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Velnacrine is the main liver metabolite of tacrine, and Hoechst-Roussel developed it under the name Mentane hoping that using the metabolite directly, rather than relying on the body to convert tacrine into it, might dodge tacrine's notorious liver-toxicity problem. It did not; clinical trials found the same pattern of asymptomatic but concerning liver-enzyme elevations that had plagued tacrine, and researchers built a statistical risk model (called PROPP) just to try to predict which Alzheimer's patients would develop hepatotoxicity before exposing them to the drug. Hoechst-Roussel ultimately dropped velnacrine after regulators would not approve it on the safety data submitted, a case of a cleaner metabolite turning out to share its parent drug's core problem.
- acetylcholinesterase inhibition supporting cognitive benefit in Alzheimer's disease trials, similar in principle to tacrine
- asymptomatic, reversible liver-enzyme elevations in a substantial share of treated patients, closely resembling tacrine's hepatotoxicity pattern
- Velnacrine was marketed under the development name Mentane and got as far as being reviewed by regulators before Hoechst-Roussel withdrew it rather than pursue approval on its liver-safety data.
Mechanism
Reversible inhibitor; the principal 1-hydroxy of tacrine, sharing tacrine's core acridine-derived structure and mechanism of boosting by blocking its breakdown.
Dosingtypical ranges, not medical advice
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Safetyrisks and cautions, not medical advice
Liver numbers are the whole story. In the 24-week trials abnormal liver function tests appeared in 105 of 297 patients on velnacrine against 4 of 152 on placebo, an odds ratio above twenty, and 135 patients had treatment stopped for safety reasons, mostly hepatic. The injury was hepatocellular and reversible on stopping, the same pattern as tacrine, which is precisely why the hope that dosing tacrine's own metabolite would sidestep the problem failed. One dose group was halted after four days when a participant had a tonic seizure. The FDA advisory committee voted unanimously against approval.
History
Developed by Hoechst-Roussel Pharmaceuticals as Mentane through the late 1980s and early 1990s; reached clinical trials for Alzheimer's disease but showed hepatotoxicity closely resembling tacrine's, and the company withdrew the drug rather than pursue approval.
Subjective profileweighing the evidence above
Proof that being 'just the metabolite' of a hepatotoxic drug does not make you a safer drug.
Resources
This entry is here for reference.
Research
- 1.Clinical trials with velnacrine: (PROPP) the physician reference of predicted probabilities--a statistical model for the estimation of hepatotoxicity risk with velnacrine maleate
- 2.Cytotoxicity of tacrine and velnacrine metabolites in cultured rat, dog and human hepatocytes
2 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Why would using tacrine's own metabolite not fix tacrine's liver problem?
Researchers hoped skipping the metabolic conversion step might reduce toxic byproduct formation, but velnacrine caused the same reversible hepatocellular injury pattern seen with tacrine, suggesting the acridine core itself, not just the conversion process, was the issue.
What was the PROPP model built for velnacrine?
PROPP (physician reference of predicted probabilities) was a statistical model developed during velnacrine's trials to estimate an individual patient's risk of hepatotoxicity before starting treatment.
Adverse effects
- asymptomatic, reversible liver-enzyme elevations in a substantial share of treated patients, closely resembling tacrine's hepatotoxicity pattern