Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Donepezil: Difference between pages

{{Short description|Medication used for dementia}}

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{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 461091154

| width = 200

| alt =

| caption =

| chirality = [[Racemic mixture]]

| USAN = Donepezil hydrochloride

<!-- Clinical data -->

| pronounce =

| tradename = Aricept, Adlarity, others

| Drugs.com = {{drugs.com|monograph|donepezil}}

| DailyMedID = Donepezil

| pregnancy_AU = B3

| pregnancy_AU_comment =

| pregnancy_category=

| routes_of_administration = [[Oral administration|By mouth]], [[transdermal patch|transdermal]]

| class =

| ATC_prefix = N06

| ATC_suffix = DA02

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment =

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM<!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment = <ref>{{cite web |title=Donepezil Hydrochloride 10 mg Film-coated tablets |url=https://www.medicines.org.uk/emc/product/6065/smpc#gref |website=Electronic Medicines Compendium |access-date=8 September 2022 |archive-date=8 September 2022 |archive-url=https://web.archive.org/web/20220908031120/https://www.medicines.org.uk/emc/product/6065/smpc#gref |url-status=dead }}</ref>

| legal_US = Rx-only

| legal_US_comment = <ref name="Aricept FDA label">{{cite web | title=Aricept- donepezil hydrochloride tablet, film coated Aricept ODT- donepezil hydrochloride tablet, orally disintegrating | website=DailyMed | date=23 December 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=98e451e1-e4d7-4439-a675-c5457ba20975 | access-date=15 March 2022}}</ref><ref name="Adlarity FDA label">{{cite web | title=Adlarity- donepezil hydrochloride patch | website=DailyMed | date=11 March 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1cb44c65-00e8-4b5c-99c2-ad15173115a0 | access-date=19 June 2022}}</ref>

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability = 100%<ref name=Kum2020/><ref name="Seltzer 2005 pp. 527–536">{{cite journal | vauthors = Seltzer B | title = Donepezil: a review | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 1 | issue = 3 | pages = 527–536 | date = October 2005 | pmid = 16863459 | doi = 10.1517/17425255.1.3.527 | publisher = Informa Healthcare | quote = there is a linear relationship between dose and pharmacodynamic effects, measured as red blood cell acetylcholinesterase inhibition and clinical efficacy. Despite being 96% bound to plasma proteins, it has few interactions with other drugs, and the 5-mg dose can be given safely to patients with mild-to-moderate hepatic and renal-disease. | s2cid = 32689288 }}</ref>

| protein_bound = 96%, [[albumin]] (about 75%) and [[alpha1-acid glycoprotein]] (21%).<ref name="Seltzer 2005 pp. 527–536"/><ref name=Kum2020/>

| metabolism = [[CYP2D6]], [[CYP3A4]], and [[glucuronidation]].<ref name=Kum2020/> Four major metabolites, two of which are active.<ref name="Seltzer 2005 pp. 527–536"/><ref name=Kum2020/>

| metabolites =

| onset = Peak plasma levels in 3–4 h.<ref name="Seltzer 2005 pp. 527–536"/><ref name=Kum2020/>

| elimination_half-life = 70 hours<ref name="Asiri Mostafa 2010 pp. 117–150">{{cite book | vauthors = Asiri YA, Mostafa GA | title=Profiles of Drug Substances, Excipients and Related Methodology | chapter=Donepezil | publisher=Elsevier | year=2010 | volume=35 | isbn=978-0-12-380884-4 | issn=1871-5125 | doi=10.1016/s1871-5125(10)35003-5 | pages=117–50 | pmid=22469221 | s2cid=206178636 | quote=Plasma donepezil concentrations decline with a half-life of approximately 70 h. Sex, race, and smoking history have no clinically significant influence on plasma concentrations of donepezil [46–51].}}</ref> Around 100 hours in elderly patients.<ref name=Kum2020/>

| duration_of_action = With daily dosing, steady-state concentration is reached in 15–21 days.<ref name="Seltzer 2005 pp. 527–536"/><ref name=Kum2020/>

| excretion = 0.11–0.13 (L/h/kg); excreted mostly by the kidneys. Around 17% is excreted unchanged in the urine. About 15% to 20% is excreted in feces.<ref name=Kum2020/><ref name="Seltzer 2005 pp. 527–536"/> Steady-state clearance is similar at all ages.<ref name=Kum2020/>

<!-- Identifiers -->

| CAS_supplemental =

| IUPHAR_ligand = 6599

| NIAID_ChemDB =

| PDB_ligand = E20

| synonyms =

<!-- Chemical and physical data -->

| IUPAC_name = (''RS'')-2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one

| C=24 | H=29 | N=1 | O=3

| SMILES = O=C2c1cc(OC)c(OC)cc1CC2CC4CCN(Cc3ccccc3)CC4

| StdInChI_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Donepezil''', sold under the brand name '''Aricept''' among others, is a [[medication]] used to treat [[dementia]] of the [[Alzheimer's disease|Alzheimer's type]].<ref name="Aricept FDA label" /><ref name="Adlarity FDA label" /><ref name=AHFS2019/> It appears to result in a small benefit in mental function and ability to function.<ref>{{cite journal | vauthors = Birks JS, Harvey RJ | title = Donepezil for dementia due to Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 6 | pages = CD001190 | date = June 2018 | pmid = 29923184 | pmc = 6513124 | doi = 10.1002/14651858.CD001190.pub3 }}</ref> Use, however, has not been shown to change the progression of the disease.<ref>{{cite journal | title = Dementia – Caring, Ethics, Ethnical and Economical Aspects: A Systematic Review | journal = SBU Systematic Reviews | date = June 2008 | pmid = 28876770 | author1 = Swedish Council on Health Technology Assessment }}</ref> Treatment should be stopped if no benefit is seen.<ref name=BNF76/> It is taken [[Oral administration|by mouth]] or via a [[transdermal patch]].<ref name="Aricept FDA label" /><ref name="Adlarity FDA label" /><ref name=AHFS2019/>

<!-- Side effects and mechanism -->

Common side effects include nausea, trouble sleeping, aggression, diarrhea, feeling tired, and muscle cramps.<ref name=AHFS2019>{{cite web |title=Donepezil Hydrochloride Monograph for Professionals |url=https://www.drugs.com/monograph/donepezil.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=4 February 2019 }}</ref><ref name=BNF76>{{cite book| ref = {{harvid | BNF76 |2018 }} | title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=978-0-85711-338-2|pages=300|edition=76}}</ref> Serious side effects may include [[arrhythmia|abnormal heart rhythms]], [[urinary incontinence]], and [[seizure]]s.<ref name=AHFS2019/> Donepezil is a [[central nervous system|centrally]] acting reversible [[acetylcholinesterase inhibitor]] and structurally unrelated to other [[anticholinesterase|anticholinesterase agents]].<ref name=AHFS2019/><ref name=Kum2020/>

<!-- History and culture -->

Donepezil was approved for medical use in the United States in 1996.<ref name=AHFS2019/> It is available as a [[generic medication]].<ref name=BNF76/> In 2021, it was the 131st most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Donepezil - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Donepezil | access-date = 14 January 2024}}</ref>

==Medical uses==

===Alzheimer's disease===

There is no evidence that donepezil or other similar agents alter the course or progression of [[Alzheimer's disease]]. Six-to-twelve-month controlled studies have shown modest benefits in cognition or behavior.<ref name=":0">{{cite journal | vauthors = Steele LS, Glazier RH | title = Is donepezil effective for treating Alzheimer's disease? | journal = Canadian Family Physician | volume = 45 | pages = 917–919 | date = April 1999 | pmid = 10216789 | pmc = 2328349 }}</ref> The UK [[National Institute for Health and Care Excellence|National Institute for Clinical Excellence]] (NICE) recommends donepezil as an option in the management of mild to moderate Alzheimer's disease.<ref name=NICE2011>{{cite web |title=Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease {{!}} Guidance and guidelines {{!}} NICE |url=https://www.nice.org.uk/guidance/TA217/chapter/1-Guidance |website=www.nice.org.uk |access-date=4 February 2019 |date=23 March 2011}}</ref> The person should, however, be reviewed frequently and if there is no significant benefit it should be stopped.<ref name=NICE2011/> In 2006, the U.S. [[Food and Drug Administration]] (FDA) also approved donepezil for treatment of mild, moderate and severe [[dementia]] in Alzheimer's disease.<ref>{{cite press release | title = FDA Approves Expanded Use of Treatment for Patients With Severe Alzheimer's Disease | date = 13 October 2006 | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108768.htm | work = FDA | archive-url = https://web.archive.org/web/20090710031727/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108768.htm | archive-date = 10 July 2009 | url-status = dead }}</ref>

===Other===

* [[Lewy body dementia]]: Some studies have shown benefits of donepezil for the treatment of cognitive and behavioral symptoms in Lewy body dementia.<ref name=Kum2020/>

* [[Traumatic brain injury]]: Some research suggests an improvement in memory dysfunction in patients with traumatic brain injury with donepezil use.<ref name=Kum2020/>

* [[Vascular dementia]]: Studies have shown that donepezil may improve cognition in patients with vascular dementia but not overall global functioning.<ref name=Kum2020/>

* Dementia associated with [[Parkinson disease]]: Some evidence suggests that donepezil can improve cognition, executive function, and global status in Parkinson disease dementia.<ref name=Kum2020>{{cite book | vauthors = Kumar A, Sharma S | chapter = Donepezil | title = StatPearls | publisher=StatPearls Publishing | location=Treasure Island (FL) | year=2020 | pmid=30020629 | url=http://www.ncbi.nlm.nih.gov/books/NBK513257/ | access-date=12 April 2020}}</ref>

== Adverse effects ==

In clinical trials the most common adverse events leading to discontinuation were [[nausea]], [[diarrhea]], and vomiting.<ref name="Aricept FDA label" /><ref>{{cite journal | vauthors = Noetzli M, Eap CB | title = Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease | journal = Clinical Pharmacokinetics | volume = 52 | issue = 4 | pages = 225–241 | date = April 2013 | pmid = 23408070 | doi = 10.1007/s40262-013-0038-9 | s2cid = 1686999 }}</ref> Other side effects included difficulty sleeping, muscle cramps and loss of appetite. Most side effects were observed in patients taking the 23&nbsp;mg dose compared to 10&nbsp;mg or lower doses. Side effects are mild and transient in most patients, lasting up to three weeks and usually improved even with continued use.<ref name="Aricept FDA label"/><ref name=Kum2020/>

Donepezil, like other cholinesterase inhibitors, can cause nightmares due to enhanced activation of the [[visual association cortex]] during [[REM sleep]].<ref name=Kum2020/> Dosing donepezil in the morning can reduce the frequency of nightmares.<ref name=Kum2020/>

===Precautions===

Donepezil should be used with caution in people with [[heart disease]], cardiac conduction disturbances, [[chronic obstructive pulmonary disease]], [[asthma]], severe cardiac [[arrhythmia]] and [[sick sinus syndrome]].<ref name="Aricept FDA label"/>

People with [[peptic ulcer disease]] or taking [[NSAID]]s should use with caution because increased risk of gastrointestinal bleeding was noted.<ref name="Aricept FDA label"/> Slow heart beat and fainting in people with heart problems were also seen. These symptoms may appear more frequent when initiating treatment or increasing the donepezil dose. Although occurrence of seizures is rare, people who have a predisposition to seizures should be treated with caution.<ref name="Aricept FDA label" />

If daily donepezil has suspended for 7 days or less, restarting at the same dose is recommended, while if the suspension lasts longer than 7 days, retitrate from 5&nbsp;mg daily is suggested.<ref name="Aricept 2019">{{cite web | title=Donepezil: MedlinePlus Drug Information | website=MedlinePlus | date=22 December 2019 | url=https://medlineplus.gov/druginfo/meds/a697032.html | access-date=31 December 2019 | quote=If you forget to take a dose of donepezil, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. If you do not take donepezil, for 1 week or longer, you should call your doctor before starting to take this medication again.}}</ref><ref>{{cite web| url=http://www.bucksformulary.nhs.uk/docs/Guideline_786FM.pdf | archive-url=https://web.archive.org/web/20191231175346/http://www.bucksformulary.nhs.uk/docs/Guideline_786FM.pdf | url-status=dead | archive-date=31 December 2019 | title= Table 4. NHS Guideline | page= 6 of 11 | quote= Re-titration following AChEI missed doses or planned treatment breaks }}</ref>

== Mechanism of action ==

Donepezil binds and reversibly inhibits enzymes called [[cholinesterase]]s, especially [[acetylcholinesterase]], thus inhibiting hydrolysis of acetylcholine. This increases acetylcholine concentrations at cholinergic synapses.<ref name=Kum2020/>

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.<ref name="pmid63862">{{cite journal | vauthors = Davies P, Maloney AJ | title = Selective loss of central cholinergic neurons in Alzheimer's disease | journal = Lancet | volume = 2 | issue = 8000 | pages = 1403 | date = December 1976 | pmid = 63862 | doi = 10.1016/s0140-6736(76)91936-x | s2cid = 43250282 }}</ref><ref name="pmid9316159">{{cite journal | vauthors = Kása P, Rakonczay Z, Gulya K | title = The cholinergic system in Alzheimer's disease | journal = Progress in Neurobiology | volume = 52 | issue = 6 | pages = 511–535 | date = August 1997 | pmid = 9316159 | doi = 10.1016/s0301-0082(97)00028-2 | s2cid = 8460305 }}</ref>

In addition to its actions as an acetylcholinesterase inhibitor, donepezil has been found to act as a potent [[agonist]] of the [[sigma-1 receptor|σ₁ receptor]] (K_i = 14.6 nM), and has been shown to produce specific [[nootropic|antiamnestic]] effects in animals mainly via this action.<ref name="MauriceSu2009">{{cite journal | vauthors = Maurice T, Su TP | title = The pharmacology of sigma-1 receptors | journal = Pharmacology & Therapeutics | volume = 124 | issue = 2 | pages = 195–206 | date = November 2009 | pmid = 19619582 | pmc = 2785038 | doi = 10.1016/j.pharmthera.2009.07.001 }}</ref>

Some noncholinergic mechanisms have also been proposed.<ref name=Kum2020/> Donepezil upregulates the [[nicotinic receptor]]s in the [[cortical neurons]], adding to [[neuroprotective]] activity.<ref name=Kum2020/> It inhibits [[Sodium channel#Voltage-gated sodium channels|voltage-activated sodium currents]] reversibly and delays rectifier [[Voltage-gated potassium channel|potassium currents]] and fast transient potassium currents, although this action is unlikely to contribute to clinical effects.<ref name=Kum2020/>

==Synergy==

Donepezil was claimed to act [[synergistically]] with an agent called [[FK962]] [283167-06-6]<ref name="McCarthyOwens2011">{{cite journal | vauthors = McCarthy AD, Owens IJ, Bansal AT, McTighe SM, Bussey TJ, Saksida LM | title = FK962 and donepezil act synergistically to improve cognition in rats: potential as an add-on therapy for Alzheimer's disease | journal = Pharmacology, Biochemistry, and Behavior | volume = 98 | issue = 1 | pages = 76–80 | date = March 2011 | pmid = 21130801 | doi = 10.1016/j.pbb.2010.11.019 | s2cid = 26055819 | author-link6 = Lisa Saksida }}</ref> & [[FK960]] [133920-70-4].<ref name="Tokita2002">{{cite journal | vauthors = Tokita K, Yamazaki S, Yamazaki M, Matsuoka N, Mutoh S | title = Combination of a novel antidementia drug FK960 with donepezil synergistically improves memory deficits in rats | journal = Pharmacology, Biochemistry, and Behavior | volume = 73 | issue = 3 | pages = 511–519 | date = October 2002 | pmid = 12151024 | doi = 10.1016/S0091-3057(02)00819-5 | s2cid = 35007246 }}</ref> {potential activation of [[Somatostatin#Brain|somatostatinergic neurotransmission]]} However, the development was discontinued after Phase II "since the data reviewed did not indicate clear efficacy of the compound for the treatment of mild to moderate Alzheimer's disease."<ref>{{Cite web |date=18 July 2006 |title=Astellas Discontinues Development of Alzheimer's Disease Compound FK962 |url=https://www.astellas.com/en/system/files/news/2018-06/060718-1_eg_0.pdf |access-date=3 September 2023 |website=Astrellas}}</ref>

== Stereochemistry ==

Donepezil medications are [[racemates]].<ref name="Rote Liste">Rote Liste Service GmbH (Hrsg.): ''Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte)''. Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, {{ISBN|978-3-946057-10-9}}, S. 178.</ref>

{| class="wikitable" style="text-align:center"

|- class="hintergrundfarbe6"

! colspan="2"| Enantiomers

|-

| [[File:(R)-Donepezil Structural Formula V1.svg|300 px]]<br /><small>(''R'')-Donepezil</small>

| [[File:(S)-Donepezil Structural Formula V1.svg|300 px]]<br /><small>(''S'')-Donepezil</small>

|}

==History==

[[File:AChE inhibited by donepezil 1EVE.png|thumb|Donepezil inhibiting [[Pacific electric ray|''Torpedo californica'']] acetylcholinesterase<ref>{{Proteopedia|1eve}}</ref>]]

[[File:Aricept 10mg 000195lg.jpg|right|thumb|10 mg Aricept pill]]

Research leading to the development of donepezil began in 1983, at [[Eisai (company)|Eisai]], and in 1996, Eisai received [[Approved drug|approval]] from the United States [[Food and Drug Administration]] (FDA) for donepezil under the brand ''Aricept'', which it co-marketed with [[Pfizer]].<ref>{{cite journal | vauthors = Rodrigues Simões MC, Dias Viegas FP, Moreira MS, de Freitas Silva M, Riquiel MM, da Rosa PM, Castelli MR, dos Santos MH, Soares MG, Viegas C | title = Donepezil: an important prototype to the design of new drug candidates for Alzheimer's disease | journal = Mini Reviews in Medicinal Chemistry | volume = 14 | issue = 1 | pages = 2–19 | date = January 2014 | pmid = 24251806 | doi = 10.2174/1389557513666131119201353 }}</ref> The team at Eisai was led by [[Hachiro Sugimoto]].<ref>{{cite web | title = Developed the magic bullet for Alzheimer's disease after overcoming many difficulties (Hachiro Sugimoto) | url = https://yab.yomiuri.co.jp/adv/chuo/dy/people/20100819.html | access-date = 11 January 2017 | publisher = Chuo University Gakuin Jihou (ChuOnline) | archive-url = https://web.archive.org/web/20200215155529/https://yab.yomiuri.co.jp/adv/chuo/dy/people/20100819.html | archive-date = 15 February 2020 | url-status = live}}</ref>

As of 2011, Aricept was the world's best-selling Alzheimer's disease treatment.<ref name=bb2011>{{cite news |title=Eisai Aricept Patch for Alzheimer's Isn't Ready for Approval | vauthors = Matsuyama K |agency=Bloomberg |date=25 April 2011 |access-date=25 April 2011 |url=https://www.bloomberg.com/news/2011-04-25/eisai-says-fda-indicates-aricept-nda-not-ready-for-approval.html | archive-url = https://web.archive.org/web/20121105060229/http://www.bloomberg.com/news/2011-04-25/eisai-says-fda-indicates-aricept-nda-not-ready-for-approval.html | archive-date = 5 November 2012 | url-status = dead }}</ref> The first generic donepezil became available in November 2010, with the US FDA approval of a formulation prepared by [[Ranbaxy Laboratories|Ranbaxy Labs]].<ref>{{cite news |title=Ranbaxy gets FDA nod for Alzheimer's drug |url=http://www.indianexpress.com/news/ranbaxy-gets-fda-nod-for-alzheimers-drug/718059/ |newspaper=[[The Indian Express]] |publisher=Indian Express Group |location=[[New Delhi, India]] |date=30 November 2010 |at=IndianExpress.com |access-date=25 April 2011}}</ref>

==Research==

Donepezil has been tested in other [[cognitive disorder]]s, including [[Lewy body dementia]],<ref name="pmid11215841">{{cite journal | vauthors = Rojas-Fernandez CH | title = Successful use of donepezil for the treatment of dementia with Lewy bodies | journal = The Annals of Pharmacotherapy | volume = 35 | issue = 2 | pages = 202–205 | date = February 2001 | pmid = 11215841 | doi = 10.1345/aph.10192 | s2cid = 24685121 }}</ref> and [[vascular dementia]],<ref name="pmid14974068">{{cite journal | vauthors = Malouf R, Birks J | title = Donepezil for vascular cognitive impairment | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD004395 | year = 2004 | pmid = 14974068 | doi = 10.1002/14651858.CD004395.pub2 | veditors = Malouf R }}</ref> but it is not currently approved for these indications. Donepezil has also been found to improve [[sleep apnea]] in people with Alzheimer's.<ref name="pmid18198262">{{cite journal | vauthors = Moraes W, Poyares D, Sukys-Claudino L, Guilleminault C, Tufik S | title = Donepezil improves obstructive sleep apnea in Alzheimer disease: a double-blind, placebo-controlled study | journal = Chest | volume = 133 | issue = 3 | pages = 677–683 | date = March 2008 | pmid = 18198262 | doi = 10.1378/chest.07-1446 | url = http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=18198262 | url-status = dead | archive-url = https://archive.today/20130414104959/http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=18198262 | archive-date = 14 April 2013 }}</ref> It also improves gait in people with mild Alzheimer's.<ref>{{cite journal | vauthors = Montero-Odasso M, Muir-Hunter SW, Oteng-Amoako A, Gopaul K, Islam A, Borrie M, Wells J, Speechley M | title = Donepezil improves gait performance in older adults with mild Alzheimer's disease: a phase II clinical trial | journal = Journal of Alzheimer's Disease | volume = 43 | issue = 1 | pages = 193–199 | date = January 2015 | pmid = 25079803 | doi = 10.3233/JAD-140759 }}</ref>

Donepezil has also been studied in people with [[mild cognitive impairment]], [[schizophrenia]], [[attention deficit disorder]], post-[[coronary artery bypass surgery]] cognitive impairment,<ref name="pmid17514186">{{cite journal | vauthors = Doraiswamy PM, Babyak MA, Hennig T, Trivedi R, White WD, Mathew JP, Newman MF, Blumenthal JA | title = Donepezil for cognitive decline following coronary artery bypass surgery: a pilot randomized controlled trial | journal = Psychopharmacology Bulletin | volume = 40 | issue = 2 | pages = 54–62 | year = 2007 | pmid = 17514186 }}</ref> cognitive impairment associated with [[multiple sclerosis]], [[CADASIL syndrome]], and [[Down syndrome]]. A three-year [[National Institutes of Health]] trial in people 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.<ref>{{cite journal | vauthors = Jelic V, Kivipelto M, Winblad B | title = Clinical trials in mild cognitive impairment: lessons for the future | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 77 | issue = 4 | pages = 429–438 | date = April 2006 | pmid = 16306154 | pmc = 2077499 | doi = 10.1136/jnnp.2005.072926 }}</ref> In a secondary analysis, a subgroup of individuals with the [[apolipoprotein E4]] genotype showed sustained benefits with donepezil throughout the study.<ref>{{cite journal | vauthors = 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 | title = Vitamin E and donepezil for the treatment of mild cognitive impairment | journal = The New England Journal of Medicine | volume = 352 | issue = 23 | pages = 2379–2388 | date = June 2005 | pmid = 15829527 | doi = 10.1056/nejmoa050151 | collaboration = Alzheimer's Disease Cooperative Study Group | author-link13 = Christopher H. van Dyck | author-link5 = Rachelle Doody | doi-access = free }}</ref> At this time, though, donepezil is not indicated for [[neuroprotection|prevention of dementia]].

=== Cognitive enhancement ===

Donepezil has shown mixed results for improving cognitive abilities in healthy individuals.<ref>{{cite journal | vauthors = Chuah LY, Chee MW | title = Cholinergic augmentation modulates visual task performance in sleep-deprived young adults | journal = The Journal of Neuroscience | volume = 28 | issue = 44 | pages = 11369–11377 | date = October 2008 | pmid = 18971479 | pmc = 6671517 | doi = 10.1523/JNEUROSCI.4045-08.2008 }}</ref><ref>{{cite journal | vauthors = Silver MA, Shenhav A, D'Esposito M | title = Cholinergic enhancement reduces spatial spread of visual responses in human early visual cortex | journal = Neuron | volume = 60 | issue = 5 | pages = 904–914 | date = December 2008 | pmid = 19081383 | pmc = 2640421 | doi = 10.1016/j.neuron.2008.09.038 }}</ref><ref name=":1">{{cite journal | vauthors = Zaninotto AL, Bueno OF, Pradella-Hallinan M, Tufik S, Rusted J, Stough C, Pompéia S | title = Acute cognitive effects of donepezil in young, healthy volunteers | journal = Human Psychopharmacology | volume = 24 | issue = 6 | pages = 453–464 | date = August 2009 | pmid = 19637397 | doi = 10.1002/hup.1044 | s2cid = 22391336 }}</ref><ref name=":2">{{cite journal | vauthors = Balsters JH, O'Connell RG, Martin MP, Galli A, Cassidy SM, Kilcullen SM, Delmonte S, Brennan S, Meaney JF, Fagan AJ, Bokde AL, Upton N, Lai R, Laruelle M, Lawlor B, Robertson IH | title = Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers | journal = PLOS ONE | volume = 6 | issue = 9 | pages = e24126 | date = 8 September 2011 | pmid = 21931653 | pmc = 3169575 | doi = 10.1371/journal.pone.0024126 | bibcode = 2011PLoSO...624126B | doi-access = free }}</ref> A 2009 double-blind, placebo controlled study (n=24) investigating donepezil's effects across a variety of memory tests in reported an improvement in spatial memory accuracy both before (90 minutes after dosing) and at theoretical T_max (210&nbsp;minutes after dosing).<ref name=":1" /> However, a later 2011 paper featuring two study double-blind, placebo controlled experiments evaluating donepezil's effects in older but healthy subjects reported impairment after acute (5&nbsp;hours after dose) and chronic (4&nbsp;weeks) donepezil administration.<ref name=":2" />

===ADHD===

The addition of donepezil with existing ADHD medications has shown mixed results.<ref name="Elbe 2019 p. ">{{cite book | vauthors = Elbe D | title=Clinical handbook of psychotropic drugs for children and adolescents | publisher=Hogrefe | location=Boston, MA | year=2019 | isbn=978-1-61676-550-7 | oclc=1063705924 | pages=366–69}}</ref> In those with [[Tourette syndrome]] and ADHD, donepezil may reduce [[tic]]s while it had no effect on ADHD's symptoms.<ref name="Elbe 2019 p. "/>

===Pervasive developmental disorder===

Donepezil, along with other [[cholinesterase inhibitor]]s, is suggested as having potential for trouble behaviors: [[irritability]], [[hyperactivity]], and difficulty in [[social communication]] which are typically seen in those with [[pervasive developmental disorder]], [[pervasive developmental disorder not otherwise specified]], and [[autism spectrum disorder|autism-spectrum disorder]].<ref name="Elbe 2019 p. "/>

===Anorexia nervosa===

Donepezil is furthermore suggested as a feasible therapeutic option for [[anorexia nervosa]]. Emerging literature reports that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons.<ref>{{cite journal | vauthors = Favier M, Janickova H, Justo D, Kljakic O, Runtz L, Natsheh JY, Pascoal TA, Germann J, Gallino D, Kang JI, Meng XQ, Antinora C, Raulic S, Jacobsen JP, Moquin L, Vigneault E, Gratton A, Caron MG, Duriez P, Brandon MP, Neto PR, Chakravarty MM, Herzallah MM, Gorwood P, Prado MA, Prado VF, El Mestikawy S | title = Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating | journal = The Journal of Clinical Investigation | volume = 130 | issue = 12 | pages = 6616–6630 | date = December 2020 | pmid = 33164988 | doi = 10.1172/JCI138532 | pmc = 7685731 }}</ref> Based on the physiopathology of anorexia nervosa, namely in terms of cholinergic deficiencies, the effects of donepezil and other drugs that act as cholinesterase inhibitors could thus be effective in the treatment of the disorder.<ref>{{cite journal | vauthors = Halabe Bucay A | title = Donepezil (aricept) as a treatment for anorexia nervosa: a very feasible therapeutic possibility | journal = Expert Opinion on Investigational Drugs | volume = 18 | issue = 5 | pages = 569–571 | date = May 2009 | pmid = 19388874 | doi = 10.1517/13543780902810360 | s2cid = 72686919 }}</ref> However, no trial to date supports this hypothesis.

== References ==

{{reflist}}

== Further reading ==

* {{cite book | vauthors = Brenner GD, Brenner GM |title=Pharmacology |publisher=W. B. Saunders |location=Philadelphia |year=2000 |isbn=978-0-7216-7757-6 }}

* {{cite book |title=Compendium of Pharmaceuticals and Specialities |publisher=Canadian Pharmacists Association |year=2000 |edition=25th |isbn=978-0-919115-76-7 | vauthors = Welbanks L }}

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