Medicinal Chemistry of Multiple Sclerosis: Focus on Cladribine

Author(s): Tamás Biernacki, Dániel Sandi, Krisztina Bencsik, László Vécsei*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 20 , Issue 4 , 2020


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Graphical Abstract:


Abstract:

Background: In the recent years, many novel Disease-Modifying Drugs (DMD) have been introduced to the market in the treatment of multiple sclerosis.

Objectives: To provide the reader with an up to date, compact review on the pharmacokinetic properties, mechanism of action, and clinical attributes of one of the most recently approved drugs in the therapy of multiple sclerosis, cladribine.

Conclusion: Cladribine tablets proved to be a highly efficient treatment choice for Relapsing- Remitting Multiple Sclerosis (RRMS), especially for patients with high disease activity. It is the first DMD for MS with a complex mechanism of action, by inhibiting the adenosine-deaminase enzyme it increases the intracellular levels of deoxyadenosine triphosphate, which with relative selectivity depletes both T- and B-cells lines simultaneously. However long term follow-up safety and effectiveness data are still missing, and clear treatment protocols are lacking beyond the first two treatment years cladribine should prove to be a valuable addition to the therapeutic palette of RRMS, and potentially for Clinically Isolated Syndrome (CIS) as well.

Keywords: Cladribine, mechanism of action, multiple sclerosis, efficacy, safety, dosing.

[1]
Browne, P.; Chandraratna, D.; Angood, C.; Tremlett, H.; Baker, C.; Taylor, B.V.; Thompson, A.J. Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology, 2014, 83(11), 1022-1024.
[http://dx.doi.org/10.1212/WNL.0000000000000768] [PMID: 25200713]
[2]
Pugliatti, M.; Rosati, G.; Carton, H.; Riise, T.; Drulovic, J.; Vécsei, L.; Milanov, I. The epidemiology of multiple sclerosis in Europe. Eur. J. Neurol., 2006, 13(7), 700-722.
[http://dx.doi.org/10.1111/j.1468-1331.2006.01342.x] [PMID: 16834700]
[3]
Kingwell, E.; Marriott, J.J.; Jetté, N.; Pringsheim, T.; Makhani, N.; Morrow, S.A.; Fisk, J.D.; Evans, C.; Béland, S.G.; Kulaga, S.; Dykeman, J.; Wolfson, C.; Koch, M.W.; Marrie, R.A. Incidence and prevalence of multiple sclerosis in Europe: A systematic review. BMC Neurol., 2013, 13, 128.
[http://dx.doi.org/10.1186/1471-2377-13-128] [PMID: 24070256]
[4]
Zsiros, V.; Fricska-Nagy, Z.; Füvesi, J.; Kincses, Z.T.; Langane, E.; Paulik, E.; Vécsei, L.; Bencsik, K. Prevalence of multiple sclerosis in Csongrád County, Hungary. Acta Neurol. Scand., 2014, 130(5), 277-282.
[http://dx.doi.org/10.1111/ane.12219] [PMID: 24611546]
[5]
Bencsik, K.; Sandi, D.; Biernacki, T.; Kincses, Z.; Füvesi, J.; Fricska-Nagy, Z.; Vécsei, L. The multiple sclerosis registry of szeged. Ideggyogy. Sz., 2017, 70(9-10), 301-306.
[http://dx.doi.org/10.18071/isz.70.0301] [PMID: 29870621]
[6]
Sandi, D.; Zsiros, V.; Füvesi, J.; Kincses, Z.T.; Fricska-Nagy, Z.; Lencsés, G.; Vécsei, L.; Bencsik, K. Mortality in Hungarian patients with multiple sclerosis between 1993 and 2013. J. Neurol. Sci., 2016, 367, 329-332.
[http://dx.doi.org/10.1016/j.jns.2016.06.035] [PMID: 27423613]
[7]
Lublin, F.D.; Reingold, S.C. Defining the clinical course of multiple sclerosis: Results of an international survey. Neurology, 1996, 46(4), 907-911.
[http://dx.doi.org/10.1212/WNL.46.4.907] [PMID: 8780061]
[8]
Polman, C.H.; Reingold, S.C.; Banwell, B.; Clanet, M.; Cohen, J.A.; Filippi, M.; Fujihara, K.; Havrdova, E.; Hutchinson, M.; Kappos, L.; Lublin, F.D.; Montalban, X.; O’Connor, P.; Sandberg-Wollheim, M.; Thompson, A.J.; Waubant, E.; Weinshenker, B.; Wolinsky, J.S. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol., 2011, 69(2), 292-302.
[http://dx.doi.org/10.1002/ana.22366] [PMID: 21387374]
[9]
Thompson, A.J.; Banwell, B.L.; Barkhof, F.; Carroll, W.M.; Coetzee, T.; Comi, G.; Correale, J.; Fazekas, F.; Filippi, M.; Freedman, M.S.; Fujihara, K.; Galetta, S.L.; Hartung, H.P.; Kappos, L.; Lublin, F.D.; Marrie, R.A.; Miller, A.E.; Miller, D.H.; Montalban, X.; Mowry, E.M.; Sorensen, P.S.; Tintoré, M.; Traboulsee, A.L.; Trojano, M.; Uitdehaag, B.M.J.; Vukusic, S.; Waubant, E.; Weinshenker, B.G.; Reingold, S.C.; Cohen, J.A. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol., 2018, 17(2), 162-173.
[http://dx.doi.org/10.1016/S1474-4422(17)30470-2] [PMID: 29275977]
[10]
Lublin, F.D.; Reingold, S.C.; Cohen, J.A.; Cutter, G.R.; Sørensen, P.S.; Thompson, A.J.; Wolinsky, J.S.; Balcer, L.J.; Banwell, B.; Barkhof, F.; Bebo, B., Jr; Calabresi, P.A.; Clanet, M.; Comi, G.; Fox, R.J.; Freedman, M.S.; Goodman, A.D.; Inglese, M.; Kappos, L.; Kieseier, B.C.; Lincoln, J.A.; Lubetzki, C.; Miller, A.E.; Montalban, X.; O’Connor, P.W.; Petkau, J.; Pozzilli, C.; Rudick, R.A.; Sormani, M.P.; Stüve, O.; Waubant, E.; Polman, C.H. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology, 2014, 83(3), 278-286.
[http://dx.doi.org/10.1212/WNL.0000000000000560] [PMID: 24871874]
[11]
Lassmann, H. Pathology and disease mechanisms in different stages of multiple sclerosis. J. Neurol. Sci., 2013, 333(1-2), 1-4.
[http://dx.doi.org/10.1016/j.jns.2013.05.010] [PMID: 23735777]
[12]
Stys, P.K.; Zamponi, G.W.; van Minnen, J.; Geurts, J.J. Will the real multiple sclerosis please stand up? Nat. Rev. Neurosci., 2012, 13(7), 507-514.
[http://dx.doi.org/10.1038/nrn3275] [PMID: 22714021]
[13]
Yadav, S.K.; Mindur, J.E.; Ito, K.; Dhib-Jalbut, S. Advances in the immunopathogenesis of multiple sclerosis. Curr. Opin. Neurol., 2015, 28(3), 206-219.
[http://dx.doi.org/10.1097/WCO.0000000000000205] [PMID: 25887768]
[14]
Miljković, D.; Spasojević, I. Multiple sclerosis: Molecular mechanisms and therapeutic opportunities. Antioxid. Redox Signal., 2013, 19(18), 2286-2334.
[http://dx.doi.org/10.1089/ars.2012.5068] [PMID: 23473637]
[15]
Kebir, H.; Ifergan, I.; Alvarez, J.I.; Bernard, M.; Poirier, J.; Arbour, N.; Duquette, P.; Prat, A. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann. Neurol., 2009, 66(3), 390-402.
[http://dx.doi.org/10.1002/ana.21748] [PMID: 19810097]
[16]
Kleinewietfeld, M.; Hafler, D.A. Regulatory T cells in autoimmune neuroinflammation. Immunol. Rev., 2014, 259(1), 231-244.
[http://dx.doi.org/10.1111/imr.12169] [PMID: 24712469]
[17]
Lucchinetti, C.; Brück, W.; Parisi, J.; Scheithauer, B.; Rodriguez, M.; Lassmann, H. Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann. Neurol., 2000, 47(6), 707-717.
[http://dx.doi.org/10.1002/1531-8249(200006)47:6<707:AID-ANA3>3.0.CO;2-Q] [PMID: 10852536]
[18]
Constantinescu, C.S.; Hilliard, B.; Ventura, E.; Wysocka, M.; Showe, L.; Lavi, E.; Fujioka, T.; Scott, P.; Trinchieri, G.; Rostami, A. Modulation of susceptibility and resistance to an autoimmune model of multiple sclerosis in prototypically susceptible and resistant strains by neutralization of interleukin-12 and interleukin-4, respectively. Clin. Immunol., 2001, 98(1), 23-30.
[http://dx.doi.org/10.1006/clim.2000.4944] [PMID: 11141323]
[19]
Voskuhl, R.R.; Martin, R.; Bergman, C.; Dalal, M.; Ruddle, N.H.; McFarland, H.F. T helper 1 (Th1) functional phenotype of human myelin basic protein-specific T lymphocytes. Autoimmunity, 1993, 15(2), 137-143.
[http://dx.doi.org/10.3109/08916939309043888] [PMID: 7692995]
[20]
Bettelli, E.; Carrier, Y.; Gao, W.; Korn, T.; Strom, T.B.; Oukka, M.; Weiner, H.L.; Kuchroo, V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 2006, 441(7090), 235-238.
[http://dx.doi.org/10.1038/nature04753] [PMID: 16648838]
[21]
Edwards, L.J.; Robins, R.A.; Constantinescu, C.S. Th17/Th1 phenotype in demyelinating disease. Cytokine, 2010, 50(1), 19-23.
[http://dx.doi.org/10.1016/j.cyto.2009.12.003] [PMID: 20045653]
[22]
Nyirenda, M.H.; Sanvito, L.; Darlington, P.J.; O’Brien, K.; Zhang, G.X.; Constantinescu, C.S.; Bar-Or, A.; Gran, B. TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J. Immunol., 2011, 187(5), 2278-2290.
[http://dx.doi.org/10.4049/jimmunol.1003715] [PMID: 21775683]
[23]
Sinha, S.; Itani, F.R.; Karandikar, N.J. Immune regulation of multiple sclerosis by CD8+ T cells. Immunol. Res., 2014, 59(1-3), 254-265.
[http://dx.doi.org/10.1007/s12026-014-8529-9] [PMID: 24845461]
[24]
Lehmann-Horn, K.; Kinzel, S.; Weber, M.S. Deciphering the role of b cells in multiple sclerosis-towards specific targeting of pathogenic function. Int. J. Mol. Sci., 2017, 18(10), E2048
[http://dx.doi.org/10.3390/ijms18102048] [PMID: 28946620]
[25]
Weber, M.S.; Hemmer, B.; Cepok, S. The role of antibodies in multiple sclerosis. Biochim. Biophys. Acta, 2011, 1812(2), 239-245.
[http://dx.doi.org/10.1016/j.bbadis.2010.06.009] [PMID: 20600871]
[26]
Reiber, H.; Ungefehr, S.; Jacobi, C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult. Scler., 1998, 4(3), 111-117.
[http://dx.doi.org/10.1177/135245859800400304] [PMID: 9762657]
[27]
Mathias, A.; Perriard, G.; Canales, M.; Soneson, C.; Delorenzi, M.; Schluep, M.; Du Pasquier, R.A. Increased ex vivo antigen presentation profile of B cells in multiple sclerosis. Mult. Scler., 2017, 23(6), 802-809.
[http://dx.doi.org/10.1177/1352458516664210] [PMID: 27503907]
[28]
Harp, C.T.; Ireland, S.; Davis, L.S.; Remington, G.; Cassidy, B.; Cravens, P.D.; Stuve, O.; Lovett-Racke, A.E.; Eagar, T.N.; Greenberg, B.M.; Racke, M.K.; Cowell, L.G.; Karandikar, N.J.; Frohman, E.M.; Monson, N.L. Memory B cells from a subset of treatment-naïve relapsing-remitting multiple sclerosis patients elicit CD4(+) T-cell proliferation and IFN-γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Eur. J. Immunol., 2010, 40(10), 2942-2956.
[http://dx.doi.org/10.1002/eji.201040516] [PMID: 20812237]
[29]
Lanzavecchia, A. Antigen-specific interaction between T and B cells. Nature, 1985, 314(6011), 537-539.
[http://dx.doi.org/10.1038/314537a0] [PMID: 3157869]
[30]
Pöllinger, B.; Krishnamoorthy, G.; Berer, K.; Lassmann, H.; Bösl, M.R.; Dunn, R.; Domingues, H.S.; Holz, A.; Kurschus, F.C.; Wekerle, H. Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. J. Exp. Med., 2009, 206(6), 1303-1316.
[http://dx.doi.org/10.1084/jem.20090299] [PMID: 19487416]
[31]
Krishnamoorthy, G.; Lassmann, H.; Wekerle, H.; Holz, A. Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J. Clin. Invest., 2006, 116(9), 2385-2392.
[http://dx.doi.org/10.1172/JCI28330] [PMID: 16955140]
[32]
Molnarfi, N.; Schulze-Topphoff, U.; Weber, M.S.; Patarroyo, J.C.; Prod’homme, T.; Varrin-Doyer, M.; Shetty, A.; Linington, C.; Slavin, A.J.; Hidalgo, J.; Jenne, D.E.; Wekerle, H.; Sobel, R.A.; Bernard, C.C.; Shlomchik, M.J.; Zamvil, S.S. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J. Exp. Med., 2013, 210(13), 2921-2937.
[http://dx.doi.org/10.1084/jem.20130699] [PMID: 24323356]
[33]
Barr, T.A.; Shen, P.; Brown, S.; Lampropoulou, V.; Roch, T.; Lawrie, S.; Fan, B.; O’Connor, R.A.; Anderton, S.M.; Bar-Or, A.; Fillatreau, S.; Gray, D. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J. Exp. Med., 2012, 209(5), 1001-1010.
[http://dx.doi.org/10.1084/jem.20111675] [PMID: 22547654]
[34]
Bjarnadóttir, K.; Benkhoucha, M.; Merkler, D.; Weber, M.S.; Payne, N.L.; Bernard, C.C.A.; Molnarfi, N.; Lalive, P.H. B cell-derived transforming growth factor-β1 expression limits the induction phase of autoimmune neuroinflammation. Sci. Rep., 2016, 6, 34594.
[http://dx.doi.org/10.1038/srep34594] [PMID: 27708418]
[35]
Major, E.O.; Nath, A. A link between long-term natalizumab dosing in MS and PML: Putting the puzzle together. Neurol. Neuroimmunol. Neuroinflamm., 2016, 3(3), e235
[http://dx.doi.org/10.1212/NXI.0000000000000235] [PMID: 27213175]
[36]
Giovannoni, G.; Kappos, L.; Gold, R.; Khatri, B.O.; Selmaj, K.; Umans, K.; Greenberg, S.J.; Sweetser, M.; Elkins, J.; McCroskery, P. Safety and tolerability profile of daclizumab in patients with relapsing-remitting multiple sclerosis: An integrated analysis of clinical studies. Mult. Scler. Relat. Disord., 2016, 9, 36-46.
[http://dx.doi.org/10.1016/j.msard.2016.05.010] [PMID: 27645341]
[37]
Holmøy, T.; von der Lippe, H.; Leegaard, T.M. Listeria monocytogenes infection associated with alemtuzumab -- a case for better preventive strategies. BMC Neurol., 2017, 17(1), 65.
[http://dx.doi.org/10.1186/s12883-017-0848-8] [PMID: 28376817]
[38]
Giovannoni, G.; Comi, G.; Cook, S.; Rammohan, K.; Rieckmann, P.; Soelberg Sørensen, P.; Vermersch, P.; Chang, P.; Hamlett, A.; Musch, B.; Greenberg, S.J. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med., 2010, 362(5), 416-426.
[http://dx.doi.org/10.1056/NEJMoa0902533] [PMID: 20089960]
[39]
Beutler, E. Cladribine (2-chlorodeoxyadenosine). Lancet, 1992, 340(8825), 952-956.
[http://dx.doi.org/10.1016/0140-6736(92)92826-2] [PMID: 1357355]
[40]
Piro, L.D.; Carrera, C.J.; Carson, D.A.; Beutler, E. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N. Engl. J. Med., 1990, 322(16), 1117-1121.
[http://dx.doi.org/10.1056/NEJM199004193221605] [PMID: 1969613]
[41]
Lauria, F.; Cencini, E.; Forconi, F. Alternative methods of cladribine administration. Leuk. Lymphoma, 2011, 52(Suppl. 2), 34-37.
[http://dx.doi.org/10.3109/10428194.2011.570395] [PMID: 21504286]
[42]
Johnston, J.B. Mechanism of action of pentostatin and cladribine in hairy cell leukemia. Leuk. Lymphoma, 2011, 52(Suppl. 2), 43-45.
[http://dx.doi.org/10.3109/10428194.2011.570394] [PMID: 21463108]
[43]
Van den Neste, E.; Cardoen, S.; Offner, F.; Bontemps, F. Old and new insights into the mechanisms of action of two nucleoside analogs active in lymphoid malignancies: Fludarabine and cladribine. (review). Int. J. Oncol., 2005, 27(4), 1113-1124.
[http://dx.doi.org/10.3892/ijo.27.4.1113] [PMID: 16142330]
[44]
Wataya, Y.; Hirota, Y.; Hiramoto-Yoshioka, A.; Tanaka, S.; Otani, T.; Minowada, J.; Matsuda, A.; Ueda, T. The mechanism of 2-chlorodeoxyadenosine-induced cell death. Adv. Exp. Med. Biol., 1989, 253B, 227-234.
[http://dx.doi.org/10.1007/978-1-4684-5676-9_34] [PMID: 2575349]
[45]
Griffig, J.; Koob, R.; Blakley, R.L. Mechanisms of inhibition of DNA synthesis by 2-chlorodeoxyadenosine in human lymphoblastic cells. Cancer Res., 1989, 49(24 Pt 1), 6923-6928.
[PMID: 2573423]
[46]
Van Den Neste, E.; Cardoen, S.; Husson, B.; Rosier, J.F.; Delacauw, A.; Ferrant, A.; Van den Berghe, G.; Bontemps, F. 2-Chloro-2′-deoxyadenosine inhibits DNA repair synthesis and potentiates UVC cytotoxicity in chronic lymphocytic leukemia B lymphocytes. Leukemia, 2002, 16(1), 36-43.
[http://dx.doi.org/10.1038/sj.leu.2402331] [PMID: 11840261]
[47]
Chunduru, S.K.; Appleman, J.R.; Blakley, R.L. Activity of human DNA polymerases alpha and beta with 2-chloro-2′-deoxyadenosine 5′-triphosphate as a substrate and quantitative effects of incorporation on chain extension. Arch. Biochem. Biophys., 1993, 302(1), 19-30.
[http://dx.doi.org/10.1006/abbi.1993.1175] [PMID: 8470896]
[48]
Parker, W.B.; Bapat, A.R.; Shen, J.X.; Townsend, A.J.; Cheng, Y.C. Interaction of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase. Mol. Pharmacol., 1988, 34(4), 485-491.
[PMID: 3050447]
[49]
Hentosh, P.; Koob, R.; Blakley, R.L. Incorporation of 2-halogeno-2′-deoxyadenosine 5-triphosphates into DNA during replication by human polymerases alpha and beta. J. Biol. Chem., 1990, 265(7), 4033-4040.
[PMID: 2303492]
[50]
Richardson, D.S.; Allen, P.D.; Kelsey, S.M.; Newland, A.C. Effects of PARP inhibition on drug and Fas-induced apoptosis in leukaemic cells. Adv. Exp. Med. Biol., 1999, 457, 267-279.
[http://dx.doi.org/10.1007/978-1-4615-4811-9_29] [PMID: 10500802]
[51]
Pettitt, A.R.; Sherrington, P.D.; Cawley, J.C. Role of poly(ADP-ribosyl)ation in the killing of chronic lymphocytic leukemia cells by purine analogues. Cancer Res., 2000, 60(15), 4187-4193.
[PMID: 10945628]
[52]
Galmarini, C.M.; Voorzanger, N.; Falette, N.; Jordheim, L.; Cros, E.; Puisieux, A.; Dumontet, C. Influence of p53 and p21(WAF1) expression on sensitivity of cancer cells to cladribine. Biochem. Pharmacol., 2003, 65(1), 121-129.
[http://dx.doi.org/10.1016/S0006-2952(02)01448-X] [PMID: 12473386]
[53]
Achanta, G.; Pelicano, H.; Feng, L.; Plunkett, W.; Huang, P. Interaction of p53 and DNA-PK in response to nucleoside analogues: Potential role as a sensor complex for DNA damage. Cancer Res., 2001, 61(24), 8723-8729.
[PMID: 11751391]
[54]
Chow, K.U.; Nowak, D.; Boehrer, S.; Ruthardt, M.; Knau, A.; Hoelzer, D.; Mitrou, P.S.; Weidmann, E. Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activation. Biochem. Pharmacol., 2003, 66(5), 711-724.
[http://dx.doi.org/10.1016/S0006-2952(03)00410-6] [PMID: 12948851]
[55]
Borner, M.M.; Joncourt, F.; Hotz, M.A. Similarity of apoptosis induction by 2-chlorodeoxyadenosine and cisplatin in human mononuclear blood cells. Br. J. Cancer, 1997, 76(11), 1448-1454.
[http://dx.doi.org/10.1038/bjc.1997.577] [PMID: 9400941]
[56]
Szondy, Z. The 2-chlorodeoxyadenosine-induced cell death signalling pathway in human thymocytes is different from that induced by 2-chloroadenosine. Biochem. J., 1995, 311(Pt 2), 585-588.
[http://dx.doi.org/10.1042/bj3110585] [PMID: 7487899]
[57]
Mackus, W.J.; Kater, A.P.; Grummels, A.; Evers, L.M.; Hooijbrink, B.; Kramer, M.H.; Castro, J.E.; Kipps, T.J.; van Lier, R.A.; van Oers, M.H.; Eldering, E. Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation. Leukemia, 2005, 19(3), 427-434.
[http://dx.doi.org/10.1038/sj.leu.2403623] [PMID: 15674362]
[58]
Adams, J.M. Ways of dying: Multiple pathways to apoptosis. Genes Dev., 2003, 17(20), 2481-2495.
[http://dx.doi.org/10.1101/gad.1126903] [PMID: 14561771]
[59]
Gartenhaus, R.B.; Wang, P.; Hoffman, M.; Janson, D.; Rai, K.R. The induction of p53 and WAF1/CIP1 in chronic lymphocytic leukemia cells treated with 2-chlorodeoxyadenosine. J. Mol. Med. (Berl.), 1996, 74(3), 143-147.
[http://dx.doi.org/10.1007/BF01575446] [PMID: 8846164]
[60]
Bellosillo, B.; Villamor, N.; López-Guillermo, A.; Marcé, S.; Bosch, F.; Campo, E.; Montserrat, E.; Colomer, D. Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in Beta-cell chronic lymphocytic leukemia. Blood, 2002, 100(5), 1810-1816.
[http://dx.doi.org/10.1182/blood-2001-12-0327] [PMID: 12176904]
[61]
Dewson, G.; Snowden, R.T.; Almond, J.B.; Dyer, M.J.; Cohen, G.M. Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells. Oncogene, 2003, 22(17), 2643-2654.
[http://dx.doi.org/10.1038/sj.onc.1206326] [PMID: 12730678]
[62]
Johnston, J.B.; Daeninck, P.; Verburg, L.; Lee, K.; Williams, G.; Israels, L.G.; Mowat, M.R.; Begleiter, A. P53, MDM-2, BAX and BCL-2 and drug resistance in chronic lymphocytic leukemia. Leuk. Lymphoma, 1997, 26(5-6), 435-449.
[http://dx.doi.org/10.3109/10428199709050881] [PMID: 9389352]
[63]
Nomura, Y.; Inanami, O.; Takahashi, K.; Matsuda, A.; Kuwabara, M. 2-Chloro-2′-deoxyadenosine induces apoptosis through the Fas/Fas ligand pathway in human leukemia cell line MOLT-4. Leukemia, 2000, 14(2), 299-306.
[http://dx.doi.org/10.1038/sj.leu.2401649] [PMID: 10673748]
[64]
Marzo, I.; Pérez-Galán, P.; Giraldo, P.; Rubio-Félix, D.; Anel, A.; Naval, J. Cladribine induces apoptosis in human leukaemia cells by caspase-dependent and -independent pathways acting on mitochondria. Biochem. J., 2001, 359(Pt 3), 537-546.
[http://dx.doi.org/10.1042/bj3590537] [PMID: 11672427]
[65]
Sampath, D.; Plunkett, W. The role of c-Jun kinase in the apoptotic response to nucleoside analogue-induced DNA damage. Cancer Res., 2000, 60(22), 6408-6415.
[PMID: 11103806]
[66]
Friesen, C.; Herr, I.; Krammer, P.H.; Debatin, K.M. Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat. Med., 1996, 2(5), 574-577.
[http://dx.doi.org/10.1038/nm0596-574] [PMID: 8616718]
[67]
Korsen, M.; Bragado Alonso, S.; Peix, L.; Bröker, B.M.; Dressel, A. Cladribine exposure results in a sustained modulation of the cytokine response in human peripheral blood mononuclear cells. PLoS One, 2015, 10(6)e0129182
[http://dx.doi.org/10.1371/journal.pone.0129182] [PMID: 26086440]
[68]
Liliemark, J. The clinical pharmacokinetics of cladribine. Clin. Pharmacokinet., 1997, 32(2), 120-131.
[http://dx.doi.org/10.2165/00003088-199732020-00003] [PMID: 9068927]
[69]
Savic, R.M.; Novakovic, A.M.; Ekblom, M.; Munafo, A.; Karlsson, M.O. Population pharmacokinetics of cladribine in patients with multiple sclerosis. Clin. Pharmacokinet., 2017, 56(10), 1245-1253.
[http://dx.doi.org/10.1007/s40262-017-0516-6] [PMID: 28255849]
[71]
PACTRIMS. 2017. Mult. Scler., 2018, 24(3), 368-423.
[http://dx.doi.org/10.1177/1352458517751792] [PMID: 29347859]
[79]
Fazekas, F.; Barkhof, F.; Filippi, M.; Grossman, R.I.; Li, D.K.; McDonald, W.I.; McFarland, H.F.; Paty, D.W.; Simon, J.H.; Wolinsky, J.S.; Miller, D.H. The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology, 1999, 53(3), 448-456.
[http://dx.doi.org/10.1212/WNL.53.3.448] [PMID: 10449103]
[80]
Kurtzke, J.F. Rating neurologic impairment in multiple sclerosis: An Expanded Disability Status Scale (EDSS). Neurology, 1983, 33(11), 1444-1452.
[http://dx.doi.org/10.1212/WNL.33.11.1444] [PMID: 6685237]
[81]
De Stefano, N.; Airas, L.; Grigoriadis, N.; Mattle, H.P.; O’Riordan, J.; Oreja-Guevara, C.; Sellebjerg, F.; Stankoff, B.; Walczak, A.; Wiendl, H.; Kieseier, B.C. Clinical relevance of brain volume measures in multiple sclerosis. CNS Drugs, 2014, 28(2), 147-156.
[http://dx.doi.org/10.1007/s40263-014-0140-z] [PMID: 24446248]
[82]
De Stefano, N.; Giorgio, A.; Battaglini, M.; De Leucio, A.; Hicking, C.; Dangond, F.; Giovannoni, G.; Sormani, M.P. Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets. Mult. Scler., 2018, 24(2), 222-226.
[http://dx.doi.org/10.1177/1352458517690269] [PMID: 28140753]
[83]
Giovannoni, G.; Turner, B.; Gnanapavan, S.; Offiah, C.; Schmierer, K.; Marta, M. Is it time to target No Evident Disease Activity (NEDA) in multiple sclerosis? Mult. Scler. Relat. Disord., 2015, 4(4), 329-333.
[http://dx.doi.org/10.1016/j.msard.2015.04.006] [PMID: 26195051]
[84]
Giovannoni, G.; Cook, S.; Rammohan, K.; Rieckmann, P.; Sørensen, P.S.; Vermersch, P.; Hamlett, A.; Viglietta, V.; Greenberg, S. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: A post-hoc and subgroup analysis. Lancet Neurol., 2011, 10(4), 329-337.
[http://dx.doi.org/10.1016/S1474-4422(11)70023-0] [PMID: 21397565]
[85]
Giovannoni, G.; Soelberg Sorensen, P.; Cook, S. Efficacy of Cladribine Tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study. Mult. Scler., 2018, 25(6), 819-827.
[86]
Bermel, R.A.; You, X.; Foulds, P.; Hyde, R.; Simon, J.H.; Fisher, E.; Rudick, R.A. Predictors of long-term outcome in multiple sclerosis patients treated with interferon β. Ann. Neurol., 2013, 73(1), 95-103.
[http://dx.doi.org/10.1002/ana.23758] [PMID: 23378325]
[87]
Dobson, R.; Rudick, R.A.; Turner, B.; Schmierer, K.; Giovannoni, G. Assessing treatment response to interferon-β: Is there a role for MRI? Neurology, 2014, 82(3), 248-254.
[http://dx.doi.org/10.1212/WNL.0000000000000036] [PMID: 24336144]
[88]
Río, J.; Castilló, J.; Rovira, A.; Tintoré, M.; Sastre-Garriga, J.; Horga, A.; Nos, C.; Comabella, M.; Aymerich, X.; Montalbán, X. Measures in the first year of therapy predict the response to interferon beta in MS. Mult. Scler., 2009, 15(7), 848-853.
[http://dx.doi.org/10.1177/1352458509104591] [PMID: 19542263]
[89]
Río, J.; Rovira, A.; Tintoré, M.; Sastre-Garriga, J.; Castilló, J.; Auger, C.; Nos, C.; Comabella, M.; Tur, C.; Vidal, Á.; Montalbán, X. Evaluating the response to glatiramer acetate in Relapsing-Remitting Multiple Sclerosis (RRMS) patients. Mult. Scler., 2014, 20(12), 1602-1608.
[http://dx.doi.org/10.1177/1352458514527863] [PMID: 24622350]
[90]
Río, J.; Ruiz-Peña, J.L. Short-term suboptimal response criteria for predicting long-term non-response to first-line disease modifying therapies in multiple sclerosis: A systematic review and meta-analysis. J. Neurol. Sci., 2016, 361, 158-167.
[http://dx.doi.org/10.1016/j.jns.2015.12.043] [PMID: 26810535]
[91]
Prosperini, L.; Mancinelli, C.R.; De Giglio, L.; De Angelis, F.; Barletta, V.; Pozzilli, C. Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis. Mult. Scler., 2014, 20(5), 566-576.
[http://dx.doi.org/10.1177/1352458513502399] [PMID: 23999607]
[92]
Giovannoni, G.; Soelberg Sorensen, P.; Cook, S. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study. Mult. Scler., 2017, 24(12), 1594-1604.
[93]
Giovannoni, G. Cladribine to treat relapsing forms of multiple sclerosis. Neurotherapeutics, 2017, 14(4), 874-887.
[http://dx.doi.org/10.1007/s13311-017-0573-4] [PMID: 29168160]
[94]
Cook, S.; Vermersch, P.; Comi, G.; Giovannoni, G.; Rammohan, K.; Rieckmann, P.; Sørensen, P.S.; Hamlett, A.; Miret, M.; Weiner, J.; Viglietta, V.; Musch, B.; Greenberg, S.J. Safety and tolerability of cladribine tablets in multiple sclerosis: The CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study. Mult. Scler., 2011, 17(5), 578-593.
[http://dx.doi.org/10.1177/1352458510391344] [PMID: 21228029]
[95]
Soelberg-Sorensen, P.D.F.; Hicking, C.; Giovannoni, G. Absolute lymphocyte count recovery in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets 3.5 mg/kg in CLARITY and CLARITY Extension (P5.379). Neurology, 2017, 88(16)
[96]
Baker, D.; Herrod, S.S.; Alvarez-Gonzalez, C.; Zalewski, L.; Albor, C.; Schmierer, K. Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol. Neuroimmunol. Neuroinflamm., 2017, 4(4), e360
[http://dx.doi.org/10.1212/NXI.0000000000000360] [PMID: 28626781]


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VOLUME: 20
ISSUE: 4
Year: 2020
Published on: 10 April, 2020
Page: [269 - 285]
Pages: 17
DOI: 10.2174/1389557519666191015201755
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