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Amyotrofik Lateral Skleroz Patofizyolojisi ve Tedavi Yaklaşımları

Year 2023, Volume: 43 Issue: 1, 50 - 69, 01.03.2023

Zeynep Yıldırım Dicle Naz Toktaş Öznur Demir Zülfiye Gül Burcu Şen Utsukarçi

https://doi.org/10.52794/hujpharm.1064372
Cited By: 1

Abstract

Ülkemizde her yıl 1500 ile 4500 kişiye tanısı konulan ALS ilerleyici kas fonksiyon kaybı ile kendini gösteren ölümcül bir nörodejeneratif hastalık olarak bilinmektedir. Günden güne bireylerin kendi temel ihtiyaçlarını dahi tek başına karşılayamadığı bu hastalığın patogenezinde glutamat eksitotoksisitesi ve genetik faktörler en önemli etmenler olarak görülmektedir. Birçok semptomatik ve tedaviye yönelik ilaç araştırmaları devam etse de tedavi protokolünde yalnızca FDA onaylı riluzol ve edaravon yer almaktadır. Bunun yanı sıra hem hastalığın önlenmesi ve tedavi edilmesi hem de semptomların iyileştirilmesi ve hastaların yaşam kalitesinin arttırılmasında hücre bazlı tedavilerden ve fitoterapiden de yararlanılmaktadır. Bu çalışma ile ALS hastalığının patogenezine, tedavisine ve tedavisindeki gelişmelere yer verilerek ilaçların tedavi potansiyelleri incelenmiş ve yeni çalışmalara yol göstermesi amacıyla bir değerlendirme hazırlanmıştır.

Keywords

Amyotrofik lateral skleroz nörodejenerasyon patogenez riluzol

References

  • 1. Longinetti E, Wallin AR, Samuelson K, Press Y, Zachau A, Ronnevi LO, Kierkegaard M, Andersen PM, Hillert J, Fang F, Ingree C: The Swedish Motor Neuron Disease Quality Registry. Amyotrophic Lateral Sclerosis and Frontotemporal Degener 2018, 19: 528-537.
  • 2. Palese F, Sartori A, Veriello L, Ros S, Passadore P, Manganotti P, Barbone F, Pisa FE: Epidemiology of Amyotrophic Lateral Sclerosis in Friuli-Venezia Giulia, North-Eastern Italy, 2002-2014: A Retrospective Population Based Study. Amyotrophic Lateral Sclerosis Frontotemporal Degener 2019, 20: 90-99.
  • 3. Marangoz AD, Erdoğan Ç: Amyotrofik Lateral Skleroz (ALS) Hastalığının Patogenezi. Pamukkale Tıp Dergisi 2020, 13 (2): 477-484.
  • 4. Alankaya N: Amyotrofik lateral skleroz ve bakım. Türkiye Klinikleri Journal of Internal Medicine Nursing-Special Topics 2016, 2 (2): 73-9.
  • 5. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC: Amyotrophic Lateral Sclerosis. Lancet 2011, 377: 942–955.
  • 6. Nelson LM, Topol B, Kaye W, Williamson D, Horton DK, Mehta P, Wagner T: Estimation of The Prevalence of Amyotrophic Lateral Sclerosis in The United States Using National Administrative Healthcare Data From 2002 to 2004 and Capture-Recapture Methodology. Neuroepidemiology 2018, 51: 149-157.
  • 7. Jun KY, Park J, Oh KW, Kim EM, Bae JS, Kim I, Kim SH: Epidemiology of ALS in Korea Using Nationwide Big Data. Journal of Neurology Neurosurgery and Psychiatry 2019, 90 (4): 395-403.
  • 8. Logroscino G, Traynor BJ, Hardiman O, Chiò A, Mitchell D, Swingler RJ, Millul A, Benn E, Beghi E: Incidence of Amyotrophic Lateral Sclerosis in Europe. Journal of Neurology Neurosurgery and Psychiatry 2010, 81: 385-390.
  • 9. Ludolph A, Drory V, Hardiman O, Nakano I, Ravits J, Robberecht W, Shefner J: A Revision of The El Escorial Criteria. Informa Healthcare 2015, DOI: 10.3109/21678421.2015.1049183.
  • 10. Hardiman O, Van Den Berg LH, Kiernan MC: Clinical diagnosis and management of amyotrophic lateral sclerosis. Nature Reviews Neurology 2011, 7 (11): 639-649.
  • 11. Miller RG, Munsat TL, Swash M, Brooks BR: Consensus Guidelines for The Design and İmplementation of Clinical Trials in ALS, Journal of The Neurological Sciences 1992, 169: 2-12.
  • 12. Daube JR: Elektrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron disorders. Muscle & Nerve 2000, 23 (10): 1488-1502.
  • 13. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O: Amyotrophic lateral sclerosis mimic syndromes. Archives of Neurology 2000, 57(1):109-113.
  • 14. Turner MR, Kiernan MC, Leigh PN, Talbot K: Biomarkers in amyotrophic lateral sclerosis. The Lancet Neurology 2009, 8(1):94-109.
  • 15. Renton AE, Chiò A, Traynor BJ: State of play in amyotrophic lateral sclerosis genetics. Nature neuroscience 2014, 17 (1): 17-23.
  • 16. Rohrer JD, Isaacs AM, Mizielinska S, Mead S, Lashley T, Wray S, Sidle K, Fratta P, Orrell RW, Hardy J, Holton J, Revesz T, Rossor MN, Warren JD: C9orf72 Expansions İn Frontotemporal Dementia And Amyotrophic Lateral Sclerosis. Lancet Neurology 2015, 14: 291-301.
  • 17. Pioro EP: Antioxidant Therapy in ALS. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2000, 1 (4): 5-15.
  • 18. Vukosavic S, Dubois‐Dauphin M, Romero N, Przedborski S: Bax and Bcl‐2 ınteraction in a transgenic mouse model of familial amyotrophic lateral sclerosis. Journal Of Neurochemistry 1999, 73(6):2460-2468.
  • 19. Ito D, Suzuki N: Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS. Neurology 2011, 77 (17): 1636-1643.
  • 20. Lee JK, Shin JH, Lee JE, Choi EJ: Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 2015, 1852 (11): 2517-2524.
  • 21. Foran E, Trotti D: Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxidants & Redox Signaling 2009, 11 (7): 1587-1602.
  • 22. Tefera TW, Borges K: Metabolic dysfunctions in amyotrophic lateral sclerosis pathogenesis and potential metabolic treatments. Frontiers in Neuroscience 2017, 10:611.
  • 23. Tadic V, Prell T, Lautenschlaeger J, Grosskreutz J: The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis. Frontiers in Cellular Neuroscience 2014, 8:147.
  • 24. Thonhoff JR, Simpson EP, Appel SH: Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis. Current Opinion in Neurology 2018, 31(5):635-639.
  • 25. Simpson EP, Yen AA, Appel SH: Oxidative stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis. Current Opinion İn Rheumatology 2003, 15(6):730-736.
  • 26. Nassif M, Matus S, Castillo K, Hetz C: Amyotrophic Lateral Sclerosis Pathogenesis: A Journey Through The Secretory Pathway. Antioxidants Redox Signaling 2010, 13 (12): 1955-1989.
  • 27. Quigley EM: Microbiota-brain-gut axis and neurodegenerative diseases. Current neurology and neuroscience reports 2017, 17 (12): 1-9.
  • 28. Foran E, Trotti D: Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxidants & Redox Signaling 2009, 11 (7): 1587-1602.
  • 29. McDonnell ME, Vera MD, Blass BE, Pelletier JC, King RC, Fernandez-Metzler C, Smith GR, Wrobel J, Chen S, Wall BA, Reitz AB: Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling. Bioorganic & Medicinal Chemistry 2012, 20 (18): 5642-5648.
  • 30. Zhao H, Ji ZH, Liu C, Yu XY: Neuroprotective mechanisms of 9-hydroxy epinootkatol against glutamate-induced neuronal apoptosis in primary neuron culture. Journal of Molecular Neuroscience 2015, 56(4):808–814.
  • 31. Bensimon G, Lacomblez L, Meininger V, ALS/Riluzole Study Group: A controlled trial of riluzole in amyotrophic lateral sclerosis. The New England Journal Of Medicine 1994, 330 (9): 585-591.
  • 32. Jaiswal MK: Riluzole And Edaravone: A Tale of Two Amyotrophic Lateral Sclerosis Drugs. Medicinal Research Reviews 2019, 39 (2): 733-748.L
  • 33. Lee J, Ryu H, Kowall NW: Motor Neuronal Protection by L-Arginine Prolongs Survival of Mutant SOD1 (G93a) ALS Mice. Biochemical and Biophysical Research Communications 2009, 384 (4): 524-529.
  • 34. Thomas AG, Corse AM, Coccia CF, Wozniak KM, Hartman T, Jada P, Chandran M, Rothstein JF, Dalcanto M, Slusher BS: Naaladase (GCP II) inhibitors protect in models of amyotrophic lateral sclerosis (ALS). Journal Of Neurochemistry 2008, 81:60-63.
  • 35. Gerber YN, Privat A, Perrin FE: Gacyclidine improves the survival and reduces motor deficits in a mouse model of amyotrophic lateral sclerosis. Frontiers in Cellular Neuroscience 2013, 7: 280.
  • 36. Nagańska E, Matyja E, Taraszewska A, Rafałowska J: Protective Effect of Valproic Acid on Cultured Motor Neurons Under Glutamate Excitotoxic Conditions. Ultrastructural Study. Folia Neuropathologica 2015, 53 (4): 309-316, DOI: 10.5114/Fn.2015.56545.
  • 37. Blin O, Pouget J, Aubrespy G, Guelton C, Crevat A, Serratrice G: A double-blind placebo-controlled trial ofl-threonine in amyotrophic lateral sclerosis. Journal Of Neurology 1992, 239 (2): 79–81.
  • 38. Trojsi F, Siciliano M, Passaniti C, Bisecco A, Russo A, Lavorgna L, Esposito S, Ricciardi D, Monsurrò MR, Tedeschi G, Santangelo G: Vitamin D supplementation has no effects on progression of motor dysfunction in amyotrophic lateral sclerosis (ALS). European Journal Of Clinical Nutrition 2020, 74(1):167-175.
  • 39. Aizawa H, Kato H, Oba K, Kawahara T, Okubo Y, Saito T, Naito M, Urushitani M, Tamaoka A, Nakamagoe K, Ishii K, Kanda T, Katsuno M, Atsuta N, Maeda Y, Nagai M, Nishiyama K, Ishiura H, Toda T, Kawata A, Abe K, Yabe I, Takahashi-Iwata I, Sasaki H, Warita H, Aoki M, Sobue G, Mizusawa H, Matsuyama Y, Haga T, Kwak S: Safety and efficacy of perampanel for sporadic amyotrophic lateral sclerosis: a multicentre, double-blind, randomised phase 2 trial. The Lancet 2020.
  • 40. Smith R, Pioro E, Myers K, Sirdofsky M, Goslin K, Meekins G, Yu H, Wymer J, Cudkowicz M, Macklin EA, Schoenfeld D, Pattee G: Enhanced bulbar function in amyotrophic lateral sclerosis: the nuedexta treatment trial. Neurotherapeutics 2017, 14(3):762–772.
  • 41. Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown Jr RH, Zhang H, Schoenfeld DA, Shefner J, Matson S, Matson WR, Ferrante RJ, The Northeast ALS and The National Va ALS Research Consortiums (Appendix): Phase 2 study of sodium phenylbutyrate in ALS. Amyotrophic Lateral Sclerosis 2009, 10 (2): 99-106.
  • 42. Ryberg H, Askmark H, Persson LI. A Double‐Blind Randomized Clinical Trial in Amyotrophic Lateral Sclerosis Using Lamotrigine: Effects on Csf Glutamate, Aspartate, Branched‐Chain Amino Acid Levels and Clinical Parameters. Acta neurologica scandinavica 2003, 108: 1‐8.
  • 43. Miller RG, Shepherd R, Dao H, Khramstov A, Mendoza M, Graves J, Smith S: Controlled Trial of Nimodipine in Amyotrophic Lateral Sclerosis. Neuromuscular Disorders 1996, 6 (2): 101-104.
  • 44. Weiss MD, Macklin EA, Simmons Z, Knox AS, Greenblatt DJ, Atassi N, Graves M, Parziale N, Salameh JS, Quinn C, Brown RH, Distad JB, Trivedi J, Shefner JM, Barohn RJ, Pestronk A, Swenson A, Cudkowicz ME, Mexiletine ALS Study Group: A randomized trial of mexiletine in ALS: safety and effects on muscle cramps and progression. Neurology 2016, 86(16):1474‐1481.
  • 45. Shibuya K, Misawa S, Kimura H, Noto Y-I, Sato Y, Sekiguchi Y, Iwai Y, Mitsuma S, Beppu M, Watanabe K, Fujimaki Y, Tsuji Y, Shimizu T, Mizuno T, Nakagawa M, Sawaguchi K, Hanaoka H, Kuwabara S: A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: efficacy and safety of sodium channel blocker phase II trial. Amyotrophic Lateral Sclerosis an Frontotemporal Degeneration 2015, 16(5-6):353‐358.
  • 46. Paizs M, Tortarolo M, Bendotti C, Engelhardt JI, Siklós L: Talampanel Reduces The Level of Motoneuronal Calcium in Transgenic Mutant SOD1 Mice Only if Applied Presymptomatically. Amyotrophic Lateral Sclerosis 2011, 12 (5): 340-344, DOI: 10.3109/17482968.2011.584627.
  • 47. Kaji R, Imai T, Iwasaki Y, Okamoto K, Nakagawa M, Ohashi Y, Takase T, Hanada T, Shimizu H, Tashiro K, Kuzuhara S: Ultra-High-Dose Methylcobalamin in Amyotrophic Lateral Sclerosis: A Long-Term Phase II/III Randomised Controlled Study. Journal of Neurology Neurosurgery and Psychiatry 2019, 90, 451-457.
  • 48. De Carvalho M, Pinto S, Costa J, Evangelista T, Ohana B, Pinto A: A randomized, placebo‐controlled trial of memantine for functional disability in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 2010, 11 (5): 456-460.
  • 49. Yamamoto M, Tanaka F, Tatsumi H, Sobue G: A strategy for developing effective amyotropic lateral sclerosis pharmacotherapy: from clinical trials to novel pharmacotherapeutic strategies. Expert Opinion On Pharmacotherapy 2008, 9(11):1845-1857.
  • 50. Cudkowicz ME, Titus S, Kearney M, Yu H, Sherman A, Schoenfeld D, Hayden D, Shui A, Brooks B, Conwit R, Felsenstein D, Greenblatt DJ, Keroack M, Kissel JT, Miller R, Rosenfeld J, Rothstein JD, Simpson E, Tolkoff-Rubin N, Zinman L, Shefner JM, Ceftriaxone Study Investigators: Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. The Lancet Neurology 2014, 13 (11): 1083-1091.
  • 51. Miller RG, Moore DH, Gelinas DF, Dronsky V, Mendoza M, Barohn RJ, Bryan W, Ravits J, Yuen E, Neville H, Ringel S, Bromberg M, Petajan J, Amato AA, Jackson C, Johnson W, Mandler R, Bosch P, Smith B, Graves M, Ross M, Sorenson EJ, Kelkar P, Parry G, Olney R: Phase III Randomized Trial of Gabapentin in Patients with Amyotrophic Lateral Sclerosis. Neurology 2001, 56 (7): 843–848.
  • 52. Cudkowicz ME, Shefner JM, Schoenfeld DA, Brown Jr RH, Johnson H, Qureshi M, Jacobs M, Rothstein JD, Appel SH, Pascuzzi RM, Heiman-Patterson TD, Donofrio PD, David WS, Russell JA, Tandan R, Pioro EP, Felice KJ, Rosenfeld J, Mandler RN, Sachs GM, Brale WG, Raynor EM, Baquis GD, Belsh JM, Novella S, Goldstein J, Hulihan J: A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis, Neurology 2003, 61 (4), 456–464.
  • 53. Patten SA, Aggad D, Martinez J, Tremblay E, Petrillo J, Armstrong GAB, La Fontaine A, Maios C, Liao M, Ciura S, Wen XY, Rafuse V, Ichida J, Zinman L, Julien JP, Kabashi E, Robitaille R, Korngut L, Parker JA, Drapeau P: Neuroleptics as Therapeutic Compounds Stabilizing Neuromuscular Transmission in Amyotrophic Lateral Sclerosis. JCI Insight 2017, 2: e97152.
  • 54. Zhang X, Chen S, Lu K, Wang F, Deng J, Xu Z, Wang X, Zhou Q, Le W, Zhao, Y: Verapamil ameliorates motor neuron degeneration and improves lifespan in the SOD1G93A mouse model of ALS by enhancing autophagic flux. Aging and disease 2019, 10(6):1159.
  • 55. Andrews, J: Amyotrophic lateral sclerosis: clinical management and research update. Current Neurology and Neuroscience Reports 2009, 9 (1): 59-68.
  • 56. The Italian ALS Study Group: Branched‐chain amino acids and amyotrophic lateral sclerosis. Neurology 1993, 43(12):2466-2466.
  • 57. Vukosavic S, Dubois‐Dauphin M, Romero N, Przedborski S: Bax and Bcl‐2 ınteraction in a transgenic mouse model of familial amyotrophic lateral sclerosis. Journal Of Neurochemistry 1999, 73(6):2460-2468.
  • 58. Sathasivam S, Ince PG, Shaw PJ: Apoptosis in amyotrophic lateral sclerosis: a review of the evidence. Neuropathology and applied neurobiology 2001, 27(4):257-274.
  • 59. Katsumata R, Ishigaki S, Katsuno M, Kawai K, Sone J, Huang Z, Adachi H, Tanaka F, Urano F, Sobue G: C-Abl İnhibition Delays Motor Neuron Degeneration in The G93a Mouse, An Animal Model of Amyotrophic Lateral Sclerosis. Plos One 2012, 7 (9): e46185.
  • 60. Zhang Y, Cook A, Kim J, Baranov SV, Jiang J, Smith K, Cormier K, Bennett E, Browser RP, Day AL, Carlisle DL, Ferrante RJ, Wang X, Friedlander RM: Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiology of Disease 2013, 55:26-35.
  • 61. Lauria G, Campanella A, Filippini G, Martini A, Penza P, Maggi L, Antozzi C, Ciano C, Beretta P, Caldiroli D, Ghelma F, Ferrara G, Ghezii P, Mantegazze R: Erythropoietin in Amyotrophic Lateral Sclerosis: A Pilot, Randomized, Double-Blind, Placebo-Controlled Study of Safety and Tolerability. Informa Healthcare 2009, 10: 410-415.
  • 62. Scelsa SN, MacGowan DJL, Mitsumoto H, Imperato T, LeValley AJ, Liu MH, DelBene M, Kim MY: A pilot, double-blind, placebo-controlled trial of indinavir in patients with ALS. Neurology 2005, 64(7):1298–300.
  • 63. Miller R, Bradley W, Cudkowicz M, Hubble J, Meinenger V, Mitsumoto H, Moore D, Pohlmann H, Sauer D, Silani V, Strong M, Swash M, Vernotica E, The TCH346 Study Group: Phase II/III Randomized Trial of TCH346 in Patients with ALS. Neurology 2007, 69 (8): 776‐784.
  • 64. Yoshino H, Kimura A: Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (phase II study). Amyotrophic Lateral Sclerosis 2006, 7(4):247-251.
  • 65. Matteo V, Esposito E: Biochemical and Therapeutic Effects of Antioxidants in the Treatment of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis. Current Drug Targets-CNS & Neurological Disorders 2003, 2 (2): 95-107.
  • 66. Okada M, Yamashita S, Ueyama H, Ishizaki M, Maeda Y, Ando Y: Long-Term Effects of Edaravone on Survival of Patients with Amyotrophic Lateral Sclerosis. eNeurologicALSci 2018, 11: 11-14.
  • 67. Abe K, Aoki M, Tsuji S, Itoyama Y, Sobue G, Togo M, Hamada C, Tanaka M, Akimoto M, Nakamura K, Takahashi F, Kondo K, Yoshino H: Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. The Lancet Neurology 2017, 16 (7), 505-512.
  • 68. Hayes-Punzo A, Mulcrone P, Meyer M, McHugh J, Svendsen CN, Suzuki M: Gonadectomy and dehydroepiandrosterone (DHEA) do not modulate disease progression in the G93A mutant SOD1 rat model of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 2012, 13 (3): 311-314.
  • 69. Petri S, Calingasan NY, ALSaied OA, Wille E, Kiaei M, Friedman JE, Baranova O, Chavez JC, Beal MF: The Lipophilic Metal Chelators DP‐109 And DP‐460 Are Neuroprotective in A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. Journal of Neurochemistry 2007, 102 (3): 991-1000.
  • 70. Kupershmidt L, Weinreb O, Amit T, Mandel S, Carri MT, Youdim MBH: Neuroprotective and Neuritogenic Activities of Novel Multimodal İron‐Chelating Drugs in Motor‐Neuron‐Like Nsc‐34 Cells and Transgenic Mouse Model of Amyotrophic Lateral Sclerosis, The Faseb Journal 2009, 23 (11): 3766-3779.
  • 71. Petri S, Kiaei M, Kipiani K, Chen J, Calingasan NY, Crow JP, Beal MF: Additive Neuroprotective Effects of A Histone Deacetylase İnhibitor and A Catalytic Antioxidant in A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. Neurobiology of Disease 2006, 22 (1): 40-49.
  • 72. Orrell RW: AEOL-10150 (Aeolus), Current Opinion in Investigational Drugs (London, England: 2000) 2006, 7 (1): 70-80.
  • 73. Nicholson K, Can J, Macklin EA, Levine-Weinberg M, Breen C, Bakshi R, Grasso DL, Wils AM, Jahandideh S, Taylor AA, Beaulieu D, Ennist DL, Andronesi O, Ratai EM, Schwarzschild MA, Cudkowicz M, Paganoni S: Pilot Trial of İnosine to Elevate Urate Levels in Amyotrophic Lateral Sclerosis. Annals of Clinical and Translational Neurology 2018, 5 (12): 1522-1533.
  • 74. Martinez A, Palomo Ruiz M, Del V, Perez DI, Gil C: Drugs in Clinical Development for The Treatment of Amyotrophic Lateral Sclerosis. Expert Opinion on Investigational Drugs 2017, 26 (4): 403–414.
  • 75. Desnuelle C, Dib M, Garrel C, Favier A: A double-blind, placebo-controlled randomized clinical trial of α-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2001, 2 (1): 9-18.
  • 76. Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton M, Urbinelli L, Qureshi M, Zhang H, Pestronk A, Caress J, Donofrio P, Sorenson E, Bradley W, Lomen-Hoerth C, Pioro E, Rezania K, Ross M, Pascuzzi R, Heiman-Patterson T, Tandan R, Mitsumoto H, Rothstein J, Smith-Palmer T, MacDonald D, Burke D: A clinical trial of creatine in ALS. Neurology 2004, 63(9):1656 –1661.
  • 77. Rosenfeld J, King RM, Jackson, CE, Bedlack RS, Barohn RJ, Dick A, Phillips LH, Chapin J, Gelinas DF, Lou JS: Creatine Monohydrate in ALS: Effects on Strength, Fatigue, Respiratory Status and ALSFRS. Amyotrophic Lateral Sclerosis 2009, 9 (5): 266-272.
  • 78. Kaufmann P, Thompson JLP, Levy G, Buchsbaum R, Shefner J, Krivickas LS, Katz J, Rollins Y, Barohn RJ, Jackson CE, Tiryaki E, Lomen-Hoerth C, Armon C, Tandan R, Rudnicki SA, Rezania K, Sufit R, Pestronk A, Novella SP, Heiman-Patterson T, Kasarskis EJ, Pioro EP, Montes J, Arbing R, Vecchio D, Barsdorf A, Mitsumoto H, Levin B: Phase II Trial of Coq10 for ALS Finds İnsufficient Evidence to Justify Phase III†. Annals of Neurology 2009, 66 (2): 235-244.
  • 79. Kwieciński H, Janik P, Jamrozik Z, Opuchlik A: The Effect of Selegiline and Vitamin E in The Treatment of ALS: An Open Randomized Clinical Trials. Neurologia i Neurochirurgia Polska 2001, 35 (1): 101-106.
  • 80. Statland JM, Moore D, Wang Y, Walsh M, Mozaffar T, Elman L, Nations SP, Mitsumoto H, Fernandes A, Saperstein D, Hayat G, Herbelin L, Karam C, Katz J, Wilkins HM, Agbas A, Swerdlow RH, Santella RM, Dimachkie MM, Barohn RJ: Rasagiline for amyotrophic lateral sclerosis: a randomized, controlled trial. Muscle & Nerve 2019, 59(2):201-207.
  • 81. Louwerse ES, Weverling GJ, Bossuyt PMM: Randomized, Double-Blind, Controlled Trial of Acetylcysteine in Amyotrophic Lateral Sclerosis. Archives of Neurology 1995, 52 (6): 559-564.
  • 82. Nagata E, Ogino M, Iwamoto K, Kitagawa Y, Iwasaki Y, Yoshii F, Ikeda JE: Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients. Plos One 2016, 11 (3): e0149509.
  • 83. Cudkowicz ME, van den Berg LH, Shefner JM, Mitsumoto H, Mora JS, Ludolph A, Hardiman O, Bozik ME, Ingersoll EW, Archibald D, Meyers AL, Dong Y, Farwell WR, Kerr DA: Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. The Lancet Neurology 2013, 12 (11): 1059-1067.
  • 84. Hottinger AF, Fine EG, Gurney ME, Zurn AD, Aebischer P: The copper chelator d‐penicillamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis. European Journal of Neuroscience 1997, 9 (7): 1548-1551.
  • 85. Li W, Fotinos A, Wu Q, Chen Y, Zhu Y, Baranov S, Tu Y, Zhou EW, Sinha B, Kristal BS, Wang X: N-Acetyl-L-Tryptophan Delays Disease Onset and Extends Survival in An Amyotrophic Lateral Sclerosis Transgenic Mouse Model. Neurobiology of Disease 2015, 80: 93-103.
  • 86. Evans MC, Gaillard PJ, De Boer M, Appeldoorn C, Dorland R, Sibson NR, Turner MR, Anthony DC, Stolp HB: CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis. Acta Neuropathologica Communications 2014, 2 (1): 1-13.
  • 87. Ahn SW, Jeon GS, Kim MJ, Shon JH, Kim JE, Shin JY, Kim SM, Kim SH, Ye IH, Lee KW, Hong YH, Sung JJ: Neuroprotective effects of JGK-263 in transgenic SOD1-G93A mice of amyotrophic lateral sclerosis. Journal of The Neurological Sciences 2014, 340 (1-2): 112-116.
  • 88. Lee SH, Choi SM, Yang EJ: Melittin Ameliorates The Inflammation of Organs in An Amyotrophic Lateral Sclerosis Animal Model. Experimental Neurobiology 2014, 23 (1): 86.
  • 89. Kumar S, Phaneuf D, Julien JP: Withaferin-A Treatment Alleviates Tar DNA-Binding Protein-43 Pathology and Improves Cognitive Function in A Mouse Model of Ftld. Neurotherapeutics 2020, 1-11.
  • 90. Urbi B, Owusu MA, Hughes I, Katz M, Broadley S, Sabet A: Effects of cannabinoids in amyotrophic lateral sclerosis (ALS) murine models: a systematic review and meta-analysis. Journal Of Neurochemistry 2019, 149(2):284-297.
  • 91. Pascuzzi R: Cc100: Phase 1 Multiple-Dose Safety And Tolerability İn Subjects With ALS (Cc100b). 2017.
  • 92. Grievink HW, Heuberger JA, Huang F, Chaudhary R, Birkhoff WA, Tonn GR, Mosesova S, Erickson R, Moerland M, Haddick PC, Scearce-Levie K, Ho C, Groeneveld GJ: DNL 104, a centrally penetrant RIPK 1 inhibitor, inhibits RIP 1 kinase phosphorylation in a randomized phase I ascending dose study in healthy volunteers. Clinical Pharmacology & Therapeutics 2020, 107 (2): 406-414.
  • 93. Maier A, Deigendesch N, Muller K, Weishaupt JH, Krannich A, Rohle R, Meissner F, Molawi K, Munch C, Holm T, Meyer R, Meyer T, Zychlinsky A: Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis-A Pilot Study. Plos One 2015, 10 (10): e0139684.
  • 94. Clinical Trials.; 2021 Nisan 25. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03456882 [İnternet sitesi]
  • 95. Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, Drachman DB, Northeast ALS Consortium: Trial of celecoxib in amyotrophic lateral sclerosis. Annals Of Neurology 2006, 60 (1): 22-31.
  • 96. Stommel IW, Cohen JA, Fadul CE, Cogbill CH, Graber DJ, Kingman L, Mackenzie T, Smith JYC, Harris BT: Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotrophic Lateral Sclerosis 2009, 10(5-6):393‐404.
  • 97. Gordon PH, Doorish C, Montes J, Mosley RL, Diamond B, MacArthur RB, Weimer LH, Kaufmann P, Hays AP, Rowland LP, Gendelman HE, Przedborski S, Mitsumoto H: Randomized controlled phase II trial of glatiramer acetate in ALS. Neurology 2006, 66 (7): 1117–1119.
  • 98. Mora JS, Genge A, Chio A, Estol CJ, Chaverri D, Hernández M, Marín S, Mascias J, Rodriguez GE, Povedano M, Paipa A, Dominguez R, Gamez J, Salvado M, Lunetta C, Ballario C, Riva N, Mandrioli J, Moussy A, Kinet JP, Auclair C, Dubreuil P, Arnold V, Mansfield CD, Hermine O: Masitinib As An Add-On Therapy To Riluzole İn Patients With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2020, 21 (1-2): 5-14.
  • 99. Berry JD, Paganoni S, Atassi N, Macklin EA, Goyal N, Rivner M, Simpson E, Appel S, Grasso DL, Mejia NI, Mateen F, Gill A, Vieira F, Tassinari V, Perrin S: Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability. Muscle & Nerve 2017, 56 (6): 1077-1084.
  • 100. Lingor P, Weber M, Camu W, Friede T, Hilgers R, Leha A, Neuwirth C, Günther R, Benatar M, Kuzma-Kozakiewicz M, Bidner H, Blankenstein C, Frontini R, Ludolph A, Koch JC: ROCK-ALS: Protocol for A Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of The Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis. Frontiers in Neurology 2019, 10.
  • 101. Meininger V, Asselain B, Guillet P, Leigh PN, Ludolph A, Lacomblez L, Robberecht W: Pentoxifylline in ALS: a double-blind, randomized, multicenter, placebo-controlled trial. Neurology 2006, 66 (1): 88-92.
  • 102. Lindhorst S, Cudkowicz M: Is Pentoxifylline Safe and Effective in Patients with Amyotrophic Lateral Sclerosis. Nature Clinical Practice Neurology 2006, 2 (7): 364–365.
  • 103. Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R: Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. The Lancet Neurology 2007, 6 (12): 1045-1053.
  • 104. Clinical Trials.; 2021 Nisan 18. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT03039673 [İnternet sitesi]
  • 105. Mandrioli J, D'Amico R, Zucchi E, Gessani A, Fini N, Fasano A, Caponnetto C, Chiò A, Dalla-Bella E, Lunetta C, Mazzini L, Marinou K, Sorarù G, de Biasi S, Lo Tartoaro D, Pinti M, Cossarizza A: Rapamycin Treatment for Amyotrophic Lateral Sclerosis: Protocol for A Phase II Randomized, Double‐Blind, Placebo‐Controlled, Multicenter, Clinical Trial (RAP‐ALS Trial). Medicine (Baltimore) 2018, 97: e11119.
  • 106. Clinical Trials.; 2021 Nisan 27. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03693781 [İnternet sitesi]
  • 107. Thonhoff JR, Beers DR, Zhao W, Pleitez M, Simpson EP, Berry JD, Cudkowicz ME, Appel SH: Expanded autologous regulatory T-lymphocyte infusions in ALS: a phase I, first-in-human study. Neurology-Neuroimmunology Neuroinflammation 2018, 5(4).
  • 108. Clinical Trials.; 2021 Nisan 29. Erişim yeri: https://clinicaltrials.gov/ct2/show/results/NCT04055623 [İnternet sitesi]
  • 109. Clinical Trials.; 2021 Nisan 18. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03127267 [İnternet sitesi]
  • 110. Clinical Trials.; 2021 Nisan 28. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03981536 [İnternet sitesi]
  • 111. Fournier CN, Schoenfeld D, Berry JD, Cudkowicz ME, Chan J, Quinn C, Brown RH, Salameh JS, Tansey MG, Beers DR, Appel SH, Glass JD: An open label study of a novel immunosuppression intervention for the treatment of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2018, 19 (3-4): 242-249.
  • 112. Beghi E, Chiò A, Inghilleri M, Mazzini L, Micheli A, Mora G, Poloni M, Riva R, Serlenga L, Testa D, Tonali P, The Italian Amyotrophic Lateral Sclerosis Study Group: A randomized controlled trial of recombinant interferon beta-1a in ALS. Neurology 2000, 54 (2): 469-469.
  • 113. ALSUntangled Group: ALSUntangled 58: Azathioprine. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2020, 1-3.
  • 114. Smith SA, Miller RG, Murphy JR, Ringel SP: Treatment of ALS with high dose pulse cyclophosphamide. Journal of the neurological sciences 1994, 124:84-87.
  • 115. Meucci N, Nobile-Orazio E: Intravenous immunoglobulin therapy in amyotrophic lateral sclerosis. Journal of neurology 1996, 243(2):117-120.
  • 116. Drachman DB, Chaudhry V, Cornblath D, Kuncl RW, Pestronk A, Clawson L, Mellits ED, Quaskey S, Quinn T, Calkins A, Order, S. Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 1994, 35(2):142-150.
  • 117. Lu H, Le WD, Xie YY, Wang XP: Current therapy of drugs in amyotrophic lateral sclerosis. Current neuropharmacology 2016, 14 (4): 314-321.; Kazak F, Yarım GF: Beyin Kaynaklı Nörotrofik Faktör. Atatürk Üniversitesi Veteriner Bilimleri Dergisi 2015, 10 (2): 120-129.
  • 118. Sun W, Funakoshi H, Nakamura T: Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. The Journal of Neuroscience 2002, 22(15):6537–6548.
  • 119. Manabe Y, Nagano I, Gazi MSA, Murakami T, Shiote M, Shoji M, Kitagawa H, Abe K: Glial Cell Line-Derived Neurotrophic Factor Protein Prevents Motor Neuron Loss of Transgenic Model Mice for Amyotrophic Lateral Sclerosis. Neurological Research 2003, 25 (2): 195–200.
  • 120. ALS CNTF Treatment Study Group: A double‐blind placebo‐controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 1996, 46 (5): 1244‐1249.
  • 121. Zinman L, Cudkowicz M: Emerging targets and treatments in amyotrophic lateral sclerosis. The Lancet Neurology 2011, 10(5):481–490.
  • 122. Wobst HJ, Mack KL, Brown DG, Brandon NJ, Shorter J: The clinical trial landscape in amyotrophic lateral sclerosis—past, present, and future. Medicinal research reviews 2020, 40(4):1352-1384.
  • 123. Sufit RL, Ajroud-Driss S, Casey P, Kessler JA: Open label study to assess the safety of vm202 in subjects with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration 2017, 18(3-4):269-278.
  • 124. Meininger V, Bensimon G, Bradley WG, Brooks BR, Douillet P, Eisen AA, Lacomblez L, Leigh PN, Robberecht W: Efficacy and Safety of Xaliproden in Amyotrophic Lateral Sclerosis: Results of Two Phase III Trials. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2004, 5 (2): 107-117.
  • 125. The BDNF Study Group: A controlled trial of recombinant methionyl human BDNF in ALS. Neurology 1999, 52(7):1427‐1427.
  • 126. Caroscio JT, Cohen JA, Zawodniak J, Takai V, Shapiro A, Blaustein S, Mulvihill MN, Loucas SP, Gudesblatt M, Rube D, Yahr MD: A double‐blind, placebo‐controlled trial of TRH in amyotrophic lateral sclerosis. Neurology 1986, 36 (2): 141-141.
  • 127. Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, Barkhaus PE, Bosch P, Boylan K, David WS, Feldman E, Glass J, Gutmann L, Katz J, King W, Luciano CA, McCluskey LF, Nash S, Newman DS, Pascuzzi RM, Pioro E, Sams LJ, Scelsa S, Simpson EP, Subramony SH, Tiryaki E, Thornton CA: Subcutaneous Igf‐1 is not beneficial in 2‐year ALS trial. Neurology 2008, 71(22):1770‐1775.
  • 128. Duffy LM, Chapman AL, Shaw PJ, Grierson AJ: The role of mitochondria in the pathogenesis of amyotrophic lateral sclerosis. Neuropathology and Applied Neurobiology 2011, 37 (4): 336-352.
  • 129. Lenglet T, Lacomblez L, Abitbol JL, Ludolph A, Mora JS, Robberecht W, Shaw PJ, Pruss RM, Cuvier V, Meininger V: A Phase II-III Trial of Olesoxime in Subjects with Amyotrophic Lateral Sclerosis. European Journal of Neurology 2014, 21: 529–536.
  • 130. Martin LJ, Fancelli D, Wong M, Niedwiecki M, Ballarini M, Plyte S, Chang Q: Gnx-4728, A Novel Small Molecule Drug İnhibitor of Mitochondrial Permeability Transition, is Therapeutic in A Mouse Model of Amyotrophic Lateral Sclerosis. Frontiers in Cellular Neuroscience 2014, https://Doi.Org/10.3389/Fncel.2014.00433.
  • 131. Wang H, Guan Y, Wang X, Smith K, Cormier K, Zhu S, Stravrovskaya IG, Huo C, Ferrante RJ, Kristal BS, Frienlander RM: Nortriptyline delays disease onset in models of chronic neurodegeneration. European Journal Of Neuroscience 2007, 26(3):633-641.
  • 132. Karlsson J, Fong KSK, Hansson MJ, Elmér E, Csiszar K, Keep MF:, Life Span Extension And Reduced Neuronal Death After Weekly İntraventricular Cyclosporin İnjections in The G93a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. Journal of neurosurgery 2004, 101 (1): 128–137.
  • 133. Pieper AA, McKnight SL, Ready JM: P7C3 and An Unbiased Approach to Drug Discovery for Neurodegenerative Diseases. Chemical Society Reviews 2014, 43: 6716-6726.
  • 134. Zhang JJ, Zhou QM, Chen S, Le WD: Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1‐G93A mouse model. CNS Neuroscience & Therapeutics 2018, 24(12):1163-1174.
  • 135. Chiò A, Borghero G, Calvo A, Capasso M, Caponnetto C, Corbo M, Giannini F, Logroscino G, Mandrioli J, Marcello N, Mazzini L, Moglia C, Monsurrò MR, Mora G, Patti F, Perini M, Pietrini V, Pisano F, Pupillo E, Sabatelli M, Salvi F, Silani V, Simone IL, Sorarù G, Tola MR, Volanti P, Beghi E: Lithium carbonate in amyotrophic lateral sclerosis lack of efficacy in a dose-finding trial. Neurology 2010, 75 (7): 619-625.
  • 136. Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S, Paparelliet A: Lithium delays progression of amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences 2008, 105 (6): 2052-2057.
  • 137. Chen PC, Hsieh YC, Huang CC, Hu CJ: Tamoxifen for amyotrophic lateral sclerosis: a randomized double-blind clinical trial. Medicine 2020, 99 (22): e20423.
  • 138. Clinical Trials.; 2021 Nisan 25. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03508453 [İnternet sitesi]
  • 139. Wang IF, Tsai KJ, Shen CKJ: Autophagy activation ameliorates neuronal pathogenesis of FTLD-U mice: a new light for treatment of TARDBP/TDP-43 proteinopathies. Autophagy 2013, 9(2):239-240.
  • 140. Webster CP, Smith EF, Shaw PJ, De Vos KJ: Protein homeostasis in amyotrophic lateral sclerosis: therapeutic opportunities?. Frontiers in Molecular Neuroscience 2017, 10:123.
  • 141. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ: Protein aggregation in amyotrophic lateral sclerosis. Acta neuropathologica 2013, 125 (6): 777-794.
  • 142. Chang CF, Lee YC, Lee KH, Lin HC, Chen CL, Shen CKJ, Huang CC: Therapeutic effect of berberine on TDP-43-related pathogenesis in FTLD And ALS. Journal of Biomedical Science 2016, 23 (1): 1-12.
  • 143. Lange DJ, Andersen PM, Remanan R, Marklund S, Benjamin D: Pyrimethamine Decreases Levels of SOD1 in Leukocytes and Cerebrospinal Fluid of ALS Patients: A Phase I Pilot Study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2013, 14 (3): 199-204.
  • 144. Clinical Trials.; 2021 Nisan 27. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03580616 [İnternet sitesi]
  • 145. Benatar M, Wuu J, Andersen PM, Atassi N, David W, Cudkowicz M, Schoenfeld D: Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology 2018, 90 (7): 565-574.
  • 146. Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, Bostrom A, Theodoss J, Al-Nakhala BM, Vieira FG, Ramasubbu J, Heywood JA: Design, power, and interpretation of studies in the standard murine model of ALS. Amyotrophic Lateral Sclerosis 2008, 9(1):4-15.
  • 147. Alfahad T, Nath A: Retroviruses and amyotrophic lateral sclerosis. Antiviral Research 2013, 99 (2): 180-187.
  • 148. Gold J, Rowe DB, Kiernan MC, Vucic S, Mathers S, Van Eijk RP, Nath A, Montojo MG, Norato G, Santamaria UA, Rogers ML, Malaspina A, Lombardi V, Mehta PR, Westeneng HJ, Van Den Berg LH, Al-Chalabi A: Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the lighthouse trial. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2019, 20 (7-8): 595-604.
  • 149. Percy AK, Davis LE, Johnston DM, Drachman DB: Failure of isoprinosine in amyotrophic lateral sclerosis. New England Journal of Medicine 1971, 285 (12).
  • 150. Norris FH, Calanchinii PR, Fallat RJ, Panchari S, Jewett B: The administration of guanidine in amyotrophic lateral sclerosis. Neurology 1974, 24(8):721-721.
  • 151. Mora JS, Munsat TL, Kao KP, Finison LJ, Hedlund W, Bradley GA, Scheife, R, Georgiades JA: Intrathecal administration of natural human interferon alpha in amyotrophic lateral sclerosis. Neurology 1986, 36 (8): 1137-1137.
  • 152. Warita H, Kato M, Asada R, Yamashita A, Hayata D, Adachi K, Aoki M: Safety, tolerability, and pharmacodynamics of intrathecal injection of recombinant human HGF (KP‐100) in subjects with amyotrophic lateral sclerosis: a phase I trial. The journal of clinical pharmacology 2019, 59(5):677-687.
  • 153. Clinical Trials.; 2021 Nisan 27. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03626012 [İnternet sitesi]
  • 154. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT00886977 [İnternet sitesi]
  • 155. Clinical Trials.; 2021 Nisan 19. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03127514 [İnternet sitesi]
  • 156. Juntas-Morales R, Pageot N, Bendarraz A, Alphandéry S, Sedel F, Seigle S, Camu W, High-dose pharmaceutical grade biotin (MD1003) in amyotrophic lateral sclerosis: A pilot study. EClinicalMedicine 2020, 19, 100254.
  • 157. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT02450552 [İnternet sitesi]
  • 158. De La Rubia JE, Drehmer E, Platero JL, Benlloch M, Caplliure-Llopis J, Villaron-Casales C, Bernardo ND, Alarcòn J, Fuente C, Carrera S, Sancho D, Garcia-Pardo P, Pascual R, Juarez M, Cuerda-Ballester M, Forner A, Sancho-Castillo S, Barrios C, Obrador E, Marchio P, Salvador R, Holmes HE, Dellinger RW, Guarente L, Estrela JM: Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study. Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration 2019, 20 (1-2): 115-122.
  • 159. Beghi E, Pupillo E, Bonito V, Buzzi P, Caponnetto C, Chiò A, Corbo M, Giannini F, Inghilleri M, La Bella V, Logroscino G, Lorusso L, Lunetta C, Mazzini L, Messina P, Mora G, Perini M, Quadrelli ML, Silani V, Simone IL, Tremolizzo L, The Italian Amyotrophic Lateral Sclerosis Study Group: Randomized double‐blind placebo‐controlled trial of acetyl‐l‐carnitine for ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2013, 14 (5-6): 397-405.
  • 160. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT02469896 [İnternet sitesi]
  • 161. Clinical Trials.; 2021 Mayıs 11. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT02238626 [İnternet sitesi]
  • 162. Miller RG, Block G, Katz JS, Et Al. Randomized Phase 2 Trial Of Np001‐A Novel İmmune Regulator: Safety And Early Efficacy in ALS. Neurol Neuroimmunol Neuroinflamm. 2015;2: E100.
  • 163. Kovalchuk MO, Heuberger JA, Sleutjes BT, Ziagkos D, van den Berg LH, Ferguson TA, Franssen H, Groeneveld GJ: Acute effects of riluzole and retigabine on axonal excitability in patients with amyotrophic lateral sclerosis: a randomized, double‐blind, placebo‐controlled, crossover trial. Clinical Pharmacology & Therapeutics 2018, 104 (6): 1136-1145.
  • 164. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT00748501 [İnternet sitesi]
  • 165. Meininger, V., Genge, A., Van Den Berg, L. H., Robberecht, W., Ludolph, A., Chio, A., Kim SH, Leigh N, Kiernan MC, Shefner, J. M., Desnuelle C, Morrison KE, Petri S, Boswell D, Temple J, Mohindra R, Davies M, Bullman J, Rees P, Lavrov A: Safety and Efficacy of Ozanezumab in Patients with Amyotrophic Lateral Sclerosis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial. The Lancet Neurology 2017, 16 (3): 208–216.
  • 166. VanMeter S, Becker P, Mackey L, Fang L, Zhao E: Post hoc analysis using PRO‐ACT database to evaluate repository corticotropin injection (H.P. Acthar® Gel) as a potential treatment for ALS (P5.327). Neurology 2018.
  • 167. Dupuis L, Dengler R, Heneka MT, Meyer T, Zierz S, Kassubek J, Fischer W, Steiner F, Lindauer E, Otto M, Dreyhaupt J, Grehl T, Hermann A, Winkler AS, The GERP ALS Study Group: A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PloS One 2012, 7 (6): e37885.
  • 168. Moreau C, Danel V, Devedjian JC, Grolez G, Timmerman K, Laloux C, Petrault M, Gouel F, Jonneaux A, Dutheil M, Lachaud C, Lopes R, Kuchcinski G, Auger F, Kyheng M, Duhamel A, Pérez T, Pradat PF, Blasco H, Veyrat-Durebex C, Corcia P, Oeckl P, Otto M, Dupuis L, Garçon G, Defebvre L, Cabantchik ZL, Duce J, Bordet R, Devos D: Could Conservative İron Chelation Lead to Neuroprotection in Amyotrophic Lateral Sclerosis?. Antioxidants Redox Signaling 2018, 29: 742‐748.
  • 169. Clinical Trials.; 2021 Nisan 30. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04082832 [İnternet sitesi]
  • 170. Kindy M, Lupinacci P, Chau R, Shum T, Ko D: A Phase 2a Randomized, Double-Blind, Placebo-Controlled Pilot Trial of GM604 in Patients with Amyotrophic Lateral Sclerosis (ALS Protocol GALS-001) and A Single Compassionate Patient Treatment (Protocol GALS-C). F1000research 2017, 6: 230.
  • 171. Clinical Trials.; 2021 Nisan 27. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03800524 [İnternet sitesi]
  • 172. Clinical Trials.; 2021 Mayıs 3. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04248465 [İnternet sitesi]
  • 173. Clinical Trials.; 2021 Ağustos 31. Erişim yeri: https://clinicaltrials.gov/ct2/show/record/NCT03505021 [İnternet siesi]
  • 174. Clinical Trials.; 2021 Nisan 30. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04220021 [İnternet sitesi]
  • 175. Clinical Trials.; 2021 Nisan 30. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04057898 [İnternet sitesi]
  • 176. Clinical Trials.; 2021 Mayıs 3. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04494256 [İnternet sitesi]
  • 177. Clinical Trials.; 2021 Mayıs 3. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT04322149 [İnternet sitesi]
  • 178. Clinical Trials.; 2021 Mayıs 3. Erişim yeri: https://www.clinicaltrials.gov/ct2/show/study/NCT04856982 [İnternet sitesi]
  • 179. Andrews JA, Miller TM, Vijayakumar V, Stoltz R, James JK, Meng L, Wolff AA, Malik FI: CK‐2127107 amplifies skeletal muscle response to nerve activation in humans. Muscle & Nerve 2018, 57 (5): 729-734.
  • 180. Clinical Trials.; 2021 Ağustos 25. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT05021536 [İnternet sitesi]
  • 181. Clnical Trials.; 2020 Eylül 11. Erişim yeri: https://clinicaltrials.gov/ct2/show/results/NCT03160898 [İnternet sitesi]
  • 182. Mitchell JD, Borasio GD: Amyotrophic Lateral Sclerosis. The Lancet 2007, 369 (9578): 2031-2041.
  • 183. Clinical Trials.; 2021 Nisan 20. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT03186040 [İnternet sitesi]
  • 184. Clinical Trials.; 2021 Nisan 25. Erişim yeri: https://www.clinicaltrials.gov/ct2/show/results/NCT03472950 [İnternet sitesi]
  • 185. Chandrashekhar S, Hamasaki A, McCalley A, Herbelin L, Pasnoor M, Jawdat O, Dimachkie M, Barohn R, Statland J: Open-label pilot study of ranolazine for cramps in amyotrophic lateral sclerosis (ALS). (2374). Neurology 2020, 94 (15).
  • 186. Clinical Trials.; 2021 Nisan 25. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT03482050 [İnternet sitesi]
  • 187. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/results/NCT02478450 [İnternet sitesi]
  • 188. Clinical Trials.; 2021 Nisan 18. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT02943850 [İnternet sitesi]
  • 189. Clinical Trials.; 2021 Nisan 20. Erişim yeri: https://clinicaltrials.gov/ct2/show/results/NCT03280056 [İnternet sitesi]
  • 190. Oh KW, Noh MY, Kwon MS, Kim HY, Oh SI, Park J, Kim HJ, Ki CS, Kim SH: Repeated intrathecal mesenchymal stem cells for amyotrophic lateral sclerosis. Annals of Neurology 2018, 84 (3): 361-373.
  • 191. Jaradat N, Hawash M, Zaid AN, Natsheh A-R, Yousef R, AbuHasan Q: The Neuroprotective Role of Origanum syriacum L. and Lavandula dentata L. Essential Oils through Their Effects on AMPA Receptors. BioMed Research International 2019.
  • 192. Kumar V, Gupta P, Hassan MI: Mechanism and implications of Traditional Chinese medicine in amyotrophic lateral sclerosis therapy. Journal of Proteins and Proteomics 2019, 10(2): 131-147.

An Evaluation of Amyotrophic Lateral Sclerosis and Current Situation in Its Treatment

Year 2023, Volume: 43 Issue: 1, 50 - 69, 01.03.2023

Zeynep Yıldırım Dicle Naz Toktaş Öznur Demir Zülfiye Gül Burcu Şen Utsukarçi

https://doi.org/10.52794/hujpharm.1064372
Cited By: 1

Abstract

ALS, which is diagnosed in 1500 to 4500 people every year in our country, is known as a fatal neurodegenerative disease manifested by progressive loss of muscle function. Glutamate excitotoxicity and genetic factors are seen as the most important factors in the pathogenesis of this disease, where individuals cannot even meet their own basic needs day by day. Although research on a lot of symptomatic and therapeutic drugs continues, only FDA-approved riluzole and edaravone are included in the treatment protocol. In addition, cell-based therapies and phytotherapy have also been used in both the prevention and treatment of the disease, the improvement of the symptoms, and the improvement of the quality of life of the patients. In this study, the pathogenesis of ALS disease, its treatment, and the development of the treatment were included, the treatment potentials of drugs were examined and an evaluation was prepared to guide future studies.

Keywords

Amyotrophic lateral sclerosis neurodegeneration pathogenesis riluzole

References

  • 1. Longinetti E, Wallin AR, Samuelson K, Press Y, Zachau A, Ronnevi LO, Kierkegaard M, Andersen PM, Hillert J, Fang F, Ingree C: The Swedish Motor Neuron Disease Quality Registry. Amyotrophic Lateral Sclerosis and Frontotemporal Degener 2018, 19: 528-537.
  • 2. Palese F, Sartori A, Veriello L, Ros S, Passadore P, Manganotti P, Barbone F, Pisa FE: Epidemiology of Amyotrophic Lateral Sclerosis in Friuli-Venezia Giulia, North-Eastern Italy, 2002-2014: A Retrospective Population Based Study. Amyotrophic Lateral Sclerosis Frontotemporal Degener 2019, 20: 90-99.
  • 3. Marangoz AD, Erdoğan Ç: Amyotrofik Lateral Skleroz (ALS) Hastalığının Patogenezi. Pamukkale Tıp Dergisi 2020, 13 (2): 477-484.
  • 4. Alankaya N: Amyotrofik lateral skleroz ve bakım. Türkiye Klinikleri Journal of Internal Medicine Nursing-Special Topics 2016, 2 (2): 73-9.
  • 5. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC: Amyotrophic Lateral Sclerosis. Lancet 2011, 377: 942–955.
  • 6. Nelson LM, Topol B, Kaye W, Williamson D, Horton DK, Mehta P, Wagner T: Estimation of The Prevalence of Amyotrophic Lateral Sclerosis in The United States Using National Administrative Healthcare Data From 2002 to 2004 and Capture-Recapture Methodology. Neuroepidemiology 2018, 51: 149-157.
  • 7. Jun KY, Park J, Oh KW, Kim EM, Bae JS, Kim I, Kim SH: Epidemiology of ALS in Korea Using Nationwide Big Data. Journal of Neurology Neurosurgery and Psychiatry 2019, 90 (4): 395-403.
  • 8. Logroscino G, Traynor BJ, Hardiman O, Chiò A, Mitchell D, Swingler RJ, Millul A, Benn E, Beghi E: Incidence of Amyotrophic Lateral Sclerosis in Europe. Journal of Neurology Neurosurgery and Psychiatry 2010, 81: 385-390.
  • 9. Ludolph A, Drory V, Hardiman O, Nakano I, Ravits J, Robberecht W, Shefner J: A Revision of The El Escorial Criteria. Informa Healthcare 2015, DOI: 10.3109/21678421.2015.1049183.
  • 10. Hardiman O, Van Den Berg LH, Kiernan MC: Clinical diagnosis and management of amyotrophic lateral sclerosis. Nature Reviews Neurology 2011, 7 (11): 639-649.
  • 11. Miller RG, Munsat TL, Swash M, Brooks BR: Consensus Guidelines for The Design and İmplementation of Clinical Trials in ALS, Journal of The Neurological Sciences 1992, 169: 2-12.
  • 12. Daube JR: Elektrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron disorders. Muscle & Nerve 2000, 23 (10): 1488-1502.
  • 13. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O: Amyotrophic lateral sclerosis mimic syndromes. Archives of Neurology 2000, 57(1):109-113.
  • 14. Turner MR, Kiernan MC, Leigh PN, Talbot K: Biomarkers in amyotrophic lateral sclerosis. The Lancet Neurology 2009, 8(1):94-109.
  • 15. Renton AE, Chiò A, Traynor BJ: State of play in amyotrophic lateral sclerosis genetics. Nature neuroscience 2014, 17 (1): 17-23.
  • 16. Rohrer JD, Isaacs AM, Mizielinska S, Mead S, Lashley T, Wray S, Sidle K, Fratta P, Orrell RW, Hardy J, Holton J, Revesz T, Rossor MN, Warren JD: C9orf72 Expansions İn Frontotemporal Dementia And Amyotrophic Lateral Sclerosis. Lancet Neurology 2015, 14: 291-301.
  • 17. Pioro EP: Antioxidant Therapy in ALS. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2000, 1 (4): 5-15.
  • 18. Vukosavic S, Dubois‐Dauphin M, Romero N, Przedborski S: Bax and Bcl‐2 ınteraction in a transgenic mouse model of familial amyotrophic lateral sclerosis. Journal Of Neurochemistry 1999, 73(6):2460-2468.
  • 19. Ito D, Suzuki N: Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS. Neurology 2011, 77 (17): 1636-1643.
  • 20. Lee JK, Shin JH, Lee JE, Choi EJ: Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 2015, 1852 (11): 2517-2524.
  • 21. Foran E, Trotti D: Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxidants & Redox Signaling 2009, 11 (7): 1587-1602.
  • 22. Tefera TW, Borges K: Metabolic dysfunctions in amyotrophic lateral sclerosis pathogenesis and potential metabolic treatments. Frontiers in Neuroscience 2017, 10:611.
  • 23. Tadic V, Prell T, Lautenschlaeger J, Grosskreutz J: The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis. Frontiers in Cellular Neuroscience 2014, 8:147.
  • 24. Thonhoff JR, Simpson EP, Appel SH: Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis. Current Opinion in Neurology 2018, 31(5):635-639.
  • 25. Simpson EP, Yen AA, Appel SH: Oxidative stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis. Current Opinion İn Rheumatology 2003, 15(6):730-736.
  • 26. Nassif M, Matus S, Castillo K, Hetz C: Amyotrophic Lateral Sclerosis Pathogenesis: A Journey Through The Secretory Pathway. Antioxidants Redox Signaling 2010, 13 (12): 1955-1989.
  • 27. Quigley EM: Microbiota-brain-gut axis and neurodegenerative diseases. Current neurology and neuroscience reports 2017, 17 (12): 1-9.
  • 28. Foran E, Trotti D: Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxidants & Redox Signaling 2009, 11 (7): 1587-1602.
  • 29. McDonnell ME, Vera MD, Blass BE, Pelletier JC, King RC, Fernandez-Metzler C, Smith GR, Wrobel J, Chen S, Wall BA, Reitz AB: Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling. Bioorganic & Medicinal Chemistry 2012, 20 (18): 5642-5648.
  • 30. Zhao H, Ji ZH, Liu C, Yu XY: Neuroprotective mechanisms of 9-hydroxy epinootkatol against glutamate-induced neuronal apoptosis in primary neuron culture. Journal of Molecular Neuroscience 2015, 56(4):808–814.
  • 31. Bensimon G, Lacomblez L, Meininger V, ALS/Riluzole Study Group: A controlled trial of riluzole in amyotrophic lateral sclerosis. The New England Journal Of Medicine 1994, 330 (9): 585-591.
  • 32. Jaiswal MK: Riluzole And Edaravone: A Tale of Two Amyotrophic Lateral Sclerosis Drugs. Medicinal Research Reviews 2019, 39 (2): 733-748.L
  • 33. Lee J, Ryu H, Kowall NW: Motor Neuronal Protection by L-Arginine Prolongs Survival of Mutant SOD1 (G93a) ALS Mice. Biochemical and Biophysical Research Communications 2009, 384 (4): 524-529.
  • 34. Thomas AG, Corse AM, Coccia CF, Wozniak KM, Hartman T, Jada P, Chandran M, Rothstein JF, Dalcanto M, Slusher BS: Naaladase (GCP II) inhibitors protect in models of amyotrophic lateral sclerosis (ALS). Journal Of Neurochemistry 2008, 81:60-63.
  • 35. Gerber YN, Privat A, Perrin FE: Gacyclidine improves the survival and reduces motor deficits in a mouse model of amyotrophic lateral sclerosis. Frontiers in Cellular Neuroscience 2013, 7: 280.
  • 36. Nagańska E, Matyja E, Taraszewska A, Rafałowska J: Protective Effect of Valproic Acid on Cultured Motor Neurons Under Glutamate Excitotoxic Conditions. Ultrastructural Study. Folia Neuropathologica 2015, 53 (4): 309-316, DOI: 10.5114/Fn.2015.56545.
  • 37. Blin O, Pouget J, Aubrespy G, Guelton C, Crevat A, Serratrice G: A double-blind placebo-controlled trial ofl-threonine in amyotrophic lateral sclerosis. Journal Of Neurology 1992, 239 (2): 79–81.
  • 38. Trojsi F, Siciliano M, Passaniti C, Bisecco A, Russo A, Lavorgna L, Esposito S, Ricciardi D, Monsurrò MR, Tedeschi G, Santangelo G: Vitamin D supplementation has no effects on progression of motor dysfunction in amyotrophic lateral sclerosis (ALS). European Journal Of Clinical Nutrition 2020, 74(1):167-175.
  • 39. Aizawa H, Kato H, Oba K, Kawahara T, Okubo Y, Saito T, Naito M, Urushitani M, Tamaoka A, Nakamagoe K, Ishii K, Kanda T, Katsuno M, Atsuta N, Maeda Y, Nagai M, Nishiyama K, Ishiura H, Toda T, Kawata A, Abe K, Yabe I, Takahashi-Iwata I, Sasaki H, Warita H, Aoki M, Sobue G, Mizusawa H, Matsuyama Y, Haga T, Kwak S: Safety and efficacy of perampanel for sporadic amyotrophic lateral sclerosis: a multicentre, double-blind, randomised phase 2 trial. The Lancet 2020.
  • 40. Smith R, Pioro E, Myers K, Sirdofsky M, Goslin K, Meekins G, Yu H, Wymer J, Cudkowicz M, Macklin EA, Schoenfeld D, Pattee G: Enhanced bulbar function in amyotrophic lateral sclerosis: the nuedexta treatment trial. Neurotherapeutics 2017, 14(3):762–772.
  • 41. Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown Jr RH, Zhang H, Schoenfeld DA, Shefner J, Matson S, Matson WR, Ferrante RJ, The Northeast ALS and The National Va ALS Research Consortiums (Appendix): Phase 2 study of sodium phenylbutyrate in ALS. Amyotrophic Lateral Sclerosis 2009, 10 (2): 99-106.
  • 42. Ryberg H, Askmark H, Persson LI. A Double‐Blind Randomized Clinical Trial in Amyotrophic Lateral Sclerosis Using Lamotrigine: Effects on Csf Glutamate, Aspartate, Branched‐Chain Amino Acid Levels and Clinical Parameters. Acta neurologica scandinavica 2003, 108: 1‐8.
  • 43. Miller RG, Shepherd R, Dao H, Khramstov A, Mendoza M, Graves J, Smith S: Controlled Trial of Nimodipine in Amyotrophic Lateral Sclerosis. Neuromuscular Disorders 1996, 6 (2): 101-104.
  • 44. Weiss MD, Macklin EA, Simmons Z, Knox AS, Greenblatt DJ, Atassi N, Graves M, Parziale N, Salameh JS, Quinn C, Brown RH, Distad JB, Trivedi J, Shefner JM, Barohn RJ, Pestronk A, Swenson A, Cudkowicz ME, Mexiletine ALS Study Group: A randomized trial of mexiletine in ALS: safety and effects on muscle cramps and progression. Neurology 2016, 86(16):1474‐1481.
  • 45. Shibuya K, Misawa S, Kimura H, Noto Y-I, Sato Y, Sekiguchi Y, Iwai Y, Mitsuma S, Beppu M, Watanabe K, Fujimaki Y, Tsuji Y, Shimizu T, Mizuno T, Nakagawa M, Sawaguchi K, Hanaoka H, Kuwabara S: A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: efficacy and safety of sodium channel blocker phase II trial. Amyotrophic Lateral Sclerosis an Frontotemporal Degeneration 2015, 16(5-6):353‐358.
  • 46. Paizs M, Tortarolo M, Bendotti C, Engelhardt JI, Siklós L: Talampanel Reduces The Level of Motoneuronal Calcium in Transgenic Mutant SOD1 Mice Only if Applied Presymptomatically. Amyotrophic Lateral Sclerosis 2011, 12 (5): 340-344, DOI: 10.3109/17482968.2011.584627.
  • 47. Kaji R, Imai T, Iwasaki Y, Okamoto K, Nakagawa M, Ohashi Y, Takase T, Hanada T, Shimizu H, Tashiro K, Kuzuhara S: Ultra-High-Dose Methylcobalamin in Amyotrophic Lateral Sclerosis: A Long-Term Phase II/III Randomised Controlled Study. Journal of Neurology Neurosurgery and Psychiatry 2019, 90, 451-457.
  • 48. De Carvalho M, Pinto S, Costa J, Evangelista T, Ohana B, Pinto A: A randomized, placebo‐controlled trial of memantine for functional disability in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 2010, 11 (5): 456-460.
  • 49. Yamamoto M, Tanaka F, Tatsumi H, Sobue G: A strategy for developing effective amyotropic lateral sclerosis pharmacotherapy: from clinical trials to novel pharmacotherapeutic strategies. Expert Opinion On Pharmacotherapy 2008, 9(11):1845-1857.
  • 50. Cudkowicz ME, Titus S, Kearney M, Yu H, Sherman A, Schoenfeld D, Hayden D, Shui A, Brooks B, Conwit R, Felsenstein D, Greenblatt DJ, Keroack M, Kissel JT, Miller R, Rosenfeld J, Rothstein JD, Simpson E, Tolkoff-Rubin N, Zinman L, Shefner JM, Ceftriaxone Study Investigators: Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. The Lancet Neurology 2014, 13 (11): 1083-1091.
  • 51. Miller RG, Moore DH, Gelinas DF, Dronsky V, Mendoza M, Barohn RJ, Bryan W, Ravits J, Yuen E, Neville H, Ringel S, Bromberg M, Petajan J, Amato AA, Jackson C, Johnson W, Mandler R, Bosch P, Smith B, Graves M, Ross M, Sorenson EJ, Kelkar P, Parry G, Olney R: Phase III Randomized Trial of Gabapentin in Patients with Amyotrophic Lateral Sclerosis. Neurology 2001, 56 (7): 843–848.
  • 52. Cudkowicz ME, Shefner JM, Schoenfeld DA, Brown Jr RH, Johnson H, Qureshi M, Jacobs M, Rothstein JD, Appel SH, Pascuzzi RM, Heiman-Patterson TD, Donofrio PD, David WS, Russell JA, Tandan R, Pioro EP, Felice KJ, Rosenfeld J, Mandler RN, Sachs GM, Brale WG, Raynor EM, Baquis GD, Belsh JM, Novella S, Goldstein J, Hulihan J: A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis, Neurology 2003, 61 (4), 456–464.
  • 53. Patten SA, Aggad D, Martinez J, Tremblay E, Petrillo J, Armstrong GAB, La Fontaine A, Maios C, Liao M, Ciura S, Wen XY, Rafuse V, Ichida J, Zinman L, Julien JP, Kabashi E, Robitaille R, Korngut L, Parker JA, Drapeau P: Neuroleptics as Therapeutic Compounds Stabilizing Neuromuscular Transmission in Amyotrophic Lateral Sclerosis. JCI Insight 2017, 2: e97152.
  • 54. Zhang X, Chen S, Lu K, Wang F, Deng J, Xu Z, Wang X, Zhou Q, Le W, Zhao, Y: Verapamil ameliorates motor neuron degeneration and improves lifespan in the SOD1G93A mouse model of ALS by enhancing autophagic flux. Aging and disease 2019, 10(6):1159.
  • 55. Andrews, J: Amyotrophic lateral sclerosis: clinical management and research update. Current Neurology and Neuroscience Reports 2009, 9 (1): 59-68.
  • 56. The Italian ALS Study Group: Branched‐chain amino acids and amyotrophic lateral sclerosis. Neurology 1993, 43(12):2466-2466.
  • 57. Vukosavic S, Dubois‐Dauphin M, Romero N, Przedborski S: Bax and Bcl‐2 ınteraction in a transgenic mouse model of familial amyotrophic lateral sclerosis. Journal Of Neurochemistry 1999, 73(6):2460-2468.
  • 58. Sathasivam S, Ince PG, Shaw PJ: Apoptosis in amyotrophic lateral sclerosis: a review of the evidence. Neuropathology and applied neurobiology 2001, 27(4):257-274.
  • 59. Katsumata R, Ishigaki S, Katsuno M, Kawai K, Sone J, Huang Z, Adachi H, Tanaka F, Urano F, Sobue G: C-Abl İnhibition Delays Motor Neuron Degeneration in The G93a Mouse, An Animal Model of Amyotrophic Lateral Sclerosis. Plos One 2012, 7 (9): e46185.
  • 60. Zhang Y, Cook A, Kim J, Baranov SV, Jiang J, Smith K, Cormier K, Bennett E, Browser RP, Day AL, Carlisle DL, Ferrante RJ, Wang X, Friedlander RM: Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiology of Disease 2013, 55:26-35.
  • 61. Lauria G, Campanella A, Filippini G, Martini A, Penza P, Maggi L, Antozzi C, Ciano C, Beretta P, Caldiroli D, Ghelma F, Ferrara G, Ghezii P, Mantegazze R: Erythropoietin in Amyotrophic Lateral Sclerosis: A Pilot, Randomized, Double-Blind, Placebo-Controlled Study of Safety and Tolerability. Informa Healthcare 2009, 10: 410-415.
  • 62. Scelsa SN, MacGowan DJL, Mitsumoto H, Imperato T, LeValley AJ, Liu MH, DelBene M, Kim MY: A pilot, double-blind, placebo-controlled trial of indinavir in patients with ALS. Neurology 2005, 64(7):1298–300.
  • 63. Miller R, Bradley W, Cudkowicz M, Hubble J, Meinenger V, Mitsumoto H, Moore D, Pohlmann H, Sauer D, Silani V, Strong M, Swash M, Vernotica E, The TCH346 Study Group: Phase II/III Randomized Trial of TCH346 in Patients with ALS. Neurology 2007, 69 (8): 776‐784.
  • 64. Yoshino H, Kimura A: Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (phase II study). Amyotrophic Lateral Sclerosis 2006, 7(4):247-251.
  • 65. Matteo V, Esposito E: Biochemical and Therapeutic Effects of Antioxidants in the Treatment of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis. Current Drug Targets-CNS & Neurological Disorders 2003, 2 (2): 95-107.
  • 66. Okada M, Yamashita S, Ueyama H, Ishizaki M, Maeda Y, Ando Y: Long-Term Effects of Edaravone on Survival of Patients with Amyotrophic Lateral Sclerosis. eNeurologicALSci 2018, 11: 11-14.
  • 67. Abe K, Aoki M, Tsuji S, Itoyama Y, Sobue G, Togo M, Hamada C, Tanaka M, Akimoto M, Nakamura K, Takahashi F, Kondo K, Yoshino H: Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. The Lancet Neurology 2017, 16 (7), 505-512.
  • 68. Hayes-Punzo A, Mulcrone P, Meyer M, McHugh J, Svendsen CN, Suzuki M: Gonadectomy and dehydroepiandrosterone (DHEA) do not modulate disease progression in the G93A mutant SOD1 rat model of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 2012, 13 (3): 311-314.
  • 69. Petri S, Calingasan NY, ALSaied OA, Wille E, Kiaei M, Friedman JE, Baranova O, Chavez JC, Beal MF: The Lipophilic Metal Chelators DP‐109 And DP‐460 Are Neuroprotective in A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. Journal of Neurochemistry 2007, 102 (3): 991-1000.
  • 70. Kupershmidt L, Weinreb O, Amit T, Mandel S, Carri MT, Youdim MBH: Neuroprotective and Neuritogenic Activities of Novel Multimodal İron‐Chelating Drugs in Motor‐Neuron‐Like Nsc‐34 Cells and Transgenic Mouse Model of Amyotrophic Lateral Sclerosis, The Faseb Journal 2009, 23 (11): 3766-3779.
  • 71. Petri S, Kiaei M, Kipiani K, Chen J, Calingasan NY, Crow JP, Beal MF: Additive Neuroprotective Effects of A Histone Deacetylase İnhibitor and A Catalytic Antioxidant in A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. Neurobiology of Disease 2006, 22 (1): 40-49.
  • 72. Orrell RW: AEOL-10150 (Aeolus), Current Opinion in Investigational Drugs (London, England: 2000) 2006, 7 (1): 70-80.
  • 73. Nicholson K, Can J, Macklin EA, Levine-Weinberg M, Breen C, Bakshi R, Grasso DL, Wils AM, Jahandideh S, Taylor AA, Beaulieu D, Ennist DL, Andronesi O, Ratai EM, Schwarzschild MA, Cudkowicz M, Paganoni S: Pilot Trial of İnosine to Elevate Urate Levels in Amyotrophic Lateral Sclerosis. Annals of Clinical and Translational Neurology 2018, 5 (12): 1522-1533.
  • 74. Martinez A, Palomo Ruiz M, Del V, Perez DI, Gil C: Drugs in Clinical Development for The Treatment of Amyotrophic Lateral Sclerosis. Expert Opinion on Investigational Drugs 2017, 26 (4): 403–414.
  • 75. Desnuelle C, Dib M, Garrel C, Favier A: A double-blind, placebo-controlled randomized clinical trial of α-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2001, 2 (1): 9-18.
  • 76. Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton M, Urbinelli L, Qureshi M, Zhang H, Pestronk A, Caress J, Donofrio P, Sorenson E, Bradley W, Lomen-Hoerth C, Pioro E, Rezania K, Ross M, Pascuzzi R, Heiman-Patterson T, Tandan R, Mitsumoto H, Rothstein J, Smith-Palmer T, MacDonald D, Burke D: A clinical trial of creatine in ALS. Neurology 2004, 63(9):1656 –1661.
  • 77. Rosenfeld J, King RM, Jackson, CE, Bedlack RS, Barohn RJ, Dick A, Phillips LH, Chapin J, Gelinas DF, Lou JS: Creatine Monohydrate in ALS: Effects on Strength, Fatigue, Respiratory Status and ALSFRS. Amyotrophic Lateral Sclerosis 2009, 9 (5): 266-272.
  • 78. Kaufmann P, Thompson JLP, Levy G, Buchsbaum R, Shefner J, Krivickas LS, Katz J, Rollins Y, Barohn RJ, Jackson CE, Tiryaki E, Lomen-Hoerth C, Armon C, Tandan R, Rudnicki SA, Rezania K, Sufit R, Pestronk A, Novella SP, Heiman-Patterson T, Kasarskis EJ, Pioro EP, Montes J, Arbing R, Vecchio D, Barsdorf A, Mitsumoto H, Levin B: Phase II Trial of Coq10 for ALS Finds İnsufficient Evidence to Justify Phase III†. Annals of Neurology 2009, 66 (2): 235-244.
  • 79. Kwieciński H, Janik P, Jamrozik Z, Opuchlik A: The Effect of Selegiline and Vitamin E in The Treatment of ALS: An Open Randomized Clinical Trials. Neurologia i Neurochirurgia Polska 2001, 35 (1): 101-106.
  • 80. Statland JM, Moore D, Wang Y, Walsh M, Mozaffar T, Elman L, Nations SP, Mitsumoto H, Fernandes A, Saperstein D, Hayat G, Herbelin L, Karam C, Katz J, Wilkins HM, Agbas A, Swerdlow RH, Santella RM, Dimachkie MM, Barohn RJ: Rasagiline for amyotrophic lateral sclerosis: a randomized, controlled trial. Muscle & Nerve 2019, 59(2):201-207.
  • 81. Louwerse ES, Weverling GJ, Bossuyt PMM: Randomized, Double-Blind, Controlled Trial of Acetylcysteine in Amyotrophic Lateral Sclerosis. Archives of Neurology 1995, 52 (6): 559-564.
  • 82. Nagata E, Ogino M, Iwamoto K, Kitagawa Y, Iwasaki Y, Yoshii F, Ikeda JE: Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients. Plos One 2016, 11 (3): e0149509.
  • 83. Cudkowicz ME, van den Berg LH, Shefner JM, Mitsumoto H, Mora JS, Ludolph A, Hardiman O, Bozik ME, Ingersoll EW, Archibald D, Meyers AL, Dong Y, Farwell WR, Kerr DA: Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. The Lancet Neurology 2013, 12 (11): 1059-1067.
  • 84. Hottinger AF, Fine EG, Gurney ME, Zurn AD, Aebischer P: The copper chelator d‐penicillamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis. European Journal of Neuroscience 1997, 9 (7): 1548-1551.
  • 85. Li W, Fotinos A, Wu Q, Chen Y, Zhu Y, Baranov S, Tu Y, Zhou EW, Sinha B, Kristal BS, Wang X: N-Acetyl-L-Tryptophan Delays Disease Onset and Extends Survival in An Amyotrophic Lateral Sclerosis Transgenic Mouse Model. Neurobiology of Disease 2015, 80: 93-103.
  • 86. Evans MC, Gaillard PJ, De Boer M, Appeldoorn C, Dorland R, Sibson NR, Turner MR, Anthony DC, Stolp HB: CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis. Acta Neuropathologica Communications 2014, 2 (1): 1-13.
  • 87. Ahn SW, Jeon GS, Kim MJ, Shon JH, Kim JE, Shin JY, Kim SM, Kim SH, Ye IH, Lee KW, Hong YH, Sung JJ: Neuroprotective effects of JGK-263 in transgenic SOD1-G93A mice of amyotrophic lateral sclerosis. Journal of The Neurological Sciences 2014, 340 (1-2): 112-116.
  • 88. Lee SH, Choi SM, Yang EJ: Melittin Ameliorates The Inflammation of Organs in An Amyotrophic Lateral Sclerosis Animal Model. Experimental Neurobiology 2014, 23 (1): 86.
  • 89. Kumar S, Phaneuf D, Julien JP: Withaferin-A Treatment Alleviates Tar DNA-Binding Protein-43 Pathology and Improves Cognitive Function in A Mouse Model of Ftld. Neurotherapeutics 2020, 1-11.
  • 90. Urbi B, Owusu MA, Hughes I, Katz M, Broadley S, Sabet A: Effects of cannabinoids in amyotrophic lateral sclerosis (ALS) murine models: a systematic review and meta-analysis. Journal Of Neurochemistry 2019, 149(2):284-297.
  • 91. Pascuzzi R: Cc100: Phase 1 Multiple-Dose Safety And Tolerability İn Subjects With ALS (Cc100b). 2017.
  • 92. Grievink HW, Heuberger JA, Huang F, Chaudhary R, Birkhoff WA, Tonn GR, Mosesova S, Erickson R, Moerland M, Haddick PC, Scearce-Levie K, Ho C, Groeneveld GJ: DNL 104, a centrally penetrant RIPK 1 inhibitor, inhibits RIP 1 kinase phosphorylation in a randomized phase I ascending dose study in healthy volunteers. Clinical Pharmacology & Therapeutics 2020, 107 (2): 406-414.
  • 93. Maier A, Deigendesch N, Muller K, Weishaupt JH, Krannich A, Rohle R, Meissner F, Molawi K, Munch C, Holm T, Meyer R, Meyer T, Zychlinsky A: Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis-A Pilot Study. Plos One 2015, 10 (10): e0139684.
  • 94. Clinical Trials.; 2021 Nisan 25. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03456882 [İnternet sitesi]
  • 95. Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, Drachman DB, Northeast ALS Consortium: Trial of celecoxib in amyotrophic lateral sclerosis. Annals Of Neurology 2006, 60 (1): 22-31.
  • 96. Stommel IW, Cohen JA, Fadul CE, Cogbill CH, Graber DJ, Kingman L, Mackenzie T, Smith JYC, Harris BT: Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotrophic Lateral Sclerosis 2009, 10(5-6):393‐404.
  • 97. Gordon PH, Doorish C, Montes J, Mosley RL, Diamond B, MacArthur RB, Weimer LH, Kaufmann P, Hays AP, Rowland LP, Gendelman HE, Przedborski S, Mitsumoto H: Randomized controlled phase II trial of glatiramer acetate in ALS. Neurology 2006, 66 (7): 1117–1119.
  • 98. Mora JS, Genge A, Chio A, Estol CJ, Chaverri D, Hernández M, Marín S, Mascias J, Rodriguez GE, Povedano M, Paipa A, Dominguez R, Gamez J, Salvado M, Lunetta C, Ballario C, Riva N, Mandrioli J, Moussy A, Kinet JP, Auclair C, Dubreuil P, Arnold V, Mansfield CD, Hermine O: Masitinib As An Add-On Therapy To Riluzole İn Patients With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2020, 21 (1-2): 5-14.
  • 99. Berry JD, Paganoni S, Atassi N, Macklin EA, Goyal N, Rivner M, Simpson E, Appel S, Grasso DL, Mejia NI, Mateen F, Gill A, Vieira F, Tassinari V, Perrin S: Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability. Muscle & Nerve 2017, 56 (6): 1077-1084.
  • 100. Lingor P, Weber M, Camu W, Friede T, Hilgers R, Leha A, Neuwirth C, Günther R, Benatar M, Kuzma-Kozakiewicz M, Bidner H, Blankenstein C, Frontini R, Ludolph A, Koch JC: ROCK-ALS: Protocol for A Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of The Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis. Frontiers in Neurology 2019, 10.
  • 101. Meininger V, Asselain B, Guillet P, Leigh PN, Ludolph A, Lacomblez L, Robberecht W: Pentoxifylline in ALS: a double-blind, randomized, multicenter, placebo-controlled trial. Neurology 2006, 66 (1): 88-92.
  • 102. Lindhorst S, Cudkowicz M: Is Pentoxifylline Safe and Effective in Patients with Amyotrophic Lateral Sclerosis. Nature Clinical Practice Neurology 2006, 2 (7): 364–365.
  • 103. Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R: Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. The Lancet Neurology 2007, 6 (12): 1045-1053.
  • 104. Clinical Trials.; 2021 Nisan 18. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT03039673 [İnternet sitesi]
  • 105. Mandrioli J, D'Amico R, Zucchi E, Gessani A, Fini N, Fasano A, Caponnetto C, Chiò A, Dalla-Bella E, Lunetta C, Mazzini L, Marinou K, Sorarù G, de Biasi S, Lo Tartoaro D, Pinti M, Cossarizza A: Rapamycin Treatment for Amyotrophic Lateral Sclerosis: Protocol for A Phase II Randomized, Double‐Blind, Placebo‐Controlled, Multicenter, Clinical Trial (RAP‐ALS Trial). Medicine (Baltimore) 2018, 97: e11119.
  • 106. Clinical Trials.; 2021 Nisan 27. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03693781 [İnternet sitesi]
  • 107. Thonhoff JR, Beers DR, Zhao W, Pleitez M, Simpson EP, Berry JD, Cudkowicz ME, Appel SH: Expanded autologous regulatory T-lymphocyte infusions in ALS: a phase I, first-in-human study. Neurology-Neuroimmunology Neuroinflammation 2018, 5(4).
  • 108. Clinical Trials.; 2021 Nisan 29. Erişim yeri: https://clinicaltrials.gov/ct2/show/results/NCT04055623 [İnternet sitesi]
  • 109. Clinical Trials.; 2021 Nisan 18. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03127267 [İnternet sitesi]
  • 110. Clinical Trials.; 2021 Nisan 28. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03981536 [İnternet sitesi]
  • 111. Fournier CN, Schoenfeld D, Berry JD, Cudkowicz ME, Chan J, Quinn C, Brown RH, Salameh JS, Tansey MG, Beers DR, Appel SH, Glass JD: An open label study of a novel immunosuppression intervention for the treatment of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2018, 19 (3-4): 242-249.
  • 112. Beghi E, Chiò A, Inghilleri M, Mazzini L, Micheli A, Mora G, Poloni M, Riva R, Serlenga L, Testa D, Tonali P, The Italian Amyotrophic Lateral Sclerosis Study Group: A randomized controlled trial of recombinant interferon beta-1a in ALS. Neurology 2000, 54 (2): 469-469.
  • 113. ALSUntangled Group: ALSUntangled 58: Azathioprine. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2020, 1-3.
  • 114. Smith SA, Miller RG, Murphy JR, Ringel SP: Treatment of ALS with high dose pulse cyclophosphamide. Journal of the neurological sciences 1994, 124:84-87.
  • 115. Meucci N, Nobile-Orazio E: Intravenous immunoglobulin therapy in amyotrophic lateral sclerosis. Journal of neurology 1996, 243(2):117-120.
  • 116. Drachman DB, Chaudhry V, Cornblath D, Kuncl RW, Pestronk A, Clawson L, Mellits ED, Quaskey S, Quinn T, Calkins A, Order, S. Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 1994, 35(2):142-150.
  • 117. Lu H, Le WD, Xie YY, Wang XP: Current therapy of drugs in amyotrophic lateral sclerosis. Current neuropharmacology 2016, 14 (4): 314-321.; Kazak F, Yarım GF: Beyin Kaynaklı Nörotrofik Faktör. Atatürk Üniversitesi Veteriner Bilimleri Dergisi 2015, 10 (2): 120-129.
  • 118. Sun W, Funakoshi H, Nakamura T: Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. The Journal of Neuroscience 2002, 22(15):6537–6548.
  • 119. Manabe Y, Nagano I, Gazi MSA, Murakami T, Shiote M, Shoji M, Kitagawa H, Abe K: Glial Cell Line-Derived Neurotrophic Factor Protein Prevents Motor Neuron Loss of Transgenic Model Mice for Amyotrophic Lateral Sclerosis. Neurological Research 2003, 25 (2): 195–200.
  • 120. ALS CNTF Treatment Study Group: A double‐blind placebo‐controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 1996, 46 (5): 1244‐1249.
  • 121. Zinman L, Cudkowicz M: Emerging targets and treatments in amyotrophic lateral sclerosis. The Lancet Neurology 2011, 10(5):481–490.
  • 122. Wobst HJ, Mack KL, Brown DG, Brandon NJ, Shorter J: The clinical trial landscape in amyotrophic lateral sclerosis—past, present, and future. Medicinal research reviews 2020, 40(4):1352-1384.
  • 123. Sufit RL, Ajroud-Driss S, Casey P, Kessler JA: Open label study to assess the safety of vm202 in subjects with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration 2017, 18(3-4):269-278.
  • 124. Meininger V, Bensimon G, Bradley WG, Brooks BR, Douillet P, Eisen AA, Lacomblez L, Leigh PN, Robberecht W: Efficacy and Safety of Xaliproden in Amyotrophic Lateral Sclerosis: Results of Two Phase III Trials. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2004, 5 (2): 107-117.
  • 125. The BDNF Study Group: A controlled trial of recombinant methionyl human BDNF in ALS. Neurology 1999, 52(7):1427‐1427.
  • 126. Caroscio JT, Cohen JA, Zawodniak J, Takai V, Shapiro A, Blaustein S, Mulvihill MN, Loucas SP, Gudesblatt M, Rube D, Yahr MD: A double‐blind, placebo‐controlled trial of TRH in amyotrophic lateral sclerosis. Neurology 1986, 36 (2): 141-141.
  • 127. Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, Barkhaus PE, Bosch P, Boylan K, David WS, Feldman E, Glass J, Gutmann L, Katz J, King W, Luciano CA, McCluskey LF, Nash S, Newman DS, Pascuzzi RM, Pioro E, Sams LJ, Scelsa S, Simpson EP, Subramony SH, Tiryaki E, Thornton CA: Subcutaneous Igf‐1 is not beneficial in 2‐year ALS trial. Neurology 2008, 71(22):1770‐1775.
  • 128. Duffy LM, Chapman AL, Shaw PJ, Grierson AJ: The role of mitochondria in the pathogenesis of amyotrophic lateral sclerosis. Neuropathology and Applied Neurobiology 2011, 37 (4): 336-352.
  • 129. Lenglet T, Lacomblez L, Abitbol JL, Ludolph A, Mora JS, Robberecht W, Shaw PJ, Pruss RM, Cuvier V, Meininger V: A Phase II-III Trial of Olesoxime in Subjects with Amyotrophic Lateral Sclerosis. European Journal of Neurology 2014, 21: 529–536.
  • 130. Martin LJ, Fancelli D, Wong M, Niedwiecki M, Ballarini M, Plyte S, Chang Q: Gnx-4728, A Novel Small Molecule Drug İnhibitor of Mitochondrial Permeability Transition, is Therapeutic in A Mouse Model of Amyotrophic Lateral Sclerosis. Frontiers in Cellular Neuroscience 2014, https://Doi.Org/10.3389/Fncel.2014.00433.
  • 131. Wang H, Guan Y, Wang X, Smith K, Cormier K, Zhu S, Stravrovskaya IG, Huo C, Ferrante RJ, Kristal BS, Frienlander RM: Nortriptyline delays disease onset in models of chronic neurodegeneration. European Journal Of Neuroscience 2007, 26(3):633-641.
  • 132. Karlsson J, Fong KSK, Hansson MJ, Elmér E, Csiszar K, Keep MF:, Life Span Extension And Reduced Neuronal Death After Weekly İntraventricular Cyclosporin İnjections in The G93a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. Journal of neurosurgery 2004, 101 (1): 128–137.
  • 133. Pieper AA, McKnight SL, Ready JM: P7C3 and An Unbiased Approach to Drug Discovery for Neurodegenerative Diseases. Chemical Society Reviews 2014, 43: 6716-6726.
  • 134. Zhang JJ, Zhou QM, Chen S, Le WD: Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1‐G93A mouse model. CNS Neuroscience & Therapeutics 2018, 24(12):1163-1174.
  • 135. Chiò A, Borghero G, Calvo A, Capasso M, Caponnetto C, Corbo M, Giannini F, Logroscino G, Mandrioli J, Marcello N, Mazzini L, Moglia C, Monsurrò MR, Mora G, Patti F, Perini M, Pietrini V, Pisano F, Pupillo E, Sabatelli M, Salvi F, Silani V, Simone IL, Sorarù G, Tola MR, Volanti P, Beghi E: Lithium carbonate in amyotrophic lateral sclerosis lack of efficacy in a dose-finding trial. Neurology 2010, 75 (7): 619-625.
  • 136. Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S, Paparelliet A: Lithium delays progression of amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences 2008, 105 (6): 2052-2057.
  • 137. Chen PC, Hsieh YC, Huang CC, Hu CJ: Tamoxifen for amyotrophic lateral sclerosis: a randomized double-blind clinical trial. Medicine 2020, 99 (22): e20423.
  • 138. Clinical Trials.; 2021 Nisan 25. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03508453 [İnternet sitesi]
  • 139. Wang IF, Tsai KJ, Shen CKJ: Autophagy activation ameliorates neuronal pathogenesis of FTLD-U mice: a new light for treatment of TARDBP/TDP-43 proteinopathies. Autophagy 2013, 9(2):239-240.
  • 140. Webster CP, Smith EF, Shaw PJ, De Vos KJ: Protein homeostasis in amyotrophic lateral sclerosis: therapeutic opportunities?. Frontiers in Molecular Neuroscience 2017, 10:123.
  • 141. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ: Protein aggregation in amyotrophic lateral sclerosis. Acta neuropathologica 2013, 125 (6): 777-794.
  • 142. Chang CF, Lee YC, Lee KH, Lin HC, Chen CL, Shen CKJ, Huang CC: Therapeutic effect of berberine on TDP-43-related pathogenesis in FTLD And ALS. Journal of Biomedical Science 2016, 23 (1): 1-12.
  • 143. Lange DJ, Andersen PM, Remanan R, Marklund S, Benjamin D: Pyrimethamine Decreases Levels of SOD1 in Leukocytes and Cerebrospinal Fluid of ALS Patients: A Phase I Pilot Study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2013, 14 (3): 199-204.
  • 144. Clinical Trials.; 2021 Nisan 27. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03580616 [İnternet sitesi]
  • 145. Benatar M, Wuu J, Andersen PM, Atassi N, David W, Cudkowicz M, Schoenfeld D: Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology 2018, 90 (7): 565-574.
  • 146. Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, Bostrom A, Theodoss J, Al-Nakhala BM, Vieira FG, Ramasubbu J, Heywood JA: Design, power, and interpretation of studies in the standard murine model of ALS. Amyotrophic Lateral Sclerosis 2008, 9(1):4-15.
  • 147. Alfahad T, Nath A: Retroviruses and amyotrophic lateral sclerosis. Antiviral Research 2013, 99 (2): 180-187.
  • 148. Gold J, Rowe DB, Kiernan MC, Vucic S, Mathers S, Van Eijk RP, Nath A, Montojo MG, Norato G, Santamaria UA, Rogers ML, Malaspina A, Lombardi V, Mehta PR, Westeneng HJ, Van Den Berg LH, Al-Chalabi A: Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the lighthouse trial. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2019, 20 (7-8): 595-604.
  • 149. Percy AK, Davis LE, Johnston DM, Drachman DB: Failure of isoprinosine in amyotrophic lateral sclerosis. New England Journal of Medicine 1971, 285 (12).
  • 150. Norris FH, Calanchinii PR, Fallat RJ, Panchari S, Jewett B: The administration of guanidine in amyotrophic lateral sclerosis. Neurology 1974, 24(8):721-721.
  • 151. Mora JS, Munsat TL, Kao KP, Finison LJ, Hedlund W, Bradley GA, Scheife, R, Georgiades JA: Intrathecal administration of natural human interferon alpha in amyotrophic lateral sclerosis. Neurology 1986, 36 (8): 1137-1137.
  • 152. Warita H, Kato M, Asada R, Yamashita A, Hayata D, Adachi K, Aoki M: Safety, tolerability, and pharmacodynamics of intrathecal injection of recombinant human HGF (KP‐100) in subjects with amyotrophic lateral sclerosis: a phase I trial. The journal of clinical pharmacology 2019, 59(5):677-687.
  • 153. Clinical Trials.; 2021 Nisan 27. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03626012 [İnternet sitesi]
  • 154. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT00886977 [İnternet sitesi]
  • 155. Clinical Trials.; 2021 Nisan 19. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03127514 [İnternet sitesi]
  • 156. Juntas-Morales R, Pageot N, Bendarraz A, Alphandéry S, Sedel F, Seigle S, Camu W, High-dose pharmaceutical grade biotin (MD1003) in amyotrophic lateral sclerosis: A pilot study. EClinicalMedicine 2020, 19, 100254.
  • 157. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT02450552 [İnternet sitesi]
  • 158. De La Rubia JE, Drehmer E, Platero JL, Benlloch M, Caplliure-Llopis J, Villaron-Casales C, Bernardo ND, Alarcòn J, Fuente C, Carrera S, Sancho D, Garcia-Pardo P, Pascual R, Juarez M, Cuerda-Ballester M, Forner A, Sancho-Castillo S, Barrios C, Obrador E, Marchio P, Salvador R, Holmes HE, Dellinger RW, Guarente L, Estrela JM: Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study. Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration 2019, 20 (1-2): 115-122.
  • 159. Beghi E, Pupillo E, Bonito V, Buzzi P, Caponnetto C, Chiò A, Corbo M, Giannini F, Inghilleri M, La Bella V, Logroscino G, Lorusso L, Lunetta C, Mazzini L, Messina P, Mora G, Perini M, Quadrelli ML, Silani V, Simone IL, Tremolizzo L, The Italian Amyotrophic Lateral Sclerosis Study Group: Randomized double‐blind placebo‐controlled trial of acetyl‐l‐carnitine for ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2013, 14 (5-6): 397-405.
  • 160. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT02469896 [İnternet sitesi]
  • 161. Clinical Trials.; 2021 Mayıs 11. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT02238626 [İnternet sitesi]
  • 162. Miller RG, Block G, Katz JS, Et Al. Randomized Phase 2 Trial Of Np001‐A Novel İmmune Regulator: Safety And Early Efficacy in ALS. Neurol Neuroimmunol Neuroinflamm. 2015;2: E100.
  • 163. Kovalchuk MO, Heuberger JA, Sleutjes BT, Ziagkos D, van den Berg LH, Ferguson TA, Franssen H, Groeneveld GJ: Acute effects of riluzole and retigabine on axonal excitability in patients with amyotrophic lateral sclerosis: a randomized, double‐blind, placebo‐controlled, crossover trial. Clinical Pharmacology & Therapeutics 2018, 104 (6): 1136-1145.
  • 164. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT00748501 [İnternet sitesi]
  • 165. Meininger, V., Genge, A., Van Den Berg, L. H., Robberecht, W., Ludolph, A., Chio, A., Kim SH, Leigh N, Kiernan MC, Shefner, J. M., Desnuelle C, Morrison KE, Petri S, Boswell D, Temple J, Mohindra R, Davies M, Bullman J, Rees P, Lavrov A: Safety and Efficacy of Ozanezumab in Patients with Amyotrophic Lateral Sclerosis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial. The Lancet Neurology 2017, 16 (3): 208–216.
  • 166. VanMeter S, Becker P, Mackey L, Fang L, Zhao E: Post hoc analysis using PRO‐ACT database to evaluate repository corticotropin injection (H.P. Acthar® Gel) as a potential treatment for ALS (P5.327). Neurology 2018.
  • 167. Dupuis L, Dengler R, Heneka MT, Meyer T, Zierz S, Kassubek J, Fischer W, Steiner F, Lindauer E, Otto M, Dreyhaupt J, Grehl T, Hermann A, Winkler AS, The GERP ALS Study Group: A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PloS One 2012, 7 (6): e37885.
  • 168. Moreau C, Danel V, Devedjian JC, Grolez G, Timmerman K, Laloux C, Petrault M, Gouel F, Jonneaux A, Dutheil M, Lachaud C, Lopes R, Kuchcinski G, Auger F, Kyheng M, Duhamel A, Pérez T, Pradat PF, Blasco H, Veyrat-Durebex C, Corcia P, Oeckl P, Otto M, Dupuis L, Garçon G, Defebvre L, Cabantchik ZL, Duce J, Bordet R, Devos D: Could Conservative İron Chelation Lead to Neuroprotection in Amyotrophic Lateral Sclerosis?. Antioxidants Redox Signaling 2018, 29: 742‐748.
  • 169. Clinical Trials.; 2021 Nisan 30. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04082832 [İnternet sitesi]
  • 170. Kindy M, Lupinacci P, Chau R, Shum T, Ko D: A Phase 2a Randomized, Double-Blind, Placebo-Controlled Pilot Trial of GM604 in Patients with Amyotrophic Lateral Sclerosis (ALS Protocol GALS-001) and A Single Compassionate Patient Treatment (Protocol GALS-C). F1000research 2017, 6: 230.
  • 171. Clinical Trials.; 2021 Nisan 27. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT03800524 [İnternet sitesi]
  • 172. Clinical Trials.; 2021 Mayıs 3. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04248465 [İnternet sitesi]
  • 173. Clinical Trials.; 2021 Ağustos 31. Erişim yeri: https://clinicaltrials.gov/ct2/show/record/NCT03505021 [İnternet siesi]
  • 174. Clinical Trials.; 2021 Nisan 30. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04220021 [İnternet sitesi]
  • 175. Clinical Trials.; 2021 Nisan 30. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04057898 [İnternet sitesi]
  • 176. Clinical Trials.; 2021 Mayıs 3. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT04494256 [İnternet sitesi]
  • 177. Clinical Trials.; 2021 Mayıs 3. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT04322149 [İnternet sitesi]
  • 178. Clinical Trials.; 2021 Mayıs 3. Erişim yeri: https://www.clinicaltrials.gov/ct2/show/study/NCT04856982 [İnternet sitesi]
  • 179. Andrews JA, Miller TM, Vijayakumar V, Stoltz R, James JK, Meng L, Wolff AA, Malik FI: CK‐2127107 amplifies skeletal muscle response to nerve activation in humans. Muscle & Nerve 2018, 57 (5): 729-734.
  • 180. Clinical Trials.; 2021 Ağustos 25. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT05021536 [İnternet sitesi]
  • 181. Clnical Trials.; 2020 Eylül 11. Erişim yeri: https://clinicaltrials.gov/ct2/show/results/NCT03160898 [İnternet sitesi]
  • 182. Mitchell JD, Borasio GD: Amyotrophic Lateral Sclerosis. The Lancet 2007, 369 (9578): 2031-2041.
  • 183. Clinical Trials.; 2021 Nisan 20. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT03186040 [İnternet sitesi]
  • 184. Clinical Trials.; 2021 Nisan 25. Erişim yeri: https://www.clinicaltrials.gov/ct2/show/results/NCT03472950 [İnternet sitesi]
  • 185. Chandrashekhar S, Hamasaki A, McCalley A, Herbelin L, Pasnoor M, Jawdat O, Dimachkie M, Barohn R, Statland J: Open-label pilot study of ranolazine for cramps in amyotrophic lateral sclerosis (ALS). (2374). Neurology 2020, 94 (15).
  • 186. Clinical Trials.; 2021 Nisan 25. Erişim yeri: https://clinicaltrials.gov/ct2/show/study/NCT03482050 [İnternet sitesi]
  • 187. Clinical Trials.; 2021 Nisan 15. Erişim yeri: https://clinicaltrials.gov/ct2/show/results/NCT02478450 [İnternet sitesi]
  • 188. Clinical Trials.; 2021 Nisan 18. Erişim yeri: https://clinicaltrials.gov/ct2/show/NCT02943850 [İnternet sitesi]
  • 189. Clinical Trials.; 2021 Nisan 20. Erişim yeri: https://clinicaltrials.gov/ct2/show/results/NCT03280056 [İnternet sitesi]
  • 190. Oh KW, Noh MY, Kwon MS, Kim HY, Oh SI, Park J, Kim HJ, Ki CS, Kim SH: Repeated intrathecal mesenchymal stem cells for amyotrophic lateral sclerosis. Annals of Neurology 2018, 84 (3): 361-373.
  • 191. Jaradat N, Hawash M, Zaid AN, Natsheh A-R, Yousef R, AbuHasan Q: The Neuroprotective Role of Origanum syriacum L. and Lavandula dentata L. Essential Oils through Their Effects on AMPA Receptors. BioMed Research International 2019.
  • 192. Kumar V, Gupta P, Hassan MI: Mechanism and implications of Traditional Chinese medicine in amyotrophic lateral sclerosis therapy. Journal of Proteins and Proteomics 2019, 10(2): 131-147.
There are 192 citations in total.

Details

Primary Language Turkish
Subjects Pharmacology and Pharmaceutical Sciences
Journal Section Review Articles
Authors

Zeynep Yıldırım 0000-0003-4192-8887

Dicle Naz Toktaş 0000-0002-8165-8618

Öznur Demir 0000-0003-4079-7600

Zülfiye Gül 0000-0002-8872-0074

Burcu Şen Utsukarçi 0000-0002-2720-9686

Publication Date March 1, 2023
Acceptance Date February 14, 2023
Published in Issue Year 2023 Volume: 43 Issue: 1

Cite

Vancouver Yıldırım Z, Toktaş DN, Demir Ö, Gül Z, Şen Utsukarçi B. Amyotrofik Lateral Skleroz Patofizyolojisi ve Tedavi Yaklaşımları. HUJPHARM. 2023;43(1):50-69.

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