In vitro pharmacokinetics of anti-psoriatic fumaric acid esters

Litjens, Nicolle H.R.; Strijen, E. Van; Gulpen, Co van; Mattie, H.; Dissel, Jaap T. van; Thio, H. Bing; Nibbering, Peter H.

doi:10.1186/1471-2210-4-22

Cited by 64 publications

(36 citation statements)

References 18 publications

(15 reference statements)

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“…4,9,23,24 Assessment of the in vitro effects of both MMF and DMF on human T-cell subset survival and apoptotic cell death within PBMC demonstrated that exposure to DMF (but not MMF) induced dose-dependent apoptotic T-cell losses. Although early work with FAEs suggested that the only active metabolite was MMF (with DMF rapidly converting to MMF in vivo), 25 our findings are consistent with multiple studies that have since attributed important biological activities also to DMF. 4,9,24,26 A degree of systemic penetrance of DMF has been reported, with DMF-glutathione conjugates being measureable in the plasma and brain of rats following oral administration of DMF, 27 and similar DMF-derived conjugates found in the urine of DMF-treated psoriasis patients.…”

Section: Discussionsupporting

confidence: 90%

Dimethyl fumarate–induced lymphopenia in MS due to differential T-cell subset apoptosis

Ghadiri

Rezk

Li³

et al. 2017

Neurol Neuroimmunol Neuroinflamm

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Objective:To examine the mechanism underlying the preferential CD8+ vs CD4+ T-cell lymphopenia induced by dimethyl fumarate (DMF) treatment of MS.Methods:Total lymphocyte counts and comprehensive T-cell subset analyses were performed in high-quality samples obtained from patients with MS prior to and serially following DMF treatment initiation. Random coefficient mixed-effects analysis was used to model the trajectory of T-cell subset losses in vivo. Survival and apoptosis of distinct T-cell subsets were assessed following in vitro exposure to DMF.Results:Best-fit modeling indicated that the DMF-induced preferential reductions in CD8+ vs CD4+ T-cell counts nonetheless followed similar depletion kinetics, suggesting a similar rather than distinct mechanism involved in losses of both the CD8+ and CD4+ T cells. In vitro, DMF exposure resulted in dose-dependent reductions in T-cell survival, which were found to reflect apoptotic cell death. This DMF-induced apoptosis was greater for CD8+ vs CD4+, as well as for memory vs naive, and conventional vs regulatory T-cell subsets, a pattern which mirrored preferential T-cell subset losses that we observed during in vivo treatment of patients.Conclusions:Differential apoptosis mediated by DMF may underlie the preferential lymphopenia of distinct T-cell subsets, including CD8+ and memory T-cell subsets, seen in treated patients with MS. This differential susceptibility of distinct T-cell subsets to DMF-induced apoptosis may contribute to both the safety and efficacy profiles of DMF in patients with MS.

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Section: Discussionsupporting

confidence: 90%

Dimethyl fumarate–induced lymphopenia in MS due to differential T-cell subset apoptosis

Ghadiri

Rezk

Li³

et al. 2017

Neurol Neuroimmunol Neuroinflamm

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“…F and G). The relative importance of DMF and its metabolite MMF in mediating the biological effects of this medication is disputed, however we noted significant effects with both DMF and MMF at biologically relevant concentrations .…”

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confidence: 54%

Dimethyl fumarate treatment alters NK cell function in multiple sclerosis

2017

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“…Furthermore, DMF can induce apoptosis in human T cells (13), suppress chemokine production in human keratinocytes and peripheral blood mononuclear cells (14), inhibit keratinocyte proliferation (15), shift cytokine secretion away from a Th1 cytokine profile towards a Th2 immune response (16) and deprive different cell types of glutathione (17–19). Nevertheless, in recent in vivo studies, DMF could not be detected in the blood of healthy subjects after intake of fumarates, whereas the concentration of monomethylfumarate (MMF) increased (20), suggesting that DMF functions as a prodrug for its main metabolite MMF (21). MMF has been shown to induce selectively the expression of Th2‐type cytokines (22), to downregulate Th1 lymphocyte responses through modulation of dendritic cell polarization (23) and to inhibit monocyte‐derived dendritic cell differentiation, the latter function being similar to DMF (12).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of endothelial adhesion molecules by dimethylfumarate, but not monomethylfumarate, and impairment of dynamic lymphocyte-endothelial cell interactions

Wallbrecht¹,

Drick²,

Hund

et al. 2011

Experimental Dermatology

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Although fumaric acid esters (FAE) have a decade-long firm place in the therapeutic armamentarium for psoriasis, their pleiotropic mode of action is not yet fully understood. While most previous studies have focused on the effects of FAE on leucocytes, we have addressed their activity on macro- and microvascular endothelial cells. As detected both on mRNA and protein levels, dimethylfumarate effected a profound reduction of TNFα-induced expression of E-selectin (CD62E), ICAM-1 (CD54) and VCAM-1 (CD106) on two different endothelial cell populations in a concentration-dependent manner. This reduction of several endothelial adhesion molecules was accompanied by a dramatic diminution of both rolling and firm adhesive interactions between endothelial cells and lymphocytes in a dynamic flow chamber system. Dimethylfumarate, at a concentration of 50 μm, reduced lymphocyte rolling on endothelial cells by 85.9% (P<0.001 compared to untreated controls), and it diminished the number of adherent cells by 88% (P<0.001). In contrast, monomethylfumarate (MMF) influenced neither surface expression of adhesion molecules nor interactions between endothelial cells and lymphocytes. These observations demonstrate that endothelial cells, in addition to the known effects on leucocytes, undergo profound functional changes in response to dimethylfumarate. These changes are accompanied by severely impaired dynamic interactions with lymphocytes, which constitute the critical initial step of leucocyte recruitment to inflamed tissues in psoriasis and other TNF-related inflammatory disorders.

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In vitro pharmacokinetics of anti-psoriatic fumaric acid esters

Cited by 64 publications

References 18 publications

Dimethyl fumarate–induced lymphopenia in MS due to differential T-cell subset apoptosis

Dimethyl fumarate–induced lymphopenia in MS due to differential T-cell subset apoptosis

Dimethyl fumarate treatment alters NK cell function in multiple sclerosis

Downregulation of endothelial adhesion molecules by dimethylfumarate, but not monomethylfumarate, and impairment of dynamic lymphocyte-endothelial cell interactions

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