HDAC inhibitor
Histone deacetylase inhibitor
- Histones stay acetylated → silenced genes re-expressed
- Differentiation and apoptosis of malignant cells
- Thrombocytopenia
- Teratogenic (neural tube defects)
HDAC inhibitor (1/2)
- Alters gene transcription by preventing histone deacetylation
- Used in cutaneous T-cell lymphoma; valproate has weak activity
- Cytopenias class-wide; thrombocytopenia is the dose-limiting one
HDAC inhibitor (2/2)
- HDAC3's deacetylase activity sets cardiac repolarization — losing that activity alone prolongs QT
- Inhibition downregulates the repolarizing potassium-channel genes: KCNH2, KCNE1, KCNIP2
- 11 of the 13 congenital long-QT genes fall — the channels are made fewer, not blocked
- So there is no hERG blockade here, unlike the drugs behind most drug-induced QT
- Modest where it has been measured carefully: romidepsin's peak mean QTcF rise was 10.1 ms, with no patient above 450 ms
- And inflated even there by a mean 18 bpm rise in heart rate and by QT-prolonging antiemetics given before the infusion
- Givinostat is where it matters — dosed chronically in Duchenne; withhold if QTc exceeds 500 ms or rises more than 60 ms from baseline
- Valproate carries no QT signal at all
Drugs with this mechanism (11)
- Belinostat — IV HDAC inhibitor for peripheral T-cell lymphoma; UGT1A1-cleared.
- Givinostat — HDAC inhibitor that slows functional decline in Duchenne muscular dystrophy.
- Panobinostat — Oral HDAC inhibitor for myeloma; long half-life and marked QT risk.
- Romidepsin — Cyclic-peptide HDAC inhibitor for cutaneous T-cell lymphoma.
- Sodium butyrate — Short-chain fatty acid and HDAC inhibitor, taken as a supplement.
- Valproic acid — Broad-spectrum anticonvulsant and mood stabilizer; highly teratogenic and metabolically burdensome.
- Divalproex DR — Delayed-release broad-spectrum antiseizure drug and mood stabilizer; highly teratogenic.
- Divalproex ER — Extended-release broad-spectrum antiseizure drug and mood stabilizer; highly teratogenic.
- Valproate sodium IV — Intravenous valproate for seizures when oral therapy is unavailable; broad-spectrum but highly teratogenic.
- Divalproex sprinkle — Valproate sprinkle capsule for seizures; useful when intact tablets cannot be swallowed.
- Vorinostat — First-approved HDAC inhibitor, for cutaneous T-cell lymphoma.
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