Identifying the active pharmaceutical ingredient from a mixture of fumaric acid esters for the treatment of psoriasis: Hints from in vitro investigations

Authors

DOI:

https://doi.org/10.18063/apm.v2i1.325

Keywords:

dimethylfumarate (DMF), monoethylfumarate (MEF), monomethylfumarate (MMF), fumaric acid esters, psoriasis

Abstract

A mixture of fumaric acid esters (FAEs) is approved for the oral therapy of psoriasis. However, for a long time the active ingredient of this mixture was unknown. We reviewed the in vitro data available for the different FAEs present in the multi compound drug and elaborate how they may contribute to possible clinical effects. Although helpful overall, many in vitro data must be viewed critically because the concentrations used in the experiments exceed the plasma levels reached in patients. The data suggest that dimethylfumarate (DMF) is the most active compound, mediating the major therapeutic effect after metabolization into MMF via an according receptor expressed on target cells. Identifying the active pharmaceutical ingredient within a mixture of compounds helps to subsequently eliminate unnecessary, potentially harmful compounds. This provides a promising example for an alternative precision medicine approach in clinical practice.

Author Biography

Lilla Landeck, Department of Dermatology, Ernst von Bergmann General Hospital, Potsdam

Dr Lilla Landeck, MD is an Associate Professor in Dermatology and Chief Physician of the Department of Dermatology, Ernst von Bergmann General Hospital in Potsdam. Dr Landeck’s research is focused on investigating the genetic and environmental factors that underpin eczematous skin diseases and how findings from this work can be translated into improved diagnosis and treatment of these conditions.

References

Nimmesgern E, Benediktsson I, Norstedt I, 2017, Personalized medicine in Europe. Clinical and Translational Science, vol.10(2): 61–63. https://dx.doi.org/10.1111/cts.12446

Hagedorn M, Kalkoff K W, Kiefer G, et al., 1975, Fumarsäuremonoäthylester: Wirkung auf DNA-synthese und erste tierexperimentelle befunde (German) [Fumaric acid monoethylester: Effect on DNA-synthesis and preliminary findings in experimental studies in animals]. Archives of Dermatological Research, vol.254(1): 67–73. https://dx.doi.org/10.1007/BF00561536

Petres J, Kalkoff K W, Baron D, et al., 1975, Der Einfluss von Fumarsäuremonoäthylester auf die Nucleinsäure- und Proteinsynthese PHA-stimulierter menschlicher Lymphocyten (German) [The effect of fumaric acid monoethylester on the synthesis of nucleic acids and proteins of PHA-stimulated human lymphocytes]. Archiv fur Dermatologische Forschung, vol.251(4): 295–300. https://dx.doi.org/10.1007/BF00562233

Nibbering P H, Thio B, Zomerdijk T P, et al., 1993, Effects of monomethylfumarate on human granulocytes. Journal of Investigative Dermatology, vol.101(1): 37–42. https://dx.doi.org/10.1111/1523-1747.ep12358715

Sebok B, Bonnekoh B, Geisel J, et al.,1994, Antiproliferative and cytotoxic profiles of antipsoriatic fumaric acid derivatives in keratinocyte cultures. European Journal of Pharmacology, vol.270(1): 79–87. https://dx.doi.org/10.1016/0926-6917(94)90083-3

de Jong R, Bezemer A C, Zomerdijk T P, et al.,1996, Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate. European Journal of Immunology, vol.26(9): 2067–2074. https://dx.doi.org/10.1002/eji.1830260916

Vandermeeren M, Janssens S, Borgers M, et al., 1997, Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells. Biochemical and Biophysical Research Communications, vol.234(1): 19–23. https://dx.doi.org/10.1006/bbrc.1997.6570

Brennan M S, Matos M F, Li B, et al., 2015, Dimethyl fumarate and monoethylfumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro. PLoS One, vol.10(3): e0120254. https://dx.doi.org/10.1371/journal.pone.0120254

Gillard G O, Collette B, Anderson J, et al., 2015, DMF, but not other fumarates, inhibits NF-kappaB activity in vitro in an Nrf2-independent manner. Journal of Neuroimmunology, vol.283: 74–85. https://dx.doi.org/10.1016/j.jneuroim.2015.04.006

Thio H B, Zomerdijk T P, Oudshoorn C, et al., 1994, Fumaric acid derivatives evoke a transient increase in intracellular free calcium concentration and inhibit the proliferation of human keratinocytes. British Journal of Dermatology, vol.131(6): 856–861. https://dx.doi.org/10.1111/j.1365-2133.1994.tb08589.x

Sebok B, Bonnekoh B, Vetter R, et al., 1998, The antipsoriatic dimethyl-fumarate suppresses interferon-gamma-induced ICAM-1 and HLA-DR expression on hyperproliferative keratinocytes. Quantification by a culture plate-directed APAAP-ELISA technique. European Journal of Dermatology, vol.8(1): 29–32.

Sebök B, Gollnick H, Mahrle G, et al., 2000, Dimethylfumarate is the Fumaderm-compound with the strongest induction of apoptosis-phenomena in lympho-histiocytic U-937 cells. Zeitschrift fur Hautkrankheiten, vol.76: 347–351.

Lehmann J C, Listopad J J, Rentzsch C U, et al., 2007, Dimethylfumarate induces immunosuppression via glutathione depletion and subsequent induction of heme oxygenase 1. Journal of Investigative Dermatology, vol.127(4): 835–845. https://dx.doi.org/10.1038/sj.jid.5700686

Wallbrecht K, Drick N, Hund A C, et al., 2011, Downregulation of endothelial adhesion molecules by dimethylfumarate, but not monomethylfumarate, and impairment of dynamic lymphocyte-endothelial cell interactions. Experimental Dermatology, vol.20(12): 980–985. https://dx.doi.org/10.1111/j.1600-0625.2011.01376.x

McGuire V A, Ruiz-Zorrilla Diez T, Emmerich C H, et al., 2016, Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Scientific Reports, vol.6(31159): 31159. https://dx.doi.org/10.1038/srep31159

Helwa I, Choudhary V, Chen X, et al., 2017, The anti-psoriatic drug monomethylfumarate increases nuclear factor erythroid 2-related factor 2 (Nrf2) levels and induces aquaporin-3 (AQP3) mRNA and protein expression. Journal of Pharmacology and Experimental Therapeutics,vol.362(2): 243–253. https://dx.doi.org/10.1124/jpet.116.239715

Ghoreschi K, Bruck J, Kellerer C, et al., 2011, Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. Journal of Experimental Medicine, vol.208(11): 2291–2303. https://dx.doi.org/10.1084/jem.20100977

Tahvili S, Zandieh B, Amirghofran Z, 2015, The effect of dimethyl fumarate on gene expression and the level of cytokines related to different T helper cell subsets in peripheral blood mononuclear cells of patients with psoriasis. International Journal of Dermatology, vol.54(7): e254–260. https://dx.doi.org/10.1111/ijd.12834

Rostami-Yazdi M, Clement B, Mrowietz U, 2010, Pharmacokinetics of anti-psoriatic fumaric acid esters in psoriasis patients. Archives of Dermatological Research, vol.302(7): 531–538. https://dx.doi.org/10.1007/s00403-010-1061-4

Mrowietz U, Christophers E, Altmeyer P, 1999, Treatment of severe psoriasis with fumaric acid esters: Scientific background and guidelines for therapeutic use. British Journal of Dermatology, vol.141(3): 424–429. https://dx.doi.org/10.1046/j.1365-2133.1999.03034.x

Ockenfels H M, Schultewolter T, Ockenfels G, et al., 1998, The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network. British Journal of Dermatology, vol.139(3): 390–395. https://dx.doi.org/10.1046/j.1365-2133.1998.02400.x

Nibbering P H, Thio B, Bezemer A C, et al., 1997, Intracellular signalling by binding sites for the antipsoriatic agent monomethylfumarate on human granulocytes. British Journal of Dermatology, vol.137(1): 65–75. https://dx.doi.org/10.1046/j.1365-2133.1997.1769185.x

Asadullah K, Schmid H, Friedrich M, et al., 1997, Influence of monomethylfumarate on monocytic cytokine formation-explanation for adverse and therapeutic effects in psoriasis? Archives of Dermatological Research, vol.289(11): 623–630. https://dx.doi.org/10.1007/s004030050251

Gillard G, Huss D, Anderson J, et al., 2014, Fumarate esters are distinguished by differential inhibition of the NF-κB mediated proinflammatory response. Minerva Medica, vol.52(2): 428

Menter A, Korman N J, Elmets C A, et al., 2009, Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. Journal of the American Academy of Dermatology, vol.60(4): 643–659. https://dx.doi.org/10.1016/j.jaad.2009.03.027

Hoxtermann S, Nuchel C, Altmeyer P, 1998, Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis. Dermatology, vol.196(2): 223–230. https://dx.doi.org/10.1159/000017903

Loewe R, Holnthoner W, Groger M, et al., 2002, Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells. Journal of Immunology, vol.168(9): 4781–4787. https://dx.doi.org/10.4049/jimmunol.168.9.4781

Hund A C, Lockmann A, Schon M P, 2016, Mutually enhancing anti-inflammatory activities of dimethyl fumarate and NF-kappaB inhibitors-implications for dose-sparing combination therapies. Experimental Dermatology, vol.25(2): 124–130. https://dx.doi.org/10.1111/exd.12892

Christophers E, Metzler G, Rocken M, 2014, Bimodal immune activation in psoriasis. British Journal of Dermatology, vol.170(1): 59–65. https://dx.doi.org/10.1111/bjd.12631

Hoffmann JHO, Schaekel K, Hartl D, et al., 2017, Dimethyl fumarate modulates neutrophil extracellular trap formation in a glutathione and superoxide-dependent manner. British Journal of Dermatology. https://dx.doi.org/10.1111/bjd.15839

Warnatsch A, Ioannou M, Wang Q, et al., 2015, Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science, vol.349(6245): 316–320. https://dx.doi.org/10.1126/science.aaa8064

Linker R A, Lee D H, Ryan S, et al., 2011, Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain, vol.134(Pt 3): 678–692. https://dx.doi.org/10.1093/brain/awq386

Scannevin R H, Chollate S, Jung M Y, et al., 2012, Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. Journal of Pharmacology and Experimental Therapeutics, vol.341(1): 274–284. https://dx.doi.org/10.1124/jpet.111.190132

Itoh K, Wakabayashi N, Katoh Y, et al., 2003, Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Journal of Genes to Cells, vol.8(4): 379–391. https://dx.doi.org/10.1046/j.1365-2443.2003.00640.x

Kobayashi A, Kang M I, Okawa H, et al., 2004, Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Molecular and Cellular Biology, vol.24(16): 7130–7139. https://dx.doi.org/10.1128/MCB.24.16.7130-7139.2004

Itoh K, Chiba T, Takahashi S, et al., 1997, An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochemical and Biophysical Research Communications, vol.236(2): 313–322. https://dx.doi.org/10.1006/bbrc.1997.6943

Nguyen T, Sherratt PJ, Pickett C B, 2003, Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annual Review of Pharmacology and Toxicology, vol.43: 233–260. https://dx.doi.org/10.1146/annurev.pharmtox.43.100901.140229

Bollag W B, Xie D, Zheng X, et al., 2007, A potential role for the phospholipase D2-aquaporin-3 signaling module in early keratinocyte differentiation: production of a phosphatidylglycerol signaling lipid. Journal of Investigative Dermatology, vol.127(12): 2823–2831. https://dx.doi.org/10.1038/sj.jid.5700921

Choudhary V, Olala L O, Qin H, et al., 2015, Aquaporin-3 re-expression induces differentiation in a phospholipase D2-dependent manner in aquaporin-3-knockout mouse keratinocytes. Journal of Investigative Dermatology, vol.135(2): 499–507. https://dx.doi.org/10.1038/jid.2014.412

Geisel J, Bruck J, Glocova I, et al., 2014, Sulforaphane protects from T cell-mediated autoimmune disease by inhibition of IL-23 and IL-12 in dendritic cells. Journal of Immunology, vol.192(8): 3530–3539. https://dx.doi.org/10.4049/jimmunol.1300556

Arbiser J L, 2011, Fumarate esters as angiogenesis inhibitors: Key to action in psoriasis. Journal of Investigative Dermatology, vol.131(6): 1189–1191. https://dx.doi.org/10.1038/jid.2011.45

Garcia-Caballero M, Mari-Beffa M, Medina MA, et al., 2011, Dimethylfumarate inhibits angiogenesis in vitro and in vivo: A possible role for its antipsoriatic effect? Journal of Investigative Dermatology, vol.131(6): 1347–1355. https://dx.doi.org/10.1038/jid.2010.416

Meissner M, Doll M, Hrgovic I, et al., 2011, Suppression of VEGFR2 expression in human endothelial cells by dimethylfumarate treatment: Evidence for anti-angiogenic action. Journal of Investigative Dermatology, vol.131(6): 1356–1364. https://dx.doi.org/10.1038/jid.2011.46

Treumer F, Zhu K, Glaser R, et al., 2003, Dimethylfumarate is a potent inducer of apoptosis in human T cells. Journal of Investigative Dermatology, vol.121(6): 1383–1388. https://dx.doi.org/10.1111/j.1523-1747.2003.12605.x

Rubant S A, Ludwig R J, Diehl S, et al., 2008, Dimethylfumarate reduces leukocyte rolling in vivo through modulation of adhesion molecule expression. Journal of Investigative Dermatology, vol.128(2): 326–331. https://dx.doi.org/10.1038/sj.jid.5700996

Brennan M, Allaire N, Huss D, et al., 2014, Dimethyl fumarate and monomethyl fumarate are distinguished by non-overlapping pharmacodynamic effects in vivo. Neurology, vol.82: P1.206.

Mrowietz U, Szepietowski J C, Loewe R, et al., 2017, Efficacy and safety of LAS41008 (dimethyl fumarate) in adults with moderate-to-severe chronic plaque psoriasis: A randomized, double-blind, Fumaderm(R)- and placebo-controlled trial (BRIDGE). British Journal of Dermatology, vol.176(3): 615–623. https://dx.doi.org/10.1111/bjd.14947

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Published

2017-12-12

Issue

Vol 2, Issue 1

Section

Review Articles

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