Abstract & Commentary
Source: Otto M, et al. Efficacy of flupirtine on cognitive function in patients with CJD: A double-blind study. Neurology. 2004;62:714-718.
This report described the results of a double-blind, placebo-controlled study of flupirtine maleate (FLU), a triaminopyridine compound in patients with Creutzfeldt-Jakob disease (CJD). Twenty-eight patients were randomized oral treatment with either flupirtine (n = 13) or matching placebo (n = 15). The patients had to achieve at least 50% in 2 of the subscales of the dementia tests employed for inclusion in the study. Otto and colleagues used standardized questionnaires to monitor the progression of the disease. The main outcome variable was the cognitive part of the Alzheimer’s Disease Assessment Scale (ADAS-Cog). Otto et al used the difference between the baseline and the best score under treatment as the primary efficacy variable. They also examined 2 other cognitive tests and survival. The patients were well matched at the time of randomization. The patients with flupirtine showed significantly less deterioration in the dementia tests than the patients treated with placebo. The mean change in the ADAS-Cog (baseline to best) was 8.4 in the flupirtine group and 20.6 in the placebo group (P < .02). Otto et al concluded that flupirtine has beneficial effects on cognitive function in patients with CJD.
Commentary
This is the first treatment that has shown any clinical benefits in patients with CJD in a double-blind trial. Flupirtine maleate is a centrally acting non-opioid analgesic that has been in clinical use since 1986. In addition to its analgesic and muscle relaxant properties, flupirtine has been shown to be a drug with an intriguing spectrum of effects relevant to neuroprotection. To date, there is evidence for at least 3 mechanisms of action that suggest the neuroprotective potential of flupirtine: 1) it has anti-oxidant properties; 2) it is involved in protection against glutamate-mediated excitotoxicity; and 3) it interferes with apoptotic pathways.
The rationale for carrying out the trial was based on in vitro studies, which have shown the neurotoxicity caused by the PrP106-126 fragment was greatly reduced following coincubation with flupirtine. It was demonstrated that flupirtine increased Bcl-2, which has effects in preventing apoptosis, and glutathione levels, which can prevent oxidative damage. A number of other studies have shown that flupirtine has anti-apoptotic effects. This has been particularly shown recently in in vitro cell models of Batten disease. In vitro, it also shows beneficial effects in blocking b-amyloid toxicity. Flupirtine has effects in blocking excitotoxicity in vitro, too.
The results of the neuropsychological evaluations in the present study were based on relatively short durations of treatment. The median treatment time for the flupirtine group was 29 days for the intention-to-treat cohort, and the median for the placebo group was 20.5 days. As noted, there was less of deterioration in the ADAS-Cog with flupirtine treatment. In addition, there were trends for improvement in the Mini-Mental Status Examinations (MMSE) score. The 2 groups started with MMSE scores of 19.2 in the flupirtine group and 20.5 in the placebo group. The decrease in MMSE score was 3.3 points in the flupirtine group and 8.0 points in the placebo group (P = .07). A similar result was obtained for another cognitive test. In the cognitive part of the Kessler Dementia Scale, there was a significant difference in deterioration with flupirtine. The survival analysis showed that the mean survival in the flupirtine group was 141 days vs 97 days in the placebo group. This, however, did not reach significance with a P = .19 using standard Kaplan-Meir survival analysis.
These results appear promising.
As noted, this is the first test of any agent that has shown any efficacy in
CJD. The present results must be interpreted with caution due to the marked
variability in CJD, as well as the small number of patients examined. It is
possible that this is a symptomatic effect. There are excellent rodent models
of CJD. CJD can be reliably transmitted to certain transgenic mice. It would,
therefore, be extremely valuable to test flupirtine in these models. If a benefit
were demonstrated in these models, it would be valuable to pursue other studies
with flupirtine in CJD.
— M. Flint Beal, MD, Professor and Chairman; Department of Neurology;
Cornell University Medical College, New York, NY and Editor of Neurology
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