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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

Alzheimer's disease

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] The UK National Institute for Clinical Excellence (NICE) recommends donepezil as an option in the management of mild to moderate Alzheimer's disease.^[4] The person should; however, be reviewed frequently and if there is no significant benefit it should be stopped.^[4]

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

Adverse effects

In clinical trials the most common adverse events leading to discontinuation were nausea, diarrhea, and vomiting.^[5]^[6]

Contraindications

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.^[7]

Mechanism of action

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.^[8]^[9] It is noted that the hippocampal formation plays 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

Donepezil has been tested (off label) in other cognitive disorders, including Lewy body dementia,^[10] and vascular dementia,^[11] but it is not currently approved for these indications. Donepezil has also been found to improve sleep apnea in Alzheimer's patients.^[12]

Donepezil has also been studied in patients with mild cognitive impairment, schizophrenia, attention deficit disorder, post-Coronary artery bypass surgery cognitive impairment,^[13] 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.^[14] 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.^[15]^[16]

Development and marketing

Donepezil inhibiting Torpedo californica acetylcholinesterase. See Proteopedia 1eve.

10mg Aricept pill

Research leading to the development of donepezil began in 1983 at Eisai, and 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.^[17] As of 2011, Aricept was the world's best-selling Alzheimer's disease treatment.^[18] The first generic donepezil became available in November 2010 with the USFDA approval of a formulation prepared by Ranbaxy Labs.^[19] In April 2011 a second generic formulation, from Wockhardt, received tentative USFDA marketing approval.^[20]

References

^ 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.
^ "aricept". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
^ Steele LS, Glazier RH (April 1999). "Is donepezil effective for treating Alzheimer's disease?". Can Fam Physician 45: 917–9. PMC 2328349. PMID 10216789.
^ ^a ^b https://www.nice.org.uk/guidance/TA217/chapter/1-Guidance
^ "www.accessdata.fda.gov" (PDF).
^ Noetzli M1, Eap CB. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease. Clin Pharmacokinet. 2013 Apr;52(4):225-41. PMID 23408070
^ Aricept (donepezil hydrochloride) package insert. Woodcliff Lake, NJ: Eisai Co., Ltd.; 2010 Nov.
^ 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.
^ Kása P, Rakonczay Z, Gulya K (August 1997). "The cholinergic system in Alzheimer's disease". Prog. Neurobiol. 52 (6): 511–35. doi:10.1016/s0301-0082(97)00028-2. PMID 9316159. Retrieved 2014-12-23.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ "Alzheimer's Drug Shows Promise As Treatment for Autism -- Arehart-Treichel". Psychiatric News (pn.psychiatryonline.org). 2001-11-16. Retrieved 2009-08-18.
^ Donepezil hydrochloride: a double-blind study in autistic children
^ Rodrigues Simões MC. et al. Donepezil: an important prototype to the design of new drug candidates for Alzheimer's disease. Mini Rev Med Chem. 2014 Jan;14(1):2-19. PMID 24251806
^ Kanoko Matsuyama (25 April 2011). "Eisai Aricept Patch for Alzheimer’s Isn’t Ready for Approval". Bloomberg. Retrieved 25 April 2011.
^ "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.
^ Staff Writer (25 April 2011). "Wockhardt Obtains US FDA Nod For Generic Version Of Aricept Tablets". RTTNews. Retrieved 25 April 2011.

External links

Brenner, George D.; George M., PhD. Brenner (2000). Pharmacology. Philadelphia: W. B. Saunders. ISBN 0-7216-7757-6.
Acting Editor-in-Chief Louise Welbanks. (2000). Compendium of Pharmaceuticals and Specialities, 2000 (25th ed.). Canadian Pharmaceutical Assn. ISBN 0-919115-76-4.
Official Aricept product site
Aricept entry at Drugs.com
http://www.websciences.org/cftemplate/NAPS/archives/indiv.cfm?ID=20081395
3D Molecular structure of Donepezil
Acetylcholinesterase: A gorge-ous enzyme QUite Interesting PDB Structure article at PDBe

UpToDate Contents

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1. 認知症治療におけるコリンエステラーゼ阻害剤 cholinesterase inhibitors in the treatment of dementia
2. 重度認知症患者の緩和ケア palliative care of patients with advanced dementia
3. 離人症性障害の治療 treatment of depersonalization disorder
4. 大脳皮質基底核変性症 corticobasal degeneration
5. 認知症の治療 treatment of dementia

English Journal

Conformational analysis and parallel QM/MM X-ray refinement of protein bound anti-Alzheimer drug donepezil.

Fu Z, Li X, Miao Y, Merz KM Jr.SourceDepartment of Chemistry and the Quantum Theory Project, 2328 New Physics Building, P.O. Box 118435, University of Florida, Gainesville, Florida, 32611-8435.
Journal of chemical theory and computation.J Chem Theory Comput.2013 Dec 3;9(3):1686-1693. Epub 2013 Feb 18.
The recognition and association of donepezil with acetylcholinesterase (AChE) has been extensively studied in the past several decades because of the former's use as a palliative treatment for mild Alzheimer disease. Herein we examine the conformational properties of donepezil and we re-examine the
PMID 23526889

Working memory deficits and related disinhibition of the cAMP/PKA/CREB are alleviated by prefrontal α4β2*-nAChRs stimulation in aged mice.

Vandesquille M, Baudonnat M, Decorte L, Louis C, Lestage P, Béracochéa D.SourceCNRS, Univ. Bordeaux, INCIA UMR 5287, Bordeaux, France; Institut de Recherches SERVIER (IDRS), Croissy-sur-Seine, France.
Neurobiology of aging.Neurobiol Aging.2013 Jun;34(6):1599-609. doi: 10.1016/j.neurobiolaging.2012.10.006. Epub 2013 Jan 23.
The present study investigates in aged mice the working memory (WM) enhancing potential of the selective α4β2* nicotinic receptor agonist S 38232 as compared with the cholinesterase inhibitor donepezil, and their effect on cAMP response element binding protein (CREB) phosphorylation (pCREB) as a m
PMID 23352115

Japanese Journal

日中の幻視が「前の人」から「横の影」へとdonepezilにより変遷したレビー小体型認知症の1症例

井上弘寿,加藤敏
精神医学 54(10), 1023-1032, 2012-10-00
NAID 40019469535

ドネペジルとメマンチンの併用効果 : 脳血流変化と臨床効果に関して (特集新しいアルツハイマー型認知症治療薬の使用経験) -- (メマンチンの使用経験)

金谷潔史,阿部晋衛,酒井稔他
老年精神医学雑誌 23(9), 1083-1086, 2012-09-00
NAID 40019439098

身体愁訴を主訴として受診し,その改善にドネペジル塩酸塩が有効であった高齢者の一例 (特集新しいアルツハイマー型認知症治療薬の使用経験) -- (ドネペジルの使用経験)

稲村圭亮,品川俊一郎
老年精神医学雑誌 23(9), 1051-1054, 2012-09-00
NAID 40019438997

Related Pictures

★リンクテーブル★

リンク元	「コリンエステラーゼ阻害薬」「ドネペジル」「Aricept」
拡張検索	「donepezil hydrochloride」

「コリンエステラーゼ阻害薬」

Donepezil
Systematic (IUPAC) name
	(RS)-2-[(1-benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one
Clinical data
Trade names	Aricept
AHFS/Drugs.com	monograph
MedlinePlus	a697032
Pregnancy; category	C;
Legal status	℞ (Prescription only);
Routes of; administration	Oral tablet, 5,10 & 23mg
Pharmacokinetic data
Bioavailability	100 (%)
Protein binding	96%
Biological half-life	70 hours
Excretion	0,11-0,13 (l/h/kg)
Identifiers
CAS Registry Number	120014-06-4
ATC code	N06DA02
PubChem	CID: 3152
IUPHAR/BPS	6599
DrugBank	DB00843
ChemSpider	3040
UNII	8SSC91326P
KEGG	D07869
ChEBI	CHEBI:53289
ChEMBL	CHEMBL502
PDB ligand ID	E20 (PDBe, RCSB PDB)
Chemical data
Formula	C24H29NO3
Molecular mass	379.492 g/mol
	SMILES O=C2c1cc(OC)c(OC)cc1CC2CC4CCN(Cc3ccccc3)CC4 ;
	InChI InChI=1S/C24H29NO3/c1-27-22-14-19-13-20(24(26)21(19)15-23(22)28-2)12-17-8-10-25(11-9-17)16-18-6-4-3-5-7-18/h3-7,14-15,17,20H,8-13,16H2,1-2H3 ; Key:ADEBPBSSDYVVLD-UHFFFAOYSA-N ;
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英: cholinesterase inhibitor cholinesterase inhibitors
同: 抗コリンエステラーゼ薬 anticholinesterase
関: アセチルコリン、アセチルコリン受容体、副交感神経