Different Fumaric Acid Esters Elicit Distinct Pharmacologic Responses
Autor: | Suzanne Szak, Robert H. Scannevin, Ralf Gold, Robert Hoepner, Katrin Strassburger-Krogias, Maximilian Pistor, Melanie S. Brennan, Andrew T. Chan, Davide Gianni, Brian T. Wipke, Ankur M. Thomas |
---|---|
Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Multiple Sclerosis Dimethyl Fumarate Lymphocyte 610 Medicine & health Pharmacology medicine.disease_cause Article Rats Sprague-Dawley Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system Fumarates Pharmacokinetics Gene expression otorhinolaryngologic diseases medicine Animals Humans Retrospective Studies Dimethyl fumarate business.industry Gene Expression Profiling biochemical phenomena metabolism and nutrition Rats Mice Inbred C57BL Macaca fascicularis Cross-Sectional Studies 030104 developmental biology medicine.anatomical_structure Neurology chemistry Pharmacodynamics embryonic structures Female Neurology (clinical) business Immunosuppressive Agents 030217 neurology & neurosurgery Oxidative stress CD8 |
Zdroj: | Wipke, Brian T; Hoepner, Robert; Strassburger-Krogias, Katrin; Thomas, Ankur M; Gianni, Davide; Szak, Suzanne; Brennan, Melanie S; Pistor, Maximilian; Gold, Ralf; Chan, Andrew; Scannevin, Robert H (2021). Different Fumaric Acid Esters Elicit Distinct Pharmacologic Responses. Neurology: Neuroimmunology and Neuroinflammation, 8(2) Wolters Kluwer Health 10.1212/NXI.0000000000000950 Neurology® Neuroimmunology & Neuroinflammation article-version (Version of Record) 3 |
ISSN: | 2332-7812 |
Popis: | ObjectiveTo test the hypothesis that dimethyl fumarate (DMF, Tecfidera) elicits different biological changes from DMF combined with monoethyl fumarate (MEF) (Fumaderm, a psoriasis therapy), we investigated DMF and MEF in rodents and cynomolgus monkeys. Possible translatability of findings was explored with lymphocyte counts from a retrospective cohort of patients with MS.MethodsIn rodents, we evaluated pharmacokinetic and pharmacodynamic effects induced by DMF and MEF monotherapies or in combination (DMF/MEF). Clinical implications were investigated in a retrospective, observational analysis of patients with MS treated with DMF/MEF (n = 36).ResultsIn rodents and cynomolgus monkeys, monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited higher brain penetration, whereas MEF was preferentially partitioned into the kidney. In mice, transcriptional profiling for DMF and MEF alone identified both common and distinct pharmacodynamic responses, with almost no overlap between DMF- and MEF-induced differentially expressed gene profiles in immune tissues. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated oxidative stress response pathway was exclusively regulated by DMF, whereas apoptosis pathways were activated by MEF. DMF/MEF treatment demonstrated that DMF and MEF functionally interact to modify DMF- and MEF-specific responses in unpredictable ways. In patients with MS, DMF/MEF treatment led to early and pronounced suppression of lymphocytes, predominantly CD8+ T cells. In a multivariate regression analysis, the absolute lymphocyte count (ALC) was associated with age at therapy start, baseline ALC, and DMF/MEF dosage but not with previous immunosuppressive medication and sex. Furthermore, the ALC increased in a small cohort of patients with MS (n = 6/7) after switching from DMF/MEF to DMF monotherapy.ConclusionsFumaric acid esters exhibit different biodistribution and may elicit different biological responses; furthermore, pharmacodynamic effects of combinations differ unpredictably from monotherapy. The strong potential to induce lymphopenia in patients with MS may be a result of activation of apoptosis pathways by MEF compared with DMF. |
Databáze: | OpenAIRE |
Externí odkaz: |