TY - JOUR
T1 - The rise and fall of dimebon
AU - Bezprozvanny, Ilya
PY - 2010/10
Y1 - 2010/10
N2 - Dimebon (latrepirdine) was developed and used in Russia as an over-thecounter oral antihistamine for allergy treatment. In the early 1990s, Dimebon was characterized as a low-affinity NMDA receptor antagonist by Dr. Sergey Bachurin and his colleagues. An initial small-scale, open-label trial of Dimebon in 14 Alzheimer's disease (AD) patients demonstrated potential efficacy. Dimebon was then patented for the treatment of neurodegenerative disorders and licensed by Medivation. Extremely promising results were obtained in a double-blind, placebocontrolled, phase II AD trial in 183 patients; however, a phase II trial of Dimebon in 91 Huntington's disease patients was much less successful. Recently, a phase III AD trial of Dimebon in 598 patients failed to result in any significant improvement in primary or secondary outcomes. The failure of Dimebon may be in large part due to insufficient understanding of its mechanism of action. The NMDA receptor blocking activity of Dimebon is too weak to be physiologically relevant, while the proposed "novel mitochondrial mechanism of action" lacks credible scientific evidence or a molecular target. Independent studies indicate that the clinical effects of Dimebon most likely result from inhibition of histamine H1 and serotonin 5-HT 6 receptors. Careful preclinical studies of novel potential therapies are needed to minimize chances of making similar costly mistakes in the future.
AB - Dimebon (latrepirdine) was developed and used in Russia as an over-thecounter oral antihistamine for allergy treatment. In the early 1990s, Dimebon was characterized as a low-affinity NMDA receptor antagonist by Dr. Sergey Bachurin and his colleagues. An initial small-scale, open-label trial of Dimebon in 14 Alzheimer's disease (AD) patients demonstrated potential efficacy. Dimebon was then patented for the treatment of neurodegenerative disorders and licensed by Medivation. Extremely promising results were obtained in a double-blind, placebocontrolled, phase II AD trial in 183 patients; however, a phase II trial of Dimebon in 91 Huntington's disease patients was much less successful. Recently, a phase III AD trial of Dimebon in 598 patients failed to result in any significant improvement in primary or secondary outcomes. The failure of Dimebon may be in large part due to insufficient understanding of its mechanism of action. The NMDA receptor blocking activity of Dimebon is too weak to be physiologically relevant, while the proposed "novel mitochondrial mechanism of action" lacks credible scientific evidence or a molecular target. Independent studies indicate that the clinical effects of Dimebon most likely result from inhibition of histamine H1 and serotonin 5-HT 6 receptors. Careful preclinical studies of novel potential therapies are needed to minimize chances of making similar costly mistakes in the future.
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U2 - 10.1358/dnp.2010.23.8.1500435
DO - 10.1358/dnp.2010.23.8.1500435
M3 - Review article
C2 - 21031168
AN - SCOPUS:77957138323
SN - 0214-0934
VL - 23
SP - 518
EP - 523
JO - Drug News and Perspectives
JF - Drug News and Perspectives
IS - 8
ER -