Expertos Invitados





MITOXANTRONA: ¿CUAL ES EL FUTURO? NUEVOS AGENTES INMUNOSUPRESORES POTENCIALES PARA TRATAR LA ESCLEROSIS MULTIPLE

(especial para SIIC © Derechos reservados)
La información disponible actualmente permite afirmar que la mitoxantrona es eficaz y relativamente segura para controlar la esclerosis múltiple de rápida evolución y la progresión de la discapacidad con la cual se asocia; además, una variedad de fármacos inmunosupresores (previamente empleados con otras indicaciones o creados recientemente) pueden constituir alternativas terapéuticas promisorias.
Autor:
Richard e Gonsette
Columnista Experto de SIIC
Artículos publicados por Richard e Gonsette
Recepción del artículo
2 de Octubre, 2006 		Aprobación
9 de Noviembre, 2006
Primera edición
4 de Mayo, 2007 		Segunda edición, ampliada y corregida
7 de Junio, 2021

MITOXANTRONA: ¿CUAL ES EL FUTURO? NUEVOS AGENTES INMUNOSUPRESORES POTENCIALES PARA TRATAR LA ESCLEROSIS MULTIPLE

Resumen
Desde que la mitoxantrona fuera autorizada para tratar la esclerosis múltiple de rápida evolución, se ha adquirido una cantidad notable de conocimientos acerca de sus mecanismos de acción, su eficacia y su toxicidad a largo plazo. Por otra parte, observaciones recientes sugieren firmemente que la administración temprana de fármacos inmunosupresores como la mitoxantrona y el alemtuzumab es concluyentemente más eficaz que la de interferón beta y acetato de glatiramer para retrasar la aparición de discapacidad irreversible. Por consiguiente, la posible eficacia de agentes inmunosupresores novedosos, usados en otras enfermedades autoinmunes, el trasplante de órganos y la terapia del cáncer para tratar la esclerosis múltiple, ha recibido atención creciente. Esos agentes incluyen anticuerpos monoclonales dirigidos contra células B, linfocitos, monocitos, receptores de interleuquina-2 (IL-2) e integrina alfa 4, así como moléculas originales (pixantrona, derivados del isoxazol) y una nueva generación de fármacos inmunosupresores (fingolimod), con acción sobre el receptor para esfingosina-1-fosfato, el cual modula la recirculación linfocitaria. Además, se han actualizado los beneficios de inmunosupresores previamente usados como tratamiento no autorizado para la esclerosis múltiple, tales como la ciclofosfamida y la cladribina. Esta revisión considera la información más reciente acerca de la eficacia y la seguridad de la mitoxantrona y de las nuevas terapias experimentales, actualmente en evolución.

Palabras clave
fingolimod, esclerosis múltiple, inmunosupresión, mitoxantrona, natalizumab


Artículo completo
(castellano)
Extensión:  +/-17.12 páginas impresas en papel A4
Exclusivo para suscriptores/assinantes

Mitoxantrone: What Comes Next? New Potential Immunosuppressants in Multiple Sclerosis

Abstract
Since the approval of mitoxantrone for the treatment of aggressive multiple sclerosis, an interesting amount has been learned about its mechanisms of action, its efficacy and its long-term toxicities. On the other hand, recent observations strongly suggest that early administration of potent immunosuppressants such as mitoxantrone and alemtuzumab are definitely more efficacious than interferons beta and copaxone to delay the development of irreversible disability. The potential efficacy in multiple sclerosis of recent immunosuppressants used in other autoimmune diseases, organ transplantation and cancer therapy has thus received increasing attention. Those agents encompass monoclonal antibodies targeting B cells, lymphocytes and monocytes, IL2 receptor, a4 integrin as well as new molecules (pixantrone, isoxazole derivatives) and a new generation immunosuppressants (fingolimod) targeting the sphingosine 1-phosphate 1 receptor which modulates lymphocyte re-circulation. In addition, the benefit of immunosuppressants previously used as off-label treatments of multiple sclerosis such as cyclophosphamide and cladribine has been revisited. This review addresses the most recent data concerning the efficacy and safety of mitoxantrone and those new experimental therapies currently in progress.

Key words
multiple sclerosis, immunosuppression, mitoxantrone, natalizumab, fingolimod


Full text
(english)
 para suscriptores/ assinantes
Clasificación en siicsalud
Artículos originales > Expertos del Mundo >
página   www.siicsalud.com/des/expertocompleto.php/

Especialidades
Principal: Neurología
Relacionadas: Farmacología, Inmunología, Medicina Farmacéutica, Medicina Interna



Comprar este artículo
Extensión: 17.12 páginas impresas en papel A4

file05.gif (1491 bytes) Artículos seleccionados para su compra



Enviar correspondencia a:
Richard E Gonsette, National Center for Multiple Sclerosis, 1820, Vanheylenstraat 16, B, Melsbroek, Bélgica
Bibliografía del artículo
1. Neuhaus O, Kieseier BC, Hartung HP. Mechanisms of mitoxantrone in multiple sclerosis-what is known? J Neurol Sci 223:25-7, 2004.
2. Gbadamosi J, Buhmann C, Tessmer W, Moench A, Haag F, Heesen C. Effects of mitoxantrone on multiple sclerosis patients' lymphocyte subpopulations and production of immunoglobulin, TNF-alpha and IL-10. Eur Neurol 49:137-41, 2003.
3. Putzki N, Kumar M, Vago S, Kreutzfelder E, Limmroth V. Mitoxantrone treatment leads to a persistent and selective decrease of the B cell count in patients with multiple sclerosis. Neurology 66(Suppl 2):A370, abstract P06.160, 2006.
4. Neuhaus O, Wiendl H, Kieseier BC et al. Multiple sclerosis: Mitoxantrone promotes differential effects on immunocompetent cells in vitro. J Neuroimmunol 168:128-37, 2005.
5. Mergenthaler HG, Bruhl P, Ehninger G, Heidemann E. Comparative in vitro toxicity of mitoxantrone and adriamycin in human granulocyte-macrophage progenitor cells. Cancer Chemother Pharmacol 20:8-12, 1987.
6. Neuhaus O, Kieseier BC, Hartung HP. Mitoxantrone in multiple sclerosis. Adv Neurol 2006; 98: 293-302, .
7. Angelucci F, Mirabella M, Caggiula M et al. Effect of mitoxantrone on cytokine and BDNF production by peripheral blood mononuclear cells in secondary progressive multiple sclerosis patients. Neurology 64(Suppl 1):A195, abstract P03.126, 2006.
8. Correale J, Rush C, Amengual A, Goicochea MT. Mitoxantrone as rescue therapy in worsening relapsing-remitting MS patients receiving IFN-beta. J Neuroimmunol 162:173-83, 2005.
9. Gonsette RE. Mitoxantrone in progressive multiple sclerosis: when and how to treat? J Neurol Sci 206:203-8, 2003.
10. Edan G, Miller D, Clanet M et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry 62:112-8, 1997.
11. Jeffery DR, Chepuri N, Durden D, Burdette J. A pilot trial of combination therapy with mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging. Mult Scler 11:296-301, 2005.
12. Krapf H, Mauch E, Fetzer U, Laufen H, Kornhuber HH. Serial gadolinium-enhanced magnetic resonance imaging in patients with multiple sclerosis treated with mitoxantrone. Neuroradiology 37:113-9, 1995.
13. Zingler VC, Strupp M, Jahn K, Gross A, Hohlfeld R, Brandt T. The effect of combined mitoxantrone and methylprednisolone therapy in primary and secondary progressive multiple sclerosis. An applied study in 65 patients. Nervenarzt 76:740-7, 2005.
14. Ostberg A, Pittas F, Taylor B. Use of low-dose mitozantrone to treat aggressive multiple sclerosis: a single-centre open-label study using patient self-assessment and clinical measures of multiple sclerosis status. Intern Med J 35:382-7, 2005.
15. Hartung HP, Gonsette R, Konig N et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 360:2018-25, 2002.
16. Le Page E, Leray E, Taurin G, Coustans M, Chaperon J, Edan G. Mitoxantrone as induction therapy in aggressive relapsing remitting multiple sclerosis: a descriptive analysis of 100 consecutive patients. Rev Neurol 162:185-94, 2006.
17. Debouverie M, Vandenberghe N, Morrissey SP et al. Predictive parameters of mitoxantrone effectiveness in the treatment of multiple sclerosis. Mult Scler 10:407-12, 2004.
18. Bennet R, Al-Sabbagh A. Continuing evaluation of the safety and tolerability of mitoxantrone in worsening multiple sclerosis: the RENEW study. Neurology 66(Suppl 2):A20, abstract P01.068, 2006.
19. Le Page E, Leray E, Chaperon J, Edan G. 5-year follow-up after mitoxantrone treatment start: an observational study of 100 consecutive patients with aggressive relapsing remitting multiple sclerosis. Neurology 66(Suppl 2):A33, abstract P01.082, 2006.
20. Le Page E, Leray E, Brochet B. Safety profile of mitoxantrone in a french cohort of 802 multiple sclerosis patients : a 5-years follow-up study. Neurology 66(Suppl 2):A63, abstract S02.006, 2006.
21. Olindo S, Guillon B, Helias J, Phillibert B, Magne C, Feve JR. Decrease in heart ventricular ejection fraction during multiple sclerosis. Eur J Neurol 9:287-91, 2002.
22. Huettemann E, Sakka SG. Anaesthesia and anti-cancer chemotherapeutic drugs. Curr Opin Anaesthesiol 18:307-14, 2005.
23. Goffette S, Van Pesch V, Vanoverschelde JL, Morandini E, Sindic CJ. Severe delayed heart failure in three multiple sclerosis patients previously treated with mitoxantrone. J Neurol 252:1217-22, 2005.
24. Pattoneri P, Pela G, Montanari E, Pesci I, Moruzzi P, Borghetti A Evaluation of the myocardial performance index for early detection of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis. Eur J Echocardiogr [Epub ahead of print] 2006.
25. Herman EH, Zhang J, Rifai N. The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity. Cancer Chemother Pharmacol 48:297-304, 2001.
26. Bernitsas E, Wei W, Mikol DD. Suppression of mitoxantrone cardiotoxicity in multiple sclerosis patients by dexrazoxane. Ann Neurol 59:206-9, 2006.
27. Gieseler F, Clark M, Stiebeling K, Puschmann M, Valsamas S. Induction of apoptosis by idarubicin: how important is the plasma peak? Int J Clin Pharmacol Ther 38:217-21, 2000.
28. Hortobagyi GN, Frye D, Buzdar AU et al. Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63:37-45, 1989.
29. Mariko K, Chow E, Reed D. A pilot study of mitoxantrone plus derazoxane versus mitoxantrone in patients with relapsing remitting, secondary progressive and progressive relapsing MS. Neurology 64(Suppl 1):A330, abstract P05.139, 2005.
30. Krapcho AP, Landi JJ, Hacker MP, McCormack JJ. Synthesis and antineoplastic evaluations of 5,8-bis[(aminoalkyl)amino]-1-azaanthracene-9,10-diones. J Med Chem 28:1124-6, 1985.
31. Gonsette RE, Dubois B. Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity. J Neurol Sci 223:81-6, 2004.
32. Cavaletti G, Cavalletti E, Crippa L et al. Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis. J Neuroimmunol 151:55-65, 2004.
33. Mazzanti B, Biagioli T, Aldinucci A et al. Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis. J Neuroimmunol 168:111-7, 2005.
34. Ghalie RG, Mauch E, Edan G et al. A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis. Mult Scler 8:441-5, 2002.
35. Vicari AM, Ciceri F, Folli F et al. Acute promyelocytic leukemia following mitoxantrone as single agent for the treatment of multiple sclerosis. Leukemia 12:441-2, 1998.
36. Brassat D, Recher C, Waubant E et al. Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS. Neurology 59:954-5, 2002.
37. Tanasescu R, Debouverie M, Pittion S, Anxionnat R, Vespignani H. Acute myeloid leukaemia induced by mitoxantrone in a multiple sclerosis patient. J Neurol 251:762-3, 2004.
38. Heesen C, Bruegmann M, Gbdamosi J, Koch E, Monch A, Buhmann C, Therapy-related acute myelogenous leukaemia (t-AML) in a patient with multiple sclerosis treated with mitoxantrone. Mult Scler 9:213-4, 2003.
39. Cattaneo C, Almici C, Borlenghi E, Motta M, Rossi G. A case of acute promyelocytic leukaemia following mitoxantrone treatment of multiple sclerosis. Leukemia 17:985-6, 2003.
40. Mogenet I, Simiand-Erdociain E, Canonge JM, Pris J. Acute myelogenous leukemia following mitoxantrone treatment for multiple sclerosis. Ann Pharmacother 37:747-8, 2003.
41. Delisse B, de Seze J, Mackowiak A et al. Therapy related acute myeloblastic leukaemia after mitoxantrone treatment in a patient with multiple sclerosis. Mult Scler 10:92, 2004.
42. Voltz R, Starck M, Zingler V, Strupp M, Kolb HJ. Mitoxantrone therapy in multiple sclerosis and acute leukaemia: a case report out of 644 treated patients. Mult Scler 10:472-4, 2004.
43. Novoselac AV, Reddy S, Sanmugarajah J. Acute promyelocytic leukemia in a patient with multiple sclerosis following treatment with mitoxantrone. Leukemia 18:1561-2, 2004.
44. Pedersen-Bjergaard J, Philip P, Larsen SO, Jensen G, Byrsting K. Chromosome aberrations and prognostic factors in therapy-related myelodysplasia and acute nonlymphocytic leukemia. Blood 76:1083-91, 1990.
45. Weiner HL. Immunosuppressive treatment in multiple sclerosis. J Neurol Sci 223:1-11, 2004.
46. Perini P, Calabrese M, Tiberio M, Ranzato F, Battistin L, Gallo P. Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis: A comparative study. J Neurol [Epub ahead of print] 2006.
47. Krishnan C, Drachman D, McArthur J et al. High-dose cyclophosphamide in the treatment of aggressive multiple sclerosis. Neurology 66(Suppl 2):A30, abstract P01.072, 2006.
48. Caon C, Din M, Madak S, Tselis A, Lisak R, Khan O. Two year open-label observational study comparing monthly intravenous cyclophosphamide and every three month iv mitoxantrone in worsening MS patients. Neurology 64(Suppl 1):A329, abstract P05.137, 2005.
49. Sipe JC. Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother 5:721-7, 2005.
50. Filippi M, Rovaris M, Iannucci G, Mennea S, Sormani MP, Comi G. Whole brain volume changes in patients with progressive MS treated with cladribine. Neurology 55:1714-8, 2000.
51. Noseworthy JH, Wolinsky JS, Lublin FD et al. Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators. Neurology 54:1726-33, 2000.
52. Tan IL, Lycklama A Nijeholt GJ, Polman CH, Ader HJ, Barkhof F. Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials. Mult Scler 6:99-104, 2000.
53. O'Connor PW, Li D, Freedman MS et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 66:894-900, 2006.
54. Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 64:987-91, 2005.
55. Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK. Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 62:258-64, 2005.
56. Stuve O, Cepok S, Elias B et al. Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis. Arch Neurol 62:1620-3, 2005.
57. Petereit HF, Rubbert A. Effective suppression of cerebrospinal fluid B cells by rituximab and cyclophosphamide in progressive multiple sclerosis. Arch Neurol 62:1641-2, 2005.
58. Cree BA, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64:1270-2, 2005.
59. Coles AJ, Cox A, Le Page E et al. The window of therapeutic opportunity in multiple sclerosis.Evidence from monoclonal antibody therapy. J Neurol 253:98-108, 2006.
60. Coles AJ, Wing MG, Molyneux P et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 46:296-304, 1999.
61. Rose JW, Watt HE, White AT, Carlson NG. Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann Neurol 56:864-7, 2004.
62. Bielekova B, Richert N, Howard T et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci USA 101:8705-8, 2004.
63. Stuve O, Marra CM, Jerome KR et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 59:743-7, 2006.
64. Niino M, Bodner C, Simard ML et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol 59:748-54, 2006.
65. Deloire MS, Touil T, Brochet B, Dousset V, Caille JM, Petry KG. Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment. Mult Scler 10:540-8, 2004.
66. Polman CH, O'Connor PW, Havrdova E et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899-910, 2006.
67. Rudick RA, Stuart WH, Calabresi PA et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354:911-23, 2006.
68. Olsson T, Jacobaeus E, Brundin L. JC viral DNA in a cohort of relapsing-remitting multiple sclerosis patients. Mult Scler 11(Suppl 1):S178, Poster P671, 2005.
69. Brinkmann V, Cyster JG, Hla T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant 4:1019-25, 2004.
70. Fujino M, Funeshima N, Kitazawa Y et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 305:70-7, 2003.
71. Rausch M, Hiestand P, Foster CA, Baumann DR, Cannet C, Rudin M. Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J Magn Reson Imaging 20:16-24, 2004.
72. Vaessen LM, Van Besouw NM, Mol WM, Ijzermans JN, Weimar W. FTY720 treatment of kidney transplant patients: a differential effect on B cells, naive T cells, memory T cells and NK cells. Transpl Immunol 15:281-8, 2006.
73. Lei G, Amemiya H, Suzuki S et al. New immunosuppressive reagent, FTY 720, spares immunologic memory. Transplant Proc 32:1628, 2000.
74. Fujii R, Kanai T, Nemoto Y et al. FTY720 suppresses CD4+CD44highCD62L-effector memory T cell-mediated colitis. Am J Physiol Gastrointest Liver Physiol [Epub ahead of print] 2006.
75. Kappos L, Rado EW, Antel J et al. Promising results with a novel oral immunomodulator FTY720 in relapsing remitting multiple sclerosis. Mult Scler 11(Suppl 1):S13, abstract 64, 2005.
76. O'Connor P, Antel J, Comi G et al. Oral FTY720 in relapsing MS: results of the dose-blinded, active drug extension phase of a phase II study. Neurology 66(Suppl 2):A123, abstract S12.003, 2006.
77. Berger JR, Houff S. Progressive multifocal leukoencephalopathy: lessons from AIDS and natalizumab. Neurol Res 28:299-305, 2006.
78. Du Pasquier RA, Stein MC, Lima MA, Dang X, Jean-Jacques J, Zheng Y, Letvin NL, Koralnik IJ. JC virus induces a vigorous CD8(+) cytotoxic T cell response in multiple sclerosis patients. J Neuroimmunol [Epub ahead of print] 2006.
79. Han S, Zhang X, Wang G et al. FTY720 suppresses humoral immunity by inhibiting germinal center reaction. Blood 104:4129-33, 2004.
80. Pinschewer DD, Ochsenbein AF, Odermatt B, Brinkmann V, Hengartner H, Zinkernagel RM. FTY720 Immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J Immunol 164:5761-70, 2000.
 
 
 
 
 
 
 
 
 
 
 
 
Está expresamente prohibida la redistribución y la redifusión de todo o parte de los contenidos de la Sociedad Iberoamericana de Información Científica (SIIC) S.A. sin previo y expreso consentimiento de SIIC.
ua31618
Home

Copyright siicsalud © 1997-2024 ISSN siicsalud: 1667-9008