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3,6-dimethyl-9-(2-methyl-pyridyl-5)-ethyl-1,2,3,4-tetrahydro-γ-carboline dihydrochloride, Dimebolin, Latrepirdine, Pf-01913539
Approved in 1983 as an antihistamine in Russia
Small molecule with a broad and pleiotropic spectrum of pharmacological properties.
Has activity as an inhibitor of cholinesterase and NMDA receptors. Inhibits neuronal death, potentially by mitochondrial-mediated inhibition of apoptosis.
investigational in U.S.
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induced by human Huntington protein (htt) (unpublished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.
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
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.
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
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
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
In January 2012 Pfizer and Medivation released a statement
reporting disappointing results of their large
multi-center CONCERT trial. For details see ARF News
For a list of clinical trials of Dimebon on
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
Golubeva MI. [Preclinical study of the safety of the
antihistaminic preparation dimebon] Farmakol Toksikol.
1985 May-Jun ;48(3):114-9. Abstract