Velnacrine for Alzheimer's disease.
Birks J., Wilcock GG.
BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Velnacrine is a derivative of tacrine. OBJECTIVES: To determine the clinical efficacy and safety of velnacrine for patients with dementia of Alzheimer's type. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 8 January 2004 using the terms velnacr* and 'HP 029'. The CDCIG SR is regularly updated and contains records from all major health care databases and a great many ongoing trial databases. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with velnacrine was administered to patients with dementia of the Alzheimer's type for more than two weeks and its effects compared with those of placebo in a parallel group of patients. DATA COLLECTION AND ANALYSIS: One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data. MAIN RESULTS: Four trials, involving 899 participants, were included. Cutler 1990 reported only the adverse events, and omitted the results for the placebo group. Medication was stopped for all in the highest dose group after the fourth day because one member suffered a tonic seizure. It is not possible to report any comparisons with placebo. Antuono 1995 reported benefit for velnacrine at endpoint for the CGI-C, and the Physical Self-maintenance Scale (PGIR), but not for the Carers Assessment of Time Activity (CATS). These results could not be checked because the relevant information was not reported, and we cannot assess the effect on the results of the higher number of non-completers from the velnacrine group. Treatment was discontinued because of safety reasons in 135 patients, mostly due to an abnormal liver function tests. There was a significant difference in favour of placebo compared with the combined treatment group for the number with an abnormal liver function test before the end of treatment at 24 weeks [105/297 vs 4/152, OR =20.23, 95% CI 7.29 to 56.18, p<0.00001]. There was a significant difference in favour of placebo compared with the combined treatment group for the number of withdrawals before the end of treatment at 24 weeks [130/297 vs 39/152, OR =2.26, 95% CI 1.47 to 3.47, p=0.0002]. Results are available for the dose replication phases of Zemlan 1996a and Zemlan 1996b. All the patients had taken velnacrine within two weeks prior to this phase and were identified as responders to velnacrine defined by improvement on the ADAS-Cog. Both studies reported a significant benefit for velnacrine compared with placebo for the ADAS-cog, but the results could not be checked because the relevant information was not reported. Neither study reported any benefit for velnacrine for the other efficacy measures. There was a significant difference in favour of placebo compared with the treatment group for the number with elevated liver transaminases before the end of treatment at 6 weeks [45/153 vs 29/156, OR =1.82, 95% CI 1.07 to 3.11, p=0.03]. There was a significant difference in favour of placebo compared with the treatment group for the number of withdrawals before the end of treatment at 6 weeks [68/211 vs 47/215, OR =1.70, 95% CI 1.10 to 2.62, p=0.02]. REVIEWERS' CONCLUSIONS: There has been no research into the use of velnacrine as a cognitive enhancer in the treatment of Alzheimer's disease since 1994. The FDA peripheral and CNS drug advisory board voted unanimously against recommending approval. This review shows the toxic nature of velnacrine, and provides no evidence of efficacy. There are no grounds for further research into velnacrine.