Velnacrine in Alzheimer’s Disease
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Velnacrine is an hydroxylated derivative of the acetylcholinesterase inhibitor tacrine. The ability of velnacrine to increase cholinergic neurotransmission in vitro provides the rationale for its investigation as a potential treatment in patients with Alzheimer’s disease, who are known to have reduced acetylcholine levels in the central nervous system. Single doses of velnacrine (100 or 150mg) attenuated cognitive impairment induced by central cholinergic blockade in healthy volunteers, and memory improved significantly in a small number of patients with Alzheimer’s disease administered a 75mg dose.
Evidence of efficacy for velnacrine is limited to results of briefly reported placebo-controlled studies. When administered in dosages of up to 225 mg/day for 6 weeks, velnacrine appeared to confer modest benefit in about one-third of 423 patients with Alzheimer’s disease enrolled in a US dose-finding trial. Velnacrine 150 mg/day for 10 days was also considered superior to placebo in a small European trial involving 35 patients, notably in its effects on language, praxis and memory. Fuller results are anticipated from a 6-month investigation demonstrating efficacy for velnacrine 150 or 225 mg/day at 12-week interim analysis. Of interest is the finding from this trial that caregiver time assessed at 24 weeks was shorter for velnacrine compared with placebo recipients.
The development of elevated plasma hepatic enzyme levels leading to treatment discontinuation in 27% of participants in the US trial, combined with the appearance of neutropenia in a few patients, has cast doubt over the tolerability profile of velnacrine. Ongoing investigations are endeavouring to identify the mechanism of the hepatotoxic effect, to establish whether a dose-response relationship exists, and to define possible subpopulations that may respond to velnacrine and those who may be at particular risk of developing hepatotoxicity. Other reported adverse events severe enough to cause treatment withdrawal have included rash, nausea, diarrhoea, headache and dizziness/fainting.
In summary, questions surrounding the tolerability and efficacy of velnacrine must be resolved before its early promise as a treatment in Alzheimer’s disease can be realised. Nonetheless, given the limited therapeutic options presently, available, the drug may yet prove to be of value in at least some patients with Alzheimer’s disease.
KeywordsAdis International Limited Tacrine Caregiver Time Velnacrine Elevated Hepatic Enzyme Level
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