Drug Summary: Dimebon (pronounced dee-meh-bon) is an anti-inflammatory drug with a 20-year history of use in Russia. Its potential as a neuroprotective agent was recently recognized when a large chemical library screen found that the class of molecules it belongs to, gamma-carbolines was most likely to be effective in blocking NMDA receptors (see Glutamate excitotoxicity below). Studies are now being undertaken to assess its efficacy. Reports focused on Dimebon’s use in HD are not yet available, but studies testing its potential in treating Alzheimer’s Disease have had encouraging results. These studies have included both lab studies (using rats and nerve cells in culture) and clinical studies with Alzheimer’s patients. Dimebon has been shown to be helpful in treating problems common to the two diseases, including glutamateexcitotoxicity and low levels of acetylcholine. Clinical studies indicate that its protective effects in these cases make a significant difference in alleviating symptoms and improving overall quality of life.
Glutamate excitotoxicity
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Glutamate is a normal excitatoryneurotransmitter which means it is a routine part of nerve impulse transmission. When present in excessive amounts though, glutamate can cause a chain of reactions that ultimately leads to nerve cell death. This process is called “excitotoxicity" because glutamate over-excites the nerve cell and becomes bad for it, or toxic. Cell death can also occur at normal glutamate levels if nerve cells become hypersensitive to glutamate. Such hypersensitivity is thought to be the reason glutamate excitotoxicity exists with HD. For a more detailed explanation of this process, please see Glutamate Toxicity: Disease Mechanism V.
In rat studies, Dimebon has been shown to work against glutamate excitotoxicity in two main ways. First, Dimebon acts as an antagonist to glutamate by binding to receptors on the surface of the nerve cells called NMDA receptors. In other words, Dimebon binds to the NMDA receptor on the surface of a nerve cell and prevents it from bringing glutamate into the cell. This activity could prevent cell death whether there are abnormally high levels of glutamate in the brain or, as is most likely in Huntington’s, nerve cells are hypersensitive to normal levels of glutamate.
Dimebon also counters excitotoxicity by blocking calcium ion (Ca2+) channels located within the external surface of nerve cells. This activity prevents the influx of Ca2+ ions that normally results from hypersensitivity to glutamate. (For more information about this process please see Glutamate Toxicity: Disease Mechanism V) When blocked, Ca2+ cannot get into the cell to activate free radicals and other damaging molecules that ultimately cause cell death. In this way, Dimebon can stop a cell from progressing towards cell death even if glutamate is able to over-excite it.
So Dimebon helps prevent nerve cell death by preventing glutamate from over-stimulating nerve cells and preventing over-excited cells from taking in large amounts of Ca2+. How else might Dimebon help treat HD?
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 are likely to be similar.
In a 2001study by Bachurin, S. et al. (see “For further reading" below), rats were given a neurotoxin that selectively kills cholinergic nerve cells. 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.
The second study was a preliminary clinical trial with 15 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.
In September 2006, results of Phase 2 FDA testing 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. Hardly any side-effects were discovered; most 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 will bring treatment to a full year. Results from this study are expected in the second quarter of 2007. Medivation plans to move on to global trials with thousands of participants in 2008 and, assuming positive results, apply for FDA approval in 2010.
So what about Huntington’s?
Currently there are no published results for studies of Dimebon in persons with HD. Medivation started Phase I-IIa trials, which establish safe dosage and begin testing in individuals with the targeted disease, in October of 2006. These trials are being done in cooperation with the Huntington’s Study Group. They plan to publish results in the second half of 2007. Positive results are expected because of similarities between many symptoms of HD and Alzheimer’s disease. You can stay updated on the progress of both Alzheimer’s and Huntington’s trials by checking press releases on the Medivation web-site http://www.medivation.net/html/page.news.html or by returning to the HOPES site in the second half of 2007 when results of HD trials are published. We’ll do our best to keep you posted!
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For further reading:
Bachurin S., Bukatina, E., Lermontova, N., Tkachenko, S., Afanasiev, A., Grigoriev, V., Grigorieva, I., Ivanov, YU., Sablin, S. & Zefirov, N.: Antihistamine Agent Dimebon As a Novel Neuroprotector and a Cognition Enhancer. Annals of the New York Academy of Sciences 939: 425-435, 2001 This scientific study includes information on many aspects of Dimebon’s potential use in Alzheimer’s disease. It is easy to get bogged down in details and scientific language but if you stick to the introduction, results, and discussion you will find it informative.
Medivation (September 21, 2006). Medivation’s Dimebon Meets All Five Efficacy Endpoints in Phase 2 Alzheimer’s Disease Study. Press Release. Click here to read this article. This is an easy-to-read press release by the company that owns rights to develop and test Dimebon as a neuroprotective drug in the US.
Medivation (October 19, 2006). Medivation Begins Phase 1-2a Trial of Dimebon in Huntington’s Disease. Press Release. Click here to read this article. Another easy-to-read press release from Medivation.
Last Modified: 05/26/2008
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