Latrepirdine

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Structural formula
Structural formula of latrepirdine
General
Non-proprietary name Latrepirdine
other names
  • Dimebolin (Russian non-proprietary name)
  • 2,3,4,5-Tetrahydro-2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl) -1 H -pyrido [4,3- b ] indole ( IUPAC )
Molecular formula C 21 H 25 N 3
External identifiers / databases
CAS number 3613-73-8
EC number 638-815-4
ECHA InfoCard 100.119.053
PubChem 197033
Wikidata Q408580
Drug information
ATC code

R06 AX

Drug class

Antihistamine

properties
Molar mass 319,44 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 319
P: ?
Toxicological data

178 mg kg −1 ( LD 50 ,  mouse ,  ip )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Latrepirdine or Dimebolin ( Russian non-proprietary name ) is a drug from the group of antihistamines that is used to treat allergic reactions. The active ingredient has so far only been approved as a component of pharmaceuticals in Russia and other successor states of the former Soviet Union .

Clinical information

application areas

Approved areas of application

In the successor states of the Soviet Union, latrepirdine is used to treat hay fever , hives , food , cosmetics , house dust or drug allergies , Quincke's edema , atopic eczema in house dust allergy , in allergic and inflammatory diseases of the eye , inflammatory reactions in burns as well as in neurodermatitis and other eczema approved.

Further possible areas of application

Latrepirdine is currently being investigated as a potential treatment in Alzheimer's disease and Huntington 's disease . However, there is no official approval for use in these diseases.

Contraindications

LATREPIRDINE is contraindicated in hypersensitivity to the active substance, in pregnancy and in breast-feeding be applied.

Drug interactions

If latrepirdine is taken at the same time as sleeping pills , anxiolytics , antidepressants , antipsychotics or opioids , the effects on the central nervous system may be amplified .

unwanted effects

Known side effects are dry mouth, numbness of the oral mucosa, drowsiness and decreased ability to concentrate.

Mechanism of action

The effects of latrepirdine on H 1 histamine receptors were already described in the 1980s. Inhibitory effects on monoamine oxidase type B were also described in the 1980s . The active ingredient is also said to reduce the permeability of blood vessel walls and to have local anesthetic and sedative effects.

In 2000, tacrine- like effects on learning behavior were described in Alzheimer's animal models. The same working group presented research results in 2001 that describe the inhibitory effects on acetylcholinesterase , on the NMDA receptor and on calcium channels . Furthermore, latrepirdine is said to be an antagonist of the 5-ht 6 serotonin receptor . The cellular point of attack of the latrepirdine should be the mitochondria . Latrepirdine also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ).

After the clinical validation of the effects of latrepirdine in patients with Alzheimer's disease, a US research group described that the active substance would increase the concentration of beta-amyloid in the brain of rodents . This observation could call into question the previous beta-amyloid hypothesis about the development of Alzheimer's disease.

Development history

Latrepirdine was first mentioned in the accessible literature in 1971. However, the drug was apparently synthesized in the Soviet Union as early as the 1960s, where it was first approved as a component of a medicinal product in 1983. In 2000, Russian scientists described neuroprotective effects. A year later, this observation was supplemented by initial clinical experience in Alzheimer's patients.

The US company Medivation secured rights to the development of the active ingredient in 2003. Clinical work began in 2005 for Alzheimer's and 2007 for Huntington's disease. The positive results of the first major Alzheimer's study in the 2008 journal Lancet published.

Since 2008 latrepirdine has been studied jointly by the companies Medivation and Pfizer for the treatment of Alzheimer's and Huntington's disease. The investigations into the active substance reached phase III. In mid-2009, the manufacturers announced that the active ingredient, originally known under the Russian non-proprietary name Dimebolin, would be given the international non-proprietary name Latrepirdine and recognized by the US Medicines Agency as a development candidate for the treatment of rare diseases for Huntington's disease . In March 2010 it became known that one of the registration studies in the Alzheimer's application area had negative results. In June 2010, the two manufacturing companies announced that two more Phase III studies had been started in connection with the treatment of Alzheimer's disease.

In January 2012, Pfizer announced that the further clinical development of latrepirdine would be discontinued. The reason for this are unsatisfactory study results that could not confirm the first positive results.

Trade names

Latrepirdin is sold in Russia and other successor states of the former Soviet Union under the trade name Dimebon (manufacturer: Organika) and is only available on prescription there.

Individual evidence

  1. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . What is shown is a label for 1H-pyrido (4,3-b) indole, 2,3,4,5-tetrahydro-2,8-dimethyl-5- (2- (6-methyl-3 -pyridyl) ethyl) - in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on July 7, 2020.
  2. ↑ a b Farmakol Toksikol. 31, 1968, p. 105, quoted from RTECS .
  3. ↑ a b c d Ministry of Health of the USSR: О разрешении к медицинскому применению новых лекарственных средств, вспомогательного вещества и стандарта, применяемого при анализе лекарственного средства. ( Memento of the original from December 13, 2007 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. Enactment of November 23, 1983. Retrieved September 19, 2009. @1@ 2Template: Webachiv / IABot / www.bestpravo.ru
  4. ↑ a b c R. S. Doody, SI Gavrilova, M. Sano 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. In: Lancet. 372, 2008, pp. 207-215. PMID 18640457 .
  5. ↑ a b c Medivation Inc. (July 30, 2009): Pfizer and Medivation Initiate Phase 3 Trial of Dimebon in Patients with Huntington Disease. ( Memento of the original from November 2, 2009 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved September 17, 2009. @1@ 2Template: Webachiv / IABot / investors.medivation.com
  6. ↑ IA Matvejewa: О действии димебона на гистаминовые рецепторы. In: Farmakol Toksikol. 46, 1983, pp. 27-29. PMID 6225678 .
  7. ^ SK Schadurskaja, AI Khomenko, VA Perewerzew, AI Balaklewskij. Нейромедиаторные механизмы деиствия антигистаминного препарата димебона на мозг. In: Biull Eksp Biol Med. 101, 1986, pp. 700-702. PMID 2873848 .
  8. ↑ a b N. N. Lermontova, NV Lukoyanov, TP Serkova et al: Dimebon improves learning in animals with experimental Alzheimer's disease. In: Bull Exp Biol Med. 129, 2000, pp. 544-546. PMID 11022244 .
  9. ↑ a b S. Bach urine, E. Bukatina, N. Lermontova include: antihistamines agent Dimebon as a novel neuro-protector and a cognition enhancer. In: Ann NY Acad Sci. 939, 2001, pp. 425-435. PMID 11462798 .
  10. ↑ H. Schaffhauser, JR Mathiasen, A. Dicamillo et al .: Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. In: Biochem Pharmacol . 78, 2009, pp. 1035-1042. PMID 19549510
  11. ↑ SO Bachurin, EP Shevtsova, EG Kireeva et al .: Mitochondria as a target for neurotoxins and neuroprotective agents. In: Ann NY Acad Sci. 993, 2003, pp. 334-344. PMID 1285332 .
  12. ↑ J. Kornhuber, M. Muehlbacher, S. Trapp, S. Pechmann, A. Friedl, M. Reichel, C. Mühle, L. Terfloth, T. Groemer, G. Spitzer, K. Liedl, E. Gulbins, P Tripal: Identification of novel functional inhibitors of acid sphingomyelinase . In: PLoS ONE . tape 6 , no. 8 , 2011, p. e23852 , doi : 10.1371 / journal.pone.0023852 .
  13. ↑ JW Steele, SH Kim, JR Cirrito et al: Acute dosing of latrepirdine (Dimebon TM ), a possible Alzheimer therapeutic, elevates extracellular amyloid-beta levels in vitro and in vivo. In: Mol Neurodegener. 4, 2009, p. 51. PMID 20017949 .
  14. ↑ MG Romanovskaya: Влийание ципрогептадина и димебона на бактериальную инфекцию у животных, полутных, полутных, полусных, полусных. In: Farmakol Toksikol. 34, 1971, pp. 698-701. PMID 5139793
  15. ↑ Medivation Inc. (September 9, 2005): Medivation Announces First Patient Dosed In Phase II Trial With Dimebon For Treating Alzheimer's Disease. ( Memento of the original from September 4, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved September 17, 2009. @1@ 2Template: Webachiv / IABot / investors.medivation.com
  16. ↑ Medivation Inc. (July 30, 2007): Medivation Announces Treatment of First Patient in Phase 2 Trial of Dimebon (TM) in Huntington's Disease. ( Memento of the original from March 3, 2008 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved September 17, 2009. @1@ 2Template: Webachiv / IABot / investors.medivation.com
  17. ↑ German-language summary of the publication by RS Doody et al. ( Lancet. 372, 2008, pp. 207–215) at Wissenschaft-online.de . Retrieved September 21, 2009.
  18. ^ Medivation Inc. (September 3, 2008): Pfizer and Medivation Enter into Global Agreement to Co-Develop and Market Dimebon for the Treatment of Alzheimer's and Huntington's Diseases. ( Memento of the original from August 25, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved September 17, 2009. @1@ 2Template: Webachiv / IABot / investors.medivation.com
  19. ↑ Medivation Inc. (June 9, 2008): Medivation Initiates Second Pivotal Phase 3 Trial of Dimebon in Patients With Alzheimer's Disease. ( Memento of the original from March 4, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved September 17, 2009. @1@ 2Template: Webachiv / IABot / investors.medivation.com
  20. ↑ Tess Stynes ​​(March 3, 2010): Pfizer drug candidate Dimebon fails in phase III study. Dow Jones Newswires. Accessed April 4, 2010.
  21. ↑ Pharmacy Drugs (June 25, 2010): Pfizer And Medivation Initiate Two Phase 3 Trials Of Dimebon In Patients With Moderate-To-Severe Alzheimer's Disease ( Memento of July 10, 2012 in the web archive archive.today ). Discuss Pharmacy. Accessed July 31, 2010.
  22. ↑ Veelbelovend 'Alzheimermiddel struikelt in laatste right lijn . In: De Standaard . Retrieved January 19, 2012.

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