Therapeutic approaches to multiple sclerosis: An update on failed, interrupted, or inconclusive trials of neuroprotective and alternative treatment strategies

BioDrugs

Volumn 24, Issue 5, 2010, Pages 317-330

  Meuth, Sven G ^a,b   Bittner, Stefan ^a   Ulzheimer, Jochen C ^a,c   Kleinschnitz, Christoph ^a   Kieseier, Bernd C ^d   Wiendl, Heinz ^b  

^a UNIVERSITY OF WÜRZBURG   (Germany)

^b UNIVERSITY OF MÜNSTER   (Germany)

^c CARITAS KRANKENHAUS   (Germany)

^d HEINRICH HEINE UNIVERSITY   (Germany)

Author keywords

biological toxins, therapeutic use; immunoglobulins, therapeutic use; multiple sclerosis; neuroprotectants, therapeutic use; research and development; testosterone, therapeutic use; vitamin D analogues, therapeutic use.

Indexed keywords

BEE VENOM; BRAIN DERIVED NEUROTROPHIC FACTOR; CALCITRIOL; CHAPERONIN; COLECALCIFEROL; FLECAINIDE; HEAT SHOCK PROTEIN 10; IMMUNOGLOBULIN; LAMOTRIGINE; METHYLPREDNISOLONE; NEUROTROPHIC FACTOR; PHENYTOIN; RECOMBINANT HUMAN INSULIN LIKE GROWTH FACTOR 1; RILUZOLE; SODIUM CHANNEL BLOCKING AGENT; SOMATOMEDIN C; TESTOSTERONE; UNCLASSIFIED DRUG; VITAMIN D;

AMYOTROPHIC LATERAL SCLEROSIS; CLINICAL TRIAL; DRUG INHIBITION; DRUG MECHANISM; ENCEPHALITIS; EXCITOTOXICITY; EXPERIMENTAL AUTOIMMUNE ENCEPHALITIS; HUMAN; HYPERCALCEMIA; MULTIPLE SCLEROSIS; NEUROPROTECTION; NUCLEAR MAGNETIC RESONANCE IMAGING; OPTIC NEURITIS; PRIORITY JOURNAL; REVIEW; VITAMIN SUPPLEMENTATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; CLINICAL TRIALS AS TOPIC; CLINICAL TRIALS DATA MONITORING COMMITTEES; COMPLEMENTARY THERAPIES; HUMANS; IMMUNOLOGIC FACTORS; MULTIPLE SCLEROSIS; NEUROPROTECTIVE AGENTS; RESEARCH DESIGN; SODIUM CHANNEL BLOCKERS; TESTOSTERONE; TREATMENT OUTCOME; VITAMIN D; VITAMINS;

EID: 77956166486     PISSN: 11738804     EISSN: 1179190X     Source Type: Journal    
DOI: 10.2165/11537190-000000000-00000     Document Type: Review

References (85)

1. Friese MA, Montalban X, Willcox N, et al. The value of animal models for drug development in multiple sclerosis. Brain 2006; 129: 1940-1952
2. Hohlfeld R, Wiendl H. The ups and downs of multiple sclerosis therapeutics. Ann Neurol 2001 Mar; 49 (3): 281-284
3. Wiendl H, Hohlfeld R. Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials. BioDrugs 2002; 16 (3): 183-200
4. Kleinschnitz C, Meuth SG, Kieseier BC, et al. Immunotherapeutic approaches in MS: update on pathophysiology and emerging agents or strategies Endocr Metab Immune Disord Drug Targets 2007 Mar; 7 (1): 35-63
5. Ulzheimer JC, Meuth SG, Bittner S, et al. Therapeutic approaches to multiple sclerosis: an update on failed, interrupted, or inconclusive trials of im-munomodulatory treatment strategies. Biodrugs 2010; 24 (4): 249-274
6. Artemiadis AK, Anagnostouli MC. Apoptosis of oligodendrocytes and post-translational modifications of myelin basic protein in multiple sclerosis: possible role for the early stages of multiple sclerosis. Eur Neurol 2010; 63 (2): 65-72
7. Aarts MM, Tymianski M. Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. Curr Mol Med 2004 Mar; 4 (2): 137-147
8. Duprat F, Lesage F, Patel AJ, et al. The neuroprotective agent riluzole acti-vatesthe twoPdomainK(+)channelsTREK-1 andTRAAK. MolPharmacol 2000 May; 57 (5): 906-912
9. Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000 Jan; 6 (1): 67-70
10. Kalkers NF, BarkhofF, Bergers E,et al. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult Scler 2002 Dec; 8 (6): 532-533
11. Killestein J, Kalkers NF, Polman CH. Glutamate inhibition in MS: the neuro-protective properties of riluzole. J Neurol Sci 2005 Jun 15; 233 (1-2): 113-115
12. Linker R, Gold R, Luhder F. Function of neurotrophic factors beyond the nervous system: inflammation and autoimmune demyelination. Crit Rev Immunol 2009; 29 (1): 43-68
13. Azoulay D, Vachapova V, Shihman B, et al. Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: reversal by glatiramer acetate. J Neuroimmunol 2005 Oct; 167 (1-2): 215-218
14. Castellano V, White LJ. Serum brain-derived neurotrophic factor response to aerobic exercise in multiple sclerosis. J Neurol Sci 2008 Jun 15; 269 (1-2): 85-91
15. Sarchielli P, Zaffaroni M, Floridi A, et al. Production of brain-derived neu-rotrophic factor by mononuclear cells of patients with multiple sclerosis treated with glatiramer acetate, interferon-beta 1a, and high doses of im-munoglobulins. Mult Scler 2007 Apr; 13 (3): 313-331
16. Blanco Y, Saiz A, Costa M, et al. Evolution of brain-derived neurotrophic factor levels after autologous hematopoietic stem cell transplantation in multiple sclerosis. Neurosci Lett 2005 May 20-27; 380 (1-2): 122-126
17. Liu X, Yao DL, Webster H. Insulin-like growth factor I treatment reduces clinical deficits and lesion severity in acute demyelinating experimental autoimmune encephalomyelitis. Mult Scler 1995 Apr; 1 (1): 2-9
18. Yao DL, Liu X, Hudson LD, et al. Insulin-like growth factor I treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci\USA 1995 Jun 20; 92 (13): 6190-6194
19. Ochs G, Penn RD, York M, et al. A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000 Jun; 1 (3): 201-206
20. Frank JA, Richert N, Lewis B, et al. A pilot study of recombinant insulin-like growth factor-1 inseven multiple sclerosis patients. Mult Scler 2002 Feb; 8 (1): 24-29
21. Harness J,Cavanagh A, Morton H, et al. A protective effect of early pregnancy factor on experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein. J Neurol Sci 2003 Dec 15; 216 (1): 33-41
22. Zhang B, Harness J, Somodevilla-Torres MJ, et al. Early pregnancy factor suppresses experimental autoimmune encephalomyelitis induced in Lewis rats with myelin basic protein and in SJL/J mice with myelin proteolipid protein peptide 139-151. J Neurol Sci 2000 Dec 15; 182 (1): 5-15
23. Zhang B, Walsh MD, Nguyen KB, et al. Early pregnancy factor treatment suppresses the inflammatory response and adhesion molecule expression in the spinal cord of SJL/J mice with experimental autoimmune encephalomye-litis and the delayed-type hypersensitivity reaction to trinitrochlorobenzene in normal BALB/c mice. J Neurol Sci 2003 Aug 15; 212 (1-2): 37-46
24. Athanasas-Platsis S, Zhang B, Hillyard NC, et al. Early pregnancy factor suppresses the infiltration of lymphocytes and macrophages in the spinal cord of rats during experimental autoimmune encephalomyelitis but has no effect on apoptosis. J Neurol Sci 2003 Oct 15; 214 (1-2): 27-36
25. Johnson BJ, Le TT, Dobbin CA, et al. Heat shock protein 10 inhibits lipopolysaccharide-induced inflammatory mediator production. J Biol Chem 2005 Feb 11; 280 (6): 4037-4047
26. Broadley SA, Vanags D, Williams B, et al. Results of a phase IIa clinical trial of an anti-inflammatory molecule, chaperonin 10, in multiple sclerosis. Mult Scler 2009 Mar; 15 (3): 329-336
27. Craner MJ, Lo AC, Black JA, et al. Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination. Brain 2003 Jul; 126 (Pt 7): 1552-1561
28. Meuth SG, Melzer N, Kleinschnitz C, et al. [Multiple sclerosis: a channelo-pathy? Targeting ion channels and transporters in inflammatory neuro-degeneration]. Nervenarzt 2009 Apr; 80 (4): 422-429
29. Lo AC, Saab CY, Black JA, et al. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuro-inflammation in vivo. J Neurophysiol 2003 Nov; 90 (5): 3566-3571
30. Bechtold DA, Kapoor R, Smith KJ. Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann Neurol 2004 May; 55 (5): 607-616
31. Bechtold DA, Miller SJ, Dawson AC, et al. Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J Neurol 2006 Dec; 253 (12): 1542-1551
32. Waxman SG. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status. Nat Clin Pract Neurol 2008 Mar; 4 (3): 159-169
33. Black JA, LiuS,CarrithersM,etal. Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Ann Neurol 2007 Jul; 62 (1): 21-33
34. Kapoor R. Sodium channel blockers and neuroprotection in multiple sclerosis using lamotrigine. J Neurol Sci 2008 Nov 15; 274 (1-2): 54-56
35. Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis:arandomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 2010; 9: 681-688
36. Kapoor R. Neuroprotection in multiple sclerosis: therapeutic strategies and clinical trial design. Curr Opin Neurol 2006 Jun; 19 (3): 255-259
37. Bayary J, Dasgupta S, Misra N, et al. Intravenous immunoglobulin in auto-immune disorders: an insight into the immunoregulatory mechanisms. Int Immunopharmacol 2006 Apr; 6 (4): 528-534
38. Hartung HP. Advances in the understanding of the mechanism of action of IVIg. J Neurol 2008 Jul; 255 Suppl. 3: 3-6
39. Achiron A, Gabbay U, Gilad R, et al. Intravenous immunoglobulin treat-ment in multiple sclerosis: effect on relapses. Neurology 1998 Feb; 50 (2): 398-402
40. Fazekas F, Deisenhammer F, Strasser-Fuchs S, et al. Randomised placebo-controlled trialof monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997; 349: 589-593
41. Haas J. High dose IVIg in the post partum period for prevention of exacerba-tions in MS. Multiple Sclerosis 2000; 6 Suppl. 2: 18-20
42. Sorensen PS, Wanscher B, Jensen CV, et al. Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 1998 May; 50 (5): 1273-1281
43. Stangel M, Hartung HP. Despair of repair. J Neurol Neurosurg Psychiatry 2002 Jan; 72 (1): 1-4
44. Achiron A, Kishner I, Dolev M, et al. Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses inmultiple sclerosis. J Neurol 2004 Sep; 251 (9): 1133-1137
45. Haas J, Maas-Enriquez M, Hartung HP. Intravenous immunoglobulins in the treatment of relapsing remitting multiple sclerosis: results of a retrospective multicenter observational study over five years. Mult Scler 2005 Oct; 11 (5): 562-567
46. Weber-Schoendorfer C, Schaefer C. Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study. Mult Scler 2009 Sep; 15 (9): 1037-1042
47. Gray O, McDonnell GV, Forbes RB. Intravenous immunoglobulins for multi-ple sclerosis. Cochrane Database Syst Rev 2003; (4): CD002936
48. Sorensen PS, Fazekas F, Lee M. Intravenous immunoglobulin G for the treat-ment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol 2002 Nov; 9 (6): 557-563
49. Fergusson D, Hutton B, Sharma M, et al. Use of intravenous immunoglobulin for treatment of neurologic conditions: a systematic review. Transfusion 2005 Oct; 45 (10): 1640-1657
50. Achiron A, Kishner I, Sarova-Pinhas I, et al. Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Arch Neurol 2004 Oct; 61 (10): 1515-1520
51. Fazekas F, Lublin FD, Li D, et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology 2008 Jul 22; 71 (4): 265-271
52. FazekasF, Sorensen PS, Filippi M, et al. MRI results from the European Study on Intravenous Immunoglobulin in Secondary Progressive Multiple Sclerosis (ESIMS). Mult Scler 2005 Aug; 11 (4): 433-440
53. Hommes OR, Sorensen PS, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlledtrial. Lancet 2004 Sep 25-Oct 1; 364 (9440): 1149-1156
54. Pohlau D,Przuntek H,SailerM,et al. Intravenous immunoglobulin inprimary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study. Mult Scler 2007 Nov;13(9) 1107-1117
55. Visser LH, Beekman R, Tijssen CC, et al. A randomized, double-blind, placebo-controlled pilot study of i.v. immune globulins in combination with i.v. methylprednisolone in the treatment of relapses in patients with MS. Mult Scler 2004 Feb; 10 (1): 89-91
56. Sorensen PS, Haas J, Sellebjerg F, et al. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology 2004 Dec 14; 63 (11): 2028-2033
57. Roed HG, Langkilde A, Sellebjerg F, et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology 2005 Mar 8; 64 (5): 804-810
58. Tselis A, Perumal J, Caon C, et al. Treatment of corticosteroid refractory optic neuritis in multiple sclerosis patients with intravenous immunoglobulin. Eur J Neurol 2008 Nov; 15 (11): 1163-1167
59. Smolders J, Damoiseaux J, Menheere P, et al. Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol 2008 Feb; 194 (1-2): 7-17
60. Lemire JM, Archer DC. 1,25-dihydroxyvitamin D3 prevents the in vivo in-duction of murine experimental autoimmune encephalomyelitis. J Clin Invest 1991 Mar; 87 (3): 1103-1107
61. Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci\USA 1996 Jul 23; 93 (15): 7861-7864
62. Spach KM, Nashold FE, Dittel BN, et al. IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune en-cephalomyelitis. J Immunol 2006 Nov 1; 177 (9): 6030-6037
63. Munger KL, Levin LI, Hollis BW,et al. Serum 25-hydroxyvitamin Dlevels and risk of multiple sclerosis. JAMA 2006 Dec 20; 296 (23): 2832-2838
64. Islam T, Gauderman WJ, Cozen W, et al. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology 2007 Jul 24; 69 (4): 381-388
65. Kampman MT, Wilsgaard T, Mellgren SI. Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle. J Neurol 2007 Apr; 254 (4): 471-477
66. van der Mei IA, Ponsonby AL, Dwyer T, et al. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. J Neurol 2007 May; 254 (5): 581-590
67. Smolders J, Menheere P, Kessels A, et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler 2008 Nov; 14 (9): 1220-1224
68. Mahon BD, Gordon SA, Cruz J, et al. Cytokine profile in patients with mul-tiple sclerosis following vitamin D supplementation. J Neuroimmunol 2003 Jan; 134 (1-2): 128-132
69. Kimball SM, Ursell MR, O'Connor P, et al. Safety of vitamin D3 in adults with multiple sclerosis. Am J Clin Nutr 2007 Sep; 86 (3): 645-651
70. Achiron A, BarakY, Miron S, et al. Alfacalcidol treatment in multiple sclerosis [letter]. Clin Neuropharmacol 2003 Mar-Apr; 26 (2): 53
71. Wingerchuk DM, Lesaux J, Rice GP, et al. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 2005 Sep; 76 (9): 1294-1296
72. Pozzilli C, Tomassini V, Marinelli F, et al. 'Gender gap' in multiple sclerosis: magnetic resonance imaging evidence. Eur J Neurol 2003 Jan; 10 (1): 95-97
73. TomassiniV, Onesti E,Mainero C, et al. Sex hormones modulate brain damage in multiple sclerosis: MRI evidence. JNeurol Neurosurg Psychiatry 2005 Feb; 76 (2): 272-275
74. Palaszynski KM, Liu H,Loo KK,et al. Estriol treatment ameliorates disease in males with experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neuroimmunol 2004 Apr; 149 (1-2): 84-89
75. Pike CJ, Carroll JC, Rosario ER, et al. Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol 2009 Jul; 30 (2): 239-258
76. Caruso A, Di Giorgi Gerevini V, Castiglione M, et al. Testosterone amplifies excitotoxic damage of cultured oligodendrocytes. J Neurochem 2004 Mar; 88 (5): 1179-1185
77. Sicotte NL, Giesser BS, Tandon V, et al. Testosterone treatment in multiple sclerosis: a pilot study. Arch Neurol 2007 May; 64 (5): 683-688
78. Reske D, Haupt WF, Petereit HF. Gender change and its impact on the course of multiple sclerosis. Acta Neurol Scand 2006 May; 113 (5): 347-349
79. University of California, Los Angeles. A combination trial of Copaxone plus estriol in relapsing remitting multiple sclerosis (RRMS) (estriol in MS) [ClinicalTrials.gov identifier NCT00451204]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL http://www.clinical trials.gov [Accessed 2010 Jun 29]
80. Castro HJ, Mendez-Lnocencio JI, Omidvar B, et al. A phase I study of the safety of honeybee venom extract as a possible treatment for patients with progressive forms of multiple sclerosis. Allergy Asthma Proc 2005 Nov-Dec; 26 (6): 470-476
81. Wesselius T, Heersema DJ, Mostert JP, et al. A randomized crossover study of bee sting therapy for multiple sclerosis. Neurology 2005 Dec 13; 65(11): 1764-1768
82. Lewanska M, Siger-Zajdel M, Selmaj K. No difference in efficacy of two dif-ferent doses of intravenous immunoglobulins in MS: clinical and MRI assessment. Eur J Neurol 2002 Nov; 9 (6): 565-572
83. Petereit HF, Reske D, Pukrop R, et al. No effect of intravenous immuno-globulins on cytokine-producing lymphocytes in secondary progressive multiple sclerosis. Mult Scler 2006 Feb; 12 (1): 66-71
84. Haas J, Hommes OR. A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler 2007 Aug; 13 (7): 900-908
85. Gold SM, Chalifoux S, Giesser BS, et al. Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone. J Neuroinflammation 2008; 5: 32