Dimethyl Fumarate and Monomethyl Fumarate are Distinguished by Non-Overlapping Pharmacodynamic Effects In Vivo (P1.206)
Bibliographic record
Abstract
OBJECTIVE: Determine if the pharmacodynamic and therapeutic effects of dimethyl fumarate (DMF) and monomethyl fumarate (MMF) are completely overlapping, or if distinct responses are induced in naïve and experimental autoimmune encephalomyelitis (EAE) mice. BACKGROUND: Delayed-release DMF is approved in the U.S., Canada, and Australia for the treatment of relapsing MS. It is unknown exactly how delayed-release DMF exerts clinical effects; however, DMF promotes anti-inflammatory and neuroprotective responses, both of which may impact MS pathophysiology. DMF is rapidly metabolized in vivo to MMF, and both are pharmacologically active. It is unknown if delayed-release DMF therapeutic effects are mediated through DMF, MMF, or some combination of the two. Understanding the pharmacodynamic properties of DMF and MMF would provide important insights into the delayed-release DMF mechanisms of action. DESIGN/METHODS: Naïve C57BL/6 mice were dosed orally with vehicle, DMF, or MMF and pharmacodynamic responses were evaluated in multiple tissues and whole blood. Differentially expressed genes and immune cell surface markers were identified by comparing DMF- or MMF-treated mice to matched vehicle controls. Mice in which EAE was induced by myelin oligodendrocyte glycoprotein (MOG) were evaluated for DMF or MMF therapeutic effects, and pharmacodynamic responses were also evaluated. RESULTS: In naïve animals, pharmacodynamic responses to DMF versus MMF exhibited some overlap, but multiple distinct responses to each treatment were also evident. In EAE animals, similar patterns of pharmacodynamic effects were observed, with some overlapping responses, but also numerous distinct responses unique to either DMF or MMF. DMF produced a more robust clinical effect on disease score compared to MMF. CONCLUSIONS: DMF and MMF induce some common pharmacodynamic responses, but are also clearly differentiated from each other. This indicates that DMF and MMF are not therapeutically equivalent. Thus, DMF cannot be considered simply, or only as a prodrug of MMF, as it has distinct pharmacological properties. Study Supported by: Biogen Idec, Inc.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".