Latrepirdine

{{short description|Antihistamine drug}} {{Drugbox | IUPAC_name = 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-1''H''-pyrido(4,3-b)indole | image = Latrepirdine.svg | image_class = skin-invert-image | width = 200px

| tradename = Dimebon | pregnancy_category = | legal_status = Rx-only | routes_of_administration = Oral

| bioavailability = | metabolism = | elimination_half-life = | excretion =

| CAS_number = 3613-73-8 | ATC_prefix = None | ATC_suffix = | PubChem = 197033 | ChemSpiderID = 170644 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = OD9237K1Z6 | KEGG = D09917 | ChEBI = 92976

| C=21 | H=25 | N=3 }}

'''Latrepirdine''' (INN, also known as '''dimebolin''' and sold as '''Dimebon''') is an antihistamine drug which has been used clinically in Russia since 1983.<ref name="pmid6225678">{{cite journal | vauthors = Matveeva IA | title = [Action of dimebon on histamine receptors] | language = ru | journal = Farmakologiia i Toksikologiia | volume = 46 | issue = 4 | pages = 27–29 | date = July–August 1983 | pmid = 6225678 }}</ref>

Research was conducted in both Russia and western nations into potential applications as a neuroprotective drug to treat Alzheimer's disease and, possibly, as a nootropic, as well.<ref name="pmid16250325">{{cite journal | vauthors = Shevtsova EF, Kireeva EG, Bachurin SO | title = [Mitochondria as the target for neuroprotectors] | language = ru | journal = Vestnik Rossiiskoi Akademii Meditsinskikh Nauk | issue = 9 | pages = 13–17 | year = 2005 | pmid = 16250325 }}</ref> After a major phase III clinical trial for Alzheimer's disease (AD) treatment failed to show any benefit, three other AD trials continued.<ref name=medpagetoday>[http://www.medpagetoday.com/Neurology/AlzheimersDisease/18794 Novel Alzheimer's Drug Flops], ''MedPage Today'', March 03, 2010</ref> Major industry-based development in this indication essentially stopped after another Phase III trial suffered the same fate in 2012.<ref name="ReferenceA">{{cite journal | vauthors = Sweetlove M | title = Phase III CONCERT Trial of Latrepirdine. Negative results. | journal = Pharmaceutical Medicine | date = 2012 | volume = 26 | issue = 2 | pages = 113–115 | doi = 10.1007/BF03256900 | s2cid = 699473 }}</ref> Latrepirdine failed in the phase III trial for Huntington's disease.<ref name=HD/>

== Uses == Latrepirdine is an orally active, small molecule compound that has been shown to inhibit brain cell death in animal models of Alzheimer's disease and Huntington's disease. Research suggests it may also have cognition-enhancing effects in healthy individuals, in the absence of neurodegenerative disease pathology.<ref name="pmid11462798">{{cite journal | vauthors = Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, Grigoriev V, Grigorieva I, Ivanov Y, Sablin S, Zefirov N | display-authors = 6 | title = Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer | journal = Annals of the New York Academy of Sciences | volume = 939 | issue = 1 | pages = 425–435 | date = June 2001 | pmid = 11462798 | doi = 10.1111/j.1749-6632.2001.tb03654.x | s2cid = 31389614 | bibcode = 2001NYASA.939..425B }}</ref> However, because of negative results in human clinical trials, the drug remains unlicensed for any neurodegenerative condition.<ref name=medpagetoday /><ref name=HD/>

== Clinical trials ==

=== Alzheimer's disease ===

Latrepirdine attracted renewed interest in 2009 after being shown in small preclinical trials to have positive effects on persons suffering from Alzheimer's disease. Animal studies showing potential beneficial effects on Alzheimer's disease models were shown in Russian research in 2000.<ref name="pmid11022244">{{cite journal | vauthors = Lermontova NN, Lukoyanov NV, Serkova TP, Lukoyanova EA, Bachurin SO | title = Dimebon improves learning in animals with experimental Alzheimer's disease | journal = Bulletin of Experimental Biology and Medicine | volume = 129 | issue = 6 | pages = 544–546 | date = June 2000 | pmid = 11022244 | doi = 10.1007/BF02434871 | s2cid = 32513986 }}</ref> Preliminary results from human trials have also been promising. In an initial six-month phase II trial, results have shown significant improvement over placebo at 12 months.<ref>{{cite news | title = Antihistamine Shows Promise in Treating Alzheimer's | work = The New York Times | date = 2007-06-11 | url = https://www.nytimes.com/2007/06/11/business/11drug.html?ei=5090&en=6dd260f0ecf61466&ex=1339214400&partner=rssuserland&emc=rss&pagewanted=print | vauthors = Pollack A | access-date=2010-05-01}}</ref> Latrepirdine showed promising results in a phase III-equivalent, double-blind trial in Russia with mild–moderate stage patients.<ref>{{cite news | vauthors = Crystal P, Robert J | date = 2008-07-17 | title = Old Antihistamine Pops Up as Potential Alzheimer's Therapy | url = http://www.medpagetoday.com/Geriatrics/AlzheimersDisease/tb/10174 | journal = MedPage Today}}</ref><ref name="pmid18640457">{{cite journal | vauthors = Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D | display-authors = 6 | title = 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 | journal = Lancet | volume = 372 | issue = 9634 | pages = 207–215 | date = July 2008 | pmid = 18640457 | doi = 10.1016/S0140-6736(08)61074-0 | s2cid = 205951657 | author-link1 = Rachelle Doody }}</ref> In April 2009, Pfizer and Medivation initiated a phase III trial (CONCERT study) aiming for FDA approval.<ref>{{cite web | url = http://www.reuters.com/article/pressRelease/idUS117499+15-Apr-2009+PRN20090415 | work = Reuters | title = Pfizer and Medivation Initiate Phase 3 Trial of Dimebon Added to Donepezil in Patients with Alzheimer's Disease | date = April 2009 | access-date = 2009-07-22 | archive-date = 2013-02-01 | archive-url = https://archive.today/20130201080708/http://www.reuters.com/article/pressRelease/idUS117499+15-Apr-2009+PRN20090415 | url-status = bot: unknown }}</ref> In March 2010, Pfizer announced that this clinical trial failed to show any benefit for the treatment of Alzheimer's disease patients.<ref name=medpagetoday/>

Numerous phase III trials for AD were recruiting in 2009.<ref>{{ClinicalTrialsGov|NCT00838110|A Phase 3 Study To Evaluate The Safety And Tolerability Of Dimebon Patients With Mild To Moderate Alzheimer's Disease}}</ref><ref>{{ClinicalTrialsGov|NCT00912288|A Phase 3 Efficacy Study Of Dimebon In Patients With Moderate To Severe Alzheimer's Disease}}</ref><ref>{{ClinicalTrialsGov|NCT00939783|An Extension To The B1451027 Protocol To Evaluate The Long Term Safety And Tolerability Of Dimebon In Patients With Alzheimer's Disease}}</ref><ref>{{ClinicalTrialsGov|NCT00954590|A Safety and Efficacy Study Evaluating Dimebon (Latrepirdine) in Patients With Moderate to Severe Alzheimer's Disease (CONTACT)}}</ref>

In July 2009, Pfizer and Medivation announced that "latrepirdine" was to be the proposed international nonproprietary name for latrepirdine for the treatment of Alzheimer's.{{cn|date=December 2021}}

In March 2010, the results of a clinical trial phase III were released; the investigational Alzheimer's disease drug dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease.<ref>{{cite web|url=http://www.alzforum.org/new/detail.asp?id=2387|title=Dimebon Disappoints in Phase 3 Trial - ALZFORUM|website=www.alzforum.org}}</ref> Pfizer had paid $225 million after bidding against several pharmaceutical companies to purchase the rights to Dimebon.<ref>{{cite journal |last1=Miller |first1=G |title=The Puzzling Rise and Fall of a Dark-Horse Alzheimer's Drug |journal=Science |date=2010 |volume=327 |issue=5971 |page=1309 |doi=10.1126/science.327.5971.1309 |pmid=20223954}}</ref>

With CONCERT, the remaining Pfizer and Medivation Phase III trial for latrepirdine in Alzheimer's disease failed in 2012, effectively ending the development in this indication.<ref name="ReferenceA"/>

A Cochrane meta-analysis of the three pivotal phase III efficacy trials found no significant effect of latrepirdine on cognition and function in mild-to-moderate Alzheimer's patients, though there appears to be a modest benefit for overall behavior disturbances.<ref>{{cite journal | vauthors = Chau S, Herrmann N, Ruthirakuhan MT, Chen JJ, Lanctôt KL | title = Latrepirdine for Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 4 | article-number = CD009524 | date = April 2015 | pmid = 25897825 | pmc = 7388906 | doi = 10.1002/14651858.CD009524.pub2 }}</ref> Latrepirdine thus failed to alter the existing pharmacologic management of Alzheimer's disease.

=== Huntington's disease === In April 2011, latrepirdine failed in a phase III clinical trial of patients affected with Huntington's disease.<ref name=HD>{{cite web|url=http://www.genengnews.com/gen-news-highlights/phase-iii-failure-leads-medivation-and-pfizer-to-ditch-dimebon-for-huntington-disease/81244981/|title=Phase III Failure Leads Medivation and Pfizer to Ditch Dimebon for Huntington Disease - GEN|date=2011-04-12|website=GEN}}</ref> The trial was sponsored by Medivation Inc. and Pfizer.

== Pharmacology == Latrepirdine appears to operate through multiple mechanisms of action, both blocking the action of neurotoxic beta-amyloid proteins and inhibiting L-type calcium channels,<ref name="pmid11865327">{{cite journal | vauthors = Lermontova NN, Redkozubov AE, Shevtsova EF, Serkova TP, Kireeva EG, Bachurin SO | title = Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca(2+) channels | journal = Bulletin of Experimental Biology and Medicine | volume = 132 | issue = 5 | pages = 1079–1083 | date = November 2001 | pmid = 11865327 | doi = 10.1023/A:1017972709652 | s2cid = 822340 }}</ref> modulating the action of AMPA and NMDA glutamate receptors,<ref name="pmid14968164">{{cite journal | vauthors = Grigorev VV, Dranyi OA, Bachurin SO | title = Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons | journal = Bulletin of Experimental Biology and Medicine | volume = 136 | issue = 5 | pages = 474–477 | date = November 2003 | pmid = 14968164 | doi = 10.1023/B:BEBM.0000017097.75818.14 | s2cid = 13207412 }}</ref> and may exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores,<ref name="pmid12853325">{{cite journal | vauthors = Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO | title = Mitochondria as a target for neurotoxins and neuroprotective agents | journal = Annals of the New York Academy of Sciences | volume = 993 | issue = 1 | pages = 334–44; discussion 345–9 | date = May 2003 | pmid = 12853325 | doi = 10.1111/j.1749-6632.2003.tb07541.x | s2cid = 15818833 | bibcode = 2003NYASA.993..334B }}</ref> which are believed to play a role in the cell death that is associated with neurodegenerative diseases and the aging process.<ref>{{cite press release | date = 2007-06-11 | url = http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/06-11-2007/0004605280&EDATE= | title = Medivation's Dimebon(TM) Maintains Statistically Significant Benefit on All Five Efficacy Endpoints in Alzheimer's Disease Trial After One Year of Therapy | access-date = 2020-02-23 | archive-url = https://web.archive.org/web/20120806134235/http://www2.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=%2Fwww%2Fstory%2F06-11-2007%2F0004605280&EDATE= | archive-date = 2012-08-06 }}</ref> It also blocks a number of other receptors, including α-adrenergic, 5-HT2C, 5-HT5A, and 5-HT6.<ref name="pmid18939977">{{cite journal | vauthors = Wu J, Li Q, Bezprozvanny I | title = Evaluation of Dimebon in cellular model of Huntington's disease | journal = Molecular Neurodegeneration | volume = 3 | page = 15 | date = October 2008 | pmid = 18939977 | pmc = 2577671 | doi = 10.1186/1750-1326-3-15 | doi-access = free }}</ref> Notably, latrepirdine lacks any anticholinergic effects.<ref name="pmid8100727">{{cite journal | vauthors = Gankina EM, Porodenko NV, Kondratenko TI, Severin ES, Kaminka ME, Mashkovskiĭ MD | title = [The effect of antihistaminic preparations on the binding of labelled mepyramine, ketanserin and quinuclidinyl benzilate in the rat brain] | language = ru | journal = Eksperimental'naia i Klinicheskaia Farmakologiia | volume = 56 | issue = 1 | pages = 22–24 | year = 1993 | pmid = 8100727 }}</ref>

== See also == * Cerlapirdine * Idalopirdine * List of Russian drugs

== References == {{Reflist}}

Category:H1 receptor antagonists Category:Drugs in the Soviet Union Category:Nootropics Category:Russian drugs Category:Soviet inventions Category:Tetrahydropyridoindoles