. Monoamine oxidase inhibitors, tyramine, and cheese. JAMA  1964; 188(13): 1108-10.
 [http://dx.doi.org/10.1001/jama.1964.03060390010002] [PMID: 14163106]

[71]
Knoll J. Deprenyl (selegiline): The history of its development and pharmacological action. Acta Neurol Scand Suppl  1983; 95: 57-80.
 [http://dx.doi.org/10.1111/j.1600-0404.1983.tb01517.x] [PMID: 6428148]

[72]
Suzuki O, Hattori H, Asano M, Oya M, Katsumata Y. Inhibition of monoamine oxidase by d-methamphetamine. Biochem Pharmacol  1980; 29(14): 2071-3.
 [http://dx.doi.org/10.1016/0006-2952(80)90493-1] [PMID: 6773528]

[73]
Knoll J, Ecseri Z, Kelemen K, Nievel J, Knoll B. Phenylisopropylmethylpropinylamine (E-250), a new spectrum psychic energizer. Arch Int Pharmacodyn Ther  1965; 155(1): 154-64.
 [PMID: 4378644]

[74]
Knoll J, Vizi E. ES, Somogyi G. Phenylisopro- pylmethylpropinylamine (E-250), a monoamine oxidase inhibitor antagonizing effects of tyramine. Arzneimittel-Forschung  1968; 18(1): 10.

[75]
Elsworth JD, Glover V, Reynolds GP, et al. Deprenyl administration in man: A selective monoamine oxidase B inhibitor without the ‘cheese effect’. Psychopharmacology (Berl)  1978; 57(1): 33-8.
 [http://dx.doi.org/10.1007/BF00426954] [PMID: 96466]

[76]
Magyar K, Vizi ES, Ecseri Z, Knoll J. Comparative pharmacological analysis of the optical isomers of phenyl-isopropyl-methyl-propinylamine (E-250). Acta Physiol Acad Sci Hung  1967; 32(4): 377-87.
 [PMID: 5595908]

[77]
Knoll J, Magyar K. Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol  1972; 5: 393-408.
 [PMID: 5066229]

[78]
Eldepyrl (Selegiline Hydrochloride). U.S. Food and Drug Administration. Tampa, FL: Somerset Pharmaceutical Companies. 1989.  Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020647

[79]
Zelapar (Selegiline Hydrochloride). U.S. Food and Drug Administration. Aliso Viejo, CA: Valeant Pharmaceuticals International. 2006.  Available from: https://www.google.com/search?q=Zalapar+%28Selegiline+Hydrochloride%29.+U.S.+Food+and+Drug+Administration.+Aliso+Viejo%2C+CA%3A+Valeant+Pharmaceuticals+International+%2B+2006&hl=en&ei=3XCfYdr0KLKO9u8PwPGG6Ac&ved=0ahUKEwia18n_sbP0AhUyh_0HHcC4AX0Q4dUDCA4&uact=5&oq=Zalapar+%28Selegiline+Hydrochloride%29.+U.S.+Food+and+Drug+Administration.+Aliso+Viejo%2C+CA%3A+Valeant+Pharmaceuticals+International+%2B+2006&gs_lcp=Cgdnd3Mtd2l6EANKBAhBGABQ9wNYzVNgi1ZoAnABeAGAAQCIAQCSAQCYAQCgAQGgAQKwAQDAAQE&sclient=gws-wiz

[80]
Emsam (Selegiline Transdermal System). U.S. Food and Drug Administration. Tampa, FL: Somerset Pharmaceutical Companies. 2006.  Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021336s011lbl.pdf

[81]
Stern GM, Lees AJ, Hardie RJ, Sandler M. Clinical and pharmacological problems of deprenyl (selegiline) treatment in Parkinson’s disease. Acta Neurol Scand  1983; 68: 113-6.
 [http://dx.doi.org/10.1111/j.1600-0404.1983.tb01524.x]

[82]
Elsworth JD, Sandler M, Lees AJ, Ward C, Stern GM. The contribution of amphetamine metabolites of (-)-deprenyl to its antiparkinsonian properties. J Neural Transm (Vienna)  1982; 54(1-2): 105-10.
 [http://dx.doi.org/10.1007/BF01249283] [PMID: 6809891]

[83]
Ondo WG, Hunter C, Isaacson SH, 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.
 [http://dx.doi.org/10.1016/j.parkreldis.2010.10.001] [PMID: 21084213]

[84]
Waters CH, Sethi KD, Hauser RA, Molho E, Bertoni JM. Zydis Selegiline Study Group. 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.
 [http://dx.doi.org/10.1002/mds.20036] [PMID: 15077240]

[85]
Clarke A, Brewer F, Johnson ES, et al. A new formulation of selegiline: Improved bioavailability and selectivity for MAO-B inhibition. J Neural Transm (Vienna)  2003; 110(11): 1241-55.
 [http://dx.doi.org/10.1007/s00702-003-0036-4] [PMID: 14628189]

[86]
Azzaro AJ, Ziemniak J, Kemper E, Campbell BJ, VanDenBerg C. Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): A comparison with oral selegiline capsules. J Clin Pharmacol  2007; 47(10): 1256-67.
 [http://dx.doi.org/10.1177/0091270007304779] [PMID: 17715422]

[87]
Wecker L, James S, Copeland N, Pacheco MA. Transdermal selegiline: Targeted effects on monoamine oxidases in the brain. Biol Psychiatry  2003; 54(10): 1099-104.
 [http://dx.doi.org/10.1016/S0006-3223(02)01892-9] [PMID: 14625153]

[88]
Mawhinney M, Cole D, Azzaro AJ. Daily transdermal administration of selegiline to guinea-pigs preferentially inhibits monoamine oxidase activity in brain when compared with intestinal and hepatic tissues. J Pharm Pharmacol  2003; 55(1): 27-34.
 [http://dx.doi.org/10.1111/j.2042-7158.2003.tb02430.x] [PMID: 12625864]

[89]
Youdim MBH. The active centers of monoamine oxidase types “A” and “B”: binding with (14C)-clorgyline and (14C)-deprenyl. J Neural Transm (Vienna)  1978; 43(3-4): 199-208.
 [http://dx.doi.org/10.1007/BF01246956] [PMID: 745012]

[90]
Maycock AL, Abeles RH, Salach JI, Singer TP. The action of acetylenic inhibitors on mitochondrial monoamine oxidase: structure of the flavin site in the inhibited enzyme. In: Bernheim MLC, Ed.  Monoamine Oxidase and its Inhibition.  Hoboken, NJ: Wiley Online Library 2008; pp. 33-47.

[91]
Zhao Q, Cai D, Bai Y. Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease. Int J Mol Med  2013; 32(4): 883-91.
 [http://dx.doi.org/10.3892/ijmm.2013.1450] [PMID: 23877198]

[92]
Ansari KS, Yu PH, Kruck TPA, Tatton WG. Rescue of axotomized immature rat facial motoneurons by R(-)-deprenyl: Stereospecificity and independence from monoamine oxidase inhibition. J Neurosci  1993; 13(9): 4042-53.
 [http://dx.doi.org/10.1523/JNEUROSCI.13-09-04042.1993] [PMID: 8366359]

[93]
Tatton WG, Chalmers-Redman RME, Ju WJH, et al. Propargylamines induce antiapoptotic new protein synthesis in serum- and Nerve Growth Factor (NGF)-withdrawn, NGF-differentiated PC-12 cells. J Pharmacol Exp Ther  2002; 301(2): 753-64.
 [http://dx.doi.org/10.1124/jpet.301.2.753] [PMID: 11961082]

[94]
Sharma SK, Carlson EC, Ebadi M. Neuroprotective actions of Selegiline in inhibiting 1-methyl, 4-phenyl, pyridinium ion (MPP+)-induced apoptosis in SK-N-SH neurons. J Neurocytol  2003; 32(4): 329-43.
 [http://dx.doi.org/10.1023/B:NEUR.0000011327.23739.1b] [PMID: 14724376]

[95]
Schulzer M, Mak E, Calne DB. The antiparkinson efficacy of deprenyl derives from transient improvement that is likely to be symptomatic. Ann Neurol  1992; 32(6): 795-8.
 [http://dx.doi.org/10.1002/ana.410320614] [PMID: 1471871]

[96]
Ward CD. Does selegiline delay progression of Parkinson’s disease? A critical re-evaluation of the DATATOP study. J Neurol Neurosurg Psychiatry  1994; 57(2): 217-20.
 [http://dx.doi.org/10.1136/jnnp.57.2.217] [PMID: 8126510]

[97]
Borowsky B, Adham N, Jones KA, et al. Trace amines: Identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci USA  2001; 98(16): 8966-71.
 [http://dx.doi.org/10.1073/pnas.151105198] [PMID: 11459929]

[98]
Bunzow JR, Sonders MS, Arttamangkul S, et al. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol  2001; 60(6): 1181-8.
 [http://dx.doi.org/10.1124/mol.60.6.1181] [PMID: 11723224]

[99]
Premont RT, Gainetdinov RR, Caron MG. Following the trace of elusive amines. Proc Nat  Acad Sci USA.  98(17): 9474-5.
 [http://dx.doi.org/10.1073/pnas.181356198]

[100]
Xie Z, Miller GM. β-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: Implication for modulatory roles of trace amines in brain. J Pharmacol Exp Ther  2008; 325(2): 617-28.
 [http://dx.doi.org/10.1124/jpet.107.134247] [PMID: 18182557]

[101]
Reynolds GP, Elsworth JD, Blau K, Sandler M, Lees AJ, Stern GM. Deprenyl is metabolized to methamphetamine and amphetamine in man. Br J Clin Pharmacol  1978; 6(6): 542-4.
 [http://dx.doi.org/10.1111/j.1365-2125.1978.tb00883.x] [PMID: 728327]

[102]
Yang HYT, Neff NH. β-phenylethylamine: A specific substrate for type B monoamine oxidase of brain. J Pharmacol Exp Ther  1973; 187(2): 365-71.
 [PMID: 4748552]

[103]
Timár J, Knoll B. The effect of repeated administration of (-) deprenyl on the phenylethylamine-induced stereotypy in rats. Arch Int Pharmacodyn Ther  1986; 279(1): 50-60.
 [PMID: 3083795]

[104]
Riederer P, Youdim MBH. Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with l-deprenyl. J Neurochem  1986; 46(5): 1359-65.
 [http://dx.doi.org/10.1111/j.1471-4159.1986.tb01747.x] [PMID: 2420928]

[105]
Reynolds GP, Riederer P, Sandler M, Jellinger K, Seemann D. Amphetamine and 2-phenylethylamine in post-mortem Parkinsonian brain after (-)deprenyl administration. J Neural Transm (Vienna)  1978; 43(3-4): 271-7.
 [http://dx.doi.org/10.1007/BF01246964] [PMID: 745019]

[106]
Lee DH, Mendoza M, Dvorozniak MT, Chung E, van Woert MH, Yahr MD. Platelet monoamine oxidase in Parkinson patients: Effect of L-deprenyl therapy. J Neural Transm Park Dis Dement Sect  1989; 1(3): 189-94.
 [http://dx.doi.org/10.1007/BF02248668] [PMID: 2505797]

[107]
Riederer P, Youdim MBH, Rausch WD, Birkmayer W, Jellinger K, Seemann D. On the mode of action of L-deprenyl in the human central nervous system. J Neural Transm (Vienna)  1978; 43(3-4): 217-26.
 [http://dx.doi.org/10.1007/BF01246958] [PMID: 745014]

[108]
Lamensdorf I, Porat S, Simantov R, Finberg JPM. Effect of low- dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo. Br J Pharmacol  1999; 126(4): 997-1002.
 [http://dx.doi.org/10.1038/sj.bjp.0702389] [PMID: 10193780]

[109]
Bar-Am O, Weinreb O, Amit T, Youdim MBH. The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline. J Neurochem  2010; 112(5): 1131-7.
 [http://dx.doi.org/10.1111/j.1471-4159.2009.06542.x] [PMID: 20002521]

[110]
Daberkow DP, Brown HD, Bunner KD, et al. Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals. J Neurosci  2013; 33(2): 452-63.
 [http://dx.doi.org/10.1523/JNEUROSCI.2136-12.2013] [PMID: 23303926]

[111]
Butcher SP, Fairbrother IS, Kelly JS, Arbuthnott GW. Amphetamine-induced dopamine release in the rat striatum: An in vivo microdialysis study. J Neurochem  1988; 50(2): 346-55.
 [http://dx.doi.org/10.1111/j.1471-4159.1988.tb02919.x] [PMID: 2447237]

[112]
Jedema HP, Narendran R, Bradberry CW. Amphetamine-induced release of dopamine in primate prefrontal cortex and striatum: Striking differences in magnitude and timecourse. J Neurochem  2014; 130(4): 490-7.
 [http://dx.doi.org/10.1111/jnc.12743] [PMID: 24749782]

[113]
Ren J, Xu H, Choi JK, Jenkins BG, Chen YI. Dopaminergic response to graded dopamine concentration elicited by four amphetamine doses. Synapse  2009; 63(9): 764-72.
 [http://dx.doi.org/10.1002/syn.20659] [PMID: 19484725]

[114]
Khoshbouei H, Wang H, Lechleiter JD, Javitch JA, Galli A. Amphetamine-induced dopamine efflux. A voltage-sensitive and intracellular Na+-dependent mechanism. J Biol Chem  2003; 278(14): 12070-7.
 [http://dx.doi.org/10.1074/jbc.M212815200] [PMID: 12556446]

[115]
Kantor L, Gnegy ME. Protein kinase C inhibitors block amphetamine-mediated dopamine release in rat striatal slices. J Pharmacol Exp Ther  1998; 284(2): 592-8.
 [PMID: 9454802]

[116]
Sitte HH, Huck S, Reither H, Boehm S, Singer EA, Pifl C. Carrier-mediated release, transport rates, and charge transfer induced by amphetamine, tyramine, and dopamine in mammalian cells transfected with the human dopamine transporter. J Neurochem  1998; 71(3): 1289-97.
 [http://dx.doi.org/10.1046/j.1471-4159.1998.71031289.x] [PMID: 9721755]

[117]
Khoshbouei H, Sen N, Guptaroy B, et al. N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux. PLoS Biol  2004; 2(3): E78.
 [http://dx.doi.org/10.1371/journal.pbio.0020078] [PMID: 15024426]

[118]
A mechanism for amphetamine-induced dopamine overload. PLoS Biol  2004; 2(3): e87.

[119]
Zsilla G, Földi P, Held G, Székely AM, Knoll J. The effect of repeated doses of (-) deprenyl on the dynamics of monoaminergic transmission. Comparison with clorgyline. Pol J Pharmacol Pharm  1986; 38(1): 57-67.
 [PMID: 3020531]

[120]
Finberg JPM, Gillman K.  2011.
 [http://dx.doi.org/10.1016/B978-0-12-386467-3.00009-1]

[121]
Ito D, Amano T, Sato H, Fukuuchi Y. Paroxysmal hypertensive crises induced by selegiline in a patient with Parkinson’s disease. J Neurol  2001; 248(6): 533-4.
 [http://dx.doi.org/10.1007/s004150170168] [PMID: 11499649]

[122]
Richard IH, Kurlan R, Tanner C, et al. Parkinson Study Group. Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson’s disease. Neurology  1997; 48(4): 1070-7.
 [http://dx.doi.org/10.1212/WNL.48.4.1070] [PMID: 9109902]

[123]
Zhuo C, Zhu X, Jiang R, et al. Comparison for efficacy and tolerability among ten drugs for treatment of Parkinson’s disease: A network meta-analysis. Sci Rep  2017; 8: 45865.
 [http://dx.doi.org/10.1038/srep45865] [PMID: 28374775]

[124]
Mizuno Y, Hattori N, Kondo T, et al. A Randomized double-blind placebo-controlled phase III trial of selegiline monotherapy for early Parkinson disease. Clin Neuropharmacol  2017; 40(5): 201-7.
 [http://dx.doi.org/10.1097/WNF.0000000000000239] [PMID: 28857772]

[125]
Mizuno Y, Hattori N, Kondo T, et al. Long-term selegiline monotherapy for the treatment of early Parkinson disease. Clin Neuropharmacol  2019; 42(4): 123-30.
 [http://dx.doi.org/10.1097/WNF.0000000000000343] [PMID: 31045589]

[126]
Allain H, Pollak P, Neukirch HC. Symptomatic effect of selegiline in de novo parkinsonian patients. Mov Disord  1993; 8(1 S): S36-40.
 [http://dx.doi.org/10.1002/mds.870080508]

[127]
Mally J, Kovacs AB, Stone TW. Delayed development of symptomatic improvement by (-)-deprenyl in Parkinson’s disease. J Neurol Sci  1995; 134(1-2): 143-5.
 [http://dx.doi.org/10.1016/0022-510X(95)00240-1] [PMID: 8747857]

[128]
Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med  1993; 328(3): 176-83.
 [http://dx.doi.org/10.1056/NEJM199301213280305] [PMID: 8417384]

[129]
Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science  1989; 245(4917): 519-22.
 [http://dx.doi.org/10.1126/science.2502843] [PMID: 2502843]

[130]
Pålhagen S, Heinonen EH, Hägglund J, et al. Swedish Parkinson Study Group. Selegiline delays the onset of disability in de novo parkinsonian patients. Neurology  1998; 51(2): 520-5.
 [http://dx.doi.org/10.1212/WNL.51.2.520] [PMID: 9710028]

[131]
Myllylä VV, Sotaniemi KA, Vuorinen JA, Heinonen EH. Selegiline as initial treatment in de novo parkinsonian patients. Neurology  1992; 42(2): 339-43.
 [http://dx.doi.org/10.1212/WNL.42.2.339] [PMID: 1736162]

[132]
Heinonen EH, Myllylä V. Safety of selegiline (deprenyl) in the treatment of Parkinson’s disease. Drug Saf  1998; 19(1): 11-22.
 [http://dx.doi.org/10.2165/00002018-199819010-00002] [PMID: 9673855]

[133]
Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med  1989; 321(20): 1364-71.
 [http://dx.doi.org/10.1056/NEJM198911163212004] [PMID: 2509910]

[134]
Shoulson I. The Parkinson Study Group. An interim report of the effect of selegiline (L-deprenyl) on the progression of disability in early Parkinson’s disease. Eur Neurol  1992; 32 (Suppl. 1): 46-53.
 [http://dx.doi.org/10.1159/000116869] [PMID: 1425820]

[135]
Pålhagen S, Heinonen E, Hägglund J, Kaugesaar T, Mäki-Ikola O, Palm R. Swedish Parkinson Study Group. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology  2006; 66(8): 1200-6.
 [http://dx.doi.org/10.1212/01.wnl.0000204007.46190.54] [PMID: 16540603]

[136]
Pålhagen SE, Heinonen E. Use of selegiline as monotherapy and in combination with levodopa in the management of Parkinson’s disease: Perspectives from the MONOCOMB study. Prog Neurother Neuropsychopharmacol  2008; 3(1): 49-71.
 [http://dx.doi.org/10.1017/CBO9780511666971.004]

[137]
Mizuno Y, Kondo T, Kuno S, Nomoto M, Yanagisawa N. Early addition of selegiline to L-Dopa treatment is beneficial for patients with Parkinson disease. Clin Neuropharmacol  2010; 33(1): 1-4.
 [http://dx.doi.org/10.1097/WNF.0b013e3181bbf45c] [PMID: 19935410]

[138]
Larsen JP, Boas J. Norwegian-Danish Study Group. The effects of early selegiline therapy on long-term levodopa treatment and parkinsonian disability: An interim analysis of a Norwegian-Danish 5-year study. Mov Disord  1997; 12(2): 175-82.
 [http://dx.doi.org/10.1002/mds.870120207] [PMID: 9087975]

[139]
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): 141-50.
 [http://dx.doi.org/10.1111/j.1468-1331.1999.tb00007.x] [PMID: 10053226]

[140]
Stowe R, Ives N, Clarke CE, et al. Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson’s disease. Mov Disord  2011; 26(4): 587-98.
 [http://dx.doi.org/10.1002/mds.23517] [PMID: 21370258]

[141]
Shoulson I, Oakes D, Fahn S, et al. Parkinson Study Group. 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): 604-12.
 [http://dx.doi.org/10.1002/ana.10191] [PMID: 12112107]

[142]
Durif F. Treating and preventing levodopa-induced dyskinesias: Current and future strategies. Drugs Aging  1999; 14(5): 337-45.
 [http://dx.doi.org/10.2165/00002512-199914050-00002] [PMID: 10408734]

[143]
Tsunekawa H, Takahata K, Okano M, et al. Selegiline increases on time without exacerbation of dyskinesia in 6-hydroxydopamine-lesioned rats displaying l-Dopa-induced wearing-off and abnormal involuntary movements. Behav Brain Res  2018; 347: 350-9.
 [http://dx.doi.org/10.1016/j.bbr.2018.03.002] [PMID: 29526790]

[144]
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.
 [http://dx.doi.org/10.1111/j.1468-1331.2012.03866.x] [PMID: 23279439]

[145]
Gittos MW, James JW, Wiggins LF. Derivatives of 1-aminoindane. GB1037014A, 1966.

[146]
Gittos MW, James JW, Wiggins LF. Methods of lowering blood pressure in animals by administering secondary and tertiary amines. US3513244A, 1970.

[147]
Finberg JPM. The discovery and development of rasagiline as a new anti-Parkinson medication. J Neural Transm (Vienna)  2020; 127(2): 125-30.
 [http://dx.doi.org/10.1007/s00702-020-02142-w] [PMID: 31974721]

[148]
Riederer P, Konradi C, Schay V, et al. Localization of MAO-A and MAO-B in human brain: A step in understanding the therapeutic action of L-deprenyl. Adv Neurol  1987; 45: 111-8.
 [PMID: 3030067]

[149]
Tatton WG. Selegiline can mediate neuronal rescue rather than neuronal protection. Mov Disord  1993; 8(1 S): S20-30.
 [http://dx.doi.org/10.1002/mds.870080506]

[150]
Blackwell B, Marley E, Price J, Taylor D. Hypertensive interactions between monoamine oxidase inhibitors and foodstuffs. Br J Psychiatry  1967; 113(497): 349-65.
 [http://dx.doi.org/10.1192/bjp.113.497.349] [PMID: 6034391]

[151]
Finberg JP, Tenne M, Youdim MB. Tyramine antagonistic properties of AGN 1135, an irreversible inhibitor of monoamine oxidase type B. Br J Pharmacol  1981; 73(1): 65-74.
 [http://dx.doi.org/10.1111/j.1476-5381.1981.tb16772.x] [PMID: 6793119]

[152]
Finberg JPM, Lamensdorf I, Commissiong JW, Youdim MBH. Pharmacology and neuroprotective properties of rasagiline. J Neural Transm Suppl  1996; 48(48): 95-101.
 [PMID: 8988465]

[153]
Youdim MBH, Finberg JPM, Levy R, et al. R-Enantiomer of N-propargyl-1-aminoindan, its preparation and pharmaceutical compositions containing it. EP0436492A2, 1990.

[154]
Siderowf A, Stern M, Shoulson I, et al. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol  2002; 59(12): 1937-43.
 [http://dx.doi.org/10.1001/archneur.59.12.1937] [PMID: 12470183]

[155]
Azilect (Rasagiline). Kfar Saba: Teva Pharmaceutical Industries Ltd. 2006. Available from:  https://www.biospace.com/article/releases/teva-pharmaceutical-industries-limited-announces-fda-grants-approval-of-azilect-r-rasagiline-for-parkinson-s-disease-/

[156]
Thébault JJ, Guillaume M, Levy R. Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: A potent, selective, and irreversible monoamine oxidase type B inhibitor. Pharmacotherapy  2004; 24(10 II): 1295-305.
 [http://dx.doi.org/10.1592/phco.24.14.1295.43156]

[157]
Rabey JM, Sagi I, Huberman M, et al. Rasagiline Study Group. Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson’s disease: A double-blind study as adjunctive therapy to levodopa. Clin Neuropharmacol  2000; 23(6): 324-30.
 [http://dx.doi.org/10.1097/00002826-200011000-00005] [PMID: 11575866]

[158]
Schwid SR. 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): 241-8.
 [http://dx.doi.org/10.1001/archneur.62.2.241] [PMID: 15710852]

[159]
Chen JJ, Swope DM. Clinical pharmacology of rasagiline: A novel, second-generation propargylamine for the treatment of Parkinson disease. J Clin Pharmacol  2005; 45(8): 878-94.
 [http://dx.doi.org/10.1177/0091270005277935] [PMID: 16027398]

[160]
Lecht S, Haroutiunian S, Hoffman A, Lazarovici P. Rasagiline - A novel MAO B inhibitor in Parkinson’s disease therapy. Ther Clin Risk Manag  2007; 3(3): 467-74.
 [PMID: 18488080]

[161]
Chen JJ, Swope DM, Dashtipour K. Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson’s disease. Clin Ther  2007; 29(9): 1825-49.
 [http://dx.doi.org/10.1016/j.clinthera.2007.09.021] [PMID: 18035186]

[162]
Finberg JPM. Pharmacology of Rasagiline, a new MAO-B inhibitor drug for the treatment of Parkinson’s disease with neuroprotective potential. Rambam Maimonides Med J  2010; 1(1): e0003.
 [http://dx.doi.org/10.5041/RMMJ.10003] [PMID: 23908775]

[163]
Binda C, Hubálek F, Li M, et al. Binding of rasagiline-related inhibitors to human monoamine oxidases: A kinetic and crystallographic analysis. J Med Chem  2005; 48(26): 8148-54.
 [http://dx.doi.org/10.1021/jm0506266] [PMID: 16366596]

[164]
Binda C, Hubálek F, Li M, et al. Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class. J Med Chem  2004; 47(7): 1767-74.
 [http://dx.doi.org/10.1021/jm031087c] [PMID: 15027868]

[165]
Binda C, Newton-Vinson P, Hubálek F, Edmondson DE, Mattevi A. Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat Struct Biol  2002; 9(1): 22-6.
 [http://dx.doi.org/10.1038/nsb732] [PMID: 11753429]

[166]
Binda C, Li M, Hubálek F, Restelli N, Edmondson DE, Mattevi A. Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures. Proc Natl Acad Sci USA  2003; 100(17): 9750-5.
 [http://dx.doi.org/10.1073/pnas.1633804100] [PMID: 12913124]

[167]
Finberg JPM. Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: focus on modulation of CNS monoamine neurotransmitter release. Pharmacol Ther  2014; 143(2): 133-52.
 [http://dx.doi.org/10.1016/j.pharmthera.2014.02.010] [PMID: 24607445]

[168]
Kakish J, Tavassoly O, Lee JS. Rasagiline, a suicide inhibitor of monoamine oxidases, binds reversibly to α-synuclein. ACS Chem Neurosci  2015; 6(2): 347-55.
 [http://dx.doi.org/10.1021/cn5002914] [PMID: 25514361]

[169]
Youdim MBH, Gross A, Finberg JPM. Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol  2001; 132(2): 500-6.
 [http://dx.doi.org/10.1038/sj.bjp.0703826] [PMID: 11159700]

[170]
Lamensdorf I, Youdim MBH, Finberg JPM. Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo. J Neurochem  1996; 67(4): 1532-9.
 [http://dx.doi.org/10.1046/j.1471-4159.1996.67041532.x] [PMID: 8858937]

[171]
Goggi J, Theofilopoulos S, Riaz SS, Jauniaux E, Stern GM, Bradford HF. The neuronal survival effects of rasagiline and deprenyl on fetal human and rat ventral mesencephalic neurones in culture. Neuroreport  2000; 11(18): 3937-41.
 [http://dx.doi.org/10.1097/00001756-200012180-00007] [PMID: 11192605]

[172]
Finberg JPM, Takeshima T, Johnston JM, Commissiong JW. Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor. Neuroreport  1998; 9(4): 703-7.
 [http://dx.doi.org/10.1097/00001756-199803090-00026] [PMID: 9559942]

[173]
Abu-Raya S, Blaugrund E, Trembovler V, Shilderman-Bloch E, Shohami E, Lazarovici P. Rasagiline, a monoamine oxidase-B inhibitor, protects NGF-differentiated PC12 cells against oxygen-glucose deprivation. J Neurosci Res  1999; 58(3): 456-63.
 [http://dx.doi.org/10.1002/(SICI)1097-4547(19991101)58:3<456::AID-JNR12>3.0.CO;2-S] [PMID: 10518120]

[174]
Maruyama W, Yamamoto T, Kitani K, Carrillo MC, Youdim M, Naoi M. Mechanism underlying anti-apoptotic activity of a (-)deprenyl-related propargylamine, rasagiline. Mech Ageing Dev  2000; 116(2-3): 181-91.
 [http://dx.doi.org/10.1016/S0047-6374(00)00144-5] [PMID: 10996018]

[175]
Huang W, Chen Y, Shohami E, Weinstock M. Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse. Eur J Pharmacol  1999; 366(2-3): 127-35.
 [http://dx.doi.org/10.1016/S0014-2999(98)00929-7] [PMID: 10082192]

[176]
Heikkila RE, Duvoisin RC, Finberg JPM, Youdim MBH. Prevention of MPTP-induced neurotoxicity by AGN-1133 and AGN-1135, selective inhibitors of monoamine oxidase-B. Eur J Pharmacol  1985; 116(3): 313-7.
 [http://dx.doi.org/10.1016/0014-2999(85)90168-2] [PMID: 3935467]

[177]
Maruyama W, Akao Y, Youdim MBH, Davis BA, Naoi M. Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J Neurochem  2001; 78(4): 727-35.
 [http://dx.doi.org/10.1046/j.1471-4159.2001.00448.x] [PMID: 11520893]

[178]
Maruyama W, Youdim MBH, Naoi M. Antiapoptotic properties of rasagiline, N-propargylamine-1(R)-aminoindan, and its optical (S)-isomer, TV1022. Ann N Y Acad Sci  2001; 939: 320-9.
 [http://dx.doi.org/10.1111/j.1749-6632.2001.tb03641.x] [PMID: 11462787]

[179]
Maruyama W, Takahashi T, Youdim M, Naoi M. The anti-Parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells. J Neural Transm (Vienna)  2002; 109(4): 467-81.
 [http://dx.doi.org/10.1007/s007020200038] [PMID: 11956966]

[180]
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): 913-23.
 [http://dx.doi.org/10.1046/j.1471-4159.2002.01047.x] [PMID: 12358797]

[181]
Youdim MBH, Wadia A, Tatton W, Weinstock M. The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann NY Acad Sci  2001; 939: 450-8.
 [http://dx.doi.org/10.1111/j.1749-6632.2001.tb03656.x]

[182]
Maruyama W, Akao Y, Youdim MBH, Naoi M. Neurotoxins induce apoptosis in dopamine neurons: protection by N-propargylamine-1(R)- and (S)-aminoindan, rasagiline and TV1022. J Neural Transm Suppl  2000; (60): 171-86.
 [http://dx.doi.org/10.1007/978-3-7091-6301-6_11] [PMID: 11205138]

[183]
Abu-Raya S, Tabakman R, Blaugrund E, Trembovler V, Lazarovici P. Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells. Eur J Pharmacol  2002; 434(3): 109-16.
 [http://dx.doi.org/10.1016/S0014-2999(01)01548-5] [PMID: 11779573]

[184]
Shoulson F, Kieburtz S, Siderowf B, et al. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol  2004; 61(4): 561-6.
 [http://dx.doi.org/10.1001/archneur.61.4.561] [PMID: 15096406]

[185]
 Leber P. Slowing the progression of Alzheimer disease: methodologic issues. Alzheimer Dis Assoc Disord 1997; 11: S10-21.

[186]
Hauser RA, Lew MF, Hurtig HI, et al. TEMPO Open-label Study Group. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson’s disease. Mov Disord  2009; 24(4): 564-73.
 [http://dx.doi.org/10.1002/mds.22402] [PMID: 19086083]

[187]
Ahlskog JE, Uitti RJ. Rasagiline, Parkinson neuroprotection, and delayed-start trials: Still no satisfaction? Neurology  2010; 74(14): 1143-8.
 [http://dx.doi.org/10.1212/WNL.0b013e3181d7d8e2] [PMID: 20368634]

[188]
Trudler D, Weinreb O, Mandel SA, Youdim MBH, Frenkel D. DJ-1 deficiency triggers microglia sensitivity to dopamine toward a pro-inflammatory phenotype that is attenuated by rasagiline. J Neurochem  2014; 129(3): 434-47.
 [http://dx.doi.org/10.1111/jnc.12633] [PMID: 24355073]

[189]
Chau KY, Cooper JM, Schapira AHV. Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells. Neurochem Int  2010; 57(5): 525-9.
 [http://dx.doi.org/10.1016/j.neuint.2010.06.017] [PMID: 20624440]

[190]
Carrillo MC, Minami C, Kitani K, et al. Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat. Life Sci  2000; 67(5): 577-85.
 [http://dx.doi.org/10.1016/S0024-3205(00)00643-3] [PMID: 10993123]

[191]
Drigues N, Polytrev T, Weinstock M, Youdim M. Gene expression and behavioral profile of different types of anti and non-antidepressant drugs. Neurosci Lett  2000; 55: S15.

[192]
Ma M, Wang X, Ding X, Jing J, Ma Y, Teng J. Protective effect of BAG5 on MPP+-induced apoptosis in PC12 cells. Neurol Res  2012; 34(10): 977-83.
 [http://dx.doi.org/10.1179/1743132812Y.0000000102] [PMID: 23146300]

[193]
Ou XM, Lu D, Johnson C, et al. Glyceraldehyde-3-phosphate dehydrogenase-monoamine oxidase B-mediated cell death-induced by ethanol is prevented by rasagiline and 1-R-aminoindan. Neurotox Res  2009; 16(2): 148-59.
 [http://dx.doi.org/10.1007/s12640-009-9064-7] [PMID: 19526291]

[194]
Waldmeier PC, Spooren WPJM, Hengerer B. CGP 3466 protects dopaminergic neurons in lesion models of Parkinson’s disease. Naunyn Schmiedebergs Arch Pharmacol  2000; 362(6): 526-37.
 [http://dx.doi.org/10.1007/s002100000300] [PMID: 11138845]

[195]
Yogev-Falach M, Amit T, Bar-Am O, Youdim MBH. The importance of propargylamine moiety in the anti-Parkinson drug rasagiline and its derivatives in MAPK-dependent amyloid precursor protein processing. FASEB J  2003; 17(15): 2325-7.
 [http://dx.doi.org/10.1096/fj.03-0078fje] [PMID: 14525944]

[196]
Wong FK, Lee SHW, Atcha Z, Ong ABL, Pemberton DJ, Chen WS. Rasagiline improves learning and memory in young healthy rats. Behav Pharmacol  2010; 21(4): 278-82.
 [http://dx.doi.org/10.1097/FBP.0b013e32833aec02] [PMID: 20520531]

[197]
Weinreb O, Badinter F, Amit T, Bar-Am O, Youdim MBH. Effect of long-term treatment with rasagiline on cognitive deficits and related molecular cascades in aged mice. Neurobiol Aging  2015; 36(9): 2628-36.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2015.05.009] [PMID: 26142126]

[198]
Chen JJ, Ly AV. Rasagiline: A second-generation monoamine oxidase type-B inhibitor for the treatment of Parkinson’s disease. Am J Health Syst Pharm  2006; 63(10): 915-28.
 [http://dx.doi.org/10.2146/ajhp050395] [PMID: 16675649]

[199]
Panisset M, Chen JJ, Rhyee SH, Conner J, Mathena J. STACCATO study investigators. Serotonin toxicity association with concomitant antidepressants and rasagiline treatment: Retrospective study (STACCATO). Pharmacotherapy  2014; 34(12): 1250-8.
 [http://dx.doi.org/10.1002/phar.1500] [PMID: 25314256]

[200]
Smith KM, Eyal E, Weintraub D. Combined rasagiline and antidepressant use in Parkinson disease in the ADAGIO study: Effects on nonmotor symptoms and tolerability. JAMA Neurol  2015; 72(1): 88-95.
 [http://dx.doi.org/10.1001/jamaneurol.2014.2472] [PMID: 25420207]

[201]
Aboukarr A, Giudice M. Interaction between monoamine oxidase b inhibitors and selective serotonin reuptake inhibitors. Can J Hosp Pharm  2018; 71(3): 196-207.
 [http://dx.doi.org/10.4212/cjhp.v71i3.2586] [PMID: 29955193]

[202]
Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth  2005; 95(4): 434-41.
 [http://dx.doi.org/10.1093/bja/aei210] [PMID: 16051647]

[203]
Kumai M, Maeda Y, Miura M, et al. Serotonin syndrome developing immediately after the initiation of low-dose methadone therapy: A case report. Case Rep Oncol  2020; 13(1): 281-4.
 [http://dx.doi.org/10.1159/000506443] [PMID: 32308591]

[204]
deMarcaida JA, Schwid SR, White WB, et al. Parkinson Study Group TEMPO; PRESTO Tyramine Substudy Investigators and Coordinators. Effects of tyramine administration in Parkinson’s disease patients treated with selective MAO-B inhibitor rasagiline. Mov Disord  2006; 21(10): 1716-21.
 [http://dx.doi.org/10.1002/mds.21048] [PMID: 16856145]

[205]
Goren T, Adar L, Sasson N, Weiss YM. Clinical pharmacology tyramine challenge study to determine the selectivity of the monoamine oxidase type B (MAO-B) inhibitor rasagiline. J Clin Pharmacol  2010; 50(12): 1420-8.
 [http://dx.doi.org/10.1177/0091270010369674] [PMID: 20445015]

[206]
White WB, Salzman P, Schwid SR. Parkinson’s rasagiline: Efficacy and safety in the treatment of off Parkinson Study Group. Transtelephonic home blood pressure to assess the monoamine oxidase-B inhibitor rasagiline in Parkinson disease. Hypertension  2008; 52(3): 587-93.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.108.115873] [PMID: 18678789]

[207]
Azilect. North Wales, PA: Teva Pharmaceutical USA, Inc. 2009.

[208]
Rascol O, Brooks DJ, Melamed E, et al. LARGO study group. 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): 947-54.
 [http://dx.doi.org/10.1016/S0140-6736(05)71083-7] [PMID: 15766996]

[209]
Olanow CW, Hauser RA, Jankovic J, et al. A randomized, double-blind, placebo-controlled, delayed start study to assess rasagiline as a disease modifying therapy in Parkinson’s disease (the ADAGIO study): Rationale, design, and baseline characteristics. Mov Disord  2008; 23(15): 2194-201.
 [http://dx.doi.org/10.1002/mds.22218] [PMID: 18932271]

[210]
Olanow CW, Rascol O, Hauser R, et al. ADAGIO Study Investigators. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med  2009; 361(13): 1268-78.
 [http://dx.doi.org/10.1056/NEJMoa0809335] [PMID: 19776408]

[211]
Jankovic J, Berkovich E, Eyal E, Tolosa E. Symptomatic efficacy of rasagiline monotherapy in early Parkinson’s disease: Post-hoc analyses from the ADAGIO trial. Parkinsonism Relat Disord  2014; 20(6): 640-3.
 [http://dx.doi.org/10.1016/j.parkreldis.2014.02.024] [PMID: 24637126]

[212]
Lew MF, Hauser RA, Hurtig HI, et al. Long-term efficacy of rasagiline in early Parkinson’s disease. Int J Neurosci  2010; 120(6): 404-8.
 [http://dx.doi.org/10.3109/00207451003778744] [PMID: 20504210]

[213]
Hattori N, Takeda A, Takeda S, et al. Rasagiline monotherapy in early Parkinson’s disease: A phase 3, randomized study in Japan. Parkinsonism Relat Disord  2019; 60: 146-52.
 [http://dx.doi.org/10.1016/j.parkreldis.2018.08.024] [PMID: 30205936]

[214]
Horváth K, Aschermann Z, Ács P, et al. Minimal clinically important difference on the Motor Examination part of MDS-UPDRS. Parkinsonism Relat Disord  2015; 21(12): 1421-6.
 [http://dx.doi.org/10.1016/j.parkreldis.2015.10.006] [PMID: 26578041]

[215]
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): 930-6.
 [http://dx.doi.org/10.1016/j.parkreldis.2013.06.001] [PMID: 23849501]

[216]
Hattori N, Takeda A, Takeda S, et al. Efficacy and safety of adjunctive rasagiline in Japanese Parkinson’s disease patients with wearing-off phenomena: A phase 2/3, randomized, double-blind, placebo-controlled, multicenter study. Parkinsonism Relat Disord  2018; 53: 21-7.
 [http://dx.doi.org/10.1016/j.parkreldis.2018.04.025] [PMID: 29748109]

[217]
Hattori N, Takeda A, Takeda S, et al. Long-term, open-label, phase 3 study of rasagiline in Japanese patients with early Parkinson’s disease. J Neural Transm (Vienna)  2019; 126(3): 299-308.
 [http://dx.doi.org/10.1007/s00702-018-1964-3] [PMID: 30689042]

[218]
Hattori N, Takeda A, Takeda S, et al. Long-term safety and efficacy of adjunctive rasagiline in levodopa-treated Japanese patients with Parkinson’s disease. J Neural Transm (Vienna)  2019; 126(3): 289-97.
 [http://dx.doi.org/10.1007/s00702-018-1962-5] [PMID: 30635744]

[219]
Zhang Z, Shao M, Chen S, et al. Adjunct rasagiline to treat Parkinson’s disease with motor fluctuations: A randomized, double-blind study in China. Transl Neurodegener  2018; 7(1): 14.
 [http://dx.doi.org/10.1186/s40035-018-0119-7] [PMID: 29988514]

[220]
Jiang DQ, Wang HK, Wang Y, Li MX, Jiang LL, Wang Y. Rasagiline combined with levodopa therapy versus levodopa monotherapy for patients with Parkinson’s disease: A systematic review. Neurol Sci  2020; 41(1): 101-9.
 [http://dx.doi.org/10.1007/s10072-019-04050-8] [PMID: 31446579]

[221]
O’Brien EM, Tipton KF, Strolin Benedetti M, Bonsignori A, Marrari P, Dostert P. Is the oxidation of milacemide by monoamine oxidase a major factor in its anticonvulsant actions? Biochem Pharmacol  1991; 41(11): 1731-7.
 [http://dx.doi.org/10.1016/0006-2952(91)90177-7] [PMID: 2043162]

[222]
O’Brien EM, Dostert P, Pevarello P, Tipton KF. Interactions of some analogues of the anticonvulsant milacemide with monoamine oxidase. Biochem Pharmacol  1994; 48(5): 905-14.
 [http://dx.doi.org/10.1016/0006-2952(94)90361-1] [PMID: 8093103]

[223]
Dostert P, Pevarello P, Heidempergher F, Varasi M, Bonsignori A, Roncucci R. Preparation of α-(phenylalkylamino)carboxamides as drugs. EP400495A1, US19901205, 1990.

[224]
Pevarello P, Bonsignori A, Dostert P, et al. Synthesis and anticonvulsant activity of a new class of 2-[(arylalky)amino]alkanamide derivatives. J Med Chem  1998; 41(4): 579-90.
 [http://dx.doi.org/10.1021/jm970599m] [PMID: 9484507]

[225]
Fariello RG, McArthur RA, Bonsignori A, et al. Preclinical evaluation of PNU-151774E as a novel anticonvulsant. J Pharmacol Exp Ther  1998; 285(2): 397-403.
 [PMID: 9580576]

[226]
Caccia C, Maj R, Calabresi M, et al. Safinamide: From molecular targets to a new anti-Parkinson drug. Neurolo  2006; 67(7 SUPPL. 2): S18-23.

[227]
Salvati P, Maj R, Caccia C, et al. Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound. J Pharmacol Exp Ther  1999; 288(3): 1151-9.
 [PMID: 10027853]

[228]
Pevarello P, Bonsignori A, Caccia C, et al. Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsants. Bioorg Med Chem Lett  1999; 9(17): 2521-4.
 [http://dx.doi.org/10.1016/S0960-894X(99)00415-1] [PMID: 10498200]

[229]
Grégoire L, Jourdain VA, Townsend M, Roach A, Di Paolo T. Safinamide reduces dyskinesias and prolongs L-DOPA antiparkinsonian effect in parkinsonian monkeys. Parkinsonism Relat Disord  2013; 19(5): 508-14.
 [http://dx.doi.org/10.1016/j.parkreldis.2013.01.009] [PMID: 23402994]

[230]
Maj R, Fariello RG, Ukmar G, et al. PNU-151774E protects against kainate-induced status epilepticus and hippocampal lesions in the rat. Eur J Pharmacol  1998; 359(1): 27-32.
 [http://dx.doi.org/10.1016/S0014-2999(98)00554-8] [PMID: 9831289]

[231]
Maj R, Fariello RG, Pevarello P, Varasi M, McArthur RA, Salvati P. Anticonvulsant activity of PNU-151774E in the amygdala kindled model of complex partial seizures. Epilepsia  1999; 40(11): 1523-8.
 [http://dx.doi.org/10.1111/j.1528-1157.1999.tb02035.x] [PMID: 10565578]

[232]
Cope N. Pharmacia and Upjohn merge. Independent 1995. Available from:  https://www.independent.co.uk/news/business/pharmacia-and-upjohn-merge-1597299.html Accessed 2021 Jul 11

[233]
Merck Serono returns rights to Parkinson’s drug to Newron. FierceBiotech 2011. Available from: https://www.fiercebiotech.com/biotech/merck-serono-returns-rights-to-parkinson-s-drug-to-newron Accessed 2021 Jul 11

[234]
Levin J. Newron and Zambon enter into a strategic collaboration and licence agreement for Safinamide. FierceBiotech. 2012. Available from: https://www.fiercebiotech.com/partnering/newron-and-zambon-enter-into-a-strategic-collaboration-and-licence-agreement-for Accessed 2021 Jul 11

[235]
Xadago (safinamide). European Medicines Agency. Vicenza, Italy: Zambon S.p.A. 2015. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/xadago

[236]
Xadago (safinamide). U.S. Food and Drug Administration. Louisville, KY: Zambon SpA. 2017.

[237]
Seithel-Keuth A, Johne A, Freisleben A, Kupas K, Lissy M, Krösser S. Absolute bioavailability and effect of food on the disposition of safinamide immediate release tablets in healthy adult subjects. Clin Pharmacol Drug Dev  2013; 2(1): 79-89.
 [http://dx.doi.org/10.1002/cpdd.2] [PMID: 27121562]

[238]
Marzo A, Dal Bo L, Monti NC, et al. Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. Pharmacol Res  2004; 50(1): 77-85.
 [http://dx.doi.org/10.1016/j.phrs.2003.12.004] [PMID: 15082032]

[239]
Leuratti C, Sardina M, Ventura P, Assandri A, Müller M, Brunner M. Disposition and metabolism of safinamide, a novel drug for Parkinson’s disease, in healthy male volunteers. Pharmacology  2013; 92(3-4): 207-16.
 [http://dx.doi.org/10.1159/000354805] [PMID: 24136086]

[240]
Müller T. Safinamide: an add-on treatment for managing Parkinson’s disease. Clin Pharmacol  2018; 10: 31-41.
 [http://dx.doi.org/10.2147/CPAA.S137740] [PMID: 29670409]

[241]
Borgohain R, Szasz J, Stanzione P, et al. Study 016 Investigators. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov Disord  2014; 29(2): 229-37.
 [http://dx.doi.org/10.1002/mds.25751] [PMID: 24323641]

[242]
Borgohain R, Szasz J, Stanzione P, et al. Study 018 Investigators. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Mov Disord  2014; 29(10): 1273-80.
 [http://dx.doi.org/10.1002/mds.25961] [PMID: 25044402]

[243]
Cattaneo C, Sardina M, Bonizzoni E. Safinamide as Add-On Therapy to Levodopa in Mid- to Late-Stage Parkinson’s Disease Fluctuating Patients: Post hoc Analyses of Studies 016 and SETTLE. J Parkinsons Dis  2016; 6(1): 165-73.
 [http://dx.doi.org/10.3233/JPD-150700] [PMID: 26889632]

[244]
Binda C, Wang J, Pisani L, et al. Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. J Med Chem  2007; 50(23): 5848-52.
 [http://dx.doi.org/10.1021/jm070677y] [PMID: 17915852]

[245]
Pevarello P, Traquandi G, Bonsignori A, et al. Synthesis and preliminary biological evaluation of new α-amino amide anticonvulsants incorporating a dextromethorphan moiety. Bioorg Med Chem Lett  1999; 9(13): 1783-8.
 [http://dx.doi.org/10.1016/S0960-894X(99)00271-1] [PMID: 10406642]

[246]
Desaphy JF, Farinato A, Altamura C, et al. Safinamide’s potential in treating nondystrophic myotonias: Inhibition of skeletal muscle voltage-gated sodium channels and skeletal muscle hyperexcitability in vitro and in vivo. Exp Neurol  2020; 328: 113287.
 [http://dx.doi.org/10.1016/j.expneurol.2020.113287] [PMID: 32205118]

[247]
Morari M, Brugnoli A, Pisanò CA, et al. Safinamide differentially modulates in vivo glutamate and GABA release in the rat hippocampus and basal ganglia. J Pharmacol Exp Ther  2018; 364(2): 198-206.
 [http://dx.doi.org/10.1124/jpet.117.245100] [PMID: 29167350]

[248]
Taylor CP, Meldrum BS. Na+ channels as targets for neuroprotective drugs. Trends Pharmacol Sci  1995; 16(9): 309-16.
 [http://dx.doi.org/10.1016/S0165-6147(00)89060-4] [PMID: 7482996]

[249]
Urenjak J, Obrenovitch TP. Pharmacological modulation of voltage-gated Na+ channels: A rational and effective strategy against ischemic brain damage. Pharmacol Rev  1996; 48(1): 21-67.
 [PMID: 8685246]

[250]
Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol  2010; 9(4): 413-24.
 [http://dx.doi.org/10.1016/S1474-4422(10)70059-4] [PMID: 20298965]

[251]
Lingamaneni R, Hemmings HC Jr. Effects of anticonvulsants on veratridine- and KCl-evoked glutamate release from rat cortical synaptosomes. Neurosci Lett  1999; 276(2): 127-30.
 [http://dx.doi.org/10.1016/S0304-3940(99)00810-1] [PMID: 10624808]

[252]
Ben-Ari Y. Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience  1985; 14(2): 375-403.
 [http://dx.doi.org/10.1016/0306-4522(85)90299-4] [PMID: 2859548]

[253]
Morsali D, Bechtold D, Lee W, et al. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain  2013; 136(Pt 4): 1067-82.
 [http://dx.doi.org/10.1093/brain/awt041] [PMID: 23518709]

[254]
Bechtold DA, Kapoor R, Smith KJ. Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann Neurol  2004; 55(5): 607-16.
 [http://dx.doi.org/10.1002/ana.20045] [PMID: 15122700]

[255]
Lo AC, Black JA, Waxman SG. Neuroprotection of axons with phenytoin in experimental allergic encephalomyelitis. Neuroreport  2002; 13(15): 1909-12.
 [http://dx.doi.org/10.1097/00001756-200210280-00015] [PMID: 12395089]

[256]
Lo AC, Saab CY, Black JA, Waxman SG. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J Neurophysiol  2003; 90(5): 3566-71.
 [http://dx.doi.org/10.1152/jn.00434.2003] [PMID: 12904334]

[257]
Black JA, Liu S, Carrithers M, Carrithers LM, Waxman SG. Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Ann Neurol  2007; 62(1): 21-33.
 [http://dx.doi.org/10.1002/ana.21172] [PMID: 17654737]

[258]
Sadeghian M, Mullali G, Pocock JM, Piers T, Roach A, Smith KJ. Neuroprotection by safinamide in the 6-hydroxydopamine model of Parkinson’s disease. Neuropathol Appl Neurobiol  2016; 42(5): 423-35.
 [http://dx.doi.org/10.1111/nan.12263] [PMID: 26300398]

[259]
Xu T, Sun R, Wei G, Kong S. The protective effect of safinamide in ischemic stroke mice and a brain endothelial cell line. Neurotox Res  2020; 38(3): 733-40.
 [http://dx.doi.org/10.1007/s12640-020-00246-5] [PMID: 32613602]

[260]
Li Y, Zhong W, Jiang Z, Tang X. New progress in the approaches for blood-brain barrier protection in acute ischemic stroke. Brain Res Bull  2019; 144: 46-57.
 [http://dx.doi.org/10.1016/j.brainresbull.2018.11.006] [PMID: 30448453]

[261]
Abdullahi W, Tripathi D, Ronaldson PT. Blood-brain barrier dysfunction in ischemic stroke: Targeting tight junctions and transporters for vascular protection. Am J Physiol Cell Physiol  2018; 315(3): C343-56.
 [http://dx.doi.org/10.1152/ajpcell.00095.2018] [PMID: 29949404]

[262]
Li JJ, Xing SH, Zhang J, et al. Decrease of tight junction integrity in the ipsilateral thalamus during the acute stage after focal infarction and ablation of the cerebral cortex in rats. Clin Exp Pharmacol Physiol  2011; 38(11): 776-82.
 [http://dx.doi.org/10.1111/j.1440-1681.2011.05591.x] [PMID: 21851377]

[263]
Podurgiel S, Collins-Praino LE, Yohn S, et al. Tremorolytic effects of safinamide in animal models of drug-induced parkinsonian tremor. Pharmacol Biochem Behav  2013; 105: 105-11.
 [http://dx.doi.org/10.1016/j.pbb.2013.01.015] [PMID: 23360954]

[264]
Onofrj M, Bonanni L, Thomas A. An expert opinion on safinamide in Parkinson’s disease. Expert Opin Investig Drugs  2008; 17(7): 1115-25.
 [http://dx.doi.org/10.1517/13543784.17.7.1115] [PMID: 18549347]

[265]
Schapira AH. Safinamide in the treatment of Parkinson’s disease. Expert Opin Pharmacother  2010; 11(13): 2261-8.
 [http://dx.doi.org/10.1517/14656566.2010.511612] [PMID: 20707760]

[266]
Stocchi F, Arnold G, Onofrj M, et al. Safinamide Parkinson’s Study Group. Improvement of motor function in early Parkinson disease by safinamide. Neurology  2004; 63(4): 746-8.
 [http://dx.doi.org/10.1212/01.WNL.0000134672.44217.F7] [PMID: 15326260]

[267]
Stocchi F, Vacca L, Grassini P, et al. Symptom relief in Parkinson disease by safinamide: Biochemical and clinical evidence of efficacy beyond MAO-B inhibition. Neurolo  2006; 67(7 SUPPL. 2)

[268]
Stocchi F, Borgohain R, Onofrj M, et al. Study 015 Investigators. A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson’s disease patients. Mov Disord  2012; 27(1): 106-12.
 [http://dx.doi.org/10.1002/mds.23954] [PMID: 21913224]

[269]
Grall-Bronnec M, Victorri-Vigneau C, Donnio Y, et al. Dopamine agonists and impulse control disorders: A complex association. Drug Saf  2018; 41(1): 19-75.
 [http://dx.doi.org/10.1007/s40264-017-0590-6] [PMID: 28861870]

[270]
Payer DE, Guttman M, Kish SJ, et al. [¹¹C]-(+)-PHNO PET imaging of dopamine D(2/3) receptors in Parkinson’s disease with impulse control disorders. Mov Disord  2015; 30(2): 160-6.
 [http://dx.doi.org/10.1002/mds.26135] [PMID: 25641350]

[271]
Blair HA, Dhillon S. Safinamide: A Review in Parkinson’s Disease. CNS Drugs  2017; 31(2): 169-76.
 [http://dx.doi.org/10.1007/s40263-017-0408-1] [PMID: 28110399]

[272]
Cattaneo C, Caccia C, Marzo A, Maj R, Fariello RG. Pressor response to intravenous tyramine in healthy subjects after safinamide, a novel neuroprotectant with selective, reversible monoamine oxidase B inhibition. Clin Neuropharmacol  2003; 26(4): 213-7.
 [http://dx.doi.org/10.1097/00002826-200307000-00012] [PMID: 12897643]

[273]
Di Stefano AFD, Rusca A. Pressor response to oral tyramine during co-administration with safinamide in healthy volunteers. Naunyn Schmiedebergs Arch Pharmacol  2011; 384(6): 505-15.
 [http://dx.doi.org/10.1007/s00210-011-0674-2] [PMID: 21850574]

[274]
Marquet A, Kupas K, Johne A, et al. The effect of safinamide, a novel drug for Parkinson’s disease, on pressor response to oral tyramine: A randomized, double-blind, clinical trial. Clin Pharmacol Ther  2012; 92(4): 450-7.
 [http://dx.doi.org/10.1038/clpt.2012.128] [PMID: 22948897]

[275]
Schapira AHV, Stocchi F, Borgohain R, et al. Study 017 Investigators. Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson’s disease. Eur J Neurol  2013; 20(2): 271-80.
 [http://dx.doi.org/10.1111/j.1468-1331.2012.03840.x] [PMID: 22967035]

[276]
Barone P, Fernandez H, Ferreira J, Mueller T. Safinamide as an add-on therapy to a stable dose of a single dopamine agonist: Results from a randomized, placebo-controlled, 24-week multicenter trial in early idiopathic parkinson disease (PD) patients (motion study). Neurolo  2013; 80(7 Supplement): P01.061.

[277]
Schapira AHV, Fox SH, Hauser RA, 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.
 [http://dx.doi.org/10.1001/jamaneurol.2016.4467] [PMID: 27942720]

[278]
Cattaneo C, Barone P, Bonizzoni E, Sardina M. Effects of Safinamide on Pain in Fluctuating Parkinson’s Disease Patients: A Post-Hoc Analysis. J Parkinsons Dis  2017; 7(1): 95-101.
 [http://dx.doi.org/10.3233/JPD-160911] [PMID: 27802242]

[279]
Tsuboi Y, Hattori N, Yamamoto A, Sasagawa Y, Nomoto M. ME2125-4 Study Group. Long-term safety and efficacy of safinamide as add-on therapy in levodopa-treated Japanese patients with Parkinson’s disease with wearing-off: Results of an open-label study. J Neurol Sci  2020; 416: 117012.
 [http://dx.doi.org/10.1016/j.jns.2020.117012] [PMID: 32673884]

[280]
Aarsland D, Larsen JP, Lim NG, et al. Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry  1999; 67(4): 492-6.
 [http://dx.doi.org/10.1136/jnnp.67.4.492] [PMID: 10486397]

[281]
Weintraub D, Caspell-Garcia C, Simuni T, et al. Parkinson’s Progression Markers Initiative. Neuropsychiatric symptoms and cognitive abilities over the initial quinquennium of Parkinson disease. Ann Clin Transl Neurol  2020; 7(4): 449-61.
 [http://dx.doi.org/10.1002/acn3.51022] [PMID: 32285645]

[282]
Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Recognition and treatment of depression in Parkinson’s disease. J Geriatr Psychiatry Neurol  2003; 16(3): 178-83.
 [http://dx.doi.org/10.1177/0891988703256053] [PMID: 12967062]

[283]
Dobkin RD, Rubino JT, Friedman J, Allen LA, Gara MA, Menza M. Barriers to mental health care utilization in Parkinson’s disease. J Geriatr Psychiatry Neurol  2013; 26(2): 105-16.
 [http://dx.doi.org/10.1177/0891988713481269] [PMID: 23589410]

[284]
Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci  2017; 18(7): 435-50.
 [http://dx.doi.org/10.1038/nrn.2017.62] [PMID: 28592904]

[285]
Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord  2009; 24(15): 2175-86.
 [http://dx.doi.org/10.1002/mds.22589] [PMID: 19768724]

[286]
Robinson DS, Gilmor ML, Yang Y, et al. Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials. Psychopharmacol Bull  2007; 40(3): 15-28.
 [PMID: 18007565]

[287]
Peña E, Borrué C, Mata M, et al. Impact of safinamide on depressive symptoms in Parkinson’s disease patients (SADness-PD Study): A multicenter retrospective study. Brain Sci  2021; 11(2): 232.
 [http://dx.doi.org/10.3390/brainsci11020232] [PMID: 33668408]

[288]
Barone P, Santangelo G, Morgante L, et al. A randomized clinical trial to evaluate the effects of rasagiline on depressive symptoms in non-demented Parkinson’s disease patients. Eur J Neurol  2015; 22(8): 1184-91.
 [http://dx.doi.org/10.1111/ene.12724] [PMID: 25962410]

[289]
Seppi K, Ray Chaudhuri K, Coelho M, et al. The collaborators of the Parkinson’s Disease Update on Non-Motor Symptoms Study Group on behalf of the Movement Disorders Society Evidence-Based Medicine Committee. Update on treatments for nonmotor symptoms of Parkinson’s disease-an evidence-based medicine review. Mov Disord  2019; 34(2): 180-98.
 [http://dx.doi.org/10.1002/mds.27602] [PMID: 30653247]

[290]
Weintraub D, Hauser RA, Elm JJ, Pagan F, Davis MD, Choudhry A. MODERATO Investigators. Rasagiline for mild cognitive impairment in Parkinson’s disease: A placebo-controlled trial. Mov Disord  2016; 31(5): 709-14.
 [http://dx.doi.org/10.1002/mds.26617] [PMID: 27030249]

[291]
Hanagasi HA, Gurvit H, Unsalan P, et al. The effects of rasagiline on cognitive deficits in Parkinson’s disease patients without dementia: a randomized, double-blind, placebo-controlled, multicenter study. Mov Disord  2011; 26(10): 1851-8.
 [http://dx.doi.org/10.1002/mds.23738] [PMID: 21500280]

[292]
Kuzuhara S. Drug-induced psychotic symptoms in Parkinson’s disease. Problems, management and dilemma. J Neurol  2001; 248(Suppl 3(3)): 28-31.
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DOI https://dx.doi.org/10.2174/1871527321666211231100255	Print ISSN 1871-5273
Publisher Name Bentham Science Publisher	Online ISSN 1996-3181
CNS & Neurological Disorders - Drug Targets

The Role of Monoamine Oxidase B Inhibitors in the Treatment of Parkinson’s Disease - An Update

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