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 and ECG abnormalities including bradycardia, prolongation of the QT interval, 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 Ca v 1.2‐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 ( I C aL ). (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 ( MAPD 90 ). (iii) Implanted cardiac telemeters were used to record ECG s 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 in I C aL . (ii) Ex vivo Langendorff experiments revealed that fingolimod had no significant effect on MAPD 90 . (iii) Fingolimod caused significant prolongations of the RR , PR , QT , and QT c F intervals in vivo. Reversible AV blocks were also observed in 7/7 animals. Fingolimod possesses I C aL ‐blocking properties, further contributing to its AV conduction‐slowing effects. These properties are also consistent with its mitigated effect on the QT interval in humans, despite previously shown HERG ‐blocking effect.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".