Donepezil

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Donepezil
Donepezil skeletal.svg
Systematic (IUPAC) name
(RS)-2-[(1-benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one
Clinical data
Trade namesAricept
AHFS/Drugs.commonograph
MedlinePlusa697032
  • C
Legal status
  • Prescription only
RoutesOral tablet, 5,10 & 23mg
Pharmacokinetic data
Bioavailability100 (%)
Protein binding96%
Half-life70 hours
Excretion0,11-0,13 (l/h/kg)
Identifiers
CAS number120014-06-4 YesY
ATC codeN06DA02
PubChemCID 3152
DrugBankDB00843
ChemSpider3040 YesY
UNII8SSC91326P YesY
KEGGD07869 YesY
ChEBICHEBI:53289 YesY
ChEMBLCHEMBL502 YesY
PDB ligand IDE20 (PDBe, RCSB PDB)
Chemical data
FormulaC24H29NO3 
Molecular mass379.492 g/mol
 YesY (what is this?)  (verify)
 
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Donepezil
Donepezil skeletal.svg
Systematic (IUPAC) name
(RS)-2-[(1-benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one
Clinical data
Trade namesAricept
AHFS/Drugs.commonograph
MedlinePlusa697032
  • C
Legal status
  • Prescription only
RoutesOral tablet, 5,10 & 23mg
Pharmacokinetic data
Bioavailability100 (%)
Protein binding96%
Half-life70 hours
Excretion0,11-0,13 (l/h/kg)
Identifiers
CAS number120014-06-4 YesY
ATC codeN06DA02
PubChemCID 3152
DrugBankDB00843
ChemSpider3040 YesY
UNII8SSC91326P YesY
KEGGD07869 YesY
ChEBICHEBI:53289 YesY
ChEMBLCHEMBL502 YesY
PDB ligand IDE20 (PDBe, RCSB PDB)
Chemical data
FormulaC24H29NO3 
Molecular mass379.492 g/mol
 YesY (what is this?)  (verify)

Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, and now sold as a generic by multiple suppliers, is a centrally acting reversible acetylcholinesterase inhibitor.[1] Its main therapeutic use is in the palliative treatment of Alzheimer's disease.[2] Common side effects include gastrointestinal upset. It has an oral bioavailability of 100% and easily crosses the blood–brain barrier. Because it has a biological half-life of about 70 hours, it can be taken once a day.

Medical uses[edit]

Alzheimer's disease[edit]

Currently, no definitive proof shows the use of donepezil or other similar agents alters the course or progression of Alzheimer's disease (AD). However, 6 to 12-month controlled studies have shown modest benefits in cognition and/or behavior.[3] In 2005, the UK National Institute for Clinical Excellence (NICE) withdrew its recommendation for use of the drug for mild-to-moderate AD, on the basis of no significant improvement in functional outcome, quality of life, or behavioral symptoms.[citation needed] However, NICE revised its guidelines to suggest donepezil be used in moderate-stage patients for whom the evidence is strongest.[citation needed]

In 2006 the U.S. Food and Drug Administration also approved donepezil for treatment of severe dementia.[citation needed]

Adverse effects[edit]

Common side effects include bradycardia, nausea, diarrhea, anorexia, abdominal pain, and vivid dreams.

In 2006, Eisai, the manufacturer, issued a statement that a single vascular dementia study found a difference in the percentage of study participants who died in the donepezil group (1.7%) versus the placebo group (0%). This could be due to an unusually low death rate on the placebo group. An analysis of all three vascular dementia trials, according to Eisai, "shows no statistically significant differences in observed mortality rates between the donepezil and placebo groups."

Contraindications[edit]

Donepezil should be used with caution in people with cardiac disease, cardiac conduction disturbances, chronic obstructive pulmonary disease, asthma, severe cardiac arrhythmias and sick sinus syndrome. Patients with gastrointestinal disorders should use caution because nausea or vomiting may occur. These symptoms may appear more frequent when initiating treatment or increasing the donepezil dose. Although occurrence of seizures is rare, patients who have a predisposition to seizures should be treated with caution.[4]

Mechanism of action[edit]

The precise mechanism of action of donepezil in patients with Alzheimer's disease is not fully understood. Certainly Alzheimer's disease involves a substantial loss of the elements of the cholinergic system and it is generally accepted that the symptoms of Alzheimer’s disease are related to this cholinergic deficit, particularly in the cerebral cortex and other areas of the brain.[5][6] It is note that the hippocampal formation play an important role in the processes of control of attention, memory and learning. Just the severity of the loss of cholinergic neurons of the central nervous system (CNS) has been found to correlate with the severity of cognitive impairment. Donepezil binds and inactivates reversibly the cholinesterases, thus inhibiting hydrolysis of acetylcholine. This results in an increased acetylcholine concentrations at cholinergic synapses.

Research[edit]

Donepezil has been tested (off label) in other cognitive disorders, including Lewy body dementia,[7] and vascular dementia,[8] but it is not currently approved for these indications. Donepezil has also been found to improve sleep apnea in Alzheimer's patients.[9]

Donepezil has also been studied in patients with mild cognitive impairment, schizophrenia, attention deficit disorder, post-Coronary artery bypass surgery cognitive impairment,[10] cognitive impairment associated with multiple sclerosis, CADASIL syndrome, and Down syndrome. A three-year National Institutes of Health trial in patients with mild cognitive impairment reported donepezil was superior to placebo in delaying rate of progression to dementia during the initial 18 months of the study, but this was not sustained at 36 months. In a secondary analysis, a subgroup of individuals with the apolipoprotein E4 genotype showed sustained benefits with donepezil throughout the study.[11] At this time, though, donepezil is not indicated for prevention of dementia.

A 2001 study suggested that donepezil can improve speech in autistic children. The study found the speech of autistic children that was originally mildly to moderately affected appeared to improve with the use of donepezil.[12][13]

Development and marketing[edit]

Donepezil inhibiting Torpedo californica acetylcholinesterase. See Proteopedia 1eve.
10mg Aricept pill

Research leading to the development of donepezil began in 1983 at Eisai, and the first Phase I clinical trial took place in 1989.[14] In 1996, Eisai received approval from the United States Food and Drug Administration (USFDA) for donepezil under the brand Aricept, which it co-marketed with Pfizer. As of 2011, Aricept was the world's best-selling Alzheimer's disease treatment.[15] The first generic donepezil became available in November 2010 with the USFDA approval of a formulation prepared by Ranbaxy Labs.[16] In April 2011 a second generic formulation, from Wockhardt, received tentative USFDA marketing approval.[17]

See also[edit]

References[edit]

  1. ^ Birks J, Harvey RJ (2006). Birks, Jacqueline, ed. "Donepezil for dementia due to Alzheimer's disease". Cochrane Database Syst Rev (1): CD001190. doi:10.1002/14651858.CD001190.pub2. PMID 16437430. 
  2. ^ "aricept". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
  3. ^ Steele LS, Glazier RH (April 1999). "Is donepezil effective for treating Alzheimer's disease?". Can Fam Physician 45: 917–9. PMC 2328349. PMID 10216789. 
  4. ^ Aricept (donepezil hydrochloride) package insert. Woodcliff Lake, NJ: Eisai Co., Ltd.; 2010 Nov.
  5. ^ Davies P, Maloney AJ (December 1976). "Selective loss of central cholinergic neurons in Alzheimer's disease". Lancet 2 (8000): 1403. PMID 63862. Retrieved 2014-12-23. 
  6. ^ Kása P, Rakonczay Z, Gulya K (August 1997). "The cholinergic system in Alzheimer's disease". Prog. Neurobiol. 52 (6): 511–35. PMID 9316159. Retrieved 2014-12-23. 
  7. ^ Rojas-Fernandez CH (February 2001). "Successful use of donepezil for the treatment of dementia with Lewy bodies". Ann Pharmacother 35 (2): 202–5. doi:10.1345/aph.10192. PMID 11215841. 
  8. ^ Malouf R, Birks J (2004). Malouf, Reem, ed. "Donepezil for vascular cognitive impairment". Cochrane Database Syst Rev (1): CD004395. doi:10.1002/14651858.CD004395.pub2. PMID 14974068. 
  9. ^ Moraes W, Poyares D, Sukys-Claudino L, Guilleminault C, Tufik S (March 2008). "Donepezil improves obstructive sleep apnea in Alzheimer disease: a double-blind, placebo-controlled study". Chest 133 (3): 677–83. doi:10.1378/chest.07-1446. PMID 18198262. 
  10. ^ Doraiswamy PM (2007). "Donepezil for cognitive decline following coronary artery bypass surgery: a pilot randomized controlled trial.". Psychopharmacology Bulletin 40 (2): 54–62. PMID 17514186. 
  11. ^ Petersen, RC; Thomas, RG; Grundman, M; Bennett, D; Doody, R; Ferris, S; Galasko, D; Jin, S; Kaye, J; Levey, A; Pfeiffer, E; Sano, M; van Dyck, CH; Thal, LJ; Alzheimer's Disease Cooperative Study, Group (Jun 9, 2005). "Vitamin E and donepezil for the treatment of mild cognitive impairment.". The New England Journal of Medicine 352 (23): 2379–88. doi:10.1056/nejmoa050151. PMID 15829527. 
  12. ^ "Alzheimer's Drug Shows Promise As Treatment for Autism -- Arehart-Treichel". Psychiatric News (pn.psychiatryonline.org). 2001-11-16. Retrieved 2009-08-18. 
  13. ^ Donepezil hydrochloride: a double-blind study in autistic children
  14. ^ Sugimoto, Hachiro; Ogura, Hiroo; Arai, Yasuo; Iimura, Youichi; Yamanishi, Yoshiharu (25 January 2002), "Research and Development of Donepezil Hydrochloride, a New Type of Acetylcholinesterase Inhibitor", The Japanese Journal of Pharmacology (2002) 89 (1): 7–20, doi:10.1254/jjp.89.7, retrieved 25 April 2011 
  15. ^ Kanoko Matsuyama (25 April 2011). "Eisai Aricept Patch for Alzheimer’s Isn’t Ready for Approval". Bloomberg. Retrieved 25 April 2011. 
  16. ^ "Ranbaxy gets FDA nod for Alzheimer's drug". The Indian Express (New Delhi, India: Indian Express Group). 30 November 2010. IndianExpress.com. Retrieved 25 April 2011. 
  17. ^ Staff Writer (25 April 2011). "Wockhardt Obtains US FDA Nod For Generic Version Of Aricept Tablets". RTTNews. Retrieved 25 April 2011. 

External links[edit]