Name:	Dimebon
Other Names:	3,6-dimethyl-9-(2-methyl-pyridyl-5)-ethyl-1,2,3,4-tetrahydro-γ-carboline dihydrochloride, Dimebolin, Latrepirdine, Pf-01913539
Therapeutic Applications:	Approved in 1983 as an antihistamine in Russia
Therapy Types:	Small molecule with a broad and pleiotropic spectrum of pharmacological properties.
Mechanisms:	Has activity as an inhibitor of cholinesterase and NMDA receptors. Inhibits neuronal death, potentially by mitochondrial-mediated inhibition of apoptosis.
Development Status:	investigational in U.S.
FDA Phase:	Phase III
Primary Medical Role:	Dimebon was initially characterized as an antagonist to H1- histamine receptor, and has been an approved antihistamine in Russia since 1983.
Role in Alzheimer's Disease:	As a cognitive enhancer, Dimebon has shown efficacy in all measures of cognition and behavior in mild-to-moderate Alzheimer Disease patients. Phase II clinical trial results (ClinicalTrials.gov NCT00377715) have been reported (Doody et al, 2008). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo at week 26 (p<0.0001). Patients given dimebon were significantly improved over baseline for ADAS-cog (p=0.0005). In vitro Dimebon protected primary neuron cultures against Aβ toxicity (EC50=25 μM) and inhibits both acetylcholinesterase (I50=42 μM) and butyrylcholinesterase (IC50=7.9 μM), as well as inhibiting NMDA receptors (IC50 range of 10-70 μM) (Bachurin et al., 2001; Grigoriev et al., 2003). Neuroprotective effects of Dimebon has also been observed in a transgenic Drosophila model of Huntington Disease, protecting photoreceptor neurons against death induced by human Huntington protein (htt) (unpublished data, Medivation disclosure). In a recent clinical trial in mild-to-moderate AD in Russia (completed summer 2006), Dimebon demonstrated positive clinical efficacy in cognition and behavior using five independent measures of cognitive impairment.
Pharmacological Role:	Dimebon inhibits cholinesterases, the NMDA receptor and reduces mitochondrial swelling induced by Aβ (Bachurin et al., 2003) consistent with the suggestion that Dimebon acts to block mitochondrial permeability transition pores.
Contraindications:	Unknown. Dimebon has been used as an oral antihistamine for 23 years in Russia, and has been shown to have a limited adverse effects profile.
Side Effects:	In a 6-month trial (in Russia, concluded in July 2006) Dimebon was well-tolerated. There were fewer serious adverse events in the Dimebon-treated patients than in the placebo-treated patients. The most common adverse event was dry mouth. All other gastrointestinal side effects were uncommon, occurring in less than 3 percent of patients (Medivation disclosure). Phase II clinical trial (NCT00377715, in Russia) results demonstrated that 88% patients completed the trial compared to 82% placebo group, an indication of good tolerance. Dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26) (Doody et al, 2008). Toxicological studies performed in the former Soviet Union in rats, guinea pigs, or dogs showed that administration of Dimebon at doses up to 100 times therapeutic dose did not produce physiological or pathological changes in major organs, including embryogenesis in rats (Golubeva et al., 1985; Proinova et al., 1985).
Evidence pro its efficacy:	The first clinical trial of Dimebon (by Medivation, conducted in Russia) demonstrated efficacy in five independent measures of cognitive improvement. The study randomized 183 patients to two groups: Dimebon, 20 mg. orally tid or placebo. Patients had mild to moderate Alzheimer disease (MMSE 10-24) and were not taking other medications to treat AD. Compared with patients receiving placebo, patients treated with Dimebon demonstrated highly statistically significant improvement on the study's primary efficacy endpoint, the ADAS-cog; 4.0 point improvement in the mean change from baseline to week 26 as compared to placebo (p <0.0001); and on the key secondary efficacy endpoint, the Clinical Interview-Based Impression of Change (CIBIC-Plus; 0.6 point improvement in the mean change from baseline to week 26 as compared to placebo; p <0.0001), as well as statistically significant improvements on all three of the other secondary efficacy endpoints: the Activities of Daily Living, the Neuropsychiatric Inventory, and the Mini-Mental State Examination. In addition to these improvements in comparison to placebo, Dimebon-treated patients also showed statistically significant improvement over baseline on all five efficacy endpoints used in this study (p <0.05). By contrast, placebo-treated patients deteriorated from baseline on all five endpoints (Medivation disclosure).
Evidence con its efficacy:	Dimebon is a weak inhibitor of cholinesterases, and has selectivity for butyryl cholinesterase over acetylcholinesterase, which may be of some concern for GI side effects. On March 3, 2010, Medivation announced that the Phase III study of Dimebon in approximately 600 participants (CONNECTION, NCT00675623) failed to demonstrate a statistically significant response compared to placebo in two measures of memory and cognitive function ADAS-cog and CIBIC-plus scales.
Companies:	Medivation Inc.
Notes:	In January 2012 Pfizer and Medivation released a statement reporting disappointing results of their large multi-center CONCERT trial. For details see ARF News Story. For a list of clinical trials of Dimebon on clinicaltrials.gov see Dimebon trials.

References

Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D; dimebon investigators. (2008). Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008 Jul 19; 372(9634):207-15. POW link

Grigorev VV. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med. 2003 Nov 1;136(5):474-7. Abstract

Bachurin SO. Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci. 2003 May 1;993:334-44; discussion 345-9. Abstract

Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, Grigoriev V, Grigorieva I, Ivanov Y, Sablin S, Zefirov N. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci. 2001 Jun; 939:425-35. Abstract

Proinova VA. [Evaluation of the effect of the antihistaminic preparations dimebon and diprazin on embryogenesis in rats] Farmakol Toksikol. 1985 Nov-Dec;48 (6):89-93. Abstract

Golubeva MI. [Preclinical study of the safety of the antihistaminic preparation dimebon] Farmakol Toksikol. 1985 May-Jun ;48(3):114-9. Abstract