A known anti-histamine shows promise in preventing glutamate excitotoxicity and preserving normal levels of acetylcholine.
Low levels of Acetylcholine
Acetylcholine is a neurotransmitter that is vital to proper memory function. Current research suggests that, in HD, degeneration of the basal ganglia involves the death of a great number of cholinergic nerve cells, which are the nerve cells that produce acetylcholine. This loss of cholinergic nerve cells results in low levels of acetylcholine, which likely contribute to the cognitive impairment associated with HD. Replacing acetylcholine by way of dietary supplements is sometimes suggested as a treatment for memory deficiency in neurodegenerative diseases.
Studies have suggested two ways that Dimebon might enhance cognition (memory and learning ability) in HD patients. The first of these concerns Dimebon's ability to protect nerve cells in culture from a neurotoxin. The simple prevention of nerve cell loss is surely beneficial to memory. Additionally, a high number of surviving cells can produce close to normal levels of acetylcholine. However, acetylcholine levels can also be kept at normal levels even if the neurotransmitter is only being produced in small amounts. Dimebon can do this by inhibiting two enzymes that normally break down acetylcholine. This activity by Dimebon helps keep each molecule of acetylcholine around longer, allowing small amounts to accumulate.
So we know that Dimebon can decrease cell death from excitotoxicity and that it can increase levels of acetylcholine. The question then becomes: how well might Dimebon work as a treatment for HD? The three studies outlined below—one on rats and two on humans—test Dimebon's effect on the whole individual. These studies were designed and evaluated with Alzheimer's disease in mind, but results of current and upcoming Huntington's trials may be similar.
1) In a 2001study by Bachurin, S. et al. (see "For further reading" below), rats were given a neurotoxin that selectively kills cholinergic nerve cells. Then some rats were treated with Dimebon and some were not. The rats that were given no treatment had severely reduced cognition. In comparison, rats that were treated with Dimebon showed significantly better memory and learning ability.
2) The second study was a preliminary clinical trial with 14 participants exhibiting mild to moderate Alzheimer's disease. The study lasted 8 weeks but participants showed marked improvements in cognition and independence as early as 2-4 weeks. A variety of common conditions were alleviated including depression, anxiety, tearfulness, headache and psychopathic symptoms. These improvements tended to be gradual but significant; for example, 50% of patients with headaches showed improvement at 4 weeks and 80% showed improvement at 8 weeks. This trial was also part of the Bachurin, S. et al 2001 study mentioned above.
3) In September 2006, results of a phase II study of Dimebon were reported by a company called Medivation. According to standard procedures, phase II testing uses a medium-sized group of patients to test a drug's usefulness and look for side effects. In this study, 183 individuals with mild to moderate Alzheimer's disease were treated with either Dimebon or a placebo for six months. Five different tests were used to evaluate progression of the disease and Dimebon-treated participants showed "highly statistically significant improvement" on all of them. They not only did better than placebo patients throughout the trial but also actually improved from their original, or baseline, condition. Dimebon was well tolerated and more serious adverse events occurred in the placebo group. This is certainly an advantage of using a drug with a previous history of use in humans. A large percentage of individuals (86%) chose to participate in a continuation study that brought treatment to a full year. Results from this study were announced in June 2007 and demonstrated that at one year, the benefits of Dimebon over placebo on all five efficacy endpoints were stable or greater when compared to the benefits at six months. Medivation plans to move on to global trials with a larger number of participants in 2008 and, assuming positive results, apply for FDA approval in 2010.
Last Modified: 05/22/2009
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