Fingolimod (Gilenya<sup>®</sup>) in multiple sclerosis: bradycardia, atrioventricular blocks, and mild effect on the<scp>QT</scp>c interval. Something to do with the L‐type calcium channel?
Bibliographic record
Abstract
Abstract Cardiac arrhythmias andECGabnormalities including bradycardia, prolongation of theQTinterval, and atrioventricular (AV) conduction blocks have been extensively observed with fingolimod, the first marketed oral drug for treating the relapsing‐remitting form of multiple sclerosis. This study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels: (i) in vitro, (ii) ex vivo,and (iii) in vivo. (i) Patch‐clamp experiments in whole cell configuration were performed on Cav1.2‐transfected tsA201 cells exposed to fingolimod‐phosphate 100 or 500 nmol/L (n= 27 cells, total) to measure drug effect on L‐type calcium current (ICaL). (ii) Langendorff perfusion experiments were undertaken on male Hartley guinea‐pigs isolated hearts (n= 4) exposed to fingolimod 10 and 100 nmol/L to evaluate drug‐induced effects on monophasic action potential duration measured at 90% repolarization (MAPD90). (iii) Implanted cardiac telemeters were used to recordECGs in guinea‐pigs (n= 7) treated with a single dose of fingolimod 0.0625 mg/kg suspension, administered as an oral gavage. (i) In vitro cellular experiments showed that fingolimod‐phosphate causes a concentration‐dependent reduction inICaL. (ii) Ex vivo Langendorff experiments revealed that fingolimod had no significant effect onMAPD90. (iii) Fingolimod caused significant prolongations of theRR,PR,QT, andQTcFintervals in vivo. ReversibleAVblocks were also observed in 7/7 animals. Fingolimod possessesICaL‐blocking properties, further contributing to itsAVconduction‐slowing effects. These properties are also consistent with its mitigated effect on theQTinterval in humans, despite previously shownHERG‐blocking effect.
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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) | 0.000 | 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) | 0.001 | 0.000 |
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".