Dimebolin hydrochloride (brand name Dimebon) is potentially N 1 drug for the treatment of Alzheimer's disease. Research suggests that it may also have cognition-enhancing effects in healthy individuals, in the absence of neurodegenerative disease pathology.
Generic name: dimebolin Product Brand Name: Dimebon (to be marketed in USA as Latrepirdine) Product Manufacturer: manufactured in Russia
Dimebon description
Alzheimer's disease
Recently dimebolin has attracted renewed interest after being shown 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.[4] Preliminary results from human trials have also been promising. In an initial six-month phase II trial, results have shown that at 12 months there was significant improvement over placebo.[5] Dimebolin showed promising results in a Phase III-equivalent double blind trial in Russia with mild to moderate stage patients.[6][7] Apr 2009 Pfizer and Medivation initiate a phase III trial (CONCERT study) aiming for FDA approval. [8] On July 2009 Pfizer and Medivation announced that latrepirdine will be the proposed international nonproprietary name for Dimebon for the treatment of Alzheimer's.[9]
DIMEBON WAS FIRSTLY DESIGNED IN USSR, AND CAN BE FOUND NOWADAYS ONLY IN RUSSIA
Pharmacology:
Dimebolin appears to operate through multiple mechanisms of action, both blocking the action of neurotoxic beta-amyloid proteins and inhibiting L-type calcium channels,[10] modulating the action of AMPA and NMDA glutamate receptors,[11] and may exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores,[12] which are believed to play a role in the cell death that is associated with neurodegenerative diseases and the aging process.[13] It also blocks a number of other receptors including alpha-Adrenergic receptors and the serotonin receptor subtypes 5-HT2C, 5-HT5A and 5-HT6.[14]
Usage:
20 mg orally three times daily.
References:
(1)Matveeva IA (July-August 1983). "Action of dimebon on histamine receptors" (in Russian). Farmakologiia i Toksikologiia 46 (4): 27¨C29.
(2) Shevtsova EF, Kireeva EG, Bachurin SO (2005). "Mitochondria as the target for neuroprotectors" (in Russian). Vestnik Rossiiskoi Akademii Meditsinskikh Nauk (9): 13¨C17.
(3) Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, Grigoriev V, Grigorieva I, Ivanov Y, Sablin S, Zefirov N (June 2001). "Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer". Annals of the New York Academy of Sciences (939): 425¨C435.
(4) Lermontova NN, Lukoyanov NV, Serkova TP, Lukoyanova EA, Bachurin SO (June 2000). "Dimebon improves learning in animals with experimental Alzheimer's disease". Bulletin of Experimental Biology and Medicine 129 (6): 544¨C546. doi:10.1007/BF02434871.
(5) "Antihistamine Shows Promise in Treating Alzheimer¡¯s". New York Times. 2007-06-11. http://www.nytimes.com/2007/06/11/business/11drug.html?ei=5090&en=6dd260f0ecf61466&ex=1339214400&partner=rssuserland&emc=rss&pagewanted=print.
(6) Phend Crystal, Jasmer Robert (2008-07-17). "Old Antihistamine Pops Up as Potential Alzheimer's Therapy". Medpage Today. http://www.medpagetoday.com/Geriatrics/AlzheimersDisease/tb/10174.
(7) Doody Rachelle S et al (2008-07-19). "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 372: 207¨C215. doi:10.1016/S0140-6736(08)61074-0.
(8) http://www.reuters.com/article/pressRelease/idUS117499+15-Apr-2009+PRN20090415 "Pfizer and Medivation Initiate Phase 3 Trial of Dimebon Added to Donepezil in Patients with Alzheimer's Disease"
(9) Pfizer Inc. (2009-07-30). "Pfizer And Medivation Initiate Phase 3 Trial Of Dimebon In Patients With Huntington Disease". Press release. http://newsblaze.com/story/2009073005345800002.bw/topstory.html. Retrieved July 31, 2009.
(10) Lermontova NN, Redkozubov AE, Shevtsova EF, Serkova TP, Kireeva EG, Bachurin SO (November 2001). "Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca(2+) channels". Bulletin of Experimental Biology and Medicine 132 (5): 1079-1083. doi:10.1023/A:1017972709652.
(11) Grigorev VV, Dranyi OA, Bachurin SO (November 2003). "Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons". Bull Exp Biol Med 136 (5): 474¨C477. doi:10.1023/B:BEBM.0000017097.75818.14.
(12) Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO (May 2003). "Mitochondria as a target for neurotoxins and neuroprotective agents". Annals of the New York Academy of Sciences 993: 334¨C344.
(13) "Medivation's Dimebon(TM) Maintains Statistically Significant Benefit on All Five Efficacy Endpoints in Alzheimer's Disease Trial After One Year of Therapy". Press release. 2007-06-11. http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/06-11-2007/0004605280&EDATE=.
(14) Wu J, Li Q, Bezprozvanny I. Evaluation of Dimebon in cellular model of Huntington's disease. Molecular Neurodegeneration. 2008 Oct 21;3-15. PMID 18939977
Clinical trials:
Doody RS, Gavrilova SI, et al. Effect of Dimebon on cognition, activities of daily living, behavior, and global function in patients with mild-to-moderate Alzheimer¡¯s disease: a randomized, double-blind, placebo-controlled study. The Lancet. 2008;372:207-15
Study Design: The trial enrolled 183 patients with mild-to-moderate Alzheimer¡¯s disease (mini-mental state examination [MMSE] scores 10¨C24) at 11 sites in Russia. Patients were randomly assigned to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimer¡¯s disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study.
Findings: 155 (85%) patients completed the trial - 78 [88%] in dimebon group and 77 [82%] in placebo group. Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo at week 26 (mean drug-placebo difference ¨C4∙0; p<0∙0001). Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference ¨C1¡¤9; p=0¡¤0005). Dimebon was well tolerated: 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). The percentage of patients who had adverse events in the two groups did not differ.
Interpretation: Dimebon was well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimer's disease.
Additional analyses of the dimebon pivotal study data presented at medical conferences showed that:
Dimebon is impact extended to caregivers, reducing caregiver distress and time spent caring for patients each day. Click here for abstract.
Dimebon had clinical benefit continued through 18 months. These results were based on data from a six-month, open-label extension of the 12-month placebo-controlled study of dimebon in patients with mild-to-moderate Alzheimer's disease.
Clinical Trial Status:
In order to support a broad and differentiated label, we and Pfizer have expanded our Alzheimer's Phase 3 clinical development program to include five new trials:
Phase 3 CONNECTION trial in patients with mild-to-moderate disease, for which enrollment is completed;
CONCERT study, which is currently enrolling patients who are already being treated with donepezil, the leading Alzheimer¡¯s disease medication worldwide;
safety trial in patients on a variety of background anti-dementia medications being conducted to meet international safety database requirements;
Two additional trials in patients with moderate-to-severe disease, which will begin later this year.
Dimebon notes:
Dimebon chemically known as dimebolin is an older Russian antihistamine drug that has recently been discovered to be most helpful in treating patients with Alzheimer’s disease.
Dimebon is currently in clinical trials in the United States under Medivation pharmaceutical company. As a cognitive enhancer, it has shown efficiency in all measures of cognition and behavior in mild-to-moderate Alzheimer disease patients.
Dimebon mechanism of action includes blocking the action of neurotoxic beta-amyloid proteins and inhibiting L-type calcium channels. Currently Medivation jointly owns a patent application for the use of Dimebon for the treatment of Alzheimer’s disease. Latrepirdine is the proposed generic name for Dimebon.
The predicted side effects of Dimebon include drowsiness, dry mouth and depression or depressed mood. It has been reported that customers in USA will be able to buy Dimebon by 2011. Dimebon was known in Russia by the generic name dimebonum.
Medivation Inc., of San Francisco, and Pfizer Inc., of New York, have begun two Phase III trials, called CONTACT and CONSTELLATION, of the investigational drug dimebon (latrepirdine) in patients with moderate-to-severe Alzheimer's disease. The CONTACT study will assess as primary endpoints the potential benefits of adding dimebon to ongoing treatment with donepezil HCI tablets. The CONSTELLATION study will evaluate as primary endpoints the effects of adding dimebon to memantine HCI, another standard of care, on cognition, memory and activities of daily living.
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